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Sample records for neurochemical impairments caused

  1. Vanillin Attenuated Behavioural Impairments, Neurochemical Deficts, Oxidative Stress and Apoptosis Against Rotenone Induced Rat Model of Parkinson's Disease.

    Science.gov (United States)

    Dhanalakshmi, Chinnasamy; Janakiraman, Udaiyappan; Manivasagam, Thamilarasan; Justin Thenmozhi, Arokiasamy; Essa, Musthafa Mohamed; Kalandar, Ameer; Khan, Mohammed Abdul Sattar; Guillemin, Gilles J

    2016-08-01

    Vanillin (4-hydroxy-3-methoxybenzaldehyde), a pleasant smelling organic aromatic compound, is widely used as a flavoring additive in food, beverage, cosmetic and drug industries. It is reported to cross the blood brain barrier and also displayed antioxidant and neuroprotective activities. We previously reported the neuroprotective effect of vanillin against rotenone induced in in vitro model of PD. The present experiment was aimed to analyze the neuroprotective effect of vanillin on the motor and non-motor deficits, neurochemical variables, oxidative, anti-oxidative indices and the expression of apoptotic markers against rotenone induced rat model of Parkinson's disease (PD). Rotenone treatment exhibited motor and non-motor impairments, neurochemical deficits, oxidative stress and apoptosis, whereas oral administration of vanillin attenuated the above-said indices. However further studies are needed to explore the mitochondrial protective and anti-inflammatory properties of vanillin, as these processes play a vital role in the cause and progression of PD.

  2. Neurochemical changes in the hippocampus and prefrontal cortex associated with electroacupuncture for learning and memory impairment.

    Science.gov (United States)

    He, Jian; Zhao, Congkuai; Liu, Weilin; Huang, Jia; Liang, Shengxiang; Chen, Lidian; Tao, Jing

    2018-02-01

    Electroacupuncture (EA) has been widely used to treat cognitive impairment following cerebral ischemia. However, the functional mechanisms of EA have not been fully elucidated. The aim of the present study was to investigate whether EA at the GV 20 and DU 24 acupoints can improve the learning and memory ability via alteration of the neurochemical metabolism in the hippocampus (HPC) and prefrontal cortex (PFC) of rats with ischemia and reperfusion (I/R) injury. Sprague‑Dawley male rats were randomly divided into three groups, namely the sham group (n=12), the middle cerebral artery occlusion (MCAO) group (n=12) and the EA treatment (MCAO + EA) group (n=12). MCAO was performed to establish the left focal cerebral I/R injury model, and the GV 20 and DU 24 acupoints were then stimulated with EA for 30 min per time, once daily, for 7 consecutive days. The Morris water maze (MWM) test was used to assess learning and memory ability. T2‑weighted imaging was used to assess the cerebral infarct volume. Magnetic resonance spectroscopy was used to assess neurochemical metabolism of HPC and PFC. The neurological scores of the MCAO + EA group were significantly reduced compared with those of the MCAO group 7 days after EA treatment (Pplatform area was significantly higher in the MCAO + EA group compared with that in the MCAO group (P0.05). The ratios of NAA/Cr, Cho/Cr and Glu/Cr of left‑to‑right PFC were elevated (Plearning and memory ability, possibly through increasing the levels of NAA and Cho in the HPC and PFC of rats with I/R injury.

  3. Neurochemical and Neuroanatomical Plasticity Following Memory Training and Yoga Interventions in Older Adults with Mild Cognitive Impairment

    Directory of Open Access Journals (Sweden)

    Hongyu Yang

    2016-11-01

    Full Text Available Behavioral interventions are becoming increasingly popular approaches to ameliorate age-related cognitive decline, but their underlying neurobiological mechanisms and clinical efficiency have not been fully elucidated. The present study explored brain plasticity associated with two behavioral interventions, memory enhancement training (MET and a mind-body practice (yogic meditation, in healthy seniors with mild cognitive impairment (MCI using structural magnetic resonance imaging (MRI and proton magnetic resonance spectroscopy (1H-MRS. Senior participants (age ≥ 55 years with MCI were randomized to the MET or yogic meditation interventions. For both interventions, participants completed either MET training or Kundalini yoga for 60-min sessions over 12 weeks, with 12-min daily homework assignments. Gray matter volume and metabolite concentrations in the dorsal anterior cingulate cortex (dACC and bilateral hippocampus were measured by structural MRI and 1H-MRS at baseline and after 12 weeks of training. Metabolites measured included glutamate-glutamine (Glx, choline-containing compounds (Cho, including glycerophosphocholine and phosphocholine, gamma-aminobutyric acid (GABA, and N-acetyl aspartate and N-acetylaspartyl-glutamate (NAA-NAAG. In total, 11 participants completed MET and 14 completed yogic meditation for this study. Structural MRI analysis showed an interaction between time and group in dACC, indicating a trend towards increased gray matter volume after the MET intervention. 1H-MRS analysis showed an interaction between time and group in choline-containing compounds in bilateral hippocampus, induced by significant decreases after the MET intervention. Though preliminary, our results suggest that memory training induces structural and neurochemical plasticity in seniors with mild cognitive impairment. Further research is needed to determine whether mind-body interventions like yoga yield similar neuroplastic changes.

  4. Evaluating Causes of Ecological Impairments in the Estuaries of Ukraine

    Science.gov (United States)

    Ukrainian estuaries have not undergone a systematic evaluation of the causes of ecological impairments caused by anthropogenic contamination. The objective of this evaluation is to use recently developed diagnostic tools to determine the causes of benthic ecological impairments. ...

  5. Age-Related Neurochemical Changes in the Vestibular Nuclei

    Directory of Open Access Journals (Sweden)

    Paul eSmith

    2016-03-01

    Full Text Available There is evidence that the normal aging process is associated with impaired vestibulo-ocular (VOR and vestibulo-spinal reflexes, causing reduced visual acuity and postural instability. Nonetheless, the available evidence is not entirely consistent, especially with respect to the VOR. Some recent studies have reported that VOR gain can be intact even above 80 years of age. Similarly, although there is evidence for age-related hair cell loss and neuronal loss in Scarpa’s ganglion and the vestibular nucleus complex (VNC, it is not entirely consistent. Whatever structural and functional changes occur in the VNC as a result of aging, either to cause vestibular impairment or to compensate for it, neurochemical changes must underlie them. However, the neurochemical changes that occur in the VNC with aging are poorly understood because the available literature is very limited. This review summarises and critically evaluates the available evidence relating to the noradrenaline, serotonin, dopamine, glutamate, GABA, glycine, and nitric oxide neurotransmitter systems in the aging VNC. It is concluded that, at present, it is difficult, if not impossible, to relate the neurochemical changes observed to the function of specific VNC neurons and whether the observed changes are the cause of a functional deficit in the VNC or an effect of it. A better understanding of the neurochemical changes that occur during aging may be important for the development of potential drug treatments for age-related vestibular disorders. However, this will require the use of more sophisticated methodology such as in vivo microdialysis with single neuron recording and perhaps new technologies such as optogenetics.

  6. Age-Related Neurochemical Changes in the Vestibular Nuclei.

    Science.gov (United States)

    Smith, Paul F

    2016-01-01

    There is evidence that the normal aging process is associated with impaired vestibulo-ocular reflexes (VOR) and vestibulo-spinal reflexes, causing reduced visual acuity and postural instability. Nonetheless, the available evidence is not entirely consistent, especially with respect to the VOR. Some recent studies have reported that VOR gain can be intact even above 80 years of age. Similarly, although there is evidence for age-related hair cell loss and neuronal loss in Scarpa's ganglion and the vestibular nucleus complex (VNC), it is not entirely consistent. Whatever structural and functional changes occur in the VNC as a result of aging, either to cause vestibular impairment or to compensate for it, neurochemical changes must underlie them. However, the neurochemical changes that occur in the VNC with aging are poorly understood because the available literature is very limited. This review summarizes and critically evaluates the available evidence relating to the noradrenaline, serotonin, dopamine, glutamate, GABA, glycine, and nitric oxide neurotransmitter systems in the aging VNC. It is concluded that, at present, it is difficult, if not impossible, to relate the neurochemical changes observed to the function of specific VNC neurons and whether the observed changes are the cause of a functional deficit in the VNC or an effect of it. A better understanding of the neurochemical changes that occur during aging may be important for the development of potential drug treatments for age-related vestibular disorders. However, this will require the use of more sophisticated methodology such as in vivo microdialysis with single neuron recording and perhaps new technologies such as optogenetics.

  7. Influences of Chronic Mild Stress Exposure on Motor, Non-Motor Impairments and Neurochemical Variables in Specific Brain Areas of MPTP/Probenecid Induced Neurotoxicity in Mice.

    Science.gov (United States)

    Janakiraman, Udaiyappan; Manivasagam, Thamilarasan; Thenmozhi, Arokiasamy Justin; Essa, Musthafa Mohamed; Barathidasan, Rajamani; SaravanaBabu, Chidambaram; Guillemin, Gilles J; Khan, Mohammed A S

    2016-01-01

    Parkinson's disease (PD) is regarded as a movement disorder mainly affecting the elderly population and occurs due to progressive loss of dopaminergic (DAergic) neurons in nigrostriatal pathway. Patients suffer from non-motor symptoms (NMS) such as depression, anxiety, fatigue and sleep disorders, which are not well focussed in PD research. Depression in PD is a predominant /complex symptom and its pathology lies exterior to the nigrostriatal system. The main aim of this study is to explore the causative or progressive effect of chronic mild stress (CMS), a paradigm developed as an animal model of depression in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg. body wt.) with probenecid (250 mg/kg, s.c.) (MPTP/p) induced mice model of PD. After ten i.p. injections (once in 3.5 days for 5 weeks) of MPTP/p or exposure to CMS for 4 weeks, the behavioural (motor and non-motor) impairments, levels and expressions of dopamine (DA), serotonin (5-HT), DAergic markers such as tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporters-2 (VMAT 2) and α-synuclein in nigrostriatal (striatum (ST) and substantia nigra (SN)) and extra-nigrostriatal (hippocampus, cortex and cerebellum) tissues were analysed. Significantly decreased DA and 5-HT levels, TH, DAT and VMAT 2 expressions and increased motor deficits, anhedonia-like behaviour and α-synuclein expression were found in MPTP/p treated mice. Pre and/or post exposure of CMS to MPTP/p mice further enhanced the MPTP/p induced DA and 5-HT depletion, behaviour abnormalities and protein expressions. Our results could strongly confirm that the exposure of stress after MPTP/p injections worsens the symptoms and neurochemicals status of PD.

  8. Influences of Chronic Mild Stress Exposure on Motor, Non-Motor Impairments and Neurochemical Variables in Specific Brain Areas of MPTP/Probenecid Induced Neurotoxicity in Mice.

    Directory of Open Access Journals (Sweden)

    Udaiyappan Janakiraman

    Full Text Available Parkinson's disease (PD is regarded as a movement disorder mainly affecting the elderly population and occurs due to progressive loss of dopaminergic (DAergic neurons in nigrostriatal pathway. Patients suffer from non-motor symptoms (NMS such as depression, anxiety, fatigue and sleep disorders, which are not well focussed in PD research. Depression in PD is a predominant /complex symptom and its pathology lies exterior to the nigrostriatal system. The main aim of this study is to explore the causative or progressive effect of chronic mild stress (CMS, a paradigm developed as an animal model of depression in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg. body wt. with probenecid (250 mg/kg, s.c. (MPTP/p induced mice model of PD. After ten i.p. injections (once in 3.5 days for 5 weeks of MPTP/p or exposure to CMS for 4 weeks, the behavioural (motor and non-motor impairments, levels and expressions of dopamine (DA, serotonin (5-HT, DAergic markers such as tyrosine hydroxylase (TH, dopamine transporter (DAT, vesicular monoamine transporters-2 (VMAT 2 and α-synuclein in nigrostriatal (striatum (ST and substantia nigra (SN and extra-nigrostriatal (hippocampus, cortex and cerebellum tissues were analysed. Significantly decreased DA and 5-HT levels, TH, DAT and VMAT 2 expressions and increased motor deficits, anhedonia-like behaviour and α-synuclein expression were found in MPTP/p treated mice. Pre and/or post exposure of CMS to MPTP/p mice further enhanced the MPTP/p induced DA and 5-HT depletion, behaviour abnormalities and protein expressions. Our results could strongly confirm that the exposure of stress after MPTP/p injections worsens the symptoms and neurochemicals status of PD.

  9. Taurine ameliorates neurobehavioral, neurochemical and immunohistochemical changes in sporadic dementia of Alzheimer's type (SDAT) caused by intracerebroventricular streptozotocin in rats.

    Science.gov (United States)

    Javed, Hayate; Khan, Andleeb; Vaibhav, Kumar; Moshahid Khan, Mohd; Ahmad, Ajmal; Ejaz Ahmad, Md; Ahmad, Ashafaq; Tabassum, Rizwana; Islam, Farah; Safhi, Mohammed M; Islam, Fakhrul

    2013-12-01

    Oxidative loads in the brain are involved in age related impairments like learning and memory as well as neurodegeneration. Taurine, the most abundant free amino acid in humans has many potential health benefits through its anti-oxidant and anti-inflammatory properties. Therefore, we investigated the neuroprotective potential of taurine on oxidative stress, neuronal loss and memory impairments in streptozotocin model of cognitive impairments in rats. The cognitive impairment was developed by giving single intracerebroventricular (ICV) injection of streptozotocin (STZ) 3 mg/kg body weight bilaterally. An increased latency and path length was observed in ICV-STZ group animals as compared to sham group animals and these were inhibited significantly in STZ group pre-treated with taurine (50 mg/kg body weight orally once daily for 15 days). Moreover, the significantly depleted content of GSH and elevated level of thiobarbituric acid reactive substances (TBARS) in ICV-STZ group animals were protected significantly with pre-treatment of taurine. The activity of antioxidant enzymes, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, catalase, and superoxide dismutase was decreased in STZ group as compared to sham group and pre-treatment of STZ group with taurine has protected their activities significantly. Furthermore, the increased activity of acetylcholine esterase and decreased expression of choline acetyl transferase were attenuated by the pre-treatment of taurine. Taurine also protected the morphology of the hippocampal pyramidal neurons. This study concludes that the prophylactic intervention of taurine may be used to prevent the deterioration of cognitive functions and neurobehavioral activities, often associated with the generation of free radicals.

  10. Clean Water Act 303(d) Listed Impaired Waters and their Causes of Impairment from All Years

    Data.gov (United States)

    U.S. Environmental Protection Agency — Waters identified as impaired as well as their associated causes of impairment from all approved Clean Water Act 303(d) lists submitted by the states. Includes all...

  11. Causes of visual impairment among commercial motor vehicle ...

    African Journals Online (AJOL)

    Human factor contributed 27.7% to the cause of accidents. Causes of visual impairment included refractive error, glaucoma and cataract. Conclusion: There was no statistically significant association between RTA and visual impairment but there was statistically significant association between RTA and visual field defect ...

  12. Simultaneous wireless electrophysiological and neurochemical monitoring

    Science.gov (United States)

    Murari, Kartikeya; Mollazadeh, Mohsen; Thakor, Nitish; Cauwenberghs, Gert

    2008-08-01

    Information processing and propagation in the central nervous system is mostly electrical in nature. At synapses, electrical signals cause the release of neurotransmitters like dopamine, glutamate etc., that are sensed by post-synaptic neurons resulting in signal propagation or inhibition. It can be very informative to monitor electrical and neurochemical signals simultaneously to understand the mechanisms underlying normal or abnormal brain function. We present an integrated system for the simultaneous wireless acquisition of neurophysiological and neurochemical activity. Applications of the system to neuroscience include monitoring EEG and glutamate in rat somatosensory cortex following global ischemia.

  13. Prevalence and causes of hearing impairment in Africa.

    Science.gov (United States)

    Mulwafu, W; Kuper, H; Ensink, R J H

    2016-02-01

    To systematically assess the data on the prevalence and causes of hearing impairment in Africa. Systematic review on the prevalence and causes of hearing loss in Africa. We undertook a literature search of seven electronic databases (EMBASE, PubMed, Medline, Global Health, Web of Knowledge, Academic Search Complete and Africa Wide Information) and manually searched bibliographies of included articles. The search was restricted to population-based studies on hearing impairment in Africa. Data were extracted using a standard protocol. We identified 232 articles and included 28 articles in the final analysis. The most common cut-offs used for hearing impairment were 25 and 30 dB HL, but this ranged between 15 and 40 dB HL. For a cut-off of 25 dB, the median was 7.7% for the children- or school-based studies and 17% for population-based studies. For a cut-off of 30 dB HL, the median was 6.6% for the children or school-based studies and 31% for population-based studies. In schools for the deaf, the most common cause of hearing impairment was cryptogenic deafness (50%) followed by infectious causes (43%). In mainstream schools and general population, the most common cause of hearing impairment was middle ear disease (36%), followed by undetermined causes (35%) and cerumen impaction (24%). There are very few population-based studies available to estimate the prevalence of hearing impairment in Africa. Those studies that are available use different cut-offs, making comparison difficult. However, the evidence suggests that the prevalence of hearing impairment is high and that much of it is avoidable or treatable. © 2015 John Wiley & Sons Ltd.

  14. [Vision problems causing and not causing visual impairment in a working population of Catalonia].

    Science.gov (United States)

    Guisasola, Laura; Tresserras, Ricard; Rius, Anna; López-Dóriga, Adriana; Purtí, Elisabeth

    2013-01-01

    To analyze the distribution of visual problems which cause and do not cause visual impairment in a working population, and their relation to social class. This was a cross-sectional study of 86,831 employed workers (59,397 men, and 27,421 women) in Catalonia ages 16 to 65 years who, in 2009, underwent health surveillance exams at the Asepeyo Health Prevention. The prevalence of visual problems that cause and do not cause visual impairment was calculated by age, sex and occupational social class, and associations were analyzed using logistic regression. 2.2% (95% CI 2.1-2.3) of the active working population studied had vision problems that cause visual impairment, even while wearing corrective lenses. After adjusting for age, workers in Class V show a 2.4-fold greater risk of visual impairment than those in Class I. Women, older workers and disadvantaged social groups showed the highest prevalence and risk of visual impairment. Conversely, problems resolved by vision correction that do not cause visual impairment are concentrated in non-manual workers.

  15. Causes of visual impairment in children with low vision.

    Science.gov (United States)

    Shah, Mufarriq; Khan, Mirzaman; Khan, Muhammad Tariq; Khan, Mohammad Younas; Saeed, Nasir

    2011-02-01

    To determine the main causes of visual impairment in children with low vision. To assess the need of spectacles and low vision devices (LVDs) in children and to evaluate visual outcome after using their LVDs for far and near distance. Observational study. Khyber Institute of Ophthalmic Medical Sciences, Peshawar, Pakistan, from June 2006 to December 2007. The clinical record of 270 children with low vision age 4-16 years attending the Low Vision Clinic were included. All those children, aged 4-16 years, who had corrected visual acuity (VA) less than 6/18 in the better eye after medical or surgical treatment, were included in the study. WHO low vision criteria were used to classify into visually impaired, severe visually impaired and blind. Results were described as percentage frequencies. One hundred and eighty nine (70%) were males and 81 (30%) were females. The male to female ratio was 2.3:1. The main causes of visual impairment included nystagmus (15%), Stargardt's disease (14%), maculopathies (13%), myopic macular degeneration (11%) and oculocutaneous albinism (7%). The percentages of visually impaired, severe visually impaired and blind were 33.8%, 27.2% and 39.0% respectively. Spectacles were prescribed to 146 patients and telescopes were prescribed to 75 patients. Spectacles and telescope both were prescribed to 179 patients while Ocutech telescope was prescribed to 4 patients. Retinal diseases nystagmus and macular conditions were mainly responsible for low vision in children. Visually impaired children especially with hereditary/congenital ocular anomalies benefit from refraction and low vision services which facilitate vision enhancement and inclusive education.

  16. Cross-sectional study on prevalence, causes and avoidable causes of visual impairment in Maori children.

    Science.gov (United States)

    Chong, Cheefoong; Dai, Shuan

    2013-08-02

    To provide information and comparison pertaining to visual impairment of Maori children with other children in New Zealand in particular: prevalence of blindness, causes of visual impairment, and avoidable causes of visual impairment. Retrospective data collection utilising the WHO/PBL eye examination record for children with blindness and low vision at Blind and Low Vision Education Network New Zealand (BLENNZ), Homai. Individuals not of Maori ethnicity or over the age of 16 were excluded from the study. 106 blind and 64 low-vision Maori children were studied. The main cause of blindness in Maori children is cortical visual impairment. Twenty-eight percent of causes of blindness in this population are potentially avoidable with non-accidental injury as the main cause. The prevalence of blindness and low vision in children amounts to 0.05% and 0.03%, respectively. The prevalence and causes of childhood blindness are comparable to the other ethnic groups in New Zealand. The main difference lies in avoidable causes of blindness, which appeared to be much higher in the Maori population. The leading cause of avoidable blindness in Maori children is caused by non-accidental injuries.

  17. Neurochemical aspects of childhood autism

    NARCIS (Netherlands)

    R.B. Minderaa (Ruud)

    1985-01-01

    textabstractThe topic of this thesis is neurochemical aspects of infantile autism. The experimental work is centered around the most robust and consistant neurochemical finding in child psychiatry, namely that group mean whole blood serotonin (5-Hydroxytryptamine, 5-HT) values are

  18. CSPα knockout causes neurodegeneration by impairing SNAP-25 function

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    Sharma, Manu; Burré, Jacqueline; Bronk, Peter; Zhang, Yingsha; Xu, Wei; Südhof, Thomas C

    2012-01-01

    At a synapse, the synaptic vesicle protein cysteine-string protein-α (CSPα) functions as a co-chaperone for the SNARE protein SNAP-25. Knockout (KO) of CSPα causes fulminant neurodegeneration that is rescued by α-synuclein overexpression. The CSPα KO decreases SNAP-25 levels and impairs SNARE-complex assembly; only the latter but not the former is reversed by α-synuclein. Thus, the question arises whether the CSPα KO phenotype is due to decreased SNAP-25 function that then causes neurodegeneration, or due to the dysfunction of multiple as-yet uncharacterized CSPα targets. Here, we demonstrate that decreasing SNAP-25 levels in CSPα KO mice by either KO or knockdown of SNAP-25 aggravated their phenotype. Conversely, increasing SNAP-25 levels by overexpression rescued their phenotype. Inactive SNAP-25 mutants were unable to rescue, showing that the rescue was specific. Under all conditions, the neurodegenerative phenotype precisely correlated with SNARE-complex assembly, indicating that impaired SNARE-complex assembly due to decreased SNAP-25 levels is the ultimate correlate of neurodegeneration. Our findings suggest that the neurodegeneration in CSPα KO mice is primarily produced by defective SNAP-25 function, which causes neurodegeneration by impairing SNARE-complex assembly. PMID:22187053

  19. Causes of severe visual impairment in children and their prevention.

    Science.gov (United States)

    1975-12-30

    Concerning the fact that regarding causes of congenital visual impairment or visual impairment occurring during the first years of life, especially on the aetiology many problems have never been resolved, on instigation of The Netherlands a "Committee for the special study of severe visual impairment in children" has been founded by the International Association for Prevention of Blindness. The intention was that provisionally in this committee only 5 small West European countries should be represented, having more or less the same social and hygienic conditions, so that one could expect that comparison of the gained information in these countries should give some results concerning the aetiology. The contributing countries were: Belgium, Denmark, Sweden, Norway, and The Netherlands. For this purpose criteria for definition of severe visual impairment, a questionnaire and a codinglist were drawn up. The classification scheme of causes of blindness and partial sightedness of the I.A.P.B. was utilized for answering the questions "by site and type and by aetiology" of the eye affections. The total number of children who were involved in the investigation was 4306. The investigation confirmed that heredity still occupies the first place in the aetiology of the congenital severe visual impairment. Moreover, the investigation could prove that besides the already known role of rubella, toxoplasmosis and dysoxygenation, probably also other affections occuring during pregnancy, prematurity, and too low birth weight (dysmaturity) and birth injuries, like asphyxia of the new-born child, are of great importance. Probably there is a correlation with certain eye affections (cataracta congenita and optic nerve atrophy). Attention is paid to the possibilities of prevention. From the results it appears that a renewed investigation is necessary where one should have to dispose of more and especially more reliable information concerning pregnancy and delivery. Suggestions in this

  20. Retrospective data on causes of childhood vision impairment in Eritrea.

    Science.gov (United States)

    Gyawali, Rajendra; Bhayal, Bharat Kumar; Adhikary, Rabindra; Shrestha, Arjun; Sah, Rabindra Prasad

    2017-11-22

    Proper information on causes of childhood vision loss is essential in developing appropriate strategies and programs to address such causes. This study aimed at identifying the causes of vision loss in children attending the national referral eye hospital with the only pediatric ophthalmology service in Eritrea. A retrospective data review was conducted for all the children (Causes of vision loss for children with vision impairment (recorded visual acuity less than 6/18 for distance in the better eye) was classified by the anatomical site affected and by underlying etiology based on the timing of the insult and causal factor. The medical record cards of 22,509 children were reviewed, of whom 249 (1.1%) were visually impaired. The mean age of the participants was 7.82 ± 5.43 years (range: one month to 16 years) and male to female ratio was 1:0.65. The leading causes of vision loss were cataract (19.7%), corneal scars (15.7%), refractive error and amblyopia (12.1%), optic atrophy (6.4%), phthisis bulbi (6.4%), aphakia (5.6%) and glaucoma (5.2%). Childhood factors including trauma were the leading causes identified (34.5%) whereas other causes included hereditary factors (4%), intrauterine factors (2.0%) and perinatal factors (4.4%). In 55.0% of the children, the underlying etiology could not be attributed. Over two-thirds (69.9%) of vision loss was potentially avoidable in nature. This study explored the causes of vision loss in Eritrean children using hospital based data. Cataract corneal opacities, refractive error and amblyopia, globe damage due to trauma, infection and nutritional deficiency, retinal disorders, and other congenital abnormalities were the leading causes of childhood vision impairment in children attending the tertiary eye hospital in Eritrea. As majority of the causes of vision loss was due to avoidable causes, we recommended primary level public health strategies to prevent ocular injuries, vitamin A deficiency, perinatal infections and

  1. Alcohol-related amnesia and dementia: Animal models have revealed the contributions of different etiological factors on neuropathology, neurochemical dysfunction and cognitive impairment

    Science.gov (United States)

    Vetreno, Ryan P.; Hall, Joseph M.; Savage, Lisa M.

    2011-01-01

    Chronic alcoholism is associated with impaired cognitive functioning. Over 75% of autopsied chronic alcoholics have significant brain damage and over 50% of detoxified alcoholics display some degree of learning and memory impairment. However, the relative contributions of different etiological factors to the development of alcohol-related neuropathology and cognitive impairment are questioned. One reason for this quandary is that both alcohol toxicity and thiamine deficiency result in brain damage and cognitive problems. Two alcohol-related neurological disorders, alcohol-associated dementia and Wernicke-Korsakoff syndrome have been modeled in rodents. These pre-clinical models have elucidated the relative contributions of ethanol toxicity and thiamine deficiency to the development of dementia and amnesia. What is observed in these models—from repeated and chronic ethanol exposure to thiamine deficiency—is a progression of both neural and cognitive dysregulation. Repeated binge exposure to ethanol leads to changes in neural plasticity by reducing GABAergic inhibition and facilitating glutamatergic excitation, long-term chronic ethanol exposure results in hippocampal and cortical cell loss as well as reduced hippocampal neurotrophin protein content critical for neural survival, and thiamine deficiency results in gross pathological lesions in the diencephalon, reduced neurotrophic protein levels, and neurotransmitters levels in the hippocampus and cortex. Behaviorally, after recovery from repeated or chronic ethanol exposure there is impairment in working or episodic memory that can recover with prolonged abstinence. In contrast, after thiamine deficiency there is severe and persistent spatial memory impairments and increased perseverative behavior. The interaction between ethanol and thiamine deficiency does not produce more behavioral or neural pathology, with the exception of reduction of white matter, than long-term thiamine deficiency alone. PMID:21256970

  2. Suicide: Neurochemical Approaches

    Directory of Open Access Journals (Sweden)

    Ritabrata Banerjee

    2013-10-01

    Full Text Available Despite the devastating effect of suicide on numerous lives, there is still a dearthof knowledge concerning its neurochemical aspects. There is increasing evidence that brain-derived neurotrophic factor (BDNF and Nerve growth factor (NGF are involved in the pathophysiology and treatment of depression through binding and activating their cognate receptors trk B and trk A respectively. The present study was performed to examine whether the expression profiles of BDNF and/or trk B as well as NGF and/or trk A were altered in postmortem brain in subjects who commitsuicide and whether these alterations were associated with specific psychopathologic conditions. These studies were performed in hippocampus obtained 21 suicide subjects and 19 non-psychiatric control subjects. The protein and mRNA levels of BDNF, trk B and NGF, trk A were determined with Sandwich ELISA, Western Blot and RT PCR respectively. Given the importance of BDNFand NGF along with their cognate receptors in mediating physiological functions, including cell survival and synaptic plasticity, our findings of reduced expression of BDNF, Trk B and NGF, Trk A in both protein and mRNA levels of postmortem brain in suicide subjects suggest that these molecules may play an important role in the pathophysiological aspects of suicidal behavior.

  3. Non-Word Repetition Impairment in Autism and Specific Language Impairment: Evidence for Distinct Underlying Cognitive Causes

    Science.gov (United States)

    Williams, David; Payne, Heather; Marshall, Chloe

    2013-01-01

    Language-impaired individuals with autism perform poorly on tests such as non-word repetition that are sensitive clinical markers of specific language impairment (SLI). This has fuelled the theory that language impairment in autism represents a co-morbid SLI. However, the underlying cause of these deficits may be different in each disorder. In a…

  4. Learning impairment in honey bees caused by agricultural spray adjuvants.

    Directory of Open Access Journals (Sweden)

    Timothy J Ciarlo

    Full Text Available BACKGROUND: Spray adjuvants are often applied to crops in conjunction with agricultural pesticides in order to boost the efficacy of the active ingredient(s. The adjuvants themselves are largely assumed to be biologically inert and are therefore subject to minimal scrutiny and toxicological testing by regulatory agencies. Honey bees are exposed to a wide array of pesticides as they conduct normal foraging operations, meaning that they are likely exposed to spray adjuvants as well. It was previously unknown whether these agrochemicals have any deleterious effects on honey bee behavior. METHODOLOGY/PRINCIPAL FINDINGS: An improved, automated version of the proboscis extension reflex (PER assay with a high degree of trial-to-trial reproducibility was used to measure the olfactory learning ability of honey bees treated orally with sublethal doses of the most widely used spray adjuvants on almonds in the Central Valley of California. Three different adjuvant classes (nonionic surfactants, crop oil concentrates, and organosilicone surfactants were investigated in this study. Learning was impaired after ingestion of 20 µg organosilicone surfactant, indicating harmful effects on honey bees caused by agrochemicals previously believed to be innocuous. Organosilicones were more active than the nonionic adjuvants, while the crop oil concentrates were inactive. Ingestion was required for the tested adjuvant to have an effect on learning, as exposure via antennal contact only induced no level of impairment. CONCLUSIONS/SIGNIFICANCE: A decrease in percent conditioned response after ingestion of organosilicone surfactants has been demonstrated here for the first time. Olfactory learning is important for foraging honey bees because it allows them to exploit the most productive floral resources in an area at any given time. Impairment of this learning ability may have serious implications for foraging efficiency at the colony level, as well as potentially many

  5. Rcan1 deficiency impairs neuronal migration and causes periventricular heterotopia.

    Science.gov (United States)

    Li, Yang; Wang, Jie; Zhou, Yang; Li, Dan; Xiong, Zhi-Qi

    2015-01-14

    Periventricular heterotopia (PH) is a cortical malformation characterized by aggregation of neurons lining the lateral ventricles due to abnormal neuronal migration. The molecular mechanism underlying the pathogenesis of PH is unclear. Here we show that Regulators of calcineurin 1 (Rcan1), a Down syndrome-related gene, plays an important role in radial migration of rat cortical neurons. Downregulation of Rcan1 by expressing shRNA impaired neural progenitor proliferation and led to defects in radial migration and PH. Two isoforms of Rcan1 (Rcan1-1 and Rcan1-4) are expressed in the rat brain. Migration defects due to downregulation of Rcan1 could be prevented by shRNA-resistant expression of Rcan1-1 but not Rcan1-4. Furthermore, we found that Rcan1 knockdown significantly decreased the expression level of Flna, an F-actin cross-linking protein essential for cytoskeleton rearrangement and cell migration, mutation of which causes the most common form of bilateral PH in humans. Finally, overexpression of FLNA in Rcan1 knockdown neurons prevented migration abnormalities. Together, these findings demonstrate that Rcan1 acts upstream from Flna in regulating radial migration and suggest that impairment of Rcan1-Flna pathway may underlie PH pathogenesis. Copyright © 2015 the authors 0270-6474/15/350610-11$15.00/0.

  6. Impaired standing balance : unraveling the underlying cause in elderly

    NARCIS (Netherlands)

    Pasma, Jantsje Henrieke

    2015-01-01

    Impaired balance is often seen in elderly and can result in impaired mobility and finally in falling. Failure of compensation strategies or deterioration of underlying systems involved in standing balance could result in impaired balance. To apply targeted interventions to improve balance, it is

  7. Harm to patients and others caused by impaired junior doctors ...

    African Journals Online (AJOL)

    Studies on sleep deprivation and impaired performance by medical interns in the US show that: • after 24 hours of continuous wakefulness impairments in perfor- mance are similar to those induced by a blood alcohol level of. 0.10%[8]. • medical interns working 24-hour shifts made 36% more serious medical errors and ...

  8. Bisphenol A Causes Liver Damage and Selectively Alters the Neurochemical Coding of Intrahepatic Parasympathetic Nerves in Juvenile Porcine Models under Physiological Conditions

    Directory of Open Access Journals (Sweden)

    Michael Thoene

    2017-12-01

    Full Text Available Bisphenol A (BPA is an extremely common polymer that is used in typical everyday products throughout the world, especially in food and beverage containers. Within the last ten years, it has been found that the BPA monomer tends to leach into foodstuffs, and nanogram concentrations of it may cause a variety of deleterious health effects. These health problems are very evident in developing children and in young adults. The aim of this study was to expose developing pigs to dietary BPA at both legally acceptable and ten-fold higher levels. Livers that had been exposed to BPA showed vacuolar degeneration, sinusoidal dilatation, vascular congestion and glycogen depletion that increased with exposure levels. Furthermore, the livers of these models were then examined for irregularities and double-labeled immunofluorescence was used to check the innervated hepatic samples for varying neuronal expression of selected neuronal markers in the parasympathetic nervous system (PSNS. It was found that both the PSNS and all of the neuronal markers showed increased expression, with some of them being significant even at recommended safe exposure levels. The implications are quite serious since these effects have been observed at recommended safe levels with expression increasing in-line with exposure levels. The increased neuronal markers studied here have been previously correlated with behavioral/psychological disorders of children and young adults, as well as with childhood obesity and diabetes. However, further research must be performed in order to develop a mechanism for the above-mentioned correlations.

  9. Causes of certifications for severe sight impairment (blind) and sight impairment (partial sight) in children in England and Wales.

    Science.gov (United States)

    Mitry, D; Bunce, C; Wormald, R; Leamon, S; Simkiss, P; Cumberland, P; Rahi, J; Bowman, R

    2013-11-01

    To explore and describe trends in the principal disorders/conditions ('cause') for severe sight impairment (SSI) (blind) and sight impairment (SI) (partial sight) certification in children in England and Wales since 1999. We obtained certification data for SI and SSI from a national database for all individuals aged 16 years or less at the time of certification in England and Wales for the years 1999/2000 and for the years 2007/2008-2009/2010. In total, there were 861 certifications in the year 1999/2000, rising to 1040 certifications in 2009/2010. The commonest single causes of SSI certification in 1999/2000 were cerebral visual impairment (23.2%) and optic nerve disorders (23.2%). The commonest single causes of SI certification in the same year comprised nystagmus (16.7%) and optic nerve disorders (15.5%). Cerebral visual impairment was the commonest single cause of SSI in children in England and Wales annually between 2007/2008 and 2009/2010 accounting for 21%-31% of certifications. The commonest causes of SI certification in 2009/2010 were congenital globe anomalies (18.4%) and retinal dystrophy (16.6%). The proportion of SI and SSI due to optic nerve disorders has decreased since 1999/2000. Our findings suggest that in England and Wales, cerebral visual impairment is now the commonest cause of paediatric SSI certification and hereditary retinal dystrophy and congenital globe anomalies are the commonest causes of SI certification.

  10. Hypoxia causes transgenerational impairments in reproduction of fish

    Science.gov (United States)

    Wang, Simon Yuan; Lau, Karen; Lai, Keng-Po; Zhang, Jiang-Wen; Tse, Anna Chung-Kwan; Li, Jing-Woei; Tong, Yin; Chan, Ting-Fung; Wong, Chris Kong-Chu; Chiu, Jill Man-Ying; Au, Doris Wai-Ting; Wong, Alice Sze-Tsai; Kong, Richard Yuen-Chong; Wu, Rudolf Shiu-Sun

    2016-01-01

    Hypoxia is amongst the most widespread and pressing problems in aquatic environments. Here we demonstrate that fish (Oryzias melastigma) exposed to hypoxia show reproductive impairments (retarded gonad development, decrease in sperm count and sperm motility) in F1 and F2 generations despite these progenies (and their germ cells) having never been exposed to hypoxia. We further show that the observed transgenerational reproductive impairments are associated with a differential methylation pattern of specific genes in sperm of both F0 and F2 coupled with relevant transcriptomic and proteomic alterations, which may impair spermatogenesis. The discovered transgenerational and epigenetic effects suggest that hypoxia might pose a dramatic and long-lasting threat to the sustainability of fish populations. Because the genes regulating spermatogenesis and epigenetic modifications are highly conserved among vertebrates, these results may also shed light on the potential transgenerational effects of hypoxia on other vertebrates, including humans. PMID:27373813

  11. Hearing Impairment Caused by Occupational Noise | Mets | South ...

    African Journals Online (AJOL)

    Occupational noise-induced hearing impairment is an insidiously developing injury which only becomes apparent when it affects the hearing of conversational speech. As no remedy is possible, prevention is the only answer. In view of the impending legislation in South Africa a review of the literature is presented. This is ...

  12. Prevalence and causes of blindness and visual impairment in the ...

    African Journals Online (AJOL)

    Background: Visual impairment and blindness are major public health and social problems worldwide. The problem is worse in the developing countries due to ignorance, infections, malnutrition and lack of adequate eye care services especially in the rural areas. The misfortune of losing one's eyesight is worsened by ...

  13. Prevalence and causes of visual impairment and blindness among 9980 Scandinavian adults

    DEFF Research Database (Denmark)

    Hesgaard, Helena; Vinding, Troels; La Cour, Morten

    2004-01-01

    To investigate the age-specific prevalence and causes of visual impairment and blindness in an epidemiologic study of an adult Scandinavian population.......To investigate the age-specific prevalence and causes of visual impairment and blindness in an epidemiologic study of an adult Scandinavian population....

  14. [Comparison of visual impairment caused by trachoma in China between 1978 and 2006].

    Science.gov (United States)

    Hu, Ailian; Cai, Xiaogu; Qiao, Liya; Zhang, Ye; Zhang, Xu; Sun, Baochen; Wang, Ningli

    2015-10-01

    To understand the distribution of visual impairment caused by trachoma in China and provide evidences for evaluation of eliminating blinding trachoma in China in the mission of Vision 2020. Sampling study. The results from the first year 1987 and second (year 2006) national sampling surveys of disabled persons were analyzed. Chi-square test was performed using SAS 9.30 to analyze the rates of visual impairment caused by trachoma in different groups. Unifactor and multifactor analyses were applied to analyze the relevance between visual impairment caused by trachoma and risk factors, including gender and age. The rate of visual impairment caused by trachoma was 102.01 persons/100 000 in 1987 and 17.62 persons/100 000 in 2006. The percentage of trachoma in all kinds of visual impairment was 14.25% in 1987 and 1.87% in 2006, and the difference was significant (F = 1 382.6, P visual impairment caused by trachoma. H-aggregation areas included Hubei, Sichuan, Anhui, Shannxi, Guizhou, Hunan provinces and Chongqing Municipality. Survival time without trachoma between 1987 and 2006 was significantly different (F = 2 745.9, P visual impairment caused by trachoma increased with age. Except the group of > 85 years, the rate of visual impairment caused by trachoma in all age groups in 1987 was significantly higher than that in 2006. The risk of visual impairment caused by trachoma in 1987 was 5.8 times that in 2006. If the other risk factors were not involved, the risk in 1987 was 8.75 times that in 2006. The risk in females was twice that in males. Both, the rate and risk of visual impairment caused by trachoma were significantly reduced in China. Impressive progresses were achieved in trachoma prevention and control.

  15. Causes of Childhood Vision Impairment in the School for the Blind in Eritrea.

    Science.gov (United States)

    Gyawali, Rajendra; Moodley, Vanessa R

    2017-12-01

    Our study provides the much-needed evidence on causes of childhood blindness in Eritrea. This will assist authorities to plan appropriate strategies and implement preventive, curative, and rehabilitative services to address these causes of vision loss in children in this resource-limited country. This study aims to identify the causes of severe vision impairment and blindness in children attending the only school for the blind in Eritrea. All children enrolled in the school were examined, and the World Health Organization form for the examination of visually impaired children was used to record the data. Examination included visual acuity, refraction, anterior segment, and fundus assessment. Causes of vision loss for children with severe vision impairment (visual acuity Eritrea. Despite the limitations, it is clearly shown that nearly half of the vision loss is due to avoidable causes. Thus, preventive public health strategies, specialist pediatric eye care, and rehabilitative services are recommended to address childhood vision impairment in Eritrea.

  16. Harm to patients and others caused by impaired junior doctors ...

    African Journals Online (AJOL)

    Public health officials may be held directly liable for the harm caused to patients, third parties or the junior doctors themselves, if it can be shown that they are at fault and are acting unlawfully in violation of the Constitution. Where officials carry out the unlawful orders of senior officials, including the minister of health and ...

  17. Prevalence of visual impairment in the adult Japanese population by cause and severity and future projections.

    Science.gov (United States)

    Yamada, Masakazu; Hiratsuka, Yoshimune; Roberts, Chris B; Pezzullo, M Lynne; Yates, Katie; Takano, Shigeru; Miyake, Kensaku; Taylor, Hugh R

    2010-01-01

    To present a comprehensive estimate of the total number of people with visual impairment in the adult Japanese population by age, gender, severity and cause, and to estimate future prevalence based on population projections and expected demographic changes. Definitions of visual impairment used in this study were based on the United States criteria. Total visual impairment was calculated as the sum of low vision and blindness. The prevalence estimates were based on input from a number of Japanese epidemiological surveys, census material and official population projections. There were an estimated 1.64 million people with visual impairment in 2007 in Japan. Of these, 187,800 were estimated to be blind. The prevalence of visual impairment in Japan increased with age and half of the people with visual impairment were aged 70 years or older. The leading causes of visual impairment in Japan were glaucoma (24.3%), diabetic retinopathy (20.6%), degenerative myopia (12.2%), age-related macular degeneration (10.9%), and cataract (7.2%). These five major causes comprised three-quarters of all visual impairment. The prevalence of visual impairment was projected to increase from 1.3% of the population in 2007 to 2.0% by 2050. This comprehensive study presents the prevalence of total visual impairment in the adult Japanese population. The projected increases in the prevalence of visual impairment over time reflect the demographic changes of a declining and aging Japanese population. These projections highlight that the burden of disease due to visual impairment and imposed on society is likely to increase.

  18. Causes of visual impairment among patients referred to a visual rehabilitation clinic in Iran.

    Science.gov (United States)

    Ramezani, Alireza; Pardis, Maasome; Rafati, Nasrin; Kazemi-Moghaddam, Mohsen; Katibeh, Marzieh; Rostami, Pooya; Dehghan, Mohammad Hossein; Javadi, Mohammad Ali; Rabbanikhah, Zahra

    2012-04-01

    Epidemiologic evaluation and investigating the causes of visual impairment in any society is a matter of concern and has a direct effect on the country's health care planning. In this study we describe causes of low vision and blindness in Iranian patients referred to rehabilitation clinics for taking vision aids. In this cross-sectional study, visual acuity was classified based on best-corrected visual acuity in the better eye according to the World Health Organization definition (blindness, visual acuity [VA] visual impairment, VA visual impairment, VA visual impairment, severe visual impairment and blindness were present in 122 (28.8%), 196 (46.4%) and 105 (24.8%) of the patients, respectively. The main causes of visual impairment were retinal and choroidal diseases (74.5%), optic nerve and optic tract diseases (9.8%), vitreous and globe disorders (5.3%), congenital cataract (3.1%), and glaucoma (2.6%). The distribution pattern of the causes was similar in all age subgroups. Diseases of the retina and choroid are the main cause of visual impairment among patients referred to an academic visual rehabilitation clinic in Iran.

  19. B-Vitamin Deficiency Causes Hyperhomocysteinemia and Vascular Cognitive Impairment in Mice

    National Research Council Canada - National Science Library

    Aron M. Troen; Melissa Shea-Budgell; Barbara Shukitt-Hale; Donald E. Smith; Jacob Selhub; Irwin H. Rosenberg

    2008-01-01

    .... We report here that feeding male C57BL6/J mice a B-vitamin-deficient diet for 10 weeks induced hyperhomocysteinemia, significantly impaired spatial learning and memory, and caused a significant...

  20. Prevalence and causes of blindness and visual impairment among school children in south-western Nigeria.

    Science.gov (United States)

    Ajaiyeoba, A I; Isawumi, M A; Adeoye, A O; Oluleye, T S

    2005-01-01

    The aim of the study was to assess the prevalence and identify the causes of blindness and visual impairment in school children of Ilesa-East Local Government Area of Osun State, Nigeria. A total of 1144 school children in primary and secondary schools were selected using a 2-stage random sampling method and examined to determine the prevalence and causes of blindness and visual impairment. A total of 17 (1.48%) children were blind or visually impaired. These comprised of 11 (0.96%) children who were visually impaired and 4 (0.3%) who were severely visually impaired. Only 2 (0.15%) school children were blind. The causes of visual impairment were refractive error 10 (0.87%) and immature cataract 1 (0.08%), causes of severe visual impairment included corneal opacities 2 (0.2%), amblyopia leading to squint 1 (0.08%) and 1 cataract 1 (0.08%). The causes of blindness in school children were corneal scars presumed to be due to vitamin A deficiency 1 (0.08%) and keratoconus 1 (0.08%). Causes of blindness and visual impairment in children attending regular schools in Nigeria were treatable. Prevention, early recognition and prompt treatment of these diseases by regular screening of school children would definitely reduce unnecessary visual handicap in Nigerian school children so that they can attain their full potential in the course of their education. Also, information from this study is relevant for the purpose of planning eye care programmes for the prevention of blindness in Nigerian school children. This will go a long way in the prevention of unnecessary blindness and visual impairment in school children.

  1. Deletion of PREPl causes growth impairment and hypotonia in mice.

    Directory of Open Access Journals (Sweden)

    Anna Mari Lone

    Full Text Available Genetic studies of rare diseases can identify genes of unknown function that strongly impact human physiology. Prolyl endopeptidase-like (PREPL is an uncharacterized member of the prolyl peptidase family that was discovered because of its deletion in humans with hypotonia-cystinuria syndrome (HCS. HCS is characterized by a number of physiological changes including diminished growth and neonatal hypotonia or low muscle tone. HCS patients have deletions in other genes as well, making it difficult to tease apart the specific role of PREPL. Here, we develop a PREPL null (PREPL(-/- mouse model to address the physiological role of this enzyme. Deletion of exon 11 from the Prepl gene, which encodes key catalytic amino acids, leads to a loss of PREPL protein as well as lower Prepl mRNA levels. PREPL(-/- mice have a pronounced growth phenotype, being significantly shorter and lighter than their wild type (PREPL(+/+ counterparts. A righting assay revealed that PREPL(-/- pups took significantly longer than PREPL(+/+ pups to right themselves when placed on their backs. This deficit indicates that PREPL(-/- mice suffer from neonatal hypotonia. According to these results, PREPL regulates growth and neonatal hypotonia in mice, which supports the idea that PREPL causes diminished growth and neonatal hypotonia in humans with HCS. These animals provide a valuable asset in deciphering the underlying biochemical, cellular and physiological pathways that link PREPL to HCS, and this may eventually lead to new insights in the treatment of this disease.

  2. The prevalence and causes of visual impairment in seven-year-old children.

    Science.gov (United States)

    Ghaderi, Soraya; Hashemi, Hassan; Jafarzadehpur, Ebrahim; Yekta, Abbasali; Ostadimoghaddam, Hadi; Mirzajani, Ali; Khabazkhoob, Mehdi

    2017-11-22

    To report the prevalence and causes of visual impairment in seven-year-old children in Iran and its relationship with socio-economic conditions. In a cross-sectional population-based study, first-grade students in the primary schools of eight cities in the country were randomly selected from different geographic locations using multistage cluster sampling. The examinations included visual acuity measurement, ocular motility evaluation, and cycloplegic and non-cycloplegic refraction. Using the definitions of the World Health Organization (presenting visual acuity less than or equal to 6/18 in the better eye) to estimate the prevalence of vision impairment, the present study reported presenting visual impairment in seven-year-old children. Of 4,614 selected students, 4,106 students participated in the study (response rate 89 per cent), of whom 2,127 (51.8 per cent) were male. The prevalence of visual impairment according to a visual acuity of 6/18 was 0.341 per cent (95 per cent confidence interval 0.187-0.571); 1.34 per cent (95 per cent confidence interval 1.011-1.74) of children had visual impairment according to a visual acuity of 6/18 in at least one eye. Sixty-six (1.6 per cent) and 23 (0.24 per cent) children had visual impairment according to a visual acuity of 6/12 in the worse and better eye, respectively. The most common causes of visual impairment were refractive errors (81.8 per cent) and amblyopia (14.5 per cent). Among different types of refractive errors, astigmatism was the main refractive error leading to visual impairment. According to the concentration index, the distribution of visual impairment in children from low-income families was higher. This study revealed a high prevalence of visual impairment in a representative sample of seven-year-old Iranian children. Astigmatism and amblyopia were the most common causes of visual impairment. The distribution of visual impairment was higher in children from low-income families. Cost

  3. Causes of severe visual impairment and blindness in children in the Republic of Suriname

    NARCIS (Netherlands)

    Heijthuijsen, Astrid Anna Maria; Beunders, Victoria Apollonia Annemarie; Jiawan, Dinesh; de Mesquita-Voigt, Anne-Marie Bueno; Pawiroredjo, Jerrel; Mourits, Maarten; Tanck, Michael; Verhoeff, Joost; Saeed, Peerooz

    2013-01-01

    To determine the causes of severe visual impairment and blindness (SVI/BL) in children in Suriname (Dutch Guyana) and to identify preventable and treatable causes. 4643 children under 16 years of age were recruited from two locations: 33 children attending the only school for the blind were examined

  4. Prevalence and Causes of Visual Impairment and Blindness in Shanxi Province, China.

    Science.gov (United States)

    Li, Tong; Du, Liping; Du, Lingzhen

    2015-01-01

    To estimate the prevalence and causes of visual impairment and blindness in Shanxi Province, China. Data were obtained from the Second National Sampling Survey of Disability conducted in 2006. Blindness and visual impairment were defined as best corrected visual acuity Visual acuity (VA) was measured using a Standard Logarithmic Visual Acuity E chart (Snellen) for subjects aged 7 years and older. Participants younger than 7 years were examined using special experiments or the Childhood Graphical Visual Chart. The prevalence of visual impairment and blindness in Shanxi was estimated to be 0.6% (466/75,016) among persons up to 80 years old. The prevalence in rural areas (0.7%; 351/48,137) was significantly higher than that in urban areas (0.4%; 115/26,879) and was higher in females (0.8%; 298/36,933) than in males (0.4%; 168/38,083). The most common cause of visual impairment and blindness was cataract (44.9%), followed by retinopathy and choroidopathy (12.5%), hereditary and developmental disorders (10.3%), corneal disease (5.2%), and refractive error (4.9%). Prevalences of visual impairment and blindness in women and in rural areas were higher than in men and urban areas, and increased with age. Cataract was the most prevalent cause of visual impairment and blindness. Based on the findings from this study, we suggest that provision of support and welfare services should be organized.

  5. Attenuation of neurobehavioral and neurochemical abnormalities in animal model of cognitive deficits of Alzheimer's disease by fermented soybean nanonutraceutical.

    Science.gov (United States)

    Bhatt, Prakash Chandra; Pathak, Shruti; Kumar, Vikas; Panda, Bibhu Prasad

    2018-02-01

    The present study was performed to evaluate the efficacy of nanonutraceuticals (NN) for attenuation of neurobehavioral and neurochemical abnormalities in Alzheimer's disease. Solid-state fermentation of soybean with Bacillus subtilis was performed to produce different metabolites (nattokinase, daidzin, genistin and glycitin and menaquinone-7). Intoxication of rats with colchicine caused impairment in learning and memory which was demonstrated in neurobehavioral paradigms (Morris water maze and passive avoidance) linked with decreased activity of acetylcholinesterase (AChE). NN treatment led to a significant increase in TLT in the retention trials as compared to acquisition trial TLT suggesting an improved learning and memory in rats. Further, treatment of NN caused an increase in the activity of AChE (42%), accompanied with a reduced activity of glutathione (42%), superoxide dismutase (43%) and catalase (41%). It also decreased the level of lipid peroxidation (28%) and protein carbonyl contents (30%) in hippocampus as compared to those treated with colchicine alone, suggesting a possible neuroprotective efficacy of NN. Interestingly, in silico studies also demonstrated an effective amyloid-β and BACE-1 inhibition activity. These findings clearly indicated that NN reversed colchicine-induced behavioral and neurochemical alterations through potent antioxidant activity and could possibly impart beneficial effects in cognitive defects associated with Alzheimer's disease.

  6. Self-reported visual impairment, physical activity and all-cause mortality: The HUNT Study.

    Science.gov (United States)

    Brunes, Audun; Flanders, W Dana; Augestad, Liv Berit

    2017-02-01

    To examine the associations of self-reported visual impairment and physical activity (PA) with all-cause mortality. This prospective cohort study included 65,236 Norwegians aged ⩾20 years who had participated in the Nord-Trøndelag Health Study (HUNT2, 1995-1997). Of these participants, 11,074 (17.0%) had self-reported visual impairment (SRVI). The participants' data were linked to Norway's Cause of Death Registry and followed throughout 2012. Hazard ratios and 95% confidence intervals (CI) were assessed using Cox regression analyses with age as the time-scale. The Cox models were fitted for restricted age groups (adults with self-reported no visual impairment, the multivariable hazard ratios among adults with SRVI were 2.47 (95% CI 1.94-3.13) in those aged adults aged Adults with SRVI reporting no PA were associated with an increased all-cause mortality risk. The associations attenuated with age.

  7. Prevalence, Causes and Social Factors of Visual Impairment among Chinese Adults: Based on a National Survey.

    Science.gov (United States)

    Guo, Chao; Wang, Zhenjie; He, Ping; Chen, Gong; Zheng, Xiaoying

    2017-09-08

    Visual impairment has become a global challenge, especially for developing countries. This study aims to estimate the prevalence, causes and social factors of visual impairment among Chinese adults. Data were from a nationally representative population-based cross-sectional study. The study population were 1,909,199 non-institutionalized adults aged 18 years and older in mainland China. In the survey, low vision and blindness were checked by ophthalmologists according to the WHO best-corrected visual acuity (BCVA) criteria. Population weighted numbers and prevalence of low vision and blindness with 95% confidence intervals (CIs) were estimated where appropriate. Multivariable logistic regression analysis was used to identify the social factors of visual impairment. The weighted prevalence of visual impairment was 17.17 (95% CI, 16.84-17.50) per 1000 Chinese adults aged 18 years and older. Cataract (57.35%), disorders of choroid and retina (9.80%), and disorders of cornea (6.49%) contributed more than 70 percent to the visual impairment in Chinese adults. Older age groups, young or middle-aged male adults, female elders, illiterate, rural dwellers, non-eastern residents, singles, unemployment, and from family with lower income were associated with visual impairment. More efforts are warranted to enhance treatment and rehabilitation among people with eye disorders to prevent visual impairment.

  8. Prevalence, Causes and Social Factors of Visual Impairment among Chinese Adults: Based on a National Survey

    Directory of Open Access Journals (Sweden)

    Chao Guo

    2017-09-01

    Full Text Available Visual impairment has become a global challenge, especially for developing countries. This study aims to estimate the prevalence, causes and social factors of visual impairment among Chinese adults. Data were from a nationally representative population-based cross-sectional study. The study population were 1,909,199 non-institutionalized adults aged 18 years and older in mainland China. In the survey, low vision and blindness were checked by ophthalmologists according to the WHO best-corrected visual acuity (BCVA criteria. Population weighted numbers and prevalence of low vision and blindness with 95% confidence intervals (CIs were estimated where appropriate. Multivariable logistic regression analysis was used to identify the social factors of visual impairment. The weighted prevalence of visual impairment was 17.17 (95% CI, 16.84–17.50 per 1000 Chinese adults aged 18 years and older. Cataract (57.35%, disorders of choroid and retina (9.80%, and disorders of cornea (6.49% contributed more than 70 percent to the visual impairment in Chinese adults. Older age groups, young or middle-aged male adults, female elders, illiterate, rural dwellers, non-eastern residents, singles, unemployment, and from family with lower income were associated with visual impairment. More efforts are warranted to enhance treatment and rehabilitation among people with eye disorders to prevent visual impairment.

  9. Prevalence, Causes and Social Factors of Visual Impairment among Chinese Adults: Based on a National Survey

    Science.gov (United States)

    Wang, Zhenjie; He, Ping; Chen, Gong; Zheng, Xiaoying

    2017-01-01

    Visual impairment has become a global challenge, especially for developing countries. This study aims to estimate the prevalence, causes and social factors of visual impairment among Chinese adults. Data were from a nationally representative population-based cross-sectional study. The study population were 1,909,199 non-institutionalized adults aged 18 years and older in mainland China. In the survey, low vision and blindness were checked by ophthalmologists according to the WHO best-corrected visual acuity (BCVA) criteria. Population weighted numbers and prevalence of low vision and blindness with 95% confidence intervals (CIs) were estimated where appropriate. Multivariable logistic regression analysis was used to identify the social factors of visual impairment. The weighted prevalence of visual impairment was 17.17 (95% CI, 16.84–17.50) per 1000 Chinese adults aged 18 years and older. Cataract (57.35%), disorders of choroid and retina (9.80%), and disorders of cornea (6.49%) contributed more than 70 percent to the visual impairment in Chinese adults. Older age groups, young or middle-aged male adults, female elders, illiterate, rural dwellers, non-eastern residents, singles, unemployment, and from family with lower income were associated with visual impairment. More efforts are warranted to enhance treatment and rehabilitation among people with eye disorders to prevent visual impairment. PMID:28885571

  10. Prevalence and causes of bilateral blindness and visual impairment among institutionalized elderly people in Pamplona, Spain.

    Science.gov (United States)

    Sainz-Gómez, Carmen; Fernández-Robredo, Patricia; Salinas-Alamán, Angel; Montañés, Javier Moreno; Escudero Berasategui, José Maria; Guillén-Grima, Francisco; Ruiz-Moreno, José María; García-Layana, Alfredo

    2010-01-01

    To estimate the prevalence and causes of bilateral blindness and visual impairment in an urban institutionalized population aged 65 years and older. A total of 392 nursing home residents completed a standardized eye examination, including measurement of visual acuity (VA), intraocular pressure, lens opacity grading, indirect ophthalmoscopy, and photography of the macular area. The major causes of vision loss identified for all participants were blindness and visual impairment. The average subject age was 82 years (65-97); women outnumbered men 263 to 129. The prevalence of bilateral blindness (VA > or =1.0 logarithm of the minimum angle of resolution [logMAR]) was 14.9% (43/288); the prevalence of visual impairment (VA > or =0.5 and 1.0 logMAR) was 31.9% (92/288). Blindness and visual impairment increased significantly with age (p<0.05), odds ratio (OR) 1.047 and 1.088, respectively. Cataract was the most common cause of bilateral blindness and visual impairment (27.9% and 44.6%, respectively) followed by pathologic myopia (23.3%) and age-related macular degeneration (AMD) (20.9%) for blindness, and by AMD (27.2%) and pathologic myopia (12%) for visual impairment. Fifty percent of subjects with visual loss had the potential for improved vision with medical or surgical intervention. Although the prevalences were high, these data are important since it is difficult for epidemiologic studies to include aged, institutionalized individuals, although their numbers are increasing. Recognition of the predominant causes of visual loss dependent on age is fundamental for early diagnosis and treatment of ocular diseases. Many cases of low vision can be treated with appropriate ophthalmologic care.

  11. Prevalence and Causes of Visual Impairment and Blindness among Cocoa Farmers in Ghana.

    Science.gov (United States)

    Boadi-Kusi, Samuel Bert; Hansraj, Rekha; Mashige, Khathutshelo Percy; Osafo-Kwaako, Alfred; Ilechie, Alex Azuka; Abokyi, Samuel

    2017-02-01

    To determine the prevalence and causes of visual impairment and blindness among cocoa farmers in Ghana in order to formulate early intervention strategies. A cross-sectional study using multistage random sampling from four cocoa growing districts in Ghana was conducted from November 2013 to April 2014. A total of 512 cocoa farmers aged 40 years and older were interviewed and examined. The brief interview questionnaire was administered to elicit information on the demographics and socioeconomic details of participants. The examination included assessment of visual acuity (VA), retinoscopy, subjective refraction, direct ophthalmoscopy, slit-lamp biomicroscopy and intraocular pressure (IOP). For quality assurance, a random sample of cocoa farmers were selected and re-examined independently. Moderate to severe visual impairment (VA visual impairment were cataract (45, 38.8%), uncorrected refractive error (42, 36.2%), posterior segment disorders (15, 12.9%), and corneal opacity (11, 9.5%). The prevalence of visual impairment and blindness among cocoa farmers in Ghana is relatively high. The major causes of visual impairment and blindness are largely preventable or treatable, indicating the need for early eye care service interventions.

  12. Prevalence and causes of hearing impairment in Fundong Health District, North-West Cameroon.

    Science.gov (United States)

    Ferrite, Silvia; Mactaggart, Islay; Kuper, Hannah; Oye, Joseph; Polack, Sarah

    2017-04-01

    To estimate the prevalence and causes of hearing impairment in Fundong Health District, North-West Cameroon. We selected 51 clusters of 80 people (all ages) through probability proportionate to size sampling. Initial hearing screening was undertaken through an otoacoustic emission (OAE) test. Participants aged 4+ years who failed this test in both ears or for whom an OAE reading could not be taken underwent a manual pure-tone audiometry (PTA) screening. Cases of hearing impairment were defined as those with pure-tone average ≥41 dBHL in adults and ≥35 dBHL in children in the better ear, or children under age 4 who failed the OAE test in both ears. Each case with hearing loss was examined by an ear, nose and throat nurse who indicated the main likely cause. We examined 3567 (86.9%) of 4104 eligible people. The overall prevalence of hearing impairment was 3.6% (95% confidence interval [CI]: 2.8-4.6). The prevalence was low in people aged 0-17 (1.1%, 0.7-1.8%) and 18-49 (1.1%, 0.5-2.6%) and then rose sharply in people aged 50+ (14.8%, 11.7-19.1%). Among cases, the majority were classified as moderate (76%), followed by severe (15%) and profound (9%). More than one-third of cases of hearing impairment were classified as unknown (37%) or conductive (37%) causes, while sensorineural causes were less common (26%). Prevalence of hearing impairment in North-West Cameroon is in line with the WHO estimate for sub-Saharan Africa. The majority of cases with known causes are treatable, with impacted wax playing a major role. © 2017 John Wiley & Sons Ltd.

  13. Neurochemical dementia diagnostics for Alzheimer's disease and other dementias: an ISO 15189 perspective.

    Science.gov (United States)

    Waedt, Johanna; Kleinow, Martina; Kornhuber, Johannes; Lewczuk, Piotr

    2012-10-01

    Dementia is one of the most common causes of health problems in the elderly populations of Western industrialized countries. A combined analysis of cerebrospinal fluid-based neurochemical dementia diagnostics biomarkers (amyloid-β peptides, total tau and phosphorylated forms of tau) provides sensitivity and specificity in the range of 85% for the diagnosis of Alzheimer's disease, the most common cause of dementia. The alterations occur very early in the course of neurodegeneration, enabling medical follow-up of persons with increased risk of developing dementia. With a growing number of laboratories performing neurochemical dementia diagnostics routinely, it is important to standardize protocols and laboratory performance to enable comparisons of results and their interpretations. Together with the recently published expert guidelines for sample handling and preparation, as well as the interpretation (post-analytical) algorithms developed by experienced centers, ISO 15189 norm provides an extremely useful tool for standardization of neurochemical dementia diagnostics.

  14. Causes of severe visual impairment and blindness in children in schools for the blind in Ethiopia

    Science.gov (United States)

    Kello, A B; Gilbert, C

    2003-01-01

    Aims: To determine the causes of severe visual impairment and blindness in children in schools for the blind in Ethiopia, to aid in planning for the prevention and management of avoidable causes. Methods: Children attending three schools for the blind in Ethiopia were examined during April and May 2001 using the standard WHO/PBL eye examination record for children with blindness and low vision protocol. Data were analysed for those children aged less than 16 years using the epi-info-6 programme. Results: Among 360 pupils examined, 312 (96.7%) were aged children, 295 (94.5%) were blind or severely visually impaired. The major anatomical site of visual loss was cornea/phthisis (62.4%), followed by optic nerve lesions (9.8%), cataract/aphakia (9.2%), and lesions of the uvea (8.8%). The major aetiology was childhood factors (49.8%). The aetiology was unknown in 45.1% of cases. 68% of cases were considered to be potentially avoidable. Conclusions: Vitamin A deficiency and measles were the major causes of severe visual impairment/blindness in children in schools for the blind in Ethiopia. The majority of causes acquired during childhood could be avoided through provision of basic primary healthcare services. PMID:12714383

  15. Causes of severe visual impairment and blindness in children in the Republic of Suriname.

    Science.gov (United States)

    Heijthuijsen, Astrid Anna Maria; Beunders, Victoria Apollonia Annemarie; Jiawan, Dinesh; de Mesquita-Voigt, Anne-Marie Bueno; Pawiroredjo, Jerrel; Mourits, Maarten; Tanck, Michael; Verhoeff, Joost; Saeed, Peerooz

    2013-07-01

    To determine the causes of severe visual impairment and blindness (SVI/BL) in children in Suriname (Dutch Guyana) and to identify preventable and treatable causes. 4643 children under 16 years of age were recruited from two locations: 33 children attending the only school for the blind were examined and 4610 medical records were analysed at an eye clinic. Data have been collected using the WHO Prevention of Blindness Programme eye examination record for children. 65 children were identified with SVI/BL, 58.5% were blind and 41.5% were severely visually impaired (SVI). The major anatomical site of SVI/BL was the retina in 33.8%, lens in 15.4% and normal appearing globe in 15.4%. The major underlying aetiology of SVI/BL was undetermined in 56.9% (mainly cataract and abnormality since birth) and perinatal factors 21.5% (mainly retinopathy of prematurity (ROP)). Avoidable causes of SVI/BL accounted for 40% of cases; 7.7% were preventable and 32.3% were treatable with cataracts and ROP the most common causes (15.4% and 12.3%, respectively). More than a third of the SVI/BL causes are potentially avoidable, with childhood cataract and ROP the leading causes. Corneal scarring from vitamin A deficiency does not seem to be a continuing issue in Suriname.

  16. Omeprazole impairs vascular redox biology and causes xanthine oxidoreductase-mediated endothelial dysfunction.

    Science.gov (United States)

    Pinheiro, Lucas C; Oliveira-Paula, Gustavo H; Portella, Rafael L; Guimarães, Danielle A; de Angelis, Celio D; Tanus-Santos, Jose E

    2016-10-01

    Proton pump inhibitors (PPIs) are widely used drugs that may increase the cardiovascular risk by mechanisms not entirely known. While PPIs increase asymmetric dimethylarginine (ADMA) levels and inhibit nitric oxide production, it is unknown whether impaired vascular redox biology resulting of increased xanthine oxidoreductase (XOR) activity mediates PPIs-induced endothelial dysfunction (ED). We examined whether increased XOR activity impairs vascular redox biology and causes ED in rats treated with omeprazole. We also examined whether omeprazole aggravates the ED found in hypertension. Treatment with omeprazole reduced endothelium-dependent aortic responses to acetylcholine without causing hypertension. However, omeprazole did not aggravate two-kidney, one-clip (2K1C) hypertension, nor hypertension-induced ED. Omeprazole and 2K1C increased vascular oxidative stress as assessed with dihydroethidium (DHE), which reacts with superoxide, and by the lucigenin chemiluminescence assay. The selective XOR inhibitor febuxostat blunted both effects induced by omeprazole. Treatment with omeprazole increased plasma ADMA concentrations, XOR activity and systemic markers of oxidative stress. Incubation of aortic rings with ADMA increased XOR activity, DHE fluorescence and lucigenin chemiluminescence signals, and febuxostat blunted these effects. Providing functional evidence that omeprazole causes ED by XOR-mediated mechanisms, we found that febuxostat blunted the ED caused by omeprazole treatment. This study shows that treatment with omeprazole impairs the vascular redox biology by XOR-mediated mechanisms leading to ED. While omeprazole did not further impair hypertension-induced ED, further studies in less severe animal models are warranted. Our findings may have major relevance, particularly to patients with cardiovascular diseases taking PPIs. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  17. Common Causes of Visual Impairment Among Sixth Grade Students in Boyer Ahmad city

    Directory of Open Access Journals (Sweden)

    Shahram Bamdad

    2017-04-01

    Full Text Available Background: In line with the implementation of primary health care, Knowing the factors causing visual impairment is very helpful among children and students among population of each district. That's why in this study, we intend to study common causes of visual impairment in sixth grade elementary students in Boyer Ahmad city and we compared the results with similar studies. Materials and Methods: 1850 of 4427 sixth grade elementary students selected by Cluster sampling method in 2016-17 and they examined by linear snellen chart in the respective schools in 6 meters distance. Abnormal individuals were referred to specialized centers of Ophthalmology to determine the cause of decreased vision and they examined completely by an ophthalmologist. Results: In the initial screening, of 1850 people examined, 168 students (9.1% known abnormal based on basic view of 0.8 and they were referred to specialized clinic for specialist examination. of these, 95 students reffered to ophthalmologist. In specialist examination, 70 students (8.3% of total examined patients were visually impaired which the most important were Refractive Errors(3.84%, Amblyopia(2.3% and Strabismus(0.19%. 38% of amblyopia was refractive errors. Of total number referred to an ophthalmologist, 26.3% of people were malingering which including 2.35% of general population.   Conclusion: Refractive errors was known as the most common cause of visual impairment and Amblyopia in the study group. As for to diagnosis simplicity and treatment of refractive errors we can dramatically reduced the prevalence of amblyopia and we also can reduce the incidence of malingering through cultural measures by the Broadcasting of Province.

  18. Impaired fatty acid oxidation as a cause for lipotoxicity in cardiomyocytes

    Energy Technology Data Exchange (ETDEWEB)

    Haffar, T. [Université de Montreal (Canada); Montreal Heart Institute (Canada); Bérubé-Simard, F. [Montreal Heart Institute (Canada); Bousette, N., E-mail: nicolas.bousette@umontreal.ca [Université de Montreal (Canada); Montreal Heart Institute (Canada)

    2015-12-04

    A major cause for diabetic cardiomyopathy is excess lipid accumulation. To elucidate mechanisms of lipotoxicity mediated diabetic heart disease we need to further our understanding of how lipid metabolism is altered in the diabetic heart. Here we investigated the role of lipid clearance by oxidation as a regulator of lipid-mediated toxicity (lipotoxicity). We evaluated the effect of pre-treating rat neonatal cardiomyocytes (NCMs) with either oleate (mono-unsaturated fatty acid) or palmitate (saturated fatty acid) on fatty acid oxidation (FAO) by measuring {sup 14}C–CO{sub 2} production. We evaluated carnitine palmitoyltransferase (Cpt1b) expression by western blotting and mitochondrial membrane potential by quantitative and qualitative fluorescence analyses using the JC-1 dye. We inhibited the Cpt1b pharmacologically using etomoxir and genetically by knocking down its expression using LentiVector mediated transduction of siRNAs targeting the Cpt1b gene. We found that palmitate had a slower clearance rate from NCMs than oleate, and this was associated with a significant decrease in FAO. This impairment in FAO was not the result of either loss of Cpt1b protein or mitochondrial integrity. Enhancing FAO with either oleate or carnitine was associated with a significant attenuation of palmitate mediated lipotoxicity. In contrast impairing FAO in oleate treated NCMs caused lipotoxicity. Here we demonstrate that a major difference between non-toxic unsaturated fatty acids and toxic saturated fatty acids is there ability to stimulate or inhibit fatty acid oxidation, respectively. This has important implications for diabetic cardiomyopathy since diabetic hearts consistently exhibit elevated lipid accumulation. - Highlights: • Palmitate had a slower clearance rate from NCMs than oleate. • Palmitate caused a significant decrease in fatty acid oxidation in cardiomyocytes. • Impaired FAO was not due to loss of Cpt1b protein or mitochondrial integrity. • Enhancing FAO

  19. Causes of blindness and visual impairment in the West of Scotland.

    Science.gov (United States)

    Bamashmus, M A; Matlhaga, B; Dutton, G N

    2004-03-01

    To determine the overall reported incidence and causes of registrable blindness and visual impairment in the West of Scotland and any trends that have occurred in the previous 16 years since data from the same area were published. Data for analysis were obtained from BP1 registration forms returned to the Resource Centre for the Blind serving the Strathclyde region in the West of Scotland between 1 April 1996 and 31 March 1997. A total of 1595 visually handicapped people were registered during the study year. Of these, 99 forms (6.2%) were excluded from further analysis because of insufficient information. The remaining 1496 completed BP1 Forms were in respect of 530 males and 966 females. Of these, 253 males and 450 females were legally blind (total 703 or 47.0%) and 277 males and 516 females were partially sighted (total 793 or 53.0%). The five leading causes of blindness, in decreasing frequency, were age-related macular degeneration (ARMD), glaucoma, diabetic retinopathy, myopic degeneration, and optic atrophy. ARMD and diabetic retinopathy were the most common causes of blindness in those over 65 years and persons of working age, respectively. In adults, cataract is no longer a significant cause of registrable visual impairment. The proportions of registrations owing to glaucoma, diabetic retinopathy, and myopia have not significantly changed since 1983 and the proportion owing to macular degeneration has increased. In children, congenital glaucoma, cataract, and corneal infection were no longer causes of registration, but impairment of vision caused by brain damage is now a significant contributor.

  20. Cannabinoids for the Treatment of Schizophrenia? A Balanced Neurochemical Framework for Both Adverse and Therapeutic Effects of Cannabis Use

    Directory of Open Access Journals (Sweden)

    Carissa M. Coulston

    2011-01-01

    Full Text Available Recent studies have found that cannabinoids may improve neuropsychological performance, ameliorate negative symptoms, and have antipsychotic properties for a subgroup of the schizophrenia population. These findings are in contrast to the longstanding history of adverse consequences of cannabis use, predominantly on the positive symptoms, and a balanced neurochemical basis for these opposing views is lacking. This paper details a review of the neurobiological substrates of schizophrenia and the neurochemical effects of cannabis use in the normal population, in both cortical (in particular prefrontal and subcortical brain regions. The aim of this paper is to provide a holistic neurochemical framework in which to understand how cannabinoids may impair, or indeed, serve to ameliorate the positive and negative symptoms as well as cognitive impairment. Directions in which future research can proceed to resolve the discrepancies are briefly discussed.

  1. Selective learning impairment of delayed reinforcement autoshaped behavior caused by low doses of trimethyltin.

    Science.gov (United States)

    Cohen, C A; Messing, R B; Sparber, S B

    1987-01-01

    The organometal neurotoxin trimethyltin (TMT), induces impaired learning and memory for various tasks. However, administration is also associated with other "non-specific" behavioral changes which may be responsible for effects on conditioned behaviors. To determine if TMT treatment causes a specific learning impairment, three experiments were done using variations of a delay of reinforcement autoshaping task in which rats learn to associate the presentation and retraction of a lever with the delivery of a food pellet reinforcer. No significant effects of TMT treatment were found with a short (4 s) delay of reinforcement, indicating that rats were motivated and had the sensorimotor capacity for learning. When the delay was increased to 6 s, 3.0 or 6.0 mg TMT/kg produced dose-related reductions in behaviors directed towards the lever. Performance of a group given 7.5 mg TMT/kg, while still impaired relative to controls, appeared to be better than the performance of groups given lower doses. This paradoxical effect was investigated with a latent inhibition paradigm, in which rats were pre-exposed to the Skinner boxes for several sessions without delivery of food reinforcement. Control rats showed retardation of autoshaping when food reinforcement was subsequently introduced. Rats given 7.5 mg TMT/kg exhibited elevated levels of lever responding during pre-exposure and autoshaping sessions. The results indicate that 7.5 mg TMT/kg produces learning impairments which are confounded by hyperreactivity to the environment and an inability to suppress behavior toward irrelevant stimuli. In contrast, low doses of TMT cause learning impairments which are not confounded by hyperreactivity, and may prove to be useful models for studying specific associational dysfunctions.

  2. Neurochemical differences in learning and memory paradigms among rats supplemented with anthocyanin-rich blueberry diets and exposed to acute doses of 56Fe particles

    Science.gov (United States)

    Poulose, Shibu M.; Rabin, Bernard M.; Bielinski, Donna F.; Kelly, Megan E.; Miller, Marshall G.; Thanthaeng, Nopporn; Shukitt-Hale, Barbara

    2017-02-01

    The protective effects of anthocyanin-rich blueberries (BB) on brain health are well documented and are particularly important under conditions of high oxidative stress, which can lead to "accelerated aging." One such scenario is exposure to space radiation, consisting of high-energy and -charge particles (HZE), which are known to cause cognitive dysfunction and deleterious neurochemical alterations. We recently tested the behavioral and neurochemical effects of acute exposure to HZE particles such as 56Fe, within 24-48 h after exposure, and found that radiation primarily affects memory and not learning. Importantly, we observed that specific brain regions failed to upregulate antioxidant and anti-inflammatory mechanisms in response to this insult. To further examine these endogenous response mechanisms, we have supplemented young rats with diets rich in BB, which are known to contain high amounts of antioxidant-phytochemicals, prior to irradiation. Exposure to 56Fe caused significant neurochemical changes in hippocampus and frontal cortex, the two critical regions of the brain involved in cognitive function. BB supplementation significantly attenuated protein carbonylation, which was significantly increased by exposure to 56Fe in the hippocampus and frontal cortex. Moreover, BB supplementation significantly reduced radiation-induced elevations in NADPH-oxidoreductase-2 (NOX2) and cyclooxygenase-2 (COX-2), and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) in the hippocampus and frontal cortex. Overall results indicate that 56Fe particles may induce their toxic effects on hippocampus and frontal cortex by reactive oxygen species (ROS) overload, which can cause alterations in the neuronal environment, eventually leading to hippocampal neuronal death and subsequent impairment of cognitive function. Blueberry supplementation provides an effective preventative measure to reduce the ROS load on the CNS in an event of acute HZE exposure.

  3. Prevalence and causes of visual impairment in a Brazilian population: The Botucatu Eye Study

    Directory of Open Access Journals (Sweden)

    Cordeiro Ricardo

    2009-08-01

    Full Text Available Abstract Background This paper reports population-based data on the prevalence and causes of visual impairment among children and adults in Botucatu, Brazil. Methods A population-based cross-sectional study was conducted involving a random start point and then systematic sampling of an urban Brazilian population in the city of Botucatu. There were approximately 3 300 individuals aged 1 to 91 years who were eligible to participate in the study. Of this sample, 2485 (75.3% underwent ophthalmic examination. The ophthalmic examination included uncorrected (presenting and best corrected distance visual acuity using standardized protocols. The primary cause of decreased visual acuity was identified for all patients with visual impairment. Results Presenting low vision and presenting blindness were found in 5.2% (95% CI: 4.3–6.1 and 2.2% (95% CI: 1.6–2.8 of the population, respectively. Unilateral presenting low vision and unilateral presenting blindness were found in 8.3% (95% CI: 7.2–9.5 and 3.7% (95% CI: 2.9–4.4 of the population respectively. Best corrected low vision was found in 1.3% of the population (95% CI: 0.9–1.7 and best corrected blindness was discovered in 0.4% of people (95% CI: 0.2–0.7. The main cause of presenting low vision was refractive error (72.3% and cataract was the most prevalent cause of blindness (50%. Conclusion The main causes of low vision and blindness in this Brazilian city were uncorrected refractive errors, cataract, and retinal diseases. Programs to further reduce the burden of visual impairment need to be targeted toward the correction of refractive error and surgery for cataracts.

  4. Cause of death in mild cognitive impairment: a prospective study (NEDICES).

    Science.gov (United States)

    Contador, I; Bermejo-Pareja, F; Mitchell, A J; Trincado, R; Villarejo, A; Sánchez-Ferro, Á; Benito-León, J

    2014-02-01

    Previous studies have reported the occurrence of increased mortality rates among individuals with mild cognitive impairment (MCI), but possible links between MCI subtypes and cause-specific mortality need to be explored. To examine short-term mortality (5 years), long-term mortality (13 years) and cause-specific mortality of individuals over 65 years of age suffering from MCI compared with cognitively unimpaired individuals in the Neurological Disorders in Central Spain (NEDICES) cohort. Mild cognitive impairment was classified using standardized psychometric and functional assessment in accordance with diagnostic convention. Cox's proportional hazards models, adjusted by sociodemographics and comorbidity factors, were used to assess the risk of death at 5 and 13 years of MCI subtypes compared with a reference group of older people without cognitive impairment (N = 2329). Causes of death were obtained from the National Population Register of Spain. There were 1484 deceased individuals at 13 years. MCI subtypes were defined as amnestic single domain (N = 259), amnestic multiple domain (N = 197) and non-amnestic (N = 641). After adjusting for covariates, only the amnestic multiple domain MCI subtype showed an increased hazard ratio (HR) for mortality at 5 years versus the reference group. However, the HR for mortality at 13 years was increased for all MCI subtypes. The HR by MCI subtype was 1.19 in the non-amnestic subtype (95% CI 1.05-1.36), 1.31 in the amnestic single domain subtype (95% CI 1.10-1.56) and 1.67 in the amnestic multiple domain subtype (95% CI 1.38-2.02). In terms of cause-specific mortality, the chance of death from dementia was statistically higher in all MCI subtypes. Amnestic multiple domain MCI showed the greatest risk of mortality in comparison with other MCI subtypes at different intervals. Dementia was the only cause-specific mortality that was increased in MCI individuals. © 2013 The Author(s) European Journal of Neurology © 2013 EFNS.

  5. A novel splice-site mutation in the GJB2 gene causing mild postlingual hearing impairment.

    Directory of Open Access Journals (Sweden)

    Marta Gandía

    Full Text Available The DFNB1 subtype of autosomal recessive, nonsyndromic hearing impairment, caused by mutations affecting the GJB2 (connexin-26 [corrected] gene, is highly prevalent in most populations worldwide. DFNB1 hearing impairment is mostly severe or profound and usually appears before the acquisition of speech (prelingual onset, though a small number of hypomorphic missense mutations result in mild or moderate deafness of postlingual onset. We identified a novel GJB2 splice-site mutation, c. -22-2A>C, in three siblings with mild postlingual hearing impairment that were compound heterozygous for c. -22-2A>C and c.35delG. Reverse transcriptase-PCR experiments performed on total RNA extracted from saliva samples from one of these siblings confirmed that c. -22-2A>C abolished the acceptor splice site of the single GJB2 intron, resulting in the absence of normally processed transcripts from this allele. However, we did isolate transcripts from the c. -22-2A>C allele that keep an intact GJB2 coding region and that were generated by use of an alternative acceptor splice site previously unknown. The residual expression of wild-type connexin-26 [corrected] encoded by these transcripts probably underlies the mild severity and late onset of the hearing impairment of these subjects.

  6. In vivo effect of chronic hypoxia on the neurochemical profile of the developing rat hippocampus

    OpenAIRE

    Raman, Lakshmi; Tkac, Ivan; Ennis, Kathleen; Georgieff, Michael K.; Gruetter, Rolf; Rao, Raghavendra

    2005-01-01

    The cognitive deficits observed in children with cyanotic congenital heart disease suggest involvement of the developing hippocampus. Chronic postnatal hypoxia present during infancy in these children may play a role in these impairments. To understand the biochemical mechanisms of hippocampal injury in chronic hypoxia, a neurochemical profile consisting of 15 metabolite concentrations and 2 metabolite ratios in the hippocampus was evaluated in a rat model of chronic postnatal hypoxia using i...

  7. Prevalence and Causes of Visual Impairment in Fundong District, North West Cameroon: Results of a Population-Based Survey.

    Science.gov (United States)

    Oye, Joseph; Mactaggart, Islay; Polack, Sarah; Schmidt, Elena; Tamo, Violet; Okwen, Marvice; Kuper, Hannah

    2017-12-01

    To estimate the prevalence and causes of visual impairment in Fundong Health District, North West Cameroon. A total of 51 clusters of 80 people (all ages) were sampled with probability proportionate to size and compact segment sampling. Visual acuity (VA) was measured with a tumbling "E" chart. An ophthalmic nurse examined people with VAimpairments were assessed using clinical examination, and self-reported visual problems using the Washington Group Short Set. In total, 4080 people were enumerated of whom 3567 were screened (response rate 87%). The overall prevalence of visual impairment was 2.3% (95% CI 1.8-3.0%) and blindness was 0.6% (0.3-1.0%). The prevalence of both blindness and visual impairment increased rapidly with age, so that the vast majority of cases of visual impairment (84%) and blindness (82%) were in people aged 50+. Posterior segment disease and cataract were the main causes of blindness and visual impairment, with refractive error also an important cause of visual impairment. Cataract surgical coverage (proportion of all cataracts that had received surgery) was relatively high (87% of people at VAvisual impairment, 22% had a physical impairment or epilepsy and 30% had a hearing impairment. Self-reported difficulties in vision were relatively closely related to clinical measures of visual impairment. Ophthalmic programmes in Cameroon need to incorporate control of posterior segment diseases while also working to improve outcomes after cataract surgery.

  8. Neurochemical measurements in the zebrafish brain

    Directory of Open Access Journals (Sweden)

    Lauren eJones

    2015-09-01

    Full Text Available The zebrafish is an ideal model organism for behavioural genetics and neuroscience. The high conservation of genes and neurotransmitter pathways between zebrafish and other vertebrates permits the translation of research between species. Zebrafish behaviour can be studied at both larval and adult stages and recent research has begun to establish zebrafish models for human disease. Fast scan cyclic voltammetry (FSCV is an electrochemical technique that permits the detection of neurotransmitter release and reuptake. In this study we have used in vitro FSCV to measure the release of analytes in the adult zebrafish telencephalon. We compare different stimulation methods and present a characterisation of neurochemical changes in the wild-type zebrafish brain. This study represents the first FSCV recordings in zebrafish, thus paving the way for neurochemical analysis of the fish brain.

  9. Neurochemical measurements in the zebrafish brain

    Science.gov (United States)

    Jones, Lauren J.; McCutcheon, James E.; Young, Andrew M. J.; Norton, William H. J.

    2015-01-01

    The zebrafish is an ideal model organism for behavioral genetics and neuroscience. The high conservation of genes and neurotransmitter pathways between zebrafish and other vertebrates permits the translation of research between species. Zebrafish behavior can be studied at both larval and adult stages and recent research has begun to establish zebrafish models for human disease. Fast scan cyclic voltammetry (FSCV) is an electrochemical technique that permits the detection of neurotransmitter release and reuptake. In this study we have used in vitro FSCV to measure the release of analytes in the adult zebrafish telencephalon. We compare different stimulation methods and present a characterization of neurochemical changes in the wild-type zebrafish brain. This study represents the first FSCV recordings in zebrafish, thus paving the way for neurochemical analysis of the fish brain. PMID:26441575

  10. SOME NEUROCHEMICAL DISTURBANCES IN MULTIPLE SCLEROSIS

    OpenAIRE

    Vladimir V. Markelov; Maxim V. Trushin

    2006-01-01

    ABSTRACTThe data presented in this manuscript suggest a pivotal role of the central nervous system (CNS) in the regulation of immune status. We describe here that some neurochemical disturbances may provoke development of various diseases including multiple sclerosis. Some theoretic and practical backgrounds, how to improve the multiple sclerosis sufferers and patients with other autoimmune disorders, are also given.RESUMENLos datos que presentamos en este manuscrito, sugieren un papel guia d...

  11. Trends in the incidence and causes of severe visual impairment and blindness in children from Israel.

    Science.gov (United States)

    Mezer, Eedy; Chetrit, Angela; Kalter-Leibovici, Ofra; Kinori, Michael; Ben-Zion, Itay; Wygnanski-Jaffe, Tamara

    2015-06-01

    To describe trends in the incidence and causes of legal childhood blindness in Israel, one of the few countries worldwide that maintain a national registry of the blind. We performed a historical cohort study of annual reports of the National Registry of the Blind (NRB) between 1999 and 2013. All data regarding demographic information, year of registration and cause of blindness of children 0-18 years of age registered for blind certification were obtained from the annual reports of the NRB. Causes of legal blindness analyzed were optic atrophy, retinitis pigmentosa, retinopathy of prematurity (ROP), albinism, other retinal disorders, cataract, and glaucoma. The main outcome measure was the incidence of new cases of certified legal blindness. The incidence of newly registered legally blind children in Israel almost halved from 7.7 per 100,000 in 1999 to 3.1 per 100,000 in 2013. The decline was mainly attributable to a decreased incidence of blindness resulting from retinitis pigmentosa and ROP. The incidence of registered cases due to cerebral visual impairment increased. During the past decade the incidence of severe childhood visual impairment and blindness declined in Israel. A continuous decline in consanguineous marriages among the Jewish and Arab populations in Israel may have contributed to the decrease in the rate of vision loss due to retinitis pigmentosa in children. Copyright © 2015 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.

  12. Neurochemical alterations associated with borderline personality disorder.

    Science.gov (United States)

    Atmaca, Murad; Karakoc, Tevfik; Mermi, Osman; Gurkan Gurok, M; Yildirim, Hanefi

    2015-01-01

    In neuroimaging on borderline personality disorder, prior studies focused on the hippocampus and amygdala, as mentioned above. However, no study investigated whether there were neurochemical changes in the patients with borderline personality disorder. Therefore, in the present study, we aimed to investigate neurochemical change of patients diagnosed with borderline disorder and hypothesized that neurochemicals would change in the hippocampus region of these patients. Seventeen patients and the same number of healthy control subjects were analyzed by using a 1.5 Tesla GE Signa Imaging System. N-acetylaspartate (NAA), choline compounds (CHO), and creatine (CRE) values of hippocampal region were measured. The mean NAA/CRE ratio in the hippocampus region was significantly reduced in the patients with borderline personality disorder compared to that of healthy control subjects, In addition, NAA/CHO ratio of the patients with borderline personality disorder was also significantly reduced when compared to that of healthy subjects. There was no difference in the ratio of CHO/CRE. In summary, we present evidence for reduced NAA in the patients with borderline personality disorder. © 2015, The Author(s).

  13. Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling

    DEFF Research Database (Denmark)

    Damgaard, Rune Busk; Fiil, Berthe Katrine; Speckmann, Carsten

    2013-01-01

    X-linked Inhibitor of Apoptosis (XIAP) is an essential ubiquitin ligase for pro-inflammatory signalling downstream of the nucleotide-binding oligomerization domain containing (NOD)-1 and -2 pattern recognition receptors. Mutations in XIAP cause X-linked lymphoproliferative syndrome type-2 (XLP2...... that the RIPK2 binding site in XIAP overlaps with the BIR2 IBM-binding pocket and find that a bivalent Smac mimetic compound (SMC) potently antagonises XIAP function downstream of NOD2 to limit signalling. These findings suggest that impaired immune signalling in response to NOD1/2 stimulation is a general...

  14. Impaired working memory capacity is not caused by failures of selective attention in schizophrenia.

    Science.gov (United States)

    Erickson, Molly A; Hahn, Britta; Leonard, Carly J; Robinson, Benjamin; Gray, Brad; Luck, Steven J; Gold, James

    2015-03-01

    The cognitive impairments associated with schizophrenia have long been known to involve deficits in working memory (WM) capacity. To date, however, the causes of WM capacity deficits remain unknown. The present study examined selective attention impairments as a putative contributor to observed capacity deficits in this population. To test this hypothesis, we used an experimental paradigm that assesses the role of selective attention in WM encoding and has been shown to involve the prefrontal cortex and the basal ganglia. In experiment 1, participants were required to remember the locations of 3 or 5 target items (red circles). In another condition, 3-target items were accompanied by 2 distractor items (yellow circles), which participants were instructed to ignore. People with schizophrenia (PSZ) exhibited significant impairment in memory for the locations of target items, consistent with reduced WM capacity, but PSZ and healthy control subjects did not differ in their ability to filter the distractors. This pattern was replicated in experiment 2 for distractors that were more salient. Taken together, these results demonstrate that reduced WM capacity in PSZ is not attributable to a failure of filtering irrelevant distractors. © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  15. Dietary CDP-choline supplementation prevents memory impairment caused by impoverished environmental conditions in rats.

    Science.gov (United States)

    Teather, Lisa A; Wurtman, Richard J

    2005-01-01

    We previously showed that dietary cytidine (5')-diphosphocholine (CDP-choline) supplementation could protect against the development of memory deficits in aging rats. In the present study, younger rats exposed to impoverished environmental conditions and manifesting hippocampal-dependent memory impairments similar to those observed in the aging rodents were given CDP-choline, and its effects on this cognitive deficit were assessed. Male Sprague-Dawley rats reared for 3 mo in impoverished (IC) or enriched environmental (EC) conditions concurrently received either a control diet or a diet supplemented with CDP-choline (approximately 500 mg/kg/d). After 3 mo, rats were trained to perform spatial and cued versions of the Morris water maze, and their rates of acquisition and retention were compared. Impoverished rats exhibited a selective deficit in hippocampal-dependent spatial memory which could be ameliorated by feeding them CDP-choline. The CDP-choline had no memory-enhancing effect in enriched rats, nor did it prevent the memory impairment of impoverished rats if the animals consumed it for the initial or final months instead of for the entire 3-mo period. These findings indicate that long-term dietary CDP-choline supplementation can ameliorate the hippocampal-dependent memory impairment caused by impoverished environmental conditions in rats, and suggest that its actions result, in part, from a long-term effect such as enhanced membrane phosphatide synthesis, an effect shown to require long-term dietary supplementation with CDP-choline.

  16. Prevalence and causes of visual impairment in diabetic patients in Tunisia, North Africa.

    Science.gov (United States)

    Kahloun, R; Jelliti, B; Zaouali, S; Attia, S; Ben Yahia, S; Resnikoff, S; Khairallah, M

    2014-08-01

    To investigate the prevalence and causes of blindness and partial sight among a population of Tunisian diabetic patients. A cross-sectional study of 2320 randomly identified patients with diabetes mellitus. Patient's characteristics as well as data from the last ophthalmic examination were reviewed. Of all patients examined, 60.2% were females and 39.8% were males. Mean age of patients was 54.5 years. Mean duration of diabetes was 7.6 years. Diabetic retinopathy (DR) was recorded in 26.3% of patients, and was proliferative in 3.4% of patients. The prevalence of visual impairment was 22.2%, with 4.4% patients legally blind and 17.8% partially sighted. Visual impairment was significantly associated with age ≥60 years (P10 years (P25 (P=0.014), hypertension (P<0.001), heart disease (P<0.001), peripheral neuropathy (P=0.03), vegetative neuropathy (P=0.002), macroalbuminuria (P<0.001), cataract (P<0.001), DR (P<0.001), diabetic macular edema (P<0.001), open angle glaucoma (P<0.001), intravitreal hemorrhage (P<0.001), rubeosis iridis (P<0.001), neovascular glaucoma (P<0.001), and tractional retinal detachment (P<0.001). The current report is the largest study of DR in North African region. It provides a baseline data against which future progress can be assessed. Screening and treatment can greatly reduce the incidence of visual impairment due to diabetes.

  17. Chronic exposure to low frequency noise at moderate levels causes impaired balance in mice.

    Directory of Open Access Journals (Sweden)

    Haruka Tamura

    Full Text Available We are routinely exposed to low frequency noise (LFN; below 0.5 kHz at moderate levels of 60-70 dB sound pressure level (SPL generated from various sources in occupational and daily environments. LFN has been reported to affect balance in humans. However, there is limited information about the influence of chronic exposure to LFN at moderate levels for balance. In this study, we investigated whether chronic exposure to LFN at a moderate level of 70 dB SPL affects the vestibule, which is one of the organs responsible for balance in mice. Wild-type ICR mice were exposed for 1 month to LFN (0.1 kHz and high frequency noise (HFN; 16 kHz at 70 dB SPL at a distance of approximately 10-20 cm. Behavior analyses including rotarod, beam-crossing and footprint analyses showed impairments of balance in LFN-exposed mice but not in non-exposed mice or HFN-exposed mice. Immunohistochemical analysis showed a decreased number of vestibular hair cells and increased levels of oxidative stress in LFN-exposed mice compared to those in non-exposed mice. Our results suggest that chronic exposure to LFN at moderate levels causes impaired balance involving morphological impairments of the vestibule with enhanced levels of oxidative stress. Thus, the results of this study indicate the importance of considering the risk of chronic exposure to LFN at a moderate level for imbalance.

  18. Lawn mower injuries as a cause of serious visual acuity impairment - Case reports.

    Science.gov (United States)

    Jasielska, Monika; Winiarczyk, Mateusz; Bieliński, Paweł; Mackiewicz, Jerzy

    2017-05-11

    [b]Abstract Objective.[/b] The aim of the study is to present four cases of lawn mowers injuries as a cause of serious visual acuity impairment. [b]Materials and Method[/b]. A retrospective study of four patients admitted in 2013-2015 to the Department of Vitreoretinal Surgery in Lublin with severe open or closed globe injury, one with an intraocular foreign body (IOFB). The presence of eye protective equipment was assessed, as well as visual acuity, eye tissue condition before and after treatment, and applied therapy. In all cases an improvement was achieved in local conditions. The intraocular foreign body was removed, wounds sutured and damaged tissues placed in position. All eyeballs were saved. In three cases, visual acuity was improved to a usable level. Three patients underwent pars plana vitrectomy, one with IOFB removal from the vitreous cavity. [b]Conclusions[/b]. Lawn mower induced eye injuries are a significant cause of serious visual acuity impairment or blindness. The presented study shows that lawn mower eye injuries are still a therapeutic, social and economic problem, yet are very preventable with proper eye protection and patients' education. Current prevention strategies are inadequate, and therefore should be updated.

  19. EPA Office of Water (OW): 303(d) Listed Impaired Waters by Causes of Impairment and Probable Sources

    Data.gov (United States)

    U.S. Environmental Protection Agency — Under Section 303(d) of the CWA, states, territories, and authorized tribes (referred to here as states) are required to develop lists of impaired waters. These are...

  20. Prevalence and causes of visual impairment among Saudi adults attending primary health care centers in northern Saudi Arabia

    OpenAIRE

    Al-Shaaln, Farhan Fayez; Bakrman, Marwan Abdurrahman; Ibrahim, Adel Mohammad; Aljoudi, Abdullah Srour

    2011-01-01

    BACKGROUND AND OBJECTIVES: Few studies have been conducted in Saudi Arabia to estimate the prevalence of visual impairment and its causes. The objective of this study was to estimate the prevalence of visual impairment, and identify its causes and associated factors among the adult population attending primary health care (PHC) centers in Aljouf province, in northern Saudi Arabia. DESIGN AND SETTING: A cross-sectional study during the year 2005 in PHC centers in Aljouf province in northern Sa...

  1. Causes of severe visual impairment and blindness in schools for visually handicapped children in Iran

    Science.gov (United States)

    Mirdehghan, S A; Dehghan, M H; Mohammadpour, M; Heidari, K; Khosravi, M

    2005-01-01

    Aims: This survey was conducted on children in schools for the blind in Tehran (from 2002 to 2003) to determine the causes of severe visual impairment and blindness and to identify preventable and treatable conditions. Methods: The study was performed on 362 students at different grades in three schools for the blind. Patient sex, age, family history of blindness or low vision, visual acuity, causes of blindness, and treatable and preventable conditions were studied. Results: Of the 362 cases, 210 (58%) were boys and 152 (42%) were girls. Mean age was 13.5 (SD 4) years. Severe visual loss was seen in 80.9%. Retinal diseases were the most common cause for low vision (51%); cataract, optic nerve atrophy, corneal and anterior segment diseases, glaucoma, anophthalmia, and globe malformations were other major causes of blindness. Treatable aetiologies and positive family history of blindness were seen in 25.7% and 36% of the patients, respectively. The incidence of preventable diseases, excluding familial disorders, was low. Conclusion: In addition to the prevention and treatment of some conditions, premarital genetic counselling and family planning control in families with inherited diseases could decrease the number of blind children in the future in Iran. PMID:15834095

  2. Causes of severe visual impairment and blindness in Bangladesh: a study of 1935 children.

    Science.gov (United States)

    Muhit, M A; Shah, S P; Gilbert, C E; Foster, A

    2007-08-01

    To identify the anatomical site and underlying aetiology of severe visual impairment and blindness (SVI/BL) in children in Bangladesh. A national case series. Children were recruited from all 64 districts in Bangladesh through multiple sources. Causes were determined and categorised using standard World Health Organization methods. 1935 SVI/BL children were recruited. The median age was 132 months, and boys accounted for 63.1% of the sample. The main site of abnormality was lens (32.5%), mainly unoperated cataract, followed by corneal pathology (26.6%) and disorders of the whole eye (13.1%). Lens-related blindness was the leading cause in boys (37.0%) compared with corneal blindness in girls (29.8%). In 593 children, visual loss was due to childhood factors, over 75% being attributed to vitamin A deficiency. Overall 1338 children (69.2%) had avoidable causes. Only 2% of the country's estimated SVI/BL children have access to education and rehabilitation services. This is the first large-scale study of SVI/BL children in Bangladesh over two-thirds of whom had avoidable causes. Strategies for control are discussed.

  3. Everyday memory impairment in patients with temporal lobe epilepsy caused by hippocampal sclerosis.

    Science.gov (United States)

    Rzezak, Patrícia; Lima, Ellen Marise; Gargaro, Ana Carolina; Coimbra, Erica; de Vincentiis, Silvia; Velasco, Tonicarlo Rodrigues; Leite, João Pereira; Busatto, Geraldo F; Valente, Kette D

    2017-04-01

    Patients with temporal lobe epilepsy caused by hippocampal sclerosis (TLE-HS) have episodic memory impairment. Memory has rarely been evaluated using an ecologic measure, even though performance on these tests is more related to patients' memory complaints. We aimed to measure everyday memory of patients with TLE-HS to age- and gender-matched controls. We evaluated 31 patients with TLE-HS and 34 healthy controls, without epilepsy and psychiatric disorders, using the Rivermead Behavioral Memory Test (RBMT), Visual Reproduction (WMS-III) and Logical Memory (WMS-III). We evaluated the impact of clinical variables such as the age of onset, epilepsy duration, AED use, history of status epilepticus, and seizure frequency on everyday memory. Statistical analyses were performed using MANCOVA with years of education as a confounding factor. Patients showed worse performance than controls on traditional memory tests and in the overall score of RBMT. Patients had more difficulties to recall names, a hidden belonging, to deliver a message, object recognition, to remember a story full of details, a previously presented short route, and in time and space orientation. Clinical epilepsy variables were not associated with RBMT performance. Memory span and working memory were correlated with worse performance on RBMT. Patients with TLE-HS demonstrated deficits in everyday memory functions. A standard neuropsychological battery, designed to assess episodic memory, would not evaluate these impairments. Impairment in recalling names, routes, stories, messages, and space/time disorientation can adversely impact social adaptation, and we must consider these ecologic measures with greater attention in the neuropsychological evaluation of patients with memory complaints. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Visual impairment and blindness: an overview of prevalence and causes in Brazil

    Directory of Open Access Journals (Sweden)

    Solange R. Salomão

    2009-09-01

    Full Text Available Our purpose is to provide a summary overview of blindness and visual impairment on the context of recent Brazilian ocular epidemiologic studies. Synthesis of data from two cross-sectional population-based studies - the São Paulo Eye Study and the Refractive Error in School Children Study is presented. 3678 older adults and 2441 school children were examined between July 2004 and December 2005. Prevalence of blindness in older adults using presenting visual acuity was 1.51% decreasing to 1. 07% with refractive correction. The most common causes of blindness in older adults were retinal disorders, followed by cataract and glaucoma. In school children, the prevalence of uncorrected visual impairment was 4.82% decreasing to 0.41% with refractive correction. The most common cause of visual impairment in school children was uncorrected refractive error. Visual impairment and blindness in Brazil is an important public health problem. It is a significant problem in older Brazilians, reinforcing the need to implement prevention of blindness programs for elderly people with emphasis on those without schooling. In school-children cost-effective strategies are needed to address a readily treatable cause of vision impairment - prescription and provision of glasses.Nosso objetivo é fazer uma revisão de cegueira e deficiência visual no contexto de recentes estudos epidemiológicos oculares brasileiros. É apresentada a síntese dos dados de dois estudos populacionais transversais - o Estudo Ocular de São Paulo e o Estudo de Erros Refrativos em Escolares. Entre julho de 2004 e dezembro de 2005 foram examinados 3678 adultos e 2441 escolares. A prevalência de cegueira em adultos mais velhos considerando a acuidade visual apresentada foi de 1, 51% diminuindo para 1, 07% com a correção refrativa. As causas mais comuns de cegueira em adultos mais velhos foram os distúrbios de retina, seguidos de catarata e glaucoma. Em escolares a prevalência de defici

  5. Dumping syndrome: an unusual cause of severe hyperinsulinemic hypoglycemia in neurologically impaired children with gastrostomy.

    Science.gov (United States)

    Bizzarri, C; Cervoni, M; Crea, F; Cutrera, R; Schiavino, A; Schiaffini, R; Cappa, M

    2011-02-01

    This paper describes severe hyperinsulinemic hypoglycemia during bolus enteral feeding in two neurologically impaired children. Both children were affected by dysphagia with swallowing difficulties; caloric intake was inadequate. For these reasons, percutaneous endoscopic gastrostomy had been positioned during the first months of life. In one patient due to persisting vomiting, after a few months, a gastrojejunal tube (PEG-J) was inserted. Hypoglycemia was revealed by routine blood tests, without evidence of specific symptoms. Continuous subcutaneous glucose monitoring showed wide glucose excursions, ranging from hypoglycemia to hyperglycemia. Extremely high levels of insulin were detected at the time of hypoglycemia. A diagnosis of dumping syndrome (DS) was suspected in both children. In the child with PEG, the tip of the gastrostomy catheter was found to be lying in the bulbus duodeni. Once this had been pulled back, hypoglycemic episodes disappeared. The child with PEG-J needed continuous enteral feeding to reach a normal glucose balance. DS is a relatively common complication in children with gastrostomy, but extremely irregular glucose levels, ranging from hypoglycemia to hyperglycemia, and increased insulin secretion had not been previously demonstrated. The incidence of DS is probably underestimated in children receiving enteral feeding for neurological impairment. In these patients intensive monitoring of blood glucose levels should be performed to calibrate meals. Repeated underestimated hypoglycemic episodes could worsen neurological damage and cause a deterioration in clinical conditions.

  6. Impaired Mitochondrial Energy Production Causes Light-Induced Photoreceptor Degeneration Independent of Oxidative Stress.

    Directory of Open Access Journals (Sweden)

    Manish Jaiswal

    2015-07-01

    Full Text Available Two insults often underlie a variety of eye diseases including glaucoma, optic atrophy, and retinal degeneration--defects in mitochondrial function and aberrant Rhodopsin trafficking. Although mitochondrial defects are often associated with oxidative stress, they have not been linked to Rhodopsin trafficking. In an unbiased forward genetic screen designed to isolate mutations that cause photoreceptor degeneration, we identified mutations in a nuclear-encoded mitochondrial gene, ppr, a homolog of human LRPPRC. We found that ppr is required for protection against light-induced degeneration. Its function is essential to maintain membrane depolarization of the photoreceptors upon repetitive light exposure, and an impaired phototransduction cascade in ppr mutants results in excessive Rhodopsin1 endocytosis. Moreover, loss of ppr results in a reduction in mitochondrial RNAs, reduced electron transport chain activity, and reduced ATP levels. Oxidative stress, however, is not induced. We propose that the reduced ATP level in ppr mutants underlies the phototransduction defect, leading to increased Rhodopsin1 endocytosis during light exposure, causing photoreceptor degeneration independent of oxidative stress. This hypothesis is bolstered by characterization of two other genes isolated in the screen, pyruvate dehydrogenase and citrate synthase. Their loss also causes a light-induced degeneration, excessive Rhodopsin1 endocytosis and reduced ATP without concurrent oxidative stress, unlike many other mutations in mitochondrial genes that are associated with elevated oxidative stress and light-independent photoreceptor demise.

  7. Mutant Fibulin-3 Causes Proteoglycan Accumulation and Impaired Diffusion Across Bruch's Membrane.

    Science.gov (United States)

    Zayas-Santiago, Astrid; Cross, Samuel D; Stanton, James B; Marmorstein, Alan D; Marmorstein, Lihua Y

    2017-06-01

    The mutation R345W in EFEMP1 (fibulin-3) causes macular degeneration. This study sought to determine whether proteoglycan content and diffusion across Bruch's membrane are altered in Efemp1ki/ki mice carrying this mutation or in Efemp1-/- mice. Proteoglycans in mouse Bruch's membranes were stained with Cupromeronic Blue (CB). Heparan sulfated proteoglycan (HSPG) and chondroitin/dermatan sulfate proteoglycan (C/DSPG) distributions were visualized following treatments with chondroitinase ABC (C-ABC) or nitrous acid. Total sulfated glycosaminoglycans (sGAGs) in Bruch's membrane/choroid (BrM/Ch) were measured with dimethylmethylene blue (DMMB). Matrix metalloprotease (MMP)-2, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-3 were examined by immunofluorescence and quantified using Image J. Molecules with different Stokes radius (Rs) were allowed simultaneously to diffuse through mouse BrM/Ch mounted in a modified Ussing chamber. Samples were quantified using gel exclusion chromatography. HSPGs and C/DSPGs were markedly increased in Efemp1ki/ki Bruch's membrane, and MMP-2 and MMP-9 were decreased, but TIMP-3 was increased. Diffusion across Efemp1ki/ki Bruch's membrane was impaired. In contrast, the proteoglycan amount in Efemp1-/- Bruch's membrane was not significantly different, but the size of proteoglycans was much larger. MMP-2, MMP-3, and TIMP-3 levels were similar to that of Efemp1+/+ mice, but they were localized diffusely in retinal pigment epithelium (RPE) cells instead of Bruch's membrane. Diffusion across Efemp1-/- Bruch's membrane was enhanced. Mutant fibulin-3 causes proteoglycan accumulation, reduction of MMP-2 and MMP-9, but increase of TIMP-3, and impairs diffusion across Bruch's membrane. Fibulin-3 ablation results in altered sizes of proteoglycans, altered distributions of MMP-2, MMP-9, and TIMP-3, and enhances diffusion across Bruch's membrane.

  8. Impaired fatty acid oxidation as a cause for lipotoxicity in cardiomyocytes.

    Science.gov (United States)

    Haffar, T; Bérubé-Simard, F; Bousette, N

    A major cause for diabetic cardiomyopathy is excess lipid accumulation. To elucidate mechanisms of lipotoxicity mediated diabetic heart disease we need to further our understanding of how lipid metabolism is altered in the diabetic heart. Here we investigated the role of lipid clearance by oxidation as a regulator of lipid-mediated toxicity (lipotoxicity). We evaluated the effect of pre-treating rat neonatal cardiomyocytes (NCMs) with either oleate (mono-unsaturated fatty acid) or palmitate (saturated fatty acid) on fatty acid oxidation (FAO) by measuring (14)C-CO2 production. We evaluated carnitine palmitoyltransferase (Cpt1b) expression by western blotting and mitochondrial membrane potential by quantitative and qualitative fluorescence analyses using the JC-1 dye. We inhibited the Cpt1b pharmacologically using etomoxir and genetically by knocking down its expression using LentiVector mediated transduction of siRNAs targeting the Cpt1b gene. We found that palmitate had a slower clearance rate from NCMs than oleate, and this was associated with a significant decrease in FAO. This impairment in FAO was not the result of either loss of Cpt1b protein or mitochondrial integrity. Enhancing FAO with either oleate or carnitine was associated with a significant attenuation of palmitate mediated lipotoxicity. In contrast impairing FAO in oleate treated NCMs caused lipotoxicity. Here we demonstrate that a major difference between non-toxic unsaturated fatty acids and toxic saturated fatty acids is there ability to stimulate or inhibit fatty acid oxidation, respectively. This has important implications for diabetic cardiomyopathy since diabetic hearts consistently exhibit elevated lipid accumulation. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Prevalence and Causes of Visual Impairment in a Chinese Adult Population: The Taizhou Eye Study.

    Science.gov (United States)

    Tang, Yating; Wang, Xiaofeng; Wang, Jiucun; Huang, Wei; Gao, Yaping; Luo, Yi; Lu, Yi

    2015-07-01

    To study the current prevalence and causes of low vision and blindness in an adult Chinese population. Population-based, cross-sectional study. We used a random cluster sampling method and evaluated 10 234 eligible subjects ≥45 years old (response rate, 78.1%) in the Taizhou Eye Study. Examinations were performed from July 2012 through December 2013. Participants underwent a detailed examination, including uncorrected visual acuity, best-corrected visual acuity (BCVA), intraocular pressure, axial length, slit-lamp, and fundus examinations to evaluate the prevalence and primary causes of visual impairment (VI). We defined low vision and blindness according to the World Health Organization (WHO) criteria (low vision: BCVA, eye) and United States criteria (low vision: BCVA, eye). Using the WHO BCVA criteria, the standardized prevalence of bilateral low vision and blindness were 5.1% and 1.0%, respectively. Using the United States BCVA criteria, the standardized prevalence were 12.8% and 1.5%, respectively. Using the WHO criteria, the primary causes of bilateral low vision and blindness were cataract (59.1% and 48.5%, respectively), myopic macular degeneration (17.6% and 17.2%, respectively), and age-related macular degeneration (11.6% and 10.1%, respectively). The primary causes of monocular low vision were cataract (55.6%), age-related macular degeneration (12.6%), and myopic macular degeneration (8.9%), whereas those of monocular blindness were cataract (46.8%), atrophy of eyeball or prosthetic eye (10.2%), and cornea opacity (7.3%). A further analysis revealed that in adults 45-59 years old, myopic macular degeneration (59.6% and 27.2%, respectively) and cataract (13.8% and 23.4%, respectively) were the leading causes of bilateral and monocular VI. In adults ≥60 years old, cataract (66.8% and 61.2%, respectively) and age-related macular degeneration (12.6% and 11.8%, respectively) were the primary causes of bilateral and monocular VI. The prevalence of low

  10. The Prevalence and Causes of Visual Impairment and Blindness Among Older Adults in the City of Lodz, Poland

    Science.gov (United States)

    Nowak, Michal S.; Smigielski, Janusz

    2015-01-01

    Abstract To investigate the prevalence and causes of visual impairment and blindness in a sample of Polish older adults. The study was designed in a cross-sectional and observational manner. Data concerning the vision status were assessed in 2214 eyes from 1107 subjects of European Caucasian origin; most of whom live in the city of Lodz, in central Poland. Visual impairment was defined as distance visual acuity 20/200 in better-seeing eye, and blindness was defined as BCVA ≤20/200 in both eyes (United States criteria). Visual impairment was found in 27.5% subjects in the worse-seeing eye. Multiple regression analysis showed that increasing age (OR 0.98, 95% CI 0.97–0.99) and female gender (OR 1.47, 95% CI 1.11–1.93) were independent risk factors. No association was found between visual impairment and socioeconomic status of subjects. Noncorrectable visual impairment was found in 7.0% of subjects, including 5.2% of subjects with unilateral and 1.8% of subjects with bilateral visual impairment. Low vision and blindness accounted for 1.3% and 0.5%, respectively, and were only associated with older age (OR 1.05, 95% CI 1.02–1.10). Retinal diseases represented the major cause of noncorrectable visual impairment and accounted for more than half of causes of blindness. Provision of appropriate refractive correction improves visual acuity in 75% subjects presenting with visual impairment. Retinal diseases are a major cause of noncorrectable visual impairment and blindness in this older population. PMID:25654398

  11. The prevalence and causes of visual impairment and blindness among older adults in the city of Lodz, Poland.

    Science.gov (United States)

    Nowak, Michal S; Smigielski, Janusz

    2015-02-01

    To investigate the prevalence and causes of visual impairment and blindness in a sample of Polish older adults. The study was designed in a cross-sectional and observational manner. Data concerning the vision status were assessed in 2214 eyes from 1107 subjects of European Caucasian origin; most of whom live in the city of Lodz, in central Poland. Visual impairment was defined as distance visual acuity visual acuity (BCVA) 20/200 in better-seeing eye, and blindness was defined as BCVA ≤20/200 in both eyes (United States criteria). Visual impairment was found in 27.5% subjects in the worse-seeing eye. Multiple regression analysis showed that increasing age (OR 0.98, 95% CI 0.97-0.99) and female gender (OR 1.47, 95% CI 1.11-1.93) were independent risk factors. No association was found between visual impairment and socioeconomic status of subjects. Noncorrectable visual impairment was found in 7.0% of subjects, including 5.2% of subjects with unilateral and 1.8% of subjects with bilateral visual impairment. Low vision and blindness accounted for 1.3% and 0.5%, respectively, and were only associated with older age (OR 1.05, 95% CI 1.02-1.10). Retinal diseases represented the major cause of noncorrectable visual impairment and accounted for more than half of causes of blindness. Provision of appropriate refractive correction improves visual acuity in 75% subjects presenting with visual impairment. Retinal diseases are a major cause of noncorrectable visual impairment and blindness in this older population.

  12. Behavioral metabolomics analysis identifies novel neurochemical signatures in methamphetamine sensitization

    OpenAIRE

    Adkins, Daniel E.; McClay, Joseph L.; VUNCK, SARAH A.; Batman, Angela M.; Vann, Robert E.; Clark, Shaunna L.; SOUZA,RENAN P. DE; Crowley, James J.; Sullivan, Patrick F; van den Oord, Edwin J.C.G.; Beardsley, Patrick M.

    2013-01-01

    Behavioral sensitization has been widely studied in animal models and is theorized to reflect neural modifications associated with human psychostimulant addiction. While the mesolimbic dopaminergic pathway is known to play a role, the neurochemical mechanisms underlying behavioral sensitization remain incompletely understood. In the present study, we conducted the first metabolomics analysis to globally characterize neurochemical differences associated with behavioral sensitization. Methamphe...

  13. Anthocyanin-rich extract from Hibiscus sabdariffa calyx counteracts UVC-caused impairments in rats.

    Science.gov (United States)

    Ozkol, Hatice Uce; Koyuncu, Ismail; Tuluce, Yasin; Dilsiz, Nihat; Soral, Sinan; Ozkol, Halil

    2015-01-01

    Ultraviolet radiation (UV) was reported to cause oxidative stress. Hibiscus sabdariffa L. (Malvaceae) calyx is commonly used in traditional Asian and African medicines and possesses strong antioxidant capacity due to its anthocyanin (ANTH) content. This study researched the possible protective role of Hibiscus sabdariffa calyx extract (HSCE) in UVC exposure of rats. Levels of serum enzymes, renal function tests, and some oxidant/antioxidant biomarkers of skin, lens, and retina tissues were monitored. Rats were exposed to UVC 4 h daily for 40 d and simultaneously received HSCE containing 2.5, 5, and 10 mg doses of ANTH in drinking water. Significant (p < 0.05) increases in the levels of serum aminotransferases, lactate dehydrogenase, urea, creatinine, and uric acid were noted after UVC exposure. In skin, lens, and retina tissues, total oxidant status, oxidative stress index, lipid peroxidation, and protein oxidation escalated markedly (p < 0.05) whereas total antioxidant status, reduced glutathione, and superoxide dismutase decreased dramatically (p < 0.05) related to UVC. Co-administration of HSCE with each ANTH dose significantly (p < 0.05) reversed aforementioned parameters (except total oxidant status) almost in all tissues. The LD50 of HSCE in rats was determined to be above 5000 mg/kg. Our data revealed that HSCE has a remarkable potential to counteract UVC-caused impairments, probably through its antioxidant and free radical-defusing effects. Therefore, HSCE could be useful against some cutaneous and ocular diseases in which UV and oxidative stress have a role in the etiopathogenesis.

  14. What are the causes and consequences of impaired sleep quality during and following extended hospitalisation amongst older adults?

    OpenAIRE

    AISLINN FELICITY LALOR

    2017-01-01

    Sleep is essential to everyone's health and wellbeing. Between 30-40% of people experience impaired sleep and is most common in older adults. Older adults also experience a higher number of hospitalisations in comparison to any other age group. This thesis aimed to investigate the causes and consequences of impaired sleep quality for older adults during and following hospital admission. Over 80% of older adults with self-reported poor sleep do not discuss it with any health professionals. Thi...

  15. SOME NEUROCHEMICAL DISTURBANCES IN MULTIPLE SCLEROSIS

    Directory of Open Access Journals (Sweden)

    Vladimir V. Markelov

    2006-04-01

    Full Text Available ABSTRACTThe data presented in this manuscript suggest a pivotal role of the central nervous system (CNS in the regulation of immune status. We describe here that some neurochemical disturbances may provoke development of various diseases including multiple sclerosis. Some theoretic and practical backgrounds, how to improve the multiple sclerosis sufferers and patients with other autoimmune disorders, are also given.RESUMENLos datos que presentamos en este manuscrito, sugieren un papel guia del sistema nervioso central (SNC en la regulación del estado inmune. Describimos aquí que varias alteraciones neuroquímicas pueden provocar el desarrollo de varias enfermedades, incluyendo esclerosis múltiple. También se comenta acerca del trasfondo teórico y práctico, y cómo mejorar a víctimas y pacientes con esclerosis múltiple y otras alteraciones autoinmunes.

  16. Does smoking influence the type of age related macular degeneration causing visual impairment?

    Science.gov (United States)

    Dandekar, S S; Jenkins, S A; Peto, T; Bird, A C; Webster, A R

    2006-01-01

    Aims To assess the influence of smoking on the type of age related macular degeneration (AMD) lesion causing visual impairment in a large cohort of patients with AMD at a tertiary referral UK centre. Methods Prospective, observational, cross sectional study to analyse smoking data on 711 subjects, of western European origin, in relation to the type of AMD lesion present. Colour fundus photographs were graded according to a modified version of the international classification. Multiple logistic regression analysis was performed, adjusting for age and sex using the statistical package SPSS ver 9.0 for Windows. χ2 tests were also used to assess pack year and ex‐smoker data. Results 578 subjects were graded with neovascular AMD and 133 with non‐neovascular AMD. There was no statistically significant association found between smoking status or increasing number of pack years and type of AMD lesion. The odds of “current smokers” compared to “non‐smokers” developing neovascular rather than non‐neovascular AMD when adjusted for age and sex was 1.88 (95% CI: 0.91 to 3.89; p = 0.09). Conclusions Smoking is known to be a risk factor for AMD and this study suggests that smokers are at no more risk of developing neovascular than atrophic lesions. PMID:16597668

  17. Rhizobial Plasmids That Cause Impaired Symbiotic Nitrogen Fixation and Enhanced Host Invasion

    Science.gov (United States)

    Crook, Matthew B.; Lindsay, Daniel P.; Biggs, Matthew B.; Bentley, Joshua S.; Price, Jared C.; Clement, Spencer C.; Clement, Mark J.; Long, Sharon R.; Griffitts, Joel S.

    2015-01-01

    The genetic rules that dictate legume-rhizobium compatibility have been investigated for decades, but the causes of incompatibility occurring at late stages of the nodulation process are not well understood. An evaluation of naturally diverse legume (genus Medicago) and rhizobium (genus Sinorhizobium) isolates has revealed numerous instances in which Sinorhizobium strains induce and occupy nodules that are only minimally beneficial to certain Medicago hosts. Using these ineffective strain-host pairs, we identified gain-of-compatibility (GOC) rhizobial variants. We show that GOC variants arise by loss of specific large accessory plasmids, which we call HR plasmids due to their effect on symbiotic host range. Transfer of HR plasmids to a symbiotically effective rhizobium strain can convert it to incompatibility, indicating that HR plasmids can act autonomously in diverse strain backgrounds. We provide evidence that HR plasmids may encode machinery for their horizontal transfer. On hosts in which HR plasmids impair N fixation, the plasmids also enhance competitiveness for nodule occupancy, showing that naturally occurring, transferrable accessory genes can convert beneficial rhizobia to a more exploitative lifestyle. This observation raises important questions about agricultural management, the ecological stability of mutualisms, and the genetic factors that distinguish beneficial symbionts from parasites. PMID:22746823

  18. Effects of amantadine in children with impaired consciousness caused by acquired brain injury: a pilot study.

    Science.gov (United States)

    McMahon, Mary A; Vargus-Adams, Jilda N; Michaud, Linda J; Bean, Judy

    2009-07-01

    To conduct a pilot study of amantadine in children with impaired consciousness caused by acquired brain injury, to establish design feasibility, and to assess the effect on level of arousal and consciousness. Randomized, double-blind, placebo-controlled crossover trial. Seven subjects (mean age, 12.7 yrs) with an acquired brain injury (mean duration, 6 wks) were randomized to receive either 3 wks of placebo or amantadine, followed by a 1-wk washout period and then 3 wks of the other agent. Main outcome measures were the Coma/Near-Coma Scale and Coma Recovery Scale-Revised, each done three times per week. Subjective evaluations of change in arousal and consciousness by the parent and physician were done weekly. Five subjects completed the study. There was no significant difference in the slopes of recovery during either arm for the Coma/Near-Coma Scale (P = 0.24) or the Coma Recovery Scale-Revised (P = 0.28), although improvements in consciousness were noted by the physician during weeks when amantadine was given (P = 0.02). This study suggests that amantadine facilitates recovery of consciousness in pediatric acquired brain injury and provides important information necessary to design future more definitive studies.

  19. Osteopontin impairs host defense during established gram-negative sepsis caused by Burkholderia pseudomallei (melioidosis.

    Directory of Open Access Journals (Sweden)

    Gerritje J W van der Windt

    2010-08-01

    Full Text Available Melioidosis, caused by infection with Burkholderia (B. pseudomallei, is a severe illness that is endemic in Southeast Asia. Osteopontin (OPN is a phosphorylated glycoprotein that is involved in several immune responses including induction of T-helper 1 cytokines and recruitment of inflammatory cells.OPN levels were determined in plasma from 33 melioidosis patients and 31 healthy controls, and in wild-type (WT mice intranasally infected with B. pseudomallei. OPN function was studied in experimental murine melioidosis using WT and OPN knockout (KO mice. Plasma OPN levels were elevated in patients with severe melioidosis, even more so in patients who went on to die. In patients who recovered plasma OPN concentrations had decreased after treatment. In experimental melioidosis in mice plasma and pulmonary OPN levels were also increased. Whereas WT and OPN KO mice were indistinguishable during the first 24 hours after infection, after 72 hours OPN KO mice demonstrated reduced bacterial numbers in their lungs, diminished pulmonary tissue injury, especially due to less necrosis, and decreased neutrophil infiltration. Moreover, OPN KO mice displayed a delayed mortality as compared to WT mice. OPN deficiency did not influence the induction of proinflammatory cytokines.These data suggest that sustained production of OPN impairs host defense during established septic melioidosis.

  20. Rhizobial plasmids that cause impaired symbiotic nitrogen fixation and enhanced host invasion.

    Science.gov (United States)

    Crook, Matthew B; Lindsay, Daniel P; Biggs, Matthew B; Bentley, Joshua S; Price, Jared C; Clement, Spencer C; Clement, Mark J; Long, Sharon R; Griffitts, Joel S

    2012-08-01

    The genetic rules that dictate legume-rhizobium compatibility have been investigated for decades, but the causes of incompatibility occurring at late stages of the nodulation process are not well understood. An evaluation of naturally diverse legume (genus Medicago) and rhizobium (genus Sinorhizobium) isolates has revealed numerous instances in which Sinorhizobium strains induce and occupy nodules that are only minimally beneficial to certain Medicago hosts. Using these ineffective strain-host pairs, we identified gain-of-compatibility (GOC) rhizobial variants. We show that GOC variants arise by loss of specific large accessory plasmids, which we call HR plasmids due to their effect on symbiotic host range. Transfer of HR plasmids to a symbiotically effective rhizobium strain can convert it to incompatibility, indicating that HR plasmids can act autonomously in diverse strain backgrounds. We provide evidence that HR plasmids may encode machinery for their horizontal transfer. On hosts in which HR plasmids impair N fixation, the plasmids also enhance competitiveness for nodule occupancy, showing that naturally occurring, transferrable accessory genes can convert beneficial rhizobia to a more exploitative lifestyle. This observation raises important questions about agricultural management, the ecological stability of mutualisms, and the genetic factors that distinguish beneficial symbionts from parasites.

  1. Noonan Syndrome: An Underestimated Cause of Severe to Profound Sensorineural Hearing Impairment. Which Clues to Suspect the Diagnosis?

    Science.gov (United States)

    Ziegler, Alban; Loundon, Natalie; Jonard, Laurence; Cavé, Hélène; Baujat, Geneviève; Gherbi, Souad; Couloigner, Vincent; Marlin, Sandrine

    2017-09-01

    To highlight Noonan syndrome as a clinically recognizable cause of severe to profound sensorineural hearing impairment. New clinical cases and review. Patients evaluated for etiological diagnosis by a medical geneticist in a reference center for hearing impairment. Five patients presenting with confirmed Noonan syndrome and profound sensorineural hearing impairment. Diagnostic and review of the literature. Five patients presented with profound sensorineural hearing impairment and molecularly confirmed Noonan syndrome. Sensorineural hearing impairment has been progressive for three patients. Cardiac echography identified pulmonary stenosis in two patients and was normal for the three other patients. Short stature was found in two patients. Mild intellectual disability was found in one patient. Inconspicuous clinical features as facial dysmorphism, cryptorchidism, or easy bruising were of peculiar interest to reach the diagnosis of Noonan syndrome. Profound sensorineural hearing impairment can be the main feature of Noonan syndrome. Associated features are highly variable; thus, detailed medical history and careful physical examination are mandatory to consider the diagnosis in case of a sensorineural hearing impairment.

  2. Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes.

    OpenAIRE

    Lange, P; Nyboe, J; Appleyard, M; Jensen, G; Schnohr, P

    1990-01-01

    The relation of ventilatory impairment and chronic mucus hypersecretion to death from all causes and death from obstructive lung disease (chronic bronchitis, emphysema and asthma) was studied in 13,756 men and women randomly selected from the general population of the City of Copenhagen. During the 10 year follow up 2288 subjects died. In 164 subjects obstructive lung disease was considered to be an underlying or a contributory cause of death (obstructive lung disease related death); in 73 su...

  3. Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction

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    Murrin L Charles

    2011-03-01

    Full Text Available Abstract Background Methamphetamine (METH, an addictive psycho-stimulant drug with euphoric effect is known to cause neurotoxicity due to oxidative stress, dopamine accumulation and glial cell activation. Here we hypothesized that METH-induced interference of glucose uptake and transport at the endothelium can disrupt the energy requirement of the blood-brain barrier (BBB function and integrity. We undertake this study because there is no report of METH effects on glucose uptake and transport across the blood-brain barrier (BBB to date. Results In this study, we demonstrate that METH-induced disruption of glucose uptake by endothelium lead to BBB dysfunction. Our data indicate that a low concentration of METH (20 μM increased the expression of glucose transporter protein-1 (GLUT1 in primary human brain endothelial cell (hBEC, main component of BBB without affecting the glucose uptake. A high concentration of 200 μM of METH decreased both the glucose uptake and GLUT1 protein levels in hBEC culture. Transcription process appeared to regulate the changes in METH-induced GLUT1 expression. METH-induced decrease in GLUT1 protein level was associated with reduction in BBB tight junction protein occludin and zonula occludens-1. Functional assessment of the trans-endothelial electrical resistance of the cell monolayers and permeability of dye tracers in animal model validated the pharmacokinetics and molecular findings that inhibition of glucose uptake by GLUT1 inhibitor cytochalasin B (CB aggravated the METH-induced disruption of the BBB integrity. Application of acetyl-L-carnitine suppressed the effects of METH on glucose uptake and BBB function. Conclusion Our findings suggest that impairment of GLUT1 at the brain endothelium by METH may contribute to energy-associated disruption of tight junction assembly and loss of BBB integrity.

  4. Size-dependent impairment of cognition in mice caused by the injection of gold nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yu-Shiun; Hong, Meng-Yeng; Huang, G Steve [Institute of Nanotechnology, Department of Materials Science and Engineering, National Chiao Tung University, 1001 University Road, Hsinchu 300, Taiwan (China); Hung, Yao-Ching [Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, China Medical University and Hospital, 91 Hsueh Shih Road, Taichung 404, Taiwan (China); Lin, Li-Wei [School of Chinese Medicine for Post-Baccalaureate, I-Shou University, 8 Yida Road, Yanchao Township, Kaohsiung Country 82445, Taiwan (China); Liau, Ian, E-mail: gstevehuang@mail.nctu.edu.tw [Department of Applied Chemistry, National Chiao Tung University, 1001 University Road, Hsinchu 300, Taiwan (China)

    2010-12-03

    We explored the size-dependent impairment of cognition in mice caused by the injection of gold nanoparticles (GNPs). GNPs of 17 and 37 nm in diameter were injected intraperitoneally into BALB/c mice at doses ranging from 0.5 to 14.6 mg kg{sup -1}. ICP-MS was performed on brain tissue collected 1, 14 and 21 days after the injection. A passive-avoidance test was performed on day 21. Monoamine levels were determined on day 21. The microscopic distribution of GNPs in the hippocampus was examined using coherent anti-Stokes Raman scattering (CARS) microscopy and transmission electron microscopy (TEM). The results indicated that 17 nm GNPs passed through the blood-brain barrier more rapidly than 37 nm GNPs. Treatment with 17 nm GNPs decreased the latency time, which was comparable to the effect of scopolamine treatment, while 37 nm GNPs showed no significant effect. Dopamine levels and serotonin levels in the brain were significantly altered by the injection of 17 and 37 nm GNPs. GNPs affected dopaminergic and serotonergic neurons. CARS microscopy indicated that 17 nm GNPs entered the Cornu Ammonis (CA) region of the hippocampus, while 37 nm GNPs were excluded from the CA region. TEM verified the presence of 17 nm GNPs in the cytoplasm of pyramidal cells. In this study, we showed that the ability of GNPs to damage cognition in mice was size-dependent and associated with the ability of the particles to invade the hippocampus. The dosage and duration of the treatment should be taken into account if GNPs are used in the future as vehicles to carry therapeutic agents into the brain.

  5. Postpartum estrogen withdrawal impairs hippocampal neurogenesis and causes depression- and anxiety-like behaviors in mice.

    Science.gov (United States)

    Zhang, Zhuan; Hong, Juan; Zhang, Suyun; Zhang, Tingting; Sha, Sha; Yang, Rong; Qian, Yanning; Chen, Ling

    2016-04-01

    Postpartum estrogen withdrawal is known to be a particularly vulnerable time for depressive symptoms. Ovariectomized adult mice (OVX-mice) treated with hormone-simulated pregnancy (HSP mice) followed by a subsequent estradiol benzoate (EB) withdrawal (EW mice) exhibited depression- and anxiety-like behaviors, as assessed by forced swim, tail suspension and elevated plus-maze, while HSP mice, OVX mice or EB-treated OVX mice (OVX/EB mice) did not. The survival and neurite growth of newborn neurons in hippocampal dentate gyrus were examined on day 5 after EW. Compared with controls, the numbers of 28-day-old BrdU(+) and BrdU(+)/NeuN(+) cells were increased in HSP mice but significantly decreased in EW mice; the numbers of 10-day-old BrdU(+) cells were increased in HSP mice and OVX/EB mice; and the density of DCX(+) fibers was reduced in EW mice and OVX mice. The phosphorylation of hippocampal NMDA receptor (NMDAr) NR2B subunit or Src was increased in HSP mice but decreased in EW mice. NMDAr agonist NMDA prevented the loss of 28-day-old BrdU(+) cells and the depression- and anxiety-like behaviors in EW mice. NR2B inhibitor Ro25-6981 or Src inhibitor dasatinib caused depression- and anxiety-like behaviors in HSP mice with the reduction of 28-day-old BrdU(+) cells. The hippocampal BDNF levels were reduced in EW mice and OVX mice. TrkB receptor inhibitor K252a reduced the density of DCX(+) fibers in HSP mice without the reduction of 28-day-old BrdU(+) cells, or the production of affective disorder. Collectively, these results indicate that postpartum estrogen withdrawal impairs hippocampal neurogenesis in mice that show depression- and anxiety-like behaviors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. A national survey of musculoskeletal impairment in Rwanda: prevalence, causes and service implications.

    Directory of Open Access Journals (Sweden)

    Oluwarantimi Atijosan

    Full Text Available BACKGROUND: Accurate information on the prevalence and causes of musculoskeletal impairment (MSI is lacking in low income countries. We present a new survey methodology that is based on sound epidemiological principles and is linked to the World Health Organisation's International Classification of Functioning. METHODS: Clusters were selected with probability proportionate to size. Households were selected within clusters through compact segment sampling. 105 clusters of 80 people (all ages were included. All participants were screened for MSI by a physiotherapist and medical assistant. Possible cases plus a random sample of 10% of non-MSI cases were examined further to ascertain diagnosis, aetiology, quality of life, and treatment needs. FINDINGS: 6757 of 8368 enumerated individuals (80.8% were screened. There were 352 cases, giving an overall prevalence for MSI of 5.2%. (95% CI 4.5-5.9 The prevalence of MSI increased with age and was similar in men and women. Extrapolating these estimates, there are approximately 488,000 MSI diagnoses in Rwanda. Only 8.2% of MSI cases were severe, while the majority were moderate (43.7% or mild (46.3%. Diagnostic categories comprised 11.5% congenital, 31.3% trauma, 3.8% infection, 9.0% neurological, and 44.4% non-traumatic non infective acquired. The most common individual diagnoses were joint disease (13.3%, angular limb deformity (9.7% and fracture mal- and non-union (7.2%. 96% of all cases required further treatment. INTERPRETATION: This survey demonstrates a large burden of MSI in Rwanda, which is mostly untreated. The survey methodology will be useful in other low income countries, to assist with planning services and monitoring trends.

  7. Two Disease-Causing SNAP-25B Mutations Selectively Impair SNARE C-terminal Assembly.

    Science.gov (United States)

    Rebane, Aleksander A; Wang, Bigeng; Ma, Lu; Qu, Hong; Coleman, Jeff; Krishnakumar, Shyam; Rothman, James E; Zhang, Yongli

    2018-02-16

    Synaptic exocytosis relies on assembly of three soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins into a parallel four-helix bundle to drive membrane fusion. SNARE assembly occurs by stepwise zippering of the vesicle-associated SNARE (v-SNARE) onto a binary SNARE complex on the target plasma membrane (t-SNARE). Zippering begins with slow N-terminal association followed by rapid C-terminal zippering, which serves as a power stroke to drive membrane fusion. SNARE mutations have been associated with numerous diseases, especially neurological disorders. It remains unclear how these mutations affect SNARE zippering, partly due to difficulties to quantify the energetics and kinetics of SNARE assembly. Here, we used single-molecule optical tweezers to measure the assembly energy and kinetics of SNARE complexes containing single mutations I67T/N in neuronal SNARE synaptosomal-associated protein of 25kDa (SNAP-25B), which disrupt neurotransmitter release and have been implicated in neurological disorders. We found that both mutations significantly reduced the energy of C-terminal zippering by ~10 kBT, but did not affect N-terminal assembly. In addition, we observed that both mutations lead to unfolding of the C-terminal region in the t-SNARE complex. Our findings suggest that both SNAP-25B mutations impair synaptic exocytosis by destabilizing SNARE assembly, rather than stabilizing SNARE assembly as previously proposed. Therefore, our measurements provide insights into the molecular mechanism of the disease caused by SNARE mutations. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Autism and Fragile X: Is There a Neurochemical Link?

    Directory of Open Access Journals (Sweden)

    Nagwa A. Meguid

    2014-12-01

    CONCLUSIONS: Autism and Fragile X syndrome share some neurochemical similarities with regards of high Glutamate and GABA levels while Serotonin was significantly different in the 2 disorders and may be used a unique biomarker for autism.

  9. Behavioural and histological observations of sensory impairment caused by tight ligation of the trigeminal nerve in mice.

    Science.gov (United States)

    Seino, Hiroyuki; Seo, Kenji; Maeda, Takeyasu; Someya, Genji

    2009-06-30

    Dental treatments sometimes cause sensory impairment, especially in the region innervated by the third division of the trigeminal nerve. The most frequent symptoms are loss of sensation and abnormal sensation. Although most studies have addressed the neuropathic symptom "allodynia" using experimental animal models of the infraorbital nerve, there is little information regarding the sensory impairment that frequently occurs clinically. Therefore, different experimental models are required to clarify the mechanisms of the clinical effects, and previous experimental models have been limited to rats. Here, we report a sensory impairment model in mice whose mechanical touch threshold increased after tight ligation of the mental nerve. Habituation before surgery by mechanical touching of the face enabled us to observe the long-term chronological changes in sensation. The mechanical touch thresholds within the mental nerve region were measured for 70 postoperative (PO) days. Changes in the distribution of substance P (SP) were evaluated by immunohistochemistry to clarify the involvement of axonal flow in the sensory impairment and its recovery. The mechanical touch thresholds transiently increased by PO days 2-3, but decreased to the preoperative levels at around PO day 14. Apparent SP immunoreactivity was recognizable on the medial side to the ligation at PO days 2-3 and disappeared at PO day 7. These behavioural and immunohistochemical changes appeared to exhibit similar time courses, suggesting a possible relationship between them. Therefore, we suggest that our experimental mouse model could represent a new model for clarifying the mechanism of the sensory impairment caused by peripheral nerve injury.

  10. Central Neurochemical Ultradian Variability in Depression

    Directory of Open Access Journals (Sweden)

    Ronald M. Salomon

    2006-01-01

    Full Text Available Depression is characterized by blunted behavior and neuroendocrine function that generally improve with antidepressant treatment. This study examined intrinsic variability in brain neurotransmitter function, since it may be a source of blunted behavior and neuroendocrine function in depression and a marker for the illness, and has not previously been analyzed using wavelet decomposition. To measure variability in monoamine metabolites, lumbar cerebrospinal fluid (CSF was collected in serial samples in depressed patients before and after treatment. We hypothesized that changes in variability would be observed after treatment. Mechanisms that control such variability may be critical to the pathophysiology of depression. Method: Time series data was obtained from serial ten-min sampling over a 24-hr period (N = 144 from thirteen depressed patients, with a repeat collection after 5 weeks of antidepressant (sertraline or bupropion treatment. Concentrations of tryptophan (TRP, the monoamine metabolites 5-HIAA (metabolite of serotonin and HVA (metabolite of dopamine, and the HVA:5HIAA ratio were transformed to examine power in slowly (160 min/cycle to rapidly (20 min/cycle occurring events. Power, the sum of the squares of the coefficients in each d (detail wavelet, reflects variability within a limited frequency bandwidth for that wavelet. Pre-treatment to post-treatment comparisons were conducted with repeated measures ANOVA. Results: Antidepressant treatment was associated with increased power in the d2 wavelet from the HVA (p = 0.03 and the HVA:5-HIAA ratio (p = 0.03 series. The d1 and d3 wavelets showed increased power following antidepressant treatment for the ratio series (d1, p = 0.01; d3, p = 0.05. Significant changes in power were not observed for the 5-HIAA data series. Power differences among analytes suggest that the findings are specific to each system. Conclusion: The wavelet transform analysis shows changes in neurochemical signal

  11. Prevalence and causes of visual impairment among Saudi adults attending primary health care centers in northern Saudi Arabia.

    Science.gov (United States)

    Al-Shaaln, Farhan Fayez; Bakrman, Marwan Abdurrahman; Ibrahim, Adel Mohammad; Aljoudi, Abdullah Srour

    2011-01-01

    Few studies have been conducted in Saudi Arabia to estimate the prevalence of visual impairment and its causes. The objective of this study was to estimate the prevalence of visual impairment, and identify its causes and associated factors among the adult population attending primary health care (PHC) centers in Aljouf province, in northern Saudi Arabia. A cross-sectional study during the year 2005 in PHC centers in Aljouf province in northern Saudi Arabia. A sample of 620 Saudi adults, of age 18 years and older, from the catchment area of the Aljouf PHC centers, were randomly selected through a multistage random sampling technique. Data were collected using a questionnaire about socioeconomic and related information and a visual acuity test was performed using the Snellen chart (E). Diagnosis was established according to World Health Organization (WHO) criteria. Visual impairment was categorized into blindness for a visual acuity of less than 3/60 (20/400, 0.05) in the better eye with the best correction and low vision for a best corrected visual acuity of less than 6/18 (20/60, 0.3) but not less than 3/60 (20/400, 0.05) in the better eye. Regression analysis was used to identify the predictors of visual impairment. Of 617 adult Saudis interviewed and examined, 269 (43.6%) were females. The mean (SD) age was 38.6 (16.2) years. The overall prevalence of visual impairment was 13.9% (95% CI: 11.4%-16.9%). The main medical causes of visual impairments were refractive errors (36.0%) followed by cataract (29.1%) and diabetic retinopathy (20.9%), and the least leading cause was glaucoma (5.8%). The most prominent determinants of visual impairment were age (Pvisual impairment in the study population from the Aljouf area is high. It is recommended that regular checks of visual acuity be conducted for all Saudis of age 50+ years, who attend the PHC centers.

  12. Neurochemical mechanisms underlying responses to psychostimulants

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Fowler, J.S.; Hitzemann, R.; Wang, G.J. [Brookhaven National Lab., Upton, NY (United States)]|[State Univ. of New York, Stony Brook, NY (United States)

    1994-11-01

    This study employed positron emission tomography (PET) to investigate biochemical and metabolic characteristics of the brain of individuals which could put them at risk for drug addiction. It takes advantage of the normal variability between individuals in response to psychoactive drugs to investigate relation between mental state, brain neurochemistry and metabolism and the behavioral response to drugs. We discuss its use to assess if there is an association between mental state and dompaminergic reactivity in response to the psychostimulant drug methylphenidate (MP). Changes in synaptic dopamine induced by MP were evaluated with PET and [11C]raclopride, a D{sub 2} receptor radioligand that is sensitive to endogenous dopamine. Methylpphenidate significantly decreased striatal [11C]raclopride binding. The study showed a correlation between the magnitude of the dopamine-induced changes by methylphenidate, and the mental state of the subjects. Subjects reporting high levels of anxiety and restlessness at baseline had larger changes in MP-induced dopamine changes than those that did not. Further investigations on the relation between an individual`s response to a drug and his/her mental state and personality as well as his neurochemical brain composition may enable to understand better differences in drug addiction vulnerability.

  13. Carbon Nanofiber Electrode Array for Neurochemical Monitoring

    Science.gov (United States)

    Koehne, Jessica E.

    2017-01-01

    A sensor platform based on vertically aligned carbon nanofibers (CNFs) has been developed. Their inherent nanometer scale, high conductivity, wide potential window, good biocompatibility and well-defined surface chemistry make them ideal candidates as biosensor electrodes. Here, we report using vertically aligned CNF as neurotransmitter recording electrodes for application in a smart deep brain stimulation (DBS) device. Our approach combines a multiplexed CNF electrode chip, developed at NASA Ames Research Center, with the Wireless Instantaneous Neurotransmitter Concentration Sensor (WINCS) system, developed at the Mayo Clinic. Preliminary results indicate that the CNF nanoelectrode arrays are easily integrated with WINCS for neurotransmitter detection in a multiplexed array format. In the future, combining CNF based stimulating and recording electrodes with WINCS may lay the foundation for an implantable smart therapeutic system that utilizes neurochemical feedback control while likely resulting in increased DBS application in various neuropsychiatric disorders. In total, our goal is to take advantage of the nanostructure of CNF arrays for biosensing studies requiring ultrahigh sensitivity, high-degree of miniaturization, and selective biofunctionalization.

  14. Nimodipine Prevents Memory Impairment Caused by Nitroglycerin-Induced Hypotension in Adult Mice

    Science.gov (United States)

    Bekker, Alex; Haile, Michael; Li, Yong-Sheng; Galoyan, Samuel; Garcia, Edwardo; Quartermain, David; Kamer, Angela; Blanck, Thomas

    2010-01-01

    in the NTG + NIMO groups, respectively. There were no significant differences among groups. CONCLUSION: In a PA retention paradigm, the injection of NTG immediately after learning produced a significant impairment of long-term associative memory in mice, whereas delayed induced hypotension had no effect. NIMO attenuated the disruption in consolidation of long-term memory caused by NTG but did not improve latency in the absence of hypotension. The observed effect of NIMO may have been attributable to the preservation of calcium homeostasis during hypotension, because there were no differences in the PbtO2 indices among groups. PMID:19923525

  15. Causes of visual impairment and blindness in children at Instituto Benjamin Constant Blind School, Rio de Janeiro

    Directory of Open Access Journals (Sweden)

    Daniela da Silva Verzoni

    Full Text Available Abstract Objective: To determine the main causes of visual impairment and blindness in children enrolled at Instituto Benjamin Constant blind school (IBC in 2013, to aid in planning for the prevention and management of avoidable causes of blindness. Methods: Study design: cross-sectional observational study. Data was collected from medical records of students attending IBC in 2013. Causes of blindness were classified according to WHO/PBL examination record. Data were analyzed for those children aged less than 16 years using Stata 9 program. Results: Among 355 students attending IBC in 2013, 253 (73% were included in this study. Of these children, 190 (75% were blind and 63 (25% visually impaired. The major anatomical site of visual loss was retina (42%, followed by lesions of the globe (22%, optic nerve lesions (13.8%, central nervous system (8.8% and cataract/pseudophakia/aphakia (8.8%. The etiology was unknown in 41.9% and neonatal factors accounted for 30,9% of cases. Forty-eight percent of cases were potentially avoidable. Retinopathy of prematurity (ROP was the main cause of blindness and with microphthalmia, optic nerve atrophy, cataract and glaucoma accounted for more than 50% of cases. Conclusion: Provision and improvement of ROP, cataract and glaucoma screening and treatment and programs could prevent avoidable visual impairment and blindness.

  16. Causes of visual impairment in children seen at a university-based hospital low vision service in Brazil.

    Science.gov (United States)

    de Paula, Cristina Helena Toledo; Vasconcelos, Galton Carvalho; Nehemy, Márcio Bittar; Granet, David

    2015-06-01

    To evaluate the epidemiologic characteristics of patients 0-7 years of age with visual impairment registered at a university hospital low vision service in Brazil. The medical records of visually impaired patients were retrospectively reviewed for sociodemographic characteristics and ocular and associated deficiencies. In addition to biographical information, the following data were collected: ocular disorders, diagnosis, affected anatomic region, etiology, and avoidable or unavoidable causes. A total of 229 patients were included, 65% of whom were referred from rural health centers. The mean age at first appointment was 39.4 months. Associated nonophthalmic disorders were present in 47% of patients. The most prevalent disorders were congenital cataract (14%), toxoplasmosis (14%), and congenital glaucoma (13%). The most commonly affected anatomic regions were the retina (18%) and lens (15%); 33% had a normal-appearing globe. Using World Health Organization classifications, the most prevalent underlying etiologies were undetermined (43%), perinatal/neonatal factors (22%), and intrauterine factors (20%). Avoidable causes were found in 64% of the children. The three leading causes of infant blindness in our patient cohort were congenital cataract, toxoplasmosis, and congenital glaucoma. The most commonly affected anatomic regions were retina, lens, and normal-appearing globe. The percentage of avoidable causes of impairment was high and the mean age at first appointment was late. Copyright © 2015 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.

  17. Neurochemical Alterations in Sudden Unexplained Perinatal Deaths—A Review

    Directory of Open Access Journals (Sweden)

    Nazeer Muhammad

    2018-01-01

    Full Text Available Sudden unexpected perinatal collapse is a major trauma for the parents of victims. Sudden infant death syndrome (SIDS is unexpected and mysterious death of an apparently healthy neonate from birth till 1 year of age without any known causes, even after thorough postmortem investigations. However, the incidence of sudden intrauterine unexplained death syndrome (SIUDS is seven times higher as compared with SIDS. This observation is approximated 40–80%. Stillbirth is defined as death of a fetus after 20th week of gestation or just before delivery at full term without a known reason. Pakistan has the highest burden of stillbirth in the world. This basis of SIDS, SIUDS, and stillbirths eludes specialists. The purpose of this study is to investigate factors behind failure in control of these unexplained deaths and how research may go ahead with improved prospects. Animal models and physiological data demonstrate that sleep, arousal, and cardiorespiratory malfunctioning are abnormal mechanisms in SIUDS risk factors or in newborn children who subsequently die from SIDS. This review focuses on insights in neuropathology and mechanisms of SIDS and SIUDS in terms of different receptors involved in this major perinatal demise. Several studies conducted in the past decade have confirmed neuropathological and neurochemical anomalies related to serotonin transporter, substance P, acetylcholine α7 nicotine receptors, etc., in sudden unexplained fetal and infant deaths. There is need to focus more on research in this area to unveil the major curtain to neuroprotection by underlying mechanisms leading to such deaths.

  18. Caffeine triggers behavioral and neurochemical alterations in adolescent rats.

    Science.gov (United States)

    Ardais, A P; Borges, M F; Rocha, A S; Sallaberry, C; Cunha, R A; Porciúncula, L O

    2014-06-13

    Caffeine is the psychostimulant most consumed worldwide but concerns arise about the growing intake of caffeine-containing drinks by adolescents since the effects of caffeine on cognitive functions and neurochemical aspects of late brain maturation during adolescence are poorly known. We now studied the behavioral impact in adolescent male rats of regular caffeine intake at low (0.1mg/mL), moderate (0.3mg/mL) and moderate/high (1.0mg/mL) doses only during their active period (from 7:00 P.M. to 7:00 A.M.). All tested doses of caffeine were devoid of effects on locomotor activity, but triggered anxiogenic effects. Caffeine (0.3 and 1mg/mL) improved the performance in the object recognition task, but the higher dose of caffeine (1.0mg/mL) decreased the habituation to an open-field arena, suggesting impaired non-associative memory. All tested doses of caffeine decreased the density of glial fibrillary acidic protein and synaptosomal-associated protein-25, but failed to modify neuron-specific nuclear protein immunoreactivity in the hippocampus and cerebral cortex. Caffeine (0.3-1mg/mL) increased the density of brain-derived neurotrophic factor (BDNF) and proBDNF density as well as adenosine A1 receptor density in the hippocampus, whereas the higher dose of caffeine (1mg/mL) increased the density of proBDNF and BDNF and decreased A1 receptor density in the cerebral cortex. These findings document an impact of caffeine consumption in adolescent rats with a dual impact on anxiety and recognition memory, associated with changes in BDNF levels and decreases of astrocytic and nerve terminal markers without overt neuronal damage in hippocampal and cortical regions. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. Causes of blindness and visual impairment at the school for the ...

    African Journals Online (AJOL)

    Sixty two pupils of the School for the blind and blind students in Owo High school were enrolled in this study. The subjects were interviewed and examined by the authors with the aid of WHO'S recording form for blindness and visual impairment in children. The data obtained with the study instrument was collated and ...

  20. Bombesin administration impairs memory and does not reverse memory deficit caused by sleep deprivation.

    Science.gov (United States)

    Ferreira, L B T; Oliveira, S L B; Raya, J; Esumi, L A; Hipolide, D C

    2017-07-28

    Sleep deprivation impairs performance in emotional memory tasks, however this effect on memory is not completely understood. Possible mechanisms may involve an alteration in neurotransmission systems, as shown by the fact that many drugs that modulate neural pathways can prevent memory impairment by sleep loss. Gastrin releasing peptide (GRP) is a neuropeptide that emerged as a regulatory molecule of emotional memory through the modulation of other neurotransmission systems. Thus, the present study addressed the effect of intraperitoneal (IP) administration of bombesin (BB) (2.5, 5.0 and 10.0μg/kg), a GRP agonist, on the performance of Wistar rats in a multiple trail inhibitory avoidance (MTIA) task, after sleep deprivation, using the modified multiple platforms method (MMPM). Sleep deprived animals exhibited acquisition and retention impairment that was not prevented by BB injection. In addition, non-sleep deprived animals treated with BB before and after the training session, but not before the test, have shown a retention deficit. In summary, BB did not improve the memory impairment by sleep loss and, under normal conditions, produced a memory consolidation deficit. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Neuroanatomical and Neurochemical Basis of Impulsivity

    Directory of Open Access Journals (Sweden)

    Kemal Yazici

    2010-08-01

    tis paradigm, the tendency to prefer small immediate rewards over larger, more delayed reinforcers is measured. İmpulsive choice is defined by a greater tendency to value or choose smaller, more immediate reinforcers. Impulsivity is a multi-faceted behaviour. This behaviour may be studied by subdividing it into different processes neuroanatomically and neurochemically. Neuroanatomical data support the suggestion that behavioral disinhibition (impulsive action / motoric impulsivity and delay-discounting (impulsive choice / decision making differ in the degree to which various components of frontostriatal loops are implicated in their regulation. The dorsal prefrontal cortex does not appear to be involved in mediating impulsive choice, yet does have some role in regulating inhibitory processes. In contrast, there appears to be a pronounced role for the orbitofrontal cortex and basolateral amygdala in controlling impulsive choice. Other structures, however, such as the nucleus accumbens and subthalamic nucleus may be common to both circuits. From the neurochemical perspective, dopamine system and dopamine- 2 (D2 receptors in particular, seems to be closely involved in making impulsive choice. When the noradrenaline system does not function optimally, it might contribute to increased impulsivity. Serotonin might act upon prefrontal cortex to decrease impulsive choices. Interactions between the serotonin and the dopamine systems are important in the regulation of impulsive behaviour. It is possible that various receptor subtypes of the serotonin system may exert differing and even contrasting effects on impulsive behaviour. Although it is very informative to study neurotransmitter systems separately, it should be kept in mind that there are very intimate interactions between the neurotransmitter systems mentioned above. Based on the fact that impulsivity is regulated through multiple neurotransmitters and even more receptors, one may suggest that pharmacotherapy of

  2. Visual impairment attributable to uncorrected refractive error and other causes in the Ghanaian youth: The University of Cape Coast Survey.

    Science.gov (United States)

    Abokyi, Samuel; Ilechie, Alex; Nsiah, Peter; Darko-Takyi, Charles; Abu, Emmanuel Kwasi; Osei-Akoto, Yaw Jnr; Youfegan-Baanam, Mathurin

    2016-01-01

    To determine the prevalence of visual impairment attributable to refractive error and other causes in a youthful Ghanaian population. A prospective survey of all consecutive visits by first-year tertiary students to the Optometry clinic between August, 2013 and April, 2014. Of the 4378 first-year students aged 16-39 years enumerated, 3437 (78.5%) underwent the eye examination. The examination protocol included presenting visual acuity (PVA), ocular motility, and slit-lamp examination of the external eye, anterior segment and media, and non-dilated fundus examination. Pinhole acuity and fundus examination were performed when the PVA≤6/12 in one or both eyes to determine the principal cause of the vision loss. The mean age of participants was 21.86 years (95% CI: 21.72-21.99). The prevalence of bilateral visual impairment (BVI; PVA in the better eye ≤6/12) and unilateral visual impairment UVI; PVA in the worse eye ≤6/12) were 3.08% (95% CI: 2.56-3.72) and 0.79% (95% CI: 0.54-1.14), respectively. Among 106 participants with BVI, refractive error (96.2%) and corneal opacity (3.8%) were the causes. Of the 27 participants with UVI, refractive error (44.4%), maculopathy (18.5%) and retinal disease (14.8%) were the major causes. There was unequal distribution of BVI in the different age groups, with those above 20 years having a lesser burden. Eye screening and provision of affordable spectacle correction to the youth could be timely to eliminate visual impairment. Copyright © 2014 Spanish General Council of Optometry. Published by Elsevier Espana. All rights reserved.

  3. Unfazed or Dazed and Confused: Does Early Adolescent Marijuana Use Cause Sustained Impairments in Attention and Academic Functioning?

    OpenAIRE

    Pardini, Dustin; White, Helene; Xiong, Shuangyan; Bechtold, Jordan; Chung, Tammy; Loeber, Rolf; Hipwell, Alison

    2015-01-01

    There is some suggestion that heavy marijuana use during early adolescence (prior to age 17) may cause significant impairments in attention and academic functioning that remain following sustained periods of abstinence. However, no longitudinal studies have examined whether both male and female adolescents who engage in low (less than once a month) to moderate (at least once a monthly) marijuana use experience increased problems with attention and academic performance, and whether these probl...

  4. Apoptotic Process Induced by Oxaliplatin in Rat Hippocampus Causes Memory Impairment.

    Science.gov (United States)

    Bianchi, Enrica; Di Cesare Mannelli, Lorenzo; Micheli, Laura; Farzad, Mersedez; Aglianò, Margherita; Ghelardini, Carla

    2017-01-01

    Aspects of memory involved in cognitive mechanisms were investigated in rat after oxaliplatin (OX) chemotherapy using animal behavioural assessment of passive avoidance and social learning paradigms, which are both hippocampus-sensitive. Rodents, previously subjected to 2-week OX treatment, showed passive avoidance and social learning impairment and apoptotic processes in the hippocampus. Apoptosis rate significantly increased in cultured hippocampal cells exposed to OX at increasing doses, and this effect was dose-dependent. Ex vivo experiments showed that cell damage and apoptosis were blocked in the hippocampus from OX rats cotreated with copper sulphate (CS) which precludes OX transport inside the cell. In vivo, passive avoidance and social learning impairment could not be observed in OX rats co-administered with CS. Thus, a site of action of OX treatment on memory impairment appears to be located at the hippocampus. These findings strongly support that cellular damage induced by OX in rodent hippocampus underlies the weakening of some memory functions. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  5. St John's wort (Hypericum perforatum) diminishes cognitive impairment caused by the chronic restraint stress in rats.

    Science.gov (United States)

    Trofimiuk, Emil; Walesiuk, Anna; Braszko, Jan J

    2005-03-01

    In this study we tested the hypothesis that St John's wort (Hypericum perforatum) may counteract stress-induced memory impairment. Object recognition test and Morris water maze were used to determine whether administration of H. perforatum (350 mg kg(-1) for 21 days), standardized to 0.3% hypericin content, protects against non-spatial and/or spatial memory impairments due to chronic restraint stress (2h daily for 21 days). A group of rats administered the exogenous corticosterone at the dose of 5 mg kg(-1) daily for 21 days, yielding its similar plasma levels as these observed in stress was run in parallel. In the first experiment all rats were tested for recognition memory in the object recognition test. On the following day, the animals were tested in open field and elevated "plus" maze to control for the contribution of respectively, motor and emotional effects of our treatments to the memory tests. In the second experiment, new group of stressed animals was tested for spatial memory in the water maze. We observed that H. perforatum prevented the deleterious effects of both chronic restraint stress and long-term corticosterone on learning and memory as measured in both, the object recognition and the water maze tests. The herb not only prevented stress- and corticosterone-induced memory impairments, but it significantly improved recognition memory (pstress memory disorders.

  6. Maternal Transfer of Bisphenol A During Nursing Causes Sperm Impairment in Male Offspring.

    Science.gov (United States)

    Kalb, Ana Cristina; Kalb, Ana Luiza; Cardoso, Tainã Figueiredo; Fernandes, Cristina Gevehr; Corcini, Carine Dahl; Varela Junior, Antonio Sergio; Martínez, Pablo Elías

    2016-05-01

    The health effects of environmental chemicals on animals and humans are of growing concern. Human epidemiological and animal study data indicate that reproductive disorders and diseases begin early during prenatal and postnatal development. An increase of human male reproductive disturbance in the past several decades was associated to chemicals called endocrine disruptors (ED). Bisphenol A (BPA) is a ubiquitous organic environmental contaminant with ED activity. This study verified the effect of BPA exposure via breast milk during the lactation (early postnatal) period in male mice. Dams were exposed to oral BPA (300, 900, and 3000 µg/kg/BW/day) during the breastfeeding period (21 days). BPA at all concentrations significantly impaired sperm parameters in adult mice (8 months old), but mitochondrial functionality was more affected at BPA 3000. The acrosome membrane parameter was affected by BPA concentrations from 900 to 3000, and DNA integrity showed pronounced impairment at BPA 900 and 3000. BPA 3000 treatment also induced testicular degeneration and complete aplasia in some seminiferous tubules. Testicular oxidative damage was observed, and the total antioxidant capacity was impaired in BPA 900 and 3000 treatment groups. Taken together, the present study demonstrated long-term adverse effects of BPA in male mice, including reduced sperm quality, antioxidant capacity, and changes in testicular tissue. Our results clearly demonstrate the danger of BPA transferred via lactation on sperm quality registered even after a long time-elapsed from exposure to this harmful chemical.

  7. Renal impairment and all-cause mortality in cardiovascular disease: effect modification by type 2 diabetes mellitus.

    Science.gov (United States)

    Selvarajah, Sharmini; Uiterwaal, Cuno S P M; Haniff, Jamaiyah; van der Graaf, Yolanda; Visseren, Frank L J; Bots, Michiel L

    2013-02-01

    Renal impairment and type 2 diabetes mellitus (DM) are well-known independent risk factors for mortality. The evidence of their combined effects on mortality is unclear, but of importance because it may determine aggressiveness of treatment. This study sought to assess and quantify the effect modification of diabetes on renal impairment in its association with mortality. Patients with cardiovascular disease or at high risk, recruited in the Second Manifestations of ARTerial disease cohort study, were selected. A total of 7135 patients were enrolled with 33 198 person-years of follow-up. Renal impairment was defined by albuminuria status and estimated glomerular filtration rate (eGFR). Outcome was all-cause mortality. Mortality increased progressively with each stage of renal impairment, for both albuminuria status and eGFR, for diabetics and non-diabetics. There was no effect modification by diabetes on mortality risk due to renal impairment. The relative excess risk due to interaction (RERI) for DM and microalbuminuria was 0·21 (-0·11, 0·52), for overt proteinuria -1·12 (-2·83, 0·59) and for end-stage renal failure (ESRF) 0·32 (-3·65, 4·29). The RERI for DM with eGFR of 60-89 mL/min/1·73 m(2) was -0·31(-0·92, 0·32), for eGFR of 30-59 mL/min/1·73 m(2) -0·07 (-0·76, 0·62) and for eGFR of < 30 mL/min/1·73 m(2) 0·38 (-0·85, 1·61). Type 2 diabetes mellitus does not modify nor increase the risk relation between all-cause mortality and renal impairment. These findings suggest that the hallmark for survival is the prevention and delay in progression of renal impairment in patients with cardiovascular disease. © 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.

  8. Causes of visual impairment and blindness in children in three ecological regions of Nepal: Nepal Pediatric Ocular Diseases Study.

    Science.gov (United States)

    Adhikari, Srijana; Shrestha, Mohan K; Adhikari, Kamala; Maharjan, Nhukesh; Shrestha, Ujjowala D

    2015-01-01

    To study the causes of blindness and visual impairment in children in three ecologically diverse regions of Nepal. This is a baseline survey report of a 3-year longitudinal population-based study. One district each from the three ecological regions - Terai, Hills, and Mountains - was selected for the study. Village Development Committees from each district were selected by random sampling. Three community health workers were given training on vision screening and identification of abnormal ocular conditions in children. Health workers who examined children and collected data using pretested questionnaire performed house-to-house surveys. Children with abnormal vision or ocular conditions were referred to and examined by pediatric ophthalmologists. A total of 10,950 children aged 0-10 years, 5,403 from Terai, 3,204 from Hills, and 2,343 from Mountains, were enrolled in the study. Of them, 681 (6.2%) were nonresponders. The ratio of boys to girls was 1.03:1. Prevalence of blindness was 0.068% (95% confidence interval [CI] 0.02%-0.12%) and visual impairment was 0.097% (95% CI 0.04%-0.15%). Blindness was relatively more prevalent in Terai region (0.08%, 95% CI 0.02%-0.13%). The most common cause of blindness was amblyopia (42.9%) followed by congenital cataract. Corneal opacity (39%) was the most common cause of unilateral blindness. More than two-thirds of the causes that lead to blindness and visual impairment were potentially preventable. Further, nutritional and genetic studies are needed to determine the factors associated with ocular morbidity and blindness in these regions.

  9. Association of disease-specific causes of visual impairment and 10-year mortality amongst Indigenous Australians: the Central Australian Ocular Health Study.

    Science.gov (United States)

    Estevez, José; Kaidonis, Georgia; Henderson, Tim; Craig, Jamie E; Landers, John

    2018-01-01

    Visual impairment significantly impairs the length and quality of life, but little is known of its impact in Indigenous Australians. To investigate the association of disease-specific causes of visual impairment with all-cause mortality. A retrospective cohort analysis. A total of 1347 Indigenous Australians aged over 40 years. Participants visiting remote medical clinics underwent clinical examinations including visual acuity, subjective refraction and slit-lamp examination of the anterior and posterior segments. The major ocular cause of visual impairment was determined. Patients were assessed periodically in these remote clinics for the succeeding 10 years after recruitment. Mortality rates were obtained from relevant departments. All-cause 10-year mortality and its association with disease-specific causes of visual impairment. The all-cause mortality rate for the entire cohort was 29.3% at the 10-year completion of follow-up. Of those with visual impairment, the overall mortality rate was 44.9%. The mortality rates differed for those with visual impairment due to cataract (59.8%), diabetic retinopathy (48.4%), trachoma (46.6%), 'other' (36.2%) and refractive error (33.4%) (P visual impairment from diabetic retinopathy were any more likely to die during the 10 years of follow-up when compared with those without visual impairment (HR 1.70; 95% CI, 1.00-2.87; P = 0.049). Visual impairment was associated with all-cause mortality in a cohort of Indigenous Australians. However, diabetic retinopathy was the only ocular disease that significantly increased the risk of mortality. Visual impairment secondary to diabetic retinopathy may be an important predictor of mortality. © 2017 Royal Australian and New Zealand College of Ophthalmologists.

  10. Selective Impairment of Spatial Cognition Caused by Autoantibodies to the N-Methyl-d-Aspartate Receptor

    Directory of Open Access Journals (Sweden)

    Eric H. Chang

    2015-07-01

    Full Text Available Patients with systemic lupus erythematosus (SLE experience cognitive abnormalities in multiple domains including processing speed, executive function, and memory. Here we show that SLE patients carrying antibodies that bind DNA and the GluN2A and GluN2B subunits of the N-methyl-d-aspartate receptor (NMDAR, termed DNRAbs, displayed a selective impairment in spatial recall. Neural recordings in a mouse model of SLE, in which circulating DNRAbs penetrate the hippocampus, revealed that CA1 place cells exhibited a significant expansion in place field size. Structural analysis showed that hippocampal pyramidal cells had substantial reductions in their dendritic processes and spines. Strikingly, these abnormalities became evident at a time when DNRAbs were no longer detectable in the hippocampus. These results suggest that antibody-mediated neurocognitive impairments may be highly specific, and that spatial cognition may be particularly vulnerable to DNRAb-mediated structural and functional injury to hippocampal cells that evolves after the triggering insult is no longer present.

  11. Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling

    Science.gov (United States)

    Yang, Hongwei; Tang, Ya-ping; Sun, Hao; Song, Yunping; Chen, Chu

    2013-01-01

    SUMMARY Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here we show that synaptic and cognitive impairments following repeated exposure to Δ9-tetrahydrocannabinol (Δ9-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids, in the brain. COX-2 induction by Δ9-THC is mediated via CB1 receptor-coupled G-protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks down-regulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ9-THC exposures. Ablation of COX-2 also eliminates Δ9-THC-impaired hippocampal long-term synaptic plasticity, spatial, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ9-THC in Alzheimer’s disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2. PMID:24267894

  12. Prevalence of eye diseases and causes of visual impairment in school-aged children in Western China.

    Science.gov (United States)

    Pi, Lian-Hong; Chen, Lin; Liu, Qin; Ke, Ning; Fang, Jing; Zhang, Shu; Xiao, Jun; Ye, Wei-Jiang; Xiong, Yan; Shi, Hui; Zhou, Xi-Yuan; Yin, Zheng-Qin

    2012-01-01

    The present study investigated the prevalence of refractive error, visual impairment, and eye diseases in school-aged children in western China. The survey was done in a representative county (Yongchuan District, Chongqing Municipality) of western China. Cluster random sampling was used to select children aged 6 to 15 years. We conducted door-to-door surveys and eye examinations including optometry, stereoscopic vision test, eye position and eye movement, slit lamp examination of the anterior segment, retinoscopy, and fundus examination after cycloplegia with 1% cyclopentolate. Among 3469 children, data were available for 3079 (88.76%). The prevalences of eye diseases were, in descending order, refractive error (20.69%; 637/3079), conjunctivitis (11.76%; 362/3079), amblyopia (1.88%; 58/3079), color vision defect (0.52%; 16/3079), keratitis (0.36%; 11/3079), strabismus (0.29%; 9/3079), cataract (0.23%; 7/3079), pathologic myopia (0.19%; 6/3079), and ocular trauma (0.13%; 4/3079). The prevalence of corneal leucoma, corneal staphyloma, optic neuropathy, macular degeneration, and myelinated nerve fibers was 0.03% (1/3079) for each. The prevalence of visual impairment was 7.70% (237/3079), and the major causes of visual impairment were uncorrected refractive error (86.08%; 204/237), amblyopia (9.70%; 23/237), pathologic myopia (1.27%; 3/237), congenital cataract (0.42%; 1/237), and others (2.11%; 5/237). Among school-aged children in a less developed area of western China, refractive error was the most prevalent eye disorder, and uncorrected refractive error was the main cause of visual impairment.

  13. Prevalence, causes of blindness, visual impairment and cataract surgical services in Sindhudurg district on the western coastal strip of India

    Directory of Open Access Journals (Sweden)

    Shailbala Patil

    2014-01-01

    Full Text Available Background : Konkan coast of India is geographically distinct and its pattern of blindness has never been mapped. Aim : To study the prevalence and causes of blindness and cataract surgical services in Sindhudurg district of West Coast. Subjects : Individual aged > 50 years. Materials and Methods: Rapid assessment of avoidable blindness used to map blindness pattern in the district. Statistical analysis: SPSS version 19. Results: Amongst those examined 1415 (51.7% had visual acuity (VA >20/60, 924 (33.8%, confidence interval (C.I 30.5%-36.8% had VA 20/200-<20/60(visual impairment, 266 (9.7%, C.I. 6.1%-13.3% had VA < 20/200-20/400 (severe visual impairment and 132 (4.8%, C. I. 1.1%-8.5% had VA < 20/400 (blindness by WHO standards. There was no significant gender difference in prevalence of blindness, but blindness and visual impairment was more in older and rural residing individuals. Amongst those with presenting vision < 20/200 in better eye, 309 (82.4% had cataract, 36 (9.7% had corneal scars, 13 (3.5% had diabetic retinopathyand 3 (0.8% had glaucoma. Cataract surgical coverage for the district was only 30.5%; 32% for males and 28.4% for females. Unable to afford, lack of knowledge and lack of access to services were the commonest barriers responsible for cataract patients not seeking care. Amongst those who had undergone cataract surgery, only 50% had visual acuity ≥ 20/60.46.9% of the population had spectacles for near, but only 53.3% of the population had presenting near vision < N10. Conclusion : Cataract, refractive errors and diabetes were significant causes of visual impairment and blindness.

  14. Global causes of blindness and distance vision impairment 1990-2020: a systematic review and meta-analysis.

    Science.gov (United States)

    Flaxman, Seth R; Bourne, Rupert R A; Resnikoff, Serge; Ackland, Peter; Braithwaite, Tasanee; Cicinelli, Maria V; Das, Aditi; Jonas, Jost B; Keeffe, Jill; Kempen, John H; Leasher, Janet; Limburg, Hans; Naidoo, Kovin; Pesudovs, Konrad; Silvester, Alex; Stevens, Gretchen A; Tahhan, Nina; Wong, Tien Y; Taylor, Hugh R

    2017-12-01

    Contemporary data for causes of vision impairment and blindness form an important basis of recommendations in public health policies. Refreshment of the Global Vision Database with recently published data sources permitted modelling of cause of vision loss data from 1990 to 2015, further disaggregation by cause, and forecasts to 2020. In this systematic review and meta-analysis, we analysed published and unpublished population-based data for the causes of vision impairment and blindness from 1980 to 2014. We identified population-based studies published before July 8, 2014, by searching online databases with no language restrictions (MEDLINE from Jan 1, 1946, and Embase from Jan 1, 1974, and the WHO Library Database). We fitted a series of regression models to estimate the proportion of moderate or severe vision impairment (defined as presenting visual acuity of cause, age, region, and year. We identified 288 studies of 3 983 541 participants contributing data from 98 countries. Among the global population with moderate or severe vision impairment in 2015 (216·6 million [80% uncertainty interval 98·5 million to 359·1 million]), the leading causes were uncorrected refractive error (116·3 million [49·4 million to 202·1 million]), cataract (52·6 million [18·2 million to 109·6 million]), age-related macular degeneration (8·4 million [0·9 million to 29·5 million]), glaucoma (4·0 million [0·6 million to 13·3 million]), and diabetic retinopathy (2·6 million [0·2 million to 9·9 million]). Among the global population who were blind in 2015 (36·0 million [12·9 million to 65·4 million]), the leading causes were cataract (12·6 million [3·4 million to 28·7 million]), uncorrected refractive error (7·4 million [2·4 million to 14·8 million]), and glaucoma (2·9 million [0·4 million to 9·9 million]). By 2020, among the global population with moderate or severe vision impairment (237·1 million [101·5 million to 399·0 million]), the number of

  15. A c-Myb mutant causes deregulated differentiation due to impaired histone binding and abrogated pioneer factor function.

    Science.gov (United States)

    Fuglerud, Bettina M; Lemma, Roza B; Wanichawan, Pimthanya; Sundaram, Arvind Y M; Eskeland, Ragnhild; Gabrielsen, Odd S

    2017-07-27

    The transcription factor c-Myb is involved in early differentiation and proliferation of haematopoietic cells, where it operates as a regulator of self-renewal and multi-lineage differentiation. Deregulated c-Myb plays critical roles in leukaemias and other human cancers. Due to its role as a master regulator, we hypothesized it might function as a pioneer transcription factor. Our approach to test this was to analyse a mutant of c-Myb, D152V, previously reported to cause haematopoietic defects in mice by an unknown mechanism. Our transcriptome data from K562 cells indicates that this mutation specifically affects c-Myb's ability to regulate genes involved in differentiation, causing failure in c-Myb's ability to block differentiation. Furthermore, we see a major effect of this mutation in assays where chromatin opening is involved. We show that each repeat in the minimal DNA-binding domain of c-Myb binds to histones and that D152V disrupts histone binding of the third repeat. ATAC-seq data indicates this mutation impairs the ability of c-Myb to cause chromatin opening at specific sites. Taken together, our findings support that c-Myb acts as a pioneer factor and show that D152V impairs this function. The D152V mutant is the first mutant of a transcription factor specifically destroying pioneer factor function. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  16. Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis.

    Science.gov (United States)

    Griffin, Timothy M; Huebner, Janet L; Kraus, Virginia B; Guilak, Farshid

    2009-10-01

    To test the hypothesis that obesity resulting from deletion of the leptin gene or the leptin receptor gene results in increased knee osteoarthritis (OA), systemic inflammation, and altered subchondral bone morphology. Leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) female mice compared with wild-type mice were studied, to document knee OA via histopathology. The levels of serum proinflammatory and antiinflammatory cytokines were measured using a multiplex bead immunoassay. Cortical and trabecular subchondral bone changes were documented by microfocal computed tomography, and body composition was quantified by dual x-ray absorptiometry. Adiposity was increased by approximately 10-fold in ob/ob and db/db mice compared with controls, but it was not associated with an increased incidence of knee OA. Serum cytokine levels were unchanged in ob/ob and db/db mice relative to controls, except for the level of cytokine-induced neutrophil chemoattractant (keratinocyte chemoattractant; murine analog of interleukin-8), which was elevated. Leptin impairment was associated with reduced subchondral bone thickness and increased relative trabecular bone volume in the tibial epiphysis. Extreme obesity due to impaired leptin signaling induced alterations in subchondral bone morphology without increasing the incidence of knee OA. Systemic inflammatory cytokine levels remained largely unchanged in ob/ob and db/db mice. These findings suggest that body fat, in and of itself, may not be a risk factor for joint degeneration, because adiposity in the absence of leptin signaling is insufficient to induce systemic inflammation and knee OA in female C57BL/6J mice. These results imply a pleiotropic role of leptin in the development of OA by regulating both the skeletal and immune systems.

  17. [Detection of auditory impairment in the offsprings caused by drug treatment of the dams].

    Science.gov (United States)

    Kameyama, T; Nabeshima, T; Itoh, J

    1982-12-01

    To study the auditory impairment induced by prenatal administration of aminoglycosides in the offspring, the shuttle box method to measure the auditory threshold of rats (Kameyama et al., Folia pharmacol. japon. 77, 15, 1981) was employed. Four groups of pregnant rats were administered 200 mg/kg kanamycin sulfate (KM), 200 mg/kg dihydrostreptomycin sulfate (DHSM), 100 mg/kg neomycin sulfate (NM), or 1 ml/kg saline intramuscularly from the 10th to the 19th day of pregnancy. The auditory threshold of the offspring could be measured by the shuttle box method in about 90% of the live born rats at the age of 100 days. The auditory thresholds of the groups were as follows (mean +/- S.E.): saline group, 53.8 +/- 0.6 dB (N = 36); KM group, 63.8 +/- 1.1 dB (N = 34); DHSM group, 60.0 +/- 1.2 dB (N = 29); NM group, 62.4 +/- 1.2 dB (N = 24). Auditory thresholds of drug-treated groups were significantly higher than that of the saline group. However, no increase in the auditory threshold of the mother rat was detected after treatment with aminoglycosides. In addition, the experimental procedure of the shuttle box method is very easy, and the auditory threshold of a large number of rats could be measured in a short period. These findings suggest that this method is a very useful one for screening for auditory impairment induced by prenatal drug treatment in rat offspring.

  18. RNASEH1 Mutations Impair mtDNA Replication and Cause Adult-Onset Mitochondrial Encephalomyopathy

    Science.gov (United States)

    Reyes, Aurelio; Melchionda, Laura; Nasca, Alessia; Carrara, Franco; Lamantea, Eleonora; Zanolini, Alice; Lamperti, Costanza; Fang, Mingyan; Zhang, Jianguo; Ronchi, Dario; Bonato, Sara; Fagiolari, Gigliola; Moggio, Maurizio; Ghezzi, Daniele; Zeviani, Massimo

    2015-01-01

    Chronic progressive external ophthalmoplegia (CPEO) is common in mitochondrial disorders and is frequently associated with multiple mtDNA deletions. The onset is typically in adulthood, and affected subjects can also present with general muscle weakness. The underlying genetic defects comprise autosomal-dominant or recessive mutations in several nuclear genes, most of which play a role in mtDNA replication. Next-generation sequencing led to the identification of compound-heterozygous RNASEH1 mutations in two singleton subjects and a homozygous mutation in four siblings. RNASEH1, encoding ribonuclease H1 (RNase H1), is an endonuclease that is present in both the nucleus and mitochondria and digests the RNA component of RNA-DNA hybrids. Unlike mitochondria, the nucleus harbors a second ribonuclease (RNase H2). All affected individuals first presented with CPEO and exercise intolerance in their twenties, and these were followed by muscle weakness, dysphagia, and spino-cerebellar signs with impaired gait coordination, dysmetria, and dysarthria. Ragged-red and cytochrome c oxidase (COX)-negative fibers, together with impaired activity of various mitochondrial respiratory chain complexes, were observed in muscle biopsies of affected subjects. Western blot analysis showed the virtual absence of RNase H1 in total lysate from mutant fibroblasts. By an in vitro assay, we demonstrated that altered RNase H1 has a reduced capability to remove the RNA from RNA-DNA hybrids, confirming their pathogenic role. Given that an increasing amount of evidence indicates the presence of RNA primers during mtDNA replication, this result might also explain the accumulation of mtDNA deletions and underscores the importance of RNase H1 for mtDNA maintenance. PMID:26094573

  19. CNNM2 mutations cause impaired brain development and seizures in patients with hypomagnesemia.

    Science.gov (United States)

    Arjona, Francisco J; de Baaij, Jeroen H F; Schlingmann, Karl P; Lameris, Anke L L; van Wijk, Erwin; Flik, Gert; Regele, Sabrina; Korenke, G Christoph; Neophytou, Birgit; Rust, Stephan; Reintjes, Nadine; Konrad, Martin; Bindels, René J M; Hoenderop, Joost G J

    2014-04-01

    Intellectual disability and seizures are frequently associated with hypomagnesemia and have an important genetic component. However, to find the genetic origin of intellectual disability and seizures often remains challenging because of considerable genetic heterogeneity and clinical variability. In this study, we have identified new mutations in CNNM2 in five families suffering from mental retardation, seizures, and hypomagnesemia. For the first time, a recessive mode of inheritance of CNNM2 mutations was observed. Importantly, patients with recessive CNNM2 mutations suffer from brain malformations and severe intellectual disability. Additionally, three patients with moderate mental disability were shown to carry de novo heterozygous missense mutations in the CNNM2 gene. To elucidate the physiological role of CNNM2 and explain the pathomechanisms of disease, we studied CNNM2 function combining in vitro activity assays and the zebrafish knockdown model system. Using stable Mg(2+) isotopes, we demonstrated that CNNM2 increases cellular Mg2+ uptake in HEK293 cells and that this process occurs through regulation of the Mg(2+)-permeable cation channel TRPM7. In contrast, cells expressing mutated CNNM2 proteins did not show increased Mg(2+) uptake. Knockdown of cnnm2 isoforms in zebrafish resulted in disturbed brain development including neurodevelopmental impairments such as increased embryonic spontaneous contractions and weak touch-evoked escape behaviour, and reduced body Mg content, indicative of impaired renal Mg(2+) absorption. These phenotypes were rescued by injection of mammalian wild-type Cnnm2 cRNA, whereas mammalian mutant Cnnm2 cRNA did not improve the zebrafish knockdown phenotypes. We therefore concluded that CNNM2 is fundamental for brain development, neurological functioning and Mg(2+) homeostasis. By establishing the loss-of-function zebrafish model for CNNM2 genetic disease, we provide a unique system for testing therapeutic drugs targeting CNNM2 and

  20. Causes, Prevention and Correction of Impaired Posture in Children of Primary School Age

    Directory of Open Access Journals (Sweden)

    В. А. Щирба

    2016-09-01

    Full Text Available Research Objective. The objective of our research was to provide theoretical substantiation and implement corrective gymnastics in practice for the purposes of prevention and correction of faults in schoolchildren’s posture. The main means for shaping the correct posture, preventing and correcting faults in posture are callisthenic routine and special corrective exercises. Research methods: anamnesis, somatoscopy, clinical and mathematical methods. Research results. The medical examination revealed that only six of 60 pupils had normal correctly shaped posture, which accounts for 10%. The posture of the other 90% of the pupils was impaired. The most common faults were: asymmetrical pectoral girdle and shoulder blades, stooping posture. The examination revealed 19 pupils with scoliotic posture, which accounts for 44 %. The posture of 24 pupils, or 40%, was hyperkyphotic and stooping. In other words, the posture of 84% of the pupils was scoliotic or hyperkyphotic. The rest of the pupils had flat and kypholordic posture. It is worth mentioning that some of the pupils examined had more serious disorders of their musculoskeletal system, namely: organic disorders, such as spinal disorders in the sagittal plane — the scoliosis types excluded from the study. Significantly, the first main reason of posture disorders is weakness of the pectoral muscle sling. Conclusions. The principal means of prevention and correction of impaired posture are using special physical exercises designed to create a muscular corpus and correct particular faults in posture. We therefore developed sets of exercises intended to correct posture defects and proposed them to the physical education teacher and class teachers.

  1. Absence of Carbohydrate Response Element Binding Protein in Adipocytes Causes Systemic Insulin Resistance and Impairs Glucose Transport

    Directory of Open Access Journals (Sweden)

    Archana Vijayakumar

    2017-10-01

    Full Text Available Lower adipose-ChREBP and de novo lipogenesis (DNL are associated with insulin resistance in humans. Here, we generated adipose-specific ChREBP knockout (AdChREBP KO mice with negligible sucrose-induced DNL in adipose tissue (AT. Chow-fed AdChREBP KO mice are insulin resistant with impaired insulin action in the liver, muscle, and AT and increased AT inflammation. HFD-fed AdChREBP KO mice are also more insulin resistant than controls. Surprisingly, adipocytes lacking ChREBP display a cell-autonomous reduction in insulin-stimulated glucose transport that is mediated by impaired Glut4 translocation and exocytosis, not lower Glut4 levels. AdChREBP KO mice have lower levels of palmitic acid esters of hydroxy stearic acids (PAHSAs in serum, and AT. 9-PAHSA supplementation completely rescues their insulin resistance and AT inflammation. 9-PAHSA also normalizes impaired glucose transport and Glut4 exocytosis in ChREBP KO adipocytes. Thus, loss of adipose-ChREBP is sufficient to cause insulin resistance, potentially by regulating AT glucose transport and flux through specific lipogenic pathways.

  2. The haematocrit – an important factor causing impaired haemostasis in patients with cyanotic congenital heart disease

    DEFF Research Database (Denmark)

    Jensen, A S; Johansson, P I; Idorn, L

    2013-01-01

    BACKGROUND: Patients with cyanotic congenital heart disease(CCHD) have haemostatic abnormalities, which result in an increased risk of bleeding. The cause is unknown, but recent studies have indicated that an elevated haematocrit, which is present in cyanotic patients, could be an important factor...

  3. Osteopontin Impairs Host Defense during Established Gram-Negative Sepsis Caused by Burkholderia pseudomallei (Melioidosis)

    NARCIS (Netherlands)

    van der Windt, G.J.W.; Wiersinga, W.J.; Wieland, C.W.; Tjia, I.C.S.I.; Day, N.P.; Peacock, S.J.; Florquin, S.; van der Poll, T.

    2010-01-01

    Background: Melioidosis, caused by infection with Burkholderia (B.) pseudomallei, is a severe illness that is endemic in Southeast Asia. Osteopontin (OPN) is a phosphorylated glycoprotein that is involved in several immune responses including induction of T-helper 1 cytokines and recruitment of

  4. Eye Closure Reduces the Cross-Modal Memory Impairment Caused by Auditory Distraction

    Science.gov (United States)

    Perfect, Timothy J.; Andrade, Jackie; Eagan, Irene

    2011-01-01

    Eyewitnesses instructed to close their eyes during retrieval recall more correct and fewer incorrect visual and auditory details. This study tested whether eye closure causes these effects through a reduction in environmental distraction. Sixty participants watched a staged event before verbally answering questions about it in the presence of…

  5. Impaired Standing Balance in Elderly: A New Engineering Method Helps to Unravel Causes and Effects

    NARCIS (Netherlands)

    Engelhart, D.; Pasma, J.H.; Schouten, A.C.; Meskers, C.G.M.; Maier, A.B.; Mergner, T.; van der Kooij, H.

    2014-01-01

    Deteriorated balance control is the most frequent cause of falls and injuries in the elderly. Balance control comprises a complex interplay of several underlying systems (ie, the sensory systems, the motor system, and the nervous system). Available clinical balance tests determine the patient's

  6. Prevalence and causes of visual impairment in a rural North-east China adult population: a population-based survey in Bin County, Harbin.

    Science.gov (United States)

    Song, Wulian; Sun, Xian; Shao, Zhengbo; Zhou, Xinrong; Kang, Yang; Sui, Hong; Yuan, Huiping

    2010-09-01

    To investigate the prevalence and causes of visual impairment in a rural population in north-east China.   A population-based study was conducted within Bin County, Harbin of north-east China. Low vision and blindness were defined using the World Health Organization categories of visual impairment. The prevalence of visual impairment was estimated, and causes were identified based on best-corrected visual acuity (BCVA) as well as presenting visual acuity (VA). Out of 5764 people, 4956 (86.01%) aged older than 40 participated in the study. The prevalence of visual impairment, low vision and blindness based on presenting VA was 9.6% (BCVA, 6.6%), 7.7% (BCVA, 4.9%) and 1.9% (BCVA, 1.7%), respectively. Taking the presenting VA, cataract (44%) was the most common cause for visual impairment followed by uncorrected refractive error (24%), treatable causes of visual impairment accounted for 68% of the total cases. Cataract (59%) and glaucoma (15%) were leading causes for blindness based on presenting VA. According to BCVA, cataract was the leading cause of visual impairment and blindness (58% and 60%, respectively), followed by glaucoma (17% and 15%, respectively). The prevalence of visual impairment was higher among women than men (pVisual impairment was a serious public health problem in this rural population, with most of it easily remedied. Results highlighted the need for visual impairment prevention programs to an increasing number of elderly people, with a special emphasis on female and those with little or no education. © 2009 The Authors. Journal compilation © 2009 Acta Ophthalmol.

  7. Cerebral visual impairment and intellectual disability caused by PGAP1 variants.

    Science.gov (United States)

    Bosch, Daniëlle G M; Boonstra, F Nienke; Kinoshita, Taroh; Jhangiani, Shalini; de Ligt, Joep; Cremers, Frans P M; Lupski, James R; Murakami, Yoshiko; de Vries, Bert B A

    2015-12-01

    Homozygous variants in PGAP1 (post-GPI attachment to proteins 1) have recently been identified in two families with developmental delay, seizures and/or spasticity. PGAP1 is a member of the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway and defects in this pathway are a subclass of congenital disorders of glycosylation. Here we performed whole-exome sequencing in an individual with cerebral visual impairment (CVI), intellectual disability (ID), and factor XII deficiency and revealed compound heterozygous variants in PGAP1, c.274_276del (p.(Pro92del)) and c.921_925del (p.(Lys308Asnfs*25)). Subsequently, PGAP1-deficient Chinese hamster ovary (CHO)-cell lines were transfected with either mutant or wild-type constructs and their sensitivity to phosphatidylinositol-specific phospholipase C (PI-PLC) treatment was measured. The mutant constructs could not rescue the PGAP1-deficient CHO cell lines resistance to PI-PLC treatment. In addition, lymphoblastoid cell lines (LCLs) of the affected individual showed no sensitivity to PI-PLC treatment, whereas the LCLs of the heterozygous carrier parents were partially resistant. In conclusion, we report novel PGAP1 variants in a boy with CVI and ID and a proven functional loss of PGAP1 and show, to our knowledge, for the first time this genetic association with CVI.

  8. [Exogenous putrescine causes renal function impairment and cell apoptosis in rats].

    Science.gov (United States)

    Zhou, Yueping; Xiao, Nengkan; Rong, Xinzhou; Fan, Guicheng; Liu, Sirong

    2012-11-01

    To explore the effect of exogenous putrescine on renal function and cell apoptosis in rats. Ninety SD rats were randomized into control group (n=10), high-dose putrescine group (P1 group, n=40), and low-dose putrescine group (P2 group, n=40) with intraperitoneal injections of 2 ml of normal saline, 50 µg/g putrescine, and 25 µg/g putrescine, respectively. At 24, 48, 72 and 96 h after the injections, 10 rats from each group were sacrificed to examine serum Cr and BUN levels, histological changes in the kidneys, and renal cell apoptosis (TUNEL assay). The rats in the two putrescine- treated groups showed mild edema in some renal tissues without obvious necrosis. In P1 and P2 groups, serum Cr and BUN levels differed significantly at each time point of measurement (Pputrescine-treated groups showed gradually increased renal cell apoptosis with time, reaching the peak levels at 96 h and 48 h, respectively. The peak renal cell apoptosis rates in P1 [(24.78∓2.19)%] and P2 [(26.27∓2.13)%] group were significantly higher than the rate in the control group [(4.47∓0.33)%, Pputrescine can lead to renal function impairment and induce renal cell apoptosis in rats, and the severity of these changes appeared to be associated with the blood concentration of exogenous putrescine.

  9. Diabetes insipidus as a rare cause of acute cognitive impairment in multiple sclerosis.

    Science.gov (United States)

    Tiedje, V; Schlamann, M; Führer, D; Moeller, L C

    2013-10-01

    Multiple sclerosis (MS) is a complex neurodegenerative disease presenting with a diversity of clinical symptoms including palsy and cognitive impairment. We present a 59-year-old woman with a history of secondary progressive MS since 1987, who was referred to our department because of recent onset of confusion and polydipsia. Initial lab tests showed mildly elevated serum sodium levels and low urine osmolality. Under water deprivation, diuresis and low urine osmolality persisted and serum sodium levels rose above 150 mmol/l. Oral desmopressin resulted in normalisation of serum sodium as well as urine osmolarity, confirming a diagnosis of central diabetes insipidus. As drug-induced diabetes could be excluded, pituitary magnetic resonance imaging (MRI) was performed. A demyelinating lesion was detected in the hypothalamus. The patient was started on oral desmopressin treatment (0.2 mg/day). Fluid intake and serum sodium levels have since remained normal. In summary, we report the rare case of a patient presenting with diabetes insipidus due to progressive MS. Diabetes insipidus should be considered in MS patients who develop new onset of polydipsia.

  10. Oxidative stress caused by pyocyanin impairs CFTR Cl(-) transport in human bronchial epithelial cells.

    Science.gov (United States)

    Schwarzer, Christian; Fischer, Horst; Kim, Eun-Jin; Barber, Katharine J; Mills, Aaron D; Kurth, Mark J; Gruenert, Dieter C; Suh, Jung H; Machen, Terry E; Illek, Beate

    2008-12-15

    Pyocyanin (N-methyl-1-hydroxyphenazine), a redox-active virulence factor produced by the human pathogen Pseudomonas aeruginosa, is known to compromise mucociliary clearance. Exposure of human bronchial epithelial cells to pyocyanin increased the rate of cellular release of H(2)O(2) threefold above the endogenous H(2)O(2) production. Real-time measurements of the redox potential of the cytosolic compartment using the redox sensor roGFP1 showed that pyocyanin (100 microM) oxidized the cytosol from a resting value of -318+/-5 mV by 48.0+/-4.6 mV within 2 h; a comparable oxidation was induced by 100 microM H(2)O(2). Whereas resting Cl(-) secretion was slightly activated by pyocyanin (to 10% of maximal currents), forskolin-stimulated Cl(-) secretion was inhibited by 86%. The decline was linearly related to the cytosolic redox potential (1.8% inhibition/mV oxidation). Cystic fibrosis bronchial epithelial cells homozygous for DeltaF508 CFTR failed to secrete Cl(-) in response to pyocyanin or H(2)O(2), indicating that these oxidants specifically target the CFTR and not other Cl(-) conductances. Treatment with pyocyanin also decreased total cellular glutathione levels to 62% and cellular ATP levels to 46% after 24 h. We conclude that pyocyanin is a key factor that redox cycles in the cytosol, generates H(2)O(2), depletes glutathione and ATP, and impairs CFTR function in Pseudomonas-infected lungs.

  11. Causes of childhood visual impairment and unmet low-vision care in blind school students in Ghana.

    Science.gov (United States)

    Ntim-Amponsah, C T; Amoaku, W M K

    2008-10-01

    The purpose of this study was to determine the causes of childhood visual impairment and blindness in students of a school for blind children, to determine how many students had some residual vision, and to evaluate any unmet low-vision care. A survey of students in the blind school was conducted in two parts in May-June and then October 2003. The sample consisted of 201 students who became blind before the age of 16. Information was obtained from student interviews, doctors' referral notes and ophthalmic examination of all students who consented. Students with residual vision had low-vision assessments. These investigations were supplemented with active participation of the investigators in Parent-Teacher Association meetings and focus group discussions with parents. One hundred and ninety-nine students consented and were recruited, whereas two declined. Ninety-six became visually impaired within their first year of life and 33 by the age of 5 years. Pathology of the cornea and then the lens were the commonest causes of blindness. One hundred and eight students were totally blind, whereas 87 (43.7%) had some residual vision and formed the target for the second part of the study. Fifty-one out of 77 of this target group who turned up for low-vision examination had useful residual vision by the World Health Organisation (WHO) low-vision examination chart. Spectacle magnifiers aided two students to read normal print at N5 and N8, respectively. Different visual aids would help enhance the residual vision in some of the others. Emotional trauma was apparent in parents and teachers. Children who became blind later in life remained in shock for a longer time and adapted less well to their visual impairment. Visual impairment in the population is not uncommon. Some causes are preventable. There is a significant unmet need for low-vision care, particularly amongst children in Ghana, and perhaps many countries in the West Africa subregion. It is hoped that the findings from

  12. Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes.

    Science.gov (United States)

    Lange, P; Nyboe, J; Appleyard, M; Jensen, G; Schnohr, P

    1990-08-01

    The relation of ventilatory impairment and chronic mucus hypersecretion to death from all causes and death from obstructive lung disease (chronic bronchitis, emphysema and asthma) was studied in 13,756 men and women randomly selected from the general population of the City of Copenhagen. During the 10 year follow up 2288 subjects died. In 164 subjects obstructive lung disease was considered to be an underlying or a contributory cause of death (obstructive lung disease related death); in 73 subjects it was considered to be the underlying cause of death (obstructive lung disease death). Forced expiratory volume in one second, expressed as a percentage of the predicted value (FEV1% pred), and the presence of chronic phlegm were used to characterise ventilatory function and chronic mucus hypersecretion respectively. For mortality analysis the proportional hazards regression model of Cox was used; it included age, sex, pack years, inhalation habit, body mass index, alcohol consumption, and the presence or absence of asthma, heart disease, and diabetes mellitus as confounding factors. By comparison with subjects with an FEV1 of 80% pred or more, subjects with an FEV1 below 40% pred had increased risk of dying from all causes (relative risk (RR) = 5.0 for women, 2.7 for men), a higher risk of obstructive lung disease related death (RR = 57 for women, 34 for men), and a higher risk of obstructive lung disease death (RR = 101 for women, 77 for men). Chronic mucus hypersecretion was associated with only a slightly higher risk of death from all causes (RR = 1.1 for women, 1.3 for men). The association between chronic mucus hypersecretion and obstructive lung disease death varied with the level of ventilatory function, being weak in subjects with normal ventilatory function (for an FEV1 of 80% pred the RR was 1.2), but more pronounced in subjects with reduced ventilatory function (for an FEV1 of 40% pred the RR was 4.2). A similar though statistically non-significant trend was

  13. Life quality impairment caused by hookworm-related cutaneous larva migrans in resource-poor communities in Manaus, Brazil.

    Science.gov (United States)

    Schuster, Angela; Lesshafft, Hannah; Talhari, Sinésio; Guedes de Oliveira, Silás; Ignatius, Ralf; Feldmeier, Hermann

    2011-11-01

    Hookworm-related cutaneous larva migrans (CLM) is a common but neglected tropical skin disease caused by the migration of animal hookworm larvae in the epidermis. The disease causes intense pruritus and is associated with important morbidity. The extent to which CLM impairs skin disease-associated life quality has never been studied. A modified version of the Dermatology Life Quality Index (mDLQI) was used to determine skin disease-associated life quality in 91 adult and child patients with CLM, living in resource-poor communities in Manaus, Brazil. Symptoms and signs were documented and skin disease-associated life quality was semi-quantitatively assessed using mDLQI scores. The assessment was repeated two and four weeks after treatment with ivermectin. Ninety-one point five percent of the study participants showed a considerable reduction of skin disease-associated life quality at the time of diagnosis. The degree of impairment correlated with the intensity of infection (rho = 0.76, p<0.001), the number of body areas affected (rho = 0.30; p = 0.004), and the presence of lesions on visible areas of the skin (p = 0.002). Intense pruritus, sleep disturbance (due to itching) and the feeling of shame were the most frequent skin disease-associated life quality restrictions (reported by 93.4%, 73.6%, and 64.8% of the patients, respectively). No differences were observed in skin disease-associated life quality restriction between boys and girls or men and women. Two weeks after treatment with ivermectin, skin disease-associated life quality improved significantly. After four weeks, 73.3% of the patients considered their disease-associated life quality to have returned to normal. CLM significantly impaired the skin disease-associated life quality in child and adult patients living in urban slums in North Brazil. After treatment with ivermectin, life quality normalised rapidly.

  14. Prevalence and causes of musculoskeletal impairment in Fundong District, North-West Cameroon: results of a population-based survey.

    Science.gov (United States)

    Smythe, Tracey; Mactaggart, Islay; Kuper, Hannah; Oye, Joseph; Sieyen, Nana Christopher; Lavy, Christopher; Polack, Sarah

    2017-11-01

    Epidemiological data on musculoskeletal conditions such as degenerative joint diseases and bone fractures are lacking in low- and middle-income countries. This survey aimed to estimate the prevalence and causes of musculoskeletal impairment in Fundong Health District, North-West Cameroon. Fifty-one clusters of 80 people (all ages) were selected using probability proportionate to size sampling. Households within clusters were selected by compact segment sampling. Six screening questions were asked to identify participants likely to have a musculoskeletal impairment (MSI). Participants screening positive to any screening question underwent a standardised examination by a physiotherapist to assess presence, cause, diagnosis and severity of impairment. In total, 3567 of 4080 individuals enumerated for the survey were screened (87%). The all-age prevalence of MSI was 11.6% (95% CI: 10.1-13.3). Prevalence increased with age, from 2.9% in children to 41.2% in adults 50 years and above. The majority of MSI cases (70.4%) were classified as mild, 27.2% as moderate and 2.4% as severe. Acquired non-trauma comprised 67% of the diagnoses. The remainder included trauma (14%), neurological (11%), infection (5%) and congenital (3%). The most common individual diagnosis was degenerative joint disease (43%). Over one-third (38%) of individuals with MSI had never received medical care or rehabilitation for their condition. This survey contributes to the epidemiological data on MSI in low- and middle-income countries. Nearly half of adults aged over 50 years had an MSI. There is a need to address the treatment and rehabilitative service gap for people with MSI in Cameroon. © 2017 John Wiley & Sons Ltd.

  15. Impaired popliteal artery flow-mediated dilation caused by reduced daily physical activity is prevented by increased shear stress.

    Science.gov (United States)

    Teixeira, André L; Padilla, Jaume; Vianna, Lauro C

    2017-07-01

    We recently showed that 5 days of reduced daily physical activity impair popliteal artery, but not brachial artery, flow-mediated dilation (FMD). However, the mechanisms by which physical inactivity causes leg vascular dysfunction are unclear. We reason that a reduction in leg blood flow-induced shear stress is a primary underlying mechanism by which reduced daily physical activity impairs popliteal artery FMD. Thus the purpose of this study was to determine whether increased leg blood flow and shear stress during inactivity prevent the reduction in popliteal artery FMD. Bilateral popliteal artery FMD measures were performed at baseline and after 5 days of a transition from high (>10,000 steps/day) to low levels (physical activity in 13 healthy and physically active men [20 ± 2 (SD) yr]. During the inactive period, one foot was submerged in ~42°C water (i.e., heated leg) three times a day for 30 min each period, to increase blood flow and thus shear stress, whereas the contralateral leg remained dry and served as internal control (i.e., nonheated leg). During heating, popliteal artery mean shear rate was increased in the heated leg (change of 119.3 ± 26.4%, P physical activity in the control nonheated leg (P stress during physical inactivity is a key underlying mechanism mediating leg vascular dysfunction.NEW & NOTEWORTHY We found that the impairment in popliteal artery flow-mediated dilation caused by physical inactivity can be prevented by increased shear stress. These findings indicate that reduced leg blood flow-induced shear stress during physical inactivity may be a key underlying mechanism mediating the detrimental leg vascular effects of physical inactivity. Heating the foot area may be used as a nonpharmacological therapy to combat inactivity-induced leg vascular dysfunction, especially in people who are unable or unwilling to be active. Copyright © 2017 the American Physiological Society.

  16. Conditional ablation of Raptor in the male germline causes infertility due to meiotic arrest and impaired inactivation of sex chromosomes.

    Science.gov (United States)

    Xiong, Mengneng; Zhu, Zhiping; Tian, Suwen; Zhu, Ruping; Bai, Shun; Fu, Kaiqiang; Davis, James G; Sun, Zheng; Baur, Joseph A; Zheng, Ke; Ye, Lan

    2017-09-01

    Rapamycin is a clinically important drug that is used in transplantation and cancer therapy but which causes a number of side effects, including male infertility. Its canonical target, mammalian target of rapamycin complex 1 (mTORC1), plays a key role in metabolism and binds chromatin; however, its precise role in the male germline has not been elucidated. Here, we inactivate the core component, Raptor, to show that mTORC1 function is critical for male meiosis and the inactivation of sex chromosomes. Disruption of the Raptor gene impairs chromosomal synapsis and prevents the efficient spreading of silencing factors into the XY chromatin. Accordingly, mRNA for XY-linked genes remains inappropriately expressed in Raptor-deficient mice. Molecularly, the failure to suppress gene expression corresponded with deficiencies in 2 repressive chromatin markers, H3K9 dimethylation and H3K9 trimethylation, in the XY body. Together, these results demonstrate that mTORC1 has an essential role in the meiotic progression and silencing of sex chromosomes in the male germline, which may explain the infertility that has been associated with such inhibitors as rapamycin.-Xiong, M., Zhu, Z., Tian, S., Zhu, R., Bai, S., Fu, K., Davis, J. G., Sun, Z., Baur, J. A., Zheng, K., Ye, L. Conditional ablation of Raptor in the male germline causes infertility due to meiotic arrest and impaired inactivation of sex chromosomes. © FASEB.

  17. Jumping the gun: Smoking constituent BaP causes premature primordial follicle activation and impairs oocyte fusibility through oxidative stress

    Energy Technology Data Exchange (ETDEWEB)

    Sobinoff, A.P.; Pye, V. [Reproductive Science Group, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW2308 (Australia); Nixon, B.; Roman, S.D. [Reproductive Science Group, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW2308 (Australia); ARC Centre of Excellence in Biotechnology and Development, University of Newcastle, Callaghan, NSW2308 (Australia); McLaughlin, E.A., E-mail: eileen.mclaughlin@newcastle.edu.au [Reproductive Science Group, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW2308 (Australia); ARC Centre of Excellence in Biotechnology and Development, University of Newcastle, Callaghan, NSW2308 (Australia)

    2012-04-01

    Benzo(a)pyrene (BaP) is an ovotoxic constituent of cigarette smoke associated with pre-mature ovarian failure and decreased rates of conception in IVF patients. Although the overall effect of BaP on female fertility has been documented, the exact molecular mechanisms behind its ovotoxicity remain elusive. In this study we examined the effects of BaP exposure on the ovarian transcriptome, and observed the effects of in vivo exposure on oocyte dysfunction. Microarray analysis of BaP cultured neonatal ovaries revealed a complex mechanism of ovotoxicity involving a small cohort of genes associated with follicular growth, cell cycle progression, and cell death. Histomorphological and immunohistochemical analysis supported these results, with BaP exposure causing increased primordial follicle activation and developing follicle atresia in vitro and in vivo. Functional analysis of oocytes obtained from adult Swiss mice treated neonatally revealed significantly increased levels of mitochondrial ROS/lipid peroxidation, and severely reduced sperm-egg binding and fusion in both low (1.5 mg/kg/daily) and high (3 mg/kg/daily) dose treatments. Our results reveal a complex mechanism of BaP induced ovotoxicity involving developing follicle atresia and accelerated primordial follicle activation, and suggest short term neonatal BaP exposure causes mitochondrial leakage resulting in reduced oolemma fluidity and impaired fertilisation in adulthood. This study highlights BaP as a key compound which may be partially responsible for the documented effects of cigarette smoke on follicular development and sub-fertility. -- Highlights: ► BaP exposure up-regulates canonical pathways linked with follicular growth/atresia. ► BaP causes primordial follicle activation and developing follicle atresia. ► BaP causes oocyte mitochondrial ROS and lipid peroxidation, impairing fertilisation. ► Short term neonatal BaP exposure compromises adult oocyte quality.

  18. Chronic dietary chlorpyrifos causes long-term spatial memory impairment and thigmotaxic behavior.

    Science.gov (United States)

    López-Granero, Caridad; Ruiz-Muñoz, Ana M; Nieto-Escámez, Francisco A; Colomina, María T; Aschner, Michael; Sánchez-Santed, Fernando

    2016-03-01

    Little is known about the long-term effects of chronic exposure to low-level organophosphate (OP) pesticides, and the role of neurotransmitter systems, other than the cholinergic system, in mediating OP neurotoxicity. In this study, rats were administered 5mg/kg/day of chlorpyrifos (CPF) for 6 months commencing at 3-months-of-age. The animals were examined 7 months later (at 16-months-of-age) for spatial learning and memory in the Morris water maze (MWM) and locomotor activity. In addition, we assessed the chronic effects of CPF on glutamatergic and gamma-aminobutyric acid (GABAergic) function using pharmacological challenges with dizocilpine (MK801) and diazepam. Impaired performance related to altered search patterns, including thigmotaxis and long-term spatial memory was noted in the MWM in animals exposed to CPF, pointing to dietary CPF-induced behavioral disturbances, such as anxiety. Twenty-four hours after the 31st session of repeated acquisition task, 0.1mg/kg MK801, an N-methyl-d-aspartate (NMDA) antagonist was intraperitoneally (i.p.) injected for 4 consecutive days. Decreased latencies in the MWM in the control group were noted after two sessions with MK801 treatment. Once the MWM assessment was completed, animals were administered 0.1 or 0.2mg/kg of MK801 and 1 or 3mg/kg of diazepam i.p., and tested for locomotor activity. Both groups, the CPF dietary and control, displayed analogous performance in motor activity. In conclusion, our data point to a connection between the long-term spatial memory, thigmotaxic response and CPF long after the exposure ended. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Meningioma Causing Visual Impairment: Outcomes and Toxicity After Intensity Modulated Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Maclean, Jillian, E-mail: jillian.maclean@uclh.nhs.uk [Radiotherapy Department, University College London Hospital, London (United Kingdom); Fersht, Naomi [Radiotherapy Department, University College London Hospital, London (United Kingdom); Bremner, Fion [Neuro-Ophthalmology Department, National Hospital for Neurology and Neurosurgery, London (United Kingdom); Stacey, Chris; Sivabalasingham, Suganya [Radiotherapy Department, University College London Hospital, London (United Kingdom); Short, Susan [Radiotherapy Department, University College London Hospital, London (United Kingdom); Leeds Institute of Molecular Medicine, St James University Hospital, Leeds (United Kingdom)

    2013-03-15

    Purpose: To evaluate ophthalmologic outcomes and toxicity of intensity modulated radiation therapy (IMRT) in patients with meningiomas causing visual deficits. Methods and Materials: A prospective observational study with formal ophthalmologic and clinical assessment of 30 consecutive cases of meningioma affecting vision treated with IMRT from 2007 to 2011. Prescriptions were 50.4 Gy to mean target dose in 28 daily fractions. The median follow-up time was 28 months. Twenty-six meningiomas affected the anterior visual pathway (including 3 optic nerve sheath meningiomas); 4 were posterior to the chiasm. Results: Vision improved objectively in 12 patients (40%). Improvements were in visual field (5/16 patients), color vision (4/9 patients), acuity (1/15 patients), extraocular movements (3/11 patients), ptosis (1/5 patients), and proptosis (2/6 patients). No predictors of clinical response were found. Two patients had minor reductions in tumor dimensions on magnetic resonance imaging, 1 patient had radiological progression, and the other patients were stable. One patient experienced grade 2 keratitis, 1 patient had a minor visual field loss, and 5 patients had grade 1 dry eye. Conclusion: IMRT is an effective method for treating meningiomas causing ophthalmologic deficits, and toxicity is minimal. Thorough ophthalmologic assessment is important because clinical responses often occur in the absence of radiological change.

  20. Variants in TRIM44 Cause Aniridia by Impairing PAX6 Expression.

    Science.gov (United States)

    Zhang, Xibo; Qin, Gang; Chen, Guilan; Li, Tao; Gao, Linghan; Huang, Li; Zhang, Ying; Ouyang, Ke; Wang, Yuqi; Pang, Yu; Zeng, Bo; Yu, Ling

    2015-12-01

    Congenital aniridia is a genetic disorder that manifests as iris hypoplasia and other associated ocular complications. Mutations in the paired box 6 (PAX6) gene are considered the major cause of aniridia. In this study, we identified four mutations exclusively presented in aniridia patients from a four-generation Chinese pedigree, including two single nucleotide substitutions in the 3'UTR of PAX6 (NM_000280.4:c.[*76G>A; *2977C>A]) and two missense mutations in tripartite motif containing 44 (TRIM44, NM_017583.4:c.[191C>A; 463G>A]), which lead to amino acid changes p.S64Y and p.G155R, respectively. Bioinformatic analyses revealed that the two 3'UTR mutations of PAX6 disrupted microRNA binding motifs in the wildtype 3'UTR sequence. Luciferase reporter assay and Western blotting with predicted microRNAs showed that the two 3'UTR mutations could only increase or have no effect on the expression of PAX6. Therefore, they would not be the cause of aniridia that resulted from PAX6 deficiency. Instead, we found that overexpression of TRIM44 significantly reduced the expression of PAX6 in human lens epithelial cells, and the p.G155R mutant exhibited much stronger effect than the wildtype form. We conclude that inhibition of PAX6 expression by mutant TRIM44 is a novel pathogenic mechanism for aniridia. © 2015 WILEY PERIODICALS, INC.

  1. [Immunology of HCV infection: the causes of impaired cellular immune response and the effect of antiviral treatment].

    Science.gov (United States)

    Pár, Gabriella; Berki, Tímea; Pálinkás, László; Balogh, Péter; Szereday, László; Halász, Melinda; Szekeres-Barthó, Júlia; Miseta, Attila; Hegedus, Géza; Mózsik, Gyula; Hunyady, Béla; Pár, Alajos

    2006-04-02

    The outcome of HCV infection and the response to antiviral treatment depend on both viral and host factors. Host immune response contributes not only to viral control, clinical recovery and protective immunity, but also to chronic hepatitis and liver cirrhosis. Establishing immunological status and identifying pretreatment immunological factors associated with better response to therapy might be of importance in the understanding of the successful immune response and in the future of combination therapy to HCV infection. The authors delivered a review on the immunology of HCV infection and characterized the cause of impaired cellular immune response in chronic HCV infection. Natural killer (NK) cell activity, perforin and the inhibitory CD81 HCV co-receptor expression, and Th1/Th2 cytokine production of the monocytes and lymphocytes have been investigated. 42 patients with chronic hepatitis C, out of them 25 being on interferon (PEG-IFN) + ribavirin (RBV) therapy, 12 sustained virological responders, 26 HCV carriers with normal transaminase values and 22 healthy controls were studied. NK cell activity, perforin and CD81 expression, the IFNgamma, TNFalpha, IL-2 (Th1) and IL-4, IL-6, IL-10 (Th2) production of LPS stimulated monocytes and PMA + ionomycine stimulated lymphocytes were measured by flow-cytometry. In patients with chronic hepatitis C we demonstrated decreased NK cell activity associated with increased CD81 expression. The perforin expression of lymphocytes was also impaired in HCV patients. The pretreatment capacity of the macrophages to produce TNFalpha was predictive for sustained virological response. This increased TNFalpha production of the monocytes counteracted the observed impaired Th1 type cytokine production of the lymphocytes. IL-10 and IL-4 production showed positive correlation with HCV RNA levels, and negative correlation with histological activity index was noted. PEG-IFN + RBV treatment increased NK activity, perforin expression, Th1 type

  2. Neurochemical and electrical modulation of the Locus coeruleus: contribution to CO2 drive to breathe

    Directory of Open Access Journals (Sweden)

    Debora eDe Carvalho

    2014-08-01

    Full Text Available The Locus coeruleus (LC is a dorsal pontine region, situated bilaterally on the floor of the fourth ventricle. It is considered to be the major source of noradrenergic innervation in the brain. These neurons are highly sensitive to CO2 / pH, and chemical lesions of LC neurons largely attenuate the hypercapnic ventilatory response in unanesthetized adult rats. Developmental dysfunctions in these neurons are linked to pathological conditions such as Rett and sudden infant death syndromes, which can impair the control of the cardio-respiratory system. LC is densely innervated by fibers that contain glutamate, serotonin and ATP, and these neurotransmitters strongly affect LC activity, including central chemoreflexes. Aside from neurochemical modulation, LC neurons are also strongly electrically coupled, specifically through gap junctions, which play a role in the CO2 ventilatory response. This article reviews the available data on the role of chemical and electrical neuromodulation of the LC in the control of ventilation.

  3. Neurochemical effects of extended exposure to white spirit vapour at three concentration levels.

    Science.gov (United States)

    Savolainen, H; Pfäffli, P

    1982-03-01

    Male Wistar rats were exposed to 575 (100 ppm), 2875 (500 ppm) or 5750 mg/m3 (1000 ppm) white spirit vapour for 4-17 weeks 5 days a week, 6 h daily. Perirenal fat solvent concentration corresponded in composition and concentration to those of the vapour at all times. The neurochemical effects included a dose-dependent decrease in the cerebellar succinate dehydrogenase activity for 8 weeks while creatine kinase activity increased after 12 weeks. The specific creatine kinase activity in the glial cell fraction, a marker for astroglia, did not increase suggesting proliferation of astroglial cells in the homogenate. The serum creatine kinase activity originating mainly from striated muscle was below the control range at the two higher concentrations after 12 weeks. Simultaneous analyses for isolated muscle membrane sialic acid and uronic acid residues showed decreased concentrations in proportion to lipid phosphorus or total membrane protein. Thus, the white spirit mixture has neurochemical effects possibly caused by paraffins and the same components may have caused the muscle cell membrane effects. The lowest exposure concentration represents a virtual 'no effect' level for rats in the 17-week exposure.

  4. Hydronephrosis causes salt-sensitive hypertension and impaired renal concentrating ability in mice

    DEFF Research Database (Denmark)

    Carlström, M; Sällström, J; Skøtt, O

    2007-01-01

    were measured telemetrically in adult animals on normal and high salt diets. Metabolism cages were used to study the renal excretion of electrolytes and water. Plasma samples for renin analysis were collected and renal histological changes were evaluated. RESULTS: All hydronephrotic animals developed...... salt-sensitive hypertension that correlated to the degree of hydronephrosis. In hydronephrotic animals, blood pressure increased from 114 +/- 1 mmHg on normal salt diet to 120 +/- 2 mmHg on high salt diet, compared with 103 +/- 1 to 104 +/- 1 in controls. Hydronephrotic animals showed increased......AIM: Hypertension is a common disease in the industrialized world and approximately 5% of all cases are secondary to kidney malfunction. We have recently shown that hydronephrosis due to partial unilateral ureteral obstruction (PUUO) causes salt-sensitive hypertension in rats. The mechanisms...

  5. Combined exposure to endocrine disrupting pesticides impairs parturition and causes pup mortality in rats

    DEFF Research Database (Denmark)

    Hansen, Pernille Reimer; Christiansen, Sofie; Boberg, Julie

    Risk assessment is currently based on the no observed adverse effect level (NOAELs) for single compounds. Humans are exposed to a mixture of chemicals and epidemiological studies have reported some associations between endocrine disrupting effects and combined exposure to certain pesticides....... Although laboratory animal studies have shown that some endocrine disrupting pesticides can affect reproduction and sexual differentiation, individual pesticides may appear to be present in human tissues at too low levels to cause concern for adverse reproductive effects. However, recent studies in our...... to five pesticides, i.e. procymidone, mancozeb, tebuconazole, epoxiconazole and prochloraz. Common features for the three azole fungicides are that they increase gestational length possibly because of an increase in progesterone levels in dams. Groups of 8 time-mated Wistar rats (HanTac:WH) were gavaged...

  6. Autoimmune encephalopathy associated with thyroid autoantibodies as the cause of reversible cognitive impairment

    Directory of Open Access Journals (Sweden)

    Robert Dobbin Chow

    2012-04-01

    Full Text Available We herewith describe a patient with acute confusion, expressive aphasia and generalized seizures. A through workup excluded most causes of encephalopathy. He was, however, found to have TSH = 18.6 MIU/ml, T3reverse = 0.44nmol/L, T4 = 0.8ng/dl and Anti-Thyroid-Peroxidase AB titer >1000 IU/ml. Based on the above findings the patient was diagnosed with Hashimoto's encephalopathy and his mental status showed dramatic improvement (MMS 30/30 with high dose prednisone. Hashimoto's encephalopathy is rare disorder of presumed autoimmune origin characterized by cognitive decline, seizures, neuro-psychiatric symptoms, high titers of Anti-Thyroid-Peroxidase AB, and a positive response to steroids.

  7. Homozygosity Mapping Reveals Mutations of GRXCR1 as a Cause of Autosomal-Recessive Nonsyndromic Hearing Impairment

    Science.gov (United States)

    Schraders, Margit; Lee, Kwanghyuk; Oostrik, Jaap; Huygen, Patrick L.M.; Ali, Ghazanfar; Hoefsloot, Lies H.; Veltman, Joris A.; Cremers, Frans P.M.; Basit, Sulman; Ansar, Muhammad; Cremers, Cor W.R.J.; Kunst, Henricus P.M.; Ahmad, Wasim; Admiraal, Ronald J.C.; Leal, Suzanne M.; Kremer, Hannie

    2010-01-01

    We identified overlapping homozygous regions within the DFNB25 locus in two Dutch and ten Pakistani families with sensorineural autosomal-recessive nonsyndromic hearing impairment (arNSHI). Only one of the families, W98-053, was not consanguineous, and its sibship pointed toward a reduced critical region of 0.9 Mb. This region contained the GRXCR1 gene, and the orthologous mouse gene was described to be mutated in the pirouette (pi) mutant with resulting hearing loss and circling behavior. Sequence analysis of the GRXCR1 gene in hearing-impaired family members revealed splice-site mutations in two Dutch families and a missense and nonsense mutation, respectively, in two Pakistani families. The splice-site mutations are predicted to cause frameshifts and premature stop codons. In family W98-053, this could be confirmed by cDNA analysis. GRXCR1 is predicted to contain a GRX-like domain. GRX domains are involved in reversible S-glutathionylation of proteins and thereby in the modulation of activity and/or localization of these proteins. The missense mutation is located in this domain, whereas the nonsense and splice-site mutations may result in complete or partial absence of the GRX-like domain or of the complete protein. Hearing loss in patients with GRXCR1 mutations is congenital and is moderate to profound. Progression of the hearing loss was observed in family W98-053. Vestibular dysfunction was observed in some but not all affected individuals. Quantitative analysis of GRXCR1 transcripts in fetal and adult human tissues revealed a preferential expression of the gene in fetal cochlea, which may explain the nonsyndromic nature of the hearing impairment. PMID:20137778

  8. Surgical incision-induced nociception causes cognitive impairment and reduction in synaptic NMDA receptor 2B in mice.

    Science.gov (United States)

    Zhang, Xiaoqin; Xin, Xin; Dong, Yuanlin; Zhang, Yiying; Yu, Buwei; Mao, Jianren; Xie, Zhongcong

    2013-11-06

    Postoperative cognitive dysfunction (POCD) is associated with impairments in daily functioning, and increased morbidity and mortality. However, the causes and neuropathogenesis of POCD remain largely unknown. Uncontrolled pain often occurs postoperatively. We therefore set out to determine the effects of surgical incision-induced nociception on the cognitive function and its underlying mechanisms in 3- and 9-month-old mice. The mice had surgical incision in the hindpaw and then were tested for nociceptive threshold, learning, and memory. Brain levels of NMDA receptor and cyclin-dependent kinase 5 (CDK5) were also assessed. We found that surgical incision-induced nociception in mice led to a decreased freezing time in the tone test (which assesses the hippocampus-independent learning and memory function), but not the context test, of Fear Conditioning System at 3 and 7 d, but not 30 d post incision in 9-month-old, but not 3-month-old mice. Consistently, the surgical incision selectively decreased synaptic NMDA receptor 2B levels in the medial prefrontal cortex, and increased levels of tumor necrosis factor-α and CDK5 in the cortex, but not hippocampus, of the mice. Finally, eutectic mixture of local anesthetics and CDK5 inhibitor, roscovitine, attenuated the surgical incision-induced reduction in the synaptic NMDA receptor 2B levels and learning impairment. These results suggested that surgical incision-induced nociception reduced the synaptic NMDA receptor 2B level in the medial prefrontal cortex of mice, which might lead to hippocampus-independent learning impairment, contributing to POCD. These findings call for further investigation to determine the role of surgical incision-induced nociception in POCD.

  9. Endothelin-1-Rho kinase interactions impair lung structure and cause pulmonary hypertension after bleomycin exposure in neonatal rat pups.

    Science.gov (United States)

    Gien, Jason; Tseng, Nancy; Seedorf, Gregory; Kuhn, Katherine; Abman, Steven H

    2016-12-01

    Bronchopulmonary dysplasia (BPD) is the chronic lung disease associated with premature birth, characterized by impaired vascular and alveolar growth. In neonatal rats bleomycin decreases lung growth and causes pulmonary hypertension (PH), which is poorly responsive to nitric oxide. In the developing lung, through Rho kinase (ROCK) activation, ET-1 impairs endothelial cell function; however, whether ET-1-ROCK interactions contribute to impaired vascular and alveolar growth in experimental BPD is unknown. Neonatal rats were treated daily with intraperitoneal bleomycin with and without selective ET A (BQ123/BQ610) and ET B (BQ788) receptor blockers, nonselective ET receptor blocker (ETRB) (bosentan), or fasudil (ROCK inhibitor). At day 14, lungs were harvested for morphometrics, and measurements of Fulton's index (RV/LV+S), medial wall thickness (MWT), and vessel density. Lung ET-1 protein and ROCK activity (phospho-MYPT-1:total MYPT-1 ratio) were also measured by Western blot analysis. Bleomycin increased lung ET-1 protein expression by 65%, RV/LV+S by 60%, mean linear intercept (MLI) by 212%, and MWT by 140% and decreased radial alveolar count (RAC) and vessel density by 40 and 44%, respectively (P < 0.01 for each comparison). After bleomycin treatment, fasudil and bosentan partially restored RAC and vessel density and decreased MLI, RV/LV+S, and MWT to normal values. Bleomycin increased ROCK activity by 120%, which was restored to normal values by bosentan but not selective ETRB. We conclude that ET-1-ROCK interactions contribute to decreased alveolar and vascular growth and PH in experimental BPD. We speculate that nonselective ETRB and ROCK inhibitors may be effective in the treatment of infants with BPD and PH. Copyright © 2016 the American Physiological Society.

  10. Paradoxical Sleep Deprivation Causes Cardiac Dysfunction and the Impairment Is Attenuated by Resistance Training.

    Science.gov (United States)

    Giampá, Sara Quaglia de Campos; Mônico-Neto, Marcos; de Mello, Marco Tulio; Souza, Helton de Sá; Tufik, Sergio; Lee, Kil Sun; Koike, Marcia Kiyomi; Dos Santos, Alexandra Alberta; Antonio, Ednei Luiz; Serra, Andrey Jorge; Tucci, Paulo José Ferreira; Antunes, Hanna Karen Moreira

    2016-01-01

    Paradoxical sleep deprivation activates the sympathetic nervous system and the hypothalamus-pituitary-adrenal axis, subsequently interfering with the cardiovascular system. The beneficial effects of resistance training are related to hemodynamic, metabolic and hormonal homeostasis. We hypothesized that resistance training can prevent the cardiac remodeling and dysfunction caused by paradoxical sleep deprivation. Male Wistar rats were distributed into four groups: control (C), resistance training (RT), paradoxical sleep deprivation for 96 hours (PSD96) and both resistance training and sleep deprivation (RT/PSD96). Doppler echocardiograms, hemodynamics measurements, cardiac histomorphometry, hormonal profile and molecular analysis were evaluated. Compared to the C group, PSD96 group had a higher left ventricular systolic pressure, heart rate and left atrium index. In contrast, the left ventricle systolic area and the left ventricle cavity diameter were reduced in the PSD96 group. Hypertrophy and fibrosis were also observed. Along with these alterations, reduced levels of serum testosterone and insulin-like growth factor-1 (IGF-1), as well as increased corticosterone and angiotensin II, were observed in the PSD96 group. Prophylactic resistance training attenuated most of these changes, except angiotensin II, fibrosis, heart rate and concentric remodeling of left ventricle, confirmed by the increased of NFATc3 and GATA-4, proteins involved in the pathologic cardiac hypertrophy pathway. Resistance training effectively attenuates cardiac dysfunction and hormonal imbalance induced by paradoxical sleep deprivation.

  11. Impaired plant growth and development caused by human immunodeficiency virus type 1 Tat.

    Science.gov (United States)

    Cueno, Marni E; Hibi, Yurina; Imai, Kenichi; Laurena, Antonio C; Okamoto, Takashi

    2010-10-01

    Previous attempts to express the human immunodeficiency virus 1 (HIV-1) Tat (trans-activator of transcription) protein in plants resulted in a number of physiological abnormalities, such as stunted growth and absence of seed formation, that could not be explained. In the study reported here, we expressed Tat in tomato and observed phenotypic abnormalities, including stunted growth, absence of root formation, chlorosis, and plant death, as a result of reduced cytokinin levels. These reduced levels were ascribed to a differentially expressed CKO35 in Tat-bombarded tomato. Of the two CKO isoforms that are naturally expressed in tomato, CKO43 and CKO37, only the expression of CKO37 was affected by Tat. Our analysis of the Tat confirmed that the Arg-rich and RGD motifs of Tat have functional relevance in tomato and that independent mutations at these motifs caused inhibition of the differentially expressed CKO isoform and the extracellular secretion of the Tat protein, respectively, in our Tat-bombarded tomato samples.

  12. Effects of L-carnitine and coenzyme q10 on impaired spermatogenesis caused by isoproterenol in male rats.

    Science.gov (United States)

    Ghanbarzadeh, S; Garjani, A; Ziaee, M; Khorrami, A

    2014-09-01

    Nowadays, cardiovascular diseases and male infertility are two big health problems in industrial countries.The aim of the present study was to investigate the protective role of coenzyme Q10 and L-Carnitine pretreatment in the impaired spermatogenesis caused by isoproterenol (ISO) in male rats.Thirty-two male Wistar rats were allocated in 4 groups. ISO was injected for 2 consecutive days (100 mg/kg) in ISO treated groups. Before ISO administration, pretreatment with Coenzyme Q10 (10 mg/kg/day) and L-Carnitine (350 mg/kg/day) were conducted for 20 consecutive days. Sex hormones level, malondialdehyde (MDA) and total antioxidant concentration as well as testis, epididymis and seminal vesicle weight were investigated.Increase in the concentration of MDA and decrease in total antioxidant level was observed following ISO administration. Accordingly, the sperm viability as well as testis, epididymis and seminal vesicle weights were decreased. In the case of sex hormones, the testosterone and LH levels were decreased and the concentration of FSH was increased. Pretreatment with L-carnitine and Coenzyme Q10 significantly decreased the MDA level and increased total antioxidant, LH and testosterone levels. Pretreatment with L-carnitine and Coenzyme Q10 also improved semen parameters and organs weight which were impaired by ISO administration.L-carnitine and Coenzyme Q10 pretreatment could protect spermatogenesis in male rats with ISO administration. © Georg Thieme Verlag KG Stuttgart · New York.

  13. [Possibilities for prevention and treatment of blindness and impaired vision in children caused by congenital eye diseases].

    Science.gov (United States)

    Neroev, V V; Khvatova, A V

    2007-01-01

    Blindness, disability, and impaired vision present important medicosocial problems. According to the WHO, there are 1.5 million blind children in the world. The prevalence of child blindness in Russia is 1.6, and that of impaired vision is 3.5 per 10000 children. It is considered that child blindness can be prevented in 40 to 50% of children. According to data collected during ophthalmological examinations in specialized school, blindness in 88 to 92% of cases is caused by. Presently, significant achievements have been made in treatment of congenital eye diseases. Application of modem surgical techniques in patients with cataract, aphakia, or amblyopia makes it possible to increase visual acuity to 0.3 or higher in 35% of children, and to 0.005 to 0.25 in 45% of children. Modem pathogenetically directed surgery together with timely treatment allows for the normalization of intraocular pressure and visual stabilization in 76.4 to 86.4% of children with congenital glaucoma. In this connection, the achievements of scientific research should be introduced into practice. Realization of the 1999 WHO program on liquidation of eliminable blindness include three key directions: treatment and prevention of blindness; consolidation of the infrastructure and technology of ophthalmological aid; training of specialists.

  14. The mental health of UK ex-servicemen with a combat-related or a non-combat-related visual impairment: does the cause of visual impairment matter?

    Science.gov (United States)

    Stevelink, Sharon A M; Malcolm, Estelle M; Gill, Pashyca C; Fear, Nicola T

    2015-08-01

    Since the start of the conflicts in Iraq and Afghanistan, the numbers of young service personnel who have sustained a combat-related visual impairment have increased. This cross-sectional study examined the mental well-being of ex-servicemen (aged 22-55 years) with a visual impairment and determined if the mental health of those with a combat-related visual impairment differed from those whose visual impairment is not combat-related. Male ex-service personnel with a visual impairment completed a telephone interview assessing the presence of depressive symptomatology, probable anxiety disorder, post-traumatic stress disorder (PTSD) symptomatology and alcohol misuse. Data were analysed using descriptive statistics. 77 participants were included in the study, reflecting a response rate of 76.2%. Of those with complete data (n=74), 20 ex-servicemen had a combat-related visual impairment. Among ex-service personnel with a combat-related visual impairment, 10.0% (95% CI 0 to 23.2) screened positive for a probable depression, 25.0% (95% CI 6.0 to 44.0) for probable anxiety and 10.0% (95% CI 0 to 23.2) for probable PTSD. The prevalence of probable depression and probable PTSD differed among those with a non-combat-related visual impairment, namely 18.5% (95% CI 8.1 to 28.9) and 16.7% (95% CI 6.8 to 26.7), respectively. Probable anxiety was 18.5% (95% CI 8.1 to 28.9) among non-combat-related visually impaired ex-service personnel. 45.0% (95% CI 23.2 to 66.8) of combat-related visually impaired personnel reported hazardous drinking, compared with 20.4% (95% CI 9.7 to 31.2) of those with a non-combat-related visual impairment. Mental health problems were prevalent among visually impaired younger ex-servicemen. No statistically significant differences were found in the prevalence of mental health problems among ex-servicemen with a combat-related visual impairment compared with those with a non-combat-related visual impairment. Published by the BMJ Publishing Group Limited

  15. Hearing impairment in Estonia: an algorithm to investigate genetic causes in pediatric patients.

    Science.gov (United States)

    Teek, R; Kruustük, K; Žordania, R; Joost, K; Kahre, T; Tõnisson, N; Nelis, M; Zilina, O; Tranebjaerg, L; Reimand, T; Ounap, K

    2013-01-01

    The present study was initiated to establish the etiological causes of early onset hearing loss (HL) among Estonian children between 2000-2009. The study group consisted of 233 probands who were first tested with an arrayed primer extension assay, which covers 199 mutations in 7 genes (GJB2, GJB6, GJB3, SLC26A4, SLC26A5 genes, and two mitochondrial genes - 12S rRNA, tRNASer(UCN)). From probands whose etiology of HL remained unknown, DNA analysis of congenital cytomegalovirus (CMV) infection and G-banded karyotype and/or chromosomal microarray analysis (CMA) were performed. In 110 (47%) cases, the etiology of HL was genetic and in 5 (2%) congenital CMV infection was diagnosed. We found mutations with clinical significance in GJB2 (100 children, 43%) and in 2 mitochondrial genes (2 patients, 1%). A single mutation in SLC26A4 gene was detected in 5 probands (2.2%) and was considered diagnostic. In 4 probands a heterozygous IVS2-2A>G change in the SLC26A5 gene was found. We did not find any instances of homozygosity for this splice variant in the probands. CMA identified in 4 probands chromosomal regions with the loss of one allele. In 2 of them we were able to conclude that the found abnormalities are definitely pathogenic (12q13.3-q14.2 and 17q22-23.2 microdeletion), but the pathogenity of 2 other findings (3p26.2 and 1p33 microdeletion) remained unknown. This practical diagnostic algorithm confirmed the etiology of early onset HL for 115 Estonian patients (49%). This algorithm may be generalized to other populations for clinical application.

  16. Axonal transport of TDP-43 mRNA granules in neurons is impaired by ALS-causing mutations

    Science.gov (United States)

    Carrasco, Monica A.; Williams, Luis A.; Winborn, Christina S.; Han, Steve S. W.; Kiskinis, Evangelos; Winborn, Brett; Freibaum, Brian D.; Kanagaraj, Anderson; Clare, Alison J.; Badders, Nisha M.; Bilican, Bilada; Chaum, Edward; Chandran, Siddharthan; Shaw, Christopher E.; Eggan, Kevin C.; Maniatis, Tom; Taylor, J. Paul

    2014-01-01

    Summary The RNA binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43. PMID:24507191

  17. GATA2 germline mutations impair GATA2 transcription, causing haploinsufficiency: functional analysis of the p.Arg396Gln mutation.

    Science.gov (United States)

    Cortés-Lavaud, Xabier; Landecho, Manuel F; Maicas, Miren; Urquiza, Leire; Merino, Juana; Moreno-Miralles, Isabel; Odero, María D

    2015-03-01

    Germline GATA2 mutations have been identified as the cause of familial syndromes with immunodeficiency and predisposition to myeloid malignancies. GATA2 mutations appear to cause loss of function of the mutated allele leading to haploinsufficiency; however, this postulate has not been experimentally validated as the basis of these syndromes. We hypothesized that mutations that are translated into abnormal proteins could affect the transcription of GATA2, triggering GATA2 deficiency. Chromatin immunoprecipitation and luciferase assays showed that the human GATA2 protein activates its own transcription through a specific region located at -2.4 kb, whereas the p.Thr354Met, p.Thr355del, and p.Arg396Gln germline mutations impair GATA2 promoter activation. Accordingly, GATA2 expression was decreased to ∼58% in a patient with p.Arg396Gln, compared with controls. p.Arg396Gln is the second most common mutation in these syndromes, and no previous functional analyses have been performed. We therefore analyzed p.Arg396Gln. Our data show that p.Arg396Gln is a loss-of-function mutation affecting DNA-binding ability and, as a consequence, it fails to maintain the immature characteristics of hematopoietic stem and progenitor cells, which could result in defects in this cell compartment. In conclusion, we show that human GATA2 binds to its own promoter, activating its transcription, and that the aforementioned mutations impair the transcription of GATA2. Our results indicate that they can affect other GATA2 target genes, which could partially explain the variability of symptoms in these diseases. Moreover, we show that p.Arg396Gln is a loss-of-function mutation, which is unable to retain the progenitor phenotype in cells where it is expressed. Copyright © 2015 by The American Association of Immunologists, Inc.

  18. Inertial sensor based gait analysis discriminates subjects with and without visual impairment caused by simulated macular degeneration.

    Science.gov (United States)

    Kanzler, Christoph M; Barth, Jens; Klucken, Jochen; Eskofier, Bjoern M

    2016-08-01

    Macular degeneration is the third leading cause of blindness worldwide and the leading cause of blindness in the developing world. The analysis of gait parameters can be used to assess the influence of macular degeneration on gait. This study examines the effect of macular degeneration on gait using inertial sensor based 3D spatio-temporal gait parameters. We acquired gait data from 21 young and healthy subjects during a 40 m obstacle walk. All subjects had to perform the gait trial with and without macular degeneration simulation glasses. The order of starting with or without glasses alternated between each subject in order to test for training effects. Multiple 3D spatio-temporal gait parameters were calculated for the normal vision as well as the impaired vision groups. The parameters trial time, stride time, stride time coefficient of variation (CV), stance time, stance time CV, stride length, cadence, gait velocity and angle at toe off showed statistically significant differences between the two groups. Training effects were visible for the trials which started without vision impairment. Inter-group differences in the gait pattern occurred due to an increased sense of insecurity related with the loss of visual acuity from the simulation glasses. In summary, we showed that 3D spatio-temporal gait parameters derived from inertial sensor data are viable to detect differences in the gait pattern of subjects with and without a macular degeneration simulation. We believe that this study provides the basis for an in-depth analysis regarding the impact of macular degeneration on gait.

  19. Life quality impairment caused by hookworm-related cutaneous larva migrans in resource-poor communities in Manaus, Brazil.

    Directory of Open Access Journals (Sweden)

    Angela Schuster

    2011-11-01

    Full Text Available BACKGROUND: Hookworm-related cutaneous larva migrans (CLM is a common but neglected tropical skin disease caused by the migration of animal hookworm larvae in the epidermis. The disease causes intense pruritus and is associated with important morbidity. The extent to which CLM impairs skin disease-associated life quality has never been studied. METHODS: A modified version of the Dermatology Life Quality Index (mDLQI was used to determine skin disease-associated life quality in 91 adult and child patients with CLM, living in resource-poor communities in Manaus, Brazil. Symptoms and signs were documented and skin disease-associated life quality was semi-quantitatively assessed using mDLQI scores. The assessment was repeated two and four weeks after treatment with ivermectin. RESULTS: Ninety-one point five percent of the study participants showed a considerable reduction of skin disease-associated life quality at the time of diagnosis. The degree of impairment correlated with the intensity of infection (rho = 0.76, p<0.001, the number of body areas affected (rho = 0.30; p = 0.004, and the presence of lesions on visible areas of the skin (p = 0.002. Intense pruritus, sleep disturbance (due to itching and the feeling of shame were the most frequent skin disease-associated life quality restrictions (reported by 93.4%, 73.6%, and 64.8% of the patients, respectively. No differences were observed in skin disease-associated life quality restriction between boys and girls or men and women. Two weeks after treatment with ivermectin, skin disease-associated life quality improved significantly. After four weeks, 73.3% of the patients considered their disease-associated life quality to have returned to normal. CONCLUSIONS: CLM significantly impaired the skin disease-associated life quality in child and adult patients living in urban slums in North Brazil. After treatment with ivermectin, life quality normalised rapidly.

  20. Neurochemical organization of the nucleus paramedianus dorsalis in the human

    OpenAIRE

    Baizer, Joan S.; Baker, James F.; Haas, Kristin; Lima, Raquel

    2007-01-01

    We have characterized the neurochemical organization of a small brainstem nucleus in the human brain, the nucleus paramedianus dorsalis (PMD). PMD is located adjacent and medial to the nucleus prepositus hypoglossi (PH) in the dorsal medulla, and is distinguished by the pattern of immunoreactivity of cells and fibers to several markers including calcium-binding proteins, a synthetic enzyme for nitric oxide (neuronal nitric oxide synthase, nNOS) and a nonphosphorylated neurofilament protein (a...

  1. Prevalence and causes of severe visual impairment and blindness among children in the lorestan province of iran, using the key informant method.

    Science.gov (United States)

    Razavi, Hessom; Kuper, Hannah; Rezvan, Farhad; Amelie, Khatere; Mahboobi-Pur, Hassan; Oladi, Mohammad Reza; Muhit, Mohammad; Hashemi, Hassan

    2010-03-01

    To estimate the prevalence and causes of severe visual impairment and blindness among children in Lorestan province of Iran, and to assess the feasibility of the Key Informant Method in this setting. Potential cases were identified using the Key Informant Method, in 3 counties of Lorestan province during June through August 2008, and referred for examination. Causes of severe visual impairment/blindness were determined and categorized using standard World Health Organization methods. Of 123 children referred for examination, 27 children were confirmed to have severe visual impairment/blindness or blindness. The median age was11 years (interquartile range 6-13), and 59% were girls. After adjusting for non-attenders, the estimated prevalence of severe visual impairment/blindness was 0.04% (0.03-0.05). The main site of abnormality was retina (44%), followed by disorders of the whole eye (33%). The majority of causes had a hereditary etiology (70%), which was associated with a family history of blindness (P = 0.002). Potentially avoidable causes of severe visual impairment/blindness were found in 14 children (52%). Almost all children with severe visual impairment/blindness had a history of parental consanguinity (93%). Our findings suggest a moderate prevalence of childhood blindness in the Lorestan province of Iran, a high proportion of which may be avoidable, given improved access to ophthalmic and genetic counselling services in rural areas. The Key Informant Method is feasible in Iran; future research is discussed.

  2. Behavioral metabolomics analysis identifies novel neurochemical signatures in methamphetamine sensitization.

    Science.gov (United States)

    Adkins, D E; McClay, J L; Vunck, S A; Batman, A M; Vann, R E; Clark, S L; Souza, R P; Crowley, J J; Sullivan, P F; van den Oord, E J C G; Beardsley, P M

    2013-11-01

    Behavioral sensitization has been widely studied in animal models and is theorized to reflect neural modifications associated with human psychostimulant addiction. While the mesolimbic dopaminergic pathway is known to play a role, the neurochemical mechanisms underlying behavioral sensitization remain incompletely understood. In this study, we conducted the first metabolomics analysis to globally characterize neurochemical differences associated with behavioral sensitization. Methamphetamine (MA)-induced sensitization measures were generated by statistically modeling longitudinal activity data for eight inbred strains of mice. Subsequent to behavioral testing, nontargeted liquid and gas chromatography-mass spectrometry profiling was performed on 48 brain samples, yielding 301 metabolite levels per sample after quality control. Association testing between metabolite levels and three primary dimensions of behavioral sensitization (total distance, stereotypy and margin time) showed four robust, significant associations at a stringent metabolome-wide significance threshold (false discovery rate, FDR biomarkers, and developing more comprehensive neurochemical models, of psychostimulant sensitization. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  3. Linking Essential Tremor to the Cerebellum: Neurochemical Evidence.

    Science.gov (United States)

    Marin-Lahoz, Juan; Gironell, Alexandre

    2016-06-01

    The pathophysiology and the exact anatomy of essential tremor (ET) is not well known. One of the pillars that support the cerebellum as the main anatomical locus in ET is neurochemistry. This review examines the link between neurochemical abnormalities found in ET and cerebellum. The review is based on published data about neurochemical abnormalities described in ET both in human and in animal studies. We try to link those findings with cerebellum. γ-aminobutyric acid (GABA) is the main neurotransmitter involved in the pathophysiology of ET. There are several studies about GABA that clearly points to a main role of the cerebellum. There are few data about other neurochemical abnormalities in ET. These include studies with noradrenaline, glutamate, adenosine, proteins, and T-type calcium channels. One single study reveals high levels of noradrenaline in the cerebellar cortex. Another study about serotonin neurotransmitter results negative for cerebellum involvement. Finally, studies on T-type calcium channels yield positive results linking the rhythmicity of ET and cerebellum. Neurochemistry supports the cerebellum as the main anatomical locus in ET. The main neurotransmitter involved is GABA, and the GABA hypothesis remains the most robust pathophysiological theory of ET to date. However, this hypothesis does not rule out other mechanisms and may be seen as the main scaffold to support findings in other systems. We clearly need to perform more studies about neurochemistry in ET to better understand the relations among the diverse systems implied in ET. This is mandatory to develop more effective pharmacological therapies.

  4. Age-Related Neurochemical Changes in the Vestibular Nuclei

    OpenAIRE

    Paul eSmith

    2016-01-01

    There is evidence that the normal aging process is associated with impaired vestibulo-ocular reflexes (VOR) and vestibulo-spinal reflexes, causing reduced visual acuity and postural instability. Nonetheless, the available evidence is not entirely consistent, especially with respect to the VOR. Some recent studies have reported that VOR gain can be intact even above 80 years of age. Similarly, although there is evidence for age-related hair cell loss and neuronal loss in Scarpa’s ganglion and ...

  5. Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis.

    Science.gov (United States)

    Syx, Delfien; Van Damme, Tim; Symoens, Sofie; Maiburg, Merel C; van de Laar, Ingrid; Morton, Jenny; Suri, Mohnish; Del Campo, Miguel; Hausser, Ingrid; Hermanns-Lê, Trinh; De Paepe, Anne; Malfait, Fransiska

    2015-05-01

    Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. Recently, the identification of bi-allelic variants in DSE, encoding dermatan sulfate epimerase-1 (DS-epi1), in a child with MC-EDS features, suggested locus heterogeneity for this condition. DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC-EDS caused by unique homozygous CHST14 variants and the second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype. The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1- as well as DS-epi1-deficient patients. However, in D4ST1-deficiency, the decorin GAG is completely replaced by CS, whereas in DS-epi1-deficiency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation, and connective tissue integrity. © 2015 WILEY PERIODICALS, INC.

  6. Hepatitis B virus infection status and infertility causes in couples seeking fertility treatment-Indicator of impaired immune response?

    Science.gov (United States)

    Lao, Terence T; Mak, Jennifer S M; Li, Tin-Chiu

    2017-04-01

    The relationship between hepatitis B (HBV) infection in infertile couples seeking in vitro fertilization (IVF) treatment and infertility causes is unknown. A total of 831 infertile couples attending our unit seeking IVF during January to December 2015 were recruited. HBV infection was found in 6.3% and 7.3% of female and male partners, respectively, and infection in one or both partners was associated with less primary infertility (44.2% vs 55.1%, P=.038). Infected female partners had increased tubal (69.2% vs 43.2%, Pinfertility, while infected male partners were associated with increased tubal (62.3% vs 43.4%, P=.004) causes and reduced endometriosis (62.3% vs 73.9%, P=.050). Our results suggest HBV infection in either partner was associated with tubal infertility. HBV infection in either partner probably increases the risk of pelvic infection in female partner through impaired immune response to sexually transmitted infections, with consequent tubal damage and infertility. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Effects of Gladiolus dalenii on the Stress-Induced Behavioral, Neurochemical, and Reproductive Changes in Rats

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    David Fotsing

    2017-09-01

    Full Text Available Gladiolus dalenii is a plant commonly used in many regions of Cameroon as a cure for various diseases like headaches, epilepsy, schizophrenia, and mood disorders. Recent studies have revealed that the aqueous extract of G. dalenii (AEGD exhibited antidepressant-like properties in rats. Therefore, we hypothesized that the AEGD could protect from the stress-induced behavioral, neurochemical, and reproductive changes in rats. The objective of the present study was to elucidate the effect of the AEGD on behavioral, neurochemical, and reproductive characteristics, using female rats subjected to chronic immobilization stress. The chronic immobilization stress (3 h per day for 28 days was applied to induce female reproductive and behavioral impairments in rats. The immobilization stress was provoked in rats by putting them separately inside cylindrical restrainers with ventilated doors at ambient temperature. The plant extract was given to rats orally everyday during 28 days, 5 min before induction of stress. On a daily basis, a vaginal smear was made to assess the duration of the different phases of the estrous cycle and at the end of the 28 days of chronic immobilization stress, the rat’s behavior was assessed in the elevated plus maze. They were sacrificed by cervical disruption. The organs were weighed, the ovary histology done, and the biochemical parameters assessed. The findings of this research revealed that G. dalenii increased the entries and the time of open arm exploration in the elevated plus maze. Evaluation of the biochemical parameters levels indicated that there was a significant reduction in the corticosterone, progesterone, and prolactin levels in the G. dalenii aqueous extract treated rats compared to stressed rats whereas the levels of serotonin, triglycerides, adrenaline, cholesterol, glucose estradiol, follicle stimulating hormone and luteinizing hormone were significantly increased in the stressed rats treated with, G. dalenii

  8. COL4A2 Mutations Impair COL4A1 and COL4A2 Secretion and Cause Hemorrhagic Stroke

    Science.gov (United States)

    Jeanne, Marion; Labelle-Dumais, Cassandre; Jorgensen, Jeff; Kauffman, W. Berkeley; Mancini, Grazia M.; Favor, Jack; Valant, Valerie; Greenberg, Steven M.; Rosand, Jonathan; Gould, Douglas B.

    2012-01-01

    Collagen, type IV, alpha 1 (COL4A1) and alpha 2 (COL4A2) form heterotrimers and are abundant components of basement membranes, including those of the cerebral vasculature. COL4A1 mutations are an increasingly recognized cause of multisystem disorders, including highly penetrant cerebrovascular disease and intracerebral hemorrhage (ICH). Because COL4A1 and COL4A2 are structurally and functionally associated, we hypothesized that variants in COL4A2 would also cause ICH. We sequence COL4A2 in 96 patients with ICH and identify three rare, nonsynonymous coding variants in four patients that are not present in a cohort of 144 ICH-free individuals. All three variants change evolutionarily conserved amino acids. Using a cellular assay, we show that these putative mutations cause intracellular accumulation of COL4A1 and COL4A2 at the expense of their secretion, which supports their pathogenecity. Furthermore, we show that Col4a2 mutant mice also have completely penetrant ICH and that mutations in mouse and human lead to retention of COL4A1 and COL4A2 within the endoplasmic reticulum (ER). Importantly, two of the three putative mutations found in patients trigger ER stress and activate the unfolded protein response. The identification of putative COL4A2 mutations that might contribute to ICH in human patients provides insight into the pathogenic mechanisms of this disease. Our data suggest that COL4A2 mutations impair COL4A1 and COL4A2 secretion and can also result in cytotoxicity. Finally, our findings suggest that, collectively, mutations in COL4A1 and COL4A2 contribute to sporadic cases of ICH. PMID:22209247

  9. Prevalence and Causes of Visual Impairment and Blindness in Chinese American Adults: The Chinese American Eye Study.

    Science.gov (United States)

    Varma, Rohit; Kim, Jeniffer S; Burkemper, Bruce S; Wen, Ge; Torres, Mina; Hsu, Chunyi; Choudhury, Farzana; Azen, Stanley P; McKean-Cowdin, Roberta

    2016-07-01

    Visual impairment (VI) and blindness continue to be major public health problems worldwide. Despite previously published studies on VI in Chinese and other racial/ethnic populations, there are no data specific to Chinese American adults. To determine the age- and sex-specific prevalence and causes of VI and blindness in adult Chinese Americans and to compare the prevalence to other racial/ethnic groups. In this population-based, cross-sectional study of 10 US Census tracts in the city of Monterey Park, California, 4582 Chinese American adults 50 years and older underwent complete ophthalmologic examinations, including measurement of presenting and best-corrected visual acuity (BCVA) for distance using the Early Treatment Diabetic Retinopathy Study protocol from February 1, 2010, through October 31, 2013. Age-specific prevalence and causes of VI and blindness for presenting and BCVA. Of the 5782 eligible adults, 4582 (79.2%) completed an in-clinic eye examination. Of the 4582 participants, most were born in China (3149 [68.7%]), female (2901 [63.3%]), and married (3458 [75.5%]). The mean (SD) age was 61 (9) years. The prevalence of presenting VI was 3.0% (95% CI, 2.5%-3.5%), with 60.0% of this prevalence being attributed to uncorrected refractive error. The overall age-adjusted prevalence for VI (BCVA of ≤20/40 in the better eye) was 1.2% (95% CI, 0.9%-1.5%). The overall age-adjusted prevalence of blindness (BCVA of ≤20/200 in the better-seeing eye) was 0.07% (95% CI, 0%-0.2%). The prevalence of VI and blindness was higher in older Chinese Americans compared with younger. The primary causes of VI were cataracts and myopic retinopathy; the primary cause of blindness was myopic retinopathy. The prevalence of VI in Chinese Americans is similar to that of non-Hispanic white and Latino individuals in the United States and similar to or lower than the prevalence previously reported for Chinese adults from non-US studies. The prevalence of blindness is lower than that

  10. [Diving: barometric pressure and neurochemical mechanisms].

    Science.gov (United States)

    Rostain, Jean-Claude; Balon, Norbert

    2006-01-01

    The studies of Paul Bert, presented in his book "La Pression Barométrique" in 1878, were at the origin of the modern hyperbaric physiology. Indeed his research demonstrated the effects of oxygen at high pressure, that compression effects must be dissociated from decompression effects, and that neurological troubles and death of divers during or after decompression were due to the fast rate of decompression. However, it is only in 1935 that the work of Behnke et al. attributed the complaints reported at 3 bars and above in compressed air or nitrogen-oxygen mixture to the increase in partial pressure of nitrogen which induces nitrogen narcosis. Little is known about the origins and mechanisms of this narcosis. The traditional view was that anaesthesia or narcosis occurred when the volume of a hydrophobic membrane site was caused to expand beyond a critical amount by the absorption of molecules of a narcotic gas. The observation of the pressure reversal effect during general anaesthesia has long supported this lipid theory. However, recently, protein theories have met with increasing recognition since results with gaseous anaesthetics have been interpreted as evidence for a direct gas-protein interaction. The question is to know whether inert gases, that disrupt dopamine and GABA neurotransmissions and probably glutamatergic neurotransmission, act by binding to neurotransmitter protein receptors.

  11. Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts.

    Science.gov (United States)

    Ye, Hong; Jeong, Suh Young; Ghosh, Manik C; Kovtunovych, Gennadiy; Silvestri, Laura; Ortillo, Danilo; Uchida, Naoya; Tisdale, John; Camaschella, Clara; Rouault, Tracey A

    2010-05-01

    Glutaredoxin 5 (GLRX5) deficiency has previously been identified as a cause of anemia in a zebrafish model and of sideroblastic anemia in a human patient. Here we report that GLRX5 is essential for iron-sulfur cluster biosynthesis and the maintenance of normal mitochondrial and cytosolic iron homeostasis in human cells. GLRX5, a mitochondrial protein that is highly expressed in erythroid cells, can homodimerize and assemble [2Fe-2S] in vitro. In GLRX5-deficient cells, [Fe-S] cluster biosynthesis was impaired, the iron-responsive element-binding (IRE-binding) activity of iron regulatory protein 1 (IRP1) was activated, and increased IRP2 levels, indicative of relative cytosolic iron depletion, were observed together with mitochondrial iron overload. Rescue of patient fibroblasts with the WT GLRX5 gene by transfection or viral transduction reversed a slow growth phenotype, reversed the mitochondrial iron overload, and increased aconitase activity. Decreased aminolevulinate delta, synthase 2 (ALAS2) levels attributable to IRP-mediated translational repression were observed in erythroid cells in which GLRX5 expression had been downregulated using siRNA along with marked reduction in ferrochelatase levels and increased ferroportin expression. Erythroblasts express both IRP-repressible ALAS2 and non-IRP-repressible ferroportin 1b. The unique combination of IRP targets likely accounts for the tissue-specific phenotype of human GLRX5 deficiency.

  12. Using the cre-lox recombination system to assess functional impairment caused by amino acid substitutions in yeast proteins

    Directory of Open Access Journals (Sweden)

    Shirley Renee L.

    2004-01-01

    Full Text Available A method was developed to assess the functional significance of a sequence motif in yeast Upf3p, a protein required for nonsense-mediated mRNA decay (NMD. The motif lies at the edge of the Upf3p-Upf2p interaction domain, but at the same time resembles the canonical leucine-rich nuclear export sequence (NES found in proteins that bind Crm1p exportin. To test the function of the putative NES, site-directed mutations that cause substitutions of conserved NES-A residues were first selected to identify hypermorphic alleles. Next, a portable Crm1p-binding NES from HIV-1 Rev protein that functions in yeast was fused en masse to the C-terminus of variant Upf3 proteins using loxP sites recognized by bacterial cre-recombinase. Finally, variant Upf3-Rev proteins that were functional in NMD were selected and examined for the types of amino acid substitutions present in NES-A. The mutational analysis revealed that amino acid substitutions in the Upf3 NES impair both nuclear export and the Upf2p-Upf3p interaction, both of which are required for Upf3p to function in NMD. The method described in this report could be modified for the genetic analysis of a variety of portable protein domains.

  13. Reduction of the cholesterol sensor SCAP in the brains of mice causes impaired synaptic transmission and altered cognitive function.

    Directory of Open Access Journals (Sweden)

    Ryo Suzuki

    Full Text Available The sterol sensor SCAP is a key regulator of SREBP-2, the major transcription factor controlling cholesterol synthesis. Recently, we showed that there is a global down-regulation of cholesterol synthetic genes, as well as SREBP-2, in the brains of diabetic mice, leading to a reduction of cholesterol synthesis. We now show that in mouse models of type 1 and type 2 diabetes, this is, in part, the result of a decrease of SCAP. Homozygous disruption of the Scap gene in the brains of mice causes perinatal lethality associated with microcephaly and gliosis. Mice with haploinsufficiency of Scap in the brain show a 60% reduction of SCAP protein and ~30% reduction in brain cholesterol synthesis, similar to what is observed in diabetic mice. This results in impaired synaptic transmission, as measured by decreased paired pulse facilitation and long-term potentiation, and is associated with behavioral and cognitive changes. Thus, reduction of SCAP and the consequent suppression of cholesterol synthesis in the brain may play an important role in the increased rates of cognitive decline and Alzheimer disease observed in diabetic states.

  14. Prevalence and causes of visual impairment and rate of wearing spectacles in schools for children of migrant workers in Shanghai, China.

    Science.gov (United States)

    He, Jiangnan; Lu, Lina; Zou, Haidong; He, Xiangui; Li, Qiangqiang; Wang, Weijie; Zhu, Jianfeng

    2014-12-22

    To assess the prevalence of visual impairment and rate of wearing spectacles in schools for children of migrant workers in Shanghai, China. Children from grade 1 to 5 in schools for children of migrant workers were randomly chosen for ocular examinations. All children were screened for uncorrected visual acuity and presenting visual acuity. After screening, the children whose uncorrected visual acuity was 20/40 or less received ocular motility evaluation, cycloplegic refraction/non-cycloplegic refraction, and external eye, anterior segment, media, and fundus examinations. A total of 9673 children were enumerated and 9512 (98.34%) participated in this study. The prevalence of uncorrected, presenting, and best-corrected visual acuity of 20/40 or worse in the better eye were 13.33%, 11.26%, and 0.63%, respectively. The rate of wearing spectacles of the children with visual impairment in one or both eyes was 15.50%. Of these, 26.05% were wearing spectacles with inaccurate prescriptions. Refractive error was a major cause of visual impairment, accounting for 89.48% of all the visual impairment causes. Other causes of visual impairment included amblyopia accounting for 10.12%; congenital cataract, 0.1%; congenital nystagmus, 0.1%; ocular prosthesis, 0.1%; macular degeneration, 0.05%; and opaque cornea, 0.05%. This is the first study of the prevalence and causes of visual impairment in schools for children of migrant workers in Shanghai, China. The visual impairment rate in schools for children of migrant workers in suburbs of Shanghai in the best eye before vision correction was lower than those of urban children in mainstream schools in Guangzhou in 2012, and higher than students in rural of Beijing in 1998 and in suburb of Chongqing in 2007. The refractive error was the principal cause of the visual impairment of the children of migrant workers. The rate of wearing spectacles was low and the percentage of inaccurate prescriptions, among those who wore spectacles, was

  15. Oxidation of KCNB1 Potassium Channels Causes Neurotoxicity and Cognitive Impairment in a Mouse Model of Traumatic Brain Injury.

    Science.gov (United States)

    Yu, Wei; Parakramaweera, Randika; Teng, Shavonne; Gowda, Manasa; Sharad, Yashsavi; Thakker-Varia, Smita; Alder, Janet; Sesti, Federico

    2016-10-26

    The delayed rectifier potassium (K + ) channel KCNB1 (Kv2.1), which conducts a major somatodendritic current in cortex and hippocampus, is known to undergo oxidation in the brain, but whether this can cause neurodegeneration and cognitive impairment is not known. Here, we used transgenic mice harboring human KCNB1 wild-type (Tg-WT) or a nonoxidable C73A mutant (Tg-C73A) in cortex and hippocampus to determine whether oxidized KCNB1 channels affect brain function. Animals were subjected to moderate traumatic brain injury (TBI), a condition characterized by extensive oxidative stress. Dasatinib, a Food and Drug Administration-approved inhibitor of Src tyrosine kinases, was used to impinge on the proapoptotic signaling pathway activated by oxidized KCNB1 channels. Thus, typical lesions of brain injury, namely, inflammation (astrocytosis), neurodegeneration, and cell death, were markedly reduced in Tg-C73A and dasatinib-treated non-Tg animals. Accordingly, Tg-C73A mice and non-Tg mice treated with dasatinib exhibited improved behavioral outcomes in motor (rotarod) and cognitive (Morris water maze) assays compared to controls. Moreover, the activity of Src kinases, along with oxidative stress, were significantly diminished in Tg-C73A brains. Together, these data demonstrate that oxidation of KCNB1 channels is a contributing mechanism to cellular and behavioral deficits in vertebrates and suggest a new therapeutic approach to TBI. This study provides the first experimental evidence that oxidation of a K + channel constitutes a mechanism of neuronal and cognitive impairment in vertebrates. Specifically, the interaction of KCNB1 channels with reactive oxygen species plays a major role in the etiology of mouse model of traumatic brain injury (TBI), a condition associated with extensive oxidative stress. In addition, a Food and Drug Administration-approved drug ameliorates the outcome of TBI in mouse, by directly impinging on the toxic pathway activated in response to

  16. Causes of severe visual impairment and blindness in children in schools for the blind in eastern Africa: changes in the last 14 years.

    Science.gov (United States)

    Njuguna, Margaret; Msukwa, Gerald; Shilio, Bernadeth; Tumwesigye, Cillasy; Courtright, Paul; Lewallen, Susan

    2009-01-01

    To determine the causes of severe visual impairment and blindness in children attending schools for the blind in Kenya, Malawi, Uganda, and Tanzania and to compare the findings with those of a 1994 study. Children attending schools for the blind or annexes in 4 eastern African countries were examined. The major anatomical site of and underlying etiology of severe visual impairment and blindness was recorded using the standardized World Health Organization (WHO) reporting form. A total of 1062 children aged below 16 years were examined of whom 701 (65.2%) had severe visual impairment or blindness. The major anatomical sites of visual loss overall (% and 95% CI) were cornea scar/phthisis bulbi (19%,16.1-21.9), whole globe lesions (15.7%,13.0-18.4), retina (15.4 %, 12.7-18.1), lens related disorders (13.1%, 10.7-15.5), and optic nerve disorders (12.3%, 9.9-14.7). Corneal scar/phthisis was not distributed equally among the countries and was highest in Malawi, similar to findings in 1995. The major etiology of visual loss was childhood factors (29.9%) and an estimated 40% of severe visual impairment and blindness was due to potentially avoidable causes. The major causes of severe visual impairment and blindness overall have not changed appreciably since 1995. There are important differences among countries, however, and using overall estimates for planning may be misleading.

  17. Metabolomics reveals distinct neurochemical profiles associated with stress resilience

    Directory of Open Access Journals (Sweden)

    Brooke N. Dulka

    2017-12-01

    Full Text Available Acute social defeat represents a naturalistic form of conditioned fear and is an excellent model in which to investigate the biological basis of stress resilience. While there is growing interest in identifying biomarkers of stress resilience, until recently, it has not been feasible to associate levels of large numbers of neurochemicals and metabolites to stress-related phenotypes. The objective of the present study was to use an untargeted metabolomics approach to identify known and unknown neurochemicals in select brain regions that distinguish susceptible and resistant individuals in two rodent models of acute social defeat. In the first experiment, male mice were first phenotyped as resistant or susceptible. Then, mice were subjected to acute social defeat, and tissues were immediately collected from the ventromedial prefrontal cortex (vmPFC, basolateral/central amygdala (BLA/CeA, nucleus accumbens (NAc, and dorsal hippocampus (dHPC. Ultra-high performance liquid chromatography coupled with high resolution mass spectrometry (UPLC-HRMS was used for the detection of water-soluble neurochemicals. In the second experiment, male Syrian hamsters were paired in daily agonistic encounters for 2 weeks, during which they formed stable dominant-subordinate relationships. Then, 24 h after the last dominance encounter, animals were exposed to acute social defeat stress. Immediately after social defeat, tissue was collected from the vmPFC, BLA/CeA, NAc, and dHPC for analysis using UPLC-HRMS. Although no single biomarker characterized stress-related phenotypes in both species, commonalities were found. For instance, in both model systems, animals resistant to social defeat stress also show increased concentration of molecules to protect against oxidative stress in the NAc and vmPFC. Additionally, in both mice and hamsters, unidentified spectral features were preliminarily annotated as potential targets for future experiments. Overall, these findings

  18. Cerebellar neurochemical alterations in spinocerebellar ataxia type 14 appear to include glutathione deficiency.

    Science.gov (United States)

    Doss, Sarah; Rinnenthal, Jan Leo; Schmitz-Hübsch, Tanja; Brandt, Alexander U; Papazoglou, Sebastian; Lux, Silke; Maul, Stephan; Würfel, Jens; Endres, Matthias; Klockgether, Thomas; Minnerop, Martina; Paul, Friedemann

    2015-08-01

    Autosomal dominant ataxia type 14 (SCA14) is a rare usually adult-onset progressive disorder with cerebellar neurodegeneration caused by mutations in protein kinase C gamma. We set out to examine cerebellar and extracerebellar neurochemical changes in SCA14 by MR spectroscopy. In 13 SCA14 patients and 13 healthy sex- and age-matched controls, 3-T single-voxel brain proton MR spectroscopy was performed in a cerebellar voxel of interest (VOI) at TE = 30 ms to obtain a neurochemical profile of metabolites with short relaxation times. In the cerebellum and in additional VOIs in the prefrontal cortex, motor cortex, and somatosensory cortex, a second measurement was performed at TE = 144 ms to mainly extract the total N-acetyl-aspartate (tNAA) signal besides the signals for total creatine (tCr) and total choline (tCho). The cerebellar neurochemical profile revealed a decrease in glutathione (6.12E-06 ± 2.50E-06 versus 8.91E-06 ± 3.03E-06; p = 0028) and tNAA (3.78E-05 ± 5.67E-06 versus 4.25E-05 ± 5.15E-06; p = 0023) and a trend for reduced glutamate (2.63E-05 ± 6.48E-06 versus 3.15E-05 ± 7.61E-06; p = 0062) in SCA14 compared to controls. In the tNAA-focused measurement, cerebellar tNAA (296.6 ± 42.6 versus 351.7 ± 16.5; p = 0004) and tCr (272.1 ± 25.2 versus 303.2 ± 31.4; p = 0004) were reduced, while the prefrontal, somatosensory and motor cortex remained unaffected compared to controls. Neuronal pathology in SCA14 detected by MR spectroscopy was restricted to the cerebellum and did not comprise cortical regions. In the cerebellum, we found in addition to signs of neurodegeneration a glutathione reduction, which has been associated with cellular damage by oxidative stress in other neurodegenerative diseases such as Parkinson's disease and Friedreich's ataxia.

  19. Unfazed or Dazed and Confused: Does Early Adolescent Marijuana Use Cause Sustained Impairments in Attention and Academic Functioning?

    Science.gov (United States)

    Pardini, Dustin; White, Helene R; Xiong, Shuangyan; Bechtold, Jordan; Chung, Tammy; Loeber, Rolf; Hipwell, Alison

    2015-10-01

    There is some suggestion that heavy marijuana use during early adolescence (prior to age 17) may cause significant impairments in attention and academic functioning that remain despite sustained periods of abstinence. However, no longitudinal studies have examined whether both male and female adolescents who engage in low (less than once a month) to moderate (at least once a monthly) marijuana use experience increased problems with attention and academic performance, and whether these problems remain following sustained abstinence. The current study used within-individual change models to control for all potential pre-existing and time-stable confounds when examining this potential causal association in two gender-specific longitudinal samples assessed annually from ages 11 to 16 (Pittsburgh Youth Study N = 479; Pittsburgh Girls Study N = 2296). Analyses also controlled for the potential influence of several pertinent time-varying factors (e.g., other substance use, peer delinquency). Prior to controlling for time-varying confounds, analyses indicated that adolescents tended to experience an increase in parent-reported attention and academic problems, relative to their pre-onset levels, during years when they used marijuana. After controlling for several time-varying confounds, only the association between marijuana use and attention problems in the sample of girls remained statistically significant. There was no evidence indicating that adolescents who used marijuana experienced lingering attention and academic problems, relative to their pre-onset levels, after abstaining from use for at least a year. These results suggest that adolescents who engage in low to moderate marijuana use experience an increase in observable attention and academic problems, but these problems appear to be minimal and are eliminated following sustained abstinence.

  20. Inhibition of mTOR improves the impairment of acidification in autophagic vesicles caused by hepatic steatosis

    Energy Technology Data Exchange (ETDEWEB)

    Nakadera, Eisuke [Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan); Yamashina, Shunhei, E-mail: syamashi@juntendo.ac.jp [Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan); Izumi, Kousuke; Inami, Yoshihiro; Sato, Toshifumi; Fukushima, Hirofumi; Kon, Kazuyoshi; Ikejima, Kenichi [Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan); Ueno, Takashi [Division of Proteomics and Biomolecular Science, Juntendo University, School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan); Watanabe, Sumio [Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 (Japan)

    2016-01-22

    Recent investigations revealed that dysfunction of autophagy involved in the progression of chronic liver diseases such as alcoholic and nonalcoholic steatohepatitis and hepatocellular neoplasia. Previously, it was reported that hepatic steatosis disturbs autophagic proteolysis via suppression of both autophagic induction and lysosomal function. Here, we demonstrate that autophagic acidification was altered by a decrease in lysosomal proton pump vacuolar-ATPase (V-ATPase) in steatohepatitis. The number of autophagic vesicles was increased in hepatocytes from obese KKAy mice as compared to control. Similarly, autophagic membrane protein LC3-II and lysosomal protein LAMP-2 expression were enhanced in KKAy mice liver. Nevertheless, both phospho-mTOR and p62 expression were augmented in KKAy mice liver. More than 70% of autophagosomes were stained by LysoTracker Red (LTR) in hepatocytes from control mice; however, the percentage of acidic autolysosomes was decreased in hepatocytes from KKAy mice significantly (40.1 ± 3.48%). Both protein and RNA level of V-ATPase subunits ATP6v1a, ATP6v1b, ATP6v1d in isolated lysosomes were suppressed in KKAy mice as compared to control. Interestingly, incubation with mTOR inhibitor rapamycin increased in the rate of LTR-positive autolysosomes in hepatocytes from KKAy mice and suppressed p62 accumulation in the liver from KKAy mice which correlated to an increase in the V-ATPase subunits expression. These results indicate that down-regulation of V-ATPase due to hepatic steatosis causes autophagic dysfunction via disruption of lysosomal and autophagic acidification. Moreover, activation of mTOR plays a pivotal role on dysregulation of lysosomal and autophagic acidification by modulation of V-ATPase expression and could therefore be a useful therapeutic target to ameliorate dysfunction of autophagy in NAFLD. - Highlights: • Hepatic steatosis causes accumulation of autophagic vesicles in hepatocytes. • Hepatic steatosis disturbs

  1. Population-based survey of prevalence, causes, and risk factors for blindness and visual impairment in an aging Chinese metropolitan population.

    Science.gov (United States)

    Hu, Jian-Yan; Yan, Liang; Chen, Yong-Dong; Du, Xin-Hua; Li, Ting-Ting; Liu, De-An; Xu, Dong-Hong; Huang, Yi-Min; Wu, Qiang

    2017-01-01

    To assess the prevalence, causes, and risk factors for blindness and visual impairment among elderly (≥60 years of age) Chinese people in a metropolitan area of Shanghai, China. Random cluster sampling was conducted to identify participants among residents ≥60 years of age living in the Xietu Block, Xuhui District, Shanghai, China. Presenting visual acuity (PVA) and best-corrected visual acuity (BCVA) were checked by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual chart. All eligible participants underwent a comprehensive eye examination. Blindness and visual impairment were defined according to World Health Organization (WHO) criteria. A total of 4190 persons (1688 men and 2502 women) participated in the study, and the response rate was 91.1%. Based on PVA, the prevalence of blindness was 1.1% and that of visual impairment was 7.6%. Based on BCVA, the prevalence of blindness and visual impairment decreased to 0.9% and 3.9%, respectively. Older (≥80 years of age) women, with low educational levels and smoking habits, exhibited a significantly greater chance for blindness and visual impairment than did those with high educational levels and no smoking habits (P<0.05). Based on PVA and BCVA, the main causes of blindness were cataract, myopic maculopathy, and age-related macular degeneration (AMD). Our findings help to identify the population in need of intervention, to highlight the need for additional eye healthcare services in urban China.

  2. Novel Mutations and Mutation Combinations ofTMPRSS3Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment.

    Science.gov (United States)

    Gao, Xue; Yuan, Yong-Yi; Wang, Guo-Jian; Xu, Jin-Cao; Su, Yu; Lin, Xi; Dai, Pu

    2017-01-01

    Autosomal recessive hearing impairment with postlingual onset is rare. Exceptions are caused by mutations in the TMPRSS3 gene, which can lead to prelingual (DFNB10) as well as postlingual deafness (DFNB8). TMPRSS3 mutations can be classified as mild or severe, and the phenotype is dependent on the combination of TMPRSS3 mutations. The combination of two severe mutations leads to profound hearing impairment with a prelingual onset, whereas severe mutations in combination with milder TMPRSS3 mutations lead to a milder phenotype with postlingual onset. We characterized a Chinese family (number FH1523) with not only prelingual but also postlingual hearing impairment. Three mutations in TMPRSS3 , one novel mutation c.36delC [p.(Phe13Serfs⁎12)], and two previously reported pathogenic mutations, c.916G>A (p.Ala306Thr) and c.316C>T (p.Arg106Cys), were identified. Compound heterozygous mutations of p.(Phe13Serfs⁎12) and p.Ala306Thr manifest as prelingual, profound hearing impairment in the patient (IV: 1), whereas the combination of p.Arg106Cys and p.Ala306Thr manifests as postlingual, milder hearing impairment in the patient (II: 2, II: 3, II: 5), suggesting that p.Arg106Cys mutation has a milder effect than p.(Phe13Serfs⁎12). We concluded that different combinations of TMPRSS3 mutations led to different hearing impairment phenotypes (DFNB8/DFNB10) in this family.

  3. MAGNITUDE AND CAUSES OF VISUAL IMPAIRMENT AND BLINDNESS AMONG CHILDREN ATTENDING PAEDIATRIC EYE CLINIC AT SANTHIRAM MEDICAL COLLEGE

    OpenAIRE

    Sanjeeva Kumar; Ramesh Chandra; Kishore Kumar; Sai

    2016-01-01

    BACKGROUND The number of blind years resulting from blindness in children is alarmingly high. Blindness in children can have a significant impact on their performance at school as well as their social interaction and future employment as visually impaired children have a long lifetime of blindness ahead of them. The consequences of visual impairment and blindness in children are an important public health issues with greater impact in developing countries, where 80% of the bli...

  4. Treatment with Trehalose Prevents Behavioral and Neurochemical Deficits Produced in an AAV α-Synuclein Rat Model of Parkinson's Disease.

    Science.gov (United States)

    He, Qing; Koprich, James B; Wang, Ying; Yu, Wen-bo; Xiao, Bao-guo; Brotchie, Jonathan M; Wang, Jian

    2016-05-01

    The accumulation of misfolded α-synuclein in dopamine (DA) neurons is believed to be of major importance in the pathogenesis of Parkinson's disease (PD). Animal models of PD, based on viral-vector-mediated over-expression of α-synuclein, have been developed and show evidence of dopaminergic toxicity, providing us a good tool to investigate potential therapies to interfere with α-synuclein-mediated pathology. An efficient disease-modifying therapeutic molecule should be able to interfere with the neurotoxicity of α-synuclein aggregation. Our study highlighted the ability of an autophagy enhancer, trehalose (at concentrations of 5 and 2% in drinking water), to protect against A53T α-synuclein-mediated DA degeneration in an adeno-associated virus serotype 1/2 (AAV1/2)-based rat model of PD. Behavioral tests and neurochemical analysis demonstrated a significant attenuation in α-synuclein-mediated deficits in motor asymmetry and DA neurodegeneration including impaired DA neuronal survival and DA turnover, as well as α-synuclein accumulation and aggregation in the nigrostriatal system by commencing 5 and 2% trehalose at the same time as delivery of AAV. Trehalose (0.5%) was ineffective on the above behavioral and neurochemical deficits. Further investigation showed that trehalose enhanced autophagy in the striatum by increasing formation of LC3-II. This study supports the concept of using trehalose as a novel therapeutic strategy that might prevent/reverse α-synuclein aggregation for the treatment of PD.

  5. A decade later, how much of Rwanda's musculoskeletal impairment is caused by the war in 1994 and by related violence?

    Directory of Open Access Journals (Sweden)

    Hannah Kuper

    Full Text Available BACKGROUND: In 1994 there was a horrific genocide in Rwanda following years of tension, resulting in the murder of at least 800,000 people. Although many people were injured in addition to those killed, no attempt has been made to assess the lasting burden of physical injuries related to these events. The aim of this study was to estimate the current burden of musculoskeletal impairment (MSI attributable to the 1994 war and related violence. METHODOLOGY/PRINCIPAL FINDINGS: A national cross-sectional survey of MSI was conducted in Rwanda. 105 clusters of 80 people were selected through probability proportionate to size sampling. Households within clusters were selected through compact segment sampling. Enumerated people answered a seven-question screening test to assess whether they might have an MSI. Those who were classed as potential cases in the screening test were examined and interviewed by a physiotherapist, using a standard protocol that recorded the site, nature, cause, and severity of the MSI. People with MSI due to trauma were asked whether this trauma occurred during the 1990-1994 war or during the episodes that preceded or followed this war. Out of 8,368 people enumerated, 6,757 were available for screening and examination (80.8%. 352 people were diagnosed with an MSI (prevalence=5.2%, 95% CI=4.5-5.9%. 106 cases of MSI (30.6% were classified as resulting from trauma, based on self-report and the physiotherapist's assessment. Of these, 14 people (13.2% reported that their trauma-related MSI occurred during the 1990-1994 war, and a further 7 (6.6% that their trauma-related MSI occurred during the violent episodes that preceded and followed the war, giving an overall prevalence of trauma-related MSI related to the 1990-1994 war of 0.3% (95% CI=0.2-0.4%. CONCLUSIONS/SIGNIFICANCE: A decade on, the overall prevalence of MSI was relatively high in Rwanda but few cases appeared to be the result of the 1994 war or related violence.

  6. Impairment of nitric oxide synthase but not heme oxygenase accounts for baroreflex dysfunction caused by chronic nicotine in female rats.

    Directory of Open Access Journals (Sweden)

    Mohamed A Fouda

    Full Text Available We recently reported that chronic nicotine impairs reflex chronotropic activity in female rats. Here, we sought evidence to implicate nitric oxide synthase (NOS and/or heme oxygenase (HO in the nicotine-baroreflex interaction. Baroreflex curves relating changes in heart rate to increases (phenylephrine or decreases (sodium nitroprusside in blood pressure were generated in conscious female rats treated with nicotine or saline in absence and presence of pharmacological modulators of NOS or HO activity. Compared with saline-treated rats, nicotine (2 mg/kg/day i.p., for 14 days significantly reduced the slopes of baroreflex curves, a measure of baroreflex sensitivity (BRS. Findings that favor the involvement of NOS inhibition in the nicotine effect were (i NOS inhibition (Nω-Nitro-L-arginine methyl ester, L-NAME reduced BRS in control rats but failed to do so in nicotine-treated rats, (ii L-arginine, NO donor, reversed the BRS inhibitory effect of nicotine. Alternatively, HO inhibition (zinc protoporphyrin IX, ZnPP had no effect on BRS in nicotine- or control rats and failed to reverse the beneficial effect of L-arginine on nicotine-BRS interaction. Similar to female rats, BRS was reduced by L-NAME, but not ZnPP, in male rats and the L-NAME effect was not accentuated after concomitant administration of nicotine. Baroreflex dysfunction caused by nicotine in female rats was blunted after supplementation with hemin (HO inducer but not tricarbonyldichlororuthenium(II dimer (CORM-2, a carbon monoxide (CO releasing molecule, or bilirubin, the breakdown product of heme catabolism. The facilitatory effect of hemin was abolished upon simultaneous treatment with L-NAME or 1H-[1], [2], [4] oxadiazolo[4,3-a] quinoxalin-1-one (inhibitor of soluble guanylate cyclase, sGC. The activities of HO and NOS in brainstem tissues were also significantly increased by hemin. Thus, the inhibition of NOS, but not HO, accounts for the baroreflex depressant of chronic nicotine

  7. Memantine prevents reference and working memory impairment caused by sleep deprivation in both young and aged Octodon degus.

    Science.gov (United States)

    Tarragon, Ernesto; Lopez, Dolores; Estrada, Cristina; Gonzalez-Cuello, Ana; Ros, Carmen Ma; Lamberty, Yves; Pifferi, Fabien; Cella, Massimo; Canovi, Mara; Guiso, Giovanna; Gobbi, Marco; Fernández-Villalba, Emiliano; Blin, Olivier; Bordet, Regis; Richardson, Jill C; Herrero, María Trinidad

    2014-10-01

    Memory loss is one of the key features of cognitive impairment in either aging, Mild Cognitive Impairment (MCI) or dementia. Pharmacological treatments for memory loss are today focused on addressing symptomatology. One of these approved compounds is memantine, a partial NMDA receptor antagonist that has proved its beneficial effects in cognition. The Octodon degus (O. degus) has been recently proposed as a potential model relevant for neurodegenerative diseases. However, there are no previous studies investigating the effect of pharmacological treatments for age-related cognitive impairment in this rodent. In this work we aimed to evaluate the effect of memantine on sleep deprivation (SD)-induced memory impairment in young and old O. degus. Young and old animals were trained in different behavioral paradigms validated for memory evaluation, and randomly assigned to a control (CTL, n=14) or an SD (n=14) condition, and treated with vehicle or memantine (10-mg/Kg i.p.) before the SD started. We demonstrate that SD impairs memory in both young and old animals, although the effect in the old group was significantly more severe (Pmemories. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. The impairment of glucose-stimulated insulin secretion in pancreatic β-cells caused by prolonged glucotoxicity and lipotoxicity is associated with elevated adaptive antioxidant response.

    Science.gov (United States)

    Fu, Jingqi; Cui, Qi; Yang, Bei; Hou, Yongyong; Wang, Huihui; Xu, Yuanyuan; Wang, Difei; Zhang, Qiang; Pi, Jingbo

    2017-02-01

    Type 2 diabetes (T2D) is a progressive disease characterized by sustained hyperglycemia and is frequently accompanied by hyperlipidemia. Deterioration of β-cell function in T2D patients may be caused, in part, by long-term exposure to high concentrations of glucose and/or lipids. We developed systems to study how chronic glucotoxicity and lipotoxicity might be linked to the impairment of glucose-stimulated insulin secretion (GSIS) machinery in pancreatic β-cells. INS-1 (832/13) were exposed to glucose and/or palmitate for up to 10 weeks. Chronic high glucose and/or palmitate exposure resulted in impaired GSIS accompanied by a dramatic increase in oxidative stress, as determined by basal intracellular peroxide levels. In addition, the GSIS-associated reactive oxygen species (ROS) signals, assessed as glucose-stimulated peroxide accumulation positively correlated with GSIS in glucose- and/or palmitate-exposed cells, as well as glucose-stimulated reductions in GSH/GSSG ratios. Furthermore, the impairment of GSIS caused by chronic high glucose and/or palmitate exposures were attributed to the induction of adaptive antioxidant response and mitochondrial uncoupling, which negatively regulates glucose-derived ROS generation. Taken together, persistent glucotoxicity- and/or lipotoxicity-mediated oxidative stress and subsequent adaptive antioxidant response impair glucose-derived ROS signaling and GSIS in pancreatic β-cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Clozapine protection against gestational cocaine-induced neurochemical abnormalities.

    Science.gov (United States)

    Yablonsky-Alter, Elena; Gashi, Eleonora; Lidsky, Theodore I; Wang, Hoau-Yan; Banerjee, Shailesh P

    2005-01-01

    Clozapine was found to be effective in attenuating cocaine-induced neurochemical effects. We investigate whether clozapine influences in utero cocaine exposure-induced changes in striatal dopamine levels and cortical N-methyl-D-aspartate (NMDA) receptor density in mouse and rat brains. Pregnant mice or rats were injected with cocaine (5 or 10 mg/kg intraperitoneally) or saline every 24 h throughout gestation and continued for 6 weeks following the delivery. Striatal dopamine levels measured by high-pressure liquid chromatography were found to decrease 24 to 33% in gestational cocaine exposed between the ages of 3 to 15 days, but not in 42-day-old pups. The cortical NMDA receptor densities assessed either in the presence of 100 microM glutamate or 30 microM glycine were significantly increased in 15-day-old gestational cocaine-exposed rats. Simultaneous daily administration of 3 mg/kg clozapine with 5 mg/kg cocaine to pregnant mice protected against the decrease in striatal dopamine levels or an increase in the concentration of NMDA receptor measured in the presence of 100 microM glutamate in 15-day-old pups. Clozapine did not affect striatal dopamine levels by itself or when coadministered with cocaine in 42-day-old pups. The results show gestational cocaine may induce neurochemical abnormalities in brain exhibited as an increased glutamate NMDA receptor density together with a decreased striatal dopamine level. These effects of gestational cocaine exposure may be prevented by simultaneous administration of clozapine. Thus clozapine, which is a partial agonist at the NMDA receptor, may be of value in protecting against gestational cocaine-induced adverse effects in the brain.

  10. A High-Fat Diet Causes Impairment in Hippocampal Memory and Sex-Dependent Alterations in Peripheral Metabolism

    Directory of Open Access Journals (Sweden)

    Erica L. Underwood

    2016-01-01

    Full Text Available While high-fat diets are associated with rising incidence of obesity/type-2 diabetes and can induce metabolic and cognitive deficits, sex-dependent comparisons are rarely systematically made. Effects of exclusive consumption of a high-fat diet (HFD on systemic metabolism and on behavioral measures of hippocampal-dependent memory were compared in young male and female LE rats. Littermates were fed from weaning either a HFD or a control diet (CD for 12 wk prior to testing. Sex-different effects of the HFD were observed in classic metabolic signs associated with type-2 diabetes. Males fed the HFD became obese, and had elevated fasted blood glucose levels, elevated corticosterone, and impaired glucose-tolerance, while females on the HFD exhibited only elevated corticosterone. Regardless of peripheral metabolism alteration, rats of both sexes fed the HFD were equally impaired in a spatial object recognition memory task associated with impaired hippocampal function. While the metabolic changes reported here have been characterized previously in males, the set of diet-induced effects observed here in females are novel. Impaired memory can have significant cognitive consequences, over the short-term and over the lifespan. A significant need exists for comparative research into sex-dependent differences underlying obesity and metabolic syndromes relating systemic, cognitive, and neural plasticity mechanisms.

  11. Syngeneic B16F10 Melanoma Causes Cachexia and Impaired Skeletal Muscle Strength and Locomotor Activity in Mice

    Directory of Open Access Journals (Sweden)

    Fabrício A. Voltarelli

    2017-09-01

    Full Text Available Muscle wasting has been emerging as one of the principal components of cancer cachexia, leading to progressive impairment of work capacity. Despite early stages melanomas rarely promotes weight loss, the appearance of metastatic and/or solid tumor melanoma can leads to cachexia development. Here, we investigated the B16F10 tumor-induced cachexia and its contribution to muscle strength and locomotor-like activity impairment. C57BL/6 mice were subcutaneously injected with 5 × 104 B16F10 melanoma cells or PBS as a Sham negative control. Tumor growth was monitored during a period of 28 days. Compared to Sham mice, tumor group depicts a loss of skeletal muscle, as well as significantly reduced muscle grip strength and epididymal fat mass. This data are in agreement with mild to severe catabolic host response promoted by elevated serum tumor necrosis factor-alpha (TNF-α, interleukin-6 (IL-6 and lactate dehydrogenase (LDH activity. Tumor implantation has also compromised general locomotor activity and decreased exploratory behavior. Likewise, muscle loss, and elevated inflammatory interleukin were associated to muscle strength loss and locomotor activity impairment. In conclusion, our data demonstrated that subcutaneous B16F10 melanoma tumor-driven catabolic state in response to a pro-inflammatory environment that is associated with impaired skeletal muscle strength and decreased locomotor activity in tumor-bearing mice.

  12. Effects of serotonin 2C receptor agonists on the behavioral and neurochemical effects of cocaine in squirrel monkeys.

    Science.gov (United States)

    Manvich, Daniel F; Kimmel, Heather L; Howell, Leonard L

    2012-05-01

    Accumulating evidence indicates that the serotonin system modulates the behavioral and neurochemical effects of cocaine, but the receptor subtypes mediating these effects remain unknown. Recent studies have demonstrated that pharmacological activation of the serotonin 2C receptor (5-HT(2C)R) attenuates the behavioral and neurochemical effects of cocaine in rodents, but such compounds have not been systematically evaluated in nonhuman primates. The present experiments sought to determine the impact of pretreatment with the preferential 5-HT(2C)R agonist m-chlorophenylpiperazine (mCPP) and the selective 5-HT(2C)R agonist Ro 60-0175 [(α-S)-6-chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine fumarate] on the behavioral and neurochemical effects of cocaine in squirrel monkeys. In subjects trained to lever-press according to a 300-s fixed-interval schedule of stimulus termination, pretreatment with either 5-HT(2C)R agonist dose-dependently and insurmountably attenuated the behavioral stimulant effects of cocaine. In subjects trained to self-administer cocaine, both compounds dose-dependently and insurmountably attenuated cocaine-induced reinstatement of previously extinguished responding in an antagonist-reversible manner, and the selective agonist Ro 60-0175 also attenuated the reinforcing effects of cocaine during ongoing cocaine self-administration. It is noteworthy that the selective agonist Ro 60-0175 exhibited behavioral specificity because it did not significantly alter nondrug-maintained responding. Finally, in vivo microdialysis studies revealed that pretreatment with Ro 60-0175 caused a reduction of cocaine-induced dopamine increases within the nucleus accumbens, but not the caudate nucleus. These results suggest that 5-HT(2C)R agonists functionally antagonize the behavioral effects of cocaine in nonhuman primates, possibly via a selective modulation of cocaine-induced dopamine increases within the mesolimbic dopamine system and may therefore represent a novel

  13. Neurochemical phenotype of cytoglobin‑expressing neurons in the rat hippocampus

    DEFF Research Database (Denmark)

    Hundahl, Christian Ansgar; Fahrenkrug, Jan; Hannibal, Jens

    2014-01-01

    of Cygb neurons remain uncharacterized by the neurochemical content. The aim of the present study was to provide an additional and more detailed neurochemical phenotype of Cygb-expressing neurons in the rat hippocampus. The rat hippocampus was chosen due to the abundance of Cygb, as well as this limbic...... of Cygb neurons co-expressing nNOS. Furthermore, it was shown that the majority of neurons expressing somastostatin and vasoactive intestinal peptide also co-express Cygb and nNOS. Detailed information regarding the neurochemical phenotype of Cygb neurons in the hippocampus can be a valuable tool...

  14. Human LRRK2 G2019S mutation represses post-synaptic protein PSD95 and causes cognitive impairment in transgenic mice.

    Science.gov (United States)

    Adeosun, Samuel O; Hou, Xu; Zheng, Baoying; Melrose, Heather L; Mosley, Thomas; Wang, Jun Ming

    2017-07-01

    LRRK2 G2019S mutation is associated with increased kinase activity and is the most common mutation associated with late-onset PD. However, the transgenic mouse model has not recapitulated cardinal PD-related motor phenotypes. Non-motor symptoms of PD including cognitive impairments are very common and may appear earlier than the motor symptoms. The objective of this study was to determine whether human LRRK2 with G2019S mutation causes hippocampus-dependent cognitive deficits in mice. Male (LRRK2-G2019S) LRRK2-Tg mice showed impairments in the early portion of the Two-day radial arm water maze acquisition trial as well as in the reversal learning on the third day. However, their performance was similar to Non-Tg controls in the probe trial. LRRK2-Tg mice also displayed impairments in the novel arm discrimination test but not in the spontaneous alternation test in Y-maze. Interestingly, there was no statistically significant locomotor impairment during any of these cognitive test, nor in the locomotor tests including open field, accelerating rotarod and pole tests. Expression of the postsynaptic protein PSD-95 but not the presynaptic protein synaptophysin was lower in hippocampal homogenates of LRRK2-Tg mice. Consistent with previous reports in human LRRK2 G2019S carriers, the current data suggests that cognitive dysfunctions are present in LRRK2-Tg mice even in the absence of locomotor impairment. LRRK2 G2019S mutation represses the postsynaptic protein PSD-95 but not the presynaptic protein synaptophysin. This study also suggests that mild cognitive impairment may appear earlier than motor dysfunctions in LRRK2-G2019S mutation carriers. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Impaired Driving

    Science.gov (United States)

    Impaired driving is dangerous. It's the cause of more than half of all car crashes. It means operating ... texting Having a medical condition which affects your driving For your safety and the safety of others, do not drive while impaired. Have someone else drive you or take public ...

  16. Effects of electroconvulsive seizures on depression-related behavior, memory and neurochemical changes in Wistar and Wistar-Kyoto rats.

    Science.gov (United States)

    Kyeremanteng, C; MacKay, J C; James, J S; Kent, P; Cayer, C; Anisman, H; Merali, Z

    2014-10-03

    Investigations in healthy outbred rat strains have shown a potential role for brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis in the antidepressant and memory side effects of electroconvulsive therapy (ECT, or ECS in animals). The Wistar-Kyoto (WKY) rat strain is used as a genetic model of depression yet no studies to date have directly compared the impact of ECS on the WKY strain to its healthy outbred control (Wistar). The objective of this study is to examine behavioral (antidepressant and retrograde memory) and neurochemical (BDNF and HPA axis) changes immediately (1day) and at a longer delay (7days) after repeated ECS (5 daily administrations) in WKY and Wistar rats. Male Wistar and WKY rats received 5days of repeated ECS or sham treatment and were assessed 1 and 7days later for 1) depression-like behavior and mobility; 2) retrograde memory; and 3) brain BDNF protein, brain corticotropin-releasing factor (CRF) and plasma corticosterone levels. Both strains showed the expected antidepressant response and retrograde memory impairments at 1day following ECS, which were sustained at 7days. In addition, at 1day after ECS, Wistar and WKY rats showed similar elevations in brain BDNF and extra-hypothalamic CRF and no change in plasma corticosterone. At 7days after ECS, Wistar rats showed sustained elevations of brain BDNF and CRF, whereas WKY rats showed a normalization of brain BDNF, despite sustained elevations of brain CRF. The model of 5 daily ECS was effective at eliciting behavioral and neurochemical changes in both strains. A temporal association was observed between brain CRF levels, but not BDNF, and measures of antidepressant effectiveness of ECS and retrograde memory impairments suggesting that extra-hypothalamic CRF may be a potential important contributor to these behavioral effects after repeated ECS/ECT. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Rapid recovery and altered neurochemical dependence of locomotor central pattern generation following lumbar neonatal spinal cord injury.

    Science.gov (United States)

    Züchner, Mark; Kondratskaya, Elena; Sylte, Camilla B; Glover, Joel C; Boulland, Jean-Luc

    2018-01-15

    Spinal compression injury targeted to the neonatal upper lumbar spinal cord, the region of highest hindlimb locomotor rhythmogenicity, leads to an initial paralysis of the hindlimbs. Behavioural recovery is evident within a few days and approaches normal function within about 3 weeks. Fictive locomotion in the isolated injured spinal cord cannot be elicited by a neurochemical cocktail containing NMDA, dopamine and serotonin 1 day post-injury, but can 3 days post-injury as readily as in the uninjured spinal cord. Low frequency coordinated rhythmic activity can be elicited in the isolated uninjured spinal cord by NMDA + dopamine (without serotonin), but not in the isolated injured spinal cord. In both the injured and uninjured spinal cord, eliciting bona fide fictive locomotion requires the additional presence of serotonin. Following incomplete compression injury in the thoracic spinal cord of neonatal mice 1 day after birth (P1), we previously reported that virtually normal hindlimb locomotor function is recovered within about 3 weeks despite substantial permanent thoracic tissue loss. Here, we asked whether similar recovery occurs following lumbar injury that impacts more directly on the locomotor central pattern generator (CPG). As in thoracic injuries, lumbar injuries caused about 90% neuronal loss at the injury site and increased serotonergic innervation below the injury. Motor recovery was slower after lumbar than thoracic injury, but virtually normal function was attained by P25 in both cases. Locomotor CPG status was tested by eliciting fictive locomotion in isolated spinal cords using a widely used neurochemical cocktail (NMDA, dopamine, serotonin). No fictive locomotion could be elicited 1 day post-injury, but could within 3 days post-injury as readily as in age-matched uninjured control spinal cords. Burst patterning and coordination were largely similar in injured and control spinal cords but there were differences. Notably, in both groups there

  18. Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics

    NARCIS (Netherlands)

    Lelental, N.; Brandner, S.; Kofanova, O.; Blennow, K.; Zetterberg, H.; Andreasson, U.; Engelborghs, S.; Mroczko, B.; Gabryelewicz, T.; Teunissen, C.; Mollenhauer, B.; Parnetti, L.; Chiasserini, D.; Molinuevo, J.L.; Perret-Liaudet, A.; Verbeek, M.M.; Andreasen, N.; Brosseron, F.; Bahl, J.M.; Herukka, S.K.; Hausner, L.; Frolich, L.; Labonte, A.; Poirier, J.; Miller, A.M.; Zilka, N.; Kovacech, B.; Urbani, A.; Suardi, S.; Oliveira, C. de; Baldeiras, I.; Dubois, B.; Rot, U.; Lehmann, S.; Skinningsrud, A.; Betsou, F.; Wiltfang, J.; Gkatzima, O.; Winblad, B.; Buchfelder, M.; Kornhuber, J.; Lewczuk, P.

    2016-01-01

    BACKGROUND: Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples.

  19. Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics

    NARCIS (Netherlands)

    Lelental, Natalia; Brandner, Sebastian; Kofanova, Olga; Blennow, Kaj; Zetterberg, Henrik; Andreasson, Ulf; Engelborghs, Sebastiaan; Mroczko, Barbara; Gabryelewicz, Tomasz; Teunissen, Charlotte; Mollenhauer, Brit; Parnetti, Lucilla; Chiasserini, Davide; Molinuevo, Jose Luis; Perret-Liaudet, Armand; Verbeek, Marcel M.; Andreasen, Niels; Brosseron, Frederic; Bahl, Justyna M. C.; Herukka, Sanna-Kaisa; Hausner, Lucrezia; Froelich, Lutz; Labonte, Anne; Poirier, Judes; Miller, Anne-Marie; Zilka, Norbert; Kovacech, Branislav; Urbani, Andrea; Suardi, Silvia; Oliveira, Catarina; Baldeiras, Ines; Dubois, Bruno; Rot, Uros; Lehmann, Sylvain; Skinningsrud, Anders; Betsou, Fay; Wiltfang, Jens; Gkatzima, Olymbia; Winblad, Bengt; Buchfelder, Michael; Kornhuber, Johannes; Lewczuk, Piotr

    2016-01-01

    Background: Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples.

  20. Rapid and reversible impairments of short- and long-term social recognition memory are caused by acute isolation of adult rats via distinct mechanisms.

    Directory of Open Access Journals (Sweden)

    Hadar Shahar-Gold

    Full Text Available Mammalian social organizations require the ability to recognize and remember individual conspecifics. This social recognition memory (SRM can be examined in rodents using their innate tendency to investigate novel conspecifics more persistently than familiar ones. Here we used the SRM paradigm to examine the influence of housing conditions on the social memory of adult rats. We found that acute social isolation caused within few days a significant impairment in acquisition of short-term SRM of male and female rats. Moreover, SRM consolidation into long-term memory was blocked following only one day of social isolation. Both impairments were reversible, but with different time courses. Furthermore, only the impairment in SRM consolidation was reversed by systemic administration of arginine-vasopressin (AVP. In contrast to SRM, object recognition memory was not affected by social isolation. We conclude that acute social isolation rapidly induces reversible changes in the brain neuronal and molecular mechanisms underlying SRM, which hamper its acquisition and completely block its consolidation. These changes occur via distinct, AVP sensitive and insensitive mechanisms. Thus, acute social isolation of rats swiftly causes changes in their brain and interferes with their normal social behavior.

  1. Cell Death and Learning Impairment in Mice Caused by in Vitro Modified Pro-NGF Can Be Related to Its Increased Oxidative Modifications in Alzheimer Disease

    Science.gov (United States)

    Kichev, Anton; Ilieva, Ekaterina V.; Piñol-Ripoll, Gerard; Podlesniy, Petar; Ferrer, Isidro; Portero-Otín, Manuel; Pamplona, Reinald; Espinet, Carme

    2009-01-01

    Pro-nerve growth factor (pro-NGF) is expressed at increased levels in Alzheimer’s disease (AD)-affected brains and is able to induce cell death in cultures; however, the reasons for these phenomena remain elusive. Here we show that pro-NGF in human AD-affected hippocampus and entorhinal cortex is modified by advanced glycation and lipoxidation end-products in a stage-dependent manner. These modifications block pro-NGF processing to mature NGF, thus making the proneurotrophin especially effective in inducing apoptosis of PC12 cells in culture through the p75 neurotrophin receptor. The processing of advanced glycation and lipoxidation end-products in vitro modified recombinant human pro-NGF is severely impaired, as evidenced by Western blot and by examining its physiological functionality in cell cultures. We also report that modified recombinant human pro-NGF, as well as pro-NGF isolated from human brain affected by AD, cause impairment of learning tasks when administered intracerebroventricularly in mice, which correlates with AD-associated learning impairment. Taken together, the data we present here offer a novel pathway of ethiopathogenesis in AD caused by advanced glycation and lipoxidation end-products modification of pro-NGF. PMID:19893045

  2. PI3K/Akt signal pathway involved in the cognitive impairment caused by chronic cerebral hypoperfusion in rats.

    Directory of Open Access Journals (Sweden)

    Yi Shu

    Full Text Available Chronic cerebral hypoperfusion (CCH is a common pathophysiological state that usually occurs in conditions such as vascular dementia and Alzheimer's disease, both of which are characterized by cognitive impairment. In previous studies we found that learning capacity and memory were gradually impaired with CCH, which altered the expression of synaptophysin, microtubule associated protein-2, growth associated protein-43, brain-derived neurotrophic factor, nerve growth factor, N-methyl-D-aspartate receptor subunit 1, cAMP response element-binding protein and tau hyperphosphorylation in the hippocampus. However, the molecular basis of cognitive impairment in CCH remains obscure. Here we explore the hypothesis that the phosphoinositide 3-kinase (PI3K/protein kinase B (Akt signal pathway is involved in this type of cognitive impairment. In order to determine if the expression of PI3K, Akt and phosphorylated Akt (p-Akt proteins are altered at different stages of CCH with differing levels of cognitive impairment. we performed permanent, bilateral occlusion of the common carotid arteries (2-VO to induce CCH. Adult male SD rats were randomly divided into sham-operated group, 2-VO 1 week group, 2-VO 4 weeks group and 2-VO 8 weeks group. Behavior tests were utilized to assess cognitive abilities, while western blots were utilized to evaluate protein expression. Rats in the 2-VO groups spent less time exploring novel objects than those in the sham-operated group, and the discrimination ratio of the 2-VO 8 weeks group and the sham-operated group were higher than chance (0.50. Escape latencies in the Morris water maze task in the 2-VO 1 week group were longer than those in the sham-operated group on day 4 and day 5, while escape latencies in the 2-VO 4 weeks group were longer than those in the sham-operated group from day 3 to day 5. Escape latencies in 2-VO 8 weeks group were longer than those in the sham-operated group from day 2 to day 5. NE (northeast

  3. Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioural, and neurotoxic effects of methamphetamine

    Science.gov (United States)

    Weinshenker, David; Ferrucci, Michela; Busceti, Carla L.; Biagioni, Francesca; Lazzeri, Gloria; Liles, L. Cameron; Lenzi, Paola; Murri, Luigi; Paparelli, Antonio; Fornai, Francesco

    2008-01-01

    N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions of the locus coeruleus (LC), the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP-4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine β-hydroxylase; DBH). We found that genetic deletion of DBH (DBH −/− mice) and acute treatment of wild-type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP-4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured by in vivo microdialysis of DA and 2,3-dihydroxybenzoic acid), and behavioural stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioural, and neurotoxic effects of METH. PMID:18042179

  4. Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioral, and neurotoxic effects of methamphetamine.

    Science.gov (United States)

    Weinshenker, David; Ferrucci, Michela; Busceti, Carla L; Biagioni, Francesca; Lazzeri, Gloria; Liles, L Cameron; Lenzi, Paola; Pasquali, Livia; Murri, Luigi; Paparelli, Antonio; Fornai, Francesco

    2008-04-01

    N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions of the locus coeruleus, the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP-4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine beta-hydroxylase; DBH). We found that genetic deletion of DBH (DBH-/- mice) and acute treatment of wild-type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP-4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured by in vivo microdialysis of DA and 2,3-dihydroxybenzoic acid), and behavioral stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioral, and neurotoxic effects of METH.

  5. Neurochemical imaging of Alzheimer`s disease and other degenerative dementias

    Energy Technology Data Exchange (ETDEWEB)

    Frey, K.A.; Minoshima, S.; Kuhl, D.E. [Ann Arbor, Univ. of Michigan, MI (United States). Dept. of Internal Medicine. Division of Nuclear Medicine

    1998-09-01

    A wide variety of neurochemical and functional imaging approaches have been applied to the study of progressive dementias, particularly Alzheimer`s disease (Ad) and related disorders. Despite considerable progress in the past decade, the cause(s) of most cases of Ad remain undetermined and preventive or protective therapies are lacking. Specifically-designed imaging procedures have permitted the testing of pathophysiological hypotheses of the etiology and progression of Ad, and have yielded important insights in several areas including the potential roles of cerebral cortical cholinergic lesions, cellular inflammation, and losses of cortical synapses. From the perspective of clinical diagnosis, PET glucose metabolism imaging with use of ({sup 18}F)2-fluorodeoxyglucose (FDG) is the most sensitive and specific imaging modality yet identified. The overall performance of PET FDG is favorable for routine clinical evaluation of suspected Ad, and will likely gain increasing utilization in the near future. Assessments of glucose metabolism and other, specific aspects of neurochemistry in Ad will provide direct measures of therapeutic drug actions and may permit distinction of symptomatic versus disease-modifying therapies as they are developed and introduced in clinical trials.

  6. Impaired LRP6-TCF7L2 Activity Enhances Smooth Muscle Cell Plasticity and Causes Coronary Artery Disease

    Directory of Open Access Journals (Sweden)

    Roshni Srivastava

    2015-10-01

    Full Text Available Mutations in Wnt-signaling coreceptor LRP6 have been linked to coronary artery disease (CAD by unknown mechanisms. Here, we show that reduced LRP6 activity in LRP6R611C mice promotes loss of vascular smooth muscle cell (VSMC differentiation, leading to aortic medial hyperplasia. Carotid injury augmented these effects and led to partial to total vascular obstruction. LRP6R611C mice on high-fat diet displayed dramatic obstructive CAD and exhibited an accelerated atherosclerotic burden on LDLR knockout background. Mechanistically, impaired LRP6 activity leads to enhanced non-canonical Wnt signaling, culminating in diminished TCF7L2 and increased Sp1-dependent activation of PDGF signaling. Wnt3a administration to LRP6R611C mice improved LRP6 activity, led to TCF7L2-dependent VSMC differentiation, and rescued post-carotid-injury neointima formation. These findings demonstrate the critical role of intact Wnt signaling in the vessel wall, establish a causal link between impaired LRP6/TCF7L2 activities and arterial disease, and identify Wnt signaling as a therapeutic target against CAD.

  7. Synergistic effects of cognitive impairment on physical disability in all-cause mortality among men aged 80 years and over: Results from longitudinal older veterans study.

    Directory of Open Access Journals (Sweden)

    Wan-Chen Yu

    is a major risk factor for all-cause mortality among men aged 80 years and older, and risk increased synergistically when cognitive impairment was present. Cognitive impairment alone without physical disability did not increase mortality risk in this population.

  8. [Incidence and causes of visual impairment in the district of Mahdia, in east Tunisia: Retrospective study of 1487 cases].

    Science.gov (United States)

    Ammari, W; Harrath, S; Mbarek, S; Mahmoud, A; Chebbi, W; Messaoud, R; Khairallah, M

    2016-11-01

    To study socio-demographic characteristics and main causes related to visual impairment (VI) as a function of age bracket and to analyze their trends over time in the district of Mahdia. A retrospective review was performed on 1487 cases of visual impairment registered with the social authorities in Mahdia, between 1980 and 2013. The social, demographic, vision exam findings and causes were ascertained and analyzed in an SPSS database. Incidence rates of VI and blindness due to various causes were calculated based on the demographic data from the NSI to estimate the time trends using the general linear regression model and Spearman correlation. Analyses included 1487 participants with a median age of 47 years, 40.6% of cases were aged under 45 years. Children accounted for 11.1% (165 patients), while age was between 16 and 45 years in 29.5% (439 patients), between 46 and 65 years in 31.5% (469 patients) and greater than 65 years in 27.8% (414 patients). The sex-ratio (M/F) was 1.78. Socially, 51% came from rural areas, 62% were illiterate, and 84% were unemployed. We observed blindness in 70% of participants and low vision in 30%. In children, the causes were dominated by congenital cataract and congenital glaucoma, each present in 31 children (18.8%). Between 16 and 45 years, glaucoma and hereditary dystrophies of the retina were found in 62 and 61 patients respectively (14% each). For age between 46 and 65 years, trachoma was responsible for 19.8% of cases of VI, glaucoma in 15.8% and cataract in 15.1%. Beyond 65 years, glaucoma accounted for 30.7% of the causes of VI and cataract 27.8% of cases. Trend analysis shows a significant increase in the incidence rate of visual impairment with an average of 12% per year (P=0.001). The mean age increased by 46% (P=0.003). Trachoma increased by 118% (Pvisual impairment and avoid its consequences. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  9. Neurochemical Effects of Chronic Administration of Calcitriol in Rats

    Directory of Open Access Journals (Sweden)

    Pei Jiang

    2014-12-01

    Full Text Available Despite accumulating data showing the various neurological actions of vitamin D (VD, its effects on brain neurochemistry are still far from fully understood. To further investigate the neurochemical influence of VD, we assessed neurotransmitter systems in the brain of rats following 6-week calcitriol (1,25-dihydroxyvitamin D administration (50 ng/kg/day or 100 ng/kg/day. Both the two doses of calcitriol enhanced VDR protein level without affecting serum calcium and phosphate status. Rats treated with calcitriol, especially with the higher dose, exhibited elevated γ-aminobutyric acid (GABA status. Correspondingly, the mRNA expression of glutamate decarboxylase (GAD 67 was increased. 100 ng/kg of calcitriol administration also increased glutamate and glutamine levels in the prefrontal cortex, but did not alter glutamine synthetase (GS expression. Additionally, calcitriol treatment promoted tyrosine hydroxylase (TH and tryptophan hydroxylase 2 (TPH2 expression without changing dopamine and serotonin status. However, the concentrations of the metabolites of dopamine and serotonin were increased and the drug use also resulted in a significant rise of monoamine oxidase A (MAOA expression, which might be responsible to maintain the homeostasis of dopaminergic and serotonergic neurotransmission. Collectively, the present study firstly showed the effects of calcitriol in the major neurotransmitter systems, providing new evidence for the role of VD in brain function.

  10. A neurochemical approach to valuation sensitivity over gains and losses.

    Science.gov (United States)

    Zhong, Songfa; Israel, Salomon; Xue, Hong; Sham, Pak C; Ebstein, Richard P; Chew, Soo Hong

    2009-12-07

    Prospect theory proposes the hypothesis that people have diminishing sensitivity in valuing increases in the size of monetary outcomes, for both gains and losses. For decision-making under risk, this implies a tendency to be risk-tolerant over losses while being generally risk averse over gains. We offer a neurochemistry-based model of the diminishing valuation sensitivity hypothesis. Specifically, we propose that dopamine tone modulates the sensitivity towards valuation of gains while serotonin tone modulates the sensitivity towards valuation of losses. Consequently, higher dopamine tone would yield a more concave valuation function over gains while higher serotonin tone would yield a more convex valuation function over losses. Using a neurogenetics strategy to test our neurochemical model, we find that subjects with the 9-repeat allele of DAT1 (lower DA tone) are more risk-tolerant over gains than subjects with the 10-repeat allele, and that subjects with the 10-repeat allele of STin2 (higher 5HT tone) are more risk-tolerant over losses than subjects with the 12-repeat allele. Overall, our results support the implications of our model and provide the first neurogenetics evidence that risk attitudes are partially hard-wired in differentiating between gain- and loss-oriented risks.

  11. Dyslipidemia links obesity to early cerebral neurochemical alterations.

    Science.gov (United States)

    Haley, Andreana P; Gonzales, Mitzi M; Tarumi, Takashi; Tanaka, Hirofumi

    2013-10-01

    To examine the role of hypertension, hyperglycemia, and dyslipidemia in potentially accounting for obesity-related brain vulnerability in the form of altered cerebral neurochemistry. Sixty-four adults, ages 40-60 years, underwent a health screen and proton magnetic resonance spectroscopy ((1) H MRS) of occipitoparietal gray matter to measure N-acetyl aspartate (NAA), choline (Cho), myo-inositol (mI), and glutamate (Glu) relative to creatine (Cr). The causal steps approach and nonparametric bootstrapping were utilized to assess if fasting glucose, mean arterial pressure or peripheral lipid/lipoprotein levels mediate the relationship between body mass index (BMI) and cerebral neurochemistry. Higher BMI was significantly related to higher mI/Cr, independent of age and sex. BMI was also significantly related to two of the proposed mediators, triglyceride, and HDL-cholesterol, which were also independently related to increased mI/Cr. Finally, the relationship between BMI and mI/Cr was significantly attenuated after inclusion of triglyceride and HDL-cholesterol into the model, one at a time, indicating statistical mediation. Higher triglyceride and lower HDL levels statistically account for the association between BMI and myo-inositol, pointing toward a potentially critical role for dyslipidemia in the development of cerebral neurochemical alterations in obesity. Copyright © 2013 The Obesity Society.

  12. Neurochemical background and approaches in the understanding of motion sickness

    Science.gov (United States)

    Kohl, R. L.

    1982-01-01

    The problems and nature of space motion sickness were defined. The neurochemical and neurophysiological bases of vestibular system function and of the expression of motion sickness wre reviewed. Emphasis was given to the elucidation of the neuropharmacological mechanisms underlying the effects of scopolamine and amphetamine on motion sickness. Characterization of the ascending reticular activating system and the limbic system provided clues to the etiology of the side effects of scopolamine. The interrelationship between central cholinergic pathways and the peripheral (autonomic) expression of motion sickness was described. A correlation between the stress of excessive motion and a variety of hormonal responses to that stress was also detailed. The cholinergic system is involved in the efferent modulation of the vestibular hair cells, as an afferent modulator of the vestibular nuclei, in the activation of cortical and limbic structures, in the expression of motion sickness symptoms and most likely underscores a number of the hormonal changes that occur in stressful motion environments. The role of lecithin in the regulation of the levels of neurotransmitters was characterized as a possible means by which cholinergic neurochemistry can be modulated.

  13. Social Stress and Psychosis Risk: Common Neurochemical Substrates?

    Science.gov (United States)

    Mizrahi, Romina

    2016-02-01

    Environmental risk factors have been implicated in the etiology of psychotic disorders, with growing evidence showing the adverse effects of migration, social marginalization, urbanicity, childhood trauma, social defeat, and other adverse experiences on mental health in vulnerable populations. Collectively, social stress may be one mechanism that could link these environmental risk factors. The exact mechanism(s) by which social stress can affect brain function, and in particular the molecular targets involved in psychosis (such as the dopaminergic (DA) system), is (are) not fully understood. In this review, we will discuss the interplay between social environmental risk factors and molecular changes in the human brain; in particular, we will highlight the impact of social stress on three specific neurochemical systems: DA, neuroinflammation/immune, and endocannabinoid (eCB) signaling. We have chosen the latter two molecular pathways based on emerging evidence linking schizophrenia to altered neuroinflammatory processes and cannabis use. We further identify key developmental periods in which social stress interacts with these pathways, suggesting window(s) of opportunities for novel interventions. Taken together, we suggest that they may have a key role in the pathogenesis and disease progression, possibly provide novel treatment options for schizophrenia, and perhaps even prevent it.

  14. Impairment of Barrier Properties of Erythrocyte Membranes Caused by Low Temperatures is a Result of Disorganization of Hemoglobin Supramolecular Structure.

    Science.gov (United States)

    Gulevskvy, A K; Repin, N V; Schenvavsky, I I

    The antecedence of impairment of plasmatic membrane structure and functions forms the basis of the dominative concept about mechanisms of cell cryoinjuries. A role of alterations of hemoglobin supramolecular structure in erythrocytes remains unclear. Comparison of continuity of membranes of native erythrocytes and resealed ghosts after freeze-thawing with a cryoprotectant at a low concentration (4%). Cryoresistance of native erythrocytes and resealed ghosts with and without low concentrations of cryoprotectants (4% glycerol) was compared according to egress of the following markers: hemoglobin, 14С-sucrose and K+ as well as by scanning electron microscopy. It was found that resealed erythrocyte ghosts, where hemoglobin content was 4-5 times lower than in erythrocytes, were much more cryoresistant than native erythrocytes, which was especially noticeable when a low concentration of cryoprotectant (4% glycerol) was used. These data confirm an earlier proposed hypothesis on the role of supramolecular hemoglobin structure in cryoinjury mechanisms of erythrocytes.

  15. Hearing impairment caused by mutations in two different genes responsible for nonsyndromic and syndromic hearing loss within a single family.

    Science.gov (United States)

    Niepokój, Katarzyna; Rygiel, Agnieszka M; Jurczak, Piotr; Kujko, Aleksandra A; Śniegórska, Dominika; Sawicka, Justyna; Grabarczyk, Alicja; Bal, Jerzy; Wertheim-Tysarowska, Katarzyna

    2017-11-18

    Usher syndrome is rare genetic disorder impairing two human senses, hearing and vision, with the characteristic late onset of vision loss. This syndrome is divided into three types. In all cases, the vision loss is postlingual, while loss of hearing is usually prelingual. The vestibular functions may also be disturbed in Usher type 1 and sometimes in type 3. Vestibular areflexia is helpful in making a proper diagnosis of the syndrome, but, often, the syndrome is misdiagnosed as a nonsyndromic hearing loss. Here, we present a Polish family with hearing loss, which was clinically classified as nonsyndromic. After excluding mutations in the DFNB1 locus, we implemented the next-generation sequencing method and revealed that hearing loss was syndromic and mutations in the USH2A gene indicate Usher syndrome. This research highlights the importance of molecular analysis in establishing a clinical diagnosis of congenital hearing loss.

  16. A novel mutation in CDK5RAP2 gene causes primary microcephaly with speech impairment and sparse eyebrows in a consanguineous Pakistani family

    DEFF Research Database (Denmark)

    Abdullah, Uzma; Farooq, Muhammad; Mang, Yuan

    2017-01-01

    2 mutations is still under explored as only eleven families have been reported worldwide. Here, we analyzed a consanguineous Pakistani MCPH family, characterized by moderate to severe intellectual disability, speech impairment, moderately short stature and sparse eyebrows. Whole exome sequencing...... of the proband identified a 2bp duplication in exon 34 of CDK5RAP2 that causes frame-shift, leading to a premature stop codon. The resultant transcript is resistant to nonsense mediated decay, suggesting that the mutation leads to a truncated protein lacking C-terminal domains; CDK5R1, and Cnn motif 2 (CM2...

  17. COL4A2 Mutations Impair COL4A1 and COL4A2 Secretion and Cause Hemorrhagic Stroke

    OpenAIRE

    Jeanne, Marion; Labelle-Dumais, Cassandre; Jorgensen, Jeff; Kauffman, W. Berkeley; Mancini, Grazia M.; Favor, Jack; Valant, Valerie; Greenberg, Steven M.; Rosand, Jonathan; Gould, Douglas B.

    2012-01-01

    Collagen, type IV, alpha 1 (COL4A1) and alpha 2 (COL4A2) form heterotrimers and are abundant components of basement membranes, including those of the cerebral vasculature. COL4A1 mutations are an increasingly recognized cause of multisystem disorders, including highly penetrant cerebrovascular disease and intracerebral hemorrhage (ICH). Because COL4A1 and COL4A2 are structurally and functionally associated, we hypothesized that variants in COL4A2 would also cause ICH. We sequence COL4A2 in 96...

  18. Mercury exposure and neurochemical impacts in bald eagles across several Great Lakes states.

    Science.gov (United States)

    Rutkiewicz, Jennifer; Nam, Dong-Ha; Cooley, Thomas; Neumann, Kay; Padilla, Irene Bueno; Route, William; Strom, Sean; Basu, Niladri

    2011-10-01

    In this study, we assessed mercury (Hg) exposure in several tissues (brain, liver, and breast and primary feathers) in bald eagles (Haliaeetus leucocephalus) collected from across five Great Lakes states (Iowa, Michigan, Minnesota, Ohio, and Wisconsin) between 2002-2010, and assessed relationships between brain Hg and neurochemical receptors (NMDA and GABA(A)) and enzymes (glutamine synthetase (GS) and glutamic acid decarboxylase (GAD)). Brain total Hg (THg) levels (dry weight basis) averaged 2.80 μg/g (range: 0.2-34.01), and levels were highest in Michigan birds. THg levels in liver (r(p) = 0.805) and breast feathers (r(p) = 0.611) significantly correlated with those in brain. Brain Hg was not associated with binding to the GABA(A) receptor. Brain THg and inorganic Hg (IHg) were significantly positively correlated with GS activity (THg r(p) = 0.190; IHg r(p) = 0.188) and negatively correlated with NMDA receptor levels (THg r(p) = -0245; IHg r(p) = -0.282), and IHg was negatively correlated with GAD activity (r(s) = -0.196). We also report upon Hg demethylation and relationships between Hg and Se in brain and liver. These results suggest that bald eagles in the Great Lakes region are exposed to Hg at levels capable of causing subclinical neurological damage, and that when tissue burdens are related to proposed avian thresholds approximately 14-27% of eagles studied here may be at risk.

  19. Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation

    DEFF Research Database (Denmark)

    Clayton, Emma L.; Mancuso, Renzo; Nielsen, Troels Tolstrup

    2017-01-01

    Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like c...

  20. ASC and NLRP3 impair host defense during lethal pneumonia caused by serotype 3 Streptococcus pneumoniae in mice

    NARCIS (Netherlands)

    van Lieshout, Miriam H. P.; de Vos, Alex F.; Dessing, Mark C.; de Porto, Alexander P. N. A.; de Boer, Onno J.; de Beer, Regina; Terpstra, Sanne; Florquin, Sandrine; van't Veer, Cornelis; van der Poll, Tom

    2018-01-01

    Streptococcus (S.) pneumoniae is the most common cause of community-acquired pneumonia. The Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, consisting of NLRP3, ASC (the adaptor apoptosis-associated speck-like protein containing a CARD) and caspase-1, has been implicated in

  1. Social vs. environmental stress models of depression from a behavioural and neurochemical approach.

    Science.gov (United States)

    Venzala, E; García-García, A L; Elizalde, N; Tordera, R M

    2013-07-01

    Major depression is a mental disorder often preceded by exposure to chronic stress or stressful life events. Recently, animal models based on social conflict such as chronic social defeat stress (CSDS) are proposed to be more relevant to stress-induced human psychopathology compared to environmental models like the chronic mild stress (CMS). However, while CMS reproduces specifically core depressive symptoms such as anhedonia and helplessness, CSDS studies rely on the analysis of stress-induced social avoidance, addressing different neuropsychiatric disorders. Here, we study comparatively the two models from a behavioural and neurochemical approach and their possible relevance to human depression. Mice (C57BL/6) were exposed to CMS or CSDS for six weeks and ten days. Anhedonia was periodically evaluated. A battery of test applied during the fourth week after the stress procedure included motor activity, memory, anxiety, social interaction and helplessness. Subsequently, we examined glutamate, GABA, 5-HT and dopamine levels in the prefrontal cortex, hippocampus and brainstem. CMS induced a clear depressive-like profile including anhedonia, helplessness and memory impairment. CSDS induced anhedonia, hyperactivity, anxiety and social avoidance, signs also common to anxiety and posttraumatic stress disorders. While both models disrupted the excitatory inhibitory balance in the prefrontal cortex, CMS altered importantly this balance in the brainstem. Moreover, CSDS decreased dopamine in the prefrontal cortex and brainstem. We suggests that while depressive-like behaviours might be associated to altered aminoacid neurotransmission in cortical and brain stem areas, CSDS induced anxiety behaviours might be linked to specific alteration of dopaminergic pathways involved in rewarding processes. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

  2. Impaired glycogen synthesis causes metabolic overflow reactions and affects stress responses in the cyanobacterium Synechocystis sp. PCC 6803.

    Science.gov (United States)

    Gründel, Marianne; Scheunemann, Ramon; Lockau, Wolfgang; Zilliges, Yvonne

    2012-12-01

    The biosynthesis of glycogen or starch is one of the main strategies developed by living organisms for the intracellular storage of carbon and energy. In phototrophic organisms, such polyglucans accumulate due to carbon fixation during photosynthesis and are used to provide maintenance energy for cell integrity, function and viability in dark periods. Moreover, it is assumed that glycogen enables cyanobacteria to cope with transient starvation conditions, as observed in most micro-organisms. Here, glycogen accumulates when an appropriate carbon source is available in sufficient amounts but growth is inhibited by lack of other nutrients. In this study, the role of glycogen in energy and carbon metabolism of phototrophic cyanobacteria was first analysed via a comparative physiological and metabolic characterization of knockout mutants defective in glycogen synthesis. We first proved the role of glycogen as a respiratory substrate in periods of darkness, the role of glycogen as a reserve to survive starvation periods such as nitrogen depletion and the role of glycogen synthesis as an ameliorator of carbon excess conditions in the model organism Synechocystis sp. PCC 6803. We provide striking new insights into the complex carbon and nitrogen metabolism of non-diazotrophic cyanobacteria: a phenotype of sensitivity to photomixotrophic conditions and of reduced glucose uptake, a non-bleaching phenotype based on an impaired acclimation response to nitrogen depletion and furthermore a phenotype of energy spilling. This study shows that the analysis of deficiencies in glycogen metabolism is a valuable tool for the identification of metabolic regulatory principles and signals.

  3. BMI and All-Cause Mortality in Normoglycemia, Impaired Fasting Glucose, Newly Diagnosed Diabetes, and Prevalent Diabetes: A Cohort Study.

    Science.gov (United States)

    Lee, Eun Young; Lee, Yong-Ho; Yi, Sang-Wook; Shin, Soon-Ae; Yi, Jee-Jeon

    2017-08-01

    This study examined associations between BMI and mortality in individuals with normoglycemia, impaired fasting glucose (IFG), newly diagnosed diabetes, and prevalent diabetes and identified BMI ranges associated with the lowest mortality in each group. A total of 12,815,006 adults were prospectively monitored until 2013. Diabetes status was defined as follows: normoglycemia (fasting glucose BMI (kg/m(2)) was measured. Cox proportional hazards model hazard ratios were calculated after adjusting for confounders. During a mean follow-up period of 10.5 years, 454,546 men and 239,877 women died. U-shaped associations were observed regardless of diabetes status, sex, age, and smoking history. Optimal BMI (kg/m(2)) for the lowest mortality by group was 23.5-27.9 (normoglycemia), 25-27.9 (IFG), 25-29.4 (newly diagnosed diabetes), and 26.5-29.4 (prevalent diabetes). Higher optimal BMI by worsening diabetes status was more prominent in younger ages, especially in women. The relationship between worsening diabetes status and higher mortality was stronger with lower BMI, especially at younger ages. Given the same BMI, people with prevalent diabetes had higher mortality compared with those with newly diagnosed diabetes, and this was more striking in women than men. U-curve relationships existed regardless of diabetes status. Optimal BMI for lowest mortality became gradually higher with worsening diabetes for each sex and each age-group. © 2017 by the American Diabetes Association.

  4. Sciatic nerve ligation causes impairment of mitochondria associated with changes in distribution, respiration, and cardiolipin composition in related spinal cord neurons in rats.

    Science.gov (United States)

    Keilhoff, Gerburg; Becker, Axel; Kropf, Siegfried; Schild, Lorenz

    2016-10-01

    Sciatic nerve irritation is often associated with disturbed Ca(2+) homeostasis in related neurons of the spinal cord. Since mitochondria substantially contribute to Ca(2+) homeostasis and little information is available, we studied the effects of loose sciatic nerve ligation, a chronic constriction injury (CCI), on neuronal mitochondria of the L3-L6 regions. Three groups of rats (untreated, sham operated, and ligated) were explored. For the characterization of mitochondria, specimens of the L3-L6 spinal cord regions were evaluated with respect to intracellular localization using pyruvate dehydrogenase immunohistochemistry and Mitotracker Red, and the ATP producing machinery by LC-MS/MS technique for the analysis of cardiolipin and high-resolution respirometry for the measurement of oxygen consumption. Therefore, the phospholipid cardiolipin supports electron transfer within the respiratory chain as part of mitochondrial respiration and is of high impact on the physical properties of the mitochondrial membrane system. Histological analysis of spinal cord motor neurons revealed clustering of mitochondria in ipsilateral samples from ligated animals 14 days after the insult. This phenomenon was similarly evident in the respective contralateral side. The intensity of MT-Red staining was enhanced exclusively at the ipsilateral side, indicating increased mitochondrial activity. CCI of the sciatic nerve caused massive changes in the composition of cardiolipin reflecting mitochondrial impairment in the early phase followed by regeneration processes as late response. Sciatic nerve CCI caused decrease in the capacity of mitochondrial ATP production that recovered within 14 days after treatment. In conclusion, we provide evidence that clustering of mitochondria, already verified for the spinal cord sensory neurons after CCI, also occurs in the respective motor neurons. Further we have demonstrated transient impairment of the capacity of mitochondrial ATP production in tissue

  5. Neurochemical consequence of steroid abuse: stanozolol-induced monoaminergic changes.

    Science.gov (United States)

    Tucci, Paolo; Morgese, Maria Grazia; Colaianna, Marilena; Zotti, Margherita; Schiavone, Stefania; Cuomo, Vincenzo; Trabace, Luigia

    2012-02-01

    An extensive literature has documented adverse effects on mental health in anabolic androgenic steroids (AAS) abusers. Depression seems a common adverse reaction in AAS abusers. Recently it has been reported that in a rat model of AAS abuse stanozolol induces behavioural and biochemical changes related to the pathophysiology of major depressive disorder. In the present study, we used the model of AAS abuse to examine possible changes in the monoaminergic system, a neurobiological substrate of depression, in different brain areas of stanozolol-treated animals. Wistar rats received repeated injections of stanozolol (5mg/kg, s.c.), or vehicle (propylene glycol, 1ml/kg) once daily for 4weeks. Twenty-four hours after last injection, changes of dopamine (DA) and relative metabolite levels, homovanilic acid (HVA) and 3,4-dihydroxy phenylacetic acid (DOPAC), serotonin (5-HT) and its metabolite levels, 5-hydroxy indolacetic acid (5-HIAA), and noradrenaline (NA) amount were investigated in prefrontal cortex (PFC), nucleus accumbens (NAC), striatum (STR) and hippocampus (HIPP). The analysis of data showed that after chronic stanozolol, DA levels were increased in the HIPP and decreased in the PFC. No significant changes were observed in the STR or in the NAC. 5-HT and 5-HIAA levels were decreased in all brain areas investigated after stanozolol exposure; however, the 5-HIAA/5-HT ratio was not altered. Taken together, our data indicate that chronic use of stanozolol significantly affects brain monoamines leading to neurochemical modifications possibly involved in depression and stress-related states. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Neurochemical organization of the nucleus paramedianus dorsalis in the human.

    Science.gov (United States)

    Baizer, Joan S; Baker, James F; Haas, Kristin; Lima, Raquel

    2007-10-24

    We have characterized the neurochemical organization of a small brainstem nucleus in the human brain, the nucleus paramedianus dorsalis (PMD). PMD is located adjacent and medial to the nucleus prepositus hypoglossi (PH) in the dorsal medulla and is distinguished by the pattern of immunoreactivity of cells and fibers to several markers including calcium-binding proteins, a synthetic enzyme for nitric oxide (neuronal nitric oxide synthase, nNOS) and a nonphosphorylated neurofilament protein (antibody SMI-32). In transverse sections, PMD is oval with its long axis aligned with the dorsal border of the brainstem. We identified PMD in eight human brainstems, but found some variability both in its cross-sectional area and in its A-P extent among cases. It includes calretinin immunoreactive large cells with oval or polygonal cell bodies. Cells in PMD are not immunoreactive for either calbindin or parvalbumin, but a few fibers immunoreactive to each protein are found within its central region. Cells in PMD are also immunoreactive to nNOS, and immunoreactivity to a neurofilament protein shows many labeled cells and fibers. No similar region is identified in atlases of the cat, mouse, rat or monkey brain, nor does immunoreactivity to any of the markers that delineate it in the human reveal a comparable region in those species. The territory that PMD occupies is included in PH in other species. Since anatomical and physiological data in animals suggest that PH may have multiple subregions, we suggest that the PMD in human may be a further differentiation of PH and may have functions related to the vestibular control of eye movements.

  7. Neurochemical Evidence of Potential Neurotoxicity After Prophylactic Cranial Irradiation

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    Kalm, Marie, E-mail: marie.kalm@neuro.gu.se [Department of Clinical Neuroscience and Rehabilitation, Insitute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg (Sweden); Abel, Edvard [Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg (Sweden); Wasling, Pontus [Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg (Sweden); Nyman, Jan [Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg (Sweden); Hietala, Max Albert [Department of Neurology, Karolinska University Hospital, Stockholm (Sweden); Bremell, Daniel; Hagberg, Lars [Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg (Sweden); Elam, Mikael [Department of Clinical Neuroscience and Rehabilitation, Insitute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg (Sweden); Blennow, Kaj [Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal (Sweden); Björk-Eriksson, Thomas [Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg (Sweden); Zetterberg, Henrik [Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal (Sweden); UCL Institute of Neurology, London (United Kingdom)

    2014-07-01

    Purpose: To examine whether cerebrospinal fluid biomarkers for neuroaxonal damage, neuroglial activation, and amyloid β–related processes could characterize the neurochemical response to cranial radiation. Methods and Materials: Before prophylactic cranial irradiation (PCI) of patients with small cell lung cancer, each patient underwent magnetic resonance imaging of the brain, lumbar puncture, and Mini-Mental State Examination of cognitive function. These examinations were repeated at approximately 3 and 12 months after radiation. Results: The major findings were as follows. (1) Cerebrospinal fluid markers for neuronal and neuroglial injury were elevated during the subacute phase after PCI. Neurofilament and T-tau increased 120% and 50%, respectively, after PCI (P<.05). The same was seen for the neuroglial markers YKL-40 and glial fibrillary acidic protein, which increased 144% and 106%, respectively, after PCI (P<.05). (2) The levels of secreted amyloid precursor protein-α and -β were reduced 44% and 46%, respectively, 3 months after PCI, and the levels continued to decrease as long as 1 year after treatment (P<.05). (3) Mini-Mental State Examination did not reveal any cognitive decline, indicating that a more sensitive test should be used in future studies. Conclusion: In conclusion, we were able to detect radiation therapy–induced changes in several markers reflecting neuronal injury, inflammatory/astroglial activation, and altered amyloid precursor protein/amyloid β metabolism, despite the low number of patients and quite moderate radiation doses (20-30 Gy). These changes are hypothesis generating and could potentially be used to assess the individual risk of developing long-term symptoms of chronic encephalopathy after PCI. This has to be evaluated in large studies with extended clinical follow-up and more detailed neurocognitive assessments.

  8. Prevalence and causes of visual impairment and blindness, cataract surgical coverage and outcomes of cataract surgery in Libya.

    Science.gov (United States)

    Rabiu, Muhammad Mansur; Jenf, Mansour; Fituri, Suad; Choudhury, Abdulhanan; Agbabiaka, Idris; Mousa, Ahmed

    2013-01-01

    To assess the major causes of avoidable blindness, and outcomes and barriers to cataract services in Libya. A stratified multistage cluster random sample study was conducted in the four regions of Libya. Visual acuity and lens assessment were performed on all subjects. Those with presenting visual acuity Libya needs to improve the quality of cataract surgery across all the regions. The southern region needs improvement in both quality and coverage of services.

  9. DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies.

    Science.gov (United States)

    Ji, Jianling; Lee, Hane; Argiropoulos, Bob; Dorrani, Naghmeh; Mann, John; Martinez-Agosto, Julian A; Gomez-Ospina, Natalia; Gallant, Natalie; Bernstein, Jonathan A; Hudgins, Louanne; Slattery, Leah; Isidor, Bertrand; Le Caignec, Cédric; David, Albert; Obersztyn, Ewa; Wiśniowiecka-Kowalnik, Barbara; Fox, Michelle; Deignan, Joshua L; Vilain, Eric; Hendricks, Emily; Horton Harr, Margaret; Noon, Sarah E; Jackson, Jessi R; Wilkens, Alisha; Mirzaa, Ghayda; Salamon, Noriko; Abramson, Jeff; Zackai, Elaine H; Krantz, Ian; Innes, A Micheil; Nelson, Stanley F; Grody, Wayne W; Quintero-Rivera, Fabiola

    2015-11-01

    Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from -2 SD to -5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.

  10. High Insulin Levels in KK-Ay Diabetic Mice Cause Increased Cortical Bone Mass and Impaired Trabecular Micro-Structure

    Directory of Open Access Journals (Sweden)

    Cen Fu

    2015-04-01

    Full Text Available Type 2 diabetes mellitus (T2DM is a chronic disease characterized by hyperglycemia, hyperinsulinemia and complications, including obesity and osteoporosis. Rodents have been widely used to model human T2DM and investigate its effect on the skeleton. We aimed to investigate skeletal alterations in Yellow Kuo Kondo (KK-Ay diabetic mice displaying high insulin and glucose levels. Bone mineral density (BMD, micro-architecture and bone metabolism-related genes were analyzed. The total femoral areal BMD (aBMD, cortical volumetric BMD (vBMD and thickness were significantly increased in KK-Ay mice, while the trabecular vBMD and mineralized bone volume/tissue volume (BV/TV, trabecular thickness and number were decreased compared to C57BL mice. The expression of both osteoblast-related genes, such as osteocalcin (OC, bone sialoprotein, Type I Collagen, osteonectin, RUNX2 and OSX, and osteoclast-related genes, such as TRAP and TCIRG, were up-regulated in KK-Ay mice. Correlation analyses showed that serum insulin levels were positively associated with aBMD, cortical vBMD and thickness and negatively associated with trabecular vBMD and micro-architecture. In addition, serum insulin levels were positively related to osteoblast-related and osteoclast-related gene expression. Our data suggest that high insulin levels in KK-Ay diabetic mice may increase cortical bone mass and impair trabecular micro-structure by up-regulating osteoblast-and osteoclast-related gene expression.

  11. Resection of Navigated Transcranial Magnetic Stimulation-Positive Prerolandic Motor Areas Causes Permanent Impairment of Motor Function.

    Science.gov (United States)

    Moser, Tobias; Bulubas, Lucia; Sabih, Jamil; Conway, Neal; Wildschutz, Noémie; Sollmann, Nico; Meyer, Bernhard; Ringel, Florian; Krieg, Sandro M

    2017-07-01

    Navigated transcranial magnetic stimulation (nTMS) helps to determine the distribution of motor eloquent areas prior to brain surgery. Yet, the eloquence of primary motor areas frontal to the precentral gyrus identified via nTMS is unclear. To investigate the resection of nTMS-positive prerolandic motor areas and its correlation with postsurgical impairment of motor function. Forty-three patients with rolandic or prerolandic gliomas (WHO grade I-IV) underwent nTMS prior to surgery. Only patients without ischemia within the motor system in postoperative MRI diffusion sequences were enrolled. Based on the 3-dimensional fusion of preoperative nTMS motor mapping data with postsurgical MRI scans, we identified nTMS points that were resected in the infiltration zone of the tumor. We then classified the resected points according to the localization and latency of their motor evoked potentials. Surgery-related paresis was graded as transient (≤6 weeks) or permanent (>6 weeks). Out of 43, 31 patients (72%) showed nTMS-positive motor points in the prerolandic gyri. In general, 13 out of 43 patients (30%) underwent resection of nTMS points. Ten out of these patients showed postoperative paresis. There were 2 (15%) patients with a transient and 8 (62%) with a permanent surgery-related paresis. In 3 cases (23%), motor function remained unimpaired. After resection of nTMS-positive motor points, 62% of patients suffered from a new permanent paresis. Thus, even though they are located in the superior or middle frontal gyrus, these cortical areas must undergo intraoperative mapping.

  12. Protein-Energy Malnutrition (PEM is Believed to Lead to an Increased Susceptibility to Infection, or cause Impaired Immunity

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    Mellova Amir Masrizal

    2003-08-01

    Full Text Available Infection, occurring with malnutrition, is a major cause of morbidity in all age groups and is responsible for two-thirds of all death under 5 yr of age in developing countries. Many cells of the immune system are known to depend for their function on metabolic pathways that employ various nutrients as critical factors. The most consistent changes in immune competence in PEM are in cell-mediated immunity, the bactericidal function of neutrophils, the complement system, the secretory immunoglobin A, and antibody response.

  13. WINCS Harmoni: Closed-loop dynamic neurochemical control of therapeutic interventions

    Science.gov (United States)

    Lee, Kendall H.; Lujan, J. Luis; Trevathan, James K.; Ross, Erika K.; Bartoletta, John J.; Park, Hyung Ook; Paek, Seungleal Brian; Nicolai, Evan N.; Lee, Jannifer H.; Min, Hoon-Ki; Kimble, Christopher J.; Blaha, Charles D.; Bennet, Kevin E.

    2017-04-01

    There has been significant progress in understanding the role of neurotransmitters in normal and pathologic brain function. However, preclinical trials aimed at improving therapeutic interventions do not take advantage of real-time in vivo neurochemical changes in dynamic brain processes such as disease progression and response to pharmacologic, cognitive, behavioral, and neuromodulation therapies. This is due in part to a lack of flexible research tools that allow in vivo measurement of the dynamic changes in brain chemistry. Here, we present a research platform, WINCS Harmoni, which can measure in vivo neurochemical activity simultaneously across multiple anatomical targets to study normal and pathologic brain function. In addition, WINCS Harmoni can provide real-time neurochemical feedback for closed-loop control of neurochemical levels via its synchronized stimulation and neurochemical sensing capabilities. We demonstrate these and other key features of this platform in non-human primate, swine, and rodent models of deep brain stimulation (DBS). Ultimately, systems like the one described here will improve our understanding of the dynamics of brain physiology in the context of neurologic disease and therapeutic interventions, which may lead to the development of precision medicine and personalized therapies for optimal therapeutic efficacy.

  14. Cannabinoid HU210 Protects Isolated Rat Stomach against Impairment Caused by Serum of Rats with Experimental Acute Pancreatitis

    Science.gov (United States)

    Cao, Ming-hua; Li, Yong-yu; Xu, Jing; Feng, Ya-jing; Lin, Xu-hong; Li, Kun; Han, Tong; Chen, Chang-Jie

    2012-01-01

    Acute pancreatitis (AP), especially severe acute pancreatitis often causes extra-pancreatic complications, such as acute gastrointestinal mucosal lesion (AGML) which is accompanied by a considerably high mortality, yet the pathogenesis of AP-induced AGML is still not fully understood. In this report, we investigated the alterations of serum components and gastric endocrine and exocrine functions in rats with experimental acute pancreatitis, and studied the possible contributions of these alterations in the pathogenesis of AGML. In addition, we explored the intervention effects of cannabinoid receptor agonist HU210 and antagonist AM251 on isolated and serum-perfused rat stomach. Our results showed that the AGML occurred after 5 h of AP replication, and the body homeostasis was disturbed in AP rat, with increased levels of pancreatic enzymes, lipopolysaccharide (LPS), proinflammtory cytokines and chemokines in the blood, and an imbalance of the gastric secretion function. Perfusing the isolated rat stomach with the AP rat serum caused morphological changes in the stomach, accompanied with a significant increment of pepsin and [H+] release, and increased gastrin and decreased somatostatin secretion. HU210 reversed the AP-serum-induced rat pathological alterations, including the reversal of transformation of the gastric morphology to certain degree. The results from this study prove that the inflammatory responses and the imbalance of the gastric secretion during the development of AP are responsible for the pathogenesis of AGML, and suggest the therapeutic potential of HU210 for AGML associated with acute pancreatitis. PMID:23285225

  15. Transcriptional regulation of the ABCC6 gene and the background of impaired function of missense disease-causing mutations

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    Tamás eArányi

    2013-03-01

    Full Text Available The human ABCC6 gene encodes an ABC transporter protein expressed primarily in the liver and to a lesser extent in the kidneys and the intestines. We review here the mechanisms of this restricted tissue-specific expression and the role of hepatocyte nuclear factor 4α which is responsible for the expression pattern. Detailed analyses uncovered further regulators of the expression of the gene pointing to an intronic primate-specific regulator region, an activator of the expression of the gene by binding C/EBPbeta, which interacts with other proteins acting in the proximal promoter. This regulatory network is affected by various environmental stimuli including oxidative stress and the ERK1/2 pathway. We also review here the structural and functional consequences of disease-causing missense mutations of ABCC6. A significant clustering of the missense disease-causing mutations was found at the domain-domain interfaces. This clustering means that the domain contacts are much less permissive to amino acid replacements than the rest of the protein. We summarize the experimental methods resulting in the identification of mutants with preserved transport activity but failure in intracellular targeting. These mutants are candidates for functional rescue by chemical chaperons. The results of such research can provide the basis of future allele-specific therapy of ABCC6-mediated disorders like pseudoxanthoma elasticum or the generalized arterial calcification in infancy.

  16. Impaired development of left anterior heart field by ectopic retinoic acid causes transposition of the great arteries.

    Science.gov (United States)

    Narematsu, Mayu; Kamimura, Tatsuya; Yamagishi, Toshiyuki; Fukui, Mitsuru; Nakajima, Yuji

    2015-04-30

    Transposition of the great arteries is one of the most commonly diagnosed conotruncal heart defects at birth, but its etiology is largely unknown. The anterior heart field (AHF) that resides in the anterior pharyngeal arches contributes to conotruncal development, during which heart progenitors that originated from the left and right AHF migrate to form distinct conotruncal regions. The aim of this study is to identify abnormal AHF development that causes the morphology of transposition of the great arteries. We placed a retinoic acid-soaked bead on the left or the right or on both sides of the AHF of stage 12 to 14 chick embryos and examined the conotruncal heart defect at stage 34. Transposition of the great arteries was diagnosed at high incidence in embryos for which a retinoic acid-soaked bead had been placed in the left AHF at stage 12. Fluorescent dye tracing showed that AHF exposed to retinoic acid failed to contribute to conotruncus development. FGF8 and Isl1 expression were downregulated in retinoic acid-exposed AHF, and differentiation and expansion of cardiomyocytes were suppressed in cultured AHF in medium supplemented with retinoic acid. The left AHF at the early looped heart stage, corresponding to Carnegie stages 10 to 11 (28 to 29 days after fertilization) in human embryos, is the region of the impediment that causes the morphology of transposition of the great arteries. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  17. Ageing without hearing loss or cognitive impairment causes a decrease in speech intelligibility only in informational maskers.

    Science.gov (United States)

    Rajan, R; Cainer, K E

    2008-06-23

    In most everyday settings, speech is heard in the presence of competing sounds and understanding speech requires skills in auditory streaming and segregation, followed by identification and recognition, of the attended signals. Ageing leads to difficulties in understanding speech in noisy backgrounds. In addition to age-related changes in hearing-related factors, cognitive factors also play a role but it is unclear to what extent these are generalized or modality-specific cognitive factors. We examined how ageing in normal-hearing decade age cohorts from 20 to 69 years affected discrimination of open-set speech in background noise. We used two types of sentences of similar structural and linguistic characteristics but different masking levels (i.e. differences in signal-to-noise ratios required for detection of sentences in a standard masker) so as to vary sentence demand, and two background maskers (one causing purely energetic masking effects and the other causing energetic and informational masking) to vary load conditions. There was a decline in performance (measured as speech reception thresholds for perception of sentences in noise) in the oldest cohort for both types of sentences, but only in the presence of the more demanding informational masker. We interpret these results to indicate a modality-specific decline in cognitive processing, likely a decrease in the ability to use acoustic and phonetic cues efficiently to segregate speech from background noise, in subjects aged >60.

  18. In vivo magnetic resonance studies reveal neuroanatomical and neurochemical abnormalities in the serine racemase knockout mouse model of schizophrenia.

    Science.gov (United States)

    Puhl, Matthew D; Mintzopoulos, Dionyssios; Jensen, J Eric; Gillis, Timothy E; Konopaske, Glenn T; Kaufman, Marc J; Coyle, Joseph T

    2015-01-01

    Decreased availability of the N-methyl-D-aspartate receptor (NMDAR) co-agonist D-serine is thought to promote NMDAR hypofunction and contribute to the pathophysiology of schizophrenia, including neuroanatomical abnormalities, such as cortical atrophy and ventricular enlargement, and neurochemical abnormalities, such as aberrant glutamate and γ-aminobutyric acid (GABA) signaling. It is thought that these abnormalities directly relate to the negative symptoms and cognitive impairments that are hallmarks of the disorder. Because of the genetic complexity of schizophrenia, animal models of the disorder are extremely valuable for the study of genetically predisposing factors. Our laboratory developed a transgenic mouse model lacking serine racemase (SR), the synthetic enzyme of d-serine, polymorphisms of which are associated with schizophrenia. Null mutants (SR-/-) exhibit NMDAR hypofunction and cognitive impairments. We used 9.4 T magnetic resonance imaging (MRI) and proton spectroscopy (MRS) to compare in vivo brain structure and neurochemistry in wildtype (WT) and SR-/- mice. Mice were anesthetized with isoflurane for MRI and MRS scans. Compared to WT controls, SR-/- mice exhibited 23% larger ventricular volumes (pcomparable to those previously reported in humans with schizophrenia. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Endothelin-1–Rho kinase interactions impair lung structure and cause pulmonary hypertension after bleomycin exposure in neonatal rat pups

    Science.gov (United States)

    Tseng, Nancy; Seedorf, Gregory; Kuhn, Katherine; Abman, Steven H.

    2016-01-01

    Bronchopulmonary dysplasia (BPD) is the chronic lung disease associated with premature birth, characterized by impaired vascular and alveolar growth. In neonatal rats bleomycin decreases lung growth and causes pulmonary hypertension (PH), which is poorly responsive to nitric oxide. In the developing lung, through Rho kinase (ROCK) activation, ET-1 impairs endothelial cell function; however, whether ET-1–ROCK interactions contribute to impaired vascular and alveolar growth in experimental BPD is unknown. Neonatal rats were treated daily with intraperitoneal bleomycin with and without selective ETA (BQ123/BQ610) and ETB (BQ788) receptor blockers, nonselective ET receptor blocker (ETRB) (bosentan), or fasudil (ROCK inhibitor). At day 14, lungs were harvested for morphometrics, and measurements of Fulton's index (RV/LV+S), medial wall thickness (MWT), and vessel density. Lung ET-1 protein and ROCK activity (phospho-MYPT-1:total MYPT-1 ratio) were also measured by Western blot analysis. Bleomycin increased lung ET-1 protein expression by 65%, RV/LV+S by 60%, mean linear intercept (MLI) by 212%, and MWT by 140% and decreased radial alveolar count (RAC) and vessel density by 40 and 44%, respectively (P < 0.01 for each comparison). After bleomycin treatment, fasudil and bosentan partially restored RAC and vessel density and decreased MLI, RV/LV+S, and MWT to normal values. Bleomycin increased ROCK activity by 120%, which was restored to normal values by bosentan but not selective ETRB. We conclude that ET-1–ROCK interactions contribute to decreased alveolar and vascular growth and PH in experimental BPD. We speculate that nonselective ETRB and ROCK inhibitors may be effective in the treatment of infants with BPD and PH. PMID:27760762

  20. 4-ethylphenyl-cobalamin impairs tissue uptake of vitamin B12 and causes vitamin B12 deficiency in mice.

    Directory of Open Access Journals (Sweden)

    Elena Mutti

    Full Text Available Coβ-4-ethylphenyl-cob(III alamin (EtPhCbl is an organometallic analogue of vitamin B12 (CNCbl which binds to transcobalamin (TC, a plasma protein that facilitates the cellular uptake of cobalamin (Cbl. In vitro assays with key enzymes do not convert EtPhCbl to the active coenzyme forms of Cbl suggesting that administration of EtPhCbl may cause cellular Cbl deficiency. Here, we investigate the in vivo effect of EtPhCbl in mice and its ability, if any, to induce Cbl deficiency. We show that EtPhCbl binds to mouse TC and we examined mice that received 3.5 nmol/24h EtPhCbl (n=6, 3.5 nmol/24h CNCbl (n=7 or NaCl (control group (n=5 through osmotic mini-pumps for four weeks. We analyzed plasma, urine, liver, spleen, submaxillary glands and spinal cord for Cbl and markers of Cbl deficiency including methylmalonic acid (MMA and homocysteine (tHcy. Plasma MMA (mean±SEM was elevated in animals treated with EtPhCbl (1.01±0.12 µmol/L compared to controls (0.30±0.02 µmol/L and CNCbl (0.29±0.01 µmol/L treated animals. The same pattern was observed for tHcy. Plasma total Cbl concentration was higher in animals treated with EtPhCbl (128.82±1.87 nmol/L than in CNCbl treated animals (87.64±0.93 nmol/L. However, the organ levels of total Cbl were significantly lower in animals treated with EtPhCbl compared to CNCbl treated animals or controls, notably in the liver (157.07±8.56 pmol/g vs. 603.85±20.02 pmol/g, and 443.09±12.32 pmol/g, respectively. Differences between the three groups was analysed using one-way ANOVA and, Bonferroni post-hoc test. EtPhCbl was present in all tissues, except the spinal cord, accounting for 35-90% of total Cbl. In conclusion, treatment with EtPhCbl induces biochemical evidence of Cbl deficiency. This may in part be caused by a compromised tissue accumulation of Cbl.

  1. Exposure to microgravity for 30 days onboard Bion M1 caused muscle atrophy and impaired regeneration in murine femoral Quadriceps

    Science.gov (United States)

    Radugina, E. A.; Almeida, E. A. C.; Blaber, E.; Poplinskaya, V. A.; Markitantova, Y. V.; Grigoryan, E. N.

    2018-02-01

    Mechanical unloading in microgravity during spaceflight is known to cause muscular atrophy, changes in muscle fiber composition, gene expression, and reduction in regenerative muscle growth. Although some limited data exists for long-term effects of microgravity in human muscle, these processes have mostly been studied in rodents for short periods of time. Here we report on how long-term (30-day long) mechanical unloading in microgravity affects murine muscles of the femoral Quadriceps group. To conduct these studies we used muscle tissue from 6 microgravity mice, in comparison to habitat (7), and vivarium (14) ground control mice from the NASA Biospecimen Sharing Program conducted in collaboration with the Institute for Biomedical Problems of the Russian Academy of Sciences, during the Russian Bion M1 biosatellite mission in 2013. Muscle histomorphology from microgravity specimens showed signs of extensive atrophy and regenerative hypoplasia relative to ground controls. Specifically, we observed a two-fold decrease in the number of myonuclei, compared to vivarium and ground controls, and central location of myonuclei, low density of myofibers in the tissue, and of myofibrils within a fiber, as well as fragmentation and swelling of myofibers. Despite obvious atrophy, muscle regeneration nevertheless appeared to have continued after 30 days in microgravity as evidenced by thin and short newly formed myofibers. Many of them, however, showed evidence of apoptotic cells and myofibril degradation, suggesting that long-term unloading in microgravity may affect late stages of myofiber differentiation. Ground asynchronous and vivarium control animals demonstrated normal, well-developed tissue structure with sufficient blood and nerve supply and evidence of regenerative formation of new myofibers free of apoptotic nuclei. Regenerative activity of satellite cells in muscles was observed both in microgravity and ground control groups, using Pax7 and Myogenin

  2. Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients

    Science.gov (United States)

    Sauer, Aisha V.; Hernandez, Raisa Jofra; Fumagalli, Francesca; Bianchi, Veronica; Poliani, Pietro L.; Dallatomasina, Chiara; Riboni, Elisa; Politi, Letterio S.; Tabucchi, Antonella; Carlucci, Filippo; Casiraghi, Miriam; Carriglio, Nicola; Cominelli, Manuela; Forcellini, Carlo Alberto; Barzaghi, Federica; Ferrua, Francesca; Minicucci, Fabio; Medaglini, Stefania; Leocani, Letizia; la Marca, Giancarlo; Notarangelo, Lucia D.; Azzari, Chiara; Comi, Giancarlo; Baldoli, Cristina; Canale, Sabrina; Sessa, Maria; D’Adamo, Patrizia; Aiuti, Alessandro

    2017-01-01

    Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short- and long-term enzyme replacement therapy with PEG-ADA. These included motor dysfunction, EEG alterations, sensorineural hypoacusia, white matter and ventricular alterations in MRI as well as a low mental development index or IQ. Ada-deficient mice were significantly less active and showed anxiety-like behavior. Molecular and metabolic analyses showed that this phenotype coincides with metabolic alterations and aberrant adenosine receptor signaling. PEG-ADA treatment corrected metabolic adenosine-based alterations, but not cellular and signaling defects, indicating an intrinsic nature of the neurological and behavioral phenotype in ADA deficiency. PMID:28074903

  3. Intermittent hypoxia from obstructive sleep apnea may cause neuronal impairment and dysfunction in central nervous system: the potential roles played by microglia

    Directory of Open Access Journals (Sweden)

    Yang Q

    2013-08-01

    Full Text Available Qingchan Yang,1,* Yan Wang,2,* Jing Feng,2 Jie Cao,2 Baoyuan Chen2 1Graduate School of Tianjin Medical University, 2Respiratory Department, Tianjin Medical University General Hospital, Tianjin, People's Republic of China *These authors contributed equally to this work Abstract: Obstructive sleep apnea (OSA is a common condition characterized by repetitive episodes of complete (apnea or partial (hypopnea obstruction of the upper airway during sleep, resulting in oxygen desaturation and arousal from sleep. Intermittent hypoxia (IH resulting from OSA may cause structural neuron damage and dysfunction in the central nervous system (CNS. Clinically, it manifests as neurocognitive and behavioral deficits with oxidative stress and inflammatory impairment as its pathophysiological basis, which are mediated by microglia at the cellular level. Microglia are dominant proinflammatory cells in the CNS. They induce CNS oxidative stress and inflammation, mainly through mitochondria, reduced nicotinamide adenine dinucleotide phosphate oxidase, and the release of excitatory toxic neurotransmitters. The balance between neurotoxic versus protective and anti- versus proinflammatory microglial factors might determine the final roles of microglia after IH exposure from OSA. Microglia inflammatory impairments will continue and cascade persistently upon activation, ultimately resulting in clinically significant neuron damage and dysfunction in the CNS. In this review article, we summarize the mechanisms of structural neuron damage in the CNS and its concomitant dysfunction due to IH from OSA, and the potential roles played by microglia in this process. Keywords: intermittent hypoxia, obstructive sleep apnea, microglia, inflammation, apoptosis

  4. Caffeine has greater potency and efficacy than theophylline to reverse the motor impairment caused by chronic but not acute interruption of striatal dopaminergic transmission in rats.

    Science.gov (United States)

    Acuña-Lizama, Miguel M; Bata-García, José L; Alvarez-Cervera, Fernando J; Góngora-Alfaro, José L

    2013-07-01

    In order to assess whether caffeine and theophylline have the same potency and efficacy to reverse the impairment of motor function caused by acute or chronic interruption of striatal dopamine transmission, a comparison of their dose-response relationship was made in the acute model of haloperidol-induced catalepsy, and the chronic model of unilateral lesion of the dopamine nigrostriatal pathway with 6-hydroxydopamine. At equimolar doses, both drugs reduced catalepsy intensity and increased its onset latency in a dose-dependent fashion, showing comparable potencies and attaining the maximal effect at similar doses. Catalepsy intensity: caffeine ED₅₀ = 24.1 μmol/kg [95% CI, 18.4-31.5]; theophylline ED₅₀ = 22.0 μmol/kg [95% CI, 17.0-28.4]. Catalepsy latency: caffeine ED₅₀ = 27.0 μmol/kg [95% CI, 21.1-34.6]; theophylline ED₅₀ = 28.8 μmol/kg [95% CI, 22.5-36.7]. In one group of hemiparkinsonian rats (n = 5), caffeine caused a dose-dependent recovery of the contralateral forepaw stepping: ED₅₀ = 2.4 μmol/kg/day [95% CI, 1.9-3.1]), reaching its maximum at the dose of 5.15 μmol/kg/day. When the treatment of these same rats was switched to 5.15 μmol/kg/day of theophylline, the stepping recovery was only 51 ± 12% of that induced by caffeine. Assessing the dose-response relationship of theophylline in another group of hemiparkinsonian rats (n = 7) revealed that it caused stepping recovery in an all-or-none fashion. Thus, the three lower doses had no effect, but at the dose of 5.15 μmol/kg/day theophylline suddenly increased the stepping to 56 ± 5% of the maximal effect observed when the treatment of these same rats was switched to an equimolar dose of caffeine. Increasing the dose of theophylline up to 15.45 μmol/kg/day caused no further stepping improvement since it was only 41 ± 6% of the maximal effect produced by caffeine at the dose of 5.15 μmol/kg/day. Given that theophylline showed less potency and efficacy than caffeine to reverse the

  5. CRYβA3/A1-Crystallin Knockout Develops Nuclear Cataract and Causes Impaired Lysosomal Cargo Clearance and Calpain Activation.

    Directory of Open Access Journals (Sweden)

    Shylaja Hegde

    Full Text Available βA3/A1-crystallin is an abundant structural protein of the lens that is very critical for lens function. Many different genetic mutations have been shown to associate with different types of cataracts in humans and in animal models. βA3/A1-crystallin has four Greek key-motifs that organize into two crystallin domains. It shown to bind calcium with moderate affinity and has putative calcium-binding site. Other than in the lens, βA3/A1 is also expressed in retinal astrocytes, retinal pigment epithelial (RPE cells, and retinal ganglion cells. The function of βA3/A1-crystallin in the retinal cell types is well studied; however, a clear understanding of the function of this protein in the lens has not yet been established. In the current study, we generated the βA3/A1-crystallin knockout (KO mouse and explored the function of βA3/A1-crystallin in lens development. Our results showed that βA3-KO mice develop congenital nuclear cataract and exhibit persistent fetal vasculature condition. At the cellular level KO lenses show defective lysosomal clearance and accumulation of nuclei, mitochondria, and autophagic cargo in the outer cortical region of the lens. In addition, the calcium level and the expression and activity of calpain-3 were increased in KO lenses. Taken together, these results suggest the lack of βA3-crystallin function in lenses, alters calcium homeostasis which in turn causes lysosomal defects and calpain activation. These defects are responsible for the development of nuclear cataract in KO lenses.

  6. Deletion of MgcRacGAP in the male germ cells impairs spermatogenesis and causes male sterility in the mouse.

    Science.gov (United States)

    Lorès, Patrick; Vernet, Nadège; Kurosaki, Tomohiro; Van de Putte, Tom; Huylebroeck, Danny; Hikida, Masaki; Gacon, Gérard; Touré, Aminata

    2014-02-15

    MgcRacGAP (RACGAP1) is a GTPase Activating Protein (GAP), highly produced in the mouse embryonic brain and in the human and mouse post-natal testis. MgcRacGAP negatively controls the activity of Rac and Cdc42, which are key molecular switches acting on the microtubule and actin cytoskeleton and controlling various cell processes such as proliferation, adhesion and motility. Previous studies demonstrated that MgcRacGAP plays a critical role in the cytokinesis of somatic cells; hence homozygous inactivation of the gene in the mouse and mutation in Caenorhabditis elegans led to embryonic lethality due to the inability of MgcRacGAP-null embryos to assemble the central spindle and to complete cytokinesis. In the testis, the germ cells do not complete cytokinesis and remain connected as a syncytium throughout the entire process of spermatogenesis. Interestingly, MgcRacGAP was shown to locate to the intercellular bridges, connecting these germ cells. In order to determine the function(s) of MgcRacGAP in the male germline, we generated a conditional knock-out mouse using Stra8 promoter driven Cre recombinase to induce the specific deletion of MgcRacGAP in the pre-meiotic germ cells. We found that the absence of MgcRacGAP induced a germline depletion and male sterility. Consistent with the role of MgcRacGAP in the establishment of the cytoplasm constriction during cytokinesis of the somatic cells, we observed that MgcRacGAP deletion in the germ cells prevented the formation of the intercellular bridges and induced a proliferation arrest. While we assume that inherited homozygous loss of function mutations in MgcRacGAP would be lethal in human, de novo mutations in the testis might account for some cases of non-obstructive oligo- and/or azoo-spermia syndromes, whose genetic causes are altogether still poorly defined. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. A combination of two truncating mutations in USH2A causes more severe and progressive hearing impairment in Usher syndrome type IIa

    DEFF Research Database (Denmark)

    Hartel, Bas P.; Lofgren, Maria; Huygen, Patrick L. M.

    2016-01-01

    Objectives Usher syndrome is an inherited disorder that is characterized by hearing impairment (HI), retinitis pigmentosa, and in some cases vestibular dysfunction. Usher syndrome type IIa is caused by mutations in USH2A. HI in these patients is highly heterogeneous and the present study evaluates...... the effects of different types of USH2A mutations on the audiometric phenotype. Data from two large centres of expertise on Usher Syndrome in the Netherlands and Sweden were combined in order to create a large combined sample of patients to identify possible genotype-phenotype correlations. Design...... A retrospective study on HI in 110 patients (65 Dutch and 45 Swedish) genetically diagnosed with Usher syndrome type IIa. We used methods especially designed for characterizing and testing differences in audiological phenotype between patient subgroups. These methods included Age Related Typical Audiograms (ARTA...

  8. Bone structure in two adult subjects with impaired minor spliceosome function resulting from RNU4ATAC mutations causing microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1)

    DEFF Research Database (Denmark)

    Krøigård, Anne Bruun; Frost, Morten; Larsen, Martin Jakob

    2016-01-01

    Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1), or Taybi-Linder syndrome is characterized by distinctive skeletal dysplasia, severe intrauterine and postnatal growth retardation, microcephaly, dysmorphic features, and neurological malformations. It is an autosomal recessive...... disorder caused by homozygous or compound heterozygous mutations in the RNU4ATAC gene resulting in impaired function of the minor spliceosome.Here, we present the first report on bone morphology, bone density and bone microstructure in two adult MOPD1 patients and applied radiographs, dual energy X......, cortical thickness, total bone density, cortical bone density, trabecular bone density and trabecular bone volume per tissue volume (BV/TV) were all low. These findings may correlate to the short stature and low body weight of the MOPD1 patients. Our findings suggest that minor spliceosome malfunction may...

  9. Retinopathy of prematurity as a major cause of severe visual impairment and blindness in children in schools for the blind in Guadalajara city, Mexico.

    Science.gov (United States)

    Zepeda-Romero, L C; Barrera-de-Leon, J C; Camacho-Choza, C; Gonzalez Bernal, C; Camarena-Garcia, E; Diaz-Alatorre, C; Gutierrez-Padilla, J A; Gilbert, C

    2011-11-01

    To determine the causes of blindness in students attending schools for the blind in Guadalajara city, Mexico and to assess the availability of screening for retinopathy of prematurity (ROP) in local neonatal intensive care units. Information on causes of blindness was obtained by interview with parents and teachers, review of records and examination. Causes of visual loss in children with a distance visual acuity of blind) were determined and classified according to the WHO's classification system for children. Of 153 children in the two participating schools, 144 were severely visual impaired or blind. Their ages ranged from 4 months to 15 years and 58% were female. ROP was the most common cause of visual loss (34.7%), followed by optic nerve lesions (17.4%) and glaucoma (14.6%). 25/59 (42.3%) children aged 0-4 years were blind from ROP compared with 6/32 (18.8%) children aged 10-15 years. 78% of children blind from ROP had psychomotor delay and less than half (46%) had not received treatment for ROP. All five privately funded neonatal intensive care units in the city regularly screen for ROP compared with only four of the 12 units in the public sector. ROP is the leading cause of blindness in children in Mexico despite national guidelines being in place. Health policies promoting primary prevention through improved neonatal care need to be implemented. Advocacy is required so that the time ophthalmologists spend screening and treating ROP is included in their job description and hence salaried.

  10. Toll-like receptor 2 impairs host defense in gram-negative sepsis caused by Burkholderia pseudomallei (Melioidosis.

    Directory of Open Access Journals (Sweden)

    W Joost Wiersinga

    2007-07-01

    Full Text Available Toll-like receptors (TLRs are essential in host defense against pathogens by virtue of their capacity to detect microbes and initiate the immune response. TLR2 is seen as the most important receptor for gram-positive bacteria, while TLR4 is regarded as the gram-negative TLR. Melioidosis is a severe infection caused by the gram-negative bacterium, Burkholderia pseudomallei, that is endemic in Southeast Asia. We aimed to characterize the expression and function of TLRs in septic melioidosis.Patient studies: 34 patients with melioidosis demonstrated increased expression of CD14, TLR1, TLR2, and TLR4 on the cell surfaces of monocytes and granulocytes, and increased CD14, TLR1, TLR2, TLR4, LY96 (also known as MD-2, TLR5, and TLR10 mRNA levels in purified monocytes and granulocytes when compared with healthy controls. In vitro experiments: Whole-blood and alveolar macrophages obtained from TLR2 and TLR4 knockout (KO mice were less responsive to B. pseudomallei in vitro, whereas in the reverse experiment, transfection of HEK293 cells with either TLR2 or TLR4 rendered these cells responsive to this bacterium. In addition, the lipopolysaccharide (LPS of B. pseudomallei signals through TLR2 and not through TLR4. Mouse studies: Surprisingly, TLR4 KO mice were indistinguishable from wild-type mice with respect to bacterial outgrowth and survival in experimentally induced melioidosis. In contrast, TLR2 KO mice displayed a markedly improved host defenses as reflected by a strong survival advantage together with decreased bacterial loads, reduced lung inflammation, and less distant-organ injury.Patients with melioidosis displayed an up-regulation of multiple TLRs in peripheral blood monocytes and granulocytes. Although both TLR2 and TLR4 contribute to cellular responsiveness to B. pseudomallei in vitro, TLR2 detects the LPS of B. pseudomallei, and only TLR2 impacts on the immune response of the intact host in vivo. Inhibition of TLR2 may be a novel treatment

  11. (G2019S) LRRK2 causes early-phase dysfunction of SNpc dopaminergic neurons and impairment of corticostriatal long-term depression in the PD transgenic mouse.

    Science.gov (United States)

    Chou, Jun-Shiao; Chen, Chu-Yu; Chen, Ying-Ling; Weng, Yi-Hsin; Yeh, Tu-Hsueh; Lu, Chin-Song; Chang, Ya-Ming; Wang, Hung-Li

    2014-08-01

    Twelve- to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive neuronal death of substantia nigra pars compacta (SNpc) dopaminergic cells. In the present study, we hypothesized that prior to a late-phase death of SNpc dopaminergic neurons, (G2019S) LRRK2 also causes an early-phase neuronal dysfunction of SNpc dopaminergic cells in the (G2019S) LRRK2 mouse. Eight to nine-month-old (G2019S) LRRK2 transgenic mice exhibited the symptom of hypoactivity in the absence of the degeneration of SNpc dopaminergic neurons or nigrostriatal dopaminergic terminals. Whole-cell current-clamp recordings of SNpc dopaminergic cells in brain slices demonstrated a significant decrease in spontaneous firing frequency of SNpc dopaminergic neurons of 8-month-old (G2019S) LRRK2 mice. Carbon fiber electrode amperometry recording using striatal slices showed that (G2019S) LRRK2 transgenic mice at the age of 8 to 9months display an impaired evoked dopamine release in the dorsolateral striatum. Normal nigrostriatal dopaminergic transmission is required for the induction of long-term synaptic plasticity expressed at corticostriatal glutamatergic synapses of striatal medium spiny neurons. Whole-cell voltage-clamp recordings showed that in contrast to medium spiny neurons of 8 to 9-month-old wild-type mice, high-frequency stimulation of corticostriatal afferents failed to induce long-term depression (LTD) of corticostriatal EPSCs in medium spiny neurons of (G2019S) LRRK2 mice at the same age. Our study provides the evidence that mutant (G2019S) LRRK2 causes early-phase dysfunctions of SNpc dopaminergic neurons, including a decrease in spontaneous firing rate and a reduction in evoked dopamine release, and impairment of corticostriatal LTD in the (G2019S) LRRK2 transgenic mouse. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Holmes and Horrax (1919) revisited: impaired binocular fusion as a cause of "flat vision" after right parietal brain damage - a case study.

    Science.gov (United States)

    Schaadt, Anna-Katharina; Brandt, Stephan A; Kraft, Antje; Kerkhoff, Georg

    2015-03-01

    The complete loss of binocular depth perception ("flat vision") was first thoroughly described by Holmes and Horrax (1919), and has been occasionally reported thereafter in patients with bilateral posterior-parietal lesions. Though partial spontaneous recovery occurred in some cases, the precise cause(s) of this condition remained obscure for almost a century. Here, we describe a unique patient (EH) with a large right-sided occipito-parietal hemorrhage showing a complete loss of visual depth perception for several months post-stroke. EH could well simultaneously describe multiple visual objects - hence did not show simultanagnosia - but at the same time was completely unable to estimate their distance from him. In every 3-D visual scene objects appeared equidistant to him, thus experiencing a total loss of depth perception ("flat vision"). Neurovisual assessments revealed normal functions of the eyes. EH showed bilateral lower field loss and a severely impaired binocular convergent fusion, but preserved stereopsis. Perceptual re-training of binocular fusion resulted in a progressive and finally complete recovery of objective binocular fusion values and subjective binocular depth perception in a far-to-near-space, gradient-like manner. In parallel, visual depth estimation of relative distances improved, whereas stereopsis remained unchanged. Our results show that a complete loss of 3-D depth perception can result from an isolated impairment in binocular fusion. On a neuroanatomical level, this connection could be explained by a selective lesion of area V6/V6A in the medial occipito-parietal cortex that has been associated with the integration of visual space coordinates and sustained eye-positions into a cyclopean visual 3-D percept. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Global N-linked Glycosylation is Not Significantly Impaired in Myoblasts in Congenital Myasthenic Syndromes Caused by Defective Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1

    Directory of Open Access Journals (Sweden)

    Qiushi Chen

    2015-10-01

    Full Text Available Glutamine-fructose-6-phosphate transaminase 1 (GFPT1 is the first enzyme of the hexosamine biosynthetic pathway. It transfers an amino group from glutamine to fructose-6-phosphate to yield glucosamine-6-phosphate, thus providing the precursor for uridine diphosphate N-acetylglucosamine (UDP-GlcNAc synthesis. UDP-GlcNAc is an essential substrate for all mammalian glycosylation biosynthetic pathways and N-glycan branching is especially sensitive to alterations in the concentration of this sugar nucleotide. It has been reported that GFPT1 mutations lead to a distinct sub-class of congenital myasthenic syndromes (CMS termed “limb-girdle CMS with tubular aggregates”. CMS are hereditary neuromuscular transmission disorders in which neuromuscular junctions are impaired. To investigate whether alterations in protein glycosylation at the neuromuscular junction might be involved in this impairment, we have employed mass spectrometric strategies to study the N-glycomes of myoblasts and myotubes derived from two healthy controls, three GFPT1 patients, and four patients with other muscular diseases, namely CMS caused by mutations in DOK7, myopathy caused by mutations in MTND5, limb girdle muscular dystrophy type 2A (LGMD2A, and Pompe disease. A comparison of the relative abundances of bi-, tri-, and tetra-antennary N-glycans in each of the cell preparations revealed that all samples exhibited broadly similar levels of branching. Moreover, although some differences were observed in the relative abundances of some of the N-glycan constituents, these variations were modest and were not confined to the GFPT1 samples. Therefore, GFPT1 mutations in CMS patients do not appear to compromise global N-glycosylation in muscle cells.

  14. Prevalence and causes of blindness and visual impairment and their associated risk factors, in three tribal areas of Andhra Pradesh, India.

    Science.gov (United States)

    Singh, Nakul; Eeda, Shiva Shankar; Gudapati, Bala Krishna; Reddy, Srinivasa; Kanade, Pushkar; Shantha, Ghanshyam Palamaner Subash; Rani, Padmaja Kumari; Chakrabarti, Subhabrata; Khanna, Rohit C

    2014-01-01

    To assess the prevalence of blindness and visual impairment (VI), their associated causes and underlying risk factors in three tribal areas of Andhra Pradesh, India and compare this data in conjunction with data from other countries with low and middle income settings. Using a validated Rapid Assessment of Avoidable Blindness methodology, a two stage sampling survey was performed in these areas involving probability proportionate to size sampling and compact segment sampling methods. Blindness, VI and severe visual impairment (SVI) were defined as per the WHO guidelines and Indian definitions. Based on a prior enumeration, 7281 (97.1%) subjects were enrolled (mean age = 61.0+/-7.9 years). Based on the presenting visual acuity (PVA), the prevalences of VI, SVI and blindness were 16.9% (95% CI: 15.7-18.1), 2.9% (95% CI: 2.5-3.4), and 2.3% (95% CI: 1.9-2.7), respectively. When based on the Pinhole corrected visual acuity (PCVA), the prevalences were lower in VI (6.2%, 95% CI: 5.4-6.9), SVI (1.5%, 95% CI: 1.2-1.9) and blindness (2.1%, 95% CI: 1.7-2.5). Refractive error was the major cause of VI (71.4%), whereas, cataract was the major cause of SVI and blindness (70.3%). Based on the PVA, the odds ratio (OR) of blindness increased in the age groups of 60-69 years (OR = 3.8, 95% CI: 2.8, 5.1), 70-79 years (OR = 10.6, 95% CI: 7.2, 15.5) and 80 years and above (OR = 30.7, 95% CI: 19.2, 49). The ORs were relatively higher in females (OR = 1.3, 95% CI: 1.0, 1.6) and illiterate subjects (OR = 4.3, 95% CI: 2.2, 8.5), but lower in those wearing glasses (OR = 0.2, 95% CI: 0.1, 0.4). This is perhaps the first study to assess the prevalence of blindness and VI in these tribal regions and the majority of the causes of blindness and SVI were avoidable (88.5%). These findings may be useful for planning eye care services in these underserved regions.

  15. Prevalence and causes of blindness and visual impairment and their associated risk factors, in three tribal areas of Andhra Pradesh, India.

    Directory of Open Access Journals (Sweden)

    Nakul Singh

    Full Text Available OBJECTIVE: To assess the prevalence of blindness and visual impairment (VI, their associated causes and underlying risk factors in three tribal areas of Andhra Pradesh, India and compare this data in conjunction with data from other countries with low and middle income settings. METHODS: Using a validated Rapid Assessment of Avoidable Blindness methodology, a two stage sampling survey was performed in these areas involving probability proportionate to size sampling and compact segment sampling methods. Blindness, VI and severe visual impairment (SVI were defined as per the WHO guidelines and Indian definitions. RESULTS: Based on a prior enumeration, 7281 (97.1% subjects were enrolled (mean age = 61.0+/-7.9 years. Based on the presenting visual acuity (PVA, the prevalences of VI, SVI and blindness were 16.9% (95% CI: 15.7-18.1, 2.9% (95% CI: 2.5-3.4, and 2.3% (95% CI: 1.9-2.7, respectively. When based on the Pinhole corrected visual acuity (PCVA, the prevalences were lower in VI (6.2%, 95% CI: 5.4-6.9, SVI (1.5%, 95% CI: 1.2-1.9 and blindness (2.1%, 95% CI: 1.7-2.5. Refractive error was the major cause of VI (71.4%, whereas, cataract was the major cause of SVI and blindness (70.3%. Based on the PVA, the odds ratio (OR of blindness increased in the age groups of 60-69 years (OR = 3.8, 95% CI: 2.8, 5.1, 70-79 years (OR = 10.6, 95% CI: 7.2, 15.5 and 80 years and above (OR = 30.7, 95% CI: 19.2, 49. The ORs were relatively higher in females (OR = 1.3, 95% CI: 1.0, 1.6 and illiterate subjects (OR = 4.3, 95% CI: 2.2, 8.5, but lower in those wearing glasses (OR = 0.2, 95% CI: 0.1, 0.4. CONCLUSIONS: This is perhaps the first study to assess the prevalence of blindness and VI in these tribal regions and the majority of the causes of blindness and SVI were avoidable (88.5%. These findings may be useful for planning eye care services in these underserved regions.

  16. Cortical visual impairment

    OpenAIRE

    Koželj, Urša

    2013-01-01

    In this thesis we discuss cortical visual impairment, diagnosis that is in the developed world in first place, since 20 percent of children with blindness or low vision are diagnosed with it. The objectives of the thesis are to define cortical visual impairment and the definition of characters suggestive of the cortical visual impairment as well as to search for causes that affect the growing diagnosis of cortical visual impairment. There are a lot of signs of cortical visual impairment. ...

  17. Identification of Two Disease-causing Genes TJP2 and GJB2 in a Chinese Family with Unconditional Autosomal Dominant Nonsyndromic Hereditary Hearing Impairment

    Directory of Open Access Journals (Sweden)

    Hong-Yang Wang

    2015-01-01

    Full Text Available Background: There are more than 300 genetic loci that have been found to be related to hereditary hearing impairment (HHI, including 92 causative genes for nonsyndromic hearing loss, among which 34 genes are related to autosomal dominant nonsyndromic HHI (ADNSHHI. Traditional linkage analysis and candidate gene sequencing are not effective at detecting the ADNSHHI, especially for the unconditional families that may have more than one pathogenic cause. This study identified two disease-causing genes TJP2 and GJB2 in a Chinese family with unconditional ADNSHHI. Methods: To decipher the genetic code of a Chinese family (family 686 with ADNSHHI, different gene screening techniques have been performed, including linkage analysis, candidate genes screening, high-throughput sequencing and Sanger sequencing. These techniques were done on samples obtained from this family over a period of 10 years. Results: We identified a pathogenic missense mutation, c. 2081G>A (p.G694E, in TJP2, a gene that plays a crucial role in apoptosis and age-related hearing loss (ARHL. The mutation was co-segregated in this pedigree in all, but not in the two patients who presented with different phenotypes from the other affected family members. In one of the two patients, we confirmed that the compound heterozygosity for p.Y136FNx01 and p.G45E in the GJB2 gene may account for the phenotype shown in this patient. Conclusions: We identified the co-occurrence of two genetic causes in family 686. The possible disease-causing missense mutation of TJP2 in family 686 presents an opportunity for further investigation into ARHL. It is necessary to combine various genes screening methods, especially for some unconventional cases.

  18. Nigral injection of antisense oligonucleotides to synaptotagmin I using HVJ-liposome vectors causes disruption of dopamine release in the striatum and impaired skill learning.

    Science.gov (United States)

    Akita, Hisanao; Ogata, Masanori; Jitsuki, Susumu; Ogura, Taichi; Oh-Nishi, Arata; Hoka, Sumio; Saji, Makoto

    2006-06-20

    To produce an animal model of a dopa-responsive motor disorder with depletion of dopamine (DA) release in the striatum by dysfunction of the transmitter release machinery of the nigrostriatal DA system, we performed an intra-nigral injection of an HVJ-liposome gene transfer vector containing antisense oligodeoxynucleotides (ODNs) against synaptotagmin I (SytI), a key regulator of Ca(2+)-dependent exocytosis and endocytosis in adult rats. A unilateral intra-nigral injection of HVJ-liposome vectors containing antisense ODNs against SytI (syt-AS) caused a moderate disruption of methamphetamine-induced release of DA in the treated side of the striatum, while the syt-AS treatment did not affect physiological release of DA in the treated striatum. A bilateral intra-nigral injection of HVJ-liposome vectors containing syt-AS induced an impairment of the striatal DA-mediated acquisition of skilled behavior in a rotarod task without any deficits in general motor functions, such as spontaneous locomotor activity, motor adjusting steps, equilibrium function, or muscle strength. These findings suggest that an intra-nigral treatment with HVJ-liposome vectors containing syt-AS may cause a long-lasting nigral knockdown of SytI which, in turn, leads to a moderate dysfunction of the DA release machinery in the terminals of the nigrostriatal DA system and a subsequent mild depletion of DA release in the striatum.

  19. Distinct Neurochemical Profiles of Spinocerebellar Ataxias 1, 2, 6, and Cerebellar Multiple System Atrophy

    Science.gov (United States)

    Öz, Gülin; Iltis, Isabelle; Hutter, Diane; Thomas, William; Bushara, Khalaf O.; Gomez, Christopher M.

    2011-01-01

    Hereditary and sporadic neurodegenerative ataxias are movement disorders that affect the cerebellum. Robust and objective biomarkers are critical for treatment trials of ataxias. In addition, such biomarkers may help discriminate between ataxia subtypes because these diseases display substantial overlap in clinical presentation and conventional MRI. Profiles of 10–13 neurochemical concentrations obtained in vivo by high field proton magnetic resonance spectroscopy (1H MRS) can potentially provide ataxia-type specific biomarkers. We compared cerebellar and brainstem neurochemical profiles measured at 4 T from 26 patients with spinocerebellar ataxias (SCA1, N=9; SCA2, N=7; SCA6, N=5) or cerebellar multiple system atrophy (MSA-C, N=5) and 15 age-matched healthy controls. The Scale for the Assessment and Rating of Ataxia (SARA) was used to assess disease severity. The patterns of neurochemical alterations relative to controls differed between ataxia types. Myo-inositol levels in the vermis, myo-inositol, total N-acetylaspartate, total creatine, glutamate, glutamine in the cerebellar hemispheres and myo-inositol, total N-acetylaspartate, glutamate in the pons were significantly different between patient groups (Bonferroni corrected pataxia types. Studies with higher numbers of patients and other ataxias are warranted to further investigate the clinical utility of neurochemical levels as measured by high-field MRS as ataxia biomarkers. PMID:20838948

  20. A cause of visual impairment

    African Journals Online (AJOL)

    This implies that the patients who reported to the hospital form the tip of the iceberg of patients who have undergone couching. Many of those who are yet to present to the hospital are probably still using one normal eye or they might have accepted their fate in good faith. The poor visual acuity following couching for cataract.

  1. Pathogenesis of parkinsoys disease. Microvascular and neurochemical analysis.

    OpenAIRE

    Rafael, Hernando; Departamento de Neurociencias, Universidad Nacional Autónoma de México, D.F., México

    2014-01-01

    Contrary to the hypothesis of genetic predisposition in the pathogenesis of Parkinson discase as proposed by many researchers, we suggest that an impairment of blood flow to the substantia nigra is the primary pathological process of this disease, not necessarily related to aging. Conclusion: Based ¡n histopathological and neurochenfical findings ¡n dopaminergic neurons, Parkinson's discase is due to a suboptinial and chronic reduction of arteria¡ blood flow to the mesencephalon. Therefore, r...

  2. Population-based assessment of prevalence and causes of visual impairment in the state of Telangana, India: a cross-sectional study using the Rapid Assessment of Visual Impairment (RAVI) methodology.

    Science.gov (United States)

    Marmamula, Srinivas; Khanna, Rohit C; Kunkunu, Eswararao; Rao, Gullapalli N

    2016-12-15

    To assess the prevalence and causes of visual impairment (VI) among a rural population aged 40 years and older in the state of Telangana in India. Population-based cross-sectional study. Districts of Adilabad and Mahbubnagar in south Indian state of Telangana, India. A sample of 6150 people was selected using cluster random sampling methodology. A team comprising a trained vision technician and a field worker visited the households and conducted the eye examination. Presenting, pinhole and aided visual acuity were assessed. Anterior segment was examined using a torchlight. Lens was examined using distant direct ophthalmoscopy in a semidark room. In all, 5881 (95.6%) participants were examined from 123 study clusters. Among those examined, 2723 (46.3%) were men, 4824 (82%) had no education, 2974 (50.6%) were from Adilabad district and 1694 (28.8%) of them were using spectacles at the time of eye examination. VI was defined as presenting visual acuity glasses (OR 0.19; 95% CI 0.1 to 0.2) were protective. VI was also higher in Mahbubnagar (OR 1.0 to 1.5) district. Cataract (54.7%) was the leading cause of VI followed by uncorrected refractive errors (38.6%). VI continues to remain a challenge in rural Telangana. As over 90% of the VI is avoidable, massive eye care programmes are required to address the burden of VI in Telangana. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  3. Development of intraoperative electrochemical detection: wireless instantaneous neurochemical concentration sensor for deep brain stimulation feedback.

    Science.gov (United States)

    Van Gompel, Jamie J; Chang, Su-Youne; Goerss, Stephan J; Kim, In Yong; Kimble, Christopher; Bennet, Kevin E; Lee, Kendall H

    2010-08-01

    Deep brain stimulation (DBS) is effective when there appears to be a distortion in the complex neurochemical circuitry of the brain. Currently, the mechanism of DBS is incompletely understood; however, it has been hypothesized that DBS evokes release of neurochemicals. Well-established chemical detection systems such as microdialysis and mass spectrometry are impractical if one is assessing changes that are happening on a second-to-second time scale or for chronically used implanted recordings, as would be required for DBS feedback. Electrochemical detection techniques such as fast-scan cyclic voltammetry (FSCV) and amperometry have until recently remained in the realm of basic science; however, it is enticing to apply these powerful recording technologies to clinical and translational applications. The Wireless Instantaneous Neurochemical Concentration Sensor (WINCS) currently is a research device designed for human use capable of in vivo FSCV and amperometry, sampling at subsecond time resolution. In this paper, the authors review recent advances in this electrochemical application to DBS technologies. The WINCS can detect dopamine, adenosine, and serotonin by FSCV. For example, FSCV is capable of detecting dopamine in the caudate evoked by stimulation of the subthalamic nucleus/substantia nigra in pig and rat models of DBS. It is further capable of detecting dopamine by amperometry and, when used with enzyme linked sensors, both glutamate and adenosine. In conclusion, WINCS is a highly versatile instrument that allows near real-time (millisecond) detection of neurochemicals important to DBS research. In the future, the neurochemical changes detected using WINCS may be important as surrogate markers for proper DBS placement as well as the sensor component for a "smart" DBS system with electrochemical feedback that allows automatic modulation of stimulation parameters. Current work is under way to establish WINCS use in humans.

  4. [Prevalence and causes of blindness and moderate and severe visual impairment among adults aged 50 years or above in Changji City of Xinjiang Uygur Autonomous Region: the China Nine-Province survey].

    Science.gov (United States)

    Ma, Xian-zhi; Zhao, Jia-liang; Ellwein, Leon B; Wei, Bin; Chen, Jing; Ye, Ying; Tang, Xiao-dong; Yang, Mei; Wang, Yu; Gao, Xue-cheng

    2013-09-01

    To investigate the prevalence and causes of blindness and moderate and severe visual impairment among adults aged ≥ 50 years in Changji City of Xinjiang Uygur Autonomous Region, China. It was a population-based cross-section study.Geographically defined cluster sampling was used in randomly selecting 5714 individuals aged ≥ 50 years in Changji City. The survey was preceded by a pilot study where operational methods were refined and quality assurance evaluation was carried out. All participants were enumerated through village registers followed door-to-door visits.Eligible individuals were invited to received visual acuity measurement and eye examination. Prevalence of blindness and moderate and severe visual impairment was calculated according to different age, gender or education. And the reasons of blindness were analyzed.Statistical analyses were performed using Stata/SE Statistical Software, release 9.0. Chi-square test was used to investigate the association of age, gender and education with presenting and best corrected visual acuity. Five thousands seven hundreds and fourteen individuals were enumerated and 5250 persons were examined, the response rate was 91.88%. Based on the criteria of World Health Organization visual impairment classification in 1973, the prevalence of blindness and moderate and severe visual impairment defined as best corrected visual acuity was 0.74% (39/5250) and 3.83% (201/5250) respectively. The prevalence of blindness and moderate and severe visual impairment defined as presenting visual acuity was 1.33% (70/5250) and 8.02% (421/5250) respectively. The prevalence of blindness and moderate and severe visual impairment was higher in aged (trend χ(2) = 617.06, P = 0.000) , illiterate (trend χ(2) = 222.35, P = 0.000) persons. Cataract and was the first leading cause of blindness and visual impairment, the retinal diseases, including age-related macular degeneration, high myopic retinopathy, and diabetic retinopathy, were the

  5. Transplacental exposure to AZT induces adverse neurochemical and behavioral effects in a mouse model: protection by L-acetylcarnitine.

    Directory of Open Access Journals (Sweden)

    Anna Rita Zuena

    Full Text Available Maternal-fetal HIV-1 transmission can be prevented by administration of AZT, alone or in combination with other antiretroviral drugs to pregnant HIV-1-infected women and their newborns. In spite of the benefits deriving from this life-saving prophylactic therapy, there is still considerable uncertainty on the potential long-term adverse effects of antiretroviral drugs on exposed children. Clinical and experimental studies have consistently shown the occurrence of mitochondrial dysfunction and increased oxidative stress following prenatal treatment with antiretroviral drugs, and clinical evidence suggests that the developing brain is one of the targets of the toxic action of these compounds possibly resulting in behavioral problems. We intended to verify the effects on brain and behavior of mice exposed during gestation to AZT, the backbone of antiretroviral therapy during human pregnancy. We hypothesized that glutamate, a neurotransmitter involved in excitotoxicity and behavioral plasticity, could be one of the major actors in AZT-induced neurochemical and behavioral alterations. We also assessed the antioxidant and neuroprotective effect of L-acetylcarnitine, a compound that improves mitochondrial function and is successfully used to treat antiretroviral-induced polyneuropathy in HIV-1 patients. We found that transplacental exposure to AZT given per os to pregnant mice from day 10 of pregnancy to delivery impaired in the adult offspring spatial learning and memory, enhanced corticosterone release in response to acute stress, increased brain oxidative stress also at birth and markedly reduced expression of mGluR1 and mGluR5 subtypes and GluR1 subunit of AMPA receptors in the hippocampus. Notably, administration during the entire pregnancy of L-acetylcarnitine was effective in preventing/ameliorating the neurochemical, neuroendocrine and behavioral adverse effects induced by AZT in the offspring. The present preclinical findings provide a

  6. The DYX2 locus and neurochemical signaling genes contribute to speech sound disorder and related neurocognitive domains.

    Science.gov (United States)

    Eicher, J D; Stein, C M; Deng, F; Ciesla, A A; Powers, N R; Boada, R; Smith, S D; Pennington, B F; Iyengar, S K; Lewis, B A; Gruen, J R

    2015-04-01

    A major milestone of child development is the acquisition and use of speech and language. Communication disorders, including speech sound disorder (SSD), can impair a child's academic, social and behavioral development. Speech sound disorder is a complex, polygenic trait with a substantial genetic component. However, specific genes that contribute to SSD remain largely unknown. To identify associated genes, we assessed the association of the DYX2 dyslexia risk locus and markers in neurochemical signaling genes (e.g., nicotinic and dopaminergic) with SSD and related endophenotypes. We first performed separate primary associations in two independent samples - Cleveland SSD (210 affected and 257 unaffected individuals in 127 families) and Denver SSD (113 affected individuals and 106 unaffected individuals in 85 families) - and then combined results by meta-analysis. DYX2 markers, specifically those in the 3' untranslated region of DCDC2 (P = 1.43 × 10(-4) ), showed the strongest associations with phonological awareness. We also observed suggestive associations of dopaminergic-related genes ANKK1 (P = 1.02 × 10(-2) ) and DRD2 (P = 9.22 × 10(-3) ) and nicotinic-related genes CHRNA3 (P = 2.51 × 10(-3) ) and BDNF (P = 8.14 × 10(-3) ) with case-control status and articulation. Our results further implicate variation in putative regulatory regions in the DYX2 locus, particularly in DCDC2, influencing language and cognitive traits. The results also support previous studies implicating variation in dopaminergic and nicotinic neural signaling influencing human communication and cognitive development. Our findings expand the literature showing genetic factors (e.g., DYX2) contributing to multiple related, yet distinct neurocognitive domains (e.g., dyslexia, language impairment, and SSD). How these factors interactively yield different neurocognitive and language-related outcomes remains to be elucidated. © 2015 The Authors. Genes, Brain and Behavior published by

  7. [Prevalence and causes of blindness and moderate and severe visual impairment among adults aged 50 years or above in Yongchuan District of Chongqing City: the China Nine-Province survey].

    Science.gov (United States)

    Yin, Zheng-qin; Zhao, Jia-liang; Li, Ping-hua; Ellwein, Leon b; Song, Sheng-fang; Li, Fu-liang; Wang, Ting-gang; Ren, Yi-ming; Yang, Mei; Wang, Yu; Gao, Xue-cheng

    2013-09-01

    To investigate the prevalence and causes of blindness and moderate and severe visual impairment among adults aged 50 years or above in Yongchuan of Chongqing City, China. It was a population-based cross-section study.Geographically defined cluster sampling was used in randomly selecting 5663 individuals aged ≥ 50 years in Yongchuan District. The survey was preceded by a pilot study where operational methods were refined and quality assurance evaluation was carried out. All participants were enumerated through village registers followed door-to-door visits.Eligible individuals were invited to receive visual acuity measurement and eye examination. Prevalence of blindness and moderate and severe visual impairment was calculated according to different age, gender or education. And the reasons of blindness were analyzed.Statistical analyses were performed using Stata/SE Statistical Software, release 9.0. Chi-square test was used to investigate the association of age, gender and education with presenting and best corrected visual acuity. Five thousands six hundreds and sixty-three individuals were enumerated and 5390 persons were examined, the response rate was 95.18%. Based on the criteria of World Health Organization visual impairment classification in 1973, the prevalence of blindness and moderate and severe visual impairment defined as best corrected visual acuity was 2.12% (114/5390) and 5.40% (291/5390) respectively. The prevalence of blindness and moderate and severe visual impairment defined as presenting visual acuity was 2.49% (134/5390) and 10.71% (577/5390) respectively. The prevalence of blindness and moderate and severe visual impairment was higher in aged (trend χ(2) = 951.32, P = 0.000) , female (χ(2) = 33.35, P = 0.000) and illiterate (trend χ(2) equals; 141.32, P = 0.000) persons. Cataract was still the first leading cause of blindness and visual impairment.Un-corrected refractive error also was the main cause of visual impairment. The prevalence

  8. Magnitude and Causes of Low Vision Disability (Moderate and Severe Visual Impairment) among Students of Al-Noor Institute for the Blind in Al-Hassa, Saudi Arabia: A case series.

    Science.gov (United States)

    Al-Wadani, Fahad; Khandekar, Rajiv; Al-Hussain, Muneera A; Alkhawaja, Ahmed A; Khan, Mohammed Sarfaraz; Alsulaiman, Ramzy A

    2012-02-01

    This study aimed to estimate the magnitude and causes of low vision disability (severe visual impairment [SVI] and moderate visual impairment [MVI]) among students at Al-Noor Institute for the Blind (NIB) in Al-Hassa, Saudi Arabia in 2006. An optometrist conducted refraction of 122 eyes of the 61 students (27 boys and 34 girls) with MVI (vision visual acuity was ≥6/18 and in 28 (23%) eyes, it was visual impairment in 16 (13.1%) and 9 (7.4%) eyes. These students were prescribed optical and non-optical low vision aids. Retinal disease was the main cause of SVI and MVI in our series. Some students at Al-Noor Institute for the Blind have curable low vision conditions. Rehabilitation of low vision disability should be different from that offered to the absolutely blind.

  9. Longitudinal neurochemical modifications in the aging mouse brain measured in vivo by 1H magnetic resonance spectroscopy.

    Science.gov (United States)

    Duarte, João M N; Do, Kim Q; Gruetter, Rolf

    2014-07-01

    Alterations to brain homeostasis during development are reflected in the neurochemical profile determined noninvasively by (1)H magnetic resonance spectroscopy. We determined longitudinal biochemical modifications in the cortex, hippocampus, and striatum of C57BL/6 mice aged between 3 and 24 months . The regional neurochemical profile evolution indicated that aging induces general modifications of neurotransmission processes (reduced GABA and glutamate), primary energy metabolism (altered glucose, alanine, and lactate) and turnover of lipid membranes (modification of choline-containing compounds and phosphorylethanolamine), which are all probably involved in the frequently observed age-related cognitive decline. Interestingly, the neurochemical profile was different in male and female mice, particularly in the levels of taurine that may be under the control of estrogen receptors. These neurochemical profiles constitute the basal concentrations in cortex, hippocampus, and striatum of healthy aging male and female mice. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Neuronal expression of familial Parkinson's disease A53T α-synuclein causes early motor impairment, reduced anxiety and potential sleep disturbances in mice.

    Science.gov (United States)

    Rothman, Sarah M; Griffioen, Kathleen J; Vranis, Neil; Ladenheim, Bruce; Cong, Wei-na; Cadet, Jean-Lud; Haran, Jamie; Martin, Bronwen; Mattson, Mark P

    2013-01-01

    Mutations in the human α-synuclein gene lead to early-onset Parkinson's disease (PD); however, phenotypes of α-synuclein mutant mice vary depending upon the promoter driving transgene expression. The goal of this study was to characterize behavior and neurochemical alterations in mice expressing mutant (A53T) human α-synuclein, controlled by a neuron-specific Thy-1 promoter. Our data provide important additional phenotypic and biochemical characterization of a previously generated model of PD. A53T (SNCA) and wild type (WT) littermate mice were evaluated for motor function (rotarod and stride length) and anxiety (elevated plus maze and open field) every 2 weeks. At 24 weeks mice were evaluated in a Comprehensive Lab Animal Monitoring System (CLAMS). A separate cohort of mice were euthanized at 12, 24 and 36 weeks for immunoblot analysis of α-synuclein, dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the striatum, and hypothalamic serotonin and metabolites were measured. SNCA mice display significant motor deficits at 14-18 weeks of age compared to WT mice, which progress over time. CLAMS analysis revealed an increase in activity during the dark phase and a reduction in overall estimated sleep time for SNCA mice compared to WT consistent with clinical reports of sleep abnormalities in PD. A transient change in the levels of DAT appeared at 12 weeks in the striatum and serotonin levels were also altered in the hypothalamus at this time point. This PD model displays consistent and clinically relevant motor and sleep phenotypes. Anxiety phenotypes are consistent with other α-synuclein based PD models yet incongruous with typical clinical symptoms. Early increases in serotonin levels potentially explain reductions in anxiety behaviors and sleep.

  11. Integrative pathways linking close family ties to health: A neurochemical perspective.

    Science.gov (United States)

    Uchino, Bert N; Way, Baldwin M

    2017-09-01

    The quality of one's familial life, for better or worse, has been linked to physical health. Such associations are evident across a number of acute and chronic conditions and highlight the widespread impact that close relationships have on physical health. However, the field currently lacks a complete understanding of the integrative biological pathways underlying the association between close relationships and disease risk. This article reviews the main peripheral biological and central nervous system pathways linking positive and negative familial relationship processes to physical health outcomes. It emphasizes the role of neurochemical pathways in mediating the influence of social relationships on health-relevant peripheral physiological systems using the oxytocin system as a model. Such neurochemical approaches are an important step toward a more integrative understanding of complex biological pathways and has novel theoretical and intervention implications. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  12. [Prevalence and causes of blindness and moderate and severe visual impairment among adults aged 50 years or above in Longyao County of Hebei Province:the China Nine-Province survey].

    Science.gov (United States)

    Lü, Jian-hua; Zhao, Jia-liang; Ellwein, Leon B; Li, Shan-yu; Han, Dong; Yan, Zhong-yang; Zhang, Hong-bin; Yang, Mei; Wang, Yu; Gao, Xue-cheng

    2013-09-01

    To investigate the prevalence and causes of blindness and moderate and severe visual impairment among adults aged ≥ 50 years in Longyao County, Hebei Province, China. It was a population-based cross-section study.Geographically defined cluster sampling was used in randomly selecting 5527 individuals aged ≥ 50 years in Longyao County. The survey was preceded by a pilot study where operational methods were refined and quality assurance evaluation was carried out. All participants were enumerated through village registers followed door-to-door visits.Eligible individuals were invited to receive visual acuity measurement and eye examination. Prevalence of blindness and moderate and severe visual impairment was calculated according to different age, gender or education. And the reasons of blindness were analyzed.Statistical analyses were performed using Stata/SE Statistical Software, release 9.0. Chi-square test was used to investigate the association of age, gender and education with presenting and best corrected visual acuity. Five thousands five hundreds and twenty-seven individuals were enumerated and 5051 persons were examined, the response rate was 91.39%. Based on the criteria of World Health Organization visual impairment classification in 1973, the prevalence of blindness and moderate and severe visual impairment defined as best corrected visual acuity was 1.05% (53/5051) and 3.46% (175/5051) respectively. The prevalence of blindness and moderate and severe visual impairment defined as presenting visual acuity was 1.48% (75/5051) and 7.94% (401/5051) respectively. The prevalence of blindness and moderate and severe visual impairment was higher in aged (trend χ(2) = 897.27, P = 0.000) , female (χ(2) = 30.32, P = 0.000), illiterate (trend χ(2) = 83.20, P = 0.000) persons. Cataract was still the first leading cause of blindness. Un-corrected refractive error also was the main cause of visual impairment. The prevalence of blindness and moderate and severe

  13. PAPSS2 Deficiency Causes Androgen Excess via Impaired DHEA Sulfation—In Vitro and in Vivo Studies in a Family Harboring Two Novel PAPSS2 Mutations

    Science.gov (United States)

    Oostdijk, Wilma; Idkowiak, Jan; Mueller, Jonathan W.; House, Philip J.; Taylor, Angela E.; O'Reilly, Michael W.; Hughes, Beverly A.; de Vries, Martine C.; Kant, Sarina G.; Santen, Gijs W. E.; Verkerk, Annemieke J. M. H.; Uitterlinden, André G.; Wit, Jan M.; Losekoot, Monique

    2015-01-01

    Context: PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3′-phospho-adenosine-5′-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome. Patients and Methods: We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro. Results: We identified a novel PAPSS2 frameshift mutation, c.1371del, p.W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c.809G>A, p.G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p.W462Cfs*3, showed increased 5α-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction. Conclusions: We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome. PMID:25594860

  14. A point mutation affecting an SP1 binding site in the promoter of the ferrochelatase gene impairs gene transcription and causes erythropoietic protoporphyria.

    Science.gov (United States)

    Di Pierro, Elena; Cappellini, Maria Domenica; Mazzucchelli, Renata; Moriondo, Valeria; Mologni, Daniela; Zanone Poma, Barbara; Riva, Agostino

    2005-05-01

    Clinical manifestation of erythropoietic protoporphyria (EPP) results from coinheritance of a mutated allele and a wild-type low-expressed allele of the ferrochelatase (FECH) gene. Currently, up to 90 different mutations affecting the coding region or splicing junctions of the FECH gene have been identified. Despite the high molecular heterogeneity, no functional mutations have been previously reported in the promoter region. The weaker allele expression has been controversially associated to the presence of different intragenic polymorphisms. We applied a two-step screening strategy using denaturing gradient gel electrophoresis followed by direct sequencing in order to rapidly identify FECH gene mutations in Italian EPP patients. We identified two unrelated subjects showing a normal FECH coding region but a single G>C base substitution at position -250 in the FECH promoter and the -251G, IVS1-23T, and IVS3-48C polymorphisms in trans to the substitution. To investigate the effect of the -250G>C mutation on protein binding to the FECH promoter, we conducted electro mobility shift assay (EMSA) and supershift analysis. To determine its effect on the transcriptional activity, K562 and Jurkat cell lines were transiently transfected. EMSA showed that the -250G>C mutation results in the loss of an SP1 binding site, and transient transfection assays demonstrated that such mutation strongly impairs promoter activity. Moreover, we showed that the -251A>G polymorphism, although unable to affect SP1 binding, displays a significant reduction in the transcriptional activity of the promoter. This is the first report of a mutation in the FECH promoter affecting binding of a transcription factor and causing EPP phenotype.

  15. RanBP9 overexpression down-regulates phospho-cofilin, causes early synaptic deficits and impaired learning, and accelerates accumulation of amyloid plaques in the mouse brain.

    Science.gov (United States)

    Palavicini, Juan Pablo; Wang, Hongjie; Minond, Dmitriy; Bianchi, Elisabetta; Xu, Shaohua; Lakshmana, Madepalli K

    2014-01-01

    Loss of synaptic proteins and functional synapses in the brains of patients with Alzheimer's disease (AD) as well as transgenic mouse models expressing amyloid-β protein precursor is now well established. However, the earliest age at which such loss of synapses occurs, and whether known markers of AD progression accelerate functional deficits is completely unknown. We previously showed that RanBP9 overexpression leads to enhanced amyloid plaque burden in a mouse model of AD. In this study, we found significant reductions in the levels of synaptophysin and spinophilin, compared with wild-type controls, in both the cortex and the hippocampus of 5- and 6-month old but not 3- or 4-month old APΔE9/RanBP9 triple transgenic mice, and not in APΔE9 double transgenic mice, nor in RanBP9 single transgenic mice. Interestingly, amyloid plaque burden was also increased in the APΔE9/RanBP9 mice at 5-6 months. Consistent with these results, we found significant deficits in learning and memory in the APΔE9/RanBP9 mice at 5 and 6 month. These data suggest that increased amyloid plaques and accelerated learning and memory deficits and loss of synaptic proteins induced by RanBP9 are correlated. Most importantly, APΔE9/RanBP9 mice also showed significantly reduced levels of the phosphorylated form of cofilin in the hippocampus. Taken together these data suggest that RanBP9 overexpression down-regulates cofilin, causes early synaptic deficits and impaired learning, and accelerates accumulation of amyloid plaques in the mouse brain.

  16. Disease-causing mutations affecting surface residues of mitochondrial glutaryl-CoA dehydrogenase impair stability, heteromeric complex formation and mitochondria architecture.

    Science.gov (United States)

    Schmiesing, Jessica; Lohmöller, Benjamin; Schweizer, Michaela; Tidow, Henning; Gersting, Søren W; Muntau, Ania C; Braulke, Thomas; Mühlhausen, Chris

    2017-02-01

    The neurometabolic disorder glutaric aciduria type 1 (GA1) is caused by mutations in the GCDH gene encoding the mitochondrial matrix protein glutaryl-CoA dehydrogenase (GCDH), which forms homo- and heteromeric complexes. Twenty percent of all pathogenic mutations affect single amino acid residues on the surface of GCDH resulting in a severe clinical phenotype. We report here on heterologous expression studies of 18 missense mutations identified in GA1 patients affecting surface amino acids. Western blot and pulse chase experiments revealed that the stability of half of the GCDH mutants was significantly reduced. In silico analyses showed that none of the mutations impaired the 3D structure of GCDH. Immunofluorescence co-localisation studies in HeLa cells demonstrated that all GCDH mutants were correctly translocated into mitochondria. Surprisingly, the expression of p.Arg88Cys GCDH as well as further substitutions by alanine, lysine, or methionine but not histidine or leucine resulted in the disruption of mitochondrial architecture forming longitudinal structures composed of stacks of cristae and partial loss of the outer mitochondrial membrane. The expression of mitochondrial fusion or fission proteins was not affected in these cells. Bioluminescence resonance energy transfer analyses revealed that all GCDH mutants exhibit an increased binding affinity to electron transfer flavoprotein beta, whereas only p.Tyr155His GCDH showed a reduced interaction with dihydrolipoamide succinyl transferase. Our data underscore the impact of GCDH protein interactions mediated by amino acid residues on the surface of GCDH required for proper enzymatic activity. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Acoustic trauma that can cause tinnitus impairs impulsive control but not performance accuracy in the 5-choice serial reaction time task in rats.

    Science.gov (United States)

    Zheng, Y; Hamilton, E; Stiles, L; McNamara, E; de Waele, C; Smith, P F; Darlington, C L

    2011-04-28

    Although tinnitus is an auditory disorder, it is often associated with attentional and emotional problems. Functional neuroimaging studies in humans have revealed that the hippocampus, amygdala and anterior cingulate, areas of the brain involved in emotion, attention and spatial processing, are also involved in auditory memory and tinnitus perception. However, few studies of tinnitus-evoked emotional and cognitive changes have been reported using animal models of tinnitus. In the present study, we investigated whether acoustic trauma that could cause tinnitus would affect attention and impulsivity in rats. Eight male Wistar rats were exposed to unilateral acoustic trauma (110 dB, 16 kHz for 1 h under anaesthesia) and eight rats underwent the same anaesthesia without acoustic trauma. Tinnitus was tested in noise-exposed rats using a frequency-specific shift in a discrimination function with a conditioned lick suppression paradigm. At 4 months after the noise exposure, the rats were tested in a 5-choice serial reaction time task. The behavioural procedure involved training the rats to discriminate a brief visual stimulus presented randomly in one of the five spatial locations and responding by poking its nose through the illuminated hole and collecting a food pellet from the magazine. While all of the animals performed equally well in making correct responses, the animals exposed to acoustic trauma made significantly more premature responses. The results suggest that rats exposed to acoustic trauma and some of which have chronic tinnitus are impaired in impulsive control, but not performance accuracy. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. Caffeine exposure during rat brain development causes memory impairment in a sex selective manner that is offset by caffeine consumption throughout life.

    Science.gov (United States)

    Ardais, Ana Paula; Rocha, Andréia S; Borges, Maurício Felisberto; Fioreze, Gabriela T; Sallaberry, Cássia; Mioranzza, Sabrina; Nunes, Fernanda; Pagnussat, Natália; Botton, Paulo Henrique S; Cunha, Rodrigo A; Porciúncula, Lisiane de Oliveira

    2016-04-15

    Caffeine is the psychostimulant most consumed worldwide. In moderate doses, it affords a beneficial effect in adults and upon aging, but has a deleterious effect during brain development. We now tested if caffeine consumption by rats (0.1, 0.3, 1.0 g/L in the drinking water, only during active cycle and weekdays) during adulthood could revert the potentially negative effects of caffeine during early life. Thus, we compared caffeine intake starting 15 days before mating and lasting either up to weaning (development) or up to adulthood, on behavior and synaptic proteins in male and female rats. Recognition memory was impaired only in female rats receiving caffeine (0.3 and 1.0 g/L) during development, coincident with increased proBDNF and unchanged BDNF levels in the hippocampus. Caffeine in both treatment regimens caused hyperlocomotion only in male rats, whereas anxiety-related behavior was attenuated in both sexes by caffeine (1.0 g/L) throughout life. Both caffeine treatment regimens decreased GFAP (as an astrocyte marker) and SNAP-25 (as a nerve terminals marker) in the hippocampus from male rats. TrkB receptor was decreased in the hippocampus from both sexes and treatment regimens. These findings revealed that caffeine intake during a specific time window of brain development promotes sex-dependent behavioral outcomes related to modification in BDNF signaling. Furthermore, caffeine throughout life can overcome the deleterious effects of caffeine on recognition memory during brain development in female rats. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Immunostaining of Biocytin-filled and Processed Sections for Neurochemical Markers.

    Science.gov (United States)

    Swietek, Bogumila; Gupta, Akshay; Proddutur, Archana; Santhakumar, Vijayalakshmi

    2016-12-31

    Electrophysiological recordings of cells using the patch clamp technique have allowed for the identification of different neuronal types based on firing patterns. The inclusion of biocytin/neurobiotin in the recording electrode permits post-hoc recovery of morphological details, which are necessary to determine the dendritic arborization and the regions targeted by the axons of the recorded neurons. However, given the presence of morphologically similar neurons with distinct neurochemical identities and functions, immunohistochemical staining for cell-type-specific proteins is essential to definitively identify neurons. To maintain network connectivity, brain sections for physiological recordings are prepared at a thickness of 300 µm or greater. However, this thickness often hinders immunohistological postprocessing due to issues with antibody penetration, necessitating the resectioning of the tissue. Resectioning of slices is a challenging art, often resulting in the loss of tissue and morphology of the cells from which electrophysiological data was obtained, rendering the data unusable. Since recovery of morphology would limit data loss and guide in the selection of neuronal markers, we have adopted a strategy of recovering cell morphology first, followed by secondary immunostaining. We introduce a practical approach to biocytin filling during physiological recordings and subsequent serial immunostaining for the recovery of morphology, followed by the restaining of sections to determine the neurochemical identity. We report that sections that were filled with biocytin, fixed with paraformaldehyde (PFA), stained, and coverslipped can be removed and restained with a second primary antibody days later. This restaining involves the removal of the coverslip, the washing of sections in a buffer solution, and the incubation of primary and secondary antibodies to reveal the neurochemical identity. The method is advantageous for eliminating data loss due to an inability

  20. Neurochemical dynamics of acute orofacial pain in the human trigeminal brainstem nuclear complex.

    Science.gov (United States)

    de Matos, Nuno M P; Hock, Andreas; Wyss, Michael; Ettlin, Dominik A; Brügger, Mike

    2017-09-04

    The trigeminal brainstem sensory nuclear complex is the first central relay structure mediating orofacial somatosensory and nociceptive perception. Animal studies suggest a substantial involvement of neurochemical alterations at such basal CNS levels in acute and chronic pain processing. Translating this animal based knowledge to humans is challenging. Human related examining of brainstem functions are challenged by MR related peculiarities as well as applicability aspects of experimentally standardized paradigms. Based on our experience with an MR compatible human orofacial pain model, the aims of the present study were twofold: 1) from a technical perspective, the evaluation of proton magnetic resonance spectroscopy at 3 T regarding measurement accuracy of neurochemical profiles in this small brainstem nuclear complex and 2) the examination of possible neurochemical alterations induced by an experimental orofacial pain model. Data from 13 healthy volunteers aged 19-46 years were analyzed and revealed high quality spectra with significant reductions in total N-acetylaspartate (N-acetylaspartate + N-acetylaspartylglutamate) (-3.7%, p = 0.009) and GABA (-10.88%, p = 0.041) during the pain condition. These results might reflect contributions of N-acetylaspartate and N-acetylaspartylglutamate in neuronal activity-dependent physiologic processes and/or excitatory neurotransmission, whereas changes in GABA might indicate towards a reduction in tonic GABAergic functioning during nociceptive signaling. Summarized, the present study indicates the applicability of (1)H-MRS to obtain neurochemical dynamics within the human trigeminal brainstem sensory nuclear complex. Further developments are needed to pave the way towards bridging important animal based knowledge with human research to understand the neurochemistry of orofacial nociception and pain. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Dysregulation of brain reward systems in eating disorders: neurochemical information from animal models of binge eating, bulimia nervosa, and anorexia nervosa.

    Science.gov (United States)

    Avena, Nicole M; Bocarsly, Miriam E

    2012-07-01

    Food intake is mediated, in part, through brain pathways for motivation and reinforcement. Dysregulation of these pathways may underlay some of the behaviors exhibited by patients with eating disorders. Research using animal models of eating disorders has greatly contributed to the detailed study of potential brain mechanisms that many underlie the causes or consequences of aberrant eating behaviors. This review focuses on neurochemical evidence of reward-related brain dysfunctions obtained through animal models of binge eating, bulimia nervosa, or anorexia nervosa. The findings suggest that alterations in dopamine (DA), acetylcholine (ACh) and opioid systems in reward-related brain areas occur in response to binge eating of palatable foods. Moreover, animal models of bulimia nervosa suggest that while bingeing on palatable food releases DA, purging attenuates the release of ACh that might otherwise signal satiety. Animal models of anorexia nervosa suggest that restricted access to food enhances the reinforcing effects of DA when the animal does eat. The activity-based anorexia model suggests alterations in mesolimbic DA and serotonin occur as a result of restricted eating coupled with excessive wheel running. These findings with animal models complement data obtained through neuroimaging and pharmacotherapy studies of clinical populations. Information on the neurochemical consequences of the behaviors associated with these eating disorders will be useful in understanding these complex disorders and may inform future therapeutic approaches, as discussed here. This article is part of a Special Issue entitled 'Central Control of Food Intake'. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. Behavioral and neurochemical characterization of kratom (Mitragyna speciosa) extract.

    Science.gov (United States)

    Stolt, Anne-Christin; Schröder, Helmut; Neurath, Hartmud; Grecksch, Gisela; Höllt, Volker; Meyer, Markus R; Maurer, Hans H; Ziebolz, Nancy; Havemann-Reinecke, Ursula; Becker, Axel

    2014-01-01

    Mitragyna speciosa and its extracts are named kratom (dried leaves, extract). It contains several alkaloids and is used in traditional medicine to alleviate musculoskeletal pain, hypertension, coughing, diarrhea, and as an opiate substitute for addicts. Abuse and addiction to kratom is described, and kratom has attracted increasing interest in Western countries. Individual effects of kratom on opioidergic, adrenergic, serotonergic, and dopaminergic receptors are known, but not all of the effects have been explained. Pharmacokinetic and pharmacodynamic data are needed. The effects of kratom extract on mice behavior were investigated following oral (po), intraperitoneal (ip), and intracerebroventricular (icv) application. Receptor-binding studies were performed. In μ opioid receptor knockout mice (-/-) and wild type (+/+) animals, the extract reduced locomotor activity after ip and low po doses in +/+ animals, but not after icv administration. The ip effect was counteracted by 0.3 mg/kg of apomorphine sc, suggesting dopaminergic presynaptic activity. An analgesic effect was only found in -/- mice after icv application. Norbinaltorphimine abolished the analgesic effect, but not the inhibitory effect, on locomotor activity, indicating that the analgesic effect is mediated via κ opioid receptors. Oral doses, which did not diminish locomotor activity, impaired the acquisition of shuttle box avoidance learning. There was no effect on consolidation. Binding studies showed affinity of kratom to μ, δ, and κ opioid receptors and to dopamine D1 receptors. The results obtained in drug-naïve mice demonstrate weak behavioral effects mediated via μ and κ opioid receptors.

  3. Induction of gram-negative bacterial growth by neurochemical containing banana (Musa x paradisiaca) extracts.

    Science.gov (United States)

    Lyte, M

    1997-09-15

    Bananas contain large quantities of neurochemicals. Extracts from the peel and pulp of bananas in increasing stages of ripening were prepared and evaluated for their ability to modulate the growth of non-pathogenic and pathogenic bacteria. Extracts from the peel, and to a much lesser degree the pulp, increased the growth of Gram-negative bacterial strains Escherichia coli O157:H7, Shigella flexneri, Enterobacter cloacae and Salmonella typhimurium, as well as two non-pathogenic E. coli strains, in direct relation to the content of norepinephrine and dopamine, but not serotonin. The growth of Gram-positive bacteria was not altered by any of the extracts. Supplementation of vehicle and pulp cultures with norepinephrine or dopamine yielded growth equivalent to peel cultures. Total organic analysis of extracts further demonstrated that the differential effects of peel and pulp on bacterial growth was not nutritionally based, but due to norepinephrine and dopamine. These results suggest that neurochemicals contained within foodstuffs may influence the growth of pathogenic and indigenous bacteria through direct neurochemical-bacterial interactions.

  4. Behavioral and neurochemical characterization of new mouse model of hyperphenylalaninemia.

    Directory of Open Access Journals (Sweden)

    Tiziana Pascucci

    Full Text Available Hyperphenylalaninemia (HPA refers to all clinical conditions characterized by increased amounts of phenylalanine (PHE in blood and other tissues. According to their blood PHE concentrations under a free diet, hyperphenylalaninemic patients are commonly classified into phenotypic subtypes: classical phenylketonuria (PKU (PHE > 1200 µM/L, mild PKU (PHE 600-1200 µM/L and persistent HPA (PHE 120-600 µM/L (normal blood PHE < 120 µM/L. The current treatment for hyperphenylalaninemic patients is aimed to keep blood PHE levels within the safe range of 120-360 µM/L through a PHE-restricted diet, difficult to achieve. If untreated, classical PKU presents variable neurological and mental impairment. However, even mildly elevated blood PHE levels, due to a bad compliance to dietary treatment, produce cognitive deficits involving the prefrontal cortical areas, extremely sensible to PHE-induced disturbances. The development of animal models of different degrees of HPA is a useful tool for identifying the metabolic mechanisms underlying cognitive deficits induced by PHE. In this paper we analyzed the behavioral and biochemical phenotypes of different forms of HPA (control, mild-HPA, mild-PKU and classic-PKU, developed on the base of plasma PHE concentrations. Our results demonstrated that mice with different forms of HPA present different phenotypes, characterized by increasing severity of behavioral symptoms and brain aminergic deficits moving from mild HPA to classical PKU forms. In addition, our data identify preFrontal cortex and amygdala as the most affected brain areas and confirm the highest susceptibility of brain serotonin metabolism to mildly elevated blood PHE.

  5. Behavioral and Neurochemical Characterization of New Mouse Model of Hyperphenylalaninemia

    Science.gov (United States)

    Pascucci, Tiziana; Giacovazzo, Giacomo; Andolina, Diego; Accoto, Alessandra; Fiori, Elena; Ventura, Rossella; Orsini, Cristina; Conversi, David; Carducci, Claudia; Leuzzi, Vincenzo; Puglisi-Allegra, Stefano

    2013-01-01

    Hyperphenylalaninemia (HPA) refers to all clinical conditions characterized by increased amounts of phenylalanine (PHE) in blood and other tissues. According to their blood PHE concentrations under a free diet, hyperphenylalaninemic patients are commonly classified into phenotypic subtypes: classical phenylketonuria (PKU) (PHE > 1200 µM/L), mild PKU (PHE 600-1200 µM/L) and persistent HPA (PHE 120-600 µM/L) (normal blood PHE < 120 µM/L). The current treatment for hyperphenylalaninemic patients is aimed to keep blood PHE levels within the safe range of 120-360 µM/L through a PHE-restricted diet, difficult to achieve. If untreated, classical PKU presents variable neurological and mental impairment. However, even mildly elevated blood PHE levels, due to a bad compliance to dietary treatment, produce cognitive deficits involving the prefrontal cortical areas, extremely sensible to PHE-induced disturbances. The development of animal models of different degrees of HPA is a useful tool for identifying the metabolic mechanisms underlying cognitive deficits induced by PHE. In this paper we analyzed the behavioral and biochemical phenotypes of different forms of HPA (control, mild-HPA, mild-PKU and classic-PKU), developed on the base of plasma PHE concentrations. Our results demonstrated that mice with different forms of HPA present different phenotypes, characterized by increasing severity of behavioral symptoms and brain aminergic deficits moving from mild HPA to classical PKU forms. In addition, our data identify preFrontal cortex and amygdala as the most affected brain areas and confirm the highest susceptibility of brain serotonin metabolism to mildly elevated blood PHE. PMID:24376837

  6. [Prevalence and causes of blindness and moderate and severe visual impairment among adults aged 50 years or above in Luxi County of Yunnan Province: the China Nine-Province survey].

    Science.gov (United States)

    Cai, Ning; Yuan, Yuan-sheng; Zhao, Jia-liang; Zhong, Hua; Ellwein, Leon B; Chen, Miao-miao; Dan, Ai-hua; Sun, Peng; Luo, Ting-hao; Wang, Yu; Gao, Xue-cheng

    2013-09-01

    To investigate the prevalence and causes of blindness and moderate and severe visual impairment among adults aged ≥ 50 years in Luxi County of Yunnan Province, China. It was a population-based cross-section study. Geographically defined cluster sampling was used in randomly selecting 5575 individuals aged ≥ 50 years in Luxi County. The survey was preceded by a pilot study where operational methods were refined and quality assurance evaluation was carried out. All participants were enumerated through village registers followed door-to-door visits.Eligible individuals were invited to receive visual acuity measurement and eye examination. Prevalence of blindness and moderate and severe visual impairment was calculated according to different age, gender or education. And the reasons of blindness were analyzed.Statistical analyses were performed using Stata/SE Statistical Software, release 9.0. Chi-square test was used to investigate the association of age, gender and education with presenting and best corrected visual acuity. Five thousands five hundreds and seventy-five individuals were enumerated and 5151 persons were examined, the response rate was 92.39%. Based on the criteria of World Health Organization visual impairment classification in 1973, the prevalence of blindness and moderate and severe visual impairment defined as best corrected visual acuity was 4.95% (255/5151) and 9.51% (490/5151) , respectively. The prevalence of blindness and moderate and severe visual impairment defined as presenting visual acuity was 5.40% (278/5151) and 15.84% (816/5151) , respectively. The prevalence of blindness and moderate and severe visual impairment was higher in aged (χ(2) = 1349.21, P = 0.000) , illiterate (χ(2) = 203.55, P = 0.000) persons. Cataract was still the first leading cause of blindness and visual impairment. The prevalence of blindness and moderate and severe visual impairment is highest in China Nine-Province Survey among older adults aged ≥ 50 years

  7. [Injured by Work, War, and Punishment. Causes and Consequences of Physical Impairment in the Middle Ages. Disabled, Impaired ('bresthafftigen leibs') in the Middle Ages: Annotations on a Current Field of Research].

    Science.gov (United States)

    Nolte, Cordula

    2009-01-01

    The paper provides an introduction into a current field of research on medieval culture and social life. Inspired by 'disability studies' and a 'history of disability', various historical disciplines have recently begun to cooperate in order to analyse how impaired/disabled people managed to survive and participate in social networks. However, the categories 'disability' and 'impairment' seem to be problematic with regard to medieval attitudes and behaviour. The paper highlights different strategies for coping with prolonged disease, physical defects and deformities. It argues that the topics war and fighting as well as punishment were chosen for the present focus on disability/impairment because they refer to widespread experiences and practices of different strata of medieval society.

  8. Psychosocial Impairment as a Possible Cause of Sexual Dysfunction among Young Men with Mild Androgenetic Alopecia: A Cross-sectional Crowdsourcing Web-based Study.

    Science.gov (United States)

    Molina-Leyva, Alejandro; Caparros-Del Moral, Isabel; Gomez-Avivar, Pilar; Alcalde-Alonso, Mercedes; Jimenez-Moleon, Jose Juan

    2016-04-01

    Finasteride 1 mg, one of the main treatments for male androgenetic alopecia (MAGA), may produce sexual dysfunction, but young men with MAGA could experience high psychosocial impairment because of changes in body image. Dissatisfaction with body image has been linked to an increase in problems with sexual function. To date no study has considered the possible effect of psychological impairment on sexual function of men with MAGA. Aim of our study was to explore the effect of psychosocial impairment produced by hair loss on the sexual function of men with MAGA. Cross-sectional design. In total, 190 men with MAGA ranging 18-40 years old were recruited from an Internet online community. Participants completed an online survey comprising the SKINDEX-29 and the Massachusetts General Hospital Sex Functioning Questionnaire. Individuals with MAGA and moderate to severe psychosocial impairment had a higher risk of sexual dysfunction - adjusted odds ratio 2.1 (1.2-4.0; P=0.02) - compared with subjects with mild to absent impairment. Sexual desire and sexual arousal were the most affected elements of sexual response, but an increase in erectile dysfunction and reduced global satisfaction were also reported. We present the first study exploring the influence of MAGA psychosocial impairment on sexual function. Men between 18 and 40 years of age with moderate to severe MAGA psychosocial morbidity were found to have an increased risk of sexual dysfunction. Assessment of psychological morbidity and sexual function could be critical in patients with MAGA, particularly when considering treatment with finasteride.

  9. A combination of two truncating mutations in USH2A causes more severe and progressive hearing impairment in Usher syndrome type IIa.

    Science.gov (United States)

    Hartel, Bas P; Löfgren, Maria; Huygen, Patrick L M; Guchelaar, Iris; Lo-A-Njoe Kort, Nicole; Sadeghi, Andre M; van Wijk, Erwin; Tranebjærg, Lisbeth; Kremer, Hannie; Kimberling, William J; Cremers, Cor W R J; Möller, Claes; Pennings, Ronald J E

    2016-09-01

    Usher syndrome is an inherited disorder that is characterized by hearing impairment (HI), retinitis pigmentosa, and in some cases vestibular dysfunction. Usher syndrome type IIa is caused by mutations in USH2A. HI in these patients is highly heterogeneous and the present study evaluates the effects of different types of USH2A mutations on the audiometric phenotype. Data from two large centres of expertise on Usher Syndrome in the Netherlands and Sweden were combined in order to create a large combined sample of patients to identify possible genotype-phenotype correlations. A retrospective study on HI in 110 patients (65 Dutch and 45 Swedish) genetically diagnosed with Usher syndrome type IIa. We used methods especially designed for characterizing and testing differences in audiological phenotype between patient subgroups. These methods included Age Related Typical Audiograms (ARTA) and a method to evaluate the difference in the degree of HI developed throughout life between subgroups. Cross-sectional linear regression analysis of last-visit audiograms for the best hearing ear demonstrated a gradual decline of hearing over decades. The congenital level of HI was in the range of 16-33 dB at 0.25-0.5 kHz, and in the range of 51-60 dB at 1-8 kHz. The annual threshold deterioration was in the range of 0.4-0.5 dB/year at 0.25-2 kHz and in the range of 0.7-0.8 dB/year at 4-8 kHz. Patients with two truncating mutations, including homozygotes for the common c.2299delG mutation, developed significantly more severe HI throughout life than patients with one truncating mutation combined with one nontruncating mutation, and patients with two nontruncating mutations. The results have direct implications for patient counselling in terms of prognosis of hearing and may serve as baseline measures for future (genetic) therapeutic interventions. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Apolipoprotein E4 causes age- and sex-dependent impairments of hilar GABAergic interneurons and learning and memory deficits in mice.

    Directory of Open Access Journals (Sweden)

    Laura Leung

    Full Text Available Apolipoprotein (apo E4 is the major genetic risk factor for Alzheimer's disease (AD. ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive--but not NPY- or parvalbumin-positive-interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype.

  11. Theophylline, adenosine receptor antagonist prevents behavioral, biochemical and neurochemical changes associated with an animal model of tardive dyskinesia.

    Science.gov (United States)

    Bishnoi, Mahendra; Chopra, Kanwaljit; Kulkarni, Shrinivas K

    2007-01-01

    Tardive dyskinesia is considered to be the late onset adverse effect of prolonged administration of typical neuroleptic drugs. Adenosine is now widely accepted as the major inhibitory neuromodulators in the central nervous system besides GABA. Antagonists of A2A receptors are known to confer protection against neuronal damage caused by toxins and reactive oxygen species. The present study investigated the effect of adenosine receptor antagonist, theophylline (25 and 50 mg/kg, ip) in an animal model of tardive dyskinesia by using different behavioral (orofacial dyskinetic movements, stereotypy, locomotor activity, % retention), biochemical (lipid peroxidation, reduced glutathione levels, antioxidant enzyme levels (SOD and catalase)) and neurochemical (neurotransmitter levels) parameters. Chronic administration of haloperidol (1 mg/kg ip for 21 days) significantly increased vacuous chewing movements (VCMs), tongue protrusions, facial jerking in rats which was dose-dependently inhibited by theophylline. Chronic administration of haloperidol also resulted in the increased dopamine receptor sensitivity as evidenced by increased locomotor activity and stereotypic rearing. Further, it also decreased % retention time in elevated plus maze paradigm. Pretreatment with theophylline reversed these behavioral changes. Chronic administration of haloperidol also induced oxidative damage in all the brain regions which was prevented by theophylline, especially in the striatum. Chronic administration of haloperidol resulted in a decrease in dopamine levels which was reversed by treatment with theophylline (at higher doses). The findings of the present study suggested the involvement of adenosinergic receptor system in the development of tardive dyskinesia and possible therapeutic potential of theophylline in this disorder.

  12. Behavioral and neurochemical effects of chronic L-DOPA treatment on nonmotor sequelae in the hemiparkinsonian rat.

    Science.gov (United States)

    Eskow Jaunarajs, Karen L; Dupre, Kristin B; Ostock, Corinne Y; Button, Thomas; Deak, Terrence; Bishop, Christopher

    2010-10-01

    Depression and anxiety are the prevalent nonmotor symptoms that worsen quality of life for Parkinson's disease (PD) patients. Although dopamine (DA) cell loss is a commonly proposed mechanism, the reported efficacy of DA replacement therapy with L-DOPA on affective symptoms is inconsistent. To delineate the effects of DA denervation and chronic L-DOPA treatment on affective behaviors, male Sprague-Dawley rats received unilateral 6-hydroxydopamine or sham lesions and were treated daily with L-DOPA (12 mg/kg+benserazide, 15 mg/kg, subcutaneously) or vehicle (0.9% NaCl, 0.1% ascorbic acid) for 28 days before commencing investigations into anxiety (locomotor chambers, social interaction) and depression-like behaviors (forced swim test) during the OFF phase of L-DOPA. One hour after the final treatments, rats were killed and striatum, prefrontal cortex, hippocampus, and amygdala were analyzed through high-performance liquid chromatography for monoamine levels. In locomotor chambers and social interaction, DA lesions exerted mild anxiogenic effects. Surprisingly, chronic L-DOPA treatment did not improve these effects. Although DA lesion reduced climbing behaviors on day 2 of exposure to the forced swim test, chronic L-DOPA treatment did not reverse these effects. Neurochemically, L-DOPA treatment in hemiparkinsonian rats reduced norepinephrine levels in the prefrontal cortex, striatum, and hippocampus. Collectively, these data suggest that chronic L-DOPA therapy in severely DA-lesioned rats does not improve nonmotor symptoms and may impair nondopaminergic processes, indicating that long-term L-DOPA therapy does not exert necessary neuroplastic changes for improving affect.

  13. Altered Wnt Signaling Pathway in Cognitive Impairment Caused by Chronic Intermittent Hypoxia: Focus on Glycogen Synthase Kinase-3β and β-catenin

    Directory of Open Access Journals (Sweden)

    Yue-Ying Pan

    2016-01-01

    Conclusions: Wnt/β-catenin signaling pathway abnormalities possibly play an important role in the development of cognitive deficits among mice exposed to CIH and that LiCl might attenuate CIH-induced cognitive impairment via Wnt/β-catenin signaling pathway.

  14. Mercury Vapour Long-Lasting Exposure: Lymphocyte Muscarinic Receptors as Neurochemical Markers of Accidental Intoxication

    Directory of Open Access Journals (Sweden)

    E. Roda

    2016-01-01

    Full Text Available Introduction. Chronic poisoning may result in home setting after mercury (Hg vapours inhalation from damaged devices. We report a chronic, nonoccupational Hg poisoning due to 10-year indoor exposure to mercury spillage. Case Report. A 72-year-old man with polyneuropathy of suspected toxic origin. At hospitalization, toxicological clinical evaluations confirmed the altered neurological picture documented across the last decade. Periodic blood and urine Hg levels (BHg, UHg monitoring were performed from admission (t0, until 1 year later (t2, paralleled by blood neurochemical markers assessment, that is, lymphocytes muscarinic receptors (l-MRs. At t0: BHg and UHg were 27 and 1.4 microg/L, respectively (normal values: BHg 1–4.5; UHg 0.1–4.5, associated with l-MRs increase, 185.82 femtomoL/million lymphocytes (normal range: 8.0–16.0. At t1 (two days after DMSA-mobilization test, BHg weak reduction, paralleled by UHg 3.7-fold increase, was measured together with further l-MRs enhancement (205.43 femtomoL/million lymphocytes. At t2 (eight months after two cycles of DMSA chelating therapy ending, gradual improving of clinical manifestations was accompanied by progressive decrease of BHg and UHg (4.0 and 2.8 microg/L, resp. and peripheral l-MRs neurochemical marker (24.89 femtomoL/million lymphocytes. Conclusion. l-MRs modulatory effect supports their use as peripheral neurochemical marker in Hg poisoning diagnosis and chelation therapy monitoring.

  15. Mercury Vapour Long-Lasting Exposure: Lymphocyte Muscarinic Receptors as Neurochemical Markers of Accidental Intoxication.

    Science.gov (United States)

    Roda, E; Giampreti, A; Vecchio, S; Apostoli, P; Coccini, T

    2016-01-01

    Introduction. Chronic poisoning may result in home setting after mercury (Hg) vapours inhalation from damaged devices. We report a chronic, nonoccupational Hg poisoning due to 10-year indoor exposure to mercury spillage. Case Report. A 72-year-old man with polyneuropathy of suspected toxic origin. At hospitalization, toxicological clinical evaluations confirmed the altered neurological picture documented across the last decade. Periodic blood and urine Hg levels (BHg, UHg) monitoring were performed from admission (t0), until 1 year later (t2), paralleled by blood neurochemical markers assessment, that is, lymphocytes muscarinic receptors (l-MRs). At t0: BHg and UHg were 27 and 1.4 microg/L, respectively (normal values: BHg 1-4.5; UHg 0.1-4.5), associated with l-MRs increase, 185.82 femtomoL/million lymphocytes (normal range: 8.0-16.0). At t1 (two days after DMSA-mobilization test), BHg weak reduction, paralleled by UHg 3.7-fold increase, was measured together with further l-MRs enhancement (205.43 femtomoL/million lymphocytes). At t2 (eight months after two cycles of DMSA chelating therapy ending), gradual improving of clinical manifestations was accompanied by progressive decrease of BHg and UHg (4.0 and 2.8 microg/L, resp.) and peripheral l-MRs neurochemical marker (24.89 femtomoL/million lymphocytes). Conclusion. l-MRs modulatory effect supports their use as peripheral neurochemical marker in Hg poisoning diagnosis and chelation therapy monitoring.

  16. Vascular Cognitive Impairment through the Looking Glass of Transcranial Magnetic Stimulation

    Directory of Open Access Journals (Sweden)

    Giuseppe Lanza

    2017-01-01

    Full Text Available In the last years, there has been a significant growth in the literature exploiting transcranial magnetic stimulation (TMS with the aim at gaining further insights into the electrophysiological and neurochemical basis underlying vascular cognitive impairment (VCI. Overall, TMS points at enhanced brain cortical excitability and synaptic plasticity in VCI, especially in patients with overt dementia, and neurophysiological changes seem to correlate with disease process and progress. These findings have been interpreted as part of a glutamate-mediated compensatory effect in response to vascular lesions. Although a single TMS parameter owns low specificity, a panel of measures can support the VCI diagnosis, predict progression, and possibly identify early markers of “brain at risk” for future dementia, thus making VCI a potentially preventable cause of both vascular and degenerative dementia in late life. Moreover, TMS can be also exploited to select and evaluate the responders to specific drugs, as well as to become an innovative rehabilitative tool in the attempt to restore impaired neural plasticity. The present review provides a perspective of the different TMS techniques by further understanding the cortical electrophysiology and the role of distinctive neurotransmission pathways and networks involved in the pathogenesis and pathophysiology of VCI and its subtypes.

  17. Visual Impairment

    Science.gov (United States)

    ... Staying Safe Videos for Educators Search English Español Visual Impairment KidsHealth / For Teens / Visual Impairment What's in ... with the brain, making vision impossible. What Is Visual Impairment? Many people have some type of visual ...

  18. Abeta(1-42) injection causes memory impairment, lowered cortical and serum BDNF levels, and decreased hippocampal 5-HT(2A) levels

    DEFF Research Database (Denmark)

    Christensen, R; Marcussen, Anders Bue; Wörtwein, Gitta

    2008-01-01

    Aggregation of the beta-amyloid protein (Abeta) is a hallmark of Alzheimer's disease (AD) and is believed to be causally involved in a neurodegenerative cascade. In patients with AD, reduced levels of serum Brain Derived Neurotrophic Factor (BDNF) and cortical 5-HT(2A) receptor binding has recently...... been reported but it is unknown how these changes are related to beta-amyloid accumulation. In this study we examined in rats the effect of intrahippocampal injections of aggregated Abeta(1-42) (1 microg/microl) on serum and brain BDNF or 5-HT(2A) receptor levels. A social recognition test paradigm...... was used to monitor Abeta(1-42) induced memory impairment. Memory impairment was seen 22 days after injection of Abeta(1-42) in the experimental group and until termination of the experiments. In the Abeta(1-42) injected animals we saw an abolished increase in serum BDNF levels that was accompanied...

  19. Advanced maternal age causes adverse programming of mouse blastocysts leading to altered growth and impaired cardiometabolic health in post-natal life

    OpenAIRE

    Velazquez, M.A.; Smith, C.G.C.; Smyth, N.R.; Osmond, C; Fleming, T P

    2016-01-01

    STUDY QUESTION Does advanced maternal age (AMA) in mice affect cardiometabolic health during post-natal life in offspring derived from an assisted reproduction technology (ART) procedure? SUMMARY ANSWER Offspring derived from blastocysts collected from aged female mice displayed impaired body weight gain, blood pressure, glucose metabolism and organ allometry during post-natal life compared with offspring derived from blastocysts from young females; since all blastocysts were transferred to n...

  20. Clinical pathologic case report: A 70-year-old man with inflammatory cerebral amyloid angiopathy causing headache, cognitive impairment, and aphasia.

    Science.gov (United States)

    Crotty, Grace F; McKee, Kathleen; Saadi, Altaf; Young, Andrew C; Solomon, Isaac H; Lyons, Jennifer L

    2018-03-01

    A 70-year-old man presented with two months of worsening cognitive impairment, hallucinations, and difficulty speaking, with superimposed headaches. Cerebrospinal fluid analysis was notable for lymphocytic pleocytosis and elevated protein. Imaging studies revealed multiple acute and subacute infarcts with cortical microhemorrhages. The patient underwent a stereotactic brain biopsy. In this article, we discuss the patient's differential diagnosis, pathologic findings, ultimate diagnosis, and clinical outcome. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Brain visual impairment in childhood: mini review

    OpenAIRE

    N Kozeis

    2010-01-01

    Cerebral visual impairment (CVI) is one of the leading causes of severe visual impairment in childhood. This article was written to highlight any new knowledge related to cerebral visual impairment in childhood.

  2. Microdialysis Coupled with LC-MS/MS for In Vivo Neurochemical Monitoring.

    Science.gov (United States)

    Zestos, Alexander G; Kennedy, Robert T

    2017-09-01

    Microdialysis is a powerful sampling technique used to monitor small molecules in vivo. Despite the many applications of microdialysis sampling, it is limited by the method of analyzing the resulting samples. An emerging technique for analysis of microdialysis samples is liquid chromatography-tandem mass spectrometry (LC-MS/MS). This technique is highly versatile, allowing multiplexed analysis of neurotransmitters, metabolites, and neuropeptides. Using LC-MS/MS for polar neurotransmitters is hampered by weak retention reverse phase LC columns. Several derivatization reagents have been utilized to enhance separation and resolution of neurochemicals in dialysate samples including benzoyl chloride (BzCl), dansyl chloride, formaldehyde, ethylchloroformate, and propionic anhydride. BzCl reacts with amine and phenol groups so that many neurotransmitters can be labeled. Besides improving separation on reverse phase columns, this reagent also increases sensitivity. It is available in a heavy form so that it can be used to make stable-isotope labeled internal standard for improved quantification. Using BzCl with LC-MS/MS has allowed for measuring as many as 70 neurochemicals in a single assay. With slightly different conditions, LC-MS/MS has also been used for monitoring endocannabinoids. LC-MS/MS is also useful for neuropeptide assay because it allows for highly sensitive, sequence specific measurement of most peptides. These advances have allowed for multiplexed neurotransmitter measurements in behavioral, circuit analysis, and drug effect studies.

  3. No neurochemical evidence of brain injury after blast overpressure by repeated explosions or firing heavy weapons.

    Science.gov (United States)

    Blennow, K; Jonsson, M; Andreasen, N; Rosengren, L; Wallin, A; Hellström, P A; Zetterberg, H

    2011-04-01

    Psychiatric and neurological symptoms are common among soldiers exposed to blast without suffering a direct head injury. It is not known whether such symptoms are direct consequences of blast overpressure. To examine if repeated detonating explosions or firing if of heavy weapons is associated with neurochemical evidence of brain damage. Three controlled experimental studies. In the first, army officers were exposed to repeated firing of a FH77B howitzer or a bazooka. Cerebrospinal fluid (CSF) was taken post-exposure to measure biomarkers for brain damage. In the second, officers were exposed for up to 150 blasts by firing a bazooka, and in the third to 100 charges of detonating explosives of 180 dB. Serial serum samples were taken after exposure. Results were compared with a control group consisting of 19 unexposed age-matched healthy volunteers. The CSF biomarkers for neuronal/axonal damage (tau and neurofilament protein), glial cell injury (GFAP and S-100b), blood-brain barrier damage (CSF/serum albumin ratio) and hemorrhages (hemoglobin and bilirubin) and the serum GFAP and S-100b showed normal and stable levels in all exposed officers. Repeated exposure to high-impact blast does not result in any neurochemical evidence of brain damage. These findings are of importance for soldiers regularly exposed to high-impact blast when firing artillery shells or other types of heavy weapons. © 2010 John Wiley & Sons A/S.

  4. The trace amine-associated receptor 1 modulates methamphetamine's neurochemical and behavioral effects.

    Science.gov (United States)

    Cotter, Rachel; Pei, Yue; Mus, Liudmila; Harmeier, Anja; Gainetdinov, Raul R; Hoener, Marius C; Canales, Juan J

    2015-01-01

    The newly discovered trace amine-associated receptor 1 (TAAR1) has the ability to regulate both dopamine function and psychostimulant action. Here, we tested in rats the ability of RO5203648, a selective TAAR1 partial agonist, to modulate the physiological and behavioral effects of methamphetamine (METH). In experiment 1, RO5203468 dose- and time-dependently altered METH-induced locomotor activity, manifested as an early attenuation followed by a late potentiation of METH's stimulating effects. In experiment 2, rats received a 14-day treatment regimen during which RO5203648 was co-administered with METH. RO5203648 dose-dependently attenuated METH-stimulated hyperactivity, with the effects becoming more apparent as the treatments progressed. After chronic exposure and 3-day withdrawal, rats were tested for locomotor sensitization. RO5203648 administration during the sensitizing phase prevented the development of METH sensitization. However, RO5203648, at the high dose, cross-sensitized with METH. In experiment 3, RO5203648 dose-dependently blocked METH self-administration without affecting operant responding maintained by sucrose, and exhibited lack of reinforcing efficacy when tested as a METH's substitute. Neurochemical data showed that RO5203648 did not affect METH-mediated DA efflux and uptake inhibition in striatal synaptosomes. In vivo, however, RO5203648 was able to transiently inhibit METH-induced accumulation of extracellular DA levels in the nucleus accumbens. Taken together, these data highlight the significant potential of TAAR1 to modulate METH's neurochemical and behavioral effects.

  5. Early postnatal benzo(a)pyrene exposure in Sprague-Dawley rats causes persistent neurobehavioral impairments that emerge postnatally and continue into adolescence and adulthood.

    Science.gov (United States)

    Chen, Chengzhi; Tang, Yan; Jiang, Xuejun; Qi, Youbin; Cheng, Shuqun; Qiu, Chongying; Peng, Bin; Tu, Baijie

    2012-01-01

    Previous studies have demonstrated that benzo(a)pyrene (BaP) may disrupt the development of key biological systems, thus leaving children more vulnerable to functional impairments in adulthood. The current study was conducted to determine whether neurotoxic effects of postnatal BaP exposure on behavioral performance persist in juvenile and young adult stages. Therefore, neonate Sprague-Dawley pups were given oral doses of BaP (0.02, 0.2, and 2 mg/kg/day) continuing through a period of rapid brain development (on postnatal days [PNDs] 5-11). Further, developmental milestones and behavioral endpoints assessing sensory and motor maturation were examined. Also, in this study, Morris water maze and elevated plus maze were used for evaluating the cognitive function and anxiety-like behavior. Our results showed that there was altered ontogeny in a few measures of neuromotor development; however, other developmental milestones and sensory responses were not altered significantly. Moreover, the locomotor activity deficit in BaP-treated pups was evident at PND 36 and was most pronounced in the PND 69. Also, exposure to BaP during early postnatal development had an adverse effect on adult rats (PND 70) in the elevated plus maze, and the swim maze suggests that low doses of BaP impair spatial learning functions at adult test period. In contrast, BaP exposure had no evident effect on behaviors in these two mazes for adolescent animals. These data clearly indicate that behavioral impairments resulting from postnatal BaP exposure are potentially long-lasting and may not be apparent in juveniles, but are present in young adulthood.

  6. Disease-associated missense mutations in the EVH1 domain disrupt intrinsic WASp function causing dysregulated actin dynamics and impaired dendritic cell migration.

    Science.gov (United States)

    Worth, Austen J J; Metelo, Joao; Bouma, Gerben; Moulding, Dale; Fritzsche, Marco; Vernay, Bertrand; Charras, Guillaume; Cory, Giles O C; Thrasher, Adrian J; Burns, Siobhan O

    2013-01-03

    Wiskott Aldrich syndrome (WAS), an X-linked immunodeficiency, results from loss-of-function mutations in the human hematopoietic cytoskeletal regulator gene WAS. Many missense mutations in the Ena Vasp homology1 (EVH1) domain preserve low-level WAS protein (WASp) expression and confer a milder clinical phenotype. Although disrupted binding to WASp-interacting protein (WIP) leads to enhanced WASp degradation in vivo, the intrinsic function of EVH1-mutated WASp is poorly understood. In the present study, we show that, despite mediating enhanced actin polymerization compared with wild-type WASp in vitro, EVH1 missense mutated proteins did not support full biologic function in cells, even when levels were restored by forced overexpression. Podosome assembly was aberrant and associated with dysregulated lamellipodia formation and impaired persistence of migration. At sites of residual podosome-associated actin polymerization, localization of EVH1-mutated proteins was preserved even after deletion of the entire domain, implying that WIP-WASp complex formation is not absolutely required for WASp localization. However, retention of mutant proteins in podosomes was significantly impaired and associated with reduced levels of WASp tyrosine phosphorylation. Our results indicate that the EVH1 domain is important not only for WASp stability, but also for intrinsic biologic activity in vivo.

  7. Impairments of learning and memory in the rats after brain irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Takai, Nobuhiko [National Inst. of Radiological Sciences, Chiba (Japan)

    2002-06-01

    Clinical trials of hadrontherapy have been carried out world wide at several facilities including National Institute of Radiological Sciences (NIRS). Cerebral dysfunction is one of the major concerns associated with radiotherapy of brain tumors. However, little is known about the neurochemical basis of brain dysfunction induced by proton irradiation. We investigated and reported here the early consequences of brain damages caused by proton beam. The animals that had memorized the location of the standard position were locally irradiated to brain with either 70 MeV protons or 290 MeV carbon ions. At 24 hr after irradiation, impairment of the long-term memory was not observed in the irradiated rats compared to control. Irradiated animals, however, required substantially longer time finding out the standard position than control rats when the standard platform displaced to a position different from memorized position. This follows that a single doses of 30 Gy, either protons or carbon ions, impairs the working memory of animals. Function of muscarinic acetylcholine receptors was analyzed by an in vivo binding assay using radioligand quinuclidinyl benzilate (QNB). Irradiated rats were intravenously injected with 5.5 MBq of {sup 3}H-QNB 24 hr after the irradiation, and decapitated 60 min after tracer injection. The autoradiographic studies showed an transitional increase of {sup 3}H-QNB in vivo binding in the early phase after proton irradiation, even though no change in in-vitro {sup 3}H-QNB binding was see in brain autoradiograms of irradiated rats. The cerebral blood flow and the histrogical features of brain were also changed at 3 months post-irradiation. These results indicate that the memory impairment caused by radiation is closely related to the early change of acetylcholine receptor in vivo. (author)

  8. Unique Behavioral and Neurochemical Effects Induced by Repeated Adolescent Consumption of Caffeine-Mixed Alcohol in C57BL/6 Mice.

    Science.gov (United States)

    Robins, Meridith T; Lu, Julie; van Rijn, Richard M

    2016-01-01

    The number of highly caffeinated products has increased dramatically in the past few years. Among these products, highly caffeinated energy drinks are the most heavily advertised and purchased, which has resulted in increased incidences of co-consumption of energy drinks with alcohol. Despite the growing number of adolescents and young adults reporting caffeine-mixed alcohol use, knowledge of the potential consequences associated with co-consumption has been limited to survey-based results and in-laboratory human behavioral testing. Here, we investigate the effect of repeated adolescent (post-natal days P35-61) exposure to caffeine-mixed alcohol in C57BL/6 mice on common drug-related behaviors such as locomotor sensitivity, drug reward and cross-sensitivity, and natural reward. To determine changes in neurological activity resulting from adolescent exposure, we monitored changes in expression of the transcription factor ΔFosB in the dopaminergic reward pathway as a sign of long-term increases in neuronal activity. Repeated adolescent exposure to caffeine-mixed alcohol exposure induced significant locomotor sensitization, desensitized cocaine conditioned place preference, decreased cocaine locomotor cross-sensitivity, and increased natural reward consumption. We also observed increased accumulation of ΔFosB in the nucleus accumbens following repeated adolescent caffeine-mixed alcohol exposure compared to alcohol or caffeine alone. Using our exposure model, we found that repeated exposure to caffeine-mixed alcohol during adolescence causes unique behavioral and neurochemical effects not observed in mice exposed to caffeine or alcohol alone. Based on similar findings for different substances of abuse, it is possible that repeated exposure to caffeine-mixed alcohol during adolescence could potentially alter or escalate future substance abuse as means to compensate for these behavioral and neurochemical alterations.

  9. Unique Behavioral and Neurochemical Effects Induced by Repeated Adolescent Consumption of Caffeine-Mixed Alcohol in C57BL/6 Mice.

    Directory of Open Access Journals (Sweden)

    Meridith T Robins

    Full Text Available The number of highly caffeinated products has increased dramatically in the past few years. Among these products, highly caffeinated energy drinks are the most heavily advertised and purchased, which has resulted in increased incidences of co-consumption of energy drinks with alcohol. Despite the growing number of adolescents and young adults reporting caffeine-mixed alcohol use, knowledge of the potential consequences associated with co-consumption has been limited to survey-based results and in-laboratory human behavioral testing. Here, we investigate the effect of repeated adolescent (post-natal days P35-61 exposure to caffeine-mixed alcohol in C57BL/6 mice on common drug-related behaviors such as locomotor sensitivity, drug reward and cross-sensitivity, and natural reward. To determine changes in neurological activity resulting from adolescent exposure, we monitored changes in expression of the transcription factor ΔFosB in the dopaminergic reward pathway as a sign of long-term increases in neuronal activity. Repeated adolescent exposure to caffeine-mixed alcohol exposure induced significant locomotor sensitization, desensitized cocaine conditioned place preference, decreased cocaine locomotor cross-sensitivity, and increased natural reward consumption. We also observed increased accumulation of ΔFosB in the nucleus accumbens following repeated adolescent caffeine-mixed alcohol exposure compared to alcohol or caffeine alone. Using our exposure model, we found that repeated exposure to caffeine-mixed alcohol during adolescence causes unique behavioral and neurochemical effects not observed in mice exposed to caffeine or alcohol alone. Based on similar findings for different substances of abuse, it is possible that repeated exposure to caffeine-mixed alcohol during adolescence could potentially alter or escalate future substance abuse as means to compensate for these behavioral and neurochemical alterations.

  10. The effects of DL-3-n-butylphthalide in patients with vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease: A multicentre, randomized, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Jia, Jianping; Wei, Cuibai; Liang, Junhua; Zhou, Aihong; Zuo, Xiumei; Song, Haiqing; Wu, Liyong; Chen, Xiaochun; Chen, Shengdi; Zhang, Junjian; Wu, Jiang; Wang, Kai; Chu, Lan; Peng, Dantao; Lv, Peiyuan; Guo, Hongzhi; Niu, Xiaoyuan; Chen, Yingzhu; Dong, Wanli; Han, Xiujie; Fang, Boyan; Peng, Mao; Li, Dan; Jia, Qian; Huang, Liyuan

    2016-02-01

    Vascular cognitive impairment without dementia is very common among the aged and tends to progress to dementia, but there have been no proper large-scale intervention trials dedicated to it. Vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease (hereinafter, subcortical Vascular cognitive impairment without dementia) represents a relatively homogeneous disease process and is a suitable target for therapeutic trials investigating Vascular cognitive impairment without dementia. Preclinical trials showed that dl-3-n-butylphthalide (NBP) is effective for cognitive impairment of vascular origin. In this randomized, double-blind, placebo-controlled trial, we enrolled patients aged 50-70 years who had a diagnosis of subcortical Vascular cognitive impairment without dementia at 15 academic medical centers in China. Inclusion criteria included a clinical dementia rating ≥0.5 on at least one domain and global score ≤0.5; a mini-mental state examination score ≥20 (primary school) or ≥24 (junior school or above); and brain magnetic resonance imaging consistent with subcortical ischemic small vessel disease. Patients were randomly assigned to NBP 200 mg three times daily or matched placebo (1:1) for 24 weeks according to a computer-generated randomization protocol. All patients and study personnel were masked to treatment assignment. Primary outcome measures were the changes in Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) and clinician's interview-based impression of change plus caregiver input (CIBIC-plus) after 24 weeks. All patients were monitored for adverse events (AEs). Outcome measures were analyzed for both the intention-to-treat (ITT) population and the per protocol population. This study enrolled 281 patients. NBP showed greater effects than placebo on ADAS-cog (NBP change -2.46 vs. placebo -1.39; P = .03; ITT) and CIBIC-plus (80 [57.1%] vs. 59 [42.1%] patients improved; P = .01; ITT

  11. Mephedrone in adolescent rats: residual memory impairment and acute but not lasting 5-HT depletion.

    Directory of Open Access Journals (Sweden)

    Craig P Motbey

    Full Text Available Mephedrone (4-methylmethcathinone, MMC is a popular recreational drug, yet its potential harms are yet to be fully established. The current study examined the impact of single or repeated MMC exposure on various neurochemical and behavioral measures in rats. In Experiment 1 male adolescent Wistar rats received single or repeated (once a day for 10 days injections of MMC (30 mg/kg or the comparator drug methamphetamine (METH, 2.5 mg/kg. Both MMC and METH caused robust hyperactivity in the 1 h following injection although this effect did not tend to sensitize with repeated treatment. Striatal dopamine (DA levels were increased 1 h following either METH or MMC while striatal and hippocampal serotonin (5-HT levels were decreased 1 h following MMC but not METH. MMC caused greater increases in 5-HT metabolism and greater reductions in DA metabolism in rats that had been previously exposed to MMC. Autoradiographic analysis showed no signs of neuroinflammation ([(125I]CLINDE ligand used as a marker for translocator protein (TSPO expression with repeated exposure to either MMC or METH. In Experiment 2, rats received repeated MMC (7.5, 15 or 30 mg/kg once a day for 10 days and were examined for residual behavioral effects following treatment. Repeated high (30 mg/kg dose MMC produced impaired novel object recognition 5 weeks after drug treatment. However, no residual changes in 5-HT or DA tissue levels were observed at 7 weeks post-treatment. Overall these results show that MMC causes acute but not lasting changes in DA and 5-HT tissue concentrations. MMC can also cause long-term memory impairment. Future studies of cognitive function in MMC users are clearly warranted.

  12. Effects of polychlorinated biphenyl (PCB) on regulation of thyroid-, growth-, and neurochemically related developmental processes in young rats

    Energy Technology Data Exchange (ETDEWEB)

    Juarez de Ku, L.M.

    1992-01-01

    Neonatal exposure to the toxic chemical polychlorinated biphenyl (PCB) induces hypothyroidism and retarded growth. Neonatal rats made hypothyroid by chemical or surgical means experience retarded growth and subnormal activity of choline acetyltransferase (ChAT) This study compared thyroid-, growth-, and neurochemically-related processes altered by hypothyroidism induced by other means, with PCB-induced hypothyroidism: (1) titers of thyroid stimulating hormone (TSH); (2) titers of hormones that regulate growth [growth hormone (GH), insulin-growth like factor-I (IGF-1), growth hormone releasing hormone (GHRH) and somatostatin (SS)]; or (3) brain ChAT activity. Whether PCB-induced growth retardation and other alterations are secondary to accompanying hypothyroidism rather than or in addition to a direct effect of PCB was also examined. Pregnant rats were fed chow containing 0 (controls), 62.5, 125, or 250 ppm PCB (entering offspring through placenta and milk) throughout pregnancy and lactation. Neonates exposed to PCB displayed many alterations similar to those made hypothyroid by other means: depression of overall and skeletal growth, circulating by other means: depression of overall and skeletal growth, circulating T[sub 4] levels and ChAT activity, and no change in hypothalamic GHRH and SS concentrations. Differences included a paradoxical increase in circulating GH levels, and no significant alteration of circulation IGF-1 and TSH levels and pituitary GH and TSH levels (although trends were in the expected direction). Thus, PCB-induced hypothyroidism may partially cause altered skeletal growth, circulating GH and TSH concentrations, and ChAT activity. Both T[sub 4] and T[sub 3] injections returned circulating TSH and GH levels and pituitary TSH content toward control levels; T[sub 3] restored skeletal, but not overall growth; and T[sub 4] elevated ChAT activity.

  13. An allosteric enhancer of M4 muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine

    Science.gov (United States)

    Dencker, Ditte; Weikop, Pia; Sørensen, Gunnar; Woldbye, David P. D.; Wörtwein, Gitta; Wess, Jürgen; Fink-Jensen, Anders

    2014-01-01

    Rationale The mesostriatal dopamine system plays a key role in mediating the reinforcing effects of psychostimulant drugs like cocaine. The muscarinic M4 acetylcholine receptor subtype is centrally involved in regulation of dopamine release in striatal areas. Consequently, striatal M4 receptors could be a novel target for modulating psychostimulant effects of cocaine. Objectives For the first time, we here addressed this issue by investigating the effects of a novel selective positive allosteric modulator of M4 receptors, VU0152100, on cocaine-induced behavioral and neurochemical effects in mice. Methods To investigate the effect of VU0152100 on the acute reinforcing effects of cocaine, we use an acute-cocaine self-administration model. We used in vivo microdialysis to investigate whether the effects of VU0152100 in the behavioral studies were mediated via effects on dopaminergic neurotransmission. In addition the effect of VU0152100 on cocaine-induced hyperactivity and rotarod performance was evaluated. Results We found that VU0152100 caused a prominent reduction in cocaine self-administration, cocaine-induced hyperlocomotion, and cocaine-induced striatal dopamine increase, without affecting motor performance. Consistent with these effects of VU0152100 being mediated via M4 receptors, its inhibitory effects on cocaine-induced increases in striatal dopamine were abolished in M4 receptor knockout mice. Furthermore, selective deletion of the M4 receptor gene in dopamine D1 receptor-expressing neurons resulted in a partial reduction of the VU0152100 effect, indicating that VU0152100 partly regulates dopaminergic neurotransmission via M4 receptors co-localized with D1 receptors. Conclusions These results show that positive allosteric modulators of the M4 receptor deserve attention as agents in the future treatment of cocaine abuse. PMID:22648127

  14. Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment

    DEFF Research Database (Denmark)

    Rendtorff, Nanna D; Lodahl, Marianne; Boulahbel, Houda

    2011-01-01

    DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL...... as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest......Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare...

  15. Fish Oil Attenuates Omega-6 Polyunsaturated Fatty Acid-Induced Dysbiosis and Infectious Colitis but Impairs LPS Dephosphorylation Activity Causing Sepsis

    Science.gov (United States)

    Brown, Kirsty; Rajendiran, Ethendhar; Estaki, Mehrbod; Dai, Chuanbin; Yip, Ashley; Gibson, Deanna L.

    2013-01-01

    Clinically, excessive ω-6 polyunsaturated fatty acid (PUFA) and inadequate ω-3 PUFA have been associated with enhanced risks for developing ulcerative colitis. In rodent models, ω-3 PUFAs have been shown to either attenuate or exacerbate colitis in different studies. We hypothesized that a high ω-6: ω-3 PUFA ratio would increase colitis susceptibility through the microbe-immunity nexus. To address this, we fed post-weaned mice diets rich in ω-6 PUFA (corn oil) and diets supplemented with ω-3 PUFA (corn oil+fish oil) for 5 weeks. We evaluated the intestinal microbiota, induced colitis with Citrobacter rodentium and followed disease progression. We found that ω-6 PUFA enriched the microbiota with Enterobacteriaceae, Segmented Filamentous Bacteria and Clostridia spp., all known to induce inflammation. During infection-induced colitis, ω-6 PUFA fed mice had exacerbated intestinal damage, immune cell infiltration, prostaglandin E2 expression and C. rodentium translocation across the intestinal mucosae. Addition of ω-3 PUFA on a high ω-6 PUFA diet, reversed inflammatory-inducing microbial blooms and enriched beneficial microbes like Lactobacillus and Bifidobacteria, reduced immune cell infiltration and impaired cytokine/chemokine induction during infection. While, ω-3 PUFA supplementation protected against severe colitis, these mice suffered greater mortality associated with sepsis-related serum factors such as LPS binding protein, IL-15 and TNF-α. These mice also demonstrated decreased expression of intestinal alkaline phosphatase and an inability to dephosphorylate LPS. Thus, the colonic microbiota is altered differentially through varying PUFA composition, conferring altered susceptibility to colitis. Overall, ω-6 PUFA enriches pro-inflammatory microbes and augments colitis; but prevents infection-induced systemic inflammation. In contrast, ω-3 PUFA supplementation reverses the effects of the ω-6 PUFA diet but impairs infection-induced responses

  16. Repeated mild lateral fluid percussion brain injury in the rat causes cumulative long-term behavioral impairments, neuroinflammation, and cortical loss in an animal model of repeated concussion.

    Science.gov (United States)

    Shultz, Sandy R; Bao, Feng; Omana, Vanessa; Chiu, Charlotte; Brown, Arthur; Cain, Donald Peter

    2012-01-20

    There is growing evidence that repeated brain concussion can result in cumulative and long-term behavioral symptoms, neuropathological changes, and neurodegeneration. Little is known about the factors and mechanisms that contribute to these effects. The current study addresses the need to investigate and better understand the effects of repeated concussion through the development of an animal model. Male Long-Evans rats received 1, 3, or 5 mild lateral fluid percussion injuries or sham injuries spaced 5 days apart. After the final injury, rats received either a short (24 h) or long (8 weeks) post-injury recovery period, followed by a detailed behavioral analysis consisting of tests for rodent anxiety-like behavior, cognition, social behavior, sensorimotor function, and depression-like behavior. Brains were examined immunohistochemically to assess neuroinflammation and cortical damage. Rats given 1, 3, or 5 mild percussion injuries displayed significant short-term cognitive impairments. Rats given repeated mild percussion injuries displayed significantly worse short- and long-term cognitive impairments. Rats given 5 mild percussion injuries also displayed increased anxiety- and depression-like behaviors. Neuropathological analysis revealed short-term neuroinflammation in 3-injury rats, and both short- and long-term neuroinflammation in 5-injury rats. There was also evidence that repeated injuries induced short- and long-term cortical damage. These cumulative and long-term changes are consistent with findings in human patients suffering repeated brain concussion, provide support for the use of repeated mild lateral fluid percussion injuries to study repeated concussion in the rat, and suggest that neuroinflammation may be important for understanding the cumulative and chronic effects of repeated concussion.

  17. Fish oil attenuates omega-6 polyunsaturated fatty acid-induced dysbiosis and infectious colitis but impairs LPS dephosphorylation activity causing sepsis.

    Directory of Open Access Journals (Sweden)

    Sanjoy Ghosh

    Full Text Available Clinically, excessive ω-6 polyunsaturated fatty acid (PUFA and inadequate ω-3 PUFA have been associated with enhanced risks for developing ulcerative colitis. In rodent models, ω-3 PUFAs have been shown to either attenuate or exacerbate colitis in different studies. We hypothesized that a high ω-6: ω-3 PUFA ratio would increase colitis susceptibility through the microbe-immunity nexus. To address this, we fed post-weaned mice diets rich in ω-6 PUFA (corn oil and diets supplemented with ω-3 PUFA (corn oil+fish oil for 5 weeks. We evaluated the intestinal microbiota, induced colitis with Citrobacter rodentium and followed disease progression. We found that ω-6 PUFA enriched the microbiota with Enterobacteriaceae, Segmented Filamentous Bacteria and Clostridia spp., all known to induce inflammation. During infection-induced colitis, ω-6 PUFA fed mice had exacerbated intestinal damage, immune cell infiltration, prostaglandin E2 expression and C. rodentium translocation across the intestinal mucosae. Addition of ω-3 PUFA on a high ω-6 PUFA diet, reversed inflammatory-inducing microbial blooms and enriched beneficial microbes like Lactobacillus and Bifidobacteria, reduced immune cell infiltration and impaired cytokine/chemokine induction during infection. While, ω-3 PUFA supplementation protected against severe colitis, these mice suffered greater mortality associated with sepsis-related serum factors such as LPS binding protein, IL-15 and TNF-α. These mice also demonstrated decreased expression of intestinal alkaline phosphatase and an inability to dephosphorylate LPS. Thus, the colonic microbiota is altered differentially through varying PUFA composition, conferring altered susceptibility to colitis. Overall, ω-6 PUFA enriches pro-inflammatory microbes and augments colitis; but prevents infection-induced systemic inflammation. In contrast, ω-3 PUFA supplementation reverses the effects of the ω-6 PUFA diet but impairs infection

  18. Neurochemical correlates of alloxan diabetes: glucose and related brain metabolism in the rat.

    Science.gov (United States)

    Ahmed, Nayeemunnisa; Zahra, Noor

    2011-03-01

    Diabetes mellitus is known to impair glucose metabolism. The fundamental mechanism underlying hyperglycaemia in diabetes mellitus involves decreased utilization of glucose by the brain. However, mechanisms responsible for progressive failure of glycaemic regulation in type I (IDDM) diabetes need extensive and proper understanding. Hence the present study was initiated. Type I diabetes was induced in albino rat models with alloxan monohydrate (40 mg/Kg iv). Cerebral cortex and medulla oblongata were studied 48 h after alloxanisation. Diabetes caused an elevation in glucose, glutamate, aspartate, GABA and taurine levels and a decline in the glutamine synthetase activity. The activities of brain lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) exhibited significant decrease during diabetes. Ammonia content increased (P cerebral glucose metabolism accounts for the failure of cerebral glucose homeostasis. The impairment in the glycaemic control leads to disturbances in cerebral glutamate content (resulting in calcium overload and excitotoxic injury) and brain energy metabolism as reflected by alterations occurring in adenine nucleotide and the ATPases. The failure in the maintenance of normal energy metabolism during diabetes might affect glucose homeostasis leading to gross cerebral dysfunction during diabetes.

  19. The decoding of the flouting of the Gricean relevance maxim is impaired in mental retardation caused by perinatal hypoxia. A brief report.

    Science.gov (United States)

    Tényi, Tamás; Csábi, Györgyi; Hamvas, Edina; Varga, Eszter; Herold, Róbert

    2008-12-01

    The authors examined the decoding of the flouting of the Gricean relevance maxim among children with mental retardation compared to a mental age matched control group with average intellectual capacities, where the cause of mental retardation was perinatal hypoxia. They have investigated the decoding deficit by five short "question and answer" conversation vignettes, where the flouting of the relevance maxim was presented. They have found significant deficit in the mental retardation group in their capacity to decode properly the flouting of the Gricean relevance maxim. These data are the first that point at a pragmatic language use deficit in mental retardation caused by perinatal hypoxia.

  20. Hepatitis C virus-induced NK cell activation causes metzincin-mediated CD16 cleavage and impaired antibody-dependent cytotoxicity.

    Science.gov (United States)

    Oliviero, Barbara; Mantovani, Stefania; Varchetta, Stefania; Mele, Dalila; Grossi, Giulia; Ludovisi, Serena; Nuti, Elisa; Rossello, Armando; Mondelli, Mario U

    2017-06-01

    The Fc receptor family for immunoglobulin (Ig)G type III (FcγRIII, CD16) is an activating receptor on natural killer (NK) cells and an essential mediator of antibody-dependent cellular cytotoxicity (ADCC). There is only limited information on its role during chronic hepatitis C virus (HCV) infection. We studied CD16 expression in relation to NK cell functional activity in HCV-infected patients and sought mechanistic insights into virus-induced modulation. NK cell CD16 expression and activation status were evaluated ex vivo by flow cytometry in HCV-infected patients and healthy controls (HC) as well as in vitro after co-culture with HCV-infected HuH7.5 cells. Rituximab-mediated ADCC was assessed in HC and HCV-infected patients using Daudi cells as a target. The role of metzincins in CD16 down-modulation was assessed using specific inhibitory molecules and by evaluating intracellular mRNA levels. HCV-infected patients exhibited increased frequencies of ex vivo activated NK cells and a concomitantly decreased NK CD16 expression, which resulted in impaired ADCC activity. Moreover, exposure of NK cells to culture-derived HCV recapitulated the ex vivo findings of decreased CD16 expression and increased NK cell activation. Importantly, blockade of metzincin-mediated shedding activity, including selective a disintegrin and metalloproteinase 17 (ADAM-17) inhibition, restored NK CD16 expression. Successful treatment with direct-acting antivirals partially improved NK ADCC function despite delayed CD16 reconstitution. Chronic HCV infection induces NK cell activation resulting in ADAM-17-dependent CD16 shedding and consequent impaired ADCC function. Altered ADCC may contribute to failure to eradicate HCV-infected hepatocytes. We show here that hepatitis C virus (HCV) activates natural killer (NK) lymphocytes which, as a consequence, loose their Fc receptor for IgG (CD16), an essential molecule for antibody binding. We show that this occurs through the action of enzymes named

  1. The gyri of the octopus vertical lobe have distinct neurochemical identities.

    Science.gov (United States)

    Shigeno, Shuichi; Ragsdale, Clifton W

    2015-06-15

    The cephalopod vertical lobe is the largest learning and memory structure known in invertebrate nervous systems. It is part of the visual learning circuit of the central brain, which also includes the superior frontal and subvertical lobes. Despite the well-established functional importance of this system, little is known about neuropil organization of these structures and there is to date no evidence that the five longitudinal gyri of the vertical lobe, perhaps the most distinctive morphological feature of the octopus brain, differ in their connections or molecular identities. We studied the histochemical organization of these structures in hatchling and adult Octopus bimaculoides brains with immunostaining for serotonin, octopus gonadotropin-releasing hormone (oGNRH), and octopressin-neurophysin (OP-NP). Our major finding is that the five lobules forming the vertical lobe gyri have distinct neurochemical signatures. This is most prominent in the hatchling brain, where the median and mediolateral lobules are enriched in OP-NP fibers, the lateral lobule is marked by oGNRH innervation, and serotonin immunostaining heavily labels the median and lateral lobules. A major source of input to the vertical lobe is the superior frontal lobe, which is dominated by a neuropil of interweaving fiber bundles. We have found that this neuropil also has an intrinsic neurochemical organization: it is partitioned into territories alternately enriched or impoverished in oGNRH-containing fascicles. Our findings establish that the constituent lobes of the octopus superior frontal-vertical system have an intricate internal anatomy, one likely to reflect the presence of functional subsystems within cephalopod learning circuitry. © 2015 Wiley Periodicals, Inc.

  2. Changes in neurochemicals within the ventrolateral medullary respiratory column in awake goats after carotid body denervation

    Science.gov (United States)

    Miller, Justin Robert; Neumueller, Suzanne; Muere, Clarissa; Olesiak, Samantha; Pan, Lawrence; Hodges, Matthew R.

    2013-01-01

    A current and major unanswered question is why the highly sensitive central CO2/H+ chemoreceptors do not prevent hypoventilation-induced hypercapnia following carotid body denervation (CBD). Because perturbations involving the carotid bodies affect central neuromodulator and/or neurotransmitter levels within the respiratory network, we tested the hypothesis that after CBD there is an increase in inhibitory and/or a decrease in excitatory neurochemicals within the ventrolateral medullary column (VMC) in awake goats. Microtubules for chronic use were implanted bilaterally in the VMC within or near the pre-Bötzinger Complex (preBötC) through which mock cerebrospinal fluid (mCSF) was dialyzed. Effluent mCSF was collected and analyzed for neurochemical content. The goats hypoventilated (peak +22.3 ± 3.4 mmHg PaCO2) and exhibited a reduced CO2 chemoreflex (nadir, 34.8 ± 7.4% of control ΔV̇E/ΔPaCO2) after CBD with significant but limited recovery over 30 days post-CBD. After CBD, GABA and glycine were above pre-CBD levels (266 ± 29% and 189 ± 25% of pre-CBD; P 0.05) different from control after CBD. Analyses of brainstem tissues collected 30 days after CBD exhibited 1) a midline raphe-specific reduction (P < 0.05) in the percentage of tryptophan hydroxylase–expressing neurons, and 2) a reduction (P < 0.05) in serotonin transporter density in five medullary respiratory nuclei. We conclude that after CBD, an increase in inhibitory neurotransmitters and a decrease in excitatory neuromodulation within the VMC/preBötC likely contribute to the hypoventilation and attenuated ventilatory CO2 chemoreflex. PMID:23869058

  3. REM sleep deprivation reverses neurochemical and other depressive-like alterations induced by olfactory bulbectomy.

    Science.gov (United States)

    Maturana, Maira J; Pudell, Cláudia; Targa, Adriano D S; Rodrigues, Laís S; Noseda, Ana Carolina D; Fortes, Mariana H; Dos Santos, Patrícia; Da Cunha, Cláudio; Zanata, Sílvio M; Ferraz, Anete C; Lima, Marcelo M S

    2015-02-01

    There is compelling evidence that sleep deprivation (SD) is an effective strategy in promoting antidepressant effects in humans, whereas few studies were performed in relevant animal models of depression. Acute administration of antidepressants in humans and rats generates a quite similar effect, i.e., suppression of rapid eye movement (REM) sleep. Then, we decided to investigate the neurochemical alterations generated by a protocol of rapid eye movement sleep deprivation (REMSD) in the notably known animal model of depression induced by the bilateral olfactory bulbectomy (OBX). REMSD triggered antidepressant mechanisms such as the increment of brain-derived neurotrophic factor (BDNF) levels, within the substantia nigra pars compacta (SNpc), which were strongly correlated to the swimming time (r = 0.83; P < 0.0001) and hippocampal serotonin (5-HT) content (r = 0.66; P = 0.004). Moreover, there was a strong correlation between swimming time and hippocampal 5-HT levels (r = 0.70; P = 0.003), strengthen the notion of an antidepressant effect associated to REMSD in the OBX rats. In addition, REMSD robustly attenuated the hippocampal 5-HT deficiency produced by the OBX procedure. Regarding the rebound (REB) period, we observed the occurrence of a sustained antidepressant effect, indicated mainly by the swimming and climbing times which could be explained by the maintenance of the increased nigral BDNF expression. Hence, hippocampal 5-HT levels remained enhanced in the OBX group after this period. We suggested that the neurochemical complexity inflicted by the OBX model, counteracted by REMSD, is directly correlated to the nigral BDNF expression and hippocampal 5-HT levels. The present findings provide new information regarding the antidepressant mechanisms triggered by REMSD.

  4. Previous Ketamine Produces an Enduring Blockade of Neurochemical and Behavioral Effects of Uncontrollable Stress

    Science.gov (United States)

    Dolzani, Samuel D.; Tilden, Scott; Christianson, John P.; Kubala, Kenneth H.; Bartholomay, Kristi; Sperr, Katherine; Ciancio, Nicholas; Watkins, Linda R.; Maier, Steven F.

    2016-01-01

    Recent interest in the antidepressant and anti-stress effects of subanesthetic doses of ketamine, an NMDA receptor antagonist, has identified mechanisms whereby ketamine reverses the effect of stress, but little is known regarding the prophylactic effect ketamine might have on future stressors. Here we investigate the prophylactic effect of ketamine against neurochemical and behavioral changes that follow inescapable, uncontrollable tail shocks (ISs) in Sprague Dawley rats. IS induces increased anxiety, which is dependent on activation of serotonergic (5-HT) dorsal raphe nucleus (DRN) neurons that project to the basolateral amygdala (BLA). Ketamine (10 mg/kg, i.p.) administered 2 h, 1 week, or 2 weeks before IS prevented the increased extracellular levels of 5-HT in the BLA typically produced by IS. In addition, ketamine administered at these time points blocked the decreased juvenile social investigation produced by IS. Microinjection of ketamine into the prelimbic (PL) region of the medial prefrontal cortex duplicated the effects of systemic ketamine, and, conversely, systemic ketamine effects were prevented by pharmacological inhibition of the PL. Although IS does not activate DRN-projecting neurons from the PL, IS did so after ketamine, suggesting that the prophylactic effect of ketamine is a result of altered functioning of this projection. SIGNIFICANCE STATEMENT The reported data show that systemic ketamine, given up to 2 weeks before a stressor, blunts behavioral and neurochemical effects of the stressor. The study also advances understanding of the mechanisms involved and suggests that ketamine acts at the prelimbic cortex to sensitize neurons that project to and inhibit the DRN. PMID:26740657

  5. Rapid sensing of l-leucine by human and murine hypothalamic neurons: Neurochemical and mechanistic insights.

    Science.gov (United States)

    Heeley, Nicholas; Kirwan, Peter; Darwish, Tamana; Arnaud, Marion; Evans, Mark L; Merkle, Florian T; Reimann, Frank; Gribble, Fiona M; Blouet, Clemence

    2018-02-07

    Dietary proteins are sensed by hypothalamic neurons and strongly influence multiple aspects of metabolic health, including appetite, weight gain, and adiposity. However, little is known about the mechanisms by which hypothalamic neural circuits controlling behavior and metabolism sense protein availability. The aim of this study is to characterize how neurons from the mediobasal hypothalamus respond to a signal of protein availability: the amino acid l-leucine. We used primary cultures of post-weaning murine mediobasal hypothalamic neurons, hypothalamic neurons derived from human induced pluripotent stem cells, and calcium imaging to characterize rapid neuronal responses to physiological changes in extracellular l-Leucine concentration. A neurochemically diverse subset of both mouse and human hypothalamic neurons responded rapidly to l-leucine. Consistent with l-leucine's anorexigenic role, we found that 25% of mouse MBH POMC neurons were activated by l-leucine. 10% of MBH NPY neurons were inhibited by l-leucine, and leucine rapidly reduced AGRP secretion, providing a mechanism for the rapid leucine-induced inhibition of foraging behavior in rodents. Surprisingly, none of the candidate mechanisms previously implicated in hypothalamic leucine sensing (K ATP channels, mTORC1 signaling, amino-acid decarboxylation) were involved in the acute activity changes produced by l-leucine. Instead, our data indicate that leucine-induced neuronal activation involves a plasma membrane Ca 2+ channel, whereas leucine-induced neuronal inhibition is mediated by inhibition of a store-operated Ca 2+ current. A subset of neurons in the mediobasal hypothalamus rapidly respond to physiological changes in extracellular leucine concentration. Leucine can produce both increases and decreases in neuronal Ca 2+ concentrations in a neurochemically-diverse group of neurons, including some POMC and NPY/AGRP neurons. Our data reveal that leucine can signal through novel mechanisms to rapidly

  6. Sensory receptors in the visceral pleura: neurochemical coding and live staining in whole mounts.

    Science.gov (United States)

    Pintelon, Isabel; Brouns, Inge; De Proost, Ian; Van Meir, Frans; Timmermans, Jean-Pierre; Adriaensen, Dirk

    2007-05-01

    Today, diagnosis and treatment of chest pain related to pathologic changes in the visceral pleura are often difficult. Data in the literature on the sensory innervation of the visceral pleura are sparse. The present study aimed at identifying sensory end-organs in the visceral pleura, and at obtaining more information about neurochemical coding. The immunocytochemcial data are mainly based on whole mounts of the visceral pleura of control and vagally denervated rats. It was shown that innervation of the rat visceral pleura is characterized by nerve bundles that enter in the hilus region and gradually split into slender bundles with a few nerve fibers. Separate nerve fibers regularly give rise to characteristic laminar terminals. Because of their unique association with the elastic fibers of the visceral pleura, we decided to refer to them as "visceral pleura receptors" (VPRs). Cryostat sections of rat lungs confirmed a predominant location on mediastinal and interlobar lung surfaces. VPRs can specifically be visualized by protein gene product 9.5 immunostaining, and were shown to express vesicular glutamate transporters, calbindin D28K, Na+/K+-ATPase, and P2X3 ATP-receptors. The sensory nerve fibers giving rise to VPRs appeared to be myelinated and to have a spinal origin. Because several of the investigated proteins have been reported as markers for sensory terminals in other organs, the present study revealed that VPRs display the neurochemical characteristics of mechanosensory and/or nociceptive terminals. The development of a live staining method, using AM1-43, showed that VPRs can be visualized in living tissue, offering an interesting model for future physiologic studies.

  7. Mercury exposure and neurochemical biomarkers in multiple brain regions of Wisconsin river otters (Lontra canadensis).

    Science.gov (United States)

    Dornbos, Peter; Strom, Sean; Basu, Niladri

    2013-04-01

    River otters are fish-eating wildlife that bioaccumulate high levels of mercury (Hg). Mercury is a proven neurotoxicant to mammalian wildlife, but little is known about the underlying, sub-clinical effects. Here, the overall goal was to increase understanding of Hg's neurological risk to otters. First, Hg values across several brain regions and tissues were characterized. Second, in three brain regions with known sensitivity to Hg (brainstem, cerebellum, and occipital cortex), potential associations among Hg levels and neurochemical biomarkers [N-methyl-D-aspartic acid (NMDA) and gamma-aminobutyric acid (GABAA) receptor] were explored. There were no significant differences in Hg levels across eight brain regions (rank order, highest to lowest: frontal cortex, cerebellum, temporal cortex, occipital cortex, parietal cortex, basal ganglia, brainstem, and thalamus), with mean values ranging from 0.7 to 1.3 ug/g dry weight. These brain levels were significantly lower than mean values in the muscle (2.1 ± 1.4 ug/g), liver (4.7 ± 4.3 ug/g), and fur (8.8 ± 4.8 ug/g). While a significant association was found between Hg and NMDA receptor levels in the brain stem (P = 0.028, rp = -0.293), no relationships were found in the cerebellum and occipital cortex. For the GABA receptor, no relationships were found. The lack of consistent Hg-associated neurochemical changes is likely due to low brain Hg levels in these river otters, which are amongst the lowest reported.

  8. Age-related neurochemical changes in the rhesus macaque cochlear nucleus.

    Science.gov (United States)

    Gray, Daniel T; Engle, James R; Recanzone, Gregg H

    2014-05-01

    Neurochemical changes in the expression of various proteins within the central auditory system have been associated with natural aging. These changes may compensate in part for the loss of auditory sensitivity arising from two phenomena of the aging auditory system: cochlear histopathologies and increased excitability of central auditory neurons. Recent studies in the macaque monkey have revealed age-related changes in the density of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase (NADPHd) and parvalbumin (PV)-positive cells within the inferior colliculus and superior olivary complex. The cochlear nucleus (CN), which is the first central auditory nucleus, remains unstudied. Since the CN participates in the generation of the auditory brainstem response (ABR) and receives direct innervation from the cochlea, it serves as an ideal nucleus to compare the relationship between these neurochemical changes and the physiological and peripheral changes of the aging auditory system. We used stereological sampling to calculate the densities of NADPHd and PV reactive neurons within the three subdivisions of the CN in middle-aged and aged rhesus macaques. Regression analyses of these values with ABR properties and cochlear histopathologies revealed relationships between these cell types and the changing characteristics of the aging auditory system. Our results indicate that NADPHd expression does change with age in a specific subdivision of the CN, but PV does not. Conversely, PV expression correlated with ABR amplitudes and outer hair cell loss in the cochlea, but NADPHd did not. These results indicate that NADPHd and PV may take part in distinct compensatory efforts of the aging auditory system. Copyright © 2013 Wiley Periodicals, Inc.

  9. The trace amine-associated receptor 1 modulates methamphetamine’s neurochemical and behavioural effects

    Directory of Open Access Journals (Sweden)

    Rachel eCotter

    2015-02-01

    Full Text Available The newly discovered trace amine-associated receptor 1 (TAAR1 has the ability to regulate both dopamine function and psychostimulant action. Here, we tested in rats the ability of RO5203648, a selective TAAR1 partial agonist, to modulate the physiological and behavioural effects of methamphetamine (METH. In experiment 1, RO5203468 dose- and time-dependently altered METH-induced locomotor activity, manifested as an early attenuation followed by a late potentiation of METH’s stimulating effects. In experiment 2, rats received a 14-day treatment regimen during which RO5203648 was co-administered with METH. RO5203648 dose-dependently attenuated METH-stimulated hyperactivity, with the effects becoming more apparent as the treatments progressed. After chronic exposure and 3-day withdrawal, rats were tested for locomotor sensitization. RO5203648 administration during the sensitizing phase prevented the development of METH sensitization. However, RO5203648, at the high dose, cross-sensitized with METH. In experiment 3, RO5203648 dose-dependently blocked METH self-administration without affecting operant responding maintained by sucrose, and exhibited lack of reinforcing efficacy when tested as a METH’s substitute. Neurochemical data showed that RO5203648 did not affect METH-mediated DA efflux and uptake inhibition in striatal synaptosomes. In vivo, however, RO5203648 was able to transiently inhibit METH-induced accumulation of extracellular DA levels in the nucleus accumbens. Taken together, these data highlight the significant potential of TAAR1 to modulate METH’s neurochemical and behavioural effects.

  10. The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death

    DEFF Research Database (Denmark)

    Brodehl, Andreas; Dieding, Mareike; Klauke, Bärbel

    2013-01-01

    The intermediate filament protein desmin is encoded by the gene DES and contributes to the mechanical stabilization of the striated muscle sarcomere and cell contacts within the cardiac intercalated disk. DES mutations cause severe skeletal and cardiac muscle diseases with heterogeneous phenotype...

  11. Two distinct mutations of the RET receptor causing Hirschsprung's disease impair the binding of signalling effecters to a multifunctional docking site

    NARCIS (Netherlands)

    Geneste, O; Bidaud, C; De Vita, G; Hofstra, RMW; Tartare-Deckert, S; Buys, CHCM; Lenoir, GM; Santoro, M; Billaud, M

    1999-01-01

    The RET gene codes for a transmembrane tyrosine kinase which is a subunit of a multimeric complex that acts as a receptor for four structurally related molecules: the glial cell line-derived neurotrophic factor (GDNF), neurturin, artemin and persephin, Germline mutations of RET cause a dominantly

  12. A Mutation in the Glutamate-rich Region of RBM20 Causes Dilated Cardiomyopathy through Missplicing of Titin and Impaired Frank-Starling Mechanism

    DEFF Research Database (Denmark)

    Beqqali, Abdelaziz; Bollen, Ilse A E; Rasmussen, Torsten Bloch

    2016-01-01

    Mutations in the RS-domain of RNA-binding motif protein 20 (RBM20) have recently been identified to segregate with aggressive forms of familial dilated cardiomyopathy (DCM). Loss of RBM20 in rats results in missplicing of the sarcomeric gene titin (TTN). The functional and physiological consequen......Mutations in the RS-domain of RNA-binding motif protein 20 (RBM20) have recently been identified to segregate with aggressive forms of familial dilated cardiomyopathy (DCM). Loss of RBM20 in rats results in missplicing of the sarcomeric gene titin (TTN). The functional and physiological......-rich region of RBM20. Western blot analysis of endogenous RBM20 protein revealed strongly reduced protein levels in the heart of an RBM20(E913K/+) carrier. RNA deep-sequencing demonstrated massive inclusion of exons coding for the spring region of titin in the RBM20(E913K/+) carrier. Titin isoform analysis...... was rescued by protein kinase A treatment. A mutation outside the mutational hotspot of RBM20 results in haploinsufficiency of RBM20. This leads to disturbed alternative splicing of TTN, resulting in a dramatic shift to highly compliant titin isoforms and an impaired FSM. These effects may contribute...

  13. Magnitude and Causes of Low Vision Disability (Moderate and Severe Visual Impairment among Students of Al-Noor Institute for the Blind in Al-Hassa, Saudi Arabia; A case series

    Directory of Open Access Journals (Sweden)

    Fahad Al-Wadani

    2012-02-01

    Full Text Available Objectives: This study aimed to estimate the magnitude and causes of low vision disability (severe visual impairment [SVI] and moderate visual impairment [MVI] among students at Al-Noor Institute for the Blind (NIB in Al-Hassa, Saudi Arabia in 2006. Methods: An optometrist conducted refraction of 122 eyes of the 61 students (27 boys and 34 girls with MVI (vision <6/18 to 6/60 and SVI (vision <6/60 to 3/60. Ophthalmologists examined the anterior and posterior segments, and analysed the outcomes of additional investigations to finalise the diagnosis. The results were categorised as ‘preventable’, ‘treatable’ and ‘not amenable to treatment’. The low vision care was also reviewed. Results: In 12 (9.8% eyes, visual acuity was ≥6/18 and in 28 (23% eyes, it was <3/60. MVI and SVI were found in 82 eyes (67.2%. Hereditary retinal disorders were found in 68 (55.7% eyes. Although refractive errors were found in 112 (91.8% eyes, isolated refractive error was found in only 9 students. Congenital glaucoma and cataract were responsible for visual impairment in 16 (13.1% and 9 (7.4% eyes. These students were prescribed optical and non-optical low vision aids. Conclusion: Retinal disease was the main cause of SVI and MVI in our series. Some students at Al-Noor Institute for the Blind have curable low vision conditions. Rehabilitation of low vision disability should be different from that offered to the absolutely blind.

  14. Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation.

    Science.gov (United States)

    Hedrich, Ulrike B S; Liautard, Camille; Kirschenbaum, Daniel; Pofahl, Martin; Lavigne, Jennifer; Liu, Yuanyuan; Theiss, Stephan; Slotta, Johannes; Escayg, Andrew; Dihné, Marcel; Beck, Heinz; Mantegazza, Massimo; Lerche, Holger

    2014-11-05

    Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na(+) channels in interneurons and persistent Na(+) currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca(2+) imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation. Copyright © 2014 the authors 0270-6474/14/3414874-16$15.00/0.

  15. Exposure to 900 MHz electromagnetic fields activates the mkp-1/ERK pathway and causes blood-brain barrier damage and cognitive impairment in rats.

    Science.gov (United States)

    Tang, Jun; Zhang, Yuan; Yang, Liming; Chen, Qianwei; Tan, Liang; Zuo, Shilun; Feng, Hua; Chen, Zhi; Zhu, Gang

    2015-03-19

    With the rapid increase in the number of mobile phone users, the potential adverse effects of the electromagnetic field radiation emitted by a mobile phone has become a serious concern. This study demonstrated, for the first time, the blood-brain barrier and cognitive changes in rats exposed to 900 MHz electromagnetic field (EMF) and aims to elucidate the potential molecular pathway underlying these changes. A total of 108 male Sprague-Dawley rats were exposed to a 900 MHz, 1 mW/cm(2) EMF or sham (unexposed) for 14 or 28 days (3h per day). The specific energy absorption rate (SAR) varied between 0.016 (whole body) and 2 W/kg (locally in the head). In addition, the Morris water maze test was used to examine spatial memory performance determination. Morphological changes were investigated by examining ultrastructural changes in the hippocampus and cortex, and the Evans Blue assay was used to assess blood brain barrier (BBB) damage. Immunostaining was performed to identify heme oxygenase-1 (HO-1)-positive neurons and albumin extravasation detection. Western blot was used to determine HO-1 expression, phosphorylated ERK expression and the upstream mediator, mkp-1 expression. We found that the frequency of crossing platforms and the percentage of time spent in the target quadrant were lower in rats exposed to EMF for 28 days than in rats exposed to EMF for 14 days and unexposed rats. Moreover, 28 days of EMF exposure induced cellular edema and neuronal cell organelle degeneration in the rat. In addition, damaged BBB permeability, which resulted in albumin and HO-1 extravasation were observed in the hippocampus and cortex. Thus, for the first time, we found that EMF exposure for 28 days induced the expression of mkp-1, resulting in ERK dephosphorylation. Taken together, these results demonstrated that exposure to 900 MHz EMF radiation for 28 days can significantly impair spatial memory and damage BBB permeability in rat by activating the mkp-1/ERK pathway. Copyright

  16. Interferon-gamma deficiency modifies the motor and co-morbid behavioral pathology and neurochemical changes provoked by the pesticide paraquat.

    Science.gov (United States)

    Litteljohn, D; Mangano, E; Shukla, N; Hayley, S

    2009-12-29

    In addition to nigrostriatal pathology and corresponding motor disturbances, Parkinson's disease (PD) is often characterized by co-morbid neuropsychiatric symptoms, most notably anxiety and depression. Separate lines of evidence indicate that inflammatory processes associated with microglial activation and cytokine release may be fundamental to the progression of both PD and its co-morbid psychiatric pathology. Accordingly, we assessed the contribution of the pro-inflammatory cytokine, interferon-gamma (IFN-gamma), to a range of PD-like pathology provoked by the ecologically relevant herbicide and dopamine (DA) toxin, paraquat. To this end, paraquat provoked overt motor impairment (reduced home-cage activity and impaired vertical climbing) and signs of anxiety-like behavior (reduced open field exploration) in wild-type but not IFN-gamma-deficient mice. Correspondingly, paraquat promoted somewhat divergent variations in neurochemical activity among wild-type and IFN-gamma null mice at brain sites important for both motor (striatum) and co-morbid affective pathologies (dorsal hippocampus, medial prefrontal cortex, and locus coeruleus). Specifically, the herbicide provoked a dosing regimen-dependent reduction in striatal DA levels that was prevented by IFN-gamma deficiency. In addition, the herbicide influenced serotonergic and noradrenergic activity within the dorsal hippocampus and medial prefrontal cortex; and elevated noradrenergic activity within the locus coeruleus. Although genetic ablation of IFN-gamma had relatively few effects on monoamine variations within the locus coeruleus and prefrontal cortex, loss of the pro-inflammatory cytokine did normalize the paraquat-induced noradrenergic alterations within the hippocampus. These findings further elucidate the functional implications of paraquat intoxication and suggest an important role for IFN-gamma in the striatal and motor pathology, as well as the co-morbid behavioral and hippocampal changes induced by

  17. Prevalence and causes of visual impairment and blindness among adults with diabetes mellitus aged 40 years and older receiving treatment at government health facilities in the Mopani District, South Africa

    Directory of Open Access Journals (Sweden)

    R.G. Mabaso

    2014-08-01

    Full Text Available This article presents part of the findings of a study conducted to assess the prevalence and causes of visual impairment (VI and blindness among adults with diabetes mellitus (DM receiving treatment at the government health facilities in the Mopani District, South Africa.  This health facility-based cross-sectional study was conducted among 225 Black South African diabetics (161 females and 64 males aged 40-90 years (mean= 61.50 ± 10.49 years at seven different health care facilities. All the participants were examined for VI using an auto-refractor, pinhole disc, an ophthalmoscope, and a logMAR chart. Visual impairment was defined as visual acuity (VA of worse than 6/9.5 but better and equal to 3/60, and blindness as VA of worse than 3/60 to no light perception. The prevalence of uncompensated VI and blindness in the right eyes was 70.6 and 3.6%, respectively. In the left eyes, the prevalence was 72 and 3.1% for VI and blindness respectively. The prevalence of blindness remained the same after optical compensation. The leading causes of uncompensated VI and blindness in both eyes were uncorrected refractive error (RE (49.5%, cataract (24.7%, diabetic retinopathy (3.8% and glaucoma (2.2%. Following optical compensation, the prevalence of compensated VI and blindness in the right eyes was 41.3 and 3.6%, respectively and in the left eyes, the prevalence was 42.2 and 3.1%, respectively. Uncompensated RE and cataract were the common causes of VI and blindness in this sample. The socio-economic status of this population might have contributed to these findings. These results indicate the need for affordable vision examination and spectacles provision as well as cataract surgery services in this population.

  18. Impairment of Serotonergic Transmission by the Antiparkinsonian Drug L-DOPA: Mechanisms and Clinical Implications

    Directory of Open Access Journals (Sweden)

    Cristina Miguelez

    2017-09-01

    Full Text Available The link between the anti-Parkinsonian drug L-3,4-dihydroxyphenylalanine (L-DOPA and the serotonergic (5-HT system has been long established and has received increased attention during the last decade. Most studies have focused on the fact that L-DOPA can be transformed into dopamine (DA and released from 5-HT terminals, which is especially important for the management of L-DOPA-induced dyskinesia. In patients, treatment using L-DOPA also impacts 5-HT neurotransmission; however, few studies have investigated the mechanisms of this effect. The purpose of this review is to summarize the electrophysiological and neurochemical data concerning the effects of L-DOPA on 5-HT cell function. This review will argue that L-DOPA disrupts the link between the electrical activity of 5-HT neurons and 5-HT release as well as that between 5-HT release and extracellular 5-HT levels. These effects are caused by the actions of L-DOPA and DA in 5-HT neurons, which affect 5-HT neurotransmission from the biosynthesis of 5-HT to the impairment of the 5-HT transporter. The interaction between L-DOPA and 5-HT transmission is especially relevant in those Parkinson’s disease (PD patients that suffer dyskinesia, comorbid anxiety or depression, since the efficacy of antidepressants or 5-HT compounds may be affected.

  19. Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor α1 can be ameliorated by T3 treatment

    Science.gov (United States)

    Venero, César; Guadaño-Ferraz, Ana; Herrero, Ana Isabel; Nordström, Kristina; Manzano, Jimena; de Escobar, Gabriella Moreale; Bernal, Juan; Vennström, Björn

    2005-01-01

    The transcriptional properties of unliganded thyroid hormone receptors are thought to cause the misdevelopment during hypothyroidism of several functions essential for adult life. To specifically determine the role of unliganded thyroid hormone receptor α1 (TRα1) in neuronal tissues, we introduced a mutation into the mouse TRα1 gene that lowers affinity to thyroid hormone (TH) 10-fold. The resulting heterozygous mice exhibit several distinct neurological abnormalities: extreme anxiety, reduced recognition memory, and locomotor dysfunction. The anxiety and memory deficiencies were relieved by treatment with high levels of TH in adulthood, an effect that correlated with a normalization of GABAergic inhibitory interneurons in the hippocampal CA1 region. In contrast, a post-natal TH treatment was necessary and sufficient for ameliorating the adult locomotor dysfunction. Here, the hormone treatment normalized the otherwise delayed cerebellar development. The data thus identify two novel and distinct functions of an unliganded TRα1 during development and adulthood, respectively. PMID:16131613

  20. Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin

    DEFF Research Database (Denmark)

    Kristiansen, M; Aminoff, M; Jacobsen, Christian

    2000-01-01

    Megaloblastic anemia 1 (MGA1) is an autosomal recessive disorder caused by the selective intestinal malabsorption of intrinsic factor (IF) and vitamin B(12)/cobalamin (Cbl) in complex. Most Finnish patients with MGA1 carry the disease-specific P1297L mutation (FM1) in the IF-B(12) receptor, cubilin....... By site-directed mutagenesis, mammalian expression, and functional comparison of the purified wild-type and FM1 mutant forms of the IF-Cbl-binding cubilin region (CUB domains 5-8, amino acid 928-1386), we have investigated the functional implications of the P1297L mutation. Surface plasmon resonance...... analysis revealed that the P1297L substitution specifically increases the K(d) for IF-Cbl binding several-fold, largely by decreasing the association rate constant. In agreement with the binding data, the wild-type protein, but not the FM1 mutant protein, potently inhibits 37 degrees C uptake of iodine 125...

  1. Computational modeling of stuttering caused by impairments in a basal ganglia thalamo-cortical circuit involved in syllable selection and initiation

    Science.gov (United States)

    Civier, Oren; Bullock, Daniel; Max, Ludo; Guenther, Frank H.

    2013-01-01

    A typical white-matter integrity and elevated dopamine levels have been reported for individuals who stutter. We investigated how such abnormalities may lead to speech dysfluencies due to their effects on a syllable-sequencing circuit that consists of basal ganglia (BG), thalamus, and left ventral premotor cortex (vPMC). “Neurally impaired” versions of the neurocomputational speech production model GODIVA were utilized to test two hypotheses: (1) that white-matter abnormalities disturb the circuit via corticostriatal projections carrying copies of executed motor commands, and (2) that dopaminergic abnormalities disturb the circuit via the striatum. Simulation results support both hypotheses: in both scenarios, the neural abnormalities delay readout of the next syllable’s motor program, leading to dysfluency. The results also account for brain imaging findings during dysfluent speech. It is concluded that each of the two abnormality types can cause stuttering moments, probably by affecting the same BG-thalamus-vPMC circuit. PMID:23872286

  2. Ethanol-induced impairment of polyamine homeostasis – A potential cause of neural tube defect and intrauterine growth restriction in fetal alcohol syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Haghighi Poodeh, Saeid, E-mail: saeid.haghighi@oulu.fi [Institute of Clinical Medicine, Department of Internal Medicine, and Biocenter Oulu, University of Oulu, Oulu (Finland); Medical Research Center, Oulu University Hospital, Oulu (Finland); Alhonen, Leena [Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, Kuopio (Finland); School of Pharmacy, Biocenter Kuopio, University of Eastern Finland, Kuopio (Finland); Salonurmi, Tuire; Savolainen, Markku J. [Institute of Clinical Medicine, Department of Internal Medicine, and Biocenter Oulu, University of Oulu, Oulu (Finland); Medical Research Center, Oulu University Hospital, Oulu (Finland)

    2014-03-28

    Highlights: • Polyamine pools in embryonic and extraembryonic tissues are developmentally regulated. • Alcohol administration perturbs polyamine levels in the tissues with various patterns. • Total absence of polyamines in the embryo head at 9.5 dpc is critical for development. • The deficiency is associated with reduction in endothelial cell sprouting in the head. • Retarded migration of neural crest cells may cause development of neural tube defect. - Abstract: Introduction: Polyamines play a fundamental role during embryogenesis by regulating cell growth and proliferation and by interacting with RNA, DNA and protein. The polyamine pools are regulated by metabolism and uptake from exogenous sources. The use of certain inhibitors of polyamine synthesis causes similar defects to those seen in alcohol exposure e.g. retarded embryo growth and endothelial cell sprouting. Methods: CD-1 mice received two intraperitoneal injections of 3 g/kg ethanol at 4 h intervals 8.75 days post coitum (dpc). The fetal head, trunk, yolk sac and placenta were collected at 9.5 and 12.5 dpc and polyamine concentrations were determined. Results: No measurable quantity of polyamines could be detected in the embryo head at 9.5 dpc, 12 h after ethanol exposure. Putrescine was not detectable in the trunk of the embryo at that time, whereas polyamines in yolk sac and placenta were at control level. Polyamine deficiency was associated with slow cell growth, reduction in endothelial cell sprouting, an altered pattern of blood vessel network formation and consequently retarded migration of neural crest cells and growth restriction. Discussion: Our results indicate that the polyamine pools in embryonic and extraembryonic tissues are developmentally regulated. Alcohol administration, at the critical stage, perturbs polyamine levels with various patterns, depending on the tissue and its developmental stage. The total absence of polyamines in the embryo head at 9.5 dpc may explain why this

  3. Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.

    Science.gov (United States)

    Nakazawa, Yuka; Sasaki, Kensaku; Mitsutake, Norisato; Matsuse, Michiko; Shimada, Mayuko; Nardo, Tiziana; Takahashi, Yoshito; Ohyama, Kaname; Ito, Kosei; Mishima, Hiroyuki; Nomura, Masayo; Kinoshita, Akira; Ono, Shinji; Takenaka, Katsuya; Masuyama, Ritsuko; Kudo, Takashi; Slor, Hanoch; Utani, Atsushi; Tateishi, Satoshi; Yamashita, Shunichi; Stefanini, Miria; Lehmann, Alan R; Yoshiura, Koh-ichiro; Ogi, Tomoo

    2012-05-01

    UV-sensitive syndrome (UV(S)S) is a genodermatosis characterized by cutaneous photosensitivity without skin carcinoma. Despite mild clinical features, cells from individuals with UV(S)S, like Cockayne syndrome cells, are very UV sensitive and are deficient in transcription-coupled nucleotide-excision repair (TC-NER), which removes DNA damage in actively transcribed genes. Three of the seven known UV(S)S cases carry mutations in the Cockayne syndrome genes ERCC8 or ERCC6 (also known as CSA and CSB, respectively). The remaining four individuals with UVSS , one of whom is described for the first time here, formed a separate UV(S)S-A complementation group; however, the responsible gene was unknown. Using exome sequencing, we determine that mutations in the UVSSA gene (formerly known as KIAA1530) cause UV(S)S-A. The UVSSA protein interacts with TC-NER machinery and stabilizes the ERCC6 complex; it also facilitates ubiquitination of RNA polymerase IIo stalled at DNA damage sites. Our findings provide mechanistic insights into the processing of stalled RNA polymerase and explain the different clinical features across these TC-NER–deficient disorders.

  4. Loss of fibulin-4 results in abnormal collagen fibril assembly in bone, caused by impaired lysyl oxidase processing and collagen cross-linking.

    Science.gov (United States)

    Sasaki, Takako; Stoop, Reinout; Sakai, Takao; Hess, Andreas; Deutzmann, Rainer; Schlötzer-Schrehardt, Ursula; Chu, Mon-Li; von der Mark, Klaus

    2016-03-01

    The extracellular matrix protein fibulin-4 has been shown to be indispensable for elastic fiber assembly, but there is also evidence from human mutations that it is involved in controlling skeletal development and bone stability. Fibulin-4 mutations were identified in patients suffering from vascular abnormality and/or cutis laxa, and some of these patients exhibited bone fragility, arachnodactyly and joint laxity. In order to elucidate the role of fibulin-4 in bone structure and skeletal development, we analyzed structural changes in skeletal tissues of Fbln4(-/-) mice. Immunostaining confirmed that fibulin-4 is highly expressed in cartilage, bone, ligaments and tendons. No morphological abnormalities were found in the skeleton of Fbln4(-/-) mice as compared to wild type littermates except forelimb contractures as well as unusually thick collagen fibrils. Furthermore, fibulin-4 deficiency caused enhanced susceptibility of bone collagen for acid extraction, consistent with significantly reduced lysylpyridinoline and hydroxylysylpyridinoline cross-links in bone. In accordance with that, the amount of lysyl oxidase in long bones and calvaria was strongly decreased and proteolytic activation of lysyl oxidase was reduced in fibulin-4 deficient osteoblasts, while addition of recombinant fibulin-4 rescued the activation. The finding suggested that fibulin-4 is important for the proteolytic activation of lysyl oxidase which has a pivotal role in cross-linking of collagen and elastin. Copyright © 2015 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

  5. Reduced cathepsins B and D cause impaired autophagic degradation that can be almost completely restored by overexpression of these two proteases in Sap C-deficient fibroblasts.

    Science.gov (United States)

    Tatti, Massimo; Motta, Marialetizia; Di Bartolomeo, Sabrina; Scarpa, Susanna; Cianfanelli, Valentina; Cecconi, Francesco; Salvioli, Rosa

    2012-12-01

    Saposin (Sap) C deficiency, a rare variant form of Gaucher disease, is due to mutations in the Sap C coding region of the prosaposin (PSAP) gene. Sap C is required as an activator of the lysosomal enzyme glucosylceramidase (GCase), which catalyzes glucosylceramide (GC) degradation. Deficit of either GCase or Sap C leads to the accumulation of undegraded GC and other lipids in lysosomes of monocyte/macrophage lineage. Recently, we reported that Sap C mutations affecting a cysteine residue result in increased autophagy. Here, we characterized the basis for the autophagic dysfunction. We analyzed Sap C-deficient and GCase-deficient fibroblasts and observed that autophagic disturbance was only associated with lack of Sap C. By a combined fluorescence microscopy and biochemical studies, we demonstrated that the accumulation of autophagosomes in Sap C-deficient fibroblasts is not due to enhanced autophagosome formation but to delayed degradation of autolysosomes caused, in part, to decreased amount and reduced enzymatic activity of cathepsins B and D. On the contrary, in GCase-deficient fibroblasts, the protein level and enzymatic activity of cathepsin D were comparable with control fibroblasts, whereas those of cathepsin B were almost doubled. Moreover, the enhanced expression of both these lysosomal proteases in Sap C-deficient fibroblasts resulted in close to functional autophagic degradation. Our data provide a novel example of altered autophagy as secondary event resulting from insufficient lysosomal function.

  6. Subclinical mastitis in goats is associated with upregulation of nitric oxide-derived oxidative stress that causes reduction of milk antioxidative properties and impairment of its quality.

    Science.gov (United States)

    Silanikove, Nissim; Merin, Uzi; Shapiro, Fira; Leitner, Gabriel

    2014-01-01

    The aim of this study was to verify the existence of a nitric oxide (NO) cycle in goat milk and to study how changes in it affect milk composition during subclinical mastitis. Fifteen lactating dairy goats in which one udder-half was free from bacterial infection and the contra-lateral one was naturally infected with various species of coagulase-negative staphylococci were used. In comparison to uninfected glands, subclinical mastitis was associated with a decrease in milk yield, lactose concentration, and curd yield and an increase in nitrite and nitrate concentrations and with measurements reflecting increased formation of NO-derived free-radical nitrogen dioxide. The occurrence of NO cycling in goat milk was largely confirmed. The increase in the NO-derived stress during subclinical infection was not associated with significant increase in oxidatively modified substances, 3-nitrotyrosine, and carbonyls on proteins, but with increased levels of peroxides on fat. However, the relatively modest nitrosative stress in subclinically infected glands was associated with significant reduction in total antioxidant capacity and vitamin C levels in milk. We concluded that subclinical mastitis in goats caused by coagulase-negative staphylococci imposes negative changes in milk yield, milk quality for cheese production, and negatively affects the nutritional value of milk as food. Thus, subclinical mastitis in goats should be considered as a serious economic burden both by farmers and by the dairy industry. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  7. Disruption of zebrafish cyclin G-associated kinase (GAK function impairs the expression of Notch-dependent genes during neurogenesis and causes defects in neuronal development

    Directory of Open Access Journals (Sweden)

    Szeto Daniel P

    2010-01-01

    Full Text Available Abstract Background The J-domain-containing protein auxilin, a critical regulator in clathrin-mediated transport, has been implicated in Drosophila Notch signaling. To ask if this role of auxilin is conserved and whether auxilin has additional roles in development, we have investigated the functions of auxilin orthologs in zebrafish. Results Like mammals, zebrafish has two distinct auxilin-like molecules, auxilin and cyclin G-associated kinase (GAK, differing in their domain structures and expression patterns. Both zebrafish auxilin and GAK can functionally substitute for the Drosophila auxilin, suggesting that they have overlapping molecular functions. Still, they are not completely redundant, as morpholino-mediated knockdown of the ubiquitously expressed GAK alone can increase the specification of neuronal cells, a known Notch-dependent process, and decrease the expression of Her4, a Notch target gene. Furthermore, inhibition of GAK function caused an elevated level of apoptosis in neural tissues, resulting in severe degeneration of neural structures. Conclusion In support of the notion that endocytosis plays important roles in Notch signaling, inhibition of zebrafish GAK function affects embryonic neuronal cell specification and Her4 expression. In addition, our analysis suggests that zebrafish GAK has at least two functions during the development of neural tissues: an early Notch-dependent role in neuronal patterning and a late role in maintaining the survival of neural cells.

  8. Neurochemical features of endomorphin-2-containing neurons in the submucosal plexus of the rat colon.

    Science.gov (United States)

    Li, Jun-Ping; Zhang, Ting; Gao, Chang-Jun; Kou, Zhen-Zhen; Jiao, Xu-Wen; Zhang, Lian-Xiang; Wu, Zhen-Yu; He, Zhong-Yi; Li, Yun-Qing

    2015-09-14

    To investigate the distribution and neurochemical phenotype of endomorphin-2 (EM-2)-containing neurons in the submucosal plexus of the rat colon. The mid-colons between the right and left flexures were removed from rats, and transferred into Kreb's solution. For whole-mount preparations, the mucosal, outer longitudinal muscle and inner circular muscle layers of the tissues were separated from the submucosal layer attached to the submucosal plexus. The whole-mount preparations from each rat mid-colon were mounted onto seven gelatin-coated glass slides, and processed for immunofluorescence histochemical double-staining of EM-2 with calcitonin gene-related peptide (CGRP), choline acetyltransferase (ChAT), nitric oxide synthetase (NOS), neuron-specific enolase (NSE), substance P (SP) and vasoactive intestinal peptide (VIP). After staining, all the fluorescence-labeled sections were observed with a confocal laser scanning microscope. To estimate the extent of the co-localization of EM-2 with CGRP, ChAT, NOS, NSE, SP and VIP, ganglia, which have a clear boundary and neuronal cell outline, were randomly selected from each specimen for this analysis. In the submucosal plexus of the mid-colon, many EM-2-immunoreactive (IR) and NSE-IR neuronal cell bodies were found in the submucosal plexus of the rat mid-colon. Approximately 6 ± 4.2 EM-2-IR neurons aggregated within each ganglion and a few EM-2-IR neurons were also found outside the ganglia. The EM-2-IR neurons were also immunopositive for ChAT, SP, VIP or NOS. EM-2-IR nerve fibers coursed near ChAT-IR neurons, and some of these fibers were even distributed around ChAT-IR neuronal cell bodies. Some EM-2-IR neuronal cell bodies were surrounded by SP-IR nerve fibers, but many long processes connecting adjacent ganglia were negative for EM-2 immunostaining. Long VIP-IR processes with many branches coursed through the ganglia and surrounded the EM-2-IR neurons. The percentages of the EM-2-IR neurons that were also positive for

  9. Single episode of mild murine malaria induces neuroinflammation, alters microglial profile, impairs adult neurogenesis, and causes deficits in social and anxiety-like behavior.

    Science.gov (United States)

    Guha, Suman K; Tillu, Rucha; Sood, Ankit; Patgaonkar, Mandar; Nanavaty, Ishira N; Sengupta, Arjun; Sharma, Shobhona; Vaidya, Vidita A; Pathak, Sulabha

    2014-11-01

    Cerebral malaria is associated with cerebrovascular damage and neurological sequelae. However, the neurological consequences of uncomplicated malaria, the most prevalent form of the disease, remain uninvestigated. Here, using a mild malaria model, we show that a single Plasmodium chabaudi adami infection in adult mice induces neuroinflammation, neurogenic, and behavioral changes in the absence of a blood-brain barrier breach. Using cytokine arrays we show that the infection induces differential serum and brain cytokine profiles, both at peak parasitemia and 15days post-parasite clearance. At the peak of infection, along with the serum, the brain also exhibited a definitive pro-inflammatory cytokine profile, and gene expression analysis revealed that pro-inflammatory cytokines were also produced locally in the hippocampus, an adult neurogenic niche. Hippocampal microglia numbers were enhanced, and we noted a shift to an activated profile at this time point, accompanied by a striking redistribution of the microglia to the subgranular zone adjacent to hippocampal neuronal progenitors. In the hippocampus, a distinct decline in progenitor turnover and survival was observed at peak parasitemia, accompanied by a shift from neuronal to glial fate specification. Studies in transgenic Nestin-GFP reporter mice demonstrated a decline in the Nestin-GFP(+)/GFAP(+) quiescent neural stem cell pool at peak parasitemia. Although these cellular changes reverted to normal 15days post-parasite clearance, specific brain cytokines continued to exhibit dysregulation. Behavioral analysis revealed selective deficits in social and anxiety-like behaviors, with no change observed in locomotor, cognitive, and depression-like behaviors, with a return to baseline at recovery. Collectively, these findings indicate that even a single episode of mild malaria results in alterations of the brain cytokine profile, causes specific behavioral dysfunction, is accompanied by hippocampal microglial

  10. Ethanol-induced impairment of polyamine homeostasis--a potential cause of neural tube defect and intrauterine growth restriction in fetal alcohol syndrome.

    Science.gov (United States)

    Haghighi Poodeh, Saeid; Alhonen, Leena; Salonurmi, Tuire; Savolainen, Markku J

    2014-03-28

    Polyamines play a fundamental role during embryogenesis by regulating cell growth and proliferation and by interacting with RNA, DNA and protein. The polyamine pools are regulated by metabolism and uptake from exogenous sources. The use of certain inhibitors of polyamine synthesis causes similar defects to those seen in alcohol exposure e.g. retarded embryo growth and endothelial cell sprouting. CD-1 mice received two intraperitoneal injections of 3 g/kg ethanol at 4 h intervals 8.75 days post coitum (dpc). The fetal head, trunk, yolk sac and placenta were collected at 9.5 and 12.5 dpc and polyamine concentrations were determined. No measurable quantity of polyamines could be detected in the embryo head at 9.5 dpc, 12 h after ethanol exposure. Putrescine was not detectable in the trunk of the embryo at that time, whereas polyamines in yolk sac and placenta were at control level. Polyamine deficiency was associated with slow cell growth, reduction in endothelial cell sprouting, an altered pattern of blood vessel network formation and consequently retarded migration of neural crest cells and growth restriction. Our results indicate that the polyamine pools in embryonic and extraembryonic tissues are developmentally regulated. Alcohol administration, at the critical stage, perturbs polyamine levels with various patterns, depending on the tissue and its developmental stage. The total absence of polyamines in the embryo head at 9.5 dpc may explain why this stage is so vulnerable to the development of neural tube defect, and growth restriction, the findings previously observed in fetal alcohol syndrome. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. A novel 'splice site' HCN4 Gene mutation, c.1737+1 G>T, causes familial bradycardia, reduced heart rate response, impaired chronotropic competence and increased short-term heart rate variability.

    Science.gov (United States)

    Hategan, Lidia; Csányi, Beáta; Ördög, Balázs; Kákonyi, Kornél; Tringer, Annamária; Kiss, Orsolya; Orosz, Andrea; Sághy, László; Nagy, István; Hegedűs, Zoltán; Rudas, László; Széll, Márta; Varró, András; Forster, Tamás; Sepp, Róbert

    2017-08-15

    The most important molecular determinant of heart rate regulation in sino-atrial pacemaker cells includes hyperpolarization-activated, cyclic nucleotide-gated ion channels, the major isoform of which is encoded by the HCN4 gene. Mutations affecting the HCN4 gene are associated primarily with sick sinus syndrome. A novel c.1737+1 G>T 'splice-site' HCN4 mutation was identified in a large family with familial bradycardia which co-segregated with the disease providing a two-point LOD score of 4.87. Twelve out of the 22 investigated family members [4 males, 8 females average age 36 (SD 6) years] were considered as clinically affected (heart ratesite' HCN4 gene mutation, c.1737+1 G>T, causes familial bradycardia and leads to reduced heart rate response, impaired chronotropic competence and increased short-term heart rate variability in the mutation carriers. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. From genes to behavior: investigations of neurochemical signaling come of age for the model crustacean Daphnia pulex.

    Science.gov (United States)

    Christie, Andrew E; McCoole, Matthew D

    2012-08-01

    The cladoceran crustacean Daphnia pulex has served as a standard organism for aquatic toxicity testing for decades. The model organism status of D. pulex rests largely on its remarkable ability to rapidly adapt morphologically, physiologically and behaviorally to a wide range of environmental challenges, as well as on its parthenogenetic reproduction and ease of laboratory culture. As in all multicellular organisms, neurochemical control systems are undoubtedly major contributors to the functional flexibility of Daphnia. Surprisingly, little work has focused on understanding its neurochemistry at any level. Recently, D. pulex has been the subject of extensive genome and transcriptome sequencing, and it is currently the only crustacean with a fully sequenced, publicly accessible genome. Although the molecular work was initiated for gene-based investigations of ecotoxicology and toxicogenomics, the data generated have allowed for investigations into numerous aspects of Daphnia biology, including its neurochemical signaling. This Commentary summarizes our knowledge of D. pulex neurochemistry obtained from recent genomic and transcriptomic studies, and places these data in context with other anatomical, biochemical and physiological experiments using D. pulex and its sister species Daphnia magna. Suggestions as to how the Daphnia molecular data may be useful for future investigations of crustacean neurochemical signaling are also provided.

  13. Piperine Augments the Protective Effect of Curcumin Against Lipopolysaccharide-Induced Neurobehavioral and Neurochemical Deficits in Mice.

    Science.gov (United States)

    Jangra, Ashok; Kwatra, Mohit; Singh, Tavleen; Pant, Rajat; Kushwah, Pawan; Sharma, Yogita; Saroha, Babita; Datusalia, Ashok Kumar; Bezbaruah, Babul Kumar

    2016-06-01

    The aim of the present study was to investigate the protective effects of curcumin alone and in combination with piperine against lipopolysaccharide (LPS)-induced neurobehavioral and neurochemical deficits in the mice hippocampus. Mice were treated with curcumin (100, 200, and 400 mg/kg, p.o.) and piperine (20 mg/kg, p.o.) for 7 days followed by LPS (0.83 mg/kg, i.p.) administration. Animals exhibited anxiety and depressive-like phenotype after 3 and 24 h of LPS exposure, respectively. LPS administration increased the oxido-nitrosative stress as evident by elevated levels of malondialdehyde, nitrite, and depletion of glutathione level in the hippocampus. Furthermore, we found raised level of pro-inflammatory cytokines (IL-1β and TNF-α) in the hippocampus of LPS-treated mice. Pretreatment with curcumin alleviated LPS-induced neurobehavioral and neurochemical deficits. Furthermore, co-administration of curcumin with piperine significantly potentiated the neuroprotective effect of curcumin. These results demonstrate that piperine enhanced the neuroprotective effect of curcumin against LPS-induced neurobehavioral and neurochemical deficits.

  14. Chronic combined hyperandrogenemia and western-style diet in young female rhesus macaques causes greater metabolic impairments compared to either treatment alone.

    Science.gov (United States)

    True, C A; Takahashi, D L; Burns, S E; Mishler, E C; Bond, K R; Wilcox, M C; Calhoun, A R; Bader, L A; Dean, T A; Ryan, N D; Slayden, O D; Cameron, J L; Stouffer, R L

    2017-09-01

    Does developmental exposure to the combination of hyperandrogenemia and western-style diet (WSD) worsen adult metabolic function compared to either treatment alone? Young female rhesus macaques treated for 3 years, beginning at menarche, with combined testosterone (T) and WSD have increased weight gain and insulin resistance compared to controls and animals treated with either T or WSD alone. Hyperandrogenemia is a well-established component of polycystic ovary syndrome (PCOS) and can be observed in peripubertal girls, indicating a potential pubertal onset of the disease. Obesity is often associated with hyperandrogenemia in peripubertal girls, and overweight girls appear to be at higher risk for the development of PCOS later in life. Juvenile (2.5- year old) female rhesus macaques were divided into four groups (n = 10/group): control animals receiving cholesterol implants and a control diet with 15% of calories derived from fat (C), animals receiving T implants (mean serum levels: 1.35 ± 0.01 ng/ml) and a control diet (T), animals receiving a cholesterol implant and a WSD with 36% of calories derived from fat (WSD) and animals receiving a T implant and a WSD (T + WSD). Animals were maintained on the treatments for 36 months and were 5.5 years old at study completion. Metabolic testing consisted of body measurements including weight, dual-energy X-ray absorptiometry scans, activity monitoring, and glucose tolerance testing at zero months and at least once every 12 months for the remainder of the study. Indirect calorimetry and serum hormone assays were performed following 36 months of treatment. Body weight and fat mass gain were significantly increased in T + WSD at 24 and 36 months of treatment compared to the other three groups. Log transformed fasting insulin and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were significantly increased in T + WSD animals at 3 years of treatment compared to all other groups. T-treatment caused a greater rate of

  15. Immune deficiency caused by impaired expression of nuclear factor-κB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of the NEMO gene

    Science.gov (United States)

    Mooster, Jana L.; Cancrini, Caterina; Simonetti, Alessandra; Rossi, Paolo; Matteo, Gigliola Di; Romiti, Maria Luisa; Cesare, Silvia Di; Notarangelo, Luigi; Geha, Raif S.; McDonald, Douglas R.

    2011-01-01

    Background Nuclear factor-κB (NF-κB) is a key transcription factor that regulates both innate and adaptive immunity as well as ectodermal development. Mutations in the coding region of the IκB kinase γ/NF-κB essential modifier (NEMO) gene cause X-linked ectodermal dysplasia with immunodeficiency. Objective To determine the genetic cause of recurrent sinopulmonary infections and dysgammaglobulinemia in a patient with a normal NEMO coding sequence and his affected brother. Methods TNF-α and IFN-α production in response to Toll-like receptor (TLR) stimulation was analyzed by ELISA, NEMO mRNA levels were measured by quantitative PCR, and NEMO protein expression was measured by Western blotting. NF-κB activation was assessed by nuclear translocation of p65 and luciferase reporter gene assays. Results TLR-induced TNF-α and IFN-α production by PBMCs was impaired in the patient and his brother. Sequencing of the patient’s NEMO gene revealed a novel mutation in the 5′ untranslated region, which was also present in the brother, resulting in abnormally spliced transcripts and a 4-fold reduction in mRNA levels. NEMO protein levels in EBV transformed B cells and fibroblasts from the index patient were 8-fold lower than normal controls. NF-κB p65 nuclear translocation in the patient’s EBV B cells after TLR7 ligation was defective. NF-κB–dependent luciferase gene expression in IL-1–stimulated fibroblasts from the patient was impaired. Conclusion This is the first description of immune deficiency resulting from low expression of a normal NEMO protein. PMID:20542322

  16. Effects of melatonin on aluminium-induced neurobehavioral and neurochemical changes in aging rats.

    Science.gov (United States)

    Allagui, M S; Feriani, A; Saoudi, M; Badraoui, R; Bouoni, Z; Nciri, R; Murat, J C; Elfeki, A

    2014-08-01

    This study aimed to investigate the potential protective effects of melatonin (Mel) against aluminium-induced neurodegenerative changes in aging Wistar rats (24-28months old). Herein, aluminium chloride (AlCl3) (50mg/kg BW/day) was administered by gavage, and melatonin (Mel) was co-administered to a group of Al-treated rats by an intra-peritoneal injection at a daily dose of 10mg/kg BW for four months. The findings revealed that aluminium administration induced a significant decrease in body weight associated with marked mortality for the old group of rats, which was more pronounced in old Al-treated rats. Behavioural alterations were assessed by 'open fields', 'elevated plus maze' and 'Radial 8-arms maze' tests. The results demonstrated that Mel co-administration alleviated neurobehavioral changes in both old and old Al-treated rats. Melatonin was noted to play a good neuroprotective role, reducing lipid peroxidation (TBARs), and enhancing enzymatic (SOD, CAT and GPx) activities in the brain organs of old control and old Al-treated rats. Mel treatment also reversed the decrease of AChE activity in the brain tissues, which was confirmed by histological sections. Overall, the results showed that Mel administration can induce beneficial effects for the treatment of Al-induced neurobehavioral and neurochemical changes in the central nervous system (CNS). Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. ETIOLOGY, TRIGGERS AND NEUROCHEMICAL CIRCUITS ASSOCIATED WITH UNEXPECTED, EXPECTED, AND LABORATORY-INDUCED PANIC ATTACKS

    Science.gov (United States)

    Johnson, Philip L.; Federici, Lauren M.; Shekhar, Anantha

    2014-01-01

    Panic disorder (PD) is a severe anxiety disorder that is characterized by recurrent panic attacks (PA), which can be unexpected (uPA, i.e., no clear identifiable trigger) or expected (ePA). Panic typically involves an abrupt feeling of catastrophic fear or distress accompanied by physiological symptoms such as palpitations, racing heart, thermal sensations, and sweating. Recurrent uPA and ePA can also lead to agoraphobia, where subjects with PD avoid situations that were associated with PA. Here we will review recent developments in our understanding of PD, which includes discussions on: symptoms and signs associated with uPA and ePAs; Diagnosis of PD and the new DSM-V; biological etiology such as heritability and gene x environment and gene x hormonal development interactions; comparisons between laboratory and naturally occurring uPAs and ePAs; neurochemical systems that are associated with clinical PAs (e.g. gene associations; targets for triggering or treating PAs), adaptive fear and panic response concepts in the context of new NIH RDoc approach; and finally strengths and weaknesses of translational animal models of adaptive and pathological panic states. PMID:25130976

  18. Tris(2-chloroethyl)phosphate increases ambulatory activity in mice: pharmacological analyses of its neurochemical mechanism.

    Science.gov (United States)

    Umezu, T; Yonemoto, J; Soma, Y; Suzuki, T

    1998-01-01

    The present study was conducted to clarify the acute effect of tris(2-chloroethyl)phosphate (TRCP), an organophosphate flame-retardant, on spontaneous ambulatory activity (AA) in male ICR mice and to examine the neurochemical mechanism of this effect. Single dose administration of 200 mg/kg i.p. of TRCP increased AA in ICR mice. Neither the nicotinic cholinergic antagonist mecamylamine (MA) nor the muscarinic cholinergic antagonist scopolamine (SCP) affected the AA response to TRCP. On the other hand, the benzodiazepine agonist diazepam (DZ), the GABAA agonist muscimol (MUS) and the GABAB agonist baclofen (BAC) all attenuated the effect of TRCP. DZ and MUS blocked the increase of AA within the first 10 min after administration of TRCP. These drugs did not attenuate the AA-increasing effect of SCP, suggesting that the mechanism of TRCP action is distinct from that of SCP. MUS and BAC did, but DZ did not, inhibit the AA increasing effect of the dopaminergic agonist apomorphine (APO), suggesting that dopamine is involved in the control of AA, and that GABA can affect AA through interaction with dopaminergic neurons. These results suggest that TRCP acts as a GABA antagonist and not as a cholinergic agonist, and that TRCP increases AA in ICR mice through a GABAergic mechanism.

  19. Neurochemical factors underlying individual differences in locomotor activity and anxiety-like behavioral responses in zebrafish.

    Science.gov (United States)

    Tran, Steven; Nowicki, Magda; Muraleetharan, Arrujyan; Chatterjee, Diptendu; Gerlai, Robert

    2016-02-04

    Variation among individuals may arise for several reasons, and may have diverse underlying mechanisms. Individual differences have been studied in a variety of species, but recently a new model organism has emerged in this field that offers both sophistication in phenotypical characterization and powerful mechanistic analysis. Recently, zebrafish, one of the favorites of geneticists, have been shown to exhibit consistent individual differences in baseline locomotor activity. In the current study, we further explore this finding and examine whether individual differences in locomotor activity correlate with anxiety-like behavioral measures and with levels of dopamine, serotonin and the metabolites of these neurotransmitters. In addition, we examine whether individual differences in locomotor activity are also associated with reactivity to the locomotor stimulant effects of and neurochemical responses to acute ethanol exposure (30min long, 1% v/v ethanol bath application). Principal component analyses revealed a strong association among anxiety-like responses, locomotor activity, serotonin and dopamine levels. Furthermore, ethanol exposure was found to abolish the locomotion-dependent anxiety-like behavioral and serotonergic responses suggesting that this drug also engages a common underlying pathway. Overall, our results provide support for an important role of the serotonergic system in mediating individual differences in anxiety-like responses and locomotor activity in zebrafish and for a minor modulatory role of the dopaminergic system. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Curcumin ameliorates reserpine-induced pain-depression dyad: behavioural, biochemical, neurochemical and molecular evidences.

    Science.gov (United States)

    Arora, V; Kuhad, A; Tiwari, V; Chopra, K

    2011-11-01

    An apparent clinical relationship between pain and depression has long been recognized. Depression and pain are often diagnosed in the same patients. The emerging concept for pain-depression pathogenesis is the dysfunction of biogenic amine-mediated pain-depression control and the possible involvement of nitrodative stress-induced neurogenic inflammation. The present study was designed to investigate the effect of curcumin on reserpine-induced pain-depression dyad in rats. Administration of reserpine (1mg/kg subcutaneous daily for three consecutive days) led to a significant decrease in nociceptive threshold as evident from reduced paw withdrawal threshold in Randall Sellitto and von-Frey hair test as well as significant increase in immobility time in forced swim test. This behavioural deficit was integrated with decrease in the biogenic amine (dopamine, norepinephrine and serotonin) levels along with increased substance P concentration, nitrodative stress, inflammatory cytokines, NF-κβ and caspase-3 levels in different brain regions (cortex and hippocampus) of the reserpinised rats. Curcumin (100, 200, 300mg/kg; ip) dose dependently ameliorated the behavioural deficits associated with pain and depression by restoring behavioural, biochemical, neurochemical and molecular alterations against reserpine-induced pain-depression dyad in rats. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. Neurochemical and neuropharmacological aspects of circadian disruptions: an introduction to asynchronization.

    Science.gov (United States)

    Kohyama, Jun

    2011-06-01

    Circadian disruptions are common in modern society, and there is an urgent need for effective treatment strategies. According to standard diagnostic criteria, most adolescents showing both insomnia and daytime sleepiness are diagnosed as having behavioral-induced sleep efficiency syndrome resulting from insomnia due to inadequate sleep hygiene. However, a simple intervention of adequate sleep hygiene often fails to treat them. As a solution to this clinical problem, the present review first overviews the basic neurochemical and neuropharmachological aspects of sleep and circadian rhythm regulation, then explains several circadian disruptions from similar viewpoints, and finally introduces the clinical notion of asynchronization. Asynchronization is designated to explain the pathophysiology/pathogenesis of exhibition of both insomnia and hypersomnia in adolescents, which comprises disturbances in various aspects of biological rhythms. The major triggers for asynchronization are considered to be a combination of light exposure during the night, which disturbs the biological clock and decreases melatonin secretion, as well as a lack of light exposure in the morning, which prohibits normal synchronization of the biological clock to the 24-hour cycle of the earth and decreases the activity of serotonin. In the chronic phase of asynchronization, involvement of both wake- and sleep-promoting systems is suggested. Both conventional and alternative therapeutic approaches for potential treatment of asynchronization are suggested.

  2. Neurochemical changes in the pericalcarine cortex in congenital blindness attributable to bilateral anophthalmia.

    Science.gov (United States)

    Coullon, Gaelle S L; Emir, Uzay E; Fine, Ione; Watkins, Kate E; Bridge, Holly

    2015-09-01

    Congenital blindness leads to large-scale functional and structural reorganization in the occipital cortex, but relatively little is known about the neurochemical changes underlying this cross-modal plasticity. To investigate the effect of complete and early visual deafferentation on the concentration of metabolites in the pericalcarine cortex, (1)H magnetic resonance spectroscopy was performed in 14 sighted subjects and 5 subjects with bilateral anophthalmia, a condition in which both eyes fail to develop. In the pericalcarine cortex, where primary visual cortex is normally located, the proportion of gray matter was significantly greater, and levels of choline, glutamate, glutamine, myo-inositol, and total creatine were elevated in anophthalmic relative to sighted subjects. Anophthalmia had no effect on the structure or neurochemistry of a sensorimotor cortex control region. More gray matter, combined with high levels of choline and myo-inositol, resembles the profile of the cortex at birth and suggests that the lack of visual input from the eyes might have delayed or arrested the maturation of this cortical region. High levels of choline and glutamate/glutamine are consistent with enhanced excitatory circuits in the anophthalmic occipital cortex, which could reflect a shift toward enhanced plasticity or sensitivity that could in turn mediate or unmask cross-modal responses. Finally, it is possible that the change in function of the occipital cortex results in biochemical profiles that resemble those of auditory, language, or somatosensory cortex. Copyright © 2015 the American Physiological Society.

  3. Gene structure and mutations of glutaryl-coenzyme A dehydrogenase: Impaired association of enzyme subunits that is due to an A421V substitution causes glutaric acidemia type I in the Amish

    Energy Technology Data Exchange (ETDEWEB)

    Biery, B.J.; Stein, D.E.; Goodman, S.I. [Univ. of Colorado School of Medicine, Denver, CO (United States)] [and others

    1996-11-01

    The structure of the human glutaryl coenzyme A dehydrogenase (GCD) gene was determined to contain 11 exons and to span {approximately}7 kb. Fibroblast DNA from 64 unrelated glutaric academia type I (GA1) patients was screened for mutations by PCR amplification and analysis of SSCP. Fragments with altered electrophoretic mobility were subcloned and sequenced to detect mutations that caused GA1. This report describes the structure of the GCD gene, as well as point mutations and polymorphisms found in 7 of its 11 exons. Several mutations were found in more than one patient, but no one prevalent mutation was detected in the general population. As expected from pedigree analysis, a single mutant allele causes GA1 in the Old Order Amish of Lancaster County, Pennsylvania. Several mutations have been expressed in Escherichia coli, and all produce diminished enzyme activity. Reduced activity in GCD encoded by the A421V mutation in the Amish may be due to impaired association of enzyme subunits. 13 refs., 5 figs., 3 tabs.

  4. Behavioral and neurochemical effects of alpha lipoic acid associated with omega-3 in tardive dyskinesia induced by chronic haloperidol in rats.

    Science.gov (United States)

    de Araújo, Dayane Pessoa; Camboim, Thaisa Gracielle Martins; Silva, Ana Patrícia Magalhães; Silva, Caio da Fonseca; de Sousa, Rebeca Canuto; Barbosa, Mabson Delâno Alves; Oliveira, Lucidio Clebeson; Cavalcanti, José Rodolfo Lopes de Paiva; Lucena, Eudes Euler de Souza; Guzen, Fausto Pierdoná

    2017-07-01

    Tardive dyskinesia (TD) is characterized by involuntary movements of the lower portion of the face being related to typical antipsychotic therapy. TD is associated with the oxidative imbalance in the basal ganglia. Lipoic acid (LA) and omega-3 (ω-3) are antioxidants acting as enzyme cofactors, regenerating antioxidant enzymes. This study aimed to investigate behavioral and neurochemical effects of supplementation with LA (100 mg/kg) and ω-3 (1 g/kg) in the treatment of TD induced by chronic use of haloperidol (HAL) (1 mg/kg) in rats. Wistar male rats were used, weighing between 180-200 g. The animals were treated chronically (31 days) with LA alone or associated with HAL or ω-3. Motor behavior was assessed by open-field test, the catalepsy test, and evaluation of orofacial dyskinesia. Oxidative stress was accessed by determination of lipid peroxidation and concentration of nitrite. LA and ω-3 alone or associated caused an improvement in motor performance by increasing locomotor activity in the open-field test and decreased the permanence time on the bar in the catalepsy test and decreased the orofacial dyskinesia. LA and ω-3 showed antioxidant effects, decreasing lipid peroxidation and nitrite levels. Thus, the use of LA associated with ω-3 reduced the extrapyramidal effects produced by chronic use of HAL.

  5. Behavioral and Neurochemical Effects of Alpha-Lipoic Acid in the Model of Parkinson’s Disease Induced by Unilateral Stereotaxic Injection of 6-Ohda in Rat

    Directory of Open Access Journals (Sweden)

    Dayane Pessoa de Araújo

    2013-01-01

    Full Text Available This study aimed to investigate behavioral and neurochemical effects of α-lipoic acid (100 mg/kg or 200 mg/kg alone or associated with L-DOPA using an animal model of Parkinson’s disease induced by stereotaxic injection of 6-hydroxydopamine (6-OHDA in rat striatum. Motor behavior was assessed by monitoring body rotations induced by apomorphine, open field test and cylinder test. Oxidative stress was accessed by determination of lipid peroxidation using the TBARS method, concentration of nitrite and evaluation of catalase activity. α-Lipoic acid decreased body rotations induced by apomorphine, as well as caused an improvement in motor performance by increasing locomotor activity in the open field test and use of contralateral paw (in the opposite side of the lesion produced by 6-OHDA at cylinder test. α-lipoic acid showed antioxidant effects, decreasing lipid peroxidation and nitrite levels and interacting with antioxidant system by decreasing of endogenous catalase activity. Therefore, α-lipoic acid prevented the damage induced by 6-OHDA or by chronic use of L-DOPA in dopaminergic neurons, suggesting that α-lipoic could be a new therapeutic target for Parkinson's disease prevention and treatment.

  6. impairs gap junction function causing congenital cataract

    Indian Academy of Sciences (India)

    Navya

    2017-03-24

    , Mudanjiang,. Heilongjiang Province, China. 2 Department of Genetics, National Research Institute for Family Planning, Beijing, China. 3 Department of immunology, Basic Medical College of Harbin Medical University, ...

  7. impairs gap junction function causing congenital cataract

    Indian Academy of Sciences (India)

    LIJUAN CHEN

    2017-12-20

    Dec 20, 2017 ... 1Department of Ophthalmology, Hongqi Hospital of Mudanjiang Medical College, Mudanjiang 157000, Heilongjiang. Province, People's Republic of China. 2Department of Genetics, National Research Institute for Family Planning, Beijing 100081, People's Republic of China. 3Department of Immunology ...

  8. Behavioural and neurochemical assessment of salvinorin A abuse potential in the rat.

    Science.gov (United States)

    Serra, Veronica; Fattore, Liana; Scherma, Maria; Collu, Roberto; Spano, Maria Sabrina; Fratta, Walter; Fadda, Paola

    2015-01-01

    Salvinorin A is a recreational drug derived from Salvia divinorum, a sage species long used as an entheogen. While salvinorin A has potent hallucinogenic properties, its abuse potential has not been assessed consistently in controlled behavioural and neurochemical studies in rodents. This study aimed to assess salvinorin A abuse potential by measuring its capacity to establish and maintain self-administration behaviour and to modify dopamine (DA) levels in the nucleus accumbens (NAcc) of rats. Male Lister Hooded (LH) and Sprague-Dawley (SD) rats were allowed to self-administer salvinorin A (0.5 or 1.0 μg/kg/infusion) intravenously 2 h/day for 20 days under a continuous schedule of reinforcement and lever pressing as operandum. LH rats discriminated between the active and inactive levers but did not reach the acquisition criterion for stable self-administration (≥12 active responses vs ≤5 inactive responses for at least 5 consecutive days). SD rats discriminated between the two levers at the lower dose only but, like LH rats, never acquired stable self-administration behaviour. Systemic salvinorin A increased extracellular DA in the NAcc shell of both LH (at ≥40 μg/kg) and SD rats (at ≥5 μg/kg), but injection into the ventral tegmental area (VTA) induced no significant change in NAcc DA concentration in LH rats and only brief elevations in SD rats. Salvinorin A differs from other commonly abused compounds since although it affects accumbal dopamine transmission, yet it is unable, at least at the tested doses, to sustain stable intravenous self-administration behaviour.

  9. Peptidergic nerve fibers in the urethra: Morphological and neurochemical characteristics in female mice of reproductive age.

    Science.gov (United States)

    Barry, Christine M; Ji, Esther; Sharma, Harman; Yap, Pauline; Spencer, Nicholas J; Matusica, Dusan; Haberberger, Rainer V

    2017-10-20

    Peptidergic nerve fibers provide important contributions to urethral function. Urethral innervation of female mice is not well documented. To determine the distribution and projection sites of nerve fibers immunoreactive for vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), substance P (SP), and neuropeptide Y (NPY) in the urethra of wild-type control mice and compare innervation characteristics between the proximal and distal urethra of young nullipara and older multipara mice. Furthermore, to identify the location and neurochemical coding of the spinal afferent nerve endings in the urethra, whose sensory neurons reside in lumbosacral dorsal root ganglia (DRG). Multiple labeling immunohistochemistry of urethral sections of nulliparous (6-8 weeks old), and multiparous (9-12 months old) mice, and anterograde axonal tracing from L5-S2 (DRG) in vivo. Abundant VIP-, CGRP-, SP-, and NPY-immunoreactive nerve fibers were identified in the adventitia, muscularis, and lamina propria of proximal and distal segments of the urethra. A proportion of fibers were closely associated with blood vessels, glands, and cells immunoreactive for PGP9.5. The epithelium contained abundant nerve fibers immunoreactive for CGRP and/or SP. Epithelial innervation was increased in the distal urethra of multipara mice. Abundant fibers were traced from L5-S2 DRG to all urethral regions. We present the first identification of spinal afferent endings in the urethra. Peptidergic nerve fibers, including multiple populations of spinal afferents, provide rich innervation of the female mouse urethra. The morphology of fibers in the epithelium and other regions suggests multiple nerve-cell interactions impacting on urethral function. © 2017 Wiley Periodicals, Inc.

  10. Morphological and neurochemical differences in peptidergic nerve fibers of the mouse vagina.

    Science.gov (United States)

    Barry, Christine M; Ji, Esther; Sharma, Harman; Beukes, Lara; Vilimas, Patricia I; DeGraaf, Yvette C; Matusica, Dusan; Haberberger, Rainer V

    2017-07-01

    The vagina is innervated by a complex arrangement of sensory, sympathetic, and parasympathetic nerve fibers that contain classical transmitters plus an array of neuropeptides and enzymes known to regulate diverse processes including blood flow and nociception. The neurochemical characteristics and distributions of peptide-containing nerves in the mouse vagina are unknown. This study used multiple labeling immunohistochemistry, confocal maging and analysis to investigate the presence and colocalization of the peptides vasoactive intestinal polypeptide (VIP), calcitonin-gene related peptide (CGRP), substance P (SP), neuropeptide tyrosine (NPY), and the nitric oxide synthesizing enzyme neuronal nitric oxide synthase (nNOS) in nerve fibers of the murine vaginal wall. We compared cervical and vulvar areas of the vagina in young nullipara and older multipara C57Bl/6 mice, and identified differences including that small ganglia were restricted to cervical segments, epithelial fibers were mainly present in vulvar segments and most nerve fibers were found in the lamina propria of the cervical region of the vagina, where a higher number of fibers containing immunoreactivity for VIP, CGRP, SP, or nNOS were found. Two populations of VIP-containing fibers were identified: fibers containing CGRP and fibers containing VIP but not CGRP. Differences between young and older mice were present in multiple layers of the vaginal wall, with older mice showing overall loss of innervation of epithelium of the proximal vagina and reduced proportions of VIP, CGRP, and SP containing nerve fibers in the distal epithelium. The distal vagina also showed increased vascularization and perivascular fibers containing NPY. Immunolabeling of ganglia associated with the vagina indicated the likely origin of some peptidergic fibers. Our results reveal regional differences and age- or parity-related changes in innervation of the mouse vagina, effecting the distribution of neuropeptides with diverse roles

  11. Neurochemically defined cell columns in the nucleus prepositus hypoglossi of the cat and monkey.

    Science.gov (United States)

    Baizer, Joan S; Baker, James F

    2006-06-13

    Many studies have shown that the nucleus prepositus hypoglossi (PH) participates with the vestibular nuclear complex, the cerebellum and the oculomotor nuclei in the control of eye movements. We have looked at the neurochemical organization of PH in the cat and monkey using a recently developed antibody, 8B3, that recognizes a chondroitin sulfate proteoglycan. In the cat, immunoreactivity to 8B3 labels a set of cells in PH. On frontal sections, these cells form a cluster that is seen over the entire anterior-posterior (A-P) extent of PH, but the number of cells in the cluster changes with A-P level. Earlier studies have identified an A-P cell column in PH of the cat whose neurons synthesize nitric oxide. We have used both single- and double-label protocols to investigate the relation between the two cell groups. Single-label studies show spatial overlap but that the cells immunoreactive to nitric oxide synthase (nNOS) are more numerous than cells immunoreactive to 8B3. Double-label studies show that all cells immunoreactive to 8B3 were also immunoreactive to nNOS, but, as suggested by the single-label data, there are many nNOS-immunoreactive cells not immunoreactive to 8B3. Populations of 8B3 and nNOS-immunoreactive cells are also found in PH of squirrel and macaque monkeys. The results suggest that nNOS-immunoreactive cells in PH may consist of two functionally different populations.

  12. Enrichment of MCI and early Alzheimer's disease treatment trials using neurochemical and imaging candidate biomarkers.

    LENUS (Irish Health Repository)

    Hampel, H

    2012-02-01

    In the earliest clinical stages of Alzheimer\\'s Disease (AD), when symptoms are mild, clinical diagnosis will still be difficult. AD related molecular mechanisms precede symptoms. Biological markers can serve as early diagnostic indicators, as markers of preclinical pathological change, e.g. underlying mechanisms of action (MoA). Hypothesis based candidates are derived from structural and functional neuroimaging as well as from cerebrospinal fluid (CSF) and plasma. Unbiased exploratory approaches e.g. proteome analysis or rater independent fully automated imaging post-processing methods yield novel candidates. Recent progress in the validation of core feasible imaging and neurochemical biomarkers for functions such as early detection, classification, progression and prediction of AD is summarized. Single core feasible biomarkers can already be used to enrich populations at risk for AD and may be further enhanced using distinct combinations. Some biomarkers are currently in the process of implementation as primary or secondary outcome variables into regulatory guideline documents, e.g. regarding phase II in drug development programs as outcome measures in proof of concept or dose finding studies. There are specific biomarkers available depending on the hypothesized mechanism of action of a medicinal product, e.g. impact on the amyloidogenic cascade or on tauhyperphosphorylation. Ongoing large-scale international controlled multi-center trials will provide further validation of selected core feasible imaging and CSF biomarker candidates as outcome measures in early AD for use in phase III clinical efficacy trials. There is a need of rigorous co-development of biological trait- and statemarker candidates facilitated through planned synergistic collaboration between academic, industrial and regulatory partners.

  13. Multimodal neuroimaging based classification of autism spectrum disorder using anatomical, neurochemical, and white matter correlates.

    Science.gov (United States)

    Libero, Lauren E; DeRamus, Thomas P; Lahti, Adrienne C; Deshpande, Gopikrishna; Kana, Rajesh K

    2015-05-01

    Neuroimaging techniques, such as fMRI, structural MRI, diffusion tensor imaging (DTI), and proton magnetic resonance spectroscopy (1H-MRS) have uncovered evidence for widespread functional and anatomical brain abnormalities in autism spectrum disorder (ASD) suggesting it to be a system-wide neural systems disorder. Nevertheless, most previous studies have focused on examining one index of neuropathology through a single neuroimaging modality, and seldom using multiple modalities to examine the same cohort of individuals. The current study aims to bring together multiple brain imaging modalities (structural MRI, DTI, and 1H-MRS) to investigate the neural architecture in the same set of individuals (19 high-functioning adults with ASD and 18 typically developing (TD) peers). Morphometry analysis revealed increased cortical thickness in ASD participants, relative to typical controls, across the left cingulate, left pars opercularis of the inferior frontal gyrus, left inferior temporal cortex, and right precuneus, and reduced cortical thickness in right cuneus and right precentral gyrus. ASD adults also had reduced fractional anisotropy (FA) and increased radial diffusivity (RD) for two clusters on the forceps minor of the corpus callosum, revealed by DTI analyses. 1H-MRS results showed a reduction in the N-acetylaspartate/Creatine ratio in dorsal anterior cingulate cortex (dACC) in ASD participants. A decision tree classification analysis across the three modalities resulted in classification accuracy of 91.9% with FA, RD, and cortical thickness as key predictors. Examining the same cohort of adults with ASD and their TD peers, this study found alterations in cortical thickness, white matter (WM) connectivity, and neurochemical concentration in ASD. These findings underscore the potential for multimodal imaging to better inform on the neural characteristics most relevant to the disorder. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. NMR-Based Metabolic Profiling Reveals Neurochemical Alterations in the Brain of Rats Treated with Sorafenib.

    Science.gov (United States)

    Du, Changman; Shao, Xue; Zhu, Ruiming; Li, Yan; Zhao, Qian; Fu, Dengqi; Gu, Hui; Kong, Jueying; Luo, Li; Long, Hailei; Deng, Pengchi; Wang, Huijuan; Hu, Chunyan; Zhao, Yinglan; Cen, Xiaobo

    2015-11-01

    Sorafenib, an active multi-kinase inhibitor, has been widely used as a chemotherapy drug to treat advanced clear-cell renal cell carcinoma patients. In spite of the relative safety, sorafenib has been shown to exert a negative impact on cognitive functioning in cancer patients, specifically on learning and memory; however, the underlying mechanism remains unclear. In this study, an NMR-based metabolomics approach was applied to investigate the neurochemical effects of sorafenib in rats. Male rats were once daily administrated with 120 mg/kg sorafenib by gavage for 3, 7, and 28 days, respectively. NMR-based metabolomics coupled with histopathology examinations for hippocampus, prefrontal cortex (PFC), and striatum were performed. The (1)H NMR spectra data were analyzed by using multivariate pattern recognition techniques to show the time-dependent biochemical variations induced by sorafenib. Excellent separation was obtained and distinguishing metabolites were observed between sorafenib-treated and control rats. A total of 36 differential metabolites in hippocampus of rats treated with sorafenib were identified, some of which were significantly changed. Furthermore, these modified metabolites mainly reflected the disturbances in neurotransmitters, energy metabolism, membrane, and amino acids. However, only a few metabolites in PFC and striatum were altered by sorafenib. Additionally, no apparent histological changes in these three brain regions were observed in sorafenib-treated rats. Together, our findings demonstrate the disturbed metabonomics pathways, especially, in hippocampus, which may underlie the sorafenib-induced cognitive deficits in patients. This work also shows the advantage of NMR-based metabolomics over traditional approach on the study of biochemical effects of drugs.

  15. Neurochemical characterization of neurons expressing melanin-concentrating hormone receptor 1 in the mouse hypothalamus1

    Science.gov (United States)

    Chee, Melissa J. S.; Pissios, Pavlos; Maratos-Flier, Eleftheria

    2013-01-01

    Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that acts via MCH receptor 1 (MCHR1) in the mouse. It promotes positive energy balance thus mice lacking MCH or MCHR1 are lean, hyperactive, and resistant to diet-induced obesity. Identifying the cellular targets of MCH is an important step to understanding the mechanisms underlying MCH actions. We generated the Mchr1-cre mouse that expressed cre recombinase driven by the MCHR1 promoter and crossed it with a tdTomato reporter mouse. The resulting Mchr1-cre/tdTomato progeny expressed easily detectable tdTomato fluorescence in MCHR1 neurons, which were found throughout the olfactory system, striatum, and hypothalamus. To chemically identify MCH-targeted cell populations that play a role in energy balance, MCHR1 hypothalamic neurons were characterized by colabeling select hypothalamic neuropeptides with tdTomato fluorescence. TdTomato fluorescence colocalized with dynorphin, oxytocin, vasopressin, enkephalin, thyrothropin-releasing hormone, and corticotropin-releasing factor immunoreactive cells in the paraventricular nucleus. In the lateral hypothalamus, neurotensin but neither orexin nor MCH neurons expressed tdTomato. In the arcuate nucleus, both Neuropeptide Y and proopiomelanocortin cells expressed tdTomato. We further demonstrated that some of these arcuate neurons were also targets of leptin action. Interestingly, MCHR1 was expressed in the vast majority of leptin-sensitive proopiomelanocortin neurons, highlighting their importance for the orexigenic actions of MCH. Taken together, this study supports the use of the Mchr1-cre mouse for outlining the neuroanatomical distribution and neurochemical phenotype of MCHR1 neurons. PMID:23605441

  16. Neurochemical characterization of neurons expressing melanin-concentrating hormone receptor 1 in the mouse hypothalamus.

    Science.gov (United States)

    Chee, Melissa J S; Pissios, Pavlos; Maratos-Flier, Eleftheria

    2013-07-01

    Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that acts via MCH receptor 1 (MCHR1) in the mouse. It promotes positive energy balance; thus, mice lacking MCH or MCHR1 are lean, hyperactive, and resistant to diet-induced obesity. Identifying the cellular targets of MCH is an important step to understanding the mechanisms underlying MCH actions. We generated the Mchr1-cre mouse that expresses cre recombinase driven by the MCHR1 promoter and crossed it with a tdTomato reporter mouse. The resulting Mchr1-cre/tdTomato progeny expressed easily detectable tdTomato fluorescence in MCHR1 neurons, which were found throughout the olfactory system, striatum, and hypothalamus. To chemically identify MCH-targeted cell populations that play a role in energy balance, MCHR1 hypothalamic neurons were characterized by colabeling select hypothalamic neuropeptides with tdTomato fluorescence. TdTomato fluorescence colocalized with dynorphin, oxytocin, vasopressin, enkephalin, thyrothropin-releasing hormone, and corticotropin-releasing factor immunoreactive cells in the paraventricular nucleus. In the lateral hypothalamus, neurotensin, but neither orexin nor MCH neurons, expressed tdTomato. In the arcuate nucleus, both Neuropeptide Y and proopiomelanocortin cells expressed tdTomato. We further demonstrated that some of these arcuate neurons were also targets of leptin action. Interestingly, MCHR1 was expressed in the vast majority of leptin-sensitive proopiomelanocortin neurons, highlighting their importance for the orexigenic actions of MCH. Taken together, this study supports the use of the Mchr1-cre mouse for outlining the neuroanatomical distribution and neurochemical phenotype of MCHR1 neurons. Copyright © 2012 Wiley Periodicals, Inc.

  17. Impaired Driving. Prevention Resource Guide.

    Science.gov (United States)

    Lane, Amy

    This booklet focuses on impaired driving. The first section presents 21 facts on impaired driving. These include the number of people who lost their lives in alcohol-related crashes; the leading cause of death for young people; the average amount of alcohol consumed by people arrested for driving under the influence; the estimation that a tax…

  18. A novel point mutation of the human glucocorticoid receptor gene causes primary generalized glucocorticoid resistance through impaired interaction with the LXXLL motif of the p160 coactivators: dissociation of the transactivating and transreppressive activities.

    Science.gov (United States)

    Nicolaides, Nicolas C; Roberts, Michael L; Kino, Tomoshige; Braatvedt, Geoffrey; Hurt, Darrell E; Katsantoni, Eleni; Sertedaki, Amalia; Chrousos, George P; Charmandari, Evangelia

    2014-05-01

    Primary generalized glucocorticoid resistance is a rare genetic disorder characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. The molecular basis of the condition has been ascribed to inactivating mutations in the human glucocorticoid receptor (hGR) gene. The objective of the study was to present three new cases caused by a novel mutation in the hGR gene and to delineate the molecular mechanisms through which the mutant receptor impairs glucocorticoid signal transduction. The index case (father) and his two daughters presented with increased urinary free cortisol excretion and resistance of the hypothalamic-pituitary-adrenal axis to dexamethasone suppression in the absence of clinical manifestations suggestive of Cushing syndrome. All subjects harbored a novel, heterozygous, point mutation (T→G) at nucleotide position 1724 of the hGR gene, which resulted in substitution of valine by glycine at amino acid 575 of the receptor. Compared with the wild-type receptor, the hGRαV575G demonstrated a significant (33%) reduction in its ability to transactivate the mouse mammary tumor virus promoter in response to dexamethasone, a 50% decrease in its affinity for the ligand, and a 2.5-fold delay in nuclear translocation. Although it did not exert a dominant negative effect on the wild-type receptor and preserved its ability to bind to DNA, hGRαV575G displayed significantly enhanced (∼80%) ability to transrepress the nuclear factor-κΒ signaling pathway. Finally, the mutant receptor hGRαV575G demonstrated impaired interaction with the LXXLL motif of the glucocorticoid receptor-interacting protein 1 coactivator in vitro and in computer-based structural simulation via its defective activation function-2 (AF-2) domain. The natural mutant receptor hGRαV575G causes primary generalized glucocorticoid resistance by affecting multiple steps in the glucocorticoid signaling cascade, including the affinity for the ligand, the time required for

  19. Expanding neurochemical investigations with multi-modal recording: simultaneous fast-scan cyclic voltammetry, iontophoresis, and patch clamp measurements

    Science.gov (United States)

    Kirkpatrick, D. C.; McKinney, C. J.; Manis, P. B.

    2016-01-01

    Multi-modal recording describes the simultaneous collection of information across distinct domains. Compared to isolated measurements, such studies can more easily determine relationships between varieties of phenomena. This is useful for neurochemical investigations which examine cellular activity in response to changes in the local chemical environment. In this study, we demonstrate a method to perform simultaneous patch clamp measurements with fast-scan cyclic voltammetry (FSCV) using optically isolated instrumentation. A model circuit simulating concurrent measurements was used to predict the electrical interference between instruments. No significant impact was anticipated between methods, and predictions were largely confirmed experimentally. One exception was due to capacitive coupling of the FSCV potential waveform into the patch clamp amplifier. However, capacitive transients measured in whole-cell current clamp recordings were well below the level of biological signals, which allowed the activity of cells to be easily determined. Next, the activity of medium spiny neurons (MSNs) was examined in the presence of an FSCV electrode to determine how the exogenous potential impacted nearby cells. The activities of both resting and active MSNs were unaffected by the FSCV waveform. Additionally, application of an iontophoretic current, used to locally deliver drugs and other neurochemicals, did not affect neighboring cells. Finally, MSN activity was monitored during iontophoretic delivery of glutamate, an excitatory neurotransmitter. Membrane depolarization and cell firing were observed concurrently with chemical changes around the cell resulting from delivery. In all, we show how combined electrophysiological and electrochemical measurements can relate information between domains and increase the power of neurochemical investigations. PMID:27314130

  20. [Multilingualism and specific language impairment].

    Science.gov (United States)

    Arkkila, Eva; Smolander, Sini; Laasonen, Marja

    2013-01-01

    Specific language impairment is one of the most common developmental disturbances in childhood. With the increase of the foreign language population group an increasing number of children assimilating several languages and causing concern in language development attend clinical examinations. Knowledge of factors underlying the specific language impairment and the specific impairment in general, special features of language development of those learning several languages, as well as the assessment and support of the linguistic skills of a multilingual child is essential. The risk of long-term problems and marginalization is high for children having specific language impairment.

  1. Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.

    Science.gov (United States)

    Kalaria, Raj N

    2016-05-01

    dementia associated with cerebral small vessel disease. Greater understanding of the neurochemical and molecular investigations is needed to better define microvascular disease and vascular substrates of dementia. The investigation of relevant animal models would be valuable in exploring the pathogenesis as well as prevention of the vascular causes of cognitive impairment.

  2. Elevated mercury exposure and neurochemical alterations in little brown bats (Myotis lucifugus) from a site with historical mercury contamination.

    Science.gov (United States)

    Nam, Dong-Ha; Yates, David; Ardapple, Pedro; Evers, David C; Schmerfeld, John; Basu, Niladri

    2012-05-01

    Despite evidence of persistent methylmercury (MeHg) contamination in the South River (Virginia, USA) ecosystem, there is little information concerning MeHg-associated neurological impacts in resident wildlife. Here we determined mercury (Hg) concentrations in tissues of insectivorous little brown bats (Myotis lucifugus) collected from a reference site and a MeHg-contaminated site in the South River ecosystem. We also explored whether neurochemical biomarkers (monoamine oxidase, MAO; acetylcholinesterase, ChE; muscarinic acetylcholine receptor, mAChR; N-methyl-D-aspartate receptor, NMDAR) previously shown to be altered by MeHg in other wildlife were associated with brain Hg levels in these bats. Concentrations of Hg (total and MeHg) in tissues were significantly higher (10-40 fold difference) in South River bats when compared to reference sites. Mean tissue mercury levels (71.9 ppm dw in liver, 7.14 ppm dw in brain, 132 ppm fw in fur) in the South River bats exceed (sub)-clinical thresholds in mammals. When compared to the South River bats, animals from the reference site showed a greater ability to demethylate MeHg in brain (33.1% of total Hg was MeHg vs. 65.5%) and liver (8.9% of total Hg was MeHg vs. 50.8%) thus suggesting differences in their ability to detoxify and eliminate Hg. In terms of Hg-associated neurochemical biomarker responses, interesting biphasic responses were observed with an inflection point between 1 and 5 ppm dw in the brain. In the reference bats Hg-associated decreases in MAO (r = -0.61; p exposures, differences in Hg metabolism, and the importance of the aforementioned neurochemicals in multiple facets of animal health, altered or perhaps even a lack of expected neurochemical responses in Hg-contaminated bats raise questions about the ecological and physiological impacts of Hg on the bat population as well as the broader ecosystem in the South River.

  3. Physical Impairment

    Science.gov (United States)

    Trewin, Shari

    Many health conditions can lead to physical impairments that impact computer and Web access. Musculoskeletal conditions such as arthritis and cumulative trauma disorders can make movement stiff and painful. Movement disorders such as tremor, Parkinsonism and dystonia affect the ability to control movement, or to prevent unwanted movements. Often, the same underlying health condition also has sensory or cognitive effects. People with dexterity impairments may use a standard keyboard and mouse, or any of a wide range of alternative input mechanisms. Examples are given of the diverse ways that specific dexterity impairments and input mechanisms affect the fundamental actions of Web browsing. As the Web becomes increasingly sophisticated, and physically demanding, new access features at the Web browser and page level will be necessary.

  4. Autism: cause factors, early diagnosis and therapies.

    Science.gov (United States)

    Bhat, Shreya; Acharya, U Rajendra; Adeli, Hojjat; Bairy, G Muralidhar; Adeli, Amir

    2014-01-01

    Autism spectrum disorder (ASD) is a complex neurobiological disorder characterized by neuropsychological and behavioral deficits. Cognitive impairment, lack of social skills, and stereotyped behavior are the major autistic symptoms, visible after a certain age. It is one of the fastest growing disabilities. Its current prevalence rate in the U.S. estimated by the Centers for Disease Control and Prevention is 1 in 68 births. The genetic and physiological structure of the brain is studied to determine the pathology of autism, but diagnosis of autism at an early age is challenging due to the existing phenotypic and etiological heterogeneity among ASD individuals. Volumetric and neuroimaging techniques are explored to elucidate the neuroanatomy of the ASD brain. Nuroanatomical, neurochemical, and neuroimaging biomarkers can help in the early diagnosis and treatment of ASD. This paper presents a review of the types of autism, etiologies, early detection, and treatment of ASD.

  5. Hearing Impairments

    Science.gov (United States)

    Cavender, Anna; Ladner, Richard E.

    For many people with hearing impairments, the degree of hearing loss is only a small aspect of their disability and does not necessarily determine the types of accessibility solutions or accommodations that may be required. For some people, the ability to adjust the audio volume may be sufficient. For others, translation to a signed language may be more appropriate. For still others, access to text alternatives may be the best solution. Because of these differences, it is important for researchers in Web accessibility to understand that people with hearing impairments may have very different cultural-linguistic traditions and personal backgrounds.

  6. Vascular cognitive impairment

    Directory of Open Access Journals (Sweden)

    N.V. Vakhnina

    2014-01-01

    Full Text Available Vascular pathology of the brain is the second most common cause of cognitive impairment after Alzheimer's disease. The article describes the modern concepts of etiology, pathogenetic mechanisms, clinical features and approaches to diagnosis and therapy of vascular cognitive impairment (VCI. Cerebrovascular accident, chronic cerebral circulatory insufficiency and their combination, sometimes in combination with a concomitant neurodegenerative process, are shown to be the major types of brain lesions leading to VCI. The clinical presentation of VCI is characterized by the neuropsychological status dominated by impairment of the executive frontal functions (planning, control, attention in combination with focal neurological symptoms. The diagnosis is based on comparing of the revealed neuropsychological and neurological features with neuroimaging data. Neurometabolic, acetylcholinergic, glutamatergic, and other vasoactive drugs and non-pharmacological methods are widely used to treat VCI. 

  7. All Vision Impairment

    Science.gov (United States)

    ... Statistics and Data > All Vision Impairment All Vision Impairment Vision Impairment Defined Vision impairment is defined as the best- ... 2010 U.S. Age-Specific Prevalence Rates for Vision Impairment by Age and Race/Ethnicity Table for 2010 ...

  8. Voxel Scale Complex Networks of Functional Connectivity in the Rat Brain: Neurochemical State Dependence of Global and Local Topological Properties

    Directory of Open Access Journals (Sweden)

    Adam J. Schwarz

    2012-01-01

    Full Text Available Network analysis of functional imaging data reveals emergent features of the brain as a function of its topological properties. However, the brain is not a homogeneous network, and the dependence of functional connectivity parameters on neuroanatomical substrate and parcellation scale is a key issue. Moreover, the extent to which these topological properties depend on underlying neurochemical changes remains unclear. In the present study, we investigated both global statistical properties and the local, voxel-scale distribution of connectivity parameters of the rat brain. Different neurotransmitter systems were stimulated by pharmacological challenge (d-amphetamine, fluoxetine, and nicotine to discriminate between stimulus-specific functional connectivity and more general features of the rat brain architecture. Although global connectivity parameters were similar, mapping of local connectivity parameters at high spatial resolution revealed strong neuroanatomical dependence of functional connectivity in the rat brain, with clear differentiation between the neocortex and older brain regions. Localized foci of high functional connectivity independent of drug challenge were found in the sensorimotor cortices, consistent with the high neuronal connectivity in these regions. Conversely, the topological properties and node roles in subcortical regions varied with neurochemical state and were dependent on the specific dynamics of the different functional processes elicited.

  9. Cerebellar neurochemical and histopathological changes in rat model of Parkinson's disease induced by intrastriatal injection of rotenone.

    Science.gov (United States)

    Khadrawy, Yasser A; Mourad, Iman M; Mohammed, Haitham S; Noor, Neveen A; Aboul Ezz, Heba S

    2017-01-01

    The aim of the present work was to investigate the neurochemical changes induced in the cerebellum of rat model of Parkinson's disease (PD). Rats were divided into two groups; control and rat model of PD induced by the intrastriatal injection of rotenone. As compared to control, a significant increase in the excitatory amino acid neurotransmitters; glutamate and aspartate together with a significant decrease in the inhibitory amino acids, GABA, glycine and taurine were observed in the cerebellum of rat model of PD. This was associated with a significant increase in lipid peroxidation, nitric oxide and tumor necrosis factor-α and a significant decrease in reduced glutathione. A significant decrease in acetylcholinesterase and a significant increase in Na+,K+-ATPase were recorded in the cerebellum of rat model of PD. In addition the cerebellar sections from rat model of PD showed marked necrosis of Purkinje cells, irregular damaged cells, cytoplasmic shrinkage, necrosis and perineuronal vacuolation. The present results indicate that the disturbance in the balance between the excitatory and inhibitory amino acids may have a role in the pathogenesis of PD. According to the present neurochemical and histopathological changes, the cerebellum should be taken into consideration during the treatment of PD.

  10. Neuroendocrine and neurochemical impact of aggressive social interactions in submissive and dominant mice: implications for stress-related disorders.

    Science.gov (United States)

    Audet, Marie-Claude; Anisman, Hymie

    2010-04-01

    Social conflicts may engender stress-related behavioural and physiological disturbances in the victims of aggression. In addition, stress-like neurochemical changes and ensuing depressive and anxiety symptoms might also be evident in the perpetrators of aggressive acts. The present investigation assessed basal levels of circulating corticosterone and of brain serotonin (5-HT) and norepinephrine (NE) in pre-identified submissive and dominant mice. In addition, brain neurochemical changes were determined following a single or three 15-min aggressive episodes both in submissive mice and in those that dominated the aggressive interplay. Three minutes after single and repeated confrontations, plasma corticosterone levels and 5-HT utilization within the prefrontal cortex (PFC) and hippocampus were increased to a comparable extent in submissive and dominant animals. Interestingly, however, NE utilization within the PFC and hippocampus was augmented to a greater level in submissive mice. These results suggest that 5-HT neuronal functioning was generally responsive to aggressive events, irrespective of social rank, whereas NE neuronal activity within the PFC and hippocampus was more sensitive to the submissive/dominance attributes of the social situation. It is possible that NE and 5-HT variations associated with an aggressive experience contribute to depressive- and anxiety-like manifestations typically observed after such psychosocial stressors, particularly in submissive mice. However, given that 5-HT changes occur irrespective of social rank, these data suggest that a toll is taken on both submissive and dominant mice, leaving them vulnerable to stress-related pathology.

  11. Using position emission tomography to investigate hormone-mediated neurochemical changes across the female lifespan: implications for depression.

    Science.gov (United States)

    Zsido, Rachel G; Villringer, Arno; Sacher, Julia

    2017-12-01

    Ovarian hormones, particularly oestrogen and progesterone, undergo major fluctuations across the female lifespan. These hormone transition periods, such as the transition from pregnancy to postpartum, as well as the transition into menopause (perimenopause), are also known to be times of elevated susceptibility to depression. This study reviews how these transition periods likely influence neurochemical changes in the brain that result in disease vulnerability. While there are known associations between oestrogen/progesterone and different monoaminergic systems, the interactions and their potential implications for mood disorders are relatively unknown. Positron Emission Tomography (PET) allows for the in-vivo quantification of such neurochemical changes, and, thus, can provide valuable insight into how both subtle and dramatic shifts in hormones contribute to the elevated rates of depression during pre-menstrual, post-partum, and perimenopausal periods in a woman's life. As one better understands how to address the challenges of PET studies involving highly vulnerable populations, such as women who have recently given birth, one will gain the insight necessary to design and individualize treatment and therapy. Understanding the precise time-line in younger women when dramatic fluctuations in the hormonal milieu may contribute to brain changes may present a powerful opportunity to intervene before a vulnerable state develops into a diseased state in later life.

  12. Impaired reproduction after exposure to ADHD drugs

    DEFF Research Database (Denmark)

    Danborg, Pia Brandt; Simonsen, Anders Lykkemark; Gøtzsche, Peter C

    2017-01-01

    BACKGROUND: Few studies have reported on long-term harms caused by ADHD drugs but they are known to impair growth. OBJECTIVE: To assess whether ADHD drugs impair reproduction in mammals. METHODS: Systematic review of reproduction in studies of animals treated with ADHD drugs. DATA SOURCES: Pub....... CONCLUSION: ADHD drugs impair the reproduction in animals....

  13. Caffeine consumption prevents diabetes-induced memory impairment and synaptotoxicity in the hippocampus of NONcZNO10/LTJ mice.

    Science.gov (United States)

    Duarte, João M N; Agostinho, Paula M; Carvalho, Rui A; Cunha, Rodrigo A

    2012-01-01

    Diabetic conditions are associated with modified brain function, namely with cognitive deficits, through largely undetermined processes. More than understanding the underlying mechanism, it is important to devise novel strategies to alleviate diabetes-induced cognitive deficits. Caffeine (a mixed antagonist of adenosine A(1) and A(2A) receptors) emerges as a promising candidate since caffeine consumption reduces the risk of diabetes and effectively prevents memory deficits caused by different noxious stimuli. Thus, we took advantage of a novel animal model of type 2 diabetes to investigate the behavioural, neurochemical and morphological modifications present in the hippocampus and tested if caffeine consumption might prevent these changes. We used a model closely mimicking the human type 2 diabetes condition, NONcNZO10/LtJ mice, which become diabetic at 7-11 months when kept under an 11% fat diet. Caffeine (1 g/l) was applied in the drinking water from 7 months onwards. Diabetic mice displayed a decreased spontaneous alternation in the Y-maze accompanied by a decreased density of nerve terminal markers (synaptophysin, SNAP25), mainly glutamatergic (vesicular glutamate transporters), and increased astrogliosis (GFAP immunoreactivity) compared to their wild type littermates kept under the same diet. Furthermore, diabetic mice displayed up-regulated A(2A) receptors and down-regulated A(1) receptors in the hippocampus. Caffeine consumption restored memory performance and abrogated the diabetes-induced loss of nerve terminals and astrogliosis. These results provide the first evidence that type 2 diabetic mice display a loss of nerve terminal markers and astrogliosis, which is associated with memory impairment; furthermore, caffeine consumption prevents synaptic dysfunction and astrogliosis as well as memory impairment in type 2 diabetes.

  14. Caffeine consumption prevents diabetes-induced memory impairment and synaptotoxicity in the hippocampus of NONcZNO10/LTJ mice.

    Directory of Open Access Journals (Sweden)

    João M N Duarte

    Full Text Available Diabetic conditions are associated with modified brain function, namely with cognitive deficits, through largely undetermined processes. More than understanding the underlying mechanism, it is important to devise novel strategies to alleviate diabetes-induced cognitive deficits. Caffeine (a mixed antagonist of adenosine A(1 and A(2A receptors emerges as a promising candidate since caffeine consumption reduces the risk of diabetes and effectively prevents memory deficits caused by different noxious stimuli. Thus, we took advantage of a novel animal model of type 2 diabetes to investigate the behavioural, neurochemical and morphological modifications present in the hippocampus and tested if caffeine consumption might prevent these changes. We used a model closely mimicking the human type 2 diabetes condition, NONcNZO10/LtJ mice, which become diabetic at 7-11 months when kept under an 11% fat diet. Caffeine (1 g/l was applied in the drinking water from 7 months onwards. Diabetic mice displayed a decreased spontaneous alternation in the Y-maze accompanied by a decreased density of nerve terminal markers (synaptophysin, SNAP25, mainly glutamatergic (vesicular glutamate transporters, and increased astrogliosis (GFAP immunoreactivity compared to their wild type littermates kept under the same diet. Furthermore, diabetic mice displayed up-regulated A(2A receptors and down-regulated A(1 receptors in the hippocampus. Caffeine consumption restored memory performance and abrogated the diabetes-induced loss of nerve terminals and astrogliosis. These results provide the first evidence that type 2 diabetic mice display a loss of nerve terminal markers and astrogliosis, which is associated with memory impairment; furthermore, caffeine consumption prevents synaptic dysfunction and astrogliosis as well as memory impairment in type 2 diabetes.

  15. Specific Language Impairment, Nonverbal IQ, Attention-Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, Cochlear Implants, Bilingualism, and Dialectal Variants: Defining the Boundaries, Clarifying Clinical Conditions, and Sorting Out Causes.

    Science.gov (United States)

    Rice, Mabel L

    2016-02-01

    The purpose of this research forum article is to provide an overview of a collection of invited articles on the topic "specific language impairment (SLI) in children with concomitant health conditions or nonmainstream language backgrounds." Topics include SLI, attention-deficit/hyperactivity disorder, autism spectrum disorder, cochlear implants, bilingualism, and dialectal language learning contexts. The topic is timely due to current debates about the diagnosis of SLI. An overarching comparative conceptual framework is provided for comparisons of SLI with other clinical conditions. Comparisons of SLI in children with low-normal or normal nonverbal IQ illustrate the unexpected outcomes of 2 × 2 comparison designs. Comparative studies reveal unexpected relationships among speech, language, cognitive, and social dimensions of children's development as well as precise ways to identify children with SLI who are bilingual or dialect speakers. The diagnosis of SLI is essential for elucidating possible causal pathways of language impairments, risks for language impairments, assessments for identification of language impairments, linguistic dimensions of language impairments, and long-term outcomes. Although children's language acquisition is robust under high levels of risk, unexplained individual variations in language acquisition lead to persistent language impairments.

  16. Protective effects of forced exercise against methylphenidate-induced anxiety, depression and cognition impairment in rat.

    Science.gov (United States)

    Motaghinejad, Majid; Motevalian, Manijeh; Larijani, Setare Farokhi; Khajehamedi, Zohreh

    2015-01-01

    Methylphenidate (MPH), a neural stimulant, can cause damages to brain; the chronic neurochemical and behavioral effects of MPH remain unclear. Exercise lowers stress and anxiety and can act as non-pharmacologic neuroprotective agent. In this study protective effects of exercise in MPH-induced anxiety, depression and cognition impairment were investigated. Seventy adult male rats were divided randomly into five groups. Group 1 served as negative control, received normal saline (0.2 ml/rat) for 21 days, group 2 and 3 (as positive controls) received MPH (10 and 20 mg/kg) for 21 days. Groups 4 and 5 concurrently were treated with MPH (10 and 20 mg/kg) and forced exercise for 21 days. On day 21, Elevated Plus Maze (EPM), Open Field Test (OFT), Forced Swim Test (FST) and Tail Suspension Test (TST) were used to investigate the level of anxiety and depression in animals. In addition between 17(th) and 21(th) days, Morris Water Maze (MWM) was applied to evaluate the effect of MPH on spatial learning and memory. MPH-treated animals indicated a reflective depression and anxiety in a dose-dependent manner in FST, EPM and TST which were significantly different from the control group and also can significantly attenuate the motor activity and anxiety in OFT. Forced exercise by treadmill can attenuate MPH-induced anxiety, depression and motor activity alteration in OFT. MPH also can disturb learning and memory in MWM and forced exercise can neutralize this effect of MPH. We conclude that forced exercise can be protective in brain against MPH-induced anxiety, depression and cognition alteration.

  17. Behavioral and Neurochemical Studies in Stressed and Unstressed Rats Fed on Protein, Carbohydrate and Fat Rich Diet

    Directory of Open Access Journals (Sweden)

    Samia Moin§, Saida Haider*, Saima Khaliq1, Saiqa Tabassum and Darakhshan J. Haleem

    2012-05-01

    Full Text Available Stress produces behavioral and neurochemical deficits. To study the relationship between adaptation to stress and macronutrient intake, the present study was designed to monitor the effects of different diets on feed intake, growth rate and serotonin (5-Hydroxytryptamine, 5-HT metabolism following exposure to restraint stress in rats. Rats were divided into four groups (n=12 as control, sugar, protein and fat rich diet fed rats. After 5 weeks of treatment animals of each group were divided into unrestrained and restrained animals (n=6. Rats of restrained group were given immobilization stress for 2 hours/day for 5 days. Food intake and growth rates of unrestrained and restrained rats were monitored daily. Rats were decapitated on 6th day to collect brain samples for neurochemical estimation. Results show that sugar diet fed rats produced adaptation to stress early as compared to normal diet fed rats. Food intake and growth rates of unrestrained and restrained rats were comparable on 3rd day in sugar diet fed rats and on 4th day in normal diet fed rats. Stress decreased food intake and growth rates of protein and fat treated rats. Repeated stress did not alter brain 5-HT and 5-HIAA levels of normal diet fed rats and sugar diet fed rats. Protein diet fed restrained rats showed elevated brain 5-HT levels. Fat diet fed restrained rats significantly decreased brain TRP and 5-HIAA levels. Finding suggested that carbohydrate diet might protect against stressful conditions. Study also showed that nutritional status could alter different behaviors in response to a stressful environment.

  18. Protective effect of curcumin and its combination with piperine (bioavailability enhancer) against haloperidol-associated neurotoxicity: cellular and neurochemical evidence.

    Science.gov (United States)

    Bishnoi, Mahendra; Chopra, Kanwaljit; Rongzhu, Lu; Kulkarni, Shrinivas K

    2011-10-01

    Long-term treatment with haloperidol is associated with a number of extrapyramidal side effects, particularly the irregular movements of chorionic type. This limitation presents a marked therapeutic challenge. The present study investigates the molecular etiology of haloperidol neurotoxicity and the role of curcumin, a well-known anti-oxidant, in ameliorating these adverse effects. The redox status of haloperidol-treated brains along with NO, TNF-α, NF-kappaB p65 subunit, caspase-3, and monoamine neurotransmitters were measured in the striatum of rat brain. Chronic treatment with haloperidol (5 mg/kg, i.p., 21 days) produced orofacial dyskinetic movements which were coupled with marked increase in oxidative stress parameters, TNF-α, caspase-3 activity in cytoplasmic lysate and active p65 sub unit of NF-kappaB in nuclear lysates of the striatum. Neurochemically, chronic administration of haloperidol resulted in a significant decrease in the levels of norepinephrine, dopamine, and serotonin. The prototype atypical anti-psychotic, clozapine (10 mg/kg, i.p., 21 days) produced mild oxidative stress but did not alter any other parameters. Interestingly, co-administration of curcumin (25 and 50 mg/kg, i.p., 21 days) dose-dependently prevented all the behavioral, cellular, and neurochemical changes associated with the chronic administration of haloperidol. Curcumin per se (50 mg/kg) did not show any side effects. Co-administration of piperine significantly enhanced the effect of curcumin (25 mg/kg) but not of curcumin (50 mg/kg). Collectively, the data indicated the potential of curcumin as an adjunct to haloperidol treatment and provided initial clues to the underlying molecular mechanisms in haloperidol neurotoxicity. This study also provides a rationale for the combination of piperine and curcumin.

  19. Prior Methamphetamine Self-Administration Attenuates the Dopaminergic Deficits Caused by a Subsequent Methamphetamine Exposure

    OpenAIRE

    McFadden, Lisa M.; Vieira-Brock, Paula L.; Hanson, Glen R.; Fleckenstein, Annette E.

    2015-01-01

    Others and we have reported that prior methamphetamine (METH) exposure attenuates the persistent striatal dopaminergic deficits caused by a subsequent high-dose “binge” METH exposure. The current study investigated intermediate neurochemical changes that may contribute to, or serve to predict, this resistance. Rats self-administered METH or saline for 7 d. On the following day (specifically, 16 h after the conclusion of the final METH self-administration session), rats received a binge exposu...

  20. [Impaired consciousness].

    Science.gov (United States)

    Sugino, Tatsuya

    2013-06-01

    Consciousness disorder is one of the common signs that clinicians treat every day. It is further more frequently found in elderly patients, but it is often difficult to make an exact diagnosis and to give a suitable treatment for each case. There are many kinds of diseases or systemic disorders which impair consciousness, and moreover, various backgrounds (e.g. their lifestyle, mental problems, etc.) characteristic for aged people often make the diagnosis unclear. Therefore, it is very important for every physician assigned to emergency room to have broad viewpoint and to make careful examinations approaching such patients. Needless to say, if the patient is facing crisis, more priority should be given to emergency treatment than to precise diagnosis.

  1. Visual impairment in the hearing impaired students

    OpenAIRE

    Gogate Parikshit; Rishikeshi Nikhil; Mehata Reshma; Ranade Satish; Kharat Jitesh; Deshpande Madan

    2009-01-01

    Background : Ocular problems are more common in children with hearing problems than in normal children. Neglected visual impairment could aggravate educational and social disability. Aim : To detect and treat visual impairment, if any, in hearing-impaired children. Setting and Design : Observational, clinical case series of hearing-impaired children in schools providing special education. Materials and Methods : Hearing-impaired children in selected schools underwent detailed vis...

  2. Specific Language Impairment, Nonverbal IQ, Attention-Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, Cochlear Implants, Bilingualism, and Dialectal Variants: Defining the Boundaries, Clarifying Clinical Conditions, and Sorting out Causes

    Science.gov (United States)

    Rice, Mabel L.

    2016-01-01

    Purpose: The purpose of this research forum article is to provide an overview of a collection of invited articles on the topic "specific language impairment (SLI) in children with concomitant health conditions or nonmainstream language backgrounds." Topics include SLI, attention-deficit/hyperactivity disorder, autism spectrum disorder,…

  3. Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioural, and neurotoxic effects of methamphetamine

    OpenAIRE

    Weinshenker, David; Ferrucci, Michela; Busceti, Carla L.; Biagioni, Francesca; Lazzeri, Gloria; Liles, L. Cameron; Lenzi, Paola; Murri, Luigi; Paparelli, Antonio; Fornai, Francesco

    2007-01-01

    N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions of the locus coeruleus (LC), the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrene...

  4. Mild Cognitive Impairment.

    Science.gov (United States)

    Sanford, Angela M

    2017-08-01

    Mild cognitive impairment (MCI) occurs along a continuum from normal cognition to dementia. A roadblock to earlier diagnosis and potential treatment is the lack of consistency with screening for MCI. Universal screening would be ideal, but is limited. Once a diagnosis of MCI is made, it is important for the clinician to evaluate for reversible causes. At present time, there are no pharmacologic treatments proven to slow or cure progression of MCI to dementia; nonetheless, there is evidence that lifestyle modifications including diet, exercise, and cognitive stimulation may be effective. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Manneristic behaviors of visually impaired children.

    Science.gov (United States)

    Molloy, Alysha; Rowe, Fiona J

    2011-09-01

    To review the literature on visual impairment in children in order to determine which manneristic behaviors are associated with visual impairment, and to establish why these behaviors occur and whether severity of visual impairment influences these behaviors. A literature search utilizing PubMed, OVID, Google Scholar, and Web of Knowledge databases was performed. The University of Liverpool ( www.liv.ac.uk/orthoptics/research ) and local library facilities were also searched. The main manneristic or stereotypic behaviors associated with visual impairment are eye-manipulatory behaviors, such as eye poking and rocking. The degree of visual impairment influences the type of behavior exhibited by visually impaired children. Totally blind children are more likely to adopt body and head movements whereas sight-impaired children tend to adopt eye-manipulatory behaviors and rocking. The mannerisms exhibited most frequently are those that provide a specific stimulation to the child. Theories to explain these behaviors include behavioral, developmental, functional, and neurobiological approaches. Although the precise etiology of these behaviors is unknown, it is recognized that each of the theories is useful in providing some explanation of why certain behaviors may occur. The age at which the frequency of these behaviors decreases is associated with the child's increasing development, thus those visually impaired children with additional disabilities, whose development is impaired, are at an increased risk of developing and maintaining these behaviors. Certain manneristic behaviors of the visually impaired child may also help indicate the cause of visual impairment. There is a wide range of manneristic behaviors exhibited by visually impaired children. Some of these behaviors appear to be particularly associated with certain causes of visual impairment or severity of visual impairment, thus they may supply the practitioner with useful information. Further research into the

  6. The subchronic phencyclidine rat model: relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia.

    Science.gov (United States)

    Janhunen, Sanna K; Svärd, Heta; Talpos, John; Kumar, Gaurav; Steckler, Thomas; Plath, Niels; Lerdrup, Linda; Ruby, Trine; Haman, Marie; Wyler, Roger; Ballard, Theresa M

    2015-11-01

    Current treatments for schizophrenia have modest, if any, efficacy on cognitive dysfunction, creating a need for novel therapies. Their development requires predictive animal models. The N-methyl-D-aspartate (NMDA) hypothesis of schizophrenia indicates the use of NMDA antagonists, like subchronic phencyclidine (scPCP) to model cognitive dysfunction in adult animals. The objective of this study was to assess the scPCP model by (1) reviewing published findings of scPCP-induced neurochemical changes and effects on cognitive tasks in adult rats and (2) comparing findings from a multi-site study to determine scPCP effects on standard and touchscreen cognitive tasks. Across four research sites, the effects of scPCP (typically 5 mg/kg twice daily for 7 days, followed by at least 7-day washout) in adult male Lister Hooded rats were studied on novel object recognition (NOR) with 1-h delay, acquisition and reversal learning in Morris water maze and touchscreen-based visual discrimination. Literature findings showed that scPCP impaired attentional set-shifting (ASST) and NOR in several labs and induced a variety of neurochemical changes across different labs. In the multi-site study, scPCP impaired NOR, but not acquisition or reversal learning in touchscreen or water maze. Yet, this treatment regimen induced locomotor hypersensitivity to acute PCP until 13-week post-cessation. The multi-site study confirmed that scPCP impaired NOR and ASST only and demonstrated the reproducibility and usefulness of the touchscreen approach. Our recommendation, prior to testing novel therapeutics in the scPCP model, is to be aware that further work is required to understand the neurochemical changes and specificity of the cognitive deficits.

  7. Beyond mild cognitive impairment: vascular cognitive impairment, no dementia (VCIND)

    OpenAIRE

    Stephan, Blossom CM; Matthews, Fiona E; Khaw, Kay-Tee; Dufouil, Carole; Brayne, Carol

    2009-01-01

    Identifying the causes of dementia is important in the search for effective preventative and treatment strategies. The concept of mild cognitive impairment (MCI), as prodromal dementia, has been useful but remains controversial since in population-based studies it appears to be a limited predictor of progression to dementia. Recognising the relative contribution of neurodegenerative and vascular causes, as well as their interrelationship, may enhance predictive accuracy. The concept of vascul...

  8. Functional Circuitry Effect of Ventral Tegmental Area Deep Brain Stimulation: Imaging and Neurochemical Evidence of Mesocortical and Mesolimbic Pathway Modulation.

    Science.gov (United States)

    Settell, Megan L; Testini, Paola; Cho, Shinho; Lee, Jannifer H; Blaha, Charles D; Jo, Hang J; Lee, Kendall H; Min, Hoon-Ki

    2017-01-01

    Background: The ventral tegmental area (VTA), containing mesolimbic and mesocortical dopaminergic neurons, is implicated in processes involving reward, addiction, reinforcement, and learning, which are associated with a variety of neuropsychiatric disorders. Electrical stimulation of the VTA or the medial forebrain bundle and its projection target the nucleus accumbens (NAc) is reported to improve depressive symptoms in patients affected by severe, treatment-resistant major depressive disorder (MDD) and depressive-like symptoms in animal models of depression. Here we sought to determine the neuromodulatory effects of VTA deep brain stimulation (DBS) in a normal large animal model (swine) by combining neurochemical measurements with functional magnetic resonance imaging (fMRI). Methods: Animals (n = 8 swine) were implanted with a unilateral DBS electrode targeting the VTA. During stimulation (130 Hz frequency, 0.25 ms pulse width, and 3 V amplitude), fMRI was performed. Following fMRI, fast-scan cyclic voltammetry in combination with carbon fiber microelectrodes was performed to quantify VTA-DBS-evoked dopamine release in the ipsilateral NAc. In a subset of swine, the blood oxygen level-dependent (BOLD) percent change evoked by stimulation was performed at increasing voltages (1, 2, and 3 V). Results: A significant increase in VTA-DBS-evoked BOLD signal was found in the following regions: the ipsilateral dorsolateral prefrontal cortex, anterior and posterior cingulate, insula, premotor cortex, primary somatosensory cortex, and striatum. A decrease in the BOLD signal was also observed in the contralateral parahippocampal cortex, dorsolateral and anterior prefrontal cortex, insula, inferior temporal gyrus, and primary somatosensory cortex (Bonferroni-corrected modulation of the neural circuitry associated with VTA-DBS was characterized in a large animal. Our findings suggest that VTA-DBS could affect the activity of neural systems and brain regions implicated in

  9. Cortical Visual Impairment

    Science.gov (United States)

    ... Frequently Asked Questions Español Condiciones Chinese Conditions Cortical Visual Impairment En Español Read in Chinese What is cortical visual impairment? Cortical visual impairment (CVI) is a decreased ...

  10. Speech impairment (adult)

    Science.gov (United States)

    Language impairment; Impairment of speech; Inability to speak; Aphasia; Dysarthria; Slurred speech; Dysphonia voice disorders ... but anyone can develop a speech and language impairment suddenly, usually in a trauma. APHASIA Alzheimer disease ...

  11. Specific Language Impairment

    Science.gov (United States)

    ... Home » Health Info » Voice, Speech, and Language Specific Language Impairment On this page: What is specific language ... percent of children in kindergarten. What is specific language impairment? Specific language impairment (SLI) is a language ...

  12. Behavioral and neurochemical changes in rats simultaneously exposed to manganese and lead.

    Science.gov (United States)

    Chandra, A V; Ali, M M; Saxena, D K; Murthy, R C

    1981-11-01

    Groups of rats were exposed simultaneously to manganese chloride (3 mg Mn2+/ml water) through drinking water and lead acetate intraperitoneally at dosages of 5.0, 8.0 and 12.0 mgPb2+/kg daily for a period of 14 days. The magnitude of changes in the behavioral pattern, contents of biogenic amines and accumulation of lead in the brain of rats simultaneously exposed to the two metals was significantly greater than observed in rats after exposure to either of the metals alone. A definite dose-response relationship was, however, noticed only with the changes in the motoractivity, norepinephrine, 5-hydroxytryptamine levels and in the accumulation of lead in rats simultaneously exposed to manganese and lead. The lowering in the contents of norepinephrine after combined treatment was found to be related with the decrease in the motoractivity in the rats. The exact role of depression in the levels of dopamine and 5-hydroxytryptamine in inducing marked impairment in learning ability and increased aggressive behavior in rats after the combined exposure to manganese and lead could not be ascertained. The overall analysis of the data indicated that the simultaneous exposure to manganese and lead, particularly with highest dose of the latter, may produce serious derangements in the behavioral pattern and levels of biogenic amines in the brain of rats.

  13. Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents

    DEFF Research Database (Denmark)

    Bubser, Michael; Bridges, Thomas M; Dencker, Ditte

    2014-01-01

    Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M4 PAM VU0152100 produced...... PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801...

  14. Chronic neurochemical and behavioral changes in MPTP-lesioned C57BL/6 mice: a model for Parkinson's disease.

    Science.gov (United States)

    Sundström, E; Fredriksson, A; Archer, T

    1990-10-01

    The long-term effect of the parkinsonism inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on pre- and postsynaptic structures of the nigrostriatal and mesolimbic dopamine (DA) system in adult C57BL/6 mice (2 x 40 mg/kg s.c.) was investigated using neurochemical and behavioral methods. It was found that MPTP induced a severe depletion of striatal DA levels (-80%) that persists for 4 weeks after treatment, with less severe effects in nucleus accumbens (-36%) and the olfactory tubercle (-52%). These depletions are associated with decreased tyrosine hydroxylase (TH) activity as determined in vivo and increased turnover of DA. MPTP treatment did not induce any change in the DA2-receptor as determined by [3H]spiperone binding or by two different behavioral tests, i.e. apomorphine-induced climbing and apomorphine-induced stereotypies. No significant weight loss during 4 weeks after MPTP was found. The spontaneous motor activity in these mice was profoundly and persistently depressed (-66%) as a result of the MPTP-induced DA denervation and the motor deficit was completely reversed by L-DOPA treatment. We suggest that MPTP-treated C57BL/6 mice may serve as a suitable model for Parkinson's disease.

  15. Functional and neurochemical interactions within the amygdala-medial prefrontal cortex circuit and their relevance to emotional processing.

    Science.gov (United States)

    Delli Pizzi, Stefano; Chiacchiaretta, Piero; Mantini, Dante; Bubbico, Giovanna; Ferretti, Antonio; Edden, Richard A; Di Giulio, Camillo; Onofrj, Marco; Bonanni, Laura

    2017-04-01

    The amygdala-medial prefrontal cortex (mPFC) circuit plays a key role in emotional processing. GABA-ergic inhibition within the mPFC has been suggested to play a role in the shaping of amygdala activity. However, the functional and neurochemical interactions within the amygdala-mPFC circuits and their relevance to emotional processing remain unclear. To investigate this circuit, we obtained resting-state functional magnetic resonance imaging (rs-fMRI) and proton MR spectroscopy in 21 healthy subjects to assess the potential relationship between GABA levels within mPFC and the amygdala-mPFC functional connectivity. Trait anxiety was assessed using the State-Trait Anxiety Inventory (STAI-Y2). Partial correlations were used to measure the relationships among the functional connectivity outcomes, mPFC GABA levels and STAI-Y2 scores. Age, educational level and amount of the gray and white matters within 1 H-MRS volume of interest were included as nuisance variables. The rs-fMRI signals of the amygdala and the vmPFC were significantly anti-correlated. This negative functional coupling between the two regions was inversely correlated with the GABA+/tCr level within the mPFC and the STAI-Y2 scores. We suggest a close relationship between mPFC GABA levels and functional interactions within the amygdala-vmPFC circuit, providing new insights in the physiology of emotion.

  16. Magnesium Sulfate Prevents Neurochemical and Long-Term Behavioral Consequences of Neonatal Excitotoxic Lesions: Comparison Between Male and Female Mice.

    Science.gov (United States)

    Daher, Ismaël; Le Dieu-Lugon, Bérénice; Dourmap, Nathalie; Lecuyer, Matthieu; Ramet, Lauriane; Gomila, Cathy; Ausseil, Jérôme; Marret, Stéphane; Leroux, Philippe; Roy, Vincent; El Mestikawy, Salah; Daumas, Stéphanie; Gonzalez, Bruno; Leroux-Nicollet, Isabelle; Cleren, Carine

    2017-10-01

    Magnesium sulfate (MgSO4) administration to mothers at risk of preterm delivery is proposed as a neuroprotective strategy against neurological alterations such as cerebral palsy in newborns. However, long-term beneficial or adverse effects of MgSO4 and sex-specific sensitivity remain to be investigated. We conducted behavioral and neurochemical studies of MgSO4 effects in males and females, from the perinatal period to adolescence in a mouse model of cerebral neonatal lesion. The lesion was produced in 5-day-old (P5) pups by ibotenate intracortical injection. MgSO4 (600 mg/kg, i.p.) prior to ibotenate prevented lesion-induced sensorimotor alterations in both sexes at P6 and P7. The lesion increased glutamate level at P10 in the prefrontal cortex, which was prevented by MgSO4 in males. In neonatally lesioned adolescent mice, males exhibited more sequelae than females in motor and cognitive functions. In the perirhinal cortex of adolescent mice, the neonatal lesion induced an increase in vesicular glutamate transporter 1 density in males only, which was negatively correlated with cognitive scores. Long-term sequelae were prevented by neonatal MgSO4 administration. MgSO4 never induced short- or long-term deleterious effect on its own. These results also strongly suggest that sex-specific neuroprotection should be foreseen in preterm infants. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

  17. Differences in neurochemical profiles of two gadid species under ocean warming and acidification.

    Science.gov (United States)

    Schmidt, Matthias; Windisch, Heidrun Sigrid; Ludwichowski, Kai-Uwe; Seegert, Sean Lando Levin; Pörtner, Hans-Otto; Storch, Daniela; Bock, Christian

    2017-01-01

    Exposure to future ocean acidification scenarios may alter the behaviour of marine teleosts through interference with neuroreceptor functioning. So far, most studies investigated effects of ocean acidification on the behaviour of fish, either isolated or in combination with environmental temperature. However, only few physiological studies on this issue were conducted despite the putative neurophysiological origin of the CO2-induced behavioural changes. Here, we present the metabolic consequences of long-term exposure to projected ocean acidification (396-548 μatm PCO2 under control and 915-1272 μatm under treatment conditions) and parallel warming in the brain of two related fish species, polar cod (Boreogadus saida, exposed to 0 °C, 3 °C, 6 °C and 8 °C) and Atlantic cod (Gadus morhua, exposed to 3 °C, 8 °C, 12 °C and 16 °C). It has been shown that B. saida is behaviourally vulnerable to future ocean acidification scenarios, while G. morhua demonstrates behavioural resilience. We found that temperature alters brain osmolyte, amino acid, choline and neurotransmitter concentrations in both species indicating thermal responses particularly in osmoregulation and membrane structure. In B. saida, changes in amino acid and osmolyte metabolism at the highest temperature tested were also affected by CO2, possibly emphasizing energetic limitations. We did not observe changes in neurotransmitters, energy metabolites, membrane components or osmolytes that might serve as a compensatory mechanism against CO2 induced behavioural impairments. In contrast to B. saida, such temperature limitation was not detected in G. morhua; however, at 8 °C, CO2 induced an increase in the levels of metabolites of the glutamate/GABA-glutamine cycle potentially indicating greater GABAergic activity in G.morhua. Further, increased availability of energy-rich substrates was detected under these conditions. Our results indicate a change of GABAergic metabolism in the nervous

  18. Advances in PET Imaging of Degenerative, Cerebrovascular, and Traumatic Causes of Dementia.

    Science.gov (United States)

    Eisenmenger, Laura B; Huo, Eugene J; Hoffman, John M; Minoshima, Satoshi; Matesan, Manuela C; Lewis, David H; Lopresti, Brian J; Mathis, Chester A; Okonkwo, David O; Mountz, James M

    2016-01-01

    In this review we present the most recent advances in nuclear medicine imaging as a diagnostic and management tool for dementia. The clinical diagnosis of dementia syndromes can be challenging for physicians, particularly in the early stages of disease. Given the growing number of individuals affected by dementia, early and accurate diagnosis can lead to improved clinical management of patients. Although tests are available for exclusion of certain causes of cognitive impairment, the results rarely allow the clinician to make a definitive diagnosis. For this reason, information obtained from imaging ("imaging biomarkers") is playing an increasingly important role in the workup of patients with suspected dementia. Imaging biomarkers also provide indispensable tools for clinical and preclinical studies of dementing illnesses to elucidate their pathophysiology and to develop better therapies. A wide range of imaging has been used to diagnose and investigate neurodegenerative disorders including structural, cerebral perfusion, glucose metabolism, neurochemical, and molecular imaging. In the first section, we discuss the imaging methods used in clinical practice to diagnose dementia as well as explore additional experimental modalities that are currently used as research tools. In the second section, a comprehensive review covering the myriad aspects of vascular disease as a cause of dementia is presented and illustrated with MRI- and PET-focused case examples. In the third section, advances in imaging Alzheimer disease pathology are emphasized by reviewing current approaches for PET imaging with β-amyloid imaging agents. We provide an outline for the appropriate use criteria for β-amyloid imaging agents in dementia. In addition, the recognition of the importance of neocortical neurofibrillary tangles as related to Alzheimer disease progression has led to the development of promising tau imaging agents such as [(18)F]T807. The last section provides a history brain

  19. Mild cognitive impairment

    Directory of Open Access Journals (Sweden)

    Pavlović Dragan M.

    2009-01-01

    Full Text Available Mild cognitive impairment (MCI is a syndrome that spans the area between normal ageing and dementia. It is classified into amnestic and non-amnestic types, both with two subtypes: single domain and multiple domains. Prevalence of MCI depends on criteria and population and can vary from 0.1 to 42% persons of older age. In contrast to dementia, cognitive deterioration is less severe and activities of daily living are preserved. Most impaired higher cognitive functions in MCI are memory, executive functions, language, visuospatial functions, attention etc. Also there are depression, apathy or psychomotor agitation, and signs of psychosis. Aetiology of MCI is multiple, mostly neurodegenerative, vascular, psychiatric, internistic, neurological, traumatic and iatrogenic. Persons with amnestic MCI are at a higher risk of converting to Alzheimer's disease, while those with a single non-memory domain are at risk of developing frontotemporal dementia. Some MCI patients also progress to other dementia types, vascular among others. In contrast, some patients have a stationary course, some improve, while others even normalize. Every suspicion of MCI warrants a detailed clinical exploration to discover underlying aetiology, laboratory analyses, neuroimaging methods and some cases require a detailed neuropsychological assessment. At the present time there is no efficacious therapy for cognitive decline in MCI or the one that could postpone conversion to dementia. The treatment of curable causes, application of preventive measures and risk factor control are reasonable measures in the absence of specific therapy.

  20. Microfluidic Platform with In-Chip Electrophoresis Coupled to Mass Spectrometry for Monitoring Neurochemical Release from Nerve Cells.

    Science.gov (United States)

    Li, Xiangtang; Hu, Hankun; Zhao, Shulin; Liu, Yi-Ming

    2016-05-17

    Chemical stimulus-induced neurotransmitter release from neuronal cells is well-documented. However, the dynamic changes in neurochemical release remain to be fully explored. In this work, a three-layered microfluidic chip was fabricated and evaluated for studying the dynamics of neurotransmitter release from PC-12 cells. The chip features integration of a nanoliter sized chamber for cell perfusion, pneumatic pressure valves for fluidic control, a microfluidic channel for electrophoretic separation, and a nanoelectrospray emitter for ionization in MS detection. Deploying this platform, a microchip electrophoresis-mass spectrometric method (MCE-MS) was developed to simultaneously quantify important neurotransmitters, including dopamine (DA), serotonin (5-HT), aspartic acid (Asp), and glutamic acid (Glu) without need for labeling or enrichment. Monitoring neurotransmitter release from PC-12 cells exposed to KCl (or alcohol) revealed that all four neurotransmitters investigated were released. Two release patterns were observed, one for the two monoamine neurotransmitters (i.e., DA and 5-HT) and another for the two amino acid neurotransmitters. Release dynamics for the two monoamine neurotransmitters was significantly different. The cells released DA most quickly and heavily in response to the stimulation. After exposure to the chemical stimulus for 4 min, the DA level in the perfusate from the cells was 86% lower than that at the beginning. Very interestingly, the cells started to release 5-HT in large quantities when they stopped releasing DA. These results suggest that DA and 5-HT are packaged into different vesicle pools and they are mobilized differently in response to chemical stimuli. The microfluidic platform proposed is proven useful for monitoring cellular release in biological studies.

  1. Visual impairment in the hearing impaired students.

    Science.gov (United States)

    Gogate, Parikshit; Rishikeshi, Nikhil; Mehata, Reshma; Ranade, Satish; Kharat, Jitesh; Deshpande, Madan

    2009-01-01

    Ocular problems are more common in children with hearing problems than in normal children. Neglected visual impairment could aggravate educational and social disability. To detect and treat visual impairment, if any, in hearing-impaired children. Observational, clinical case series of hearing-impaired children in schools providing special education. Hearing-impaired children in selected schools underwent detailed visual acuity testing, refraction, external ocular examination and fundoscopy. Ocular motility testing was also performed. Teachers were sensitized and trained to help in the assessment of visual acuity using Snellen's E charts. Refractive errors and squint were treated as per standard practice. Excel software was used for data entry and SSPS for analysis. The study involved 901 hearing-impaired students between four and 21 years of age, from 14 special education schools. A quarter of them (216/901, 24%) had ocular problems. Refractive errors were the most common morbidity 167(18.5%), but only 10 children were using appropriate spectacle correction at presentation. Fifty children had visual acuity less than 20/80 at presentation; after providing refractive correction, this number reduced to three children, all of whom were provided low-vision aids. Other common conditions included strabismus in 12 (1.3%) children, and retinal pigmentary dystrophy in five (0.6%) children. Ocular problems are common in hearing-impaired children. Screening for ocular problems should be made mandatory in hearing-impaired children, as they use their visual sense to compensate for the poor auditory sense.

  2. Blast neurotrauma impairs working memory and disrupts prefrontal myo-inositol levels in rats.

    Science.gov (United States)

    Sajja, Venkata Siva Sai Sujith; Perrine, Shane A; Ghoddoussi, Farhad; Hall, Christina S; Galloway, Matthew P; VandeVord, Pamela J

    2014-03-01

    Working memory, which is dependent on higher-order executive function in the prefrontal cortex, is often disrupted in patients exposed to blast overpressure. In this study, we evaluated working memory and medial prefrontal neurochemical status in a rat model of blast neurotrauma. Adult male Sprague-Dawley rats were anesthetized with 3% isoflurane and exposed to calibrated blast overpressure (17 psi, 117 kPa) while sham animals received only anesthesia. Early neurochemical effects in the prefrontal cortex included a significant decrease in betaine (trimethylglycine) and an increase in GABA at 24 h, and significant increases in glycerophosphorylcholine, phosphorylethanolamine, as well as glutamate/creatine and lactate/creatine ratios at 48 h. Seven days after blast, only myo-inositol levels were altered showing a 15% increase. Compared to controls, short-term memory in the novel object recognition task was significantly impaired in animals exposed to blast overpressure. Working memory in control animals was negatively correlated with myo-inositol levels (r=-.759, p<0.05), an association that was absent in blast exposed animals. Increased myo-inositol may represent tardive glial scarring in the prefrontal cortex, a notion supported by GFAP changes in this region after blast overexposure as well as clinical reports of increased myo-inositol in disorders of memory. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Comprehensive characterization of neurochemicals in three zebrafish chemical models of human acute organophosphorus poisoning using liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Gómez-Canela, Cristian; Tornero-Cañadas, Daniel; Prats, Eva; Piña, Benjamí; Tauler, Romà; Raldúa, Demetrio

    2018-02-01

    There is a growing interest in biological models to investigate the effect of neurotransmitter dysregulation on the structure and function of the central nervous system (CNS) at different stages of development. Zebrafish, a vertebrate model increasingly used in neurobiology and neurotoxicology, shares the common neurotransmitter systems with mammals, including glutamate, GABA, glycine, dopamine, norepinephrine, epinephrine, serotonin, acetylcholine, and histamine. In this study, we have evaluated the performance of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the multiresidue determination of neurotransmitters and related metabolites. In a first step, ionization conditions were tested in positive electrospray mode and optimum fragmentation patterns were determined to optimize two selected reaction monitoring (SRM) transitions. Chromatographic conditions were optimized considering the chemical structure and chromatographic behavior of the analyzed compounds. The best performance was obtained with a Synergy Polar-RP column, which allowed the separation of the 38 compounds in 30 min. In addition, the performance of LC-MS/MS was studied in terms of linearity, sensitivity, intra- and inter-day precision, and overall robustness. The developed analytical method was able to quantify 27 of these neurochemicals in zebrafish chemical models for mild (P1), moderate (P2), and severe (P3) acute organophosphorus poisoning (OPP). The results show a general depression of synaptic-related neurochemicals, including the excitatory and inhibitory amino acids, as well as altered phospholipid metabolism, with specific neurochemical profiles associated to the different grades of severity. These results confirmed that the developed analytical method is a new tool for neurotoxicology research using the zebrafish model.

  4. Arterial stiffness and cognitive impairment.

    Science.gov (United States)

    Li, Xiaoxuan; Lyu, Peiyuan; Ren, Yanyan; An, Jin; Dong, Yanhong

    2017-09-15

    damages the cerebral microcirculation, which causes various phenomena associated with cerebral small vessel diseases (CSVDs), such as white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and lacunar infarctions (LIs). The mechanisms underlying the relationship between arterial stiffness and cognitive impairment may also be associated with reductions in white matter and gray matter integrity, medial temporal lobe atrophy and Aβ protein deposition. Engaging in more frequent physical exercise; increasing flavonoid and long-chain n-3 polyunsaturated fatty acid consumption; increasing tea, nitrite, dietary calcium and vitamin D intake; losing weight and taking medications intended to improve insulin sensitivity; quitting smoking; and using antihypertensive drugs and statins are early interventions and lifestyle changes that may be effective in preventing arterial stiffness and thus preventing cognitive impairment. Arterial stiffness is a sensitive predictor of cognitive impairment, and arterial stiffness severity has the potential to serve as an indicator used to facilitate treatments designed to prevent or delay the onset and progression of dementia in elderly individuals. Early treatment of arterial stiffness is beneficial and recommended. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Visual Impairment, Including Blindness

    Science.gov (United States)

    ... Who Knows What? (log-in required) Select Page Visual Impairment, Including Blindness Mar 31, 2017 Links updated, ... doesn’t wear his glasses. Back to top Visual Impairments in Children Vision is one of our ...

  6. Mild Cognitive Impairment (MCI)

    Science.gov (United States)

    Mild cognitive impairment (MCI) Overview Mild cognitive impairment (MCI) is an intermediate stage between the expected cognitive decline of normal aging and the more-serious decline of dementia. It can involve ...

  7. Kids' Quest: Vision Impairment

    Science.gov (United States)

    ... Fact Check Up Tourette Questions I Have Vision Impairment Quest Vision Fact Check Up Vision Questions I ... Tweet Share Compartir What should you know? Vision impairment means that a person’s eyesight cannot be corrected ...

  8. Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.

    Directory of Open Access Journals (Sweden)

    Cecilia Csölle

    Full Text Available Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7 results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/- displayed decreased immobility in the tail suspension test (TST and an attenuated anhedonia response in the sucrose preference test (SPT following bacterial endotoxin (LPS challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [(3H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5. An increased 5-bromo-2-deoxyuridine (BrdU incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [(3H]5-HT and an elevated number of [(3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus.

  9. Jugular venous overflow of noradrenaline from the brain: a neurochemical indicator of cerebrovascular sympathetic nerve activity in humans

    Science.gov (United States)

    Mitchell, David A; Lambert, Gavin; Secher, Niels H; Raven, Peter B; van Lieshout, Johannes; Esler, Murray D

    2009-01-01

    A novel neurochemical method was applied for studying the activity of sympathetic nerves in the human cerebral vascular system. The aim was to investigate whether noradrenaline plasma kinetic measurements made with internal jugular venous sampling reflect cerebrovascular sympathetic activity. A database was assembled of fifty-six healthy subjects in whom total body noradrenaline spillover (indicative of whole body sympathetic nervous activity), brain noradrenaline spillover and brain lipophlic noradrenaline metabolite (3,4-dihydroxyphenolglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG)) overflow rates were measured. These measurements were also made following ganglion blockade (trimethaphan, n= 6), central sympathetic inhibition (clonidine, n= 4) and neuronal noradrenaline uptake blockade (desipramine, n= 13) and in a group of patients (n= 9) with pure autonomic failure (PAF). The mean brain noradrenline spillover and brain noradrenaline metabolite overflow in healthy subjects were 12.5 ± 1.8, and 186.4 ± 25 ng min−1, respectively, with unilateral jugular venous sampling for both. Total body noradrenaline spillover was 605.8 ng min−1± 34.4 ng min−1. As expected, trimethaphan infusion lowered brain noradrenaline spillover (P= 0.03), but perhaps surprisingly increased jugular overflow of brain metabolites (P= 0.01). Suppression of sympathetic nervous outflow with clonidine lowered brain noradrenaline spillover (P= 0.004), without changing brain metabolite overflow (P= 0.3). Neuronal noradrenaline uptake block with desipramine lowered the transcranial plasma extraction of tritiated noradrenaline (P= 0.001). The PAF patients had 77% lower brain noradrenaline spillover than healthy recruits (P= 0.06), indicating that in them sympathetic nerve degeneration extended to the cerebral circulation, but metabolites overflow was similar to healthy subjects (P= 0.3). The invariable discordance between noradrenline spillover and noradrenaline metabolite overflow

  10. Wireless Instantaneous Neurotransmitter Concentration System-based amperometric detection of dopamine, adenosine, and glutamate for intraoperative neurochemical monitoring.

    Science.gov (United States)

    Agnesi, Filippo; Tye, Susannah J; Bledsoe, Jonathan M; Griessenauer, Christoph J; Kimble, Christopher J; Sieck, Gary C; Bennet, Kevin E; Garris, Paul A; Blaha, Charles D; Lee, Kendall H

    2009-10-01

    WINCS, which is designed in compliance with FDA-recognized consensus standards for medical electrical device safety, successfully measured dopamine, glutamate, and adenosine, both in vitro and in vivo. The WINCS detected striatal dopamine release at the implanted CFM during DBS of the MFB. The DBS-evoked adenosine release in the rat thalamus and MCS-evoked glutamate release in the pig cortex were also successfully measured. Overall, in vitro and in vivo testing demonstrated signals comparable to a commercial hardwired electrochemical system for FPA. By incorporating FPA, the chemical repertoire of WINCS-measurable neurotransmitters is expanded to include glutamate and other nonelectroactive species for which the evolving field of enzyme-linked biosensors exists. Because many neurotransmitters are not electrochemically active, FPA in combination with enzyme-linked microelectrodes represents a powerful intraoperative tool for rapid and selective neurochemical sampling in important anatomical targets during functional neurosurgery.

  11. Patients With Long-QT Syndrome Caused by Impaired hERG-Encoded Kv11.1 Potassium Channel Have Exaggerated Endocrine Pancreatic and Incretin Function Associated With Reactive Hypoglycemia.

    Science.gov (United States)

    Hyltén-Cavallius, Louise; Iepsen, Eva W; Wewer Albrechtsen, Nicolai J; Svendstrup, Mathilde; Lubberding, Anniek F; Hartmann, Bolette; Jespersen, Thomas; Linneberg, Allan; Christiansen, Michael; Vestergaard, Henrik; Pedersen, Oluf; Holst, Jens J; Kanters, Jørgen K; Hansen, Torben; Torekov, Signe S

    2017-05-02

    Loss-of-function mutations in hERG (encoding the Kv11.1 voltage-gated potassium channel) cause long-QT syndrome type 2 (LQT2) because of prolonged cardiac repolarization. However, Kv11.1 is also present in pancreatic α and β cells and intestinal L and K cells, secreting glucagon, insulin, and the incretins glucagon-like peptide-1 (GLP-1) and GIP (glucose-dependent insulinotropic polypeptide), respectively. These hormones are crucial for glucose regulation, and long-QT syndrome may cause disturbed glucose regulation. We measured secretion of these hormones and cardiac repolarization in response to glucose ingestion in LQT2 patients with functional mutations in hERG and matched healthy participants, testing the hypothesis that LQT2 patients have increased incretin and β-cell function and decreased α-cell function, and thus lower glucose levels. Eleven patients with LQT2 and 22 sex-, age-, and body mass index-matched control participants underwent a 6-hour 75-g oral glucose tolerance test with ECG recording and blood