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Sample records for delay disease progression

  1. Cysteine 138 mutation in HIV-1 Nef from patients with delayed disease progression

    DEFF Research Database (Denmark)

    Tolstrup, Martin; Laursen, Alex Lund; Gerstoft, J.;

    2006-01-01

    on the delayed disease status. However, the results demonstrate a high incidence of a single amino acid polymorphism (cysteine 138) in HIV-1 Nef. The allelic frequency of cysteine 138 between the delayed disease progression group and the progressor group was found to be statistically significant (P = 0.......0139). The phylogeny of isolates was investigated and the variants harbouring the cysteine 138 mutation clustered independently. CONCLUSION: The present study describes a viral genetic polymorphism related to AIDS disease progression. The polymorphism (cysteine 138) has previously been reported to confer decreased...... viral replication (Premkumar DR, et al. AIDS Res Hum Retroviruses 1996; 12(4): 337-45). A sequence database search for comparative mutations revealed a high frequency of cysteine 138 in patients with reported SP AIDS...

  2. Delayed Disease Progression in Cynomolgus Macaques Infected with Ebola Virus Makona Strain.

    Science.gov (United States)

    Marzi, Andrea; Feldmann, Friederike; Hanley, Patrick W; Scott, Dana P; Günther, Stephan; Feldmann, Heinz

    2015-10-01

    In late 2013, the largest documented outbreak of Ebola hemorrhagic fever started in Guinea and has since spread to neighboring countries, resulting in almost 27,000 cases and >11,000 deaths in humans. In March 2014, Ebola virus (EBOV) was identified as the causative agent. This study compares the pathogenesis of a new EBOV strain, Makona, which was isolated in Guinea in 2014 with the prototype strain from the 1976 EBOV outbreak in the former Zaire. Both strains cause lethal disease in cynomolgus macaques with similar pathologic changes and hallmark features of Ebola hemorrhagic fever. However, disease progression was delayed in EBOV-Makona-infected animals, suggesting decreased rather than increased virulence of this most recent EBOV strain.

  3. Can we delay the progression of chronic kidney disease (CKD) by improving collaboration between renal units and primary care teams?

    Science.gov (United States)

    Thomas, N

    2005-01-01

    This paper will discuss why nephrology teams should collaborate with primary care teams in delaying the progression of chronic kidney disease (CKD), and explain how they can collaborate to improve the outcomes for patients who eventually need dialysis. The paper will describe the staging of CKD and will discuss evidence-based guidelines for the management of CKD in the community. Practical examples of how a specialist renal nurse can improve communication with primary care and can improve the outcome of patients with early kidney disease will be described.

  4. EGFR inhibitor erlotinib delays disease progression but does not extend survival in the SOD1 mouse model of ALS.

    Directory of Open Access Journals (Sweden)

    Claire E Le Pichon

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested that inhibition of epidermal growth factor receptor (EGFR signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model of ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed to extend ALS mouse survival it did provide a modest but significant delay in the onset of multiple behavioral measures of disease progression. However, given the lack of protection of motor neuron synapses and the lack of survival extension, the small benefits observed after erlotinib treatment appear purely symptomatic, with no modification of disease course.

  5. Cerebrolysin improves symptoms and delays progression in patients with Alzheimer's disease and vascular dementia.

    Science.gov (United States)

    Allegri, R F; Guekht, A

    2012-04-01

    Dementia is the result of various cerebral disorders, leading to an acquired loss of memory and impaired cognitive ability. The most common forms are Alzheimer's disease (AD) and vascular dementia (VaD). Neurotrophic factors are essential for the survival and differentiation of developing neurons and protecting them against damage under pathologic conditions. Cerebrolysin is a peptide preparation that mimics the pleiotropic effects of neurotrophic factors. Several clinical trials investigating the therapeutic efficacy of Cerebrolysin in AD and VaD have confirmed the proof of concept. The results of these trials have shown statistically significant and clinically relevant treatment effects of Cerebrolysin on cognitive, global and functional domains in mild to moderately severe stages of dementia. Doses of 10 and 30 mL were the most effective, but higher doses of up to 60 mL turned out to be most effective in improving neuropsychiatric symptoms, which become relevant at later stages of the disease. Combining treatment with cholinesterase inhibitors and Cerebrolysin indicated long-term synergistic treatment effects in mild to moderate AD. The efficacy of Cerebrolysin persisted for up to several months after treatment suggesting Cerebrolysin has not merely symptomatic benefits, but a disease-delaying potential. This paper reviews the clinical efficacy of Cerebrolysin in the treatment of dementia. Data were obtained from international, multicenter, randomized clinical trials performed in compliance with Good Clinical Practice and the principles of the Declaration of Helsinki (1964) and subsequent revisions.

  6. Pharmacoeconomic aspects of losartan treatment to delay progression of renal disease in patients with Type 2 diabetes

    NARCIS (Netherlands)

    Postma, MJ; Kruidhof, H; de Jong-van den Berg, LTW; de Zeeuw, D

    2003-01-01

    There is growing evidence from clinical trials that losartan (Avastar(TM), Merck & Co., Inc.) and other angiotensin (A)-II-receptor antagonists have beneficial effects on the progression of renal disease among Type 2 diabetic patients beyond the benefits derived from the effect of blood-pressure low

  7. Treatment with Hydrogen-Rich Saline Delays Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Zhang, Yu; Li, Hang; Yang, Chen; Fan, Dan-Feng; Guo, Da-Zhi; Hu, Hui-Jun; Meng, Xiang-En; Pan, Shu-Yi

    2016-04-01

    Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease, and accumulating evidence indicates that oxidative mechanisms contribute to ALS pathology, but classical antioxidants have not performed well in clinical trials. The aim of this work was to investigate the effect of treatment with hydrogen molecule on the development of disease in mutant SOD1 G93A transgenic mouse model of ALS. Treatment of mutant SOD1 G93A mice with hydrogen-rich saline (HRS, i.p.) significantly delayed disease onset and prolonged survival, and attenuated loss of motor neurons and suppressed microglial and glial activation. Treatment of mutant SOD1 G93A mice with HRS inhibited the release of mitochondrial apoptogenic factors and the subsequent activation of downstream caspase-3. Furthermore, treatment of mutant SOD1 G93A mice with HRS reduced levels of protein carbonyl and 3-nitrotyrosine, and suppressed formation of reactive oxygen species (ROS), peroxynitrite, and malondialdehyde. Treatment of mutant SOD1 G93A mice with HRS preserved mitochondrial function, marked by restored activities of Complex I and IV, reduced mitochondrial ROS formation and enhanced mitochondrial adenosine triphosphate synthesis. In conclusion, hydrogen molecule may be neuroprotective against ALS, possibly through abating oxidative and nitrosative stress and preserving mitochondrial function.

  8. Selective depletion of a minor subpopulation of B-chronic lymphocytic leukemia cells is followed by a delayed but progressive loss of bulk tumor cells and disease regression

    Directory of Open Access Journals (Sweden)

    Goodell Margaret A

    2009-11-01

    Full Text Available Abstract Cancer precursor/progenitor cells may initiate and sustain the growth of tumors, but evidence for their existence in human disease is indirect, relying on their in vitro properties and animal models. More directly, specific elimination of these rare cells from cancer patients should produce a delayed but progressive disappearance of differentiated malignant progeny. Here, we describe selective eradication of a putative precursor population in a patient with B-cell chronic lymphocytic leukemia, followed 6 months later by a progressive loss of mature tumor cells without further treatment. This outcome supports the presence of a rare population of precursor/progenitor cells in human malignancies, and suggests benefit from their removal.

  9. Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse.

    Directory of Open Access Journals (Sweden)

    Ken Ikeda

    Full Text Available Edaravone, a free radical scavenger is used widely in Japanese patients with acute cerebral infarction. This antioxidant could have therapeutic potentials for other neurological diseases. Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease that affects the upper and the lower motor neuron, leading to death within 3-5 years after onset. A phase III clinical trial of edaravone suggested no significant effects in ALS patients. However, recent 2nd double-blind trial has demonstrated therapeutic benefits of edaravone in definite patients diagnosed by revised El Escorial diagnostic criteria of ALS. Two previous studies showed that edaravone attenuated motor symptoms or motor neuron degeneration in mutant superoxide dismutase 1-transgenic mice or rats, animal models of familial ALS. Herein we examined whether this radical scavenger can retard progression of motor dysfunction and neuropathological changes in wobbler mice, sporadic ALS-like model. After diagnosis of the disease onset at the postnatal age of 3-4 weeks, wobbler mice received edaravone (1 or 10 mg/kg, n = 10/group or vehicle (n = 10, daily for 4 weeks by intraperitoneal administration. Motor symptoms and neuropathological changes were compared among three groups. Higher dose (10 mg/kg of edaravone treatment significantly attenuated muscle weakness and contracture in the forelimbs, and suppressed denervation atrophy in the biceps muscle and degeneration in the cervical motor neurons compared to vehicle. Previous and the present studies indicated neuroprotective effects of edaravone in three rodent ALS-like models. This drug seems to be worth performing the clinical trial in ALS patients in the United States of American and Europe, in addition to Japan.

  10. Progressive CAG expansion in the brain of a novel R6/1-89Q mouse model of Huntington's disease with delayed phenotypic onset.

    Science.gov (United States)

    Vatsavayai, Sarat C; Dallérac, Glenn M; Milnerwood, Austen J; Cummings, Damian M; Rezaie, Payam; Murphy, Kerry P S J; Hirst, Mark C

    2007-04-30

    Transgenic models representing Huntington's disease (HD) have proved useful for understanding the cascade of molecular events leading to the disease. We report an initial characterisation of a novel transgenic mouse model derived from a spontaneous truncation event within the R6/1 transgene. The transgene is widely expressed, carries 89 CAG repeats and the animals exhibit a significantly milder neurological phenotype with delayed onset compared to R6/1. Moreover, we report evidence of progressive somatic CAG expansions in the brain starting at an early age before an overt phenotype has developed. This novel line shares a common genetic ancestry with R6/1, differing only in CAG repeat number, and therefore, provides an additional tool with which to examine early molecular and neurophysiological changes in HD.

  11. Buying time: A rationale for examining the use of circadian rhythm and sleep interventions to delay progression of Mild Cognitive Impairment to Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Glenn J Landry

    2014-12-01

    Full Text Available As of 2010, the worldwide economic impact of dementia was estimated at $604 billion USD; and without discovery of a cure or effective interventions to delay disease progression, dementia’s annual global economic impact is expected to surpass $1 trillion USD as early as 2030. Alzheimer’s disease (AD is the leading cause of dementia accounting for over 75% of all cases. Toxic accumulation of amyloid beta (AB, either by overproduction or some clearance failure, is thought to be an underlying mechanism of the neuronal cell death characteristic of AD – though this amyloid hypothesis has been increasingly challenged in recent years. A compelling alternative hypothesis points to chronic neuroinflammation as a common root in late-life degenerative diseases including AD. Apolipoprotein-E (APOE genotype is the strongest genetic risk factor for AD: Individuals with APOE-e4 genotype accumulate more AB, are at high risk of developing AD, and almost half of all AD patients have at least one e4 allele. Recent studies suggest a bidirectional relationship exists between sleep and AD pathology. Sleep may play an important role in AB clearance and getting good quality sleep versus poor quality sleep might reduce the AD risk associated with the e4 allele. Taken together, these findings are particularly important given the sleep disruptions commonly associated with AD and the increased burden disrupted sleep poses for AD caregivers. The current review aims to: 1 Identify individuals at high risk for dementia who may benefit most from sleep interventions; 2 Explore the role poor sleep quality plays in exacerbating AD type dementia; 3 Examine the science of sleep interventions to date; and 4 Provide a road map in pursuit of comprehensive sleep interventions, specifically targeted to promote cognitive function and delay progression of dementia.

  12. Rapidly progressive Alzheimer disease.

    Science.gov (United States)

    Schmidt, Christian; Wolff, Martin; Weitz, Michael; Bartlau, Thomas; Korth, Carsten; Zerr, Inga

    2011-09-01

    Different rates of progression have been observed among patients with Alzheimer disease. Risk factors that accelerate deterioration have been identified and some are being discussed, such as genetics, comorbidity, and the early appearance of Alzheimer disease motor signs. Progressive forms of Alzheimer disease have been reported with rapid cognitive decline and disease duration of only a few years. This short review aims to provide an overview of the current knowledge of rapidly progressive Alzheimer disease. Furthermore, we suggest that rapid, in this context, should be defined as a Mini-Mental State Examination score decrease of 6 points per year.

  13. Early psychosocial intervention does not delay institutionalization in persons with mild Alzheimer disease and has impact on neither disease progression nor caregivers' well-being: ALSOVA 3-year follow-up.

    Science.gov (United States)

    Koivisto, Anne M; Hallikainen, Ilona; Välimäki, Tarja; Hongisto, Kristiina; Hiltunen, Asta; Karppi, Pertti; Sivenius, Juhani; Soininen, Hilkka; Martikainen, Janne

    2016-03-01

    Early diagnosis, initiation of Alzheimer's disease (AD) therapy and programs that support care of persons with AD at home are recommended. The objective of this study was to assess the effect of early psychosocial intervention on delaying the institutionalization of persons with AD. We also assessed the influence of intervention on AD progression, behavioral symptoms, and health-related quality of life (HRQoL) in persons with AD and caregivers. Kuopio ALSOVA study, a prospective, randomized intervention study with a 3-year follow-up, was carried out at memory clinics. Home-dwelling persons with very mild or mild AD (n = 236) and AD-targeted therapy and their family caregivers (n = 236) were randomized to the intervention or control group (1:2). Psychosocial intervention including education, counseling, and social support was given during the first 2 years (16 days). The primary outcome was the cumulative risk (controlled for death) of institutionalization over 36 months. Secondary outcomes were adjusted mean changes from baseline in disease severity, cognition, daily activities, behavior, and HRQoL for persons with AD; and change in psychological distress, depression, and HRQoL for caregivers. No differences were found in nursing home placement after the 36-month follow-up between intervention and control groups. No beneficial effects of the intervention were found on the secondary outcomes. The psychosocial intervention did not delay nursing home placement in persons with AD and had no effect on patient well-being, disease progression, or AD-related symptoms or caregiver well-being. Instead of automatically providing psychosocial intervention courses, individualized support programs may be more effective. Copyright © 2015 John Wiley & Sons, Ltd.

  14. Technical Progress of China's Delayed Coking Technology

    Institute of Scientific and Technical Information of China (English)

    Zhang Lixin; Li Hejie

    2005-01-01

    This article introduces the recent advances of China in the fields of process technology of delayed coking, enlarged equipment size, hydraulic decoking, automatic control and environmental protection. By the end of 2004 the total capacity of delayed coking units in China had reached 37.24Mt/a with the maximum coke drum diameter equating to 9.4 m. This article also presents the investment in delayed cokers and the current production status while pointing out the existing problems and future development trends.

  15. Research progress of autophagy for delay aging and treatment of Alzheimer’s disease%自噬延缓衰老及治疗阿尔茨海默病的研究进展

    Institute of Scientific and Technical Information of China (English)

    陈发菊; 吴芹; 石京山

    2015-01-01

    OBJECTIVE To introduce the research progress for the treatment of Alzheimer’s disease and delay aging by autophagy as the strategy. METHODS A lot of reading literature in recent years were reviewed. RESULTS AND CONCLUSION Autophagy delay aging, enhance cognitive function, which providing ideas for the future research of new autophagy used in the treatment of AD and aging.%目的:介绍以自噬(autophagy)为策略治疗阿尔茨海默病(Alzheimer’s disease,AD)和延缓衰老的研究进展。方法:大量阅读近年来相关文献进行综述。结果和结论:自噬延缓衰老、改善AD的认知功能,为续延缓衰老和AD的治疗提供思路。

  16. BOLD delay times using group delay in sickle cell disease

    Science.gov (United States)

    Coloigner, Julie; Vu, Chau; Bush, Adam; Borzage, Matt; Rajagopalan, Vidya; Lepore, Natasha; Wood, John

    2016-03-01

    Sickle cell disease (SCD) is an inherited blood disorder that effects red blood cells, which can lead to vasoocclusion, ischemia and infarct. This disease often results in neurological damage and strokes, leading to morbidity and mortality. Functional Magnetic Resonance Imaging (fMRI) is a non-invasive technique for measuring and mapping the brain activity. Blood Oxygenation Level-Dependent (BOLD) signals contain also information about the neurovascular coupling, vascular reactivity, oxygenation and blood propagation. Temporal relationship between BOLD fluctuations in different parts of the brain provides also a mean to investigate the blood delay information. We used the induced desaturation as a label to profile transit times through different brain areas, reflecting oxygen utilization of tissue. In this study, we aimed to compare blood flow propagation delay times between these patients and healthy subjects in areas vascularized by anterior, middle and posterior cerebral arteries. In a group comparison analysis with control subjects, BOLD changes in these areas were found to be almost simultaneous and shorter in the SCD patients, because of their increased brain blood flow. Secondly, the analysis of a patient with a stenosis on the anterior cerebral artery indicated that signal of the area vascularized by this artery lagged the MCA signal. These findings suggest that sickle cell disease causes blood propagation modifications, and that these changes could be used as a biomarker of vascular damage.

  17. Psychomotor Delay, a Possible Rare Presentation of Moyamoya Disease

    Directory of Open Access Journals (Sweden)

    M.R. Ashrafi

    2011-06-01

    Full Text Available Moyamoya disease is a rare, chronic cerebrovascular occlusive disease of unknown etiology. It is characterized by progressive stenosis of the arteries of the circle of Willis leading to ischemicstrokes in young people and cerebral hemorrhage, which is more frequent in adults. Secondarily,an abnormal network of fine collateral vessels arises at the base of the brain. The term moyamoyarefers to the angiographic appearance of the cerebral vasculature. We present such a disease in an 18-month-old Iranian girl with global developmental delay, which is a very rare presentationof moyamoya disease. She was diagnosed by magnetic resonance imaging (MRI and magnetic resonance angiography (MRA.

  18. PARP inhibition delays progression of mitochondrial encephalopathy in mice.

    Science.gov (United States)

    Felici, Roberta; Cavone, Leonardo; Lapucci, Andrea; Guasti, Daniele; Bani, Daniele; Chiarugi, Alberto

    2014-07-01

    Mitochondrial disorders are deadly childhood diseases for which therapeutic remedies are an unmet need. Given that genetic suppression of the nuclear enzyme poly (adenine diphosphate-ribose) polymerase(PARP)-1 improves mitochondrial functioning, we investigated whether pharmacological inhibition of the enzyme affords protection in a mouse model of a mitochondrial disorder. We used mice lacking the Ndufs4 subunit of the respiratory complex I (Ndufs4 knockout [ KO] mice); these mice undergo progressive encephalopathy and die around postnatal day 50. Mice were treated daily with the potent PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide hydrochloride (PJ34); neurological parameters, PARP activity, and mitochondrial homeostasis were evaluated. We found that mice receiving N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide hydrochloride from postnatal day 30 to postnatal day 50 show reduced neurological impairment, and increased exploratory activity and motor skills compared with vehicle-treated animals. However, drug treatment did not delay or reduce death. We found no evidence of increased PARP activity within the brain of KO mice compared with heterozygous, healthy controls. Conversely, a 10-day treatment with the PARP inhibitor significantly reduced basal poly(ADP-ribosyl)ation in different organs of the KO mice, including brain, skeletal muscle, liver, pancreas, and spleen. In keeping with the epigenetic role of PARP-1, its inhibition correlated with increased expression of mitochondrial respiratory complex subunits and organelle number. Remarkably, pharmacological targeting of PARP reduced astrogliosis in olfactory bulb and motor cortex, but did not affect neuronal loss of KO mice. In light of the advanced clinical development of PARP inhibitors, these data emphasize their relevance to treatment of mitochondrial respiratory defects.

  19. Progression of Parkinson's Disease

    Science.gov (United States)

    ... Parkinson's is the United Parkinson’s Disease Rating Scale (UPDRS). It is more comprehensive than the Hoehn and ... on movement symptoms. In addition to these, the UPDRS takes into account cognitive difficulties, ability to carry ...

  20. Statins and progressive renal disease.

    Science.gov (United States)

    Buemi, Michele; Senatore, Massimino; Corica, Francesco; Aloisi, Carmela; Romeo, Adolfo; Cavallaro, Emanuela; Floccari, Fulvio; Tramontana, Domenico; Frisina, Nicola

    2002-01-01

    Thanks to the administration of hypocholesterolemic drugs, important advances have been made in the treatment of patients with progressive renal disease. In vitro and in vivo findings demonstrate that statins, the inhibitors of HMG-CoA reductase, can provide protection against kidney diseases characterized by inflammation and/or enhanced proliferation of epithelial cells occurring in rapidly progressive glomerulonephritis, or by increased proliferation of mesangial cells occurring in IgA nephropathy. Many of the beneficial effects obtained occur independent of reduced cholesterol levels because statins can directly inhibit the proliferation of different cell types (e.g., mesangial, renal tubular, and vascular smooth muscle cells), and can also modulate the inflammatory response, thus inhibiting macrophage recruitment and activation, as well as fibrosis. The mechanisms underlying the action of statins are not yet well understood, although recent data in the literature indicate that they can directly affect the proliferation/apoptosis balance, the down-regulation of inflammatory chemokines, and the cytogenic messages mediated by the GTPases Ras superfamily. Therefore, as well as reducing serum lipids, statins and other lipid-lowering agents may directly influence intracellular signaling pathways involved in the prenylation of low molecular weight proteins that play a crucial role in cell signal transduction and cell activation. Statins appear to have important potential in the treatment of progressive renal disease, although further studies are required to confirm this in humans.

  1. Neuropsychological Testing of Developmentally Delayed Young Children: Problems and Progress.

    Science.gov (United States)

    Stone, Nancy W.; Levin, Harvey S.

    1979-01-01

    The study involving 13 developmentally delayed children (36-66 months old) was conducted to determine the applicability of the Peabody Picture Vocabulary Test, the Motor Impersistence Test, Graphesthesia Test, and Stereognosis-Tactile Test with developmentally delayed infants and preschoolers. (SBH)

  2. How Can Coronary Heart Disease Be Prevented or Delayed?

    Science.gov (United States)

    ... page from the NHLBI on Twitter. How Can Coronary Heart Disease Be Prevented or Delayed? You can prevent ... the National Institutes of Health (NIH). Celebrating American Heart Month: NIH Advancing Heart Research 02/07/2014 ...

  3. Progression of motor symptoms in Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    Ruiping Xia; Zhi-Hong Mao

    2012-01-01

    Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms - rigidity,bradykinesia and tremor - due to loss of dopaminergic neurons.The motor symptoms of PD become progressively worse as the disease advances.PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others.In recent years,many studies have investigated the progression of the hallmark symptoms over time,and the cardinal motor symptoms have different rates of progression,with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor.The current treatment regime of dopamine-replacement therapy improves motor symptoms and alleviates disability.Increasing the dosage of dopaminergic medication is commonly used to combat the worsenirtg symptoms.However,the drug-induced involuntary body movements and motor comphcations can significantly contribute to overall disability.Further,none of the currently-available therapies can slow or halt the disease progression.Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression.In this article,the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed.

  4. Soluble RAGE Treatment Delays Progression of Amyotrophic Lateral Sclerosis in SOD1 Mice.

    Science.gov (United States)

    Juranek, Judyta K; Daffu, Gurdip K; Geddis, Matthew S; Li, Huilin; Rosario, Rosa; Kaplan, Benjamin J; Kelly, Lauren; Schmidt, Ann Marie

    2016-01-01

    The etiology of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized by progressive muscle weakness and spasticity, remains largely unknown. Approximately 5-10% of cases are familial, and of those, 15-20% are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Mutations of the SOD1 gene interrupt cellular homeostasis and contribute to cellular toxicity evoked by the presence of altered SOD1, along with other toxic species, such as advanced glycation end products (AGEs). AGEs trigger activation of their chief cell surface receptor, RAGE (receptor for advanced glycation end products), and induce RAGE-dependent cellular stress and inflammation in neurons, thereby affecting their function and leading to apoptosis. Here, we show for the first time that the expression of RAGE is higher in the SOD1 transgenic mouse model of ALS vs. wild-type mouse spinal cord. We tested whether pharmacological blockade of RAGE may delay the onset and progression of disease in this mouse model. Our findings reveal that treatment of SOD1 transgenic mice with soluble RAGE (sRAGE), a natural competitor of RAGE that sequesters RAGE ligands and blocks their interaction with cell surface RAGE, significantly delays the progression of ALS and prolongs life span compared to vehicle treatment. We demonstrate that in sRAGE-treated SOD1 transgenic animals at the final stage of the disease, a significantly higher number of neurons and lower number of astrocytes is detectable in the spinal cord. We conclude that RAGE antagonism may provide a novel therapeutic strategy for ALS intervention.

  5. Soluble RAGE Treatment Delays Progression of Amyotrophic Lateral Sclerosis in SOD1 Mice

    Directory of Open Access Journals (Sweden)

    Judyta K Juranek

    2016-05-01

    Full Text Available The etiology of amyotrophic lateral sclerosis (ALS, a fatal motor neuron disorder characterized by progressive muscle weakness and spasticity, remains largely unknown. Approximately 5-10% of cases are familial, and of those, 15-20% are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1. Mutations of the SOD1 gene interrupt cellular homeostasis and contribute to cellular toxicity evoked by the presence of altered SOD1, along with other toxic species, such as advanced glycation end products (AGEs. AGEs trigger activation of their chief cell surface receptor, RAGE (receptor for advanced glycation end products, and induce RAGE-dependent cellular stress and inflammation in neurons, thereby affecting their function and leading to apoptosis. Here, we show for the first time that the expression of RAGE is higher in the SOD1 transgenic mouse model of ALS versus wild-type mouse spinal cord. We tested whether pharmacological blockade of RAGE may delay the onset and progression of disease in this mouse model. Our findings reveal that treatment of SOD1 transgenic mice with soluble RAGE (sRAGE, a natural competitor of RAGE that sequesters RAGE ligands and blocks their interaction with cell surface RAGE, significantly delays the progression of ALS and prolongs life span compared to vehicle treatment. We demonstrate that in sRAGE-treated SOD1 transgenic animals at the final stage of the disease, a significantly higher number of neurons and lower number of astrocytes is detectable in the spinal cord. We conclude that RAGE antagonism may provide a novel therapeutic strategy for ALS intervention.

  6. Clinical features and predictors for disease natural progression in adults with Pompe disease : a nationwide prospective observational study

    NARCIS (Netherlands)

    van der Beek, Nadine A. M. E.; de Vries, Juna M.; Hagemans, Marloes L. C.; Hop, Wim C. J.; Kroos, Marian A.; Wokke, John H. J.; de Visser, Marianne; van Engelen, Baziel G. M.; Kuks, Jan B. M.; van der Kooi, Anneke J.; Notermans, Nicolette C.; Faber, Karin G.; Verschuuren, Jan J. G. M.; Reuser, Arnold J. J.; van der Ploeg, Ans T.; van Doorn, Pieter A.

    2012-01-01

    Background: Due partly to physicians' unawareness, many adults with Pompe disease are diagnosed with great delay. Besides, it is not well known which factors influence the rate of disease progression, and thus disease outcome. We delineated the specific clinical features of Pompe disease in adults,

  7. Quantifying Disease Progression in Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Simon, Neil G; Turner, Martin R; Vucic, Steve; Al-Chalabi, Ammar; Shefner, Jeremy; Lomen-Hoerth, Catherine; Kiernan, Matthew C

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic. PMID:25223628

  8. Research Progress of Liver Diseases

    Institute of Scientific and Technical Information of China (English)

    XU Lie-ming; JIA Ji-dong

    2005-01-01

    @@ Liver diseases are widespread in China.The disease mostly includes viral hepatitis,alcoholic or non alcoholic fatty degeneration or steatohepatitis, autoimmune liver disease,hepatic fibrosis/cirrhosis and hepatic cancer.The mechanism of most liver diseases was studied clearly in developed countries.

  9. Parkinson's disease showing progressive conduction aphasia

    OpenAIRE

    Sakai, Kenji; Ono, Kenjiro; Harada, Hiromi; Shima, Keisuke; Notoya, Masako; Yamada, Masahito

    2012-01-01

    Patients with Parkinson's disease (PD) may develop progressive dementia late in their clinical course. Dementia in PD is mostly related to neuropathological findings of extensive Lewy bodies (LBs), with or without the coexistence of Alzheimer's disease (AD) pathology. Aphasia has been reported in patients with LB diseases with AD pathology; however, there have been no reports of typical PD patients developing progressive aphasia during their clinical course. We describe a female PD patient wh...

  10. Sequence heterogeneity in human immunodeficiency virus type 1 nef in patients presenting with rapid progression and delayed progression to AIDS.

    Science.gov (United States)

    Gupta, Poonam; Husain, Mohammad; Hans, Charoo; Ram, Hanu; Verma, Supriya Singh; Misbah, Mohammad; Chauhan, L S; Rai, Arvind

    2014-09-01

    Genetic heterogeneity in the nef genes from human immunodeficiency virus type 1 (HIV-1)-infected rapid progressors (RPs) and long-term nonprogressors (LTNPs) was analyzed to identify various amino acid substitutions responsible for the discernible difference in disease progression. It was found that the majority of the strains characterized belonged to subtype C, followed by several BC recombinants and subtype A1. Complete nef subtype C sequences from 33 RPs and seven LTNPs were compared, and it was observed that, in the majority of the sequences from both groups, highly conserved functional motifs showed subtle changes. However, drastic changes were observed in two isolates from LTNPs where the arginine cluster was deleted, while in one of them, additionally, acidic residues were replaced by basic residues (EEEEE→RK(R)KKE). The deletion of the arginine cluster and the mutation of acidic residues to basic residues are predicted to delay disease development by abolishing CD4 downmodulation and causing diminution of major histocompatibility complex class I (MHC-I) downregulation, respectively. Nonetheless, this is an exclusive finding in these LTNPs, which necessitates their analysis at the functional level. The synonymous-to-nonsynonymous substitution ratio was greater than one in both of the groups, suggesting amino acid sequence conservation and functional robustness. Interpatient nucleotide distance within the group and between the two groups showed very little variation, confirming genetic relatedness among isolates.

  11. Delaying the onset of Alzheimer disease

    Science.gov (United States)

    Craik, Fergus I.M.; Bialystok, Ellen; Freedman, Morris

    2010-01-01

    Objectives: There is strong epidemiologic evidence to suggest that older adults who maintain an active lifestyle in terms of social, mental, and physical engagement are protected to some degree against the onset of dementia. Such factors are said to contribute to cognitive reserve, which acts to compensate for the accumulation of amyloid and other brain pathologies. We present evidence that lifelong bilingualism is a further factor contributing to cognitive reserve. Methods: Data were collected from 211 consecutive patients diagnosed with probable Alzheimer disease (AD). Patients' age at onset of cognitive impairment was recorded, as was information on occupational history, education, and language history, including fluency in English and any other languages. Following this procedure, 102 patients were classified as bilingual and 109 as monolingual. Results: We found that the bilingual patients had been diagnosed 4.3 years later and had reported the onset of symptoms 5.1 years later than the monolingual patients. The groups were equivalent on measures of cognitive and occupational level, there was no apparent effect of immigration status, and the monolingual patients had received more formal education. There were no gender differences. Conclusions: The present data confirm results from an earlier study, and thus we conclude that lifelong bilingualism confers protection against the onset of AD. The effect does not appear to be attributable to such possible confounding factors as education, occupational status, or immigration. Bilingualism thus appears to contribute to cognitive reserve, which acts to compensate for the effects of accumulated neuropathology. GLOSSARY AD = Alzheimer disease; MMSE = Mini-Mental State Examination. PMID:21060095

  12. Case reports: delayed hemolytic transfusion reaction in sickle cell disease.

    Science.gov (United States)

    Syed, S K; Sears, D A; Werch, J B; Udden, M M; Milam, J D

    1996-10-01

    This article reports the details of delayed hemolytic transfusion reactions in four patients with sickle cell disease. These cases demonstrate the characteristics of the reactions, the significant risks involved, and the principles useful in diagnosis and treatment. Patients with sickle cell disease are at particular risk for delayed hemolytic transfusion reactions because they may be transfused at intervals over many years; they frequently form alloantibodies because of antigenic differences from the donor population; and they may receive emergency care in different hospitals where transfusion records are not available. In addition, exchange transfusions, which are often used for patients with sickle cell disease and which were given in three of these cases, raise the risks through increased exposure to foreign erythrocyte antigens and through an increased volume of erythrocytes susceptible to hemolysis. It was concluded that the hazards of these transfusion reactions justify preventive measures, such as extended erythrocyte phenotyping of patients with sickle cell disease and extended phenotypic matching of transfused cells.

  13. Anti-inflammatory therapies in TRAMP mice: delay in PCa progression.

    Science.gov (United States)

    Kido, Larissa Akemi; Montico, Fabio; Sauce, Rafael; Macedo, Aline Barbosa; Minatel, Elaine; Costa, Débora Barbosa Vendramini; Carvalho, João Ernesto de; Pilli, Ronaldo Aloise; Cagnon, Valeria Helena Alves

    2016-04-01

    The aim of this study was to characterize the structural and molecular biology as well as evaluate the immediate and late responses of prostatic cancer in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model after treatment with goniothalamin (GTN) and celecoxib. The treated mice received GTN (150 mg/kg, gavage) or celecoxib (10 mg/kg, gavage) from 8 to 12 weeks of age. They were killed at different ages: the immediate-response groups at 12 weeks and the late-response groups at 22 weeks. The ventral prostate was collected for light microscopy, immunohistochemistry, western blotting, TUNEL, and ELISA. Morphological analyses indicated that GTN treatment delayed the progression of prostatic adenocarcinoma, leading to a significant decrease of prostatic lesion frequency in both experimental period responses to this treatment, mainly high-grade prostatic intraepithelial neoplasia and well-differentiated adenocarcinoma. Also, the celecoxib treatment showed a particular decrease in the proliferative processes (PCNA) in both the experimental periods. Despite celecoxib diminishing the COX2 and IGFR1 levels, GTN presented higher action spectrum considering the decrease of a greater molecular number involved in the proliferative and inflammatory processes in prostatic cancer. Goniothalamin attenuated the pro-inflammatory response in TRAMP prostatic microenvironment, delaying prostate cancer (PCa) progression. Celecoxib treatment was efficient in the regulation of COX2 in the TRAMP mice, mainly in the advanced disease grade. Finally, we concluded that inflammatory process control in early grades of PCa was crucial for the downregulation of the signaling pathways involved in the proliferative processes in advanced cancer grades.

  14. Delayed postoperative dural arteriovenous fistula presenting with progressive dementia.

    Science.gov (United States)

    Higashida, Tetsuhiro

    2015-12-09

    A 64-year-old woman underwent right suboccipital craniotomy to treat spontaneous cerebrospinal fluid (CSF) otorrhoea. Although the CSF leak was cured, the patient developed pulsatile tinnitus, ambulatory disturbance and progressive dementia. Four years after the surgery, she presented with generalised seizure. Cerebral angiography showed a dural arteriovenous fistula at the right transverse-sigmoid sinus, which was associated with sinus occlusion, retrograde blood flow in the sinus and diffuse intracranial cortical venous reflux. A combination of endovascular transarterial embolisation and transvenous embolisation with direct sinus puncture was performed. After the procedure, the patient's mental status and cognitive function improved significantly.

  15. Progressive Fault Accommodation for Time-delay Systems with Parametric Faults

    Institute of Scientific and Technical Information of China (English)

    WU Jun-sheng; WENG Zheng-xin; TIAN Zuo-hua

    2009-01-01

    The fault accommodation problem for time-delay system is studied in this paper. The progressive accommodation strategy based on the Newton-Raphson scheme is proposed to solve this problem. This accommodation scheme can significantly reduces the loss of performance and risk associated with system instability which results from the time-delay needed by fault accommodation aigorithms to provide a solution. Simulation results are given to illustrate the efficiency of the provided method.

  16. Fibrogenesis in progressive renal disease

    NARCIS (Netherlands)

    Baelde, H.

    2005-01-01

    Molecular biology offers new opportunities for experimental and clinical medicine. Promising clinical applications for patient care include identification of mRNA expression patterns (gene profiling) in diseased organs in correlation with diagnosis, prognosis, and responsiveness to different treatme

  17. Risk factors of progression of chronic kidney disease patients under conservative treatment

    Directory of Open Access Journals (Sweden)

    Tarek A. Ghonemy

    2015-10-01

    Conclusions: The most important risk factors for rapid progression are presence of diabetes, severity of proteinuria and low serum bicarbonate level in advanced stages of chronic kidney disease. Early recognition of these risk factors and their correction may retard the progression of CKD, which will delay the need for renal replacement therapy. In addition, ACEI or ARBs intake are almost renoprotective and may delay the rapid progression of chronic kidney disease especially in proteinuric patients. [Int J Res Med Sci 2015; 3(10.000: 2734-2739

  18. Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington's Disease.

    Directory of Open Access Journals (Sweden)

    Helen Budworth

    2015-08-01

    Full Text Available Huntington's Disease (HD is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. We have created an HD mouse model that resolves the effects of the inherited and somatic expansions. We show here that suppressing somatic expansion substantially delays the onset of disease in littermates that inherit the same disease-length allele. Furthermore, a pharmacological inhibitor, XJB-5-131, inhibits the lengthening of the repeat tracks, and correlates with rescue of motor decline in these animals. The results provide evidence that pharmacological approaches to offset disease progression are possible.

  19. Constant and Progressive Time Delay Procedures for Teaching Children with Autism: A Literature Review

    Science.gov (United States)

    Walker, Gabriela

    2008-01-01

    A review of 22 empirical studies examining the use of constant (CTD) and progressive (PTD) time delay procedures employed with children with autism frames an indirect analysis of the demographic, procedural, methodological, and outcome parameters of existing research. None of the previous manuscripts compared the two response prompting procedures.…

  20. Parkinson's disease showing progressive conduction aphasia.

    Science.gov (United States)

    Sakai, Kenji; Ono, Kenjiro; Harada, Hiromi; Shima, Keisuke; Notoya, Masako; Yamada, Masahito

    2012-04-01

    Patients with Parkinson's disease (PD) may develop progressive dementia late in their clinical course. Dementia in PD is mostly related to neuropathological findings of extensive Lewy bodies (LBs), with or without the coexistence of Alzheimer's disease (AD) pathology. Aphasia has been reported in patients with LB diseases with AD pathology; however, there have been no reports of typical PD patients developing progressive aphasia during their clinical course. We describe a female PD patient who later developed progressive conduction aphasia characterized by phonemic paraphasia and disturbance in repetition of short sentences without disturbance in writing or auditory comprehension. No episodes of fluctuations of attention, memory complaints, or planning errors were observed. She experienced episodes of visual hallucination. Her low scores on the Mini-Mental State Examination suggested impairment of orientation and attention, and her scores on Raven's Coloured Progressive Matrices test indicated impaired visuospatial functions. However, her cognitive deficits were not sufficiently severe to impair her daily life. Brain magnetic resonance images revealed atrophy of the left superior temporal gyrus and widening of the left sylvian fissure. [(18)F]-fluorodeoxyglucose positron emission tomography revealed glucose hypometabolism in the left cerebral hemisphere. These findings may be related to conduction aphasia. During the progression of PD lesions, the brainstem LB is assumed to take an upward course, extend to the limbic system, and then extend to the neocortex. Conduction aphasia observed in our patient may be associated with an unusual progression of the LB pathology from the brainstem to the left temporoparietal lobe.

  1. Diseases masking and delaying the diagnosis of urogenital tuberculosis.

    Science.gov (United States)

    Kulchavenya, Ekaterina; Kholtobin, Denis

    2015-12-01

    As urogenital tuberculosis (UGTB) has no specific clinical features, it is often overlooked. To identify some of the reasons for misdiagnosing UGTB we performed a systematic review. We searched in Medline/PubMed papers with keywords 'urogenital tuberculosis, rare' and 'urogenital tuberculosis, unusual'. 'Urogenital tuberculosis, rare' presented 230 articles and 'urogenital tuberculosis, unusual' presented 81 articles only, a total of 311 papers. A total of 34 papers were duplicated and so were excluded from the review. In addition, we excluded from the analysis 33 papers on epidemiological studies and literature reviews, papers describing non-TB cases and cases of TB another than urogenital organs (48 articles), cases of congenital TB (three articles), UGTB as a case of concomitant disease (16 articles), and UGTB as a complication of BCG-therapy (eight articles). We also excluded 22 articles dedicated to complications of the therapy, which made a total of 164 articles. Among the remaining 147 articles we selected 43 which described really unusual, difficult to diagnose cases. We also included in our review a WHO report from 2014, and one scientific monograph on TB urology. The most frequent reasons for delayed diagnosis were absence typical clinical features of UGTB, and the tendency of UGTB to hide behind the mask of another disease. We can conclude that actually UGTB is not rare disease, but it is often an overlooked disease. The main reasons for delayed diagnosis are vague, atypical clinical features and a low index of suspicion.

  2. Delayed access to treatments for rare diseases: who's to blame?

    Science.gov (United States)

    Feltmate, Karen; Janiszewski, Peter M; Gingerich, Sheena; Cloutier, Michael

    2015-04-01

    The development and commercialization of drugs for rare diseases, termed 'orphan drugs', has historically been economically unattractive. However, because of the introduction of legislation that provides financial and regulatory incentives for the development of orphan drugs, new developments are making their way through the regulatory approval processes. Unfortunately, delays in availability of new drugs for treating rare disease continue to persist. This paper reviews the approach of several regulatory jurisdictions to orphan drugs in an effort to determine their relative effectiveness in providing patient access. Generally speaking, regulatory authorities across jurisdictions have recognized the need to enhance timely access to safe, effective treatment for patients with rare diseases and have been able to shift the approval timelines for access to new care. The greater impediment to orphan drug access appears to be funding, particularly in publicly sponsored health-care systems. Redundancies in federal and provincial reviews of orphan drugs can result in significant delays in access to new drugs. Clearly, more must be done to accelerate access to the treatments so desperately needed by patients. Public payers must be held accountable for their process and decisions--especially for rare disease therapies.

  3. Progression of Alzheimer Disease in Europe

    DEFF Research Database (Denmark)

    Vellas, B; Hausner, L; Frolich, L

    2012-01-01

    The clinical progression of Alzheimer disease (AD) was studied in European subjects under treatment with AChE inhibitors (AChE-I) in relation to geographical location over a 2-years period. One thousand three hundred and six subjects from 11 European countries were clustered into 3 regions (North...

  4. Progression of Alzheimer Disease in Europe

    DEFF Research Database (Denmark)

    Vellas, B; Hausner, L; Frolich, L

    2012-01-01

    The clinical progression of Alzheimer disease (AD) was studied in European subjects under treatment with AChE inhibitors (AChE-I) in relation to geographical location over a 2-years period. One thousand three hundred and six subjects from 11 European countries were clustered into 3 regions (North...

  5. Epoetin beta pegol alleviates oxidative stress and exacerbation of renal damage from iron deposition, thereby delaying CKD progression in progressive glomerulonephritis rats.

    Science.gov (United States)

    Hirata, Michinori; Tashiro, Yoshihito; Aizawa, Ken; Kawasaki, Ryohei; Shimonaka, Yasushi; Endo, Koichi

    2015-12-01

    The increased deposition of iron in the kidneys that occurs with glomerulopathy hinders the functional and structural recovery of the tubules and promotes progression of chronic kidney disease (CKD). Here, we evaluated whether epoetin beta pegol (continuous erythropoietin receptor activator: CERA), which has a long half-life in blood and strongly suppresses hepcidin-25, exerts renoprotection in a rat model of chronic progressive glomerulonephritis (cGN). cGN rats showed elevated urinary total protein excretion (uTP) and plasma urea nitrogen (UN) from day 14 after the induction of kidney disease (day 0) and finally declined into end-stage kidney disease (ESKD), showing reduced creatinine clearance with glomerulosclerosis, tubular dilation, and tubulointerstitial fibrosis. A single dose of CERA given on day 1, but not on day 16, alleviated increasing uTP and UN, thereby delaying ESKD. In the initial disease phase, CERA significantly suppressed urinary 8-OHdG and liver-type fatty acid-binding protein (L-FABP), a tubular damage marker. CERA also inhibited elevated plasma hepcidin-25 levels and alleviated subsequent iron accumulation in kidneys in association with elevated urinary iron excretion and resulted in alleviation of growth of Ki67-positive tubular and glomerular cells. In addition, at day 28 when the exacerbation of uTP occurs, a significant correlation was observed between iron deposition in the kidney and urinary L-FABP. In our study, CERA mitigated increasing kidney damage, thereby delaying CKD progression in this glomerulonephritis rat model. Alleviation by CERA of the exacerbation of kidney damage could be attributable to mitigation of tubular damage that might occur with lowered iron deposition in tubules.

  6. Predictors of disease progression in HIV infection: a review

    Directory of Open Access Journals (Sweden)

    Ananworanich Jintanat

    2007-05-01

    Full Text Available Abstract During the extended clinically latent period associated with Human Immunodeficiency Virus (HIV infection the virus itself is far from latent. This phase of infection generally comes to an end with the development of symptomatic illness. Understanding the factors affecting disease progression can aid treatment commencement and therapeutic monitoring decisions. An example of this is the clear utility of CD4+ T-cell count and HIV-RNA for disease stage and progression assessment. Elements of the immune response such as the diversity of HIV-specific cytotoxic lymphocyte responses and cell-surface CD38 expression correlate significantly with the control of viral replication. However, the relationship between soluble markers of immune activation and disease progression remains inconclusive. In patients on treatment, sustained virological rebound to >10 000 copies/mL is associated with poor clinical outcome. However, the same is not true of transient elevations of HIV RNA (blips. Another virological factor, drug resistance, is becoming a growing problem around the globe and monitoring must play a part in the surveillance and control of the epidemic worldwide. The links between chemokine receptor tropism and rate of disease progression remain uncertain and the clinical utility of monitoring viral strain is yet to be determined. The large number of confounding factors has made investigation of the roles of race and viral subtype difficult, and further research is needed to elucidate their significance. Host factors such as age, HLA and CYP polymorphisms and psychosocial factors remain important, though often unalterable, predictors of disease progression. Although gender and mode of transmission have a lesser role in disease progression, they may impact other markers such as viral load. Finally, readily measurable markers of disease such as total lymphocyte count, haemoglobin, body mass index and delayed type hypersensitivity may come into favour

  7. The Viral Polymerase Inhibitor 7-Deaza-2'-C-Methyladenosine Is a Potent Inhibitor of In Vitro Zika Virus Replication and Delays Disease Progression in a Robust Mouse Infection Model.

    Directory of Open Access Journals (Sweden)

    Joanna Zmurko

    2016-05-01

    Full Text Available Zika virus (ZIKV is an emerging flavivirus typically causing a dengue-like febrile illness, but neurological complications, such as microcephaly in newborns, have potentially been linked to this viral infection. We established a panel of in vitro assays to allow the identification of ZIKV inhibitors and demonstrate that the viral polymerase inhibitor 7-deaza-2'-C-methyladenosine (7DMA efficiently inhibits replication. Infection of AG129 (IFN-α/β and IFN-γ receptor knock-out mice with ZIKV resulted in acute neutrophilic encephalitis with viral antigens accumulating in neurons of the brain and spinal cord. Additionally, high levels of viral RNA were detected in the spleen, liver and kidney, and levels of IFN-γ and IL-18 were systematically increased in serum of ZIKV-infected mice. Interestingly, the virus was also detected in testicles of infected mice. In line with its in vitro anti-ZIKV activity, 7DMA reduced viremia and delayed virus-induced morbidity and mortality in infected mice, which also validates this small animal model to assess the in vivo efficacy of novel ZIKV inhibitors. Since AG129 mice can generate an antibody response, and have been used in dengue vaccine studies, the model can also be used to assess the efficacy of ZIKV vaccines.  .

  8. Recent progress in vaccines against fungal diseases.

    Science.gov (United States)

    Cassone, Antonio; Casadevall, Arturo

    2012-08-01

    Diseases caused by fungi are increasingly impacting the health of the human population and now account for a large fraction of infectious disease complications in individuals with impaired immunity or breached tissue defenses. Antifungal therapy is often of limited effectiveness in these patients, resulting into treatment failures, chronic infections and unacceptable rates of mortality, morbidity and their associated costs. Consequently there is a real medical need for new treatments and preventive measures to combat fungal diseases and, toward this goal, safe and efficacious vaccines would constitute major progress. After decades of complacency and neglect of this critically important field of research, remarkable progress has been made in recent years. A number of highly immunogenic and protective vaccine formulations in preclinical setting have been developed, and at least two have undergone Phase 1 clinical trials as preventive and/or therapeutic tools against candidiasis.

  9. Research progress of cerebral small vessel disease

    Directory of Open Access Journals (Sweden)

    Jun-dong JIA

    2015-03-01

    Full Text Available Cerebral small vessel disease refers to a group of pathological processes with various etiologies that affect small arteries, arterioles, venules, and capillaries of the brain. Recently, the researches of cerebral small vessel disease have got initial progressions, and a definite diagnosis of this disease is comfirmed by biopsy. Given the pathological material is difficult to obtain, clinicians should pay more attention to the imaging features and clinical manifestations. Correct understanding of imaging and clinical manifestations contributes to the early identification of cerebral small vessel disease. Herein, an overview is provided on the present status, common imaging features, pathogenesis, clinical manifestations and treatment of cerebral small vessel disease. DOI: 10.3969/j.issn.1672-6731.2015.02.003

  10. [Progress in epigenetic research on Alzheimer disease].

    Science.gov (United States)

    Yang, Nannan; Wei, Yang; Xu, Qian; Tang, Beisha

    2016-04-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder, which features mainly with memory impairment as the initial symptom of progressive loss of cognitive function. Its main pathological changes include senile plaques and neurofibrillary tangles. The pathogenesis of AD is still unclear, though it may be connected with aging, genetic factors and environmental factors. Among these, aging and environmental factors can be modified by epigenetics. In this paper, advances in the study of epigenetic mechanisms related to the pathogenesis of AD are reviewed.

  11. UV-C irradiation delays mitotic progression by recruiting Mps1 to kinetochores.

    Science.gov (United States)

    Zhang, Xiaojuan; Ling, Youguo; Wang, Wenjun; Zhang, Yanhong; Ma, Qingjun; Tan, Pingping; Song, Ting; Wei, Congwen; Li, Ping; Liu, Xuedong; Ma, Runlin Z; Zhong, Hui; Cao, Cheng; Xu, Quanbin

    2013-04-15

    The effect of UV irradiation on replicating cells during interphase has been studied extensively. However, how the mitotic cell responds to UV irradiation is less well defined. Herein, we found that UV-C irradiation (254 nm) increases recruitment of the spindle checkpoint proteins Mps1 and Mad2 to the kinetochore during metaphase, suggesting that the spindle assembly checkpoint (SAC) is reactivated. In accordance with this, cells exposed to UV-C showed delayed mitotic progression, characterized by a prolonged chromosomal alignment during metaphase. UV-C irradiation also induced the DNA damage response and caused a significant accumulation of γ-H2AX on mitotic chromosomes. Unexpectedly, the mitotic delay upon UV-C irradiation is not due to the DNA damage response but to the relocation of Mps1 to the kinetochore. Further, we found that UV-C irradiation activates Aurora B kinase. Importantly, the kinase activity of Aurora B is indispensable for full recruitment of Mps1 to the kinetochore during both prometaphase and metaphase. Taking these findings together, we propose that UV irradiation delays mitotic progression by evoking the Aurora B-Mps1 signaling cascade, which exerts its role through promoting the association of Mps1 with the kinetochore in metaphase.

  12. Consequences of Delayed Dental Extraction in Lesch-Nyhan Disease.

    Science.gov (United States)

    Goodman, Emily M; Torres, Rosa J; Puig, Juan G; Jinnah, H A

    2014-09-01

    Patients with Lesch-Nyhan disease (LND) often engage in self-injurious biting. This problem requires difficult management choices, sometimes including removal of the teeth. Although many health care professionals are reluctant to remove teeth in a child because of the permanent negative cosmetic consequences of the edentulous state, disfigurement of the face and tongue from self-biting can be worse. We analyzed the records of 5 LND patients who used mouth guards to spare the teeth. Success was variable, and dental extraction ultimately was required in 4 cases. We also reviewed previously published cases on the use of dental devices to spare teeth in LND. Various devices have been recommended, but failure rates are high, and tooth extraction often is still needed. Although dental extraction is not required in all cases, it should not be delayed when biting is severe.

  13. THE IMPACT OF THE ELEVATOR GUIDES CONTAMINATION ON THE BRAKING PROCESS DELAY FOR SELECTED PROGRESSIVE GEARS

    Directory of Open Access Journals (Sweden)

    Rafał Longwic

    2017-06-01

    Full Text Available The authors’ tests results on the impact of the guiding system (the guides contamination in the friction lift on the delay of progressive gears braking process are presented in this article. The tests were conducted using a free fall method and a test bench built for that purpose. In order to render all working conditions the guiding system of tested gears was lubricated with the most commonly used lubricating agents. Solid grease (SM, mineral oil (OL, the mixture of solid grease and quartz sand (S50 as well as the mixture of mineral oil and quartz sand (O50 were used.

  14. Impact of delayed diagnosis time in estimating progression rates to hepatitis C virus-related cirrhosis and death.

    Science.gov (United States)

    Fu, Bo; Wang, Wenbin; Shi, Xin

    2015-12-01

    Delay of the diagnosis of hepatitis C virus (HCV), and its treatment to avert cirrhosis, is often present sincethe early stage of HCV progression is latent. Current methods to determine the incubation time to HCV-related cirrhosis and the duration time from cirrhosis to subsequent events (e.g. complications or death) used to be based on the time of liver biopsy diagnosis and ignore this delay which led to an interval censoring for the first event time and a double censoring for the subsequent event time. To investigate the impact of this delay in estimating HCV progression rates and relevant estimating bias, we present a correlated two-stage progression model for delayed diagnosis time and fit the developed model to the previously studied hepatitis C cohort data from Edinburgh. Our analysis shows that taking the delayed diagnosis into account gives a mildly different estimate of progression rate to cirrhosis and significantly lower estimated progression rate to HCV-related death in comparison with conventional modelling. We also find that when the delay increases, the bias in estimating progression increases significantly.

  15. Rationale for delayed-start study of pramipexole in Parkinson's disease: the PROUD study.

    Science.gov (United States)

    Schapira, Anthony H V; Albrecht, Stefan; Barone, Paolo; Comella, Cynthia L; McDermott, Michael P; Mizuno, Yoshikuni; Poewe, Werner; Rascol, Olivier; Marek, Kenneth

    2010-08-15

    Perhaps the most important unmet need in Parkinson's disease (PD) is the ability to slow or prevent progression of the neurodegeneration that underlies the motor and nonmotor features of this disorder. Pramipexole, a dopamine agonist used for the symptomatic treatment of PD, has demonstrated neuroprotective properties in laboratory studies. The PRamipexole On Underlying Disease (PROUD) study is a randomized, double-blind clinical trial evaluating the ability of pramipexole to modify disease progression using a delayed-start design. PD patients (n = 535) with mean age 62.5 years, mean duration since diagnosis of 4.4 months, and mean total Unified Parkinson's disease Rating Scale (UPDRS) score of 24.5 were recruited. In Phase I, patients were randomly assigned to be titrated to 1.5 mg pramipexole or placebo and maintained on study drug for 6-9 months. In Phase II, all patients were titrated to 1.5 mg pramipexole and maintained on study drug until the end of the study at 15 months. No rescue medication was allowed in the protocol. The primary endpoint is the change in total UPDRS score (parts I-III) from baseline to 15 months. A range of secondary endpoints separately assess UPDRS subscales, quality of life, depression, and impulse control disorders. A sub-study examined dopamine transporter uptake scans at baseline and 15 months. The results of PROUD will provide insight into the potential for early versus delayed treatment with pramipexole to modify motor outcome at 15 months in recently diagnosed PD patients.

  16. Primary progressive aphasia: from syndrome to disease.

    Science.gov (United States)

    Matías-Guiu, J A; García-Ramos, R

    2013-01-01

    Primary progressive aphasia (PPA) is a clinical syndrome characterised by a progressive decline in language and speech of neurodegenerative origin. Major breakthroughs made in recent years have lent us a better understanding of this syndrome, which may be the first manifestation of any of a number of neurodegenerative diseases. We reviewed the main aspects of PPA epidemiology, clinical manifestations, diagnosis, aetiology and treatment. Most cases manifest sporadically and the typical age of onset is between 50 and 70 years. Three clinically distinct variants have been described: nonfluent or agrammatic PPA, semantic PPA and logopenic PPA. Each of these variants tends to be associated with specific histopathological findings, but clinical diagnostic methods are imperfect predictors of underlying pathology. Anatomical and functional neuroimaging can provide useful biomarkers. Several treatments have been proposed, and while no clear benefits have been demonstrated, acetylcholinesterase inhibitors may be useful, especially in the logopenic variant. PPA is an emerging syndrome which may be more prevalent than we might expect. It was previously listed as part of the frontotemporal dementia spectrum, and it is also related to Alzheimer disease. Clinical diagnosis, complemented by a biomarker evaluation, may predict the underlying pathology, which in turn will improve treatment possibilities. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  17. Progress on Dent's disease%Dent病研究进展

    Institute of Scientific and Technical Information of China (English)

    刘妍

    2012-01-01

    There are many causes of proteinuria in children.Because proteinuria is mainly caused by glomerular diseases,renal tubulopathies are often ignored.Dent's disease is an hereditary renal tubulopathy characterized by low-molecular-weigh proteinuria,hypercalciuria,nephrocalcinosis,nephrolithiasis,and progressive renal failure.Dent's disease is mainly caused by mutations in CLCN5 and OCRL1 genes.Current treatments of the disease are still mainly symptomatic and supportive therapy,including reducing urinary calcium excretion,lightening nephrocalcinosis,and delaying the occurrence of renal insufficiency.%小儿蛋白尿的原因很多,多数是由于肾小球疾病引起,故往往忽略了肾小管疾病致蛋白尿的出现.Dent病为一种遗传性肾小管疾病,主要表现为低相对分子原量蛋白尿、高钙尿症、肾脏钙化、肾石症及进行性肾衰竭.目前主要发现CLCN5基因和OCRL1基因突变可导致Dent病的发生.Dent病的治疗目前仍以对症支持治疗为主,主要是降低尿钙排泄,减轻肾脏钙化以及延缓肾功能不全的发生.

  18. Levodopa and the progression of Parkinson's disease.

    Science.gov (United States)

    Fahn, Stanley; Oakes, David; Shoulson, Ira; Kieburtz, Karl; Rudolph, Alice; Lang, Anthony; Olanow, C Warren; Tanner, Caroline; Marek, Kenneth

    2004-12-09

    Despite the known benefit of levodopa in reducing the symptoms of Parkinson's disease, concern has been expressed that its use might hasten neurodegeneration. This study assessed the effect of levodopa on the rate of progression of Parkinson's disease. In this randomized, double-blind, placebo-controlled trial, we evaluated 361 patients with early Parkinson's disease who were assigned to receive carbidopa-levodopa at a daily dose of 37.5 and 150 mg, 75 and 300 mg, or 150 and 600 mg, respectively, or a matching placebo for a period of 40 weeks, and then to undergo withdrawal of treatment for 2 weeks. The primary outcome was a change in scores on the Unified Parkinson's Disease Rating Scale (UPDRS) between baseline and 42 weeks. Neuroimaging studies of 142 subjects were performed at baseline and at week 40 to assess striatal dopamine-transporter density with the use of iodine-123-labeled 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane ([123I]beta-CIT) uptake. The severity of parkinsonism increased more in the placebo group than in all the groups receiving levodopa: the mean difference between the total score on the UPDRS at baseline and at 42 weeks was 7.8 units in the placebo group, 1.9 units in the group receiving levodopa at a dose of 150 mg daily, 1.9 in those receiving 300 mg daily, and -1.4 in those receiving 600 mg daily (Pdisease or has a prolonged effect on the symptoms of the disease. In contrast, the neuroimaging data suggest either that levodopa accelerates the loss of nigrostriatal dopamine nerve terminals or that its pharmacologic effects modify the dopamine transporter. The potential long-term effects of levodopa on Parkinson's disease remain uncertain. Copyright 2004 Massachusetts Medical Society.

  19. Stability criteria for T-S fuzzy systems with interval time-varying delays and nonlinear perturbations based on geometric progression delay partitioning method.

    Science.gov (United States)

    Chen, Hao; Zhong, Shouming; Li, Min; Liu, Xingwen; Adu-Gyamfi, Fehrs

    2016-07-01

    In this paper, a novel delay partitioning method is proposed by introducing the theory of geometric progression for the stability analysis of T-S fuzzy systems with interval time-varying delays and nonlinear perturbations. Based on the common ratio α, the delay interval is unequally separated into multiple subintervals. A newly modified Lyapunov-Krasovskii functional (LKF) is established which includes triple-integral terms and augmented factors with respect to the length of every related proportional subintervals. In addition, a recently developed free-matrix-based integral inequality is employed to avoid the overabundance of the enlargement when dealing with the derivative of the LKF. This innovative development can dramatically enhance the efficiency of obtaining the maximum upper bound of the time delay. Finally, much less conservative stability criteria are presented. Numerical examples are conducted to demonstrate the significant improvements of this proposed approach.

  20. Monitoring Huntington’s disease progression through preclinical and early stages

    Science.gov (United States)

    Tang, Chris; Feigin, Andrew

    2012-01-01

    SUMMARY Huntington’s disease (HD) is an autosomal dominant progressive neurodegenerative disorder that typically begins in middle adulthood. The neurodegenerative process that underlies HD, however, likely begins many years before clinical diagnosis. Since genetic testing can identify individuals that will develop HD during this preclinical period, clinical trials aiming to slow disease progression will likely focus on this phase of the illness in an effort to delay disease onset. How to best measure the efficacy of potential disease-modifying therapies in preclinical HD remains a complex challenge. This article will review the clinical and imaging measures that have been assessed as potential markers of disease progression in preclinical and early symptomatic HD. PMID:23243467

  1. How pregnancy can affect autoimmune diseases progression?

    Science.gov (United States)

    Piccinni, Marie-Pierre; Lombardelli, Letizia; Logiodice, Federica; Kullolli, Ornela; Parronchi, Paola; Romagnani, Sergio

    2016-01-01

    Autoimmune disorders are characterized by tissue damage, caused by self-reactivity of different effectors mechanisms of the immune system, namely antibodies and T cells. Their occurrence may be associated with genetic and/or environmental predisposition and to some extent, have implications for fertility and obstetrics. The relationship between autoimmunity and reproduction is bidirectional. This review only addresses the impact of pregnancy on autoimmune diseases and not the influence of autoimmunity on pregnancy development. Th17/Th1-type cells are aggressive and pathogenic in many autoimmune disorders and inflammatory diseases. The immunology of pregnancy underlies the role of Th2-type cytokines to maintain the tolerance of the mother towards the fetal semi-allograft. Non-specific factors, including hormonal changes, favor a switch to Th2-type cytokine profile. In pregnancy Th2, Th17/Th2 and Treg cells accumulate in the decidua but may also be present in the mother's circulation and can regulate autoimmune responses influencing the progression of autoimmune diseases.

  2. Gaucher disease: Progress and ongoing challenges.

    Science.gov (United States)

    Mistry, Pramod K; Lopez, Grisel; Schiffmann, Raphael; Barton, Norman W; Weinreb, Neal J; Sidransky, Ellen

    Over the past decades, tremendous progress has been made in the field of Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Many of the colossal achievements took place during the course of the sixty-year tenure of Dr. Roscoe Brady at the National Institutes of Health. These include the recognition of the enzymatic defect involved, the isolation and characterization of the protein, the localization and characterization of the gene and its nearby pseudogene, as well as the identification of the first mutant alleles in patients. The first treatment for Gaucher disease, enzyme replacement therapy, was conceived of, developed and tested at the Clinical Center of the National Institutes of Health. Advances including recombinant production of the enzyme, the development of mouse models, pioneering gene therapy experiments, high throughput screens of small molecules and the generation of induced pluripotent stem cell models have all helped to catapult research in Gaucher disease into the twenty-first century. The appreciation that mutations in the glucocerebrosidase gene are an important risk factor for parkinsonism further expands the impact of this work. However, major challenges still remain, some of which are described here, that will provide opportunities, excitement and discovery for the next generations of Gaucher investigators.

  3. Clinical neurorestorative progress in Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Chen L

    2015-06-01

    Full Text Available Lin Chen,1,2 Hongyun Huang,3–5 Wei-Ming Duan,6 Gengsheng Mao3 1Department of Neurosurgery, Yuquan Hospital, Tsinghua University, 2Department of Neurosurgery, Medical Center, Tsinghua University, 3Department of Neurosurgery, General Hospital of Chinese People's Armed Police Forces, 4Center of Cell Research, Beijing Rehabilitation Hospital of Capital Medical University, 5Beijing Hongtianji Neuroscience Academy, 6Department of Anatomy, Capital Medical University, Beijing, People's Republic of China Abstract: Parkinson’s disease (PD is one of the common neurodegenerative diseases. Besides the symptomatic therapies, the increasing numbers of neurorestorative therapies have shown the potential therapeutic value of reversing the neurodegenerative process and improving the patient's quality of life. Currrently available novel clinical neurorestorative strategies include pharmacological managements (glial cell-line derived neurotrophic factor, selegiline, recombinant human erythropoietin, neuromodulation intervention (deep brain stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, tissue and cell transplantation (fetal ventral mesencephalic tissue, sympathetic neurons, carotid body cells, bone marrow stromal cells, retinal pigment epithelium cells, gene therapy, and neurorehabilitative therapy. Herein, we briefly review the progress in this field and describe the neurorestorative mechanisms of the above-mentioned therapies for PD. Keywords: Parkinson’s disease, clinical study, neurorestorative treatment, cell transplantation, neuromodulation

  4. Recent progress in hemorrhagic moyamoya disease.

    Science.gov (United States)

    Wan, Ming; Duan, Lian

    2015-04-01

    Moyamoya disease (MMD) is a chronic progressive cerebrovascular disease, which can be divided into three types: ischemic, hemorrhagic, and asymptomatic. Hemorrhagic MMD has attracted considerable attention due to its distinctive imaging features and the controversy over the treatment. This report presents a comprehensive review of the literature on hemorrhagic MMD, focusing on the epidemiological characteristics, etiology and pathogenesis, imaging features, predictors of hemorrhage, and treatment options and their efficacy of hemorrhagic MMD. Hemorrhagic MMD mainly occurs in adult patients in Asian countries, and many factors may contribute to the etiology and development of this disease. Hemorrhagic MMD has two major imaging features: the dilatation and abnormal branching of anterior choroidal artery or posterior communicating artery, and multiple microbleeds, which may predict subsequent hemorrhage. The treatment for hemorrhagic MMD is not standardized, and large sample prospective randomized clinical trials may help to determine which method is better. In hemorrhagic MMD patients, more attention should be paid to cognitive function and quality of life, and these assessments should be included in the evaluation of effectiveness of treatment modalities.

  5. Vascular contribution to Alzheimer disease: predictors of rapid progression.

    Science.gov (United States)

    Diomedi, Marina; Misaggi, Giulia

    2013-06-01

    Different courses of Alzheimer disease are observed in clinical practice. The rapidly progressive form could be associated with the presence of a major microcirculatory involvement and hemodynamic insufficiency. This short review aims to provide an overview of the current knowledge of cerebrovascular contribution to Alzheimer disease presentation and progression, hypothesizing the possible vascular markers of rapidly progressive form.

  6. Novel biomarkers for progression of chronic kidney disease

    Institute of Scientific and Technical Information of China (English)

    LIU Bi-cheng; L(U) Lin-li

    2010-01-01

    @@ CHARACTERISTICS OF THE PROGRESSION OF CHRONIC KIDNEY DISEASE (CKD) Although there are different initiators of CKD, it is generally recognized that the secondary pathological pathway is quite common to all CKD. CKD may inevitably progress to end stage renal disease (ESRD) due to a vicious cycle of nephron destruction by progressive glomerulosclerosis and tubulointerstitial fibrosis.

  7. A Three-Decade Survival Analysis of Intraventricular Conduction Delay in Adults Without Ischemic Heart Disease.

    Science.gov (United States)

    Tiosano, Shmuel; Hod, Hanoch; Oberman, Bernice; Chetrit, Angela; Dankner, Rachel

    2016-11-01

    The prognosis of an incidental finding of intraventricular conduction delay in individuals without ischemic heart disease is debatable. Intraventricular conduction delay presents electrocardiographically as bundle branch block or nonspecific intraventricular conduction delay. We aimed to assess the long-term survival of an incidental intraventricular conduction delay finding in a cohort of individuals without ischemic heart disease, followed up for 3 decades. A randomized stratified cohort of the adult Israeli population underwent medical examinations and electrocardiography between 1976 and 1982. Patients with ischemic heart disease were excluded, and the cohort was followed for all-cause mortality for a median of 30.4 years. Major intraventricular conduction delay was defined as having complete bundle branch block or nonspecific intraventricular conduction delay, and minor intraventricular conduction delay was defined as having incomplete bundle branch block. Cox proportional hazard model was performed, comparing individuals by electrocardiogram finding, adjusting for demographic, clinical, and electrocardiographic variables. Of 2465 subjects, 2385 (96.8%) were without intraventricular conduction delay, 38 (1.5%) had minor intraventricular conduction delay, and 42 (1.7%) had major intraventricular conduction delay. All-cause mortality rates were higher among minor and major intraventricular conduction delay groups (57.9% and 66.7%, P = .43 and P = .04, respectively) compared with no intraventricular conduction delay (52.1%). By controlling for sex, age, and body mass index, intraventricular conduction delay was not associated with all-cause mortality: hazard ratios, 0.82 (95% confidence interval, 0.52-1.25) and 1.06 (95% confidence interval, 0.72-1.54) for minor and major intraventricular conduction delay, respectively. Intraventricular conduction delay was not found to be an independent risk factor for all-cause mortality in individuals without ischemic heart

  8. First-aid with warm water delays burn progression and increases skin survival.

    Science.gov (United States)

    Tobalem, M; Harder, Y; Tschanz, E; Speidel, V; Pittet-Cuénod, B; Wettstein, R

    2013-02-01

    First aid treatment for thermal injuries with cold water removes heat and decreases inflammation. However, perfusion in the ischemic zone surrounding the coagulated core can be compromised by cold-induced vasoconstriction and favor burn progression. The aim of this study is to evaluate the effect of local warming on burn progression in the rat comb burn model. 24 male Wistar rats were randomly assigned to either no treatment (control) or application of cold (17 °C) or warm (37 °C) water applied for 20 min. Evolution of burn depth, interspace necrosis, and microcirculatory perfusion were assessed with histology, planimetry, respectively with Laser Doppler flowmetry after 1 h, as well as 1, 4, and 7 days. Consistent conversion from a superficial to a deep dermal burn within 24 h was obtained in control animals. Warm and cold water significantly delayed burn depth progression, however after 4 days the burn depth was similar in all groups. Interspace necrosis was significantly reduced by warm water treatment (62±4% vs. 69±5% (cold water) and 82±3% (control); pcold water and 80±2% for control, pwater provided an additional benefit by improving the microcirculatory perfusion, which translated into increased tissue survival. Copyright © 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

  9. Alcohol, coffee, fish, smoking and disease progression in multiple sclerosis

    NARCIS (Netherlands)

    D'hooghe, M. B.; Haentjens, P.; Nagels, G.; De Keyser, J.

    2012-01-01

    Background: Certain lifestyle factors might influence disease activity in multiple sclerosis (MS). Objectives: To investigate the consumption of alcoholic beverages, caffeinated drinks, fish and cigarette smoking in relation to disability progression in relapsing onset and progressive onset MS. Meth

  10. Alcohol, coffee, fish, smoking and disease progression in multiple sclerosis

    NARCIS (Netherlands)

    D'hooghe, M. B.; Haentjens, P.; Nagels, G.; De Keyser, J.

    2012-01-01

    Background: Certain lifestyle factors might influence disease activity in multiple sclerosis (MS). Objectives: To investigate the consumption of alcoholic beverages, caffeinated drinks, fish and cigarette smoking in relation to disability progression in relapsing onset and progressive onset MS. Meth

  11. Increase of Reproductive Life Span Delays Age of Onset of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Dominik Frentzel

    2017-08-01

    Full Text Available One striking observation in Parkinson’s disease (PD is the remarkable gender difference in incidence and prevalence of the disease. Data on gender differences with regard to disease onset, motor and non-motor symptoms, and dopaminergic medication are limited. Furthermore, whether estrogen status affects disease onset and progression of PD is controversially discussed. In this retrospective single center study, we extracted clinical data of 226 ambulatory PD patients and compared age of disease onset, disease stage, motor impairment, non-motor symptoms, and dopaminergic medication between genders. We applied a matched-pairs design to adjust for age and disease duration. To determine the effect of estrogen-related reproductive factors including number of children, age at menarche, and menopause on the age of onset, we applied a standardized questionnaire and performed a regression analysis. The male to female ratio in the present PD cohort was 1.9:1 (147 men vs. 79 women. Male patients showed increased motor impairment than female patients. The levodopa equivalent daily dose was increased by 18.9% in male patients compared to female patients. Matched-pairs analysis confirmed the increased dose of dopaminergic medication in male patients. No differences were observed in age of onset, type of medication, and non-motor symptoms between both groups. Female reproductive factors including number of children, age at menarche, and age at menopause were positively associated with a delay of disease onset up to 30 months. The disease-modifying role of estrogen-related outcome measures warrants further clinical and experimental studies targeting gender differences, specifically hormone-dependent pathways in PD.

  12. Increase of Reproductive Life Span Delays Age of Onset of Parkinson’s Disease

    Science.gov (United States)

    Frentzel, Dominik; Judanin, Grigorij; Borozdina, Olga; Klucken, Jochen; Winkler, Jürgen; Schlachetzki, Johannes C. M.

    2017-01-01

    One striking observation in Parkinson’s disease (PD) is the remarkable gender difference in incidence and prevalence of the disease. Data on gender differences with regard to disease onset, motor and non-motor symptoms, and dopaminergic medication are limited. Furthermore, whether estrogen status affects disease onset and progression of PD is controversially discussed. In this retrospective single center study, we extracted clinical data of 226 ambulatory PD patients and compared age of disease onset, disease stage, motor impairment, non-motor symptoms, and dopaminergic medication between genders. We applied a matched-pairs design to adjust for age and disease duration. To determine the effect of estrogen-related reproductive factors including number of children, age at menarche, and menopause on the age of onset, we applied a standardized questionnaire and performed a regression analysis. The male to female ratio in the present PD cohort was 1.9:1 (147 men vs. 79 women). Male patients showed increased motor impairment than female patients. The levodopa equivalent daily dose was increased by 18.9% in male patients compared to female patients. Matched-pairs analysis confirmed the increased dose of dopaminergic medication in male patients. No differences were observed in age of onset, type of medication, and non-motor symptoms between both groups. Female reproductive factors including number of children, age at menarche, and age at menopause were positively associated with a delay of disease onset up to 30 months. The disease-modifying role of estrogen-related outcome measures warrants further clinical and experimental studies targeting gender differences, specifically hormone-dependent pathways in PD. PMID:28871235

  13. Patterns of progression, treatment of progressive disease and post-progression survival in the New EPOC study.

    Science.gov (United States)

    Pugh, Siân A; Bowers, Megan; Ball, Alexandre; Falk, Stephen; Finch-Jones, Meg; Valle, Juan W; O'Reilly, Derek A; Siriwardena, Ajith K; Hornbuckle, Joanne; Rees, Myrddin; Rees, Charlotte; Iveson, Tim; Hickish, Tamas; Maishman, Tom; Stanton, Louise; Dixon, Elizabeth; Corkhill, Andrea; Radford, Mike; Garden, O James; Cunningham, David; Maughan, Tim S; Bridgewater, John A; Primrose, John N

    2016-08-09

    The addition of cetuximab (CTX) to perioperative chemotherapy (CT) for operable colorectal liver metastases resulted in a shorter progression-free survival. Details of disease progression are described to further inform the primary study outcome. A total of 257 KRAS wild-type patients were randomised to CT alone or CT with CTX. Data regarding sites and treatment of progressive disease were obtained for the 109 (CT n=48, CT and CTX n=61) patients with progressive disease at the cut-off date for analysis of November 2012. The liver was the most frequent site of progression (CT 67% (32/48); CT and CTX 66% (40/61)). A higher proportion of patients in the CT and group had multiple sites of progressive disease (CT 8%, 4/48; CT and CTX 23%, 14/61 P=0.04). Further treatment for progressive disease is known for 84 patients of whom 69 received further CT, most frequently irinotecan based. Twenty-two patients, 11 in each arm, received CTX as a further line agent. Both the distribution of progressive disease and further treatment are as expected for such a cohort. The pattern of disease progression seen is consistent with failure of systemic micrometastatic disease control rather than failure of local disease control following liver surgery.

  14. Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure.

    Science.gov (United States)

    Zeisberg, Michael; Tampe, Björn; LeBleu, Valerie; Tampe, Desiree; Zeisberg, Elisabeth M; Kalluri, Raghu

    2014-10-01

    Thrombospondin-1 (TSP1) is a multifunctional matricellular protein known to promote progression of chronic kidney disease. To gain insight into the underlying mechanisms through which TSP1 accelerates chronic kidney disease, we compared disease progression in Col4a3 knockout (KO) mice, which develop spontaneous kidney failure, with that of Col4a3;Tsp1 double-knockout (DKO) mice. Decline of excretory renal function was significantly delayed in the absence of TSP1. Although Col4a3;Tsp1 DKO mice did progress toward end-stage renal failure, their kidneys exhibited distinct histopathological lesions, compared with creatinine level-matched Col4a3 KO mice. Although kidneys of both Col4a3 KO and Col4a3;Tsp1 DKO mice exhibited a widened tubulointerstitium, predominant lesions in Col4a3 KO kidneys were collagen deposition and fibroblast accumulation, whereas in Col4a3;Tsp1 DKO kidney inflammation was predominant, with less collagen deposition. Altered disease progression correlated with impaired activation of transforming growth factor-β1 (TGF-β1) in vivo and in vitro in the absence of TSP1. In summary, our findings suggest that TSP1 contributes to progression of chronic kidney disease by catalyzing activation of latent TGF-β1, resulting in promotion of a fibroproliferative response over an inflammatory response. Furthermore, the findings suggest that fibroproliferative and inflammatory lesions are independent entities, both of which contribute to decline of renal function.

  15. Inhibition of monoacylglycerol lipase mediates a cannabinoid 1-receptor dependent delay of kindling progression in mice.

    Science.gov (United States)

    von Rüden, E L; Bogdanovic, R M; Wotjak, C T; Potschka, H

    2015-05-01

    Endocannabinoids, including 2-arachidonoylglycerol (2-AG), activate presynaptic cannabinoid type 1 receptors (CB1R) on inhibitory and excitatory neurons, resulting in a decreased release of neurotransmitters. The event-specific activation of the endocannabinoid system by inhibition of the endocannabinoid degrading enzymes may offer a promising strategy to selectively activate CB1Rs at the site of excessive neuronal activation with the overall goal to prevent the development epilepsy. The aim of this study was to investigate the impact of monoacylglycerol lipase (MAGL) inhibition on the development and progression of epileptic seizures in the kindling model of temporal lobe epilepsy. Therefore, we selectively blocked MAGL by JZL184 (8mg/kg, i.p.) in mice to analyze the effects of increased 2-AG levels on kindling acquisition and to exclude an anticonvulsive potential. Our results showed that JZL184 treatment significantly delayed the development of generalized seizures (p=0.0066) and decreased seizure (pkindling model of temporal lobe epilepsy, but caused only modest effects in fully kindled mice. Moreover, we proved that JZL184 treatment had no effects in conditional CB1R knockout mice lacking expression of the receptor in principle neurons of the forebrain. In conclusion, the data demonstrate that indirect CB1R agonism delays the development of generalized epileptic seizures but has no relevant acute anticonvulsive effects. Furthermore, we confirmed that the effects of JZL184 on kindling progression are CB1R mediated. Thus, the data indicate that the endocannabinoid 2-AG might be a promising target for an anti-epileptogenic approach.

  16. 'Limits and current knowledge of Pick's disease: its differential diagnosis'. A translation of the 1957 Delay, Brion, Escourolle article.

    Science.gov (United States)

    Thibodeau, Marie-Pierre; Miller, Bruce L

    2013-01-01

    This article is a translation of a French article by Delay, Brion, and Escourolle. In a seminal article published in French in 1957 these authors summarized the work of previous researchers and reviewed a wide sample of frontotemporal dementia (FTD) cases formerly referred to as Pick's disease. The authors were among the first to define the critical clinical and anatomical differences between Alzheimer's disease (AD) and FTD and they even delineated distinctive FTD subtypes making possible the advances that now constitute the base of our studies. Reviewing their work allows us to appreciate the progress research has made.

  17. Meniscal Allograft Transplantation Does Not Prevent or Delay Progression of Knee Osteoarthritis.

    Directory of Open Access Journals (Sweden)

    Catherine Van Der Straeten

    Full Text Available Meniscal tears are common knee injuries. Meniscal allograft transplantation (MAT has been advocated to alleviate symptoms and delay osteoarthritis (OA after meniscectomy. We investigated (1 the long-term outcome of MAT as a treatment of symptomatic meniscectomy, (2 most important factors affecting survivorship and (3 OA progression.From 1989 till 2013, 329 MAT were performed in 313 patients. Clinical and radiographic results and MAT survival were evaluated retrospectively. Failure was defined as conversion to knee arthroplasty (KA or total removal of the MAT.Mean age at surgery was 33 years (15-57; 60% were males. No-to-mild cartilage damage was found in 156 cases, moderate-to-severe damage in 130. Simultaneous procedures in 118 patients included cartilage procedures, osteotomy or ACL-reconstruction. At a mean follow-up of 6.8 years (0.2-24.3years, 5 patients were deceased and 48 lost (14.6%, 186 MAT were in situ (56.5% whilst 90 (27.4% had been removed, including 63 converted to a KA (19.2%. Cumulative allograft survivorship was 15.1% (95% CI:13.9-16.3 at 24.0 years. In patients <35 years at surgery, survival was significantly better (24.1% compared to ≥35 years (8.0% (p = 0.017. In knees with no-to-mild cartilage damage more allografts survived (43.0% compared to moderate-to-severe damage (6.6% (p = 0.003. Simultaneous osteotomy significantly deteriorated survival (0% at 24.0 years (p = 0.010. 61% of patients underwent at least one additional surgery (1-11 for clinical symptoms after MAT. Consecutive radiographs showed significant OA progression at a mean of 3.8 years (p<0.0001. Incremental Kellgren-Lawrence grade was +1,1 grade per 1000 days (2,7yrs.MAT did not delay or prevent tibiofemoral OA progression. 19.2% were converted to a knee prosthesis at a mean of 10.3 years. Patients younger than 35 with no-to-mild cartilage damage may benefit from MAT for relief of symptoms (survivorship 51.9% at 20.2 years, but patients and healthcare payers

  18. Pluripotent stem cells for Parkinson's disease: progress and challenges

    National Research Council Canada - National Science Library

    Zeng, Xianmin; Couture, Larry A

    2013-01-01

    Parkinson's disease (PD) is a common debilitating neurodegenerative disease. The motor symptoms of PD are caused mainly by a progressive loss of dopaminergic neurons from the substania nigra, resulting in a loss of dopamine production...

  19. TRAVELLING FRONT SOLUTIONS IN A DIFFUSIVE VECTOR DISEASE MODEL WITH SPATIO-TEMPORAL DELAY

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    This paper is concerned with travelling front solutions to a vector disease model with a spatio-temporal delay incorporated as an integral convolution over all the past time up to now and the whole one-dimensional spatial domain R.When the delay kernel is assumed to be the strong generic kernel,using the linear chain techniques and the geometric singular perturbation theory,the existence of travelling front solutions is shown for small delay.

  20. A case of progressive aphasia without dementia: "temporal" Pick's disease?

    Science.gov (United States)

    Scheltens, P; Hazenberg, G J; Lindeboom, J; Valk, J; Wolters, E C

    1990-01-01

    We report a patient who suffered from progressive aphasia for nine years, before developing mild behavioural disturbances. Sequential computed tomography (CT) scanning and magnetic resonance (MRI) imaging showed progressive bilateral temporal atrophy. The case is thought to be a temporal form of Pick's disease, in which isolated progressive aphasia was the only symptom over many years. Images PMID:2303835

  1. A new in vitro model to delay high phosphate-induced vascular calcification progression.

    Science.gov (United States)

    Ciceri, Paola; Elli, Francesca; Cappelletti, Laura; Tosi, Delfina; Braidotti, Paola; Bulfamante, Gaetano; Cozzolino, Mario

    2015-12-01

    An increasing amount of patients affected by advanced chronic kidney disease suffer from vascular calcification (VC) that associates with cardiovascular morbidity and mortality. In this study, we created a new experimental in vitro model, trying to better elucidate high phosphate (Pi)-induced VC pathogenic mechanisms. Rat aortic vascular smooth muscle cells (VSMCs) were challenged for 7-10 days with high Pi with a repeated and short suspensions of high Pi treatment (intermittent suspension, IS) that was able to induce a significant inhibition of high Pi calcification, maximal at 5 h. Interestingly, the delay in calcification is a consequence of either the absence of free Pi or calcium-phosphate crystals being comparable to the total effect obtained during the 5 h-IS. The protective effect of IS was mediated by the reduction of apoptosis as demonstrated by the action of 20 μmol/L Z-VAD-FMK and by the preservation of the pro-survival receptor Axl expression. Furthermore, autophagy, during IS, was potentiated by increasing the autophagic flux, evaluated by LC3IIB western, while treating VSMCs with 1 mmol/L valproic acid did not affect VC. Finally, IS prevented VSMC osteoblastic differentiation by preserving smooth muscle lineage markers expression. Our data support the hypothesis that to delay significantly VC is necessary and sufficient the IS of high Pi challenge. The IS was able to prevent significantly apoptosis, to induce a potentiation in autophagy, and to prevent osteoblastic differentiation by preserving SM lineage markers.

  2. Finger tapping movements of Parkinson's disease patients automatically rated using nonlinear delay differential equations

    Science.gov (United States)

    Lainscsek, C.; Rowat, P.; Schettino, L.; Lee, D.; Song, D.; Letellier, C.; Poizner, H.

    2012-03-01

    Parkinson's disease is a degenerative condition whose severity is assessed by clinical observations of motor behaviors. These are performed by a neurological specialist through subjective ratings of a variety of movements including 10-s bouts of repetitive finger-tapping movements. We present here an algorithmic rating of these movements which may be beneficial for uniformly assessing the progression of the disease. Finger-tapping movements were digitally recorded from Parkinson's patients and controls, obtaining one time series for every 10 s bout. A nonlinear delay differential equation, whose structure was selected using a genetic algorithm, was fitted to each time series and its coefficients were used as a six-dimensional numerical descriptor. The algorithm was applied to time-series from two different groups of Parkinson's patients and controls. The algorithmic scores compared favorably with the unified Parkinson's disease rating scale scores, at least when the latter adequately matched with ratings from the Hoehn and Yahr scale. Moreover, when the two sets of mean scores for all patients are compared, there is a strong (r = 0.785) and significant (p <0.0015) correlation between them.

  3. Adding Recognition Discriminability Index to the Delayed Recall Is Useful to Predict Conversion from Mild Cognitive Impairment to Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative

    Science.gov (United States)

    Russo, María J.; Campos, Jorge; Vázquez, Silvia; Sevlever, Gustavo; Allegri, Ricardo F.; Weiner, Michael W.

    2017-01-01

    Background: Ongoing research is focusing on the identification of those individuals with mild cognitive impairment (MCI) who are most likely to convert to Alzheimer's disease (AD). We investigated whether recognition memory tasks in combination with delayed recall measure of episodic memory and CSF biomarkers can predict MCI to AD conversion at 24-month follow-up. Methods: A total of 397 amnestic-MCI subjects from Alzheimer's disease Neuroimaging Initiative were included. Logistic regression modeling was done to assess the predictive value of all RAVLT measures, risk factors such as age, sex, education, APOE genotype, and CSF biomarkers for progression to AD. Estimating adjusted odds ratios was used to determine which variables would produce an optimal predictive model, and whether adding tests of interaction between the RAVLT Delayed Recall and recognition measures (traditional score and d-prime) would improve prediction of the conversion from a-MCI to AD. Results: 112 (28.2%) subjects developed dementia and 285 (71.8%) subjects did not. Of the all included variables, CSF Aβ1-42 levels, RAVLT Delayed Recall, and the combination of RAVLT Delayed Recall and d-prime were predictive of progression to AD (χ2 = 38.23, df = 14, p < 0.001). Conclusions: The combination of RAVLT Delayed Recall and d-prime measures may be predictor of conversion from MCI to AD in the ADNI cohort, especially in combination with amyloid biomarkers. A predictive model to help identify individuals at-risk for dementia should include not only traditional episodic memory measures (delayed recall or recognition), but also additional variables (d-prime) that allow the homogenization of the assessment procedures in the diagnosis of MCI.

  4. Global dynamics behaviors for new delay SEIR epidemic disease model with vertical transmission and pulse vaccination

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    A robust SEIR epidemic disease model with a profitless delay and vertical transmission is formulated, and the dynamics behaviors of the model under pulse vaccination are analyzed.By use of the discrete dynamical system determined by the the model are under appropriate conditions.Using the theory on delay functional and impulsive differential equation, the sufficient condition with time delay for the permanence of the system is obtained, and it is proved that time delays, pulse vaccination and vertical transmission can bring obvious effects on the dynamics behaviors of the model.

  5. Progress Report on Alzheimer Disease: Volume III.

    Science.gov (United States)

    National Inst. on Aging (DHHS/PHS), Bethesda, MD.

    This report summarizes advances in the understanding of Alzheimer's disease, the major cause of mental disability among older Americans. The demography of the disease is discussed, noting that approximately 2.5 million American adults are afflicted with the disease and that the large increase in the number of Alzheimer's disease patients is due to…

  6. Delayed progressive haematoma after Le Fort I osteotomy: A possible severe complication in orthognatic surgery

    Directory of Open Access Journals (Sweden)

    Dario Bertossi

    2012-01-01

    Full Text Available Although the Le Fort I osteotomy is a safe surgical technique, many complications have been reported. We present a case of an extended cervico-facial haematoma due to delayed bleeding from the terminal branches of the maxillary artery after orthognatic surgery. A 23-year-old man was referred to our observation for the surgical correction of a class III asymmetric malocclusion. The patient underwent a Le Fort I osteotomy, with impaction of the maxilla, associated with an Epker mandibular bilateral sagittal split osteotomy, with maxillary advancement and rigid internal fixation of the mandible with four miniplates and another four for the upper maxilla as well. The first post-surgery day, the patient developed a gradual dispnea together with neck swelling. By second postoperative day, the patient′s general condition improved with a progressive normalization of laboratory tests values. The Computerised Axial Tomography (CAT scan confirmed a decrease in the parapharyngeal thickening. Total recovery was achieved within two months, the final clinical check showed a healthy appearance with good occlusion. An increased knowledge of the basic biology of the Le Fort I osteotomy, the development of instruments specially designed for the Le Fort I procedure and the use of hypotensive anaesthesia could reduce the morbidity and duration of this procedure.

  7. Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival.

    Science.gov (United States)

    Saxena, Smita; Roselli, Francesco; Singh, Katyayani; Leptien, Kerstin; Julien, Jean-Pierre; Gros-Louis, Francois; Caroni, Pico

    2013-10-01

    Delaying clinical disease onset would greatly reduce neurodegenerative disease burden, but the mechanisms influencing early preclinical progression are poorly understood. Here, we show that in mouse models of familial motoneuron (MN) disease, SOD1 mutants specifically render vulnerable MNs dependent on endogenous neuroprotection signaling involving excitability and mammalian target of rapamycin (mTOR). The most vulnerable low-excitability FF MNs already exhibited evidence of pathology and endogenous neuroprotection recruitment early postnatally. Enhancing MN excitability promoted MN neuroprotection and reversed misfolded SOD1 (misfSOD1) accumulation and MN pathology, whereas reducing MN excitability augmented misfSOD1 accumulation and accelerated disease. Inhibiting metabotropic cholinergic signaling onto MNs reduced ER stress, but enhanced misfSOD1 accumulation and prevented mTOR activation in alpha-MNs. Modulating excitability and/or alpha-MN mTOR activity had comparable effects on the progression rates of motor dysfunction, denervation, and death. Therefore, excitability and mTOR are key endogenous neuroprotection mechanisms in motoneurons to counteract clinically important disease progression in ALS.

  8. Clinical Factors and Disease Course Related to Diagnostic Delay in Korean Crohn's Disease Patients: Results from the CONNECT Study.

    Directory of Open Access Journals (Sweden)

    Chang Mo Moon

    Full Text Available Diagnostic delay frequently occurs in Crohn's disease (CD patients because of diagnostic limitations. However, diagnostic delay and its related factors remain poorly defined. Therefore, we aimed to identify the predictors associated with diagnostic delay and to evaluate the impact of diagnostic delay on clinical course in a Korean CD patient cohort. We performed a multicenter retrospective analysis of 1,047 CD patients registered in the Crohn's Disease Clinical Network and Cohort study in Korea. The mean interval of diagnostic delay was 16.0 ± 33.1 months. Multivariate analysis showed that older age at diagnosis (≥40 years (p = 0.014, concomitant upper gastrointestinal (UGI disease (p = 0.012 and penetrating disease behavior at diagnosis (p = 0.001 were positively associated with long diagnostic delay (≥18 months. During the longitudinal follow-up, long diagnostic delay was independently predictive of further development of intestinal stenosis (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.07-1.93; p = 0.017, internal fistulas (HR, 1.62; 95% CI, 1.12-2.33; p = 0.011, and perianal fistulas (HR, 1.38; 95% CI, 1.06-1.80; p = 0.016. However, as for the risk of abscess formation, bowel perforation, and CD-related abdominal surgery, no significant association with diagnostic delay was observed. Older age at diagnosis, UGI involvement, and penetrating behavior are associated with long diagnostic delay in Korean CD patients. Moreover, diagnostic delay is associated with an increased risk of CD-related complications such as intestinal stenosis, internal fistulas, and perianal fistulas.

  9. Imaging of disease progression in a case of idiopathic moyamoya

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    A. Chacko

    2013-08-01

    Full Text Available Moyamoya is a rare cerebrovascular disease characterised by progressive stenosis of the terminal portion of the internal carotid artery and its main branches. We report on the progression of the disease in a 3-year-old boy, confirmed to have idiopathic Moyamoya disease, over 6 ensuing years, using serial magnetic resonance imaging with MR angiography. Comparison is also made with conventional angiography at the last visit. Characteristic imaging appearances of asymmetric narrowing of the internal carotid arteries (especially the supra-clinoid portion with numerous collateral vessels around the brainstem especially within the ambient and quadrigeminal plate cisterns are demonstrated with progression.

  10. Research progress of rehabilitation therapy in Parkinson's disease and its mechanism

    Directory of Open Access Journals (Sweden)

    Jin LIU

    2017-07-01

    Full Text Available Parkinson's disease (PD is characterized by the progressive degeneration of dopaminergic neurons in substantia nigra pars compacta. Rehabilitation therapy can delay the development of disease, improve motor symptoms and non - motor symptoms (NMS, and consequently improve the activities of daily living (ADL in patients with PD. The mechanism of rehabilitation improving the symptoms of PD is very complex, involving a variety of molecular mechanisms. Thus, this review will focus on the effect of rehabilitation therapy on PD and the underlying molecular mechanism including neurotransmitters, trophic factors, synaptic plasticity and immune system. DOI: 10.3969/j.issn.1672-6731.2017.06.003

  11. Stopping rules employing response rates, time to progression, and early progressive disease for phase II oncology trials

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    Goffin John R

    2011-12-01

    Full Text Available Abstract Background Response rate (RR, the most common early means of assessing oncology drugs, is not suitable as the sole endpoint for phase II trials of drugs which induce disease stability but not regression. Time to progression (TTP may be more sensitive to such agents, but induces recruitment delays in multistage studies. Early progressive disease (EPD is the earliest signal of time to progression, but is less intuitive to investigators, To study drugs with unknown anti-tumour effect, we designed the Combination Stopping Rule (CSR, which allows investigators to establish a hypothesis using RR and TTP, while the program also employs early progressive disease (EPD to assess for drug inactivity during the first stage of study accrual. Methods A computer program was created to generate stopping rules based on specified error rates, trial size, and RR and median TTP of interest and disinterest for a two-stage phase II trial. Rules were generated for stage II such that the null hypothesis (Hnul was rejected if either RR or TTP met desired thresholds, and accepted if both did not. Assuming an exponential distribution for progression, EPD thresholds were determined based on specified TTP values. Stopping rules were generated for stage I such that Hnul was accepted and the study stopped if both RR and EPD were unacceptable. Results Patient thresholds were generated for RR, median TTP, and EPD which achieved specified error rates and which allowed early stopping based on RR and EPD. For smaller proportional differences between interesting and disinteresting values of RR or TTP, larger trials are required to maintain alpha error, and early stopping is more common with a larger first stage. Conclusion Stopping rules are provided for phase II trials for drugs which have either a desirable RR or TTP. In addition, early stopping can be achieved using RR and EPD.

  12. Proteinuria and progression in glomerular diseases

    NARCIS (Netherlands)

    Branten, Amanda Johanna Wilhelmina

    2005-01-01

    Proteinuria is a strong predictor of progressive renal insufficiency. The precise mechanisms to explain this relationship are still unknown, although many experimental studies have shown that proteinuria may induce tubulo-interstitial injury. Many investigators have observed that tubulo-interstitial

  13. Recent progress of PET in Alzheimer's disease

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    Na NIU

    2014-03-01

    Full Text Available Alzheimer's disease is the most common cause of dementia in the current elderly population. PET can detect pathophysiological changes in Alzheimer's disease with different radiotracers. This paper will focus on evaluating the value of 18F-FDG, amyloid and tau protein PET imaging in Alzheimer's disease. PET has been demonstrated to play an important role in the research of etiology, early diagnosis, differential dignosis, prognosis and medical treatment of Alzheimer's disease. doi: 10.3969/j.issn.1672-6731.2014.03.007

  14. Progress and Challenges in Infectious Disease Cartography.

    Science.gov (United States)

    Kraemer, Moritz U G; Hay, Simon I; Pigott, David M; Smith, David L; Wint, G R William; Golding, Nick

    2016-01-01

    Quantitatively mapping the spatial distributions of infectious diseases is key to both investigating their epidemiology and identifying populations at risk of infection. Important advances in data quality and methodologies have allowed for better investigation of disease risk and its association with environmental factors. However, incorporating dynamic human behavioural processes in disease mapping remains challenging. For example, connectivity among human populations, a key driver of pathogen dispersal, has increased sharply over the past century, along with the availability of data derived from mobile phones and other dynamic data sources. Future work must be targeted towards the rapid updating and dissemination of appropriately designed disease maps to guide the public health community in reducing the global burden of infectious disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. A novel approach to delayed-start analyses for demonstrating disease-modifying effects in Alzheimer's disease.

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    Hong Liu-Seifert

    Full Text Available One method for demonstrating disease modification is a delayed-start design, consisting of a placebo-controlled period followed by a delayed-start period wherein all patients receive active treatment. To address methodological issues in previous delayed-start approaches, we propose a new method that is robust across conditions of drug effect, discontinuation rates, and missing data mechanisms. We propose a modeling approach and test procedure to test the hypothesis of noninferiority, comparing the treatment difference at the end of the delayed-start period with that at the end of the placebo-controlled period. We conducted simulations to identify the optimal noninferiority testing procedure to ensure the method was robust across scenarios and assumptions, and to evaluate the appropriate modeling approach for analyzing the delayed-start period. We then applied this methodology to Phase 3 solanezumab clinical trial data for mild Alzheimer's disease patients. Simulation results showed a testing procedure using a proportional noninferiority margin was robust for detecting disease-modifying effects; conditions of high and moderate discontinuations; and with various missing data mechanisms. Using all data from all randomized patients in a single model over both the placebo-controlled and delayed-start study periods demonstrated good statistical performance. In analysis of solanezumab data using this methodology, the noninferiority criterion was met, indicating the treatment difference at the end of the placebo-controlled studies was preserved at the end of the delayed-start period within a pre-defined margin. The proposed noninferiority method for delayed-start analysis controls Type I error rate well and addresses many challenges posed by previous approaches. Delayed-start studies employing the proposed analysis approach could be used to provide evidence of a disease-modifying effect. This method has been communicated with FDA and has been

  16. Gallstone disease is associated with arterial stiffness progression.

    Science.gov (United States)

    Yu, Kai-Jing; Zhang, Ji-Rong; Li, Ying; Huang, Xiaoyi; Liu, Tiemin; Li, Chuanfu; Wang, Rui-Tao

    2017-01-01

    Gallstones have been linked to dyslipidemia, metabolic syndrome and cardiovascular disease. Arterial stiffness is an indicator of subclinical atherosclerosis. The aim of this study was to prospectively examine the relationship between gallstone disease and arterial stiffness progression in 347 men and 454 women. These subjects were followed for 7 years. Arterial stiffness progression was measured based on increases in brachial-ankle pulse wave velocity. Changes in brachial-ankle pulse wave velocity during the study period were significantly greater in patients with gallstones than in subjects without gallstones. After adjusting for multiple risk factors, gallstone disease was found to be a significant and independent predictor of brachial-ankle pulse wave velocity progression (β=0.189; Pgallstone disease is an independent predictor of arterial stiffness progression, even after adjusting for other cardiovascular risk factors.

  17. A prediction model for progressive disease in systemic sclerosis

    Science.gov (United States)

    Meijs, Jessica; Schouffoer, Anne A; Ajmone Marsan, Nina; Stijnen, Theo; Putter, Hein; Ninaber, Maarten K; Huizinga, Tom W J; de Vries-Bouwstra, Jeska K

    2015-01-01

    Objective To develop a model that assesses the risk for progressive disease in patients with systemic sclerosis (SSc) over the short term, in order to guide clinical management. Methods Baseline characteristics and 1 year follow-up results of 163 patients with SSc referred to a multidisciplinary healthcare programme were evaluated. Progressive disease was defined as: death, ≥10% decrease in forced vital capacity, ≥15% decrease in diffusing capacity for carbon monoxide, ≥10% decrease in body weight, ≥30% decrease in estimated-glomerular filtration rate, ≥30% increase in modified Rodnan Skin Score (with Δ≥5) or ≥0.25 increase in Scleroderma Health Assessment Questionnaire. The number of patients with progressive disease was determined. Univariable and multivariable logistic regression analyses were used to assess the probability of progressive disease for each individual patient. Performance of the prediction model was evaluated using a calibration plot and area under the receiver operating characteristic curve. Results 63 patients had progressive disease, including 8 patients who died ≤18 months after first evaluation. Multivariable analysis showed that friction rubs, proximal muscular weakness and decreased maximum oxygen uptake as % predicted, adjusted for age, gender and use of immunosuppressive therapy at baseline, were significantly associated with progressive disease. Using the prediction model, the predicted chance for progressive disease increased from a pretest chance of 37% to 67–89%. Conclusions Using the prediction model, the chance for progressive disease for individual patients could be doubled. Friction rubs, proximal muscular weakness and maximum oxygen uptake as % predicted were identified as relevant parameters. PMID:26688749

  18. Traveling Wave Solutions for a Delayed SIRS Infectious Disease Model with Nonlocal Diffusion and Nonlinear Incidence

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    Xiaohong Tian

    2014-01-01

    Full Text Available A delayed SIRS infectious disease model with nonlocal diffusion and nonlinear incidence is investigated. By constructing a pair of upper-lower solutions and using Schauder's fixed point theorem, we derive the existence of a traveling wave solution connecting the disease-free steady state and the endemic steady state.

  19. Neutralization of interleukin-17A delays progression of silica-induced lung inflammation and fibrosis in C57BL/6 mice

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ying; Li, Cuiying [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China); Weng, Dong [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China); Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai (China); Song, Laiyu; Tang, Wen; Dai, Wujing; Yu, Ye; Liu, Fangwei; Zhao, Ming; Lu, Chunwei [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China); Chen, Jie, E-mail: chenjie@mail.cmu.edu.cn [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China)

    2014-02-15

    Silica exposure can cause lung inflammation and fibrosis, known as silicosis. Interleukin-17A (IL-17A) and Th17 cells play a pivotal role in controlling inflammatory diseases. However, the roles of IL-17A and Th17 cells in the progress of silica-induced inflammation and fibrosis are poorly understood. This study explored the effects of IL-17A on silica-induced inflammation and fibrosis. We used an anti-mouse IL-17A antibody to establish an IL-17A-neutralized mice model, and mice were exposed to silica to establish an experimental silicosis model. We showed that IL-17A neutralization delayed neutrophil accumulation and progression of silica-induced lung inflammation and fibrosis. IL-17A neutralization reduced the percentage of Th17 in CD4 + T cells, decreased IL-6 and IL-1β expression, and increased Tregs at an early phase of silica-induced inflammation. Neutralization of IL-17A delayed silica-induced Th1/Th2 immune and autoimmune responses. These results suggest that IL-17A neutralization alleviates early stage silica-induced lung inflammation and delays progression of silica-induced lung inflammation and fibrosis. Neutralization of IL-17A suppressed Th17 cell development by decreasing IL-6 and/or IL-1β and increased Tregs at an early phase of silica-induced inflammation. Neutralization of IL-17A also delayed the Th1/Th2 immune response during silica-induced lung inflammation and fibrosis. IL-17A may play a pivotal role in the early phase of silica-induced inflammation and may mediate the Th immune response to influence silica-induced lung inflammation and fibrosis in mice. - Highlights: • Neutralization of IL-17A alleviated silica-induced lung inflammation of early stage. • Neutralization of IL-17A decreased Th17 cells and increased Tregs. • IL-17A mediated the reciprocal relationship of Th17/Tregs by IL-6 and/or IL-1β. • Neutralization of IL-17A delayed silica-induced Th1/Th2 immune response. • Neutralization of IL-17A delayed silica-induced lung

  20. Nortriptyline推迟Huntington病小鼠的发病%NORTRIPTYLINE DELAYS DISEASE ONSET IN HUNTINGTON'S DISEASE MICE

    Institute of Scientific and Technical Information of China (English)

    管英俊; 于丽; 高海玲; 岳炳德; 马丽; 陈燕春; 赵春艳; 王红雁; Robert M.Friedlander

    2006-01-01

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disease. A cardinal histopathologic feature of HD is the progressive loss of striatal medium spiny neurons. As there is no effective treatment for this fatal disease so far, we explore the therapeutic potential of nortriptyline to identify drugs that might be effective treatments for HD. N548mu [ 1955-128] huntingtin stable ST14A cell line was cultured and incubated in the presence or absence of serial concentrations of nortriptyline. Then R6/2 transgenic HD mice were treated with nortriptyline from five to twenty-one weeks of age. Nortriptyline protected striatal cells expressing mutant huntingtin when shifted to a nonpermissive temperature. Nortriptyline delay the disease onset to 127 d in R6/2 mice as compared with 102 d in saline-treated controls, but nortriptyline did not significantly delay mortality. As a gross marker of lack of systemic toxicity, there was no significant difference in the weight of the treated and control R6/2 mice. The results demonstrate that clinically reasonable doses of one of the identified drugs, nortriptyline, delays disease onset in a mouse model of the disease more than any previously identified compound. The most desirable features of a drug for HD are minimal toxicity and the ability to extend symptom-free living. Nortriptyline appears to be one such good candidate.%Huntington病(HD)是一种常染色体显性遗传性神经退行性疾病,主要组织病理学特征是纹状体运动神经元进行性死亡,目前尚无有效治疗方法,本实验探讨了nortriptyline(去甲替林)的潜在疗效.采用N548mu[1955-128]huntingtin ST14A细胞系进行体外培养,观察不同浓度nortriptyline对细胞存活的影响.选用R6/2转基因鼠,从第5周开始每天腹腔注射nortriptyline,直至21周,对照组腹腔注射与nortriptyline组等剂量的生理盐水.结果发现,nortriptyline对移入不同温度环境的ST14A细胞

  1. A case of delayed hemolytic transfusion reaction in sickle cell disease patient

    Science.gov (United States)

    Dogra, Ashu; Sidhu, Meena

    2016-01-01

    Sickle cell disease (SCD) is autosomal recessive, genetically transmitted hemoglobinopathy responsible for considerable morbidity and mortality. It is prevalent in many parts of India including Central India, where the prevalence in different communities has ranged from 9.4% to 22%. Perioperative management may include transfusion of red blood cells. Hemolytic transfusion reactions can occur, and these can be either acute or delayed. We present a case of delayed hemolytic transfusion reaction in a patient with SCD. PMID:27605854

  2. Zinc delays the progression of obesity-related glomerulopathy in mice via down-regulating P38 MAPK-mediated inflammation.

    Science.gov (United States)

    Luo, Manyu; Luo, Ping; Zhang, Zhiguo; Payne, Kristen; Watson, Sara; Wu, Hao; Tan, Yi; Ding, Yushuang; Sun, Weixia; Yin, Xinmin; Zhang, Xiang; Liu, Gilbert; Wintergerst, Kupper; Miao, Lining; Cai, Lu

    2016-06-01

    Obesity, particularly child obesity, is one of the most common public health problems in the world and raises the risk of end-stage renal disease. Zinc (Zn) is essential for multiple organs in terms of normal structure and function; however, effects of Zn deficiency or supplementation among young individuals with obesity have not been well studied. Weaned mice were fed high-fat diets (HFD) with varied contents of Zn (Zn deficient, adequate, and supplemented) for 3 or 6 months. This study examined associations between renal pathogenesis and dietary Zn levels, specifically assessing inflammatory pathways by utilizing P38 MAPK inhibitor SB203580. HFD feeding induced typical syndromes of obesity-related renal disorders, which worsened by Zn marginal deficiency. The progression of obesity-related renal disorders was delayed by Zn supplementation. HFD induced renal inflammation, reflected by increased P38 MAPK phosphorylation along with increases of inflammatory cytokines MCP-1, IL-1β, IL-6, and TNF-α. P38 MAPK inhibition prevented renal pathological changes in mice fed with HFD and HFD/Zn deficiency. P38 MAPK mediated the renal inflammatory responses, which played a central role in the pathogenesis of HFD-induced renal disorders. Zn could delay the progression of obesity-related kidney disease by down-regulating P38 MAPK-mediated inflammation. © 2016 The Obesity Society.

  3. Modeling screening, prevention, and delaying of Alzheimer's disease: an early-stage decision analytic model

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    Siemers Eric R

    2010-04-01

    Full Text Available Abstract Background Alzheimer's Disease (AD affects a growing proportion of the population each year. Novel therapies on the horizon may slow the progress of AD symptoms and avoid cases altogether. Initiating treatment for the underlying pathology of AD would ideally be based on biomarker screening tools identifying pre-symptomatic individuals. Early-stage modeling provides estimates of potential outcomes and informs policy development. Methods A time-to-event (TTE simulation provided estimates of screening asymptomatic patients in the general population age ≥55 and treatment impact on the number of patients reaching AD. Patients were followed from AD screen until all-cause death. Baseline sensitivity and specificity were 0.87 and 0.78, with treatment on positive screen. Treatment slowed progression by 50%. Events were scheduled using literature-based age-dependent incidences of AD and death. Results The base case results indicated increased AD free years (AD-FYs through delays in onset and a reduction of 20 AD cases per 1000 screened individuals. Patients completely avoiding AD accounted for 61% of the incremental AD-FYs gained. Total years of treatment per 1000 screened patients was 2,611. The number-needed-to-screen was 51 and the number-needed-to-treat was 12 to avoid one case of AD. One-way sensitivity analysis indicated that duration of screening sensitivity and rescreen interval impact AD-FYs the most. A two-way sensitivity analysis found that for a test with an extended duration of sensitivity (15 years the number of AD cases avoided was 6,000-7,000 cases for a test with higher sensitivity and specificity (0.90,0.90. Conclusions This study yielded valuable parameter range estimates at an early stage in the study of screening for AD. Analysis identified duration of screening sensitivity as a key variable that may be unavailable from clinical trials.

  4. Delay in Diagnosis of Celiac Disease in Patients Without Gastrointestinal Complaints.

    Science.gov (United States)

    Paez, Marco A; Gramelspacher, Anna Maria; Sinacore, James; Winterfield, Laura; Venu, Mukund

    2017-06-13

    The purpose of our study is to investigate the delay in diagnosis of patients with biopsy-proven celiac disease in those who present with gastrointestinal complaints vs nongastrointestinal complaints at our tertiary care center. Celiac disease is an autoimmune disorder that affects approximately 1% of the population worldwide. Celiac disease can have variable clinical presentations; it can be characterized by predominately gastrointestinal symptoms, or it may present without any gastrointestinal symptoms. We retrospectively reviewed the charts of 687 adult patients who carried the diagnosis of celiac disease. Patients included had biopsy-proven celiac disease and were categorized based on presence or absence of gastrointestinal symptoms prior to their diagnosis. There were 101 patients with biopsy-proven celiac disease that met inclusion criteria. Fifty-two patients presented with gastrointestinal symptoms and 49 had nongastrointestinal complaints. Results from Mann-Whitney statistical analysis showed a median delay in diagnosis of 2.3 months for the gastrointestinal symptoms group and 42 months for the nongastrointestinal group (P celiac disease, the delay in diagnosis for patients without gastrointestinal symptoms remains prolonged, with an average delay of 3.5 years. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Human folliculin delays cell cycle progression through late S and G2/M-phases: effect of phosphorylation and tumor associated mutations.

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    Laura A Laviolette

    Full Text Available The Birt-Hogg-Dube disease occurs as a result of germline mutations in the human Folliculin gene (FLCN, and is characterized by clinical features including fibrofolliculomas, lung cysts and multifocal renal neoplasia. Clinical and genetic evidence suggest that FLCN acts as a tumor suppressor gene. The human cell line UOK257, derived from the renal cell carcinoma of a patient with a germline mutation in the FLCN gene, harbors a truncated version of the FLCN protein. Reconstitution of the wild type FLCN protein into UOK257 cells delays cell cycle progression, due to a slower progression through the late S and G2/M-phases. Similarly, Flcn (-/- mouse embryonic fibroblasts progress more rapidly through the cell cycle than wild type controls (Flcn (flox/flox. The reintroduction of tumor-associated FLCN mutants (FLCN ΔF157, FLCN 1-469 or FLCN K508R fails to delay cell cycle progression in UOK257 cells. Additionally, FLCN phosphorylation (on Serines 62 and 73 fluctuates throughout the cell cycle and peaks during the G2/M phase in cells treated with nocodazole. In keeping with this observation, the reintroduction of a FLCN phosphomimetic mutant into the UOK257 cell line results in faster progression through the cell cycle compared to those expressing the wild type FLCN protein. These findings suggest that the tumor suppression function of FLCN may be linked to its impact on the cell cycle and that FLCN phosphorylation is important for this activity. Additionally, these observations describe a novel in vitro assay for testing the functional significance of FLCN mutations and/or genetic polymorphisms.

  6. Delayed diagnosis of coeliac disease increases cancer risk

    Directory of Open Access Journals (Sweden)

    Di Benedetto Rita

    2007-03-01

    Full Text Available Abstract Background The association between coeliac disease (CD and neoplasms has been long established, but few data are available about the risk factors. The aim of this paper is to estimate the risk of developing a neoplasm among non diagnosed coeliac patients and to evaluate if this risk correlates with the age of patients at diagnosis of coeliac disease. Methods The study population consists of patients (n = 1968 diagnosed with CD at 20 Italian gastroenterology referral Centers between 1st January 1982 and 31st March 2005. Results The SIR for all cancers resulted to be 1.3; 95% CI = 1.0–1.7 p Conclusion Coeliac patients have an increased risk of developing cancer in relation to the age of diagnosis of CD. This risk results higher for malignancies of the gastro-intestinal sites. An accurate screening for tumors should be performed in patients diagnosed with CD in adulthood and in advancing age.

  7. Calprotectin as a biomarker for melioidosis disease progression and management

    Science.gov (United States)

    2017-04-03

    1 Calprotectin as a biomarker for melioidosis disease progression and management 1 2 Mohan Natesana, Enoka Coread, Shivankari...linked to therapeutic responses to 36 antibiotics. Our results indicate that calprotectin may be a sensitive indicator of melioidosis disease 37... hospitalization (5). Patient 52 monitoring is essential, and clinical evaluations along with blood cultures are the only tools that are 53 currently used

  8. Central Blood Pressure and Chronic Kidney Disease Progression

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    Debbie L. Cohen

    2011-01-01

    Full Text Available Hypertension, diabetes, and proteinuria are well-recognized risk factors for progressive kidney function loss. However, despite excellent antihypertensive and antidiabetic drug therapies, which also often lower urinary protein excretion, there remains a significant reservoir of patients with chronic kidney disease who are at high risk for progression to end-stage kidney disease. This has led to the search for less traditional cardiovascular risk factors that will help stratify patients at risk for more rapid kidney disease progression. Among these are noninvasive estimates of vascular structure and function. Arterial stiffness, manifested by the pulse wave velocity in the aorta, has been established in a number of studies as a significant risk factor for kidney disease progression and cardiovascular endpoints. Much less well studied in chronic kidney disease are measures of central arterial pressures. In this paper we cover the physiology behind the generation of the central pulse wave contour and the studies available using these approaches and conclude with some speculations on the rationale for why measurements of central pressure may be informative for the study of chronic kidney disease progression.

  9. Effects of a formal exercise program on Parkinson's disease: a pilot study using a delayed start design.

    Science.gov (United States)

    Park, A; Zid, D; Russell, J; Malone, A; Rendon, A; Wehr, A; Li, X

    2014-01-01

    Parkinson's Disease (PD) is a progressive neurodegenerative disease. Increasing evidence shows that physical exercise is beneficial for motor and non-motor symptoms of PD, and animal models suggest that it may help slow progression of disease. Using a randomized delayed-start design, 31 patients were randomized to an early start group (ESG) or a delayed start group (DSG) exercise program. The ESG underwent a rigorous formal group exercise program for 1 h, three days/week, for 48 weeks (November 2011-October 2012). The DSG participated in this identical exercise program from weeks 24-48. Outcome measures included the Unified Parkinson's Disease Rating Scale (UPDRS), Walking Test (get-up-and-go), Tinetti Mobility Test, PDQ-39 Questionnaire, and the Beck Depression Inventory. There was minimal attrition in this study, with only one patient dropping out. Results did not show improvement in total UPDRS scores with early exercise. At week 48, the mean change from baseline total UPDRS score was 6.33 in the ESG versus 5.13 in the DSG (p = 0.58). However, patients randomized to the ESG scored significantly better on the Beck Depression Inventory, with a mean improvement of 1.07 points relative to those in the DSG (p = 0.04). The findings demonstrate that long-term, group exercise programs are feasible in the Parkinson's disease population, with excellent adherence and minimal drop out. While the outcome measures used in our study did not provide strong evidence that exercise has a neuroprotective effect on motor function, earlier participation in a group exercise program had a significant effect on symptoms of depression. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Effects of a formal exercise program on Parkinson’s disease: A pilot study using a delayed start design

    Science.gov (United States)

    Park, A.; Zid, D.; Russell, J.; Malone, A.; Rendon, A.; Wehr, A.; Li, X.

    2014-01-01

    Introduction Parkinson’s Disease (PD) is a progressive neurodegenerative disease. Increasing evidence shows that physical exercise is beneficial for motor and non-motor symptoms of PD, and animal models suggest that it may help slow progression of disease. Methods Using a randomized delayed-start design, 31 patients were randomized to an early start group (ESG) or a delayed start group (DSG) exercise program. The ESG underwent a rigorous formal group exercise program for 1 h, three days/week, for 48 weeks (November 2011–October 2012). The DSG participated in this identical exercise program from weeks 24–48. Outcome measures included the Unified Parkinson’s Disease Rating Scale (UPDRS), Walking Test (get-up-and-go), Tinetti Mobility Test, PDQ-39 Questionnaire, and the Beck Depression Inventory. Results There was minimal attrition in this study, with only one patient dropping out. Results did not show improvement in total UPDRS scores with early exercise. At week 48, the mean change from baseline total UPDRS score was 6.33 in the ESG versus 5.13 in the DSG (p = 0.58). However, patients randomized to the ESG scored significantly better on the Beck Depression Inventory, with a mean improvement of 1.07 points relative to those in the DSG (p = 0.04). Conclusions The findings demonstrate that long-term, group exercise programs are feasible in the Parkinson’s disease population, with excellent adherence and minimal drop out. While the outcome measures used in our study did not provide strong evidence that exercise has a neuroprotective effect on motor function, earlier participation in a group exercise program had a significant effect on symptoms of depression. PMID:24209458

  11. Inflammatory Bowel Disease: Progress Towards a Gene

    Directory of Open Access Journals (Sweden)

    David A van Heel

    2000-01-01

    Full Text Available The pathogenesis of ulcerative colitis (UC and Crohn’s disease (CD is still unknown, but the importance of genetic susceptibility has been clearly shown by epidemiological data from family and twin studies. Linkage studies have identified two susceptibility loci for inflammatory bowel disease (IBD on chromosomes 12 and 16. Importantly, these linkages have been replicated by independent investigators, and studies of positional candidates within these regions continue, together with fine mapping strategies. Regions of ’suggestive’ linkage on chromosomes 1, 3, 4, 6, 7, 10, 22 and X have also been reported in individual studies. Other important candidate genes investigated include the interleukin-1 receptor antagonist, MUC3 and genes of the human leukocyte antigen (HLA system. The apparently conflicting data in different studies from around the world may be explained by ethnic differences, case mix and genetic heterogeneity. Replicated class II HLA associations include HLA DRB1*0103 and DR2 (DRB1*1502, involved in UC susceptibility, and HLA DRB1*03 and DR4 as resistance alleles for CD and UC respectively. Animal studies have provided insights from targeted mutations and quantitative trait locus analysis. The goals of continuing research include narrowing the regions of linkages and analysis of candidate genes, and possibly the application of newly developed methods using single nucleotide polymorphisms. Advances in IBD genetics hold the potential to provide knowledge about the disease pathogenesis at the molecular level, with ensuing benefits for clinical practice.

  12. Atypical presentation of Creutzfeldt-Jakob disease: a rare but important cause of rapidly progressive dementia.

    Science.gov (United States)

    Taillefer, Marguerite S; Tangarorang, Glendo L; Kuchel, George A; Menkes, Daniel L

    2011-09-01

    We report an atypical presentation of sporadic Creutzfeldt-Jakob disease (CJD) in a 74-year-old woman that illustrates the difficulty in diagnosing this rare, but important, cause of rapidly progressive dementia. Despite well-established criteria, this diagnosis is often missed or substantially delayed (Table 1). In this case, a precipitous cognitive decline associated with a urinary tract infection initiallysuggested delirium. Although atypical CJD was considered as a cause when symptoms persisted, a definitive diagnosis was established postmortem when the cerebrospinal fluid (CSF) prion protein 14-3-3 tested positive. Creutzfeldt-Jakob disease must be considered in the differential diagnosis of rapidly progressive dementia as Connecticut accounts for approximately three of the more than 200 cases diagnosed nationally.

  13. Progress in spondylarthritis immunopathogenesis of spondyloarthritis: which cells drive disease?

    OpenAIRE

    2009-01-01

    Spondyloarthritides, or SpA, form a cluster of chronic inflammatory diseases with the axial skeleton as the most typical disease localisation, although extra-articular manifestations such as intestinal inflammation may frequently occur during the course of the disease. This review summarises recent progress in our understanding of the immunopathogenesis of SpA with special emphasis on the cellular constituents considered to be responsible for the initiation and/or perpetuation of inflammation...

  14. Research progress on the red cell diseases in China

    Institute of Scientific and Technical Information of China (English)

    YUE Lan-zhu; SHAO Zong-hong

    2012-01-01

    In recent years,there have been lots of progresses in the studies on red cell diseases in China,especially bone marrow failure diseases including immune-related pancytopenia,aplastic anemia,myelodysplastic syndrome,and paroxymal nocturnal hemoglobinuria.Numerous laboratory experiments as well as clinical researches have been carried out by Chinese hematologists,which brought about much clearer pathogenesis,more rational diagnosis methods and more effective therapies for red cell diseases.

  15. Clinical features and predictors for disease natural progression in adults with Pompe disease: a nationwide prospective observational study

    Directory of Open Access Journals (Sweden)

    van der Beek Nadine AME

    2012-11-01

    Full Text Available Abstract Background Due partly to physicians’ unawareness, many adults with Pompe disease are diagnosed with great delay. Besides, it is not well known which factors influence the rate of disease progression, and thus disease outcome. We delineated the specific clinical features of Pompe disease in adults, and mapped out the distribution and severity of muscle weakness, and the sequence of involvement of the individual muscle groups. Furthermore, we defined the natural disease course and identified prognostic factors for disease progression. Methods We conducted a single-center, prospective, observational study. Muscle strength (manual muscle testing, and hand-held dynamometry, muscle function (quick motor function test, and pulmonary function (forced vital capacity in sitting and supine positions were assessed every 3–6 months and analyzed using repeated-measures ANOVA. Results Between October 2004 and August 2009, 94 patients aged between 25 and 75 years were included in the study. Although skeletal muscle weakness was typically distributed in a limb-girdle pattern, many patients had unfamiliar features such as ptosis (23%, bulbar weakness (28%, and scapular winging (33%. During follow-up (average 1.6 years, range 0.5-4.2 years, skeletal muscle strength deteriorated significantly (mean declines of −1.3% point/year for manual muscle testing and of −2.6% points/year for hand-held dynamometry; both p15 years and pulmonary involvement (forced vital capacity in sitting position Conclusions Recognizing patterns of common and less familiar characteristics in adults with Pompe disease facilitates timely diagnosis. Longer disease duration and reduced pulmonary function stand out as predictors of rapid disease progression, and aid in deciding whether to initiate enzyme replacement therapy, or when.

  16. [Progression and stagnation of periodontal disease].

    Science.gov (United States)

    Sally, K

    1990-05-01

    Local factors may contribute to acute exacerbations of the periodontal disease, however, their pathological basis is systemically established. The more bacteria and bacterial products get into the periodontal tissue the more serious is destruction. Host's resistance controls composition of the subepithelial bacterial flora. Under condition of defective phagocyte function bacteria, otherwise occurring rarely in the pocket, multiply quickly and penetrate the periodontal pocket epithelium. Specific immune defence can stop them only in the subepithelial conjunctive tissue causing its destruction. Juvenile periodontitis goes with defects of granulocyte function and an aggressive pocket flora. These patients need antibiotics taken systematically, removing of the infected pocket epithelium and regular recalls. Care of patients with adult periodontitis is limited to good oral hygiene.

  17. Motor Asymmetry and Substantia Nigra Volume Are Related to Spatial Delayed Response Performance in Parkinson Disease

    Science.gov (United States)

    Foster, Erin R.; Black, Kevin J.; Antenor-Dorsey, Jo Ann V.; Perlmutter, Joel S.; Hershey, Tamara

    2008-01-01

    Studies suggest motor deficit asymmetry may help predict the pattern of cognitive impairment in individuals with Parkinson disease (PD). We tested this hypothesis using a highly validated and sensitive spatial memory task, spatial delayed response (SDR), and clinical and neuroimaging measures of PD asymmetry. We predicted SDR performance would be…

  18. Effect of Presentation Modality on Immediate and Delayed Recall in Individuals with Alzheimer's Disease

    Science.gov (United States)

    Mahendra, Nidhi; Bayles, Kathryn A.; Harris, Frances P.

    2005-01-01

    Episodic memory (EM) deficits are the hall-mark of Alzheimer's disease (AD). Story-retelling tasks are particularly sensitive to EM impairments and require participants to recall a short story immediately and after a delay. The purpose of this study was to determine whether presentation modality influences story recall in AD participants. Thirty…

  19. Primary progressive multiple sclerosis: part of the MS disease spectrum or separate disease entity?

    Science.gov (United States)

    Antel, Jack; Antel, Samson; Caramanos, Zografos; Arnold, Douglas L; Kuhlmann, Tanja

    2012-05-01

    Multiple sclerosis (MS), the most frequent demyelinating disease, is characterized by a variable disease course. The majority of patients starts with relapsing remitting (RR) disease; approximately 50-60% of these patients progress to secondary progressive (SP) disease. Only about 15% of the patients develop a progressive disease course from onset, termed primary progressive multiple sclerosis (PPMS); the underlying pathogenic mechanisms responsible for onset of the disease with either PPMS or relapsing remitting multiple sclerosis (RRMS) are unknown. Patients with PPMS do not show a female predominance and usually have a later onset of disease compared to patients with RRMS. Monozygous twins can be concordant or discordant for disease courses indicating that the disease course is not only genetically determined. Primary progressive multiple sclerosis and secondary progressive multiple sclerosis (SPMS) share many similarities in imaging and pathological findings. Differences observed among the different disease courses are more of a quantitative than qualitative nature suggesting that the different phenotypes are part of a disease spectrum modulated by individual genetic predisposition and environmental influences. In this review, we summarize the knowledge regarding the clinical, epidemiological, imaging, and pathological characteristics of PPMS and compare those characteristics with RRMS and SPMS.

  20. State of progress in treating cystic fibrosis respiratory disease

    Directory of Open Access Journals (Sweden)

    Flume Patrick A

    2012-08-01

    Full Text Available Abstract Since the discovery of the gene associated with cystic fibrosis (CF, there has been tremendous progress in the care of patients with this disease. New therapies have entered the market and are part of the standard treatment of patients with CF, and have been associated with marked improvement in survival. Now there are even more promising therapies directed at different components of the pathophysiology of this disease. In this review, our current knowledge of the pathophysiology of lung disease in patients with CF is described, along with the current treatment of CF lung disease, and the therapies in development that offer great promise to our patients.

  1. Accuracy Improvement for Predicting Parkinson’s Disease Progression

    Science.gov (United States)

    Nilashi, Mehrbakhsh; Ibrahim, Othman; Ahani, Ali

    2016-01-01

    Parkinson’s disease (PD) is a member of a larger group of neuromotor diseases marked by the progressive death of dopamineproducing cells in the brain. Providing computational tools for Parkinson disease using a set of data that contains medical information is very desirable for alleviating the symptoms that can help the amount of people who want to discover the risk of disease at an early stage. This paper proposes a new hybrid intelligent system for the prediction of PD progression using noise removal, clustering and prediction methods. Principal Component Analysis (PCA) and Expectation Maximization (EM) are respectively employed to address the multi-collinearity problems in the experimental datasets and clustering the data. We then apply Adaptive Neuro-Fuzzy Inference System (ANFIS) and Support Vector Regression (SVR) for prediction of PD progression. Experimental results on public Parkinson’s datasets show that the proposed method remarkably improves the accuracy of prediction of PD progression. The hybrid intelligent system can assist medical practitioners in the healthcare practice for early detection of Parkinson disease. PMID:27686748

  2. Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis?

    DEFF Research Database (Denmark)

    Dalgas, Ulrik; Stenager, Egon

    2012-01-01

    It has been suggested that exercise (or physical activity) might have the potential to have an impact on multiple sclerosis (MS) pathology and thereby slow down the disease process in MS patients. The objective of this literature review was to identify the literature linking physical exercise (or...... activity) and MS disease progression. A systematic literature search was conducted in the following databases: PubMed, SweMed+, Embase, Cochrane Library, PEDro, SPORTDiscus and ISI Web of Science. Different methodological approaches to the problem have been applied including (1) longitudinal exercise......, (4) longitudinal exercise studies applying the experimental autoimmune encephalomyelitis (EAE) animal model of MS. Data from intervention studies evaluating disease progression by clinical measures (1) do not support a disease-modifying effect of exercise; however, MRI data (2), patient-reported data...

  3. Complement Biomarkers as Predictors of Disease Progression in Alzheimer's Disease.

    Science.gov (United States)

    Hakobyan, Svetlana; Harding, Katharine; Aiyaz, Mohammed; Hye, Abdul; Dobson, Richard; Baird, Alison; Liu, Benjamine; Harris, Claire Louise; Lovestone, Simon; Morgan, Bryan Paul

    2016-09-06

    There is a critical unmet need for reliable markers of disease and disease course in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). The growing appreciation of the importance of inflammation in early AD has focused attention on inflammatory biomarkers in cerebrospinal fluid or plasma; however, non-specific inflammation markers have disappointed to date. We have adopted a targeted approach, centered on an inflammatory pathway already implicated in the disease. Complement, a core system in innate immune defense and potent driver of inflammation, has been implicated in pathogenesis of AD based on a confluence of genetic, histochemical, and model data. Numerous studies have suggested that measurement of individual complement proteins or activation products in cerebrospinal fluid or plasma is useful in diagnosis, prediction, or stratification, but few have been replicated. Here we apply a novel multiplex assay to measure five complement proteins and four activation products in plasma from donors with MCI, AD, and controls. Only one complement analyte, clusterin, differed significantly between control and AD plasma (controls, 295 mg/l; AD, 388 mg/l: p converted to dementia one year later compared to non-converters; a model combining these three analytes with informative co-variables was highly predictive of conversion. The data confirm the relevance of complement biomarkers in MCI and AD and build the case for using multi-parameter models for disease prediction and stratification.

  4. Predicting Disease Progression in Scleroderma with Skin and Blood Biomarkers

    Science.gov (United States)

    2016-12-01

    98) Prescribed by ANSI Std . Z39.18 SCLERODERMA RESEARCH PROGRAM  Predicting Disease Progression in Scleroderma with Skin and Blood Biomarkers Proposal...NW, Calgary, AB T2N 4N1, Canada. 20Division of Rheumatology, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA. 21Instituto...844, 1720 2nd Ave S. Birmingham AL 35294-3408. USA qUniversity of Minnesota. Division of Rheumatic/Autoimmune Diseases. MCC 108, 420 Delaware St SE

  5. COMT Val158Met Polymorphism Modulates Huntington's Disease Progression

    Science.gov (United States)

    Rebeix, Isabelle; Dupoux, Emmanuel; Durr, Alexandra; Brice, Alexis; Charles, Perrine; Cleret de Langavant, Laurent; Youssov, Katia; Verny, Christophe; Damotte, Vincent; Azulay, Jean-Philippe; Goizet, Cyril; Simonin, Clémence; Tranchant, Christine; Maison, Patrick; Rialland, Amandine; Schmitz, David; Jacquemot, Charlotte; Fontaine, Bertrand; Bachoud-Lévi, Anne-Catherine

    2016-01-01

    Little is known about the genetic factors modulating the progression of Huntington’s disease (HD). Dopamine levels are affected in HD and modulate executive functions, the main cognitive disorder of HD. We investigated whether the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which influences dopamine (DA) degradation, affects clinical progression in HD. We carried out a prospective longitudinal multicenter study from 1994 to 2011, on 438 HD gene carriers at different stages of the disease (34 pre-manifest; 172 stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total Functional Capacity (TFC) score. We used the Unified Huntington’s Disease Rating Scale to evaluate motor, cognitive, behavioral and functional decline. We genotyped participants for COMT polymorphism (107 Met-homozygous, 114 Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also genotyped. We compared clinical progression, on each domain, between groups of COMT polymorphisms, using latent-class mixed models accounting for disease duration and number of CAG (cytosine adenine guanine) repeats. We show that HD gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism displayed slower cognitive decline. The rate of cognitive decline was greater for Met/Met homozygotes, which displayed a better maintenance of cognitive capacity in earlier stages of the disease, but had a worse performance than Val allele carriers later on. COMT polymorphism did not significantly impact functional and behavioral performance. Since COMT polymorphism influences progression in HD, it could be used for stratification in future clinical trials. Moreover, DA treatments based on the specific COMT polymorphism and adapted according to disease duration could potentially slow HD progression. PMID:27657697

  6. Vitamin D and clinical disease progression in HIV infection

    DEFF Research Database (Denmark)

    Viard, Jean-Paul; Souberbielle, Jean-Claude; Kirk, Ole

    2011-01-01

    BACKGROUND:: We examined the association between vitamin D [25(OH)D] level and disease progression in HIV infection. METHODS:: Within the EuroSIDA study, 2000 persons were randomly selected for 25(OH)D measurement in stored plasma samples closest to study entry. 25(OH)D results were stratified...

  7. Sodium intake, RAAS-blockade and progressive renal disease

    NARCIS (Netherlands)

    de Borst, Martin H; Navis, Gerjan

    2016-01-01

    Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin converting enzyme inhibitors or angiotensin receptor blockers is the current standard treatment to prevent progressive renal function loss in patients with chronic kidney disease. Yet in many patients the rena

  8. Age, CAG repeat length, and clinical progression in Huntington's disease.

    Science.gov (United States)

    Rosenblatt, Adam; Kumar, Brahma V; Mo, Alisa; Welsh, Claire S; Margolis, Russell L; Ross, Christopher A

    2012-02-01

    The objective of this study was to further explore the effect of CAG repeat length on the rate of clinical progression in patients with Huntington's disease. The dataset included records for 569 subjects followed prospectively at the Baltimore Huntington's Disease Center. Participants were seen for a mean of 7.1 visits, with a mean follow-up of 8.2 years. Subjects were evaluated using the Quantified Neurologic Examination and its Motor Impairment subscale, the Mini-Mental State Examination, and the Huntington's disease Activities of Daily Living Scale. By itself, CAG repeat length showed a statistically significant but small effect on the progression of all clinical measures. Contrary to our previous expectations, controlling for age of onset increased the correlation between CAG repeat length and progression of all variables by 69% to 159%. Graphical models further supported the idea that individuals with smaller triplet expansions experience a more gradual decline. CAG repeat length becomes an important determinant of clinical prognosis when accounting for age of onset. This suggests that the aging process itself influences clinical outcomes in Huntington's disease. Inconsistent results in prior studies examining CAG repeat length and progression may indeed reflect a lack of age adjustment.

  9. Sodium intake, RAAS-blockade and progressive renal disease

    NARCIS (Netherlands)

    de Borst, Martin H; Navis, Gerjan

    2016-01-01

    Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin converting enzyme inhibitors or angiotensin receptor blockers is the current standard treatment to prevent progressive renal function loss in patients with chronic kidney disease. Yet in many patients the rena

  10. Acetaminophen, aspirin and progression of advanced chronic kidney disease

    NARCIS (Netherlands)

    Evans, Marie; Fored, Carl Michael; Bellocco, Rino; Fitzmaurice, Garrett; Fryzek, Jon P.; McLaughlin, Joseph K.; Nyren, Olof; Elinder, Carl-Gustaf

    2009-01-01

    Background. Although many studies have investigated the possible association between analgesic use (acetaminophen and aspirin) and the development of chronic kidney disease (CKD), the effect of analgesics on the progression of established CKD of any cause has not yet been investigated. Methods. In t

  11. Acetaminophen, aspirin and progression of advanced chronic kidney disease

    NARCIS (Netherlands)

    Evans, Marie; Fored, Carl Michael; Bellocco, Rino; Fitzmaurice, Garrett; Fryzek, Jon P.; McLaughlin, Joseph K.; Nyren, Olof; Elinder, Carl-Gustaf

    2009-01-01

    Background. Although many studies have investigated the possible association between analgesic use (acetaminophen and aspirin) and the development of chronic kidney disease (CKD), the effect of analgesics on the progression of established CKD of any cause has not yet been investigated. Methods. In t

  12. Sodium intake, RAAS-blockade and progressive renal disease

    NARCIS (Netherlands)

    de Borst, Martin H; Navis, Gerjan

    Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin converting enzyme inhibitors or angiotensin receptor blockers is the current standard treatment to prevent progressive renal function loss in patients with chronic kidney disease. Yet in many patients the

  13. Exome sequencing greatly expedites the progressive research of Mendelian diseases.

    Science.gov (United States)

    Zhang, Xuejun

    2014-03-01

    The advent of whole-exome sequencing (WES) has facilitated the discovery of rare structure and functional genetic variants. Combining exome sequencing with linkage studies is one of the most efficient strategies in searching disease genes for Mendelian diseases. WES has achieved great success in the past three years for Mendelian disease genetics and has identified over 150 new Mendelian disease genes. We illustrate the workflow of exome capture and sequencing to highlight the advantages of WES. We also indicate the progress and limitations of WES that can potentially result in failure to identify disease-causing mutations in part of patients. With an affordable cost, WES is expected to become the most commonly used tool for Mendelian disease gene identification. The variants detected cumulatively from previous WES studies will be widely used in future clinical services.

  14. Peripheral Biomarkers of Parkinson's Disease Progression and Pioglitazone Effects.

    Science.gov (United States)

    Simon, David K; Simuni, Tanya; Elm, Jordan; Clark-Matott, Joanne; Graebner, Allison K; Baker, Liana; Dunlop, Susan R; Emborg, Marina; Kamp, Cornelia; Morgan, John C; Ross, G Webster; Sharma, Saloni; Ravina, Bernard

    2015-01-01

    Pioglitazone, an oral hypoglycemic agent, recently failed to show promise as a disease-modifying agent in a 44-week phase 2 placebo-controlled study in 210 Parkinson's disease (PD) subjects. We analyzed peripheral biomarkers, including leukocyte PGC-1α and target gene expression, plasma interleukin 6 (IL-6) as a marker of inflammation, and urine 8-hydroxydeoxyguanosine (8OHdG) as a marker of oxidative DNA damage. Baseline or changes from baseline in biomarker levels were not associated with the rate of progression of PD. Pioglitazone did not significantly alter biomarker levels. Other agents that more effectively target these mechanisms remain of potential interest as disease modifying therapies in PD.

  15. gems: An R Package for Simulating from Disease Progression Models

    Directory of Open Access Journals (Sweden)

    Nello Blaser

    2015-03-01

    Full Text Available Mathematical models of disease progression predict disease outcomes and are useful epidemiological tools for planners and evaluators of health interventions. The R package gems is a tool that simulates disease progression in patients and predicts the effect of different interventions on patient outcome. Disease progression is represented by a series of events (e.g., diagnosis, treatment and death, displayed in a directed acyclic graph. The vertices correspond to disease states and the directed edges represent events. The package gems allows simulations based on a generalized multistate model that can be described by a directed acyclic graph with continuous transition-specific hazard functions. The user can specify an arbitrary hazard function and its parameters. The model includes parameter uncertainty, does not need to be a Markov model, and may take the history of previous events into account. Applications are not limited to the medical field and extend to other areas where multistate simulation is of interest. We provide a technical explanation of the multistate models used by gems, explain the functions of gems and their arguments, and show a sample application.

  16. Puerarin Exerts a Delayed Inhibitory Effect on the Proliferation of Cardiomyocytes Derived from Murine ES Cells via Slowing Progression through G2/M Phase

    Directory of Open Access Journals (Sweden)

    Xueying Luo

    2016-03-01

    Full Text Available Objective: Puerarin, which shows beneficial and protective effects on cardiovascular diseases, is the main isoflavone extracted from Pueraria lobata (kudzu root. The aim of this study was to investigate the effects of puerarin on in vitro myocardial proliferation and its underlying mechanism. Methods: Myocardial differentiation of transgenic embryonic stem (ES cells was performed by embryoid body-based differentiation method. The proliferation assay of cardiomyocytes (CMs derived from ES cells (ES-CMs was performed by EdU (5-Ethynyl-2'-deoxyuridine staining. Flow cytometry was employed to determine the cell cycle distribution and apoptosis of purified ES-CMs. Quantitative real-time PCR was utilized to study the transcription of genes related to cell cycle progression. Signaling pathways relating to proliferation were studied by western blot analysis and application of specific inhibitors. Results: Puerarin exerted a delayed inhibitory effect on the proliferation of ES-CMs at the early-stage differentiation. Meanwhile, puerarin slowed progression through G2/M phase without inducing apoptosis of ES-CMs. Further assays showed that puerarin up-regulated the transcription of Cyclin A2, Cyclin B1 and Cdk1 in ES-CMs. The ERK1/2 specific inhibitor PD0325901 and the PI3K specific inhibitor Wortmannin successfully reversed puerarin-induced up-regulation of Cdk1 but not Cyclin A2 and B1. Conclusion: These findings suggest that puerarin inhibits CM proliferation via slowing progression through G2/M phase during early-stage differentiation.

  17. Recent progress in ERCP for biliary and pancreatic diseases

    Directory of Open Access Journals (Sweden)

    MIAO Lin

    2014-12-01

    Full Text Available In recent years, with the continuous development of endoscopic and interventional techniques, many new devices and methods have been used in clinical practice, and the application of endoscopic retrograde cholangiopancreatography (ERCP in biliary and pancreatic diseases has developed rapidly. This paper reviews and summarizes the recent progress in ERCP among patients with biliary and pancreatic diseases, including those with altered gastrointestinal anatomy, pregnant patients, patients with benign and malignant biliary strictures, and patients with pancreatic pseudocysts, as well as the application of SpyGlass, photodynamic therapy, and radiofrequency ablation, the management of ERCP-related duodenal perforation, and the prevention of post-ERCP pancreatitis. All the progress has made a great contribution to the diagnosis and treatment of biliary and pancreatic diseases.

  18. Disease progression and regression in sporadic small vessel disease-insights from neuroimaging.

    Science.gov (United States)

    van Leijsen, Esther M C; de Leeuw, Frank-Erik; Tuladhar, Anil M

    2017-06-01

    Cerebral small vessel disease (SVD) is considered the most important vascular contributor to the development of dementia. Comprehensive characterization of the time course of disease progression will result in better understanding of aetiology and clinical consequences of SVD. SVD progression has been studied extensively over the years, usually describing change in SVD markers over time using neuroimaging at two time points. As a consequence, SVD is usually seen as a rather linear, continuously progressive process. This assumption of continuous progression of SVD markers was recently challenged by several studies that showed regression of SVD markers. Here, we provide a review on disease progression in sporadic SVD, thereby taking into account both progression and regression of SVD markers with emphasis on white matter hyperintensities (WMH), lacunes and microbleeds. We will elaborate on temporal dynamics of SVD progression and discuss the view of SVD progression as a dynamic process, rather than the traditional view of SVD as a continuous progressive process, that might better fit evidence from longitudinal neuroimaging studies. We will discuss possible mechanisms and clinical implications of a dynamic time course of SVD, with both progression and regression of SVD markers. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  19. Pramipexole in patients with early Parkinson's disease (PROUD): a randomised delayed-start trial.

    Science.gov (United States)

    Schapira, Anthony H V; McDermott, Michael P; Barone, Paolo; Comella, Cynthia L; Albrecht, Stefan; Hsu, Helen H; Massey, Daniel H; Mizuno, Yoshikuni; Poewe, Werner; Rascol, Olivier; Marek, Kenneth

    2013-08-01

    In models of dopaminergic neuronal loss, the dopamine agonist pramipexole has exhibited neuroprotective properties. The Pramipexole On Underlying Disease (PROUD) study was designed to identify whether early versus delayed pramipexole initiation has clinical and neuroimaging benefits in patients with Parkinson's disease (PD). Between May 24, 2006, and April 22, 2009, at 98 centres, we recruited patients with PD diagnosed within 2 years and aged 30-79 years. We randomly assigned eligible patients (ratio 1:1), by a centralised, computerised randomisation schedule, to receive double-blind either placebo or pramipexole (1·5 mg a day) and followed them up for 15 months. At 9 months, or as early as 6 months if considered necessary, placebo recipients were assigned to pramipexole. In a neuroimaging substudy, striatal dopamine-transporter binding was assessed by SPECT. All patients, investigators, and independent raters were masked to study treatment. The primary endpoint was the 15-month change from baseline in total score on the unified Parkinson's disease rating scale (UPDRS). This trial is registered with ClinicalTrials.gov, number NCT00321854. Of 535 patients, 261 were randomly assigned to receive pramipexole and 274 to receive placebo. At 15 months (n=411), adjusted mean change in UPDRS total score showed no significant difference between early and delayed pramipexole (-0·4 points, 95% CI -2·2 to 1·4, p=0·65). 62 patients in the early pramipexole group and 61 patients in the delayed pramipexole group were included in the neuroimaging substudy, for which the adjusted mean 15-month change in striatal (123)I-FP-CIT binding was -15·1% (SE 2·1) for early and -14·6% (2·0) for delayed pramipexole (difference -0·5 percentage points, 95% CI -5·4 to 4·4, p=0·84). Overall, 180 (81%) of patients given early pramipexole and 179 (84%) patients given delayed pramipexole reported adverse events (most frequently nausea), and 22 (10%) patients in the early pramipexole

  20. Emerging risk factors and markers of chronic kidney disease progression.

    Science.gov (United States)

    Kronenberg, Florian

    2009-12-01

    Chronic kidney disease (CKD) is a common condition with an increasing prevalence. A number of comorbidities are associated with CKD and prognosis is poor, with many patients experiencing disease progression. Recognizing the factors associated with CKD progression enables high-risk patients to be identified and given more intensive treatment if necessary. The identification of new predictive markers might improve our understanding of the pathogenesis and progression of CKD. This Review discusses a number of emerging factors and markers for which epidemiological evidence from prospective studies indicates an association with progression of CKD. The following factors and markers are discussed: asymmetric dimethylarginine, factors involved in calcium-phosphate metabolism, adrenomedullin, A-type natriuretic peptide, N-terminal pro-brain natriuretic peptide, liver-type fatty acid binding protein, kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, apolipoprotein A-IV, adiponectin and some recently identified genetic polymorphisms. Additional epidemiological and experimental data are required before these markers can be broadly used for the prediction of CKD progression and before the risk factors can be considered as potential drug targets in clinical interventional trials.

  1. Immune Inflammation and Disease Progression in Idiopathic Pulmonary Fibrosis.

    Directory of Open Access Journals (Sweden)

    Elisabetta Balestro

    Full Text Available The clinical course in idiopathic pulmonary fibrosis (IPF is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC change/year (< or ≥10% predicted was used to define "slow" or "rapid" disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48 showed longer duration of symptoms and lower FVC than rapid progressors (n = 25. Eleven slow and 3 rapid progressors developed an acute exacerbation (AE during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005. In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression.

  2. Immune Inflammation and Disease Progression in Idiopathic Pulmonary Fibrosis.

    Science.gov (United States)

    Balestro, Elisabetta; Calabrese, Fiorella; Turato, Graziella; Lunardi, Francesca; Bazzan, Erica; Marulli, Giuseppe; Biondini, Davide; Rossi, Emanuela; Sanduzzi, Alessandro; Rea, Federico; Rigobello, Chiara; Gregori, Dario; Baraldo, Simonetta; Spagnolo, Paolo; Cosio, Manuel G; Saetta, Marina

    2016-01-01

    The clinical course in idiopathic pulmonary fibrosis (IPF) is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC) change/year (slow" or "rapid" disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48) showed longer duration of symptoms and lower FVC than rapid progressors (n = 25). Eleven slow and 3 rapid progressors developed an acute exacerbation (AE) during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005). In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression.

  3. Bronchoalveolar lavage fluid and progression of scleroderma interstitial lung disease.

    Science.gov (United States)

    De Santis, Maria; Bosello, Silvia Laura; Peluso, Giusy; Pinnelli, Michela; Alivernini, Stefano; Zizzo, Gaetano; Bocci, Mario; Capacci, Annunziata; La Torre, Giuseppe; Mannocci, Alice; Pagliari, Gabriella; Varone, Francesco; Pistelli, Roberto; Danza, Francesco Maria; Ferraccioli, Gianfranco

    2012-01-01

    So far no clinical or experimental evidences clearly explain how and which systemic sclerosis (SSc) patients will experience a functional and radiological progression of interstitial lung disease (ILD). The aim of the study was to investigate whether any bronchoalveolar lavage fluid (BALF) characteristic, compared with clinical, functional and radiological parameters, is associated with the risk of progression of ILD and worse survival in SSc patients. Lung involvement was evaluated in 110 consecutively examined SSc patients with pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT); 73 patients with evidence of ILD on HRCT underwent BAL. The progression of ILD was evaluated with PFTs and HRCT after 1-year follow-up. A 36-month survival analysis was assessed. ILD patients with alveolitis had a higher risk to have restrictive lung disease and honeycombing, to experience a worsening in honeycombing score or to develop honeycombing. ILD progression was associated with the evidence of honeycombing on HRCT, with the presence of eosinophils, with an inverted CD4/CD8 ratio and with a higher CD19 percentage count in the BALF or with a positive BALF microbiological culture. The patients with ILD had a worse overall survival. The diffuse disease was the only independent risk factor of overall mortality, and the extent of honeycombing on HRCT was the only independent risk factor of lung disease-related mortality. Our study suggests the importance of evaluating ILD with HRCT and BAL in order to characterize the risk factors of SSc lung involvement progression. © 2010 Blackwell Publishing Ltd.

  4. Aluminum involvement in the progression of Alzheimer's disease.

    Science.gov (United States)

    Walton, J R

    2013-01-01

    The neuroanatomic specificity with which Alzheimer's disease (AD) progresses could provide clues to AD etiopathology. Magnetic resonance imaging studies of AD clinical progression have confirmed general conclusions from earlier studies of AD neuropathological progression wherein neurofibrillary tangle pathology was observed to spread along a well-defined sequence of corticocortical and corticosubcortical connections, preferentially affecting certain cell types, while sparing others. Identical and non-identical twin studies have consistently shown AD has mixed (environmental and genetic) etiopathogenesis. The decades-long prodromal phase over which AD develops suggests slow but progressive accumulation of a toxic or infective agent over time. Major environmental candidates are reviewed to assess which best fits the profile of an agent that slowly accrues in susceptible cell types of AD-vulnerable brain regions to toxic levels by old age, giving rise to AD neuropathology without rapid neuronal lysis. Chronic aluminum neurotoxicity best matches this profile. Many humans routinely ingest aluminum salts as additives contained in processed foods and alum-treated drinking water. The physical properties of aluminum and ferric iron ions are similar, allowing aluminum to use mechanisms evolved for iron to enter vulnerable neurons involved in AD progression, accumulate in those neurons, and cause neurofibrillary damage. The genetic component of AD etiopathogenesis apparently involves a susceptibility gene, yet to be identified, that increases aluminum absorption because AD and Down syndrome patients have higher than normal plasma, and brain, aluminum levels. This review describes evidence for aluminum involvement in AD neuropathology and the clinical progression of sporadic AD.

  5. Caffeine, creatine, GRIN2A and Parkinson's disease progression.

    Science.gov (United States)

    Simon, David K; Wu, Cai; Tilley, Barbara C; Lohmann, Katja; Klein, Christine; Payami, Haydeh; Wills, Anne-Marie; Aminoff, Michael J; Bainbridge, Jacquelyn; Dewey, Richard; Hauser, Robert A; Schaake, Susen; Schneider, Jay S; Sharma, Saloni; Singer, Carlos; Tanner, Caroline M; Truong, Daniel; Wei, Peng; Wong, Pei Shieen; Yang, Tianzhong

    2017-04-15

    Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of PD. This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p=0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Amyotrophic Lateral Sclerosis: A Focus on Disease Progression

    Science.gov (United States)

    Calvo, Ana C.; Manzano, Raquel; Mendonça, Deise M. F.; Muñoz, María J.; Zaragoza, Pilar

    2014-01-01

    Since amyotrophic lateral sclerosis (ALS) was discovered and described in 1869 as a neurodegenerative disease in which motor neuron death is induced, a wide range of biomarkers have been selected to identify therapeutic targets. ALS shares altered molecular pathways with other neurodegenerative diseases, such as Alzheimer's, Huntington's, and Parkinson's diseases. However, the molecular targets that directly influence its aggressive nature remain unknown. What is the first link in the neurodegenerative chain of ALS that makes this disease so peculiar? In this review, we will discuss the progression of the disease from the viewpoint of the potential biomarkers described to date in human and animal model samples. Finally, we will consider potential therapeutic strategies for ALS treatment and future, innovative perspectives. PMID:25157374

  7. Exosomes-associated neurodegeneration and progression of Parkinson's disease.

    Science.gov (United States)

    Russo, Isabella; Bubacco, Luigi; Greggio, Elisa

    2012-01-01

    Growing evidence indicates the role of exosomes in a variety of physiological pathways as conveyors of biological materials from cell-to-cell. However the molecular mechanism(s) of secretion and their interaction with receiving cells are yet unclear. Recently, it is emerging that exosomes are involved in pathological processes as potential carriers in the progression of neurodegenerative pathologies associated with misfolded proteins. In the current review we will discuss some recent findings on the key role of exosomes in the spreading of the aggregated products of α-synuclein from neuron-to-neuron and of inflammatory response propagation from immune cell-to-cell; we will highlight the implication of exosomes in the neurodegeneration and progression of the disease and the their potential interplay with genes related to Parkinson's disease. Increasing our knowledge on the cell-to-cell transmissions might provide new insights into mechanism of disease onset and progression and identify novel strategies for diagnosis and therapeutic intervention in Parkinson and other neurodegenerative diseases.

  8. Disease-modifying treatments for progressive multiple sclerosis.

    Science.gov (United States)

    Comi, Giancarlo

    2013-10-01

    The last 20 years have seen major progress in the treatment of relapsing-remitting multiple sclerosis (RRMS) using a variety of drugs targeting immune dysfunction. In contrast, all clinical trials of such agents in primary progressive multiple sclerosis (PPMS) have failed and there is limited evidence of their efficacy in secondary progressive disease. Evolving concepts of the complex interplay between inflammatory and neurodegenerative processes across the course of multiple sclerosis (MS) may explain this discrepancy. This paper will provide an up-to-date overview of the rationale and results of the published clinical trials that have sought to alter the trajectory of both primary and secondary MS, considering studies involving drugs with a primary immune target and also those aiming for neuroprotection. Future areas of study will be discussed, building on these results combined with the experience of treating RRMS and new concepts emerging from laboratory science and animal models.

  9. Research progress in immunological mechanism of delayed encephalopathy after acute carbon monoxide poisoning

    Directory of Open Access Journals (Sweden)

    Kai FENG

    2014-10-01

    Full Text Available Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP is a syndrome constituted by acute dementia, psychiatric symptoms, pyramidal and extrapyramidal symptoms, which can be developed after the original clinical symptoms of carbon monoxide poisoning recovered. Lots of studies have been done to explain the mechanisms of DEACMP, and more and more researches have demonstrated that the immunological mechanism may be involved in or play an important role on the pathogenesis of the process. This article will review the researches of immunological mechanism of DEACMP in recent years and give some prompts to clinical study in the future. doi: 10.3969/j.issn.1672-6731.2014.10.006

  10. Composite end points to assess delay of disability progression by MS treatments.

    Science.gov (United States)

    Zhang, J; Waubant, E; Cutter, G; Wolinsky, Js; Leppert, D

    2014-10-01

    The Expanded Disability Status Scale (EDSS) has low sensitivity and reliability for detecting sustained disability progression (SDP) in multiple sclerosis (MS) trials. This study evaluated composite disability end points as alternatives to EDSS alone. SDP rates were determined using 96-week data from the Olympus trial (rituximab in patients with primary progressive MS). SDP was analyzed using composite disability end points: SDP in EDSS, timed 25-foot walk test (T25FWT), or 9-hole peg test (9HPT) (composite A); SDP in T25FWT or 9HPT (composite B); SDP in EDSS and (T25FWT or 9HPT) (composite C); and SDP in any two (EDSS, T25FWT, and 9HPT) (composite D). Overall agreements between EDSS and other disability measures in defining SDP were 66%-73%. Composite A showed similar treatment effect estimate versus EDSS alone with much higher SDP rates. Composite B, C, and D all showed larger treatment effect estimate with different or similar SDP rates versus EDSS alone. Using composite A (24-week confirmation only), B, C, or D could reduce sample sizes needed for MS trials. Composite end points including multiple accepted disability measures could be superior to EDSS alone in analyzing disability progression and should be considered in future MS trials. © The Author(s) 2014.

  11. State-space size considerations for disease-progression models.

    Science.gov (United States)

    Regnier, Eva D; Shechter, Steven M

    2013-09-30

    Markov models of disease progression are widely used to model transitions in patients' health state over time. Usually, patients' health status may be classified according to a set of ordered health states. Modelers lump together similar health states into a finite and usually small, number of health states that form the basis of a Markov chain disease-progression model. This increases the number of observations used to estimate each parameter in the transition probability matrix. However, lumping together observably distinct health states also obscures distinctions among them and may reduce the predictive power of the model. Moreover, as we demonstrate, precision in estimating the model parameters does not necessarily improve as the number of states in the model declines. This paper explores the tradeoff between lumping error introduced by grouping distinct health states and sampling error that arises when there are insufficient patient data to precisely estimate the transition probability matrix. Copyright © 2013 John Wiley & Sons, Ltd.

  12. Effects of Lowering LDL Cholesterol on Progression of Kidney Disease

    DEFF Research Database (Denmark)

    Haynes, Richard; Lewis, David; Emberson, Jonathan

    2014-01-01

    Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily...... with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD....... or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared...

  13. Research Progress of PET Traces for Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    TANG Cai-hua1,2;HU Kong-zhen1;TANG Gang-hua1

    2014-02-01

    Full Text Available Alzheimer’s disease (AD is unknown cause progressive degenerative diseases of central nervous system. It is a serious threat to the health of the elderly people. The diagnosis is mainly based on pathological examination after death. With the wide application of positron emission tomography (PET imaging in clinic, in vivo noninvasive imaging diagnosis of AD at the early stage become possible. PET imaging mainly depends on the positron-labeled imaging agents. The PET imaging agents can be used in the early diagnosis and differential diagnosis on AD include several kinds: PET traces for glucose metabolic, PET traces combined with amyloid proteinplaques,tau protein, neurotransmitter and receptor, activation of microglia and PET traces for cell apoptosis.The research progress of various PET tracers were reviewed that can be used in the early diagnosis and differential diagnosis on AD in recent years.

  14. Delayed increases in microvascular pathology after experimental traumatic brain injury are associated with prolonged inflammation, blood-brain barrier disruption, and progressive white matter damage.

    Science.gov (United States)

    Glushakova, Olena Y; Johnson, Danny; Hayes, Ronald L

    2014-07-01

    Traumatic brain injury (TBI) is a significant risk factor for chronic traumatic encephalopathy (CTE), Alzheimer's disease (AD), and Parkinson's disease (PD). Cerebral microbleeds, focal inflammation, and white matter damage are associated with many neurological and neurodegenerative disorders including CTE, AD, PD, vascular dementia, stroke, and TBI. This study evaluates microvascular abnormalities observed at acute and chronic stages following TBI in rats, and examines pathological processes associated with these abnormalities. TBI in adult rats was induced by controlled cortical impact (CCI) of two magnitudes. Brain pathology was assessed in white matter of the corpus callosum for 24 h to 3 months following injury using immunohistochemistry (IHC). TBI resulted in focal microbleeds that were related to the magnitude of injury. At the lower magnitude of injury, microbleeds gradually increased over the 3 month duration of the study. IHC revealed TBI-induced focal abnormalities including blood-brain barrier (BBB) damage (IgG), endothelial damage (intercellular adhesion molecule 1 [ICAM-1]), activation of reactive microglia (ionized calcium binding adaptor molecule 1 [Iba1]), gliosis (glial fibrillary acidic protein [GFAP]) and macrophage-mediated inflammation (cluster of differentiation 68 [CD68]), all showing different temporal profiles. At chronic stages (up to 3 months), apparent myelin loss (Luxol fast blue) and scattered deposition of microbleeds were observed. Microbleeds were surrounded by glial scars and co-localized with CD68 and IgG puncta stainings, suggesting that localized BBB breakdown and inflammation were associated with vascular damage. Our results indicate that evolving white matter degeneration following experimental TBI is associated with significantly delayed microvascular damage and focal microbleeds that are temporally and regionally associated with development of punctate BBB breakdown and progressive inflammatory responses. Increased

  15. Current Progress in Therapeutic Gene Editing for Monogenic Diseases.

    Science.gov (United States)

    Prakash, Versha; Moore, Marc; Yáñez-Muñoz, Rafael J

    2016-03-01

    Programmable nucleases allow defined alterations in the genome with ease-of-use, efficiency, and specificity. Their availability has led to accurate and widespread genome engineering, with multiple applications in basic research, biotechnology, and therapy. With regard to human gene therapy, nuclease-based gene editing has facilitated development of a broad range of therapeutic strategies based on both nonhomologous end joining and homology-dependent repair. This review discusses current progress in nuclease-based therapeutic applications for a subset of inherited monogenic diseases including cystic fibrosis, Duchenne muscular dystrophy, diseases of the bone marrow, and hemophilia and highlights associated challenges and future prospects.

  16. Diagnosis of Ebola Virus Disease: Progress and Prospects

    Directory of Open Access Journals (Sweden)

    Mingjuan Yang

    2015-12-01

    Full Text Available Ebola virus disease (EVD represents one of the deadliest diseases in the world, with a fatality rate of over 70% and absence of effective vaccine and treatment. Rapid and specific diagnosis of EVD is essential for isolation, treatment of patients, and prevention of outbreak spread. Although many assays for EVD diagnosis have been reported, there is still an urgent requirement for practical assays for use in resource-limited areas, like Africa. Here we summarize the progresses of EVD diagnostic techniques.

  17. Alzheimer's disease: a mathematical model for onset and progression

    CERN Document Server

    Bertsch, Michiel; Marcello, Norina; Tesi, Maria Carla; Tosin, Andrea

    2015-01-01

    In this paper we propose a mathematical model for the onset and progression of Alzheimer's disease based on transport and diffusion equations. We regard brain neurons as a continuous medium, and structure them by their degree of malfunctioning. Two different mechanisms are assumed to be relevant for the temporal evolution of the disease: i) diffusion and agglomeration of soluble polymers of amyloid, produced by damaged neurons; ii) neuron-to-neuron prion-like transmission. We model these two processes by a system of Smoluchowski equations for the amyloid concentration, coupled to a kinetic-type transport equation for the distribution function of the degree of malfunctioning of neurons. The second equation contains an integral term describing the random onset of the disease as a jump process localized in particularly sensitive areas of the brain. Even though we deliberately neglect many aspects of the complexity of the brain and the disease, numerical simulations are in good qualitative agreement with clinical...

  18. Progressive Multifocal Leukoencephalopathy: Endemic Viruses and Lethal Brain Disease.

    Science.gov (United States)

    Haley, Sheila A; Atwood, Walter J

    2017-06-21

    In 1971, the first human polyomavirus was isolated from the brain of a patient who died from a rapidly progressing demyelinating disease known as progressive multifocal leukoencephalopathy. The virus was named JC virus after the initials of the patient. In that same year a second human polyomavirus was discovered in the urine of a kidney transplant patient and named BK virus. In the intervening years it became clear that both viruses were widespread in the human population but only rarely caused disease. The past decade has witnessed the discovery of eleven new human polyomaviruses, two of which cause unusual and rare cancers. We present an overview of the history of these viruses and the evolution of JC polyomavirus-induced progressive multifocal leukoencephalopathy over three different epochs.Wereview what is currently known about JC polyomavirus, what is suspected, and what remains to be done to understand the biology of how this mostly harmless endemic virus gives rise to lethal disease. Expected final online publication date for the Annual Review of Virology Volume 4 is September 29, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  19. The Rationale for Delaying Aging and the Prevention of Age-Related Diseases

    Directory of Open Access Journals (Sweden)

    Nir Barzilai

    2012-10-01

    Full Text Available [Excerpt] We offer a different approach to delaying or preventing age-related diseases. To understand the necessity for a new approach we have plotted the mortality rates in Israelis in relation to specific age groups and diseases. With the common phenomenon of aging of Western populations it is of utmost importance to follow time-dependent and age-dependent mortality patterns to predict future needs of Western health systems. Age-specific, gender-specific, and cause-of-death-specific mortality rates were extracted from the statistical abstract of Israel1 and include data for the period of 1975–2010; these are presented in Figure 1, separately for men (A and women (B. Detailed age-specific causes of death data were available for the year 2009. Data presented were restricted to 5-year age groups starting at age 50, and for cause-specific mortality to the following age groups: 45–54, 55–64, 65–74, 75–84, and 85+. Causes of mortality were separated into malignant diseases, acute myocardial infarction, other ischemic heart diseases, other forms of heart diseases, cerebrovascular disease, diabetes mellitus, respiratory diseases, diseases of kidney, infectious diseases, all external causes, signs/symptoms and ill-defined conditions, and all other diseases. Figure 1 is similar to the one posted on the National Institute of Aging website and similar to data across the industrial world. The striking feature of this graph is that aging is a major log scale risk for most diseases, including the major killers: heart disease, cancer, diabetes, and Alzheimer’s. For example, while aging is a 100-fold risk for cardiovascular disease (CVD according to Figure 1, hypercholesterolemia is known to carry only a three-fold risk for CVD. For each of the mentioned diseases, aging is a log risk greater than the most important known risk factor for that disease.

  20. Delayed arteriosclerosis progression in high risk subjects treated with mesoglycan. Evaluation of intima-media thickness.

    Science.gov (United States)

    Laurora, G; Cesarone, M R; De Sanctis, M T; Incandela, L; Belcaro, G

    1993-08-01

    Noninvasive ultrasonic biopsy (UB) can be used to classify arteriosclerotic lesions and their progression in the carotid and femoral bifurcation. Also the evaluation of intima-media thickness (IMT) is useful to quantify the progression of early arteriosclerosis. Two randomly selected groups of asymptomatic subjects were included in a 18 month, open study. One group was treated with oral mesoglycan (200 mg/day) and one group was followed-up as control. The two groups were comparable for age and sex distribution. The average UB score was 14.4 +/- 5 in the treatment group and 14.3 +/- 8 in the control group. After 18 months the UB score was 15.7 +/- 4 in the treatment and 16.2 +/- 6 in the control group. These differences were not significant. However the average increase in IMT in 18 months in the treatment group was 0.016 mm equivalent to 0.0106 mm per year. In the control group the average increase was 0.119 equivalent to 0.0793 per year. Therefore the increase in IMT was 7.48 times greater in the control group. These differences were significant (p mesoglycan treatment. These results need to be confirmed by a larger randomised study.

  1. Effect of massage on the progress of evolution and the sequence of motion phases process in Infants with Motor delay

    Directory of Open Access Journals (Sweden)

    Ayda Ravarian

    2016-03-01

    Full Text Available Early intervention for infants with motor delay without a defined etiology have included Neurodevelopmental Therapy(NDT and Infant massage, but no comparisons have been made and beneficially is uncertain .we compared NDT to NDT techniques plus massage. To evaluate the effectiveness of adding Massage therapy (15min to NDT (45min 15 infants who diagnose with Motor Delay (ages 5-12months and moderate in Motor Quotient without defined etiology were recruited 3 times a week for 2 months. The outcomes included the Gross Motor Function Measure (GMFM, head circumference and weight gain. Children who received only routine NDT improved in Gross Motor Function Measure by 31.47 compared with 59.12 for those who received a combination of NDT and Massage (p=0.003.They show improvement in head circumference and weight gain but they are not significant b(p=0.32 and (p=0.59.NDT Techniques are helpful for these infants, and the addition of massage may augment the effects on motor progression.

  2. Bidirectional role of tumor necrosis factor-alpha in coronary microembolization: progressive contractile dysfunction versus delayed protection against infarction.

    Science.gov (United States)

    Skyschally, Andreas; Gres, Petra; Hoffmann, Simone; Haude, Michael; Erbel, Raimund; Schulz, Rainer; Heusch, Gerd

    2007-01-05

    In patients with unstable angina, plaque rupture and coronary microembolization (ME) can precede complete coronary artery occlusion and impending infarction. ME-induced microinfarcts initiate an inflammatory reaction with increased tumor necrosis factor-alpha (TNF-alpha) expression, resulting in progressive contractile dysfunction. However, TNF-alpha is not only a negative inotrope but can also protect the myocardium against infarction. In anesthetized pigs, we studied whether ME protects against infarction when TNF-alpha expression is increased. ME (group1; n=7) was induced by intracoronary infusion of microspheres (42 microm; 3000 per mL/min inflow). Controls (group 2; n=8) received saline. Groups 3 and 4 (n=4 each) were pretreated with ovine TNF-alpha antibodies (25 mg/kg body weight) 30 minutes before ME or placebo, respectively. Ischemia (90 minutes) was induced 6 hours after ME when TNF-alpha was increased (66+/-21 pg/g wet weight; mean+/-SEM) or after placebo (TNF-alpha, 21+/-10 pg/g; P<0.05). Infarct size (percentage area at risk) was determined after 2 hours of reperfusion (triphenyl tetrazolium chloride staining). ME decreased systolic wall thickening progressively over 6 hours (group 1 versus group 2, 65+/-4% versus 90+/-1%; percentage of baseline; P<0.05). TNF-alpha antibodies attenuated the progressive decrease in systolic wall thickening following ME (group 3, 77+/-5% of baseline; P<0.05 versus group 1) with no effect in controls (group 4; 90+/-8% of baseline). With ME, infarct size was decreased to 18+/-4% versus 33+/-4% in group 2 (P<0.05). The infarct size reduction was abolished by TNF-alpha antibodies (group 3 versus group 4, 29+/-3% versus 35+/-5%). In ME, TNF-alpha is responsible for both progressive contractile dysfunction and delayed protection against infarction.

  3. Delayed pneumothorax after laparoscopic sigmoid colectomy in a patient without underlying lung disease

    Directory of Open Access Journals (Sweden)

    Richie K Huynh

    2014-10-01

    Full Text Available We present an unusual case of a delayed pneumothorax occurring approximately 72 h post-operatively in a patient without any underlying lung disease who had undergone laparoscopic sigmoid colon resection. The patient was in her mid-40s with a body mass index of 28.0 and had no history of smoking. Her spontaneous pneumothorax manifested without any precipitating events or complications during recovery. There was no evidence of any infectious process. There were no central line attempts and all ports were placed intra-peritoneally, and there was no evidence of any subcutaneous emphysema. One possible mechanism of injury that we propose is barotrauma from an extended period of time in Trendelenburg position. Notably, the only abnormal finding throughout the entire post-operative period preceding the delayed pneumothorax was a PO2 desaturation the day before. This case highlights the necessity to examine and investigate any desaturation post-operatively and deliberate its possible significance. Furthermore, it demonstrates that, even during a normal recovery period for a patient without any underlying lung disease or risk factors, spontaneous pneumothorax could still develop in a delayed fashion multiple days post-operatively from a laparoscopic procedure.

  4. Progress in spondylarthritis. Immunopathogenesis of spondyloarthritis: which cells drive disease?

    Science.gov (United States)

    Melis, Lode; Elewaut, Dirk

    2009-01-01

    Spondyloarthritides, or SpA, form a cluster of chronic inflammatory diseases with the axial skeleton as the most typical disease localisation, although extra-articular manifestations such as intestinal inflammation may frequently occur during the course of the disease. This review summarises recent progress in our understanding of the immunopathogenesis of SpA with special emphasis on the cellular constituents considered to be responsible for the initiation and/or perpetuation of inflammation. There are several arguments favouring a role for haematopoietic cells in the pathophysiology of spondyloarthritis, including HLA-B27-associated dendritic cell disturbances, HLA-B27 misfolding properties and T helper 17 cells. In addition, recent studies have pointed toward a pivotal role for stromal cells. A major challenge, however, remains to determine how recently identified genetic associations such as interleukin-23 receptor polymorphisms may influence cellular targets in spondyloarthritis.

  5. Biomarkers of Renal Disease and Progression in Patients with Diabetes

    Directory of Open Access Journals (Sweden)

    Radovan Hojs

    2015-05-01

    Full Text Available Diabetes prevalence is increasing worldwide, mainly due to the increase in type 2 diabetes. Diabetic nephropathy occurs in up to 40% of people with type 1 or type 2 diabetes. It is important to identify patients at risk of diabetic nephropathy and those who will progress to end stage renal disease. In clinical practice, most commonly used markers of renal disease and progression are serum creatinine, estimated glomerular filtration rate and proteinuria or albuminuria. Unfortunately, they are all insensitive. This review summarizes the evidence regarding the prognostic value and benefits of targeting some novel risk markers for development of diabetic nephropathy and its progression. It is focused mainly on tubular biomarkers (neutrophil-gelatinase associated lipocalin, kidney injury molecule 1, liver-fatty acid-binding protein, N-acetyl-beta-d-glucosaminidase, markers of inflammation (pro-inflammatory cytokines, tumour necrosis factor-α and tumour necrosis factor-α receptors, adhesion molecules, chemokines and markers of oxidative stress. Despite the promise of some of these new biomarkers, further large, multicenter prospective studies are still needed before they can be used in everyday clinical practice.

  6. The factor structure of the UPDRS as an index of disease progression in Parkinson's disease.

    Science.gov (United States)

    Evans, Jonathan R; Mason, Sarah L; Williams-Gray, Caroline H; Foltynie, Thomas; Trotter, Matthew; Barker, Roger A

    2011-01-01

    The optimum method for evaluating disease progression in Parkinson's disease (PD) has not been established, and this has implications for clinical trials. The majority of previous studies have utilized change on the Unified Parkinson's disease Rating Scale (UPDRS) as an index of progression. However, the UPDRS has not been validated for this purpose. We utilized exploratory factor analysis (EFA) to evaluate the longitudinal properties of the UPDRS as an index of disease progression in PD. Data was derived from a representative cohort of 122 PD patients followed from diagnosis and assessed every 18-24 months for up to 7.9 years. For each subject the rate of change of each item on the UPDRS-3 was calculated and an EFA was performed using this data. Results were compared with those of previously published EFAs in cross-sectional PD cohorts. The UPDRS-3 retains a stable factor structure when used as an index of disease evolution. The 27 items reduced to 6 factors which accounted for 61.0% of the variance in disease progression. A dominant factor was identified which incorporated axial (gait/postural stability) symptoms and signs. Our analysis indicates that the UPDRS captures meaningful aspects of disease progression in PD, and that it is possible to identify symptom/sign complexes which evolve independently of one another. Progression in PD is predominantly characterized by the development of axial symptoms and signs. This result has implications for pathogenesis and should also inform natural history models of PD thereby allowing identification of meaningful outcome measures for clinical trials of disease-modifying therapies.

  7. A transcriptional network underlies susceptibility to kidney disease progression.

    Science.gov (United States)

    Laouari, Denise; Burtin, Martine; Phelep, Aurélie; Bienaime, Frank; Noel, Laure-Hélène; Lee, David C; Legendre, Christophe; Friedlander, Gérard; Pontoglio, Marco; Terzi, Fabiola

    2012-08-01

    The molecular networks that control the progression of chronic kidney diseases (CKD) are poorly defined. We have recently shown that the susceptibility to development of renal lesions after nephron reduction is controlled by a locus on mouse chromosome 6 and requires epidermal growth factor receptor (EGFR) activation. Here, we identified microphthalmia-associated transcription factor A (MITF-A), a bHLH-Zip transcription factor, as a modifier of CKD progression. Sequence analysis revealed a strain-specific mutation in the 5' UTR that decreases MITF-A protein synthesis in lesion-prone friend virus B NIH (FVB/N) mice. More importantly, we dissected the molecular pathway by which MITF-A modulates CKD progression. MITF-A interacts with histone deacetylases to repress the transcription of TGF-α, a ligand of EGFR, and antagonizes transactivation by its related partner, transcription factor E3 (TFE3). Consistent with the key role of this network in CKD, Tgfa gene inactivation protected FVB/N mice from renal deterioration after nephron reduction. These data are relevant to human CKD, as we found that the TFE3/MITF-A ratio was increased in patients with damaged kidneys. Our study uncovers a novel transcriptional network and unveils novel potential prognostic and therapeutic targets for preventing human CKD progression.

  8. Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progression.

    Science.gov (United States)

    Brandhorst, Sebastian; Wei, Min; Hwang, Saewon; Morgan, Todd E; Longo, Valter D

    2013-10-01

    Short-term starvation (STS) protects normal cells while simultaneously sensitizing malignant cells to high-dose chemotherapeutic drugs in mice and possibly patients. The fasting-dependent protection of normal cells and sensitization of malignant cells depends, in part, on reduced levels of insulin-like growth factor-1 (IGF-1) and glucose. Calorie restricted diets with defined macronutrient (carbohydrate, protein, fat) ratios were evaluated for the effects on stress sensitization markers and protection in mice treated with high-dose chemotherapy. We show that short-term CR significantly reduced both glucose and IGF-1 levels, but when specific macronutrient deficiencies were tested, only the complete lack of proteins reduced IGF-1 levels. Short-term 50% CR combined with either severe protein-deficiency or ketogenic diets improved chemotoxicity resistance similarly to the standard 50% CR, but did not result in the high protection caused by STS. Notably, a high protein diet reversed the beneficial effects of short-term CR. In a subcutaneous mouse model of glioma, feeding a low protein (4% calories from protein) diet for more than 20days did not delay tumor progression once the tumor became palpable. Also, cycles of short-term (3days) 50% CR did not augment the chemotherapy efficacy of cisplatin in a murine breast cancer model. These results indicate that the protection from chemotoxicity and retardation of the progression of certain tumors achieved with fasting is not obtained with short-term calorie and/or macronutrient restriction.

  9. Delayed identification and diagnosis of Huntington’s disease due to psychiatric symptoms

    OpenAIRE

    Pascu,Alina Mihaela; Ifteni, Petru; Teodorescu,Andreea; Burtea, Victoria; Correll, Christoph U.

    2015-01-01

    Huntington’s disease (HD) is a progressive neurodegenerative illness that affects 2–9/100.000 of the general population. The usual onset is at around age 35–40 years, but there were cases with onset above 55 years. The disease manifests clinically with many neurological and psychiatric symptoms, leading in advanced phases to dementia, but cognitive symptoms are frequently present much earlier in the disease course. HD is caused by an expanded polyglutamine stretch in the N-terminal part of a ...

  10. Progression of small vessel disease correlates with cortical thinning in Parkinson's disease.

    Science.gov (United States)

    Foo, Heidi; Mak, Elijah; Yong, Ting Ting; Wen, Ming-Ching; Chander, Russell Jude; Au, Wing Lok; Tan, Louis; Kandiah, Nagaendran

    2016-10-01

    Cerebral small-vessel disease (SVD) is a risk factor for dementia in Parkinson's disease (PD), however the pathophysiological role of SVD in PD-dementia is unclear. We investigated the impact of baseline and progression of SVD on cortical thickness and the correlation to cognition. Seventy-three mild PD patients with baseline and follow-up structural MRI scans, serial clinical and neuropsychological assessments were studied. SVD included the load of white matter hyperintensities (WMH), lacunes and perivascular spaces (PVS). WMH progression was assessed using the modified Rotterdam Progression scale, while for lacunes and PVS, development of new lesions was considered as lesion progression. Patients were classified as having SVD-progression and SVD-no-progression based on the longitudinal changes in their SVD measures. Freesurfer was used to measure baseline and follow-up regional cortical thickness and subcortical volumes and correlated to cognitive performance. Fourteen patients were classified as SVD-progression and 59 as SVD-no-progression. Over 18 months, PD SVD-progression demonstrated significant cortical thinning in the left frontal and bilateral parietal regions with associated decline in memory, executive function, and motor functions. PD SVD-progression also had reduced volumes in the nucleus accumbens and amygdala at baseline and greater atrophy in the caudate nucleus over 18 months. The extent and progression of SVD is associated with focal cerebral atrophy and domain-specific cognitive dysfunction. Measures to retard SVD may be potentially useful in preventing dementia in PD. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Measles viral load may reflect SSPE disease progression

    Directory of Open Access Journals (Sweden)

    Jin L

    2006-06-01

    Full Text Available Abstract Subacute sclerosing panencephalitis (SSPE is a rare, slowly progressive neurological disorder caused by the persistent infection with measles virus (MV. Despite much research into SSPE, its pathology remains obscure. We examined autopsy tissues of eight SSPE patients by real time quantitative PCR, immunohistochemistry and immunoblotting to determine viral load. MV N, M and H gene RNA could be detected in the central nervous system (CNS of all patients and in two non-CNS tissues of one patient. The viral burden between patients differed up to four-fold by quantitative PCR and corresponded with detection of MV protein. The level of both viral RNA and antigen in the brain may correlate with disease progression.

  12. Disease Progression in a Patient with Nonalcoholic Steatohepatitis

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    Ping-Huei Tseng

    2008-10-01

    Full Text Available Nonalcoholic steatohepatitis (NASH is a severe form of nonalcoholic fatty liver disease (NAFLD. The prevalence and clinical significance of NAFLD/NASH have been increasingly recognized in Western countries but much less known in Asian countries, including Taiwan. Here, we report the case of a 43-year-old man who had abnormal liver tests for 18 years. Retrospective evaluation of his initial clinical, laboratory and histologic findings indicated that the hepatic disorder was compatible with the diagnosis of NASH. Although his liver biochemical tests improved after taking lipid-lowering agents, a liver biopsy 17 years later demonstrated histologic progression of intralobular necroinflammation and perivenular fibrosis. These facts suggest that NASH, albeit mild and slowly progressive, indeed exists in Taiwan. After the control of chronic hepatitis B and C and westernization of the lifestyle in Taiwan, an increasing burden of NAFLD/NASH is anticipated and active prophylactic measures should be implemented.

  13. Dynamics of collateral circulation in progressive asymptomatic carotid disease.

    Science.gov (United States)

    Moll, F L; Eikelboom, B C; Vermeulen, F E; van Lier, H J; Schulte, B P

    1986-03-01

    Inadequacy of collateral arterial flow is the major risk factor for hemispheric infarction in association with spontaneous occlusion of the ipsilateral carotid artery. This prospective study was designed to measure the adaptation of collateral cerebral circulation through the circle of Willis in patients in whom a unilateral carotid stenosis of hemodynamic consequence develops asymptomatically. The collateral cerebral potential is assessed by ocular pneumoplethysmography (OPG) during proximal common carotid artery compression, measuring the collateral ophthalmic artery pressure (COAP). During an average follow-up of almost 3 years (maximum more than 7 years), 45 patients showed asymptomatic development of a unilateral hemodynamically significant carotid stenosis according to OPG evidence. In these patients the mean index COAP/brachial artery pressure did not change on the side of stenosis progression (p greater than 0.05). The developed carotid stenosis had only reduced collateral circulation to the contralateral hemisphere. The risk of inadequate collateral cerebral circulation remained during progression of asymptomatic extracranial arterial obstructive disease.

  14. Vitamin D Deficiency Accelerates Coronary Artery Disease Progression in Swine.

    Science.gov (United States)

    Chen, Songcang; Swier, Vicki J; Boosani, Chandra S; Radwan, Mohamed M; Agrawal, Devendra K

    2016-08-01

    The role of vitamin D deficiency in coronary artery disease (CAD) progression is uncertain. Chronic inflammation in epicardial adipose tissue (EAT) has been implicated in the pathogenesis of CAD. However, the molecular mechanism underlying vitamin D deficiency-enhanced inflammation in the EAT of diseased coronary arteries remains unknown. We examined a mechanistic link between 1,25-dihydroxyvitamin D-mediated suppression of nuclear factor-κB (NF-κB) transporter, karyopherin α4 (KPNA4) expression and NF-κB activation in preadipocytes. Furthermore, we determined whether vitamin D deficiency accelerates CAD progression by increasing KPNA4 and nuclear NF-κB levels in EAT. Nuclear protein levels were detected by immunofluorescence and Western blot. Exogenous KPNA4 was transported into cells by a transfection approach and constituted lentiviral vector. Swine were administered vitamin D-deficient or vitamin D-sufficient hypercholesterolemic diet. After 1 year, the histopathology of coronary arteries and nuclear protein expression of EAT were assessed. 1,25-dihydroxyvitamin D inhibited NF-κB activation and reduced KPNA4 levels through increased vitamin D receptor expression. Exogenous KPNA4 rescued 1,25-dihydroxyvitamin D-dependent suppression of NF-κB nuclear translocation and activation. Vitamin D deficiency caused extensive CAD progression and advanced atherosclerotic plaques, which are linked to increased KPNA4 and nuclear NF-κB levels in the EAT. 1,25-dihydroxyvitamin D attenuates NF-κB activation by targeting KPNA4. Vitamin D deficiency accelerates CAD progression at least, in part, through enhanced chronic inflammation of EAT by upregulation of KPNA4, which enhances NF-κB activation. These novel findings provide mechanistic evidence that vitamin D supplementation could be beneficial for the prevention and treatment of CAD. © 2016 American Heart Association, Inc.

  15. Quantifying Parkinson's disease progression by simulating gait patterns

    Science.gov (United States)

    Cárdenas, Luisa; Martínez, Fabio; Atehortúa, Angélica; Romero, Eduardo

    2015-12-01

    Modern rehabilitation protocols of most neurodegenerative diseases, in particular the Parkinson Disease, rely on a clinical analysis of gait patterns. Currently, such analysis is highly dependent on both the examiner expertise and the type of evaluation. Development of evaluation methods with objective measures is then crucial. Physical models arise as a powerful alternative to quantify movement patterns and to emulate the progression and performance of specific treatments. This work introduces a novel quantification of the Parkinson disease progression using a physical model that accurately represents the main gait biomarker, the body Center of Gravity (CoG). The model tracks the whole gait cycle by a coupled double inverted pendulum that emulates the leg swinging for the single support phase and by a damper-spring System (SDP) that recreates both legs in contact with the ground for the double phase. The patterns generated by the proposed model are compared with actual ones learned from 24 subjects in stages 2,3, and 4. The evaluation performed demonstrates a better performance of the proposed model when compared with a baseline model(SP) composed of a coupled double pendulum and a mass-spring system. The Frechet distance measured differences between model estimations and real trajectories, showing for stages 2, 3 and 4 distances of 0.137, 0.155, 0.38 for the baseline and 0.07, 0.09, 0.29 for the proposed method.

  16. Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease.

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    Michael Zeisberg

    2006-04-01

    Full Text Available Glomerular basement membrane (GBM, a key component of the blood-filtration apparatus in the in the kidney, is formed through assembly of type IV collagen with laminins, nidogen, and sulfated proteoglycans. Mutations or deletions involving alpha3(IV, alpha4(IV, or alpha5(IV chains of type IV collagen in the GBM have been identified as the cause for Alport syndrome in humans, a progressive hereditary kidney disease associated with deafness. The pathological mechanisms by which such mutations lead to eventual kidney failure are not completely understood.We showed that increased susceptibility of defective human Alport GBM to proteolytic degradation is mediated by three different matrix metalloproteinases (MMPs--MMP-2, MMP-3, and MMP-9--which influence the progression of renal dysfunction in alpha3(IV-/- mice, a model for human Alport syndrome. Genetic ablation of either MMP-2 or MMP-9, or both MMP-2 and MMP-9, led to compensatory up-regulation of other MMPs in the kidney glomerulus. Pharmacological ablation of enzymatic activity associated with multiple GBM-degrading MMPs, before the onset of proteinuria or GBM structural defects in the alpha3(IV-/- mice, led to significant attenuation in disease progression associated with delayed proteinuria and marked extension in survival. In contrast, inhibition of MMPs after induction of proteinuria led to acceleration of disease associated with extensive interstitial fibrosis and early death of alpha3(IV-/- mice.These results suggest that preserving GBM/extracellular matrix integrity before the onset of proteinuria leads to significant disease protection, but if this window of opportunity is lost, MMP-inhibition at the later stages of Alport disease leads to accelerated glomerular and interstitial fibrosis. Our findings identify a crucial dual role for MMPs in the progression of Alport disease in alpha3(IV-/- mice, with an early pathogenic function and a later protective action. Hence, we propose possible

  17. Disease progression model for Clinical Dementia Rating–Sum of Boxes in mild cognitive impairment and Alzheimer’s subjects from the Alzheimer’s Disease Neuroimaging Initiative

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    Samtani MN

    2014-05-01

    Full Text Available Mahesh N Samtani, Nandini Raghavan, Gerald Novak, Partha Nandy, Vaibhav A Narayan On behalf of the Alzheimer’s disease Neuroimaging Initiative Janssen Research and Development, LLC, Raritan, New Jersey, USA Background: The objective of this analysis was to develop a nonlinear disease progression model, using an expanded set of covariates that captures the longitudinal Clinical Dementia Rating Scale–Sum of Boxes (CDR–SB scores. These were derived from the Alzheimer’s disease Neuroimaging Initiative ADNI-1 study, of 301 Alzheimer’s disease and mild cognitive impairment patients who were followed for 2–3 years. Methods: The model describes progression rate and baseline disease score as a function of covariates. The covariates that were tested fell into five groups: a hippocampal volume; b serum and cerebrospinal fluid (CSF biomarkers; c demographics and apolipoprotein Epsilon 4 (ApoE4 allele status; d baseline cognitive tests; and e disease state and comedications. Results: Covariates associated with baseline disease severity were disease state, hippocampal volume, and comedication use. Disease progression rate was influenced by baseline CSF biomarkers, Trail-Making Test part A score, delayed logical memory test score, and current level of impairment as measured by CDR–SB. The rate of disease progression was dependent on disease severity, with intermediate scores around the inflection point score of 10 exhibiting high disease progression rate. The CDR–SB disease progression rate in a typical patient, with late mild cognitive impairment and mild Alzheimer’s disease, was estimated to be approximately 0.5 and 1.4 points/year, respectively. Conclusions: In conclusion, this model describes disease progression in terms of CDR–SB changes in patients and its dependency on novel covariates. The CSF biomarkers included in the model discriminate mild cognitive impairment subjects as progressors and nonprogressors. Therefore, the model may

  18. Listening to the Patient Voice in Narcolepsy: Diagnostic Delay, Disease Burden, and Treatment Efficacy

    Science.gov (United States)

    Maski, Kiran; Steinhart, Erin; Williams, David; Scammell, Thomas; Flygare, Julie; McCleary, Kimberly; Gow, Monica

    2017-01-01

    Study Objectives: Describe common symptoms, comorbidities, functional limitations, and treatment responsiveness among patients with narcolepsy. Investigate the effect of pediatric onset of narcolepsy symptoms on time to diagnosis of narcolepsy and presence of comorbid depression. Methods: Cross-sectional survey of 1,699 people in the United States with self-reported diagnosis of narcolepsy. We utilized mixed-methods data analyses to report study findings. Results: Most participants reported receiving a diagnosis of narcolepsy more than 1 y after symptom onset. We found that the strongest predictor of this delayed diagnosis was pediatric onset of symptoms (odds ratio = 2.4, p narcolepsy symptoms. Overall, participants reported that fatigue and cognitive difficulties were their most burdensome symptoms in addition to sleepiness and cataplexy. The majority of participants reported residual daytime fatigue and/or sleepiness despite treatment. Most participants reported they could not perform at work or school as well as they would like because of narcolepsy symptoms. Conclusions: This study provides unique insight into the narcolepsy disease experience. The study quantifies the problem of diagnostic delay for narcolepsy patients in the United States and highlights that symptoms are more likely to be missed if they develop before 18 y of age. These results suggest that narcolepsy awareness efforts should be aimed at parents, pediatric health care providers, school professionals, and children/adolescents themselves. Disease burden is high because of problems with fatigue, cognition, and persistence of residual symptoms despite treatment. Citation: Maski K, Steinhart E, Williams D, Scammell T, Flygare J, McCleary K, Gow M. Listening to the patient voice in narcolepsy: diagnostic delay, disease burden and treatment efficacy. J Clin Sleep Med. 2017;13(3):419–425. PMID:27923434

  19. Amygdalin delays cell cycle progression and blocks growth of prostate cancer cells in vitro.

    Science.gov (United States)

    Makarević, Jasmina; Tsaur, Igor; Juengel, Eva; Borgmann, Hendrik; Nelson, Karen; Thomas, Christian; Bartsch, Georg; Haferkamp, Axel; Blaheta, Roman A

    2016-02-15

    Despite impressive survival benefits from new agents to treat metastasized prostate cancer (PCa), progressive drug resistance hinders long-term response and restricts the efficacy of subsequent therapy. Due to reported antitumor activity of amygdalin and growing popularity for complementary and alternative medicine the potential of this natural, widely used substance to exert antineoplastic effects on prostate cancer cells has been assessed. LNCaP (castration-sensitive), DU-145 and PC3 cells (castration-resistant) were exposed to different concentrations of amygdalin for 24h or 2weeks. Cell growth was measured by the MTT test, clonal formation by the clonogenic assay. Flow cytometry served to investigate apoptosis and cell cycle phases. Cell cycle regulating proteins and the mTOR-akt signaling axis were analyzed by western blotting. Amygdalin dose-dependently diminished tumor cell growth with maximum effects at 10mg/ml. Apoptosis of PC3 and LNCaP but not of DU-145 cells was reduced, whereas colony formation was suppressed in all cell lines. A decrease in the number of G2/M- and S-phase cells along with an elevated number of G0/G1-phase cells was recorded. The cell cycle proteins cdk 1, cdk 2 and cdk 4 as well as cyclin A, cyclin B and cyclin D3 were modulated by amygdalin after both 24h and 2weeks. Distinct effects on p19 and p27 expression and on Akt, Rictor and Raptor activation became evident only after 2weeks. Amygdalin exhibits significant antitumor activity in both castration-sensitive and castration-resistant PCa cell lines and merits further evaluation for therapeutic purposes. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Effect of maraviroc on HIV disease progression-related biomarkers.

    Science.gov (United States)

    Romero-Sánchez, M Concepción; Machmach, Kawthar; Gonzalez-Serna, Alejandro; Genebat, Miguel; Pulido, Ildefonso; García-García, María; Alvarez-Ríos, Ana Isabel; Ferrando-Martinez, Sara; Ruiz-Mateos, Ezequiel; Leal, Manuel

    2012-11-01

    The potential effect of blocking the CCR5 receptor on HIV disease progression biomarkers is not well understood. We showed that an 8-day maraviroc (MVC) monotherapy clinical test (MCT) can be used in selecting patients to receive MVC-containing combined antiretroviral therapy (cART). Using this MCT model, we assessed the effect of MVC on several HIV disease progression biomarkers during the MCT (MVC-specific effect) and following short-term (12-week) cART. We compared 45 patients on MVC monotherapy with a control group of 25 patients on MVC-sparing cART. We found that MVC did not modify any biomarkers in patients that had no virological response after the MCT. MVC-specific effects in patients with virological responses included increased CD8(+) T-cell activation and senescence levels, preservation of an increase in soluble CD14 (sCD14), and a decrease in D dimer levels. After 12 weeks, MVC-containing cART increased CD8(+) T-cell counts and preserved CD4(+) T-cell senescence levels compared with MVC-sparing cART. Moreover, there was a decrease in sCD14 levels in patients that received MVC-containing cART. In conclusion, effects compatible with CD8(+) T-cell redistribution in peripheral blood were observed after MVC therapy. However, MVC was associated with a favorable profile in HIV disease progression biomarkers only in patients with a virological response. These results support a potential clinical benefit of a therapy which includes MVC in HIV-infected patients.

  1. Orphan drugs in development for Huntington's disease: challenges and progress

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    Burgunder JM

    2015-02-01

    Full Text Available Jean-Marc Burgunder1–4 1Swiss Huntington’s Disease Centre, Department of Neurology, University of Bern, Bern, Switzerland; 2Department of Neurology, West China Hospital, Sichuan University, Chengdu, 3Department of Neurology, Xiangya Hospital, Central South University, Changsha, 4Department of Neurology, Sun Yat-sen University, Guangzhou, People’s Republic of China Abstract: Huntington’s disease is a monogenic disorder encompassing a variable phenotype with progressive cognitive, psychiatric, and movement disorders. Knowledge of the mechanisms involved in this disorder has made substantial advances since the discovery of the gene mutation. The dynamic mutation is the expansion of a CAG (cytosine-adenine-guanine repeat in the huntingtin (HTT gene, which is transcribed into an abnormal protein with an elongated polyglutamine tract. Polyglutamine HTT accumulates and is changed in its function in multifaceted ways related to the numerous roles of the normal protein. The protein is expressed in numerous areas of the brain and also in other organs. The major brain region involved in the disease process is the striatum, but it is clear that other systems are involved as well. This accumulated knowledge has now led to the development of treatment strategies based on specific molecular pathways for symptomatic and disease course-modifying treatment. The most proximal way to handle the disturbed protein is to hinder the gene transcription, translation, and/or to increase protein clearance. Other mechanisms now being approached include modulation of energy and intracellular signaling, induction of factors potentially leading to neuroprotection, as well as modulation of glial function. Several clinical trials based on these approaches are now under way, and it is becoming clear that a future disease-modifying therapy will be a combination of several approaches harmonized with symptomatic treatments. In this review, some of the most promising and

  2. Global stability of a delayed mosquito-transmitted disease model with stage structure

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    B. G. Sampath Aruna Pradeep

    2015-01-01

    Full Text Available This article presents a new eco-epidemiological deterministic delay differential equation model considering a biological controlling approach on mosquitoes, for endemic dengue disease with variable host (human and variable vector (Aedes aegypti populations, and stage structure for mosquitoes. In this model, predator-prey interaction is considered by using larvae as prey and mosquito-fish as predator. We give a complete classification of equilibria of the model, and sufficient conditions for global stability/global attractivity of some equilibria are given by constructing suitable Lyapunov functionals and using Lyapunov-LaSalle invariance principle. Also, numerical simulations are presented to show the validity of our results.

  3. Z944, a Novel Selective T-Type Calcium Channel Antagonist Delays the Progression of Seizures in the Amygdala Kindling Model.

    Science.gov (United States)

    Casillas-Espinosa, Pablo Miguel; Hicks, Ashleigh; Jeffreys, Amy; Snutch, Terrance P; O'Brien, Terence J; Powell, Kim L

    2015-01-01

    Temporal lobe epilepsy (TLE) is the most common form of drug resistant epilepsy. Current treatment is symptomatic, suppressing seizures, but has no disease modifying effect on epileptogenesis. We examined the effects of Z944, a potent T-type calcium channel antagonist, as an anti-seizure agent and against the progression of kindling in the amygdala kindling model of TLE. The anti-seizure efficacy of Z944 (5mg/kg, 10mg/kg, 30mg/kg and 100mg/kg) was assessed in fully kindled rats (5 class V seizures) as compared to vehicle, ethosuximide (ETX, 100mg/kg) and carbamazepine (30mg/kg). Each animal received the seven treatments in a randomised manner. Seizure class and duration elicited by six post-drug stimulations was determined. To investigate for effects in delaying the progression of kindling, naive animals received Z944 (30mg/kg), ETX (100mg/kg) or vehicle 30-minutes prior to each kindling stimulation up to a maximum of 30 stimulations, with seizure class and duration recorded after each stimulation. At the completion of drug treatment, CaV3.1, CaV3.2 and CaV3.3 mRNA expression levels were assessed in the hippocampus and amygdala using qPCR. Z944 was not effective at suppressing seizures in fully kindled rats compared to vehicle. Animals receiving Z944 required significantly more stimulations to evoke a class III (pkindled state (pkindling. This could be a potential for a new therapeutic intervention to mitigate the development and progression of epilepsy.

  4. Parkinson disease and progressive supranuclear palsy: protein expression in skin

    OpenAIRE

    2016-01-01

    Abstract Objective This study characterizes the expression of tau (p‐tau) and α‐synuclein (α‐syn) by immunohistochemistry in the skin of three different populations: healthy control (HC), Parkinson disease (PD), and progressive supranuclear paralysis (PSP) subjects, with the purpose of finding a biomarker that could differentiate between subjects with PD and PSP. Material and Methods We evaluated the presence of p‐tau and α‐syn in a pilot study in the skin of three distinct groups of patients...

  5. Retrospective study of the effect of disease progression on patient reported outcomes in HER-2 negative metastatic breast cancer patients

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    Yu Elaine

    2011-06-01

    Full Text Available Abstract Background This retrospective study evaluated the impact of disease progression and of specific sites of metastasis on patient reported outcomes (PROs that assess symptom burden and health related quality of life (HRQoL in women with metastatic breast cancer (mBC. Methods HER-2 negative mBC patients (n = 102 were enrolled from 7 U.S. community oncology practices. Demographic, disease and treatment characteristics were abstracted from electronic medical records and linked to archived Patient Care Monitor (PCM assessments. The PCM is a self-report measure of symptom burden and HRQoL administered as part of routine care in participating practices. Linear mixed models were used to examine change in PCM scores over time. Results Mean age was 57 years, with 72% of patients Caucasian, and 25% African American. Median time from mBC diagnosis to first disease progression was 8.8 months. Metastasis to bone (60%, lung (28% and liver (26% predominated at initial metastatic diagnosis. Results showed that PCM items assessing fatigue, physical pain and trouble sleeping were sensitive to either general effects of disease progression or to effects associated with specific sites of metastasis. Progression of disease was also associated with modest but significant worsening of General Physical Symptoms, Treatment Side Effects, Acute Distress and Impaired Performance index scores. In addition, there were marked detrimental effects of liver metastasis on Treatment Side Effects, and of brain metastasis on Acute Distress. Conclusions Disease progression has a detrimental impact on cancer-related symptoms. Delaying disease progression may have a positive impact on patients' HRQoL.

  6. Progress Toward Eliminating Hepatitis A Disease in the United States.

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    Murphy, Trudy V; Denniston, Maxine M; Hill, Holly A; McDonald, Marian; Klevens, Monina R; Elam-Evans, Laurie D; Nelson, Noele P; Iskander, John; Ward, John D

    2016-02-12

    Hepatitis A virus (HAV) disease disproportionately affects adolescents and young adults, American Indian/Alaska Native and Hispanic racial/ethnic groups, and disadvantaged populations. During 1996-2006, the Advisory Committee on Immunization Practices (ACIP) made incremental changes in hepatitis A (HepA) vaccination recommendations to increase coverage for children and persons at high risk for HAV infection. This report examines the temporal association of ACIP-recommended HepA vaccination and disparities (on the absolute scale) in cases of HAV disease and on seroprevalence of HAV-related protection (measured as antibody to HAV [anti-HAV]). ACIP-recommended childhood HepA vaccination in the United States has eliminated most absolute disparities in HAV disease by age, race/ethnicity, and geographic area with relatively modest ≥1-dose and ≥2-dose vaccine coverage. However, the increasing proportion of cases of HAV disease among adults with identified and unidentified sources of exposure underscores the importance of considering new strategies for preventing HAV infection among U.S. adults. For continued progress to be made toward elimination of HAV disease in the United States, additional strategies are needed to prevent HAV infection among an emerging population of susceptible adults. Notably, HAV infection remains endemic in much of the world, contributing to U.S. cases through international travel and the global food economy.

  7. Immune evasion mechanisms of Entamoeba histolytica: progression to disease

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    Sharmin eBegum

    2015-12-01

    Full Text Available Entamoeba histolytica (Eh is a protozoan parasite that infects 10% of the world’s population and results in 100,000 deaths/year from amebic dysentery and/or liver abscess. In most cases, this extracellular parasite colonizes the colon by high affinity binding to MUC2 mucin without disease symptoms, whereas in some cases, Eh triggers an aggressive inflammatory response upon invasion of the colonic mucosa. The specific host-parasite factors critical for disease pathogenesis are still not well characterized. From the parasite, the signature events that lead to disease progression are cysteine protease cleavage of the C-terminus of MUC2 that dissolves the mucus layer followed by Eh binding and cytotoxicity of the mucosal epithelium. The host mounts an ineffective excessive host pro-inflammatory response following contact with host cells that causes tissue damage and participates in disease pathogenesis as Eh escapes host immune clearance by mechanisms that are not completely understood. Ameba can modulate or destroy effector immune cells by inducing neutrophil apoptosis and suppressing respiratory burst or nitric oxide (NO production from macrophages. Eh adherence to the host cells also induce multiple cytotoxic effects that can promote cell death through phagocytosis, apoptosis or by trogocytosis (ingestion of living cells that might play critical roles in immune evasion. This review focuses on the immune evasion mechanisms that Eh uses to survive and induce disease manifestation in the host.

  8. Environmental factors affecting inflammatory bowel disease: have we made progress?

    Science.gov (United States)

    Lakatos, Peter Laszlo

    2009-01-01

    The pathogenesis of inflammatory bowel disease (IBD) is only partially understood; various environmental and host (e.g. genetic, epithelial, immune, and nonimmune) factors are involved. The critical role for environmental factors is strongly supported by recent worldwide trends in IBD epidemiology. One important environmental factor is smoking. A meta-analysis partially confirms previous findings that smoking was found to be protective against ulcerative colitis and, after the onset of the disease, might improve its course, decreasing the need for colectomy. In contrast, smoking increases the risk of developing Crohn's disease and aggravates its course. The history of IBD is dotted by cyclic reports on the isolation of specific infectious agents responsible for Crohn's disease or ulcerative colitis. The more recently published cold chain hypothesis is providing an even broader platform by linking dietary factors and microbial agents. An additional, recent theory has suggested a breakdown in the balance between putative species of 'protective' versus 'harmful' intestinal bacteria - this concept has been termed dysbiosis resulting in decreased bacterial diversity. Other factors such as oral contraceptive use, appendectomy, dietary factors (e.g. refined sugar, fat, and fast food), perinatal events, and childhood infections have also been associated with both diseases, but their role is more controversial. Nonetheless, there is no doubt that economic development, leading to improved hygiene and other changes in lifestyle ('westernized lifestyle') may play a role in the increase in IBD. This review article focuses on the role of environmental factors in the pathogenesis and progression of IBDs.

  9. An alternative medical approach for the neuroprotective therapy to slow the progression of Parkinson's disease.

    Science.gov (United States)

    Muroyama, Akiko

    2013-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the core symptoms such as bradykinesia, resting tremor, rigidity and postural instability. Currently, pharmacotherapy and surgical approaches for the treatments of PD can only improve the neurological symptoms. Therefore, to search neuroprotective therapies using pharmacological and nonpharmacological approaches could be important to delay the progression of pathogenesis in PD. Coenzyme Q10 (CoQ10) is a component of the electron transport chain as well as an important antioxidant in mitochondrial and lipid membranes. The central role of CoQ10 in two areas implicated in the pathogenesis of PD, mitochondrial dysfunction and oxidative damages, suggest that it may be useful for treatment to slow the progression of PD. The neuroprotective effect of CoQ10 has been reported in several in vivo and in vitro models of neurodegenerative disorders. Although CoQ10 attenuated the toxin-induced reduction of dopamine content and tyrosine hydroxylase-immunoreactive neurons in the striatum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, it is still unknown how this nutrition affects the mitochondrial function. We demonstrated that oral administration of CoQ10 significantly attenuated the loss of dopaminergic nerve terminals induced by MPTP treatment. Furthermore, our experimental data indicate that an inhibition of mitochondrial cytochrome c release is one of the primary targets for CoQ10 and may lead to a potent neuroprotection.

  10. Acidosis: progression of chronic kidney disease and quality of life.

    Science.gov (United States)

    de-Brito Ashurst, Ione; O'Lone, Emma; Kaushik, Tarun; McCafferty, Kieran; Yaqoob, Muhammad M

    2015-06-01

    Metabolic acidosis (MA) is relatively common in patients with chronic kidney disease (CKD) particularly in stages 4 and 5. It is assumed to play a contributory role in the development of several complications including bone disease, skeletal muscle wasting, altered protein synthesis, and degradation. Recent evidence also suggests that even mild acidosis might play a role in progressive glomerular filtration rate loss. Experimental and clinical studies suggest that correction of acidosis by alkali therapy attenuates these complications and improves quality of life. Despite several recent small and single-center studies supporting this notion, more robust evidence is required with regard to the long-term benefits of alkali therapy, type of alkali supplements, and the optimal level of serum bicarbonate.

  11. Progress in treatment of nonalcoholic fatty liver disease

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    SHI Junping

    2014-08-01

    Full Text Available The incidence of nonalcoholic fatty liver disease (NAFLD increases with the prevalence of obesity, but specific treatment for this disease is lacking. First, the possible clinical benefits from different strategies of lifestyle modification, as well as the methods for improving intervention effect and existing problems, are reviewed. Second, the indications for bariatric surgery and the main research directions are briefly presented. Finally, several promising drugs including vitamin E, farnesoid X receptor agonist, intestinal probiotics, polyunsaturated fatty acids, glucagon-like peptide-1 receptor agonist, and pentoxifylline are elaborated on. The currently acquired clinical evidence and progress in basic research suggest that lifestyle modification is the basis for treatment in all patients with NAFLD, but better schemes are needed to improve the intervention effect; bariatric surgery is one of the effective therapies for NAFLD patients with morbid obesity who have no relevant contraindications; drug treatment should be selectively applied to the population with a confirmed diagnosis of NAFLD.

  12. Pharmacotherapy of Parkinson’s disease:Progress or regress?

    Directory of Open Access Journals (Sweden)

    Karolina Pytka

    2013-07-01

    Full Text Available Parkinson’s disease (PD is a chronic, progressive disease of the central nervous system (CNS,characterized by a slow loss of dopaminergic neurons in the substantia nigra, leading to significantdecrease in dopamine (DA levels in the striatum. Currently used drugs, such as levodopa(L-DOPA, amantadine, dopamine agonists (D or anticholinergic drugs, are not effective enough,and do not eliminate the causes of disease. Many research centers are conducting researchon new forms of currently used drugs (e.g. Duodopa, XP21279, IPX066, new drugs of alreadyknown groups (e.g. safinamide, medicines that suppress side effects of L-DOPA (e.g. AFQ056,fipamezole, and, finally, compounds with a novel mechanism of action (e.g. PMY50028, A2Areceptor antagonists. A lot of scientific reports indicate an important role of A2A receptorsin the regulation of the central movement system, so a new group of compounds – selectiveantagonists of A2A receptors (e.g. istradefylline, preladenant, SYN115 – has been developed and their potential use in PD has been examined. Clinical studies of A2A receptor antagonistshave shown that this group of compounds can shorten off periods and at the same time theydo not worsen dyskinesias in patients with PD. Moreover, there is ongoing research on newforms of treatment, such as gene therapy. Attempts to apply the viral vector AAV-2, whichwill be able to infect neurons with a variety of genes, including the gene of glutamate decarboxylase(GAD, neurturin (NTN, or aromatic L-amino acid decarboxylase, are currently beingcarried out. The results of phase I and II clinical studies showed some efficacy of this form oftreatment, but the method requires further studies. An analysis of potential future therapiesof Parkinson’s disease suggests that some progress in this field has been made.

  13. Economic impact of disease progression following front-line therapy in classical Hodgkin lymphoma.

    Science.gov (United States)

    Yasenchak, Christopher A; Tseng, Wan-Yu; Yap, Mark; Rembert, Debra; Patt, Debra A

    2015-01-01

    The current study aimed to assess the economic burden of progressive disease among patients with Hodgkin lymphoma (HL) receiving second- or third-line therapy in a large US network of community-based practices. This retrospective, observational cohort analysis used electronic health records to examine adult patients with classical HL who received chemotherapy between 2007 and 2011. Of 291 observations, 112 had non-progressive disease (received only one line of therapy; LOT1), 114 received second-line therapy (LOT2), and 65 received third-line therapy (LOT3). In LOT2, 49 patients (43%) underwent transplant. In LOT3, 13 patients (20%) underwent transplant. The mean total cost per line of therapy was $21 956 in LOT1, $77 219 in LOT2, and $59 442 in LOT3. When transplant was required, the mean total cost per line of therapy increased 7- to 8-fold when compared with the cost of LOT1 (approximately $154 000 for LOT2 and $193 000 for LOT3). Future therapies that intervene as early as possible in the treatment algorithm to prevent or significantly delay relapse will likely result in significant cost savings.

  14. Neglected tropical diseases: progress towards addressing the chronic pandemic.

    Science.gov (United States)

    Molyneux, David H; Savioli, Lorenzo; Engels, Dirk

    2017-01-21

    The concept of neglected tropical diseases (NTDs) emerged more than a decade ago and has been recognised as a valid way to categorise diseases that affect the poorest individuals. Substantial progress in control and elimination has been achieved and policy momentum has been generated through continued bilateral, philanthropic, and non-governmental development organisation (NGDO) support, and donations of drugs from pharmaceutical companies. WHO has defined a Roadmap to reach 2020 targets, which was endorsed by member states in a World Health Assembly Resolution in 2013. NTDs have been included within the Sustainable Development Goal targets and are a crucial component of universal health coverage, conceptualised as "leaving no one behind". WHO reported that more than 1 billion people in 88 countries have benefited from preventive chemotherapy in 2014. The research agenda has defined the need for affordable products (diagnostics, drugs and insecticides). However challenges such as insecurity and weak health systems continue to prevail in the poorest countries, inhibiting progress in scaling up and also in achieving Roadmap goals. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Alzheimer's Disease Neuroimaging Initiative 2 Clinical Core: Progress and plans.

    Science.gov (United States)

    Aisen, Paul S; Petersen, Ronald C; Donohue, Michael; Weiner, Michael W

    2015-07-01

    This article reviews the current status of the Clinical Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI), and summarizes planning for the next stage of the project. Clinical Core activities and plans were synthesized based on discussions among the Core leaders and external advisors. The longitudinal data in ADNI-2 provide natural history data on a clinical trials population and continue to inform refinement and standardization of assessments, models of trajectories, and clinical trial methods that have been extended into sporadic preclinical Alzheimer's disease (AD). Plans for the next phase of the ADNI project include maintaining longitudinal follow-up of the normal and mild cognitive impairment cohorts, augmenting specific clinical cohorts, and incorporating novel computerized cognitive assessments and patient-reported outcomes. A major hypothesis is that AD represents a gradually progressive disease that can be identified precisely in its long presymptomatic phase, during which intervention with potentially disease-modifying agents may be most useful. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  16. CT perfusion during delayed cerebral ischemia after subarachnoid hemorrhage: distinction between reversible ischemia and ischemia progressing to infarction

    Energy Technology Data Exchange (ETDEWEB)

    Cremers, Charlotte H.P. [University Medical Center Utrecht, Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, PO Box 85500, Utrecht, Utrecht (Netherlands); University Medical Center Utrecht, Department of Radiology, Utrecht (Netherlands); Vos, Pieter C. [University Medical Center Utrecht, Image Sciences Institute, Utrecht (Netherlands); Schaaf, Irene C. van der; Velthuis, Birgitta K.; Dankbaar, Jan Willem [University Medical Center Utrecht, Department of Radiology, Utrecht (Netherlands); Vergouwen, Mervyn D.I.; Rinkel, Gabriel J.E. [University Medical Center Utrecht, Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, PO Box 85500, Utrecht, Utrecht (Netherlands)

    2015-09-15

    Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) can be reversible or progress to cerebral infarction. In patients with a deterioration clinically diagnosed as DCI, we investigated whether CT perfusion (CTP) can distinguish between reversible ischemia and ischemia progressing to cerebral infarction. From a prospectively collected series of aSAH patients, we included those with DCI, CTP on the day of clinical deterioration, and follow-up imaging. In qualitative CTP analyses (visual assessment), we calculated positive and negative predictive value (PPV and NPV) with 95 % confidence intervals (95%CI) of a perfusion deficit for infarction on follow-up imaging. In quantitative analyses, we compared perfusion values of the least perfused brain tissue between patients with and without infarction by using receiver-operator characteristic curves and calculated a threshold value with PPV and NPV for the perfusion parameter with the highest area under the curve. In qualitative analyses of 33 included patients, 15 of 17 patients (88 %) with and 6 of 16 patients (38 %) without infarction on follow-up imaging had a perfusion deficit during clinical deterioration (p = 0.002). Presence of a perfusion deficit had a PPV of 71 % (95%CI: 48-89 %) and NPV of 83 % (95%CI: 52-98 %) for infarction on follow-up. Quantitative analyses showed that an absolute minimal cerebral blood flow (CBF) threshold of 17.7 mL/100 g/min had a PPV of 63 % (95%CI: 41-81 %) and a NPV of 78 % (95%CI: 40-97 %) for infarction. CTP may differ between patients with DCI who develop infarction and those who do not. For this purpose, qualitative evaluation may perform marginally better than quantitative evaluation. (orig.)

  17. Connected speech as a marker of disease progression in autopsy-proven Alzheimer's disease.

    Science.gov (United States)

    Ahmed, Samrah; Haigh, Anne-Marie F; de Jager, Celeste A; Garrard, Peter

    2013-12-01

    Although an insidious history of episodic memory difficulty is a typical presenting symptom of Alzheimer's disease, detailed neuropsychological profiling frequently demonstrates deficits in other cognitive domains, including language. Previous studies from our group have shown that language changes may be reflected in connected speech production in the earliest stages of typical Alzheimer's disease. The aim of the present study was to identify features of connected speech that could be used to examine longitudinal profiles of impairment in Alzheimer's disease. Samples of connected speech were obtained from 15 former participants in a longitudinal cohort study of ageing and dementia, in whom Alzheimer's disease was diagnosed during life and confirmed at post-mortem. All patients met clinical and neuropsychological criteria for mild cognitive impairment between 6 and 18 months before converting to a status of probable Alzheimer's disease. In a subset of these patients neuropsychological data were available, both at the point of conversion to Alzheimer's disease, and after disease severity had progressed from the mild to moderate stage. Connected speech samples from these patients were examined at later disease stages. Spoken language samples were obtained using the Cookie Theft picture description task. Samples were analysed using measures of syntactic complexity, lexical content, speech production, fluency and semantic content. Individual case analysis revealed that subtle changes in language were evident during the prodromal stages of Alzheimer's disease, with two-thirds of patients with mild cognitive impairment showing significant but heterogeneous changes in connected speech. However, impairments at the mild cognitive impairment stage did not necessarily entail deficits at mild or moderate stages of disease, suggesting non-language influences on some aspects of performance. Subsequent examination of these measures revealed significant linear trends over the

  18. Multi-delay arterial spin labeling perfusion MRI in moyamoya disease-comparison with CT perfusion imaging

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Rui [Chinese Academy of Sciences, State Key Laboratory of Brain and Cognitive Science, Beijing MRI Center for Brain Research, Institute of Biophysics, Beijing (China); University of Chinese Academy of Sciences, Graduate School, Beijing (China); UCLA-Beijing Joint Center for Advanced Brain Imaging, Beijing (China); UCLA-Beijing Joint Center for Advanced Brain Imaging, Los Angeles, CA (United States); Yu, Songlin [Capital Medical University, Department of Neurosurgery, Beijing Tiantan Hospital, Beijing (China); University of California Los Angeles, Department of Neurology, Los Angeles (United States); Alger, Jeffry R.; Wang, Danny J.J. [University of California Los Angeles, Department of Neurology, Los Angeles (United States); UCLA-Beijing Joint Center for Advanced Brain Imaging, Beijing (China); UCLA-Beijing Joint Center for Advanced Brain Imaging, Los Angeles, CA (United States); Zuo, Zhentao; Wang, Bo [Chinese Academy of Sciences, State Key Laboratory of Brain and Cognitive Science, Beijing MRI Center for Brain Research, Institute of Biophysics, Beijing (China); Chen, Juan [Beijing Hospital, Department of Radiology, Beijing (China); Wang, Rong; Zhao, Jizong [Capital Medical University, Department of Neurosurgery, Beijing Tiantan Hospital, Beijing (China); An, Jing [Siemens Shenzhen Magnetic Resonance Ltd, Shenzhen (China); Xue, Rong [Chinese Academy of Sciences, State Key Laboratory of Brain and Cognitive Science, Beijing MRI Center for Brain Research, Institute of Biophysics, Beijing (China); UCLA-Beijing Joint Center for Advanced Brain Imaging, Beijing (China); UCLA-Beijing Joint Center for Advanced Brain Imaging, Los Angeles, CA (United States)

    2014-05-15

    To present a multi-delay pseudo-continuous ASL (pCASL) protocol that offers simultaneous measurements of cerebral blood flow (CBF) and arterial transit time (ATT), and to study correlations between multi-delay pCASL and CT perfusion in moyamoya disease. A 4 post-labeling delay (PLD) pCASL protocol was applied on 17 patients with moyamoya disease who also underwent CT perfusion imaging. ATT was estimated using the multi-delay protocol and included in the calculation of CBF. ASL and CT perfusion images were rated for lesion severity/conspicuity. Pearson correlation coefficients were calculated across voxels between the two modalities in grey and white matter of each subject respectively and between normalized mean values of ASL and CT perfusion measures in major vascular territories. Significant associations between ASL and CT perfusion were detected using subjective ratings, voxel-wise analysis in grey and white matter and region of interest (ROI)-based analysis of normalized mean perfusion. The correlation between ASL CBF and CT perfusion was improved using the multi-delay pCASL protocol compared to CBF acquired at a single PLD of 2 s (P < 0.05). There is a correlation between perfusion data from ASL and CT perfusion imaging in patients with moyamoya disease. Multi-delay ASL can improve CBF quantification, which could be a prognostic imaging biomarker in patients with moyamoya disease. (orig.)

  19. Casein Kinase Iγ2 Impairs Fibroblasts Actin Stress Fibers Formation and Delays Cell Cycle Progression in G1

    Directory of Open Access Journals (Sweden)

    Mathieu Latreille

    2012-01-01

    Full Text Available Actin cytoskeleton remodeling is under the regulation of multiple proteins with various activities. Here, we demonstrate that the γ2 isoform of Casein Kinase I (CKIγ2 is part of a novel molecular path regulating the formation of actin stress fibers. We show that overexpression of CKIγ2 in fibroblasts alters cell morphology by impairing actin stress fibers formation. We demonstrate that this is concomitant with increased phosphorylation of the CDK inhibitor p27Kip and lower levels of activated RhoA, and is dependent on CKIγ2 catalytic activity. Moreover, we report that roscovitine, a potent inhibitor of cyclin-dependent kinases, including Cdk5, decreases p27Kip protein levels and restores actin stress fibers formation in CKIγ2 overexpressing cells, suggesting the existence of a CKIγ2-Cdk5-p27Kip-RhoA pathway in regulating actin remodeling. On the other hand, we also show that in a manner independent of its catalytic activity, CKIγ2 delays cell cycle progression through G1. Collectively our findings reveal that CKIγ2 is a novel player in the control of actin cytoskeleton dynamics and cell proliferation.

  20. microRNA-206 promotes skeletal muscle regeneration and delays progression of Duchenne muscular dystrophy in mice

    Science.gov (United States)

    Liu, Ning; Williams, Andrew H.; Maxeiner, Johanna M.; Bezprozvannaya, Svetlana; Shelton, John M.; Richardson, James A.; Bassel-Duby, Rhonda; Olson, Eric N.

    2012-01-01

    Skeletal muscle injury activates adult myogenic stem cells, known as satellite cells, to initiate proliferation and differentiation to regenerate new muscle fibers. The skeletal muscle–specific microRNA miR-206 is upregulated in satellite cells following muscle injury, but its role in muscle regeneration has not been defined. Here, we show that miR-206 promotes skeletal muscle regeneration in response to injury. Genetic deletion of miR-206 in mice substantially delayed regeneration induced by cardiotoxin injury. Furthermore, loss of miR-206 accelerated and exacerbated the dystrophic phenotype in a mouse model of Duchenne muscular dystrophy. We found that miR-206 acts to promote satellite cell differentiation and fusion into muscle fibers through suppressing a collection of negative regulators of myogenesis. Our findings reveal an essential role for miR-206 in satellite cell differentiation during skeletal muscle regeneration and indicate that miR-206 slows progression of Duchenne muscular dystrophy. PMID:22546853

  1. Diagnosis of Parkinson’s disease: progress and future prospects

    Directory of Open Access Journals (Sweden)

    Patel RA

    2015-07-01

    Full Text Available Roshni A Patel,1 Jennifer G Goldman2 1Rush Medical College, Rush University, Chicago, IL, USA; 2Section of Parkinson’s Disease and Movement Disorders, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA Abstract: This review focuses on methods for diagnosing Parkinson’s disease (PD, highlighting clinical, pathological, and biomarker-driven approaches. For each of these diagnostic approaches, the past, present, and future prospects of diagnosing PD will be explored. Our understanding of PD – its pathogenesis and clinical spectrum – is ever changing. PD is now recognized as a complex multisystem disorder with motor and nonmotor features, including those preceding the onset of classic motor features as well as different phenotypes, often associated with different genetic mutations. Theories regarding the pathophysiology of PD and the role of α-synuclein, its deposition outside of the central nervous system, and possible progression or propagation are discussed. It has been almost 200 years since James Parkinson first described this disorder, and since then, our understanding of the disease process has evolved and become more sophisticated. However, the clinical diagnostic criteria used have remained fairly static for decades. Proposals for redefining PD’s diagnostic criteria incorporate clinical, pathological, and biomarker-driven elements, individually and/or collectively, and may need to consider whether individualized risk and personalized profiles could be ascertained. Keywords: α-synuclein, biomarker, cerebrospinal fluid, imaging, neuropathology

  2. Blood platelets in the progression of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Nina S Gowert

    Full Text Available Alzheimer's disease (AD is characterized by neurotoxic amyloid-ß plaque formation in brain parenchyma and cerebral blood vessels known as cerebral amyloid angiopathy (CAA. Besides CAA, AD is strongly related to vascular diseases such as stroke and atherosclerosis. Cerebrovascular dysfunction occurs in AD patients leading to alterations in blood flow that might play an important role in AD pathology with neuronal loss and memory deficits. Platelets are the major players in hemostasis and thrombosis, but are also involved in neuroinflammatory diseases like AD. For many years, platelets were accepted as peripheral model to study the pathophysiology of AD because platelets display the enzymatic activities to generate amyloid-ß (Aß peptides. In addition, platelets are considered to be a biomarker for early diagnosis of AD. Effects of Aß peptides on platelets and the impact of platelets in the progression of AD remained, however, ill-defined. The present study explored the cellular mechanisms triggered by Aß in platelets. Treatment of platelets with Aß led to platelet activation and enhanced generation of reactive oxygen species (ROS and membrane scrambling, suggesting enhanced platelet apoptosis. More important, platelets modulate soluble Aß into fibrillar structures that were absorbed by apoptotic but not vital platelets. This together with enhanced platelet adhesion under flow ex vivo and in vivo and platelet accumulation at amyloid deposits of cerebral vessels of AD transgenic mice suggested that platelets are major contributors of CAA inducing platelet thrombus formation at vascular amyloid plaques leading to vessel occlusion critical for cerebrovascular events like stroke.

  3. Global gene expression profile progression in Gaucher disease mouse models

    Directory of Open Access Journals (Sweden)

    Zhang Wujuan

    2011-01-01

    Full Text Available Abstract Background Gaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide. The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells in visceral organs and their abnormal functions are obscure. Results To elucidate this pathogenic pathway, developmental global gene expression analyses were conducted in distinct Gba1 point-mutated mice (V394L/V394L and D409 V/null. About 0.9 to 3% of genes had altered expression patterns (≥ ± 1.8 fold change, representing several categories, but particularly macrophage activation and immune response genes. Time course analyses (12 to 28 wk of INFγ-regulated pro-inflammatory (13 and IL-4-regulated anti-inflammatory (11 cytokine/mediator networks showed tissue differential profiles in the lung and liver of the Gba1 mutant mice, implying that the lipid-storage macrophages were not functionally inert. The time course alterations of the INFγ and IL-4 pathways were similar, but varied in degree in these tissues and with the Gba1 mutation. Conclusions Biochemical and pathological analyses demonstrated direct relationships between the degree of tissue glucosylceramides and the gene expression profile alterations. These analyses implicate IFNγ-regulated pro-inflammatory and IL-4-regulated anti-inflammatory networks in differential disease progression with implications for understanding the Gaucher disease course and pathophysiology.

  4. Multilingualism (but not always bilingualism) delays the onset of Alzheimer disease: evidence from a bilingual community.

    Science.gov (United States)

    Chertkow, Howard; Whitehead, Victor; Phillips, Natalie; Wolfson, Christina; Atherton, Julie; Bergman, Howard

    2010-01-01

    A recent paper by Bialystok et al in Neuropsychologia (vol. 45, pgs. 459 to 464) suggested that early bilingualism produced a statistically significant 4.1-year delay in onset of memory loss symptoms in older individuals with Alzheimer disease, possibly reflecting an increase in the cognitive reserve of these individuals. That study focused on multilingual elderly patients of whom 90% were immigrants. Our memory clinic, in Montreal Canada, has the advantage of having a large set of individuals who are either multilingual immigrants to Canada, or who are nonimmigrants but raised in both official languages of Canada--French and English. We thus attempted to replicate the above findings using a larger cohort in a different setting. We examined age at diagnosis of Alzheimer disease and age at symptom onset for all unilingual versus multilingual participants, and then for those who were nonimmigrant English/French bilinguals. Overall, we found a small but significant protective effect of more than 2 languages spoken, but we found no significant benefit in bilinguals overall in relation to age at diagnosis or age at symptom onset. However, in the immigrant group, the results mirrored those of Bialystok et al with 2 or more languages delaying the diagnosis of Alzheimer disease by almost 5 years. A trend toward the same effect was also seen in nonimmigrants whose first language was French. In contrast, in nonimmigrants whose first language was English, no such effect was found. These results are discussed in relation to the earlier findings and the theory of cognitive reserve.

  5. Recovery from Multiple APAs Delays Gait Initiation in Parkinson’s Disease

    Science.gov (United States)

    Cohen, Rajal G.; Nutt, John G.; Horak, Fay B.

    2017-01-01

    Background: Freezing of gait in Parkinson’s disease (PD) has been linked with deficits in inhibitory control, but causal mechanisms are not established. Freezing at gait initiation (start hesitation) is often accompanied by multiple anticipatory postural adjustments (APAs). If inhibition deficits contribute to freezing by interfering with ability to inhibit initial weight shifts in the wrong direction, then PD subjects should experience more episodes of multiple APAs than healthy controls (HCs) do. If inhibition deficits contribute to freezing by interfering with ability to release a previously inhibited step following multiple APAs, then step onset following multiple APAs should be delayed more in people with PD than in HCs. Methods: Older adults with PD and HC subjects rapidly initiated stepping in response to a light cue in blocks of simple (SRT) and choice (CRT) conditions. We recorded kinematics and ground reaction forces, and we administered the Stroop task to assess inhibitory control. Results: Multiple APAs were more common in CRT than SRT conditions but were equally common in HC and PD subjects. Step onsets were delayed in both conditions and further delayed in trials with multiple APAs, except for HC subjects in SRT trials. Poor Stroop performance correlated with many multiple APAs, late step onset, and rearward position of center of mass (COM) at cue presentation. Forward motion of the COM during the APA was higher in trials with multiple APAs than in trials with single APAs, especially in CRT trials and in PD subjects without self-reported freezing. Conclusion: Start hesitation is not caused by multiple APAs per se, but may be associated with difficulty recovering from multiple APAs, due to difficulty releasing a previously inhibited step. PMID:28261073

  6. Z944, a Novel Selective T-Type Calcium Channel Antagonist Delays the Progression of Seizures in the Amygdala Kindling Model.

    Directory of Open Access Journals (Sweden)

    Pablo Miguel Casillas-Espinosa

    Full Text Available Temporal lobe epilepsy (TLE is the most common form of drug resistant epilepsy. Current treatment is symptomatic, suppressing seizures, but has no disease modifying effect on epileptogenesis. We examined the effects of Z944, a potent T-type calcium channel antagonist, as an anti-seizure agent and against the progression of kindling in the amygdala kindling model of TLE. The anti-seizure efficacy of Z944 (5mg/kg, 10mg/kg, 30mg/kg and 100mg/kg was assessed in fully kindled rats (5 class V seizures as compared to vehicle, ethosuximide (ETX, 100mg/kg and carbamazepine (30mg/kg. Each animal received the seven treatments in a randomised manner. Seizure class and duration elicited by six post-drug stimulations was determined. To investigate for effects in delaying the progression of kindling, naive animals received Z944 (30mg/kg, ETX (100mg/kg or vehicle 30-minutes prior to each kindling stimulation up to a maximum of 30 stimulations, with seizure class and duration recorded after each stimulation. At the completion of drug treatment, CaV3.1, CaV3.2 and CaV3.3 mRNA expression levels were assessed in the hippocampus and amygdala using qPCR. Z944 was not effective at suppressing seizures in fully kindled rats compared to vehicle. Animals receiving Z944 required significantly more stimulations to evoke a class III (p<0.05, IV (p<0.01 or V (p<0.0001 seizure, and to reach a fully kindled state (p<0.01, than animals receiving vehicle. There was no significant difference in the mRNA expression of the T-type Ca2+ channels in the hippocampus or amygdala. Our results show that selectively targeting T-type Ca2+ channels with Z944 inhibits the progression of amygdala kindling. This could be a potential for a new therapeutic intervention to mitigate the development and progression of epilepsy.

  7. Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Ditsworth, Dara; Maldonado, Marcus; McAlonis-Downes, Melissa; Sun, Shuying; Seelman, Amanda; Drenner, Kevin; Arnold, Eveline; Ling, Shuo-Chien; Pizzo, Donald; Ravits, John; Cleveland, Don W; Da Cruz, Sandrine

    2017-06-01

    Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43(Q331K) mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43(Q331K) gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types.

  8. Smart garments in chronic disease management: progress and challenges

    Science.gov (United States)

    Khosla, Ajit

    2012-10-01

    This paper presents the progress made developments in the area of Smart Garments for chronic disease management over last 10 years. A large number of health monitoring smart garments and wearable sensors have been manufactured to monitor patient's physiological parameters such as electrocardiogram, blood pressure, body temperature, heart rate, oxygen saturation, while patient is not in hospital. In last few years with the advancement in smartphones and cloud computing it is now possible to send the measure physiological data to any desired location. However there are many challenges in the development of smart garment systems. The two major challenges are development of new lightweight power sources and there is a need for global standardization and a road map for development of smart garments. In this paper we will discuss current state-of-theart smart garments and wearable sensor systems. Also discussed will be the new emerging trends in smart garment research and development.

  9. Decreased RECQL5 correlated with disease progression of osteosarcoma.

    Science.gov (United States)

    Wu, Junlong; Zhi, Liqiang; Dai, Xin; Cai, Qingchun; Ma, Wei

    2015-11-27

    Human RecQ helicase family, consisting of RECQL, RECQL4, RECQL5, BLM and WRN, has critical roles in genetic stability and tumorigenesis. Although RECQL5 has been reported to correlate with the susceptibility to malignances including osteosarcoma, the specific effect on tumor genesis and progression is not yet clarified. Here we focused on the relationship between RECQL5 expression and osteosarcoma disease progression, and further investigated the function of RECQL5 on MG-63 cell proliferation and apoptosis. By immunohistochemical analysis, qRT-PCR and western blot, we found that RECQL5 expression was downregulated in osteosarcoma tissues and cells. Patients with advanced tumor stage and low grade expressed lower RECQL5. To construct a stable RECQL5 overexpression osteosarcoma cell line (MG-63-RECQL5), RECQL5 gene was inserted into the human AAVS1 safe harbor by CRISPR/Cas9 system. The overexpression of RECQL5 was verified by qRT-PCR and western blot. Cell proliferation, cell cycle and apoptosis assay revealed that RECQL5 overexpression inhibited proliferation, induced G1-phase arrest and promoted apoptosis in MG-63 cells. Collectively, our results suggested RECQL5 as a tumor suppressor in osteosarcoma and may be a potential therapeutic target for osteosarcoma treatment.

  10. Progressive nodular histiocytosis associated with eale′s disease

    Directory of Open Access Journals (Sweden)

    Abhilasha Williams

    2015-01-01

    Full Text Available Progressive nodular histiocytosis (PNH is a rare normolipemic macrophage disorder and belongs to a subgroup of non-Langerhans cell histiocytosis (LCHs which is characterized by a progressive course with no sign of spontaneous resolution but without systemic involvement. We report a 30-year-old gentleman who presented with skin lesions all over the body associated with gradual bilateral painless loss of vision. On examination, approximately 30 to 40, skin-colored, firm, non-tender papules and nodules were noted over the body especially on the face and trunk. A skin biopsy revealed a cellular tumor in the dermis composed of oval to spindle-shaped cells, positive for CD68 but negative for S-100, CD34, CD21, CD35 and HMB45, supporting a diagnosis of spindle cell histiocytic tumor. Ophthalmic examination revealed a generalized arteriolar attenuation in both eyes. He received Tab Imatinib 400 mg OD for 5 months followed by Tab Pazopanib 800 mg OD for 4 months and both the drugs were stopped due to lack of any response in the skin lesions. We report this case due to its rarity, characteristic clinical presentation, and its association with Eale′s disease. Primary treatment remains surgical excision of bothersome lesions and optimal systemic treatment is still unknown.

  11. Treatment with interferon-alpha delays disease in swine infected with a highly virulent CSFV strain.

    Science.gov (United States)

    Fernandez-Sainz, I; Ramanathan, P; O'Donnell, V; Diaz-San Segundo, F; Velazquez-Salinas, L; Sturza, D F; Zhu, J; de los Santos, T; Borca, M V

    2015-09-01

    Interferon-alpha (IFNα) can effectively inhibit or abort a viral infection within the host. It has been reported that IFN induction and production is hindered during classical swine fever virus (CSFV) infection. Most of those studies have been performed in vitro, making it difficult to elucidate the actual role of IFNs during CSFV infection in swine. Here, we report the effect of IFNα treatment (delivered by a replication defective recombinant human adenovirus type 5, Ad5) in swine experimentally infected with highly virulent CSFV strain Brescia. Treatment with two different subtypes of IFNα delayed the appearance of CSF-related clinical signs and virus replication although it did not prevent lethal disease. This is the first report describing the effect of IFNα treatment during CSFV infection in swine. Published by Elsevier Inc.

  12. Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease: e21108

    National Research Council Canada - National Science Library

    Hideyuki Takeuchi; Hiroyuki Mizoguchi; Yukiko Doi; Shijie Jin; Mariko Noda; Jianfeng Liang; Hua Li; Yan Zhou; Rarami Mori; Satoko Yasuoka; Endong Li; Bijay Parajuli; Jun Kawanokuchi; Yoshifumi Sonobe; Jun Sato; Koji Yamanaka; Gen Sobue; Tetsuya Mizuno; Akio Suzumura

    2011-01-01

    ... neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel...

  13. Plasma viscosity increase with progression of peripheral arterial atherosclerotic disease.

    Science.gov (United States)

    Poredos, P; Zizek, B

    1996-03-01

    -macroglobulin (r=0.78, P < 0.01). These results indicate that in patients with peripheral arterial disease plasma viscosity increases with the progression of the atherosclerotic process and is correlated with the clinical stages of the disease.

  14. Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS.

    Science.gov (United States)

    Foust, Kevin D; Salazar, Desirée L; Likhite, Shibi; Ferraiuolo, Laura; Ditsworth, Dara; Ilieva, Hristelina; Meyer, Kathrin; Schmelzer, Leah; Braun, Lyndsey; Cleveland, Don W; Kaspar, Brian K

    2013-12-01

    Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting in progressive motor neuron death through one or more acquired toxicities. Involvement of wild-type SOD1 has been linked to sporadic ALS, as misfolded SOD1 has been reported in affected tissues of sporadic patients and toxicity of astrocytes derived from sporadic ALS patients to motor neurons has been reported to be reduced by lowering the synthesis of SOD1. We now report slowed disease onset and progression in two mouse models following therapeutic delivery using a single peripheral injection of an adeno-associated virus serotype 9 (AAV9) encoding an shRNA to reduce the synthesis of ALS-causing human SOD1 mutants. Delivery to young mice that develop aggressive, fatal paralysis extended survival by delaying both disease onset and slowing progression. In a later-onset model, AAV9 delivery after onset markedly slowed disease progression and significantly extended survival. Moreover, AAV9 delivered intrathecally to nonhuman primates is demonstrated to yield robust SOD1 suppression in motor neurons and glia throughout the spinal cord and therefore, setting the stage for AAV9-mediated therapy in human clinical trials.

  15. Age and Environment Influences on Mouse Prion Disease Progression: Behavioral Changes and Morphometry and Stereology of Hippocampal Astrocytes

    Directory of Open Access Journals (Sweden)

    J. Bento-Torres

    2017-01-01

    Full Text Available Because enriched environment (EE and exercise increase and aging decreases immune response, we hypothesized that environmental enrichment and aging will, respectively, delay and increase prion disease progression. Mice dorsal striatum received bilateral stereotaxic intracerebral injections of normal or ME7 prion infected mouse brain homogenates. After behavior analysis, animals were euthanized and their brains processed for astrocyte GFAP immunolabeling. Our analysis related to the environmental influence are limited to young adult mice, whereas age influence refers to aged mice raised on standard cages. Burrowing activity began to reduce in ME7-SE two weeks before ME7-EE, while no changes were apparent in ME7 aged mice (ME7-A. Object placement recognition was impaired in ME7-SE, NBH-A, and ME7-A but normal in all other groups. Object identity recognition was impaired in ME7-A. Cluster analysis revealed two morphological families of astrocytes in NBH-SE animals, three in NBH-A and ME7-A, and four in NBH-EE, ME7-SE, and ME7-EE. As compared with control groups, astrocytes from DG and CA3 prion-diseased animals show significant numerical and morphological differences and environmental enrichment did not reverse these changes but induced different morphological changes in GFAP+ hippocampal astroglia. We suggest that environmental enrichment and aging delayed hippocampal-dependent behavioral and neuropathological signs of disease progression.

  16. Age and Environment Influences on Mouse Prion Disease Progression: Behavioral Changes and Morphometry and Stereology of Hippocampal Astrocytes

    Science.gov (United States)

    Bento-Torres, J.; Sobral, L. L.; de Oliveira, R. B.; Anthony, D. C.; Vasconcelos, P. F. C.

    2017-01-01

    Because enriched environment (EE) and exercise increase and aging decreases immune response, we hypothesized that environmental enrichment and aging will, respectively, delay and increase prion disease progression. Mice dorsal striatum received bilateral stereotaxic intracerebral injections of normal or ME7 prion infected mouse brain homogenates. After behavior analysis, animals were euthanized and their brains processed for astrocyte GFAP immunolabeling. Our analysis related to the environmental influence are limited to young adult mice, whereas age influence refers to aged mice raised on standard cages. Burrowing activity began to reduce in ME7-SE two weeks before ME7-EE, while no changes were apparent in ME7 aged mice (ME7-A). Object placement recognition was impaired in ME7-SE, NBH-A, and ME7-A but normal in all other groups. Object identity recognition was impaired in ME7-A. Cluster analysis revealed two morphological families of astrocytes in NBH-SE animals, three in NBH-A and ME7-A, and four in NBH-EE, ME7-SE, and ME7-EE. As compared with control groups, astrocytes from DG and CA3 prion-diseased animals show significant numerical and morphological differences and environmental enrichment did not reverse these changes but induced different morphological changes in GFAP+ hippocampal astroglia. We suggest that environmental enrichment and aging delayed hippocampal-dependent behavioral and neuropathological signs of disease progression.

  17. The relationship between disease activity and radiologic progression in patients with rheumatoid arthritis: a longitudinal analysis.

    NARCIS (Netherlands)

    Welsing, P.M.J.; Landewe, R.B.; Riel, P.L.C.M. van; Boers, M.; Gestel, A.M. van; Linden, S.G. van der; Swinkels, H.L.; Heijde, D.M.F.M. van der

    2004-01-01

    OBJECTIVE: Radiologic progression in rheumatoid arthritis (RA) is considered the consequence of persistent inflammatory activity. To determine whether a change in disease activity is related to a change in radiologic progression in individual patients, we investigated the longitudinal relationship b

  18. Hypoxemia in patients with COPD: cause, effects, and disease progression.

    LENUS (Irish Health Repository)

    Kent, Brian D

    2012-02-01

    Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability internationally. Alveolar hypoxia and consequent hypoxemia increase in prevalence as disease severity increases. Ventilation\\/perfusion mismatch resulting from progressive airflow limitation and emphysema is the key driver of this hypoxia, which may be exacerbated by sleep and exercise. Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of COPD, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing may place a small but significant subset of COPD patients at increased risk of these complications. Long-term oxygen therapy has been shown to improve pulmonary hemodynamics, reduce erythrocytosis, and improve survival in selected patients with severe hypoxemic respiratory failure. However, the optimal treatment for patients with exertional oxyhemoglobin desaturation, isolated nocturnal hypoxemia, or mild-to-moderate resting daytime hypoxemia remains uncertain.

  19. Hypoxemia in patients with COPD: cause, effects, and disease progression

    Directory of Open Access Journals (Sweden)

    Brian D Kent

    2011-03-01

    Full Text Available Brian D Kent1,2, Patrick D Mitchell1, Walter T McNicholas1,21Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital, Dublin; 2Conway Institute of Biomolecular and Biomedical Research, University College Dublin, IrelandAbstract: Chronic obstructive pulmonary disease (COPD is a leading cause of death and disability internationally. Alveolar hypoxia and consequent hypoxemia increase in prevalence as disease severity increases. Ventilation/perfusion mismatch resulting from progressive airflow limitation and emphysema is the key driver of this hypoxia, which may be exacerbated by sleep and exercise. Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of COPD, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing may place a small but significant subset of COPD patients at increased risk of these complications. Long-term oxygen therapy has been shown to improve pulmonary hemodynamics, reduce erythrocytosis, and improve survival in selected patients with severe hypoxemic respiratory failure. However, the optimal treatment for patients with exertional oxyhemoglobin desaturation, isolated nocturnal hypoxemia, or mild-to-moderate resting daytime hypoxemia remains uncertain.Keywords: COPD, hypoxia, sleep, inflammation, pulmonary hypertension

  20. Association between time to disease progression end points and overall survival in patients with neuroendocrine tumors

    Directory of Open Access Journals (Sweden)

    Singh S

    2014-08-01

    Full Text Available Simron Singh,1 Xufang Wang,2 Calvin HL Law1 1Sunnybrook Odette Cancer Center, University of Toronto, Toronto, ON, Canada; 2Novartis Oncology, Florham Park, NJ, USA Abstract: Overall survival can be difficult to determine for slowly progressing malignancies, such as neuroendocrine tumors. We investigated whether time to disease progression is positively associated with overall survival in patients with such tumors. A literature review identified 22 clinical trials in patients with neuroendocrine tumors that reported survival probabilities for both time to disease progression (progression-free survival and time to progression and overall survival. Associations between median time to disease progression and median overall survival and between treatment effects on time to disease progression and treatment effects on overall survival were analyzed using weighted least-squares regression. Median time to disease progression was significantly associated with median overall survival (coefficient 0.595; P=0.022. In the seven randomized studies identified, the risk reduction for time to disease progression was positively associated with the risk reduction for overall survival (coefficient on −ln[HR] 0.151; 95% confidence interval −0.843, 1.145; P=0.713. The significant association between median time to disease progression and median overall survival supports the assertion that time to disease progression is an alternative end point to overall survival in patients with neuroendocrine tumors. An apparent albeit not significant trend correlates treatment effects on time to disease progression and treatment effects on overall survival. Informal surveys of physicians’ perceptions are consistent with these concepts, although additional randomized trials are needed. Keywords: neuroendocrine tumors, progression-free survival, disease progression, mortality

  1. The area under the disease progress stairs: calculation, advantage, and application.

    Science.gov (United States)

    Simko, Ivan; Piepho, Hans-Peter

    2012-04-01

    The area under the disease progress curve (AUDPC) is frequently used to combine multiple observations of disease progress into a single value. However, our analysis shows that this approach severely underestimates the effect of the first and last observation. To get a better estimate of disease progress, we have developed a new formula termed the area under the disease progress stairs (AUDPS). The AUDPS approach improves the estimation of disease progress by giving a weight closer to optimal to the first and last observations. Analysis of real data indicates that AUDPS outperforms AUDPC in most of the tested trials and may be less precise than AUDPC only when assessments in the first or last observations have a comparatively large variance. We propose using AUDPS and its standardized (sAUDPS) and relative (rAUDPS) forms when combining multiple observations from disease progress experiments into a single value.

  2. Biomarkers for Parkinson's [corrected] disease: tools to assess Parkinson's disease onset and progression.

    Science.gov (United States)

    Marek, Kenneth; Jennings, Danna; Tamagnan, Gilles; Seibyl, John

    2008-12-01

    Reliable and well-validated biomarkers for PD to identify individuals "at risk" before motor symptoms, accurately diagnose individuals at the threshold of clinical PD, and monitor PD progression throughout its course would dramatically accelerate research into both PD cause and therapeutics. Biomarkers offer the potential to provide a window onto disease mechanism, potentially generating therapeutic targets for disease. In particular, biomarkers enable investigation of the premotor period of PD before typical symptoms are manifest, but while degeneration has already begun. Given the multiple genetic causes for PD already identified, the marked variability in the loss of dopaminergic markers measured by imaging at motor symptom onset and the clear heterogeneity of clinical symptoms in PD onset and clinical progression, it is likely many biomarkers with a focus ranging from clinical symptoms to PD pathobiology to molecular genetic mechanisms will be necessary to fully map PD risk and progression. Biomarkers are also critical in new drug development for PD, both in early validation studies to assess drug dosing and to determine drug penetrance into the brain, and in later efficacy studies to complement PD clinical outcomes. During the past two decades, much progress has been made in identifying and assessing PD biomarkers, but as yet, no fully validated biomarker for PD is currently available. Nonetheless, there is increasing evidence that molecular genetics, focused -omic (proteomic, metabolomic, and transcriptomic) assessment of blood and cerebrospinal fluid, and advanced in vivo brain imaging will provide critical clues to assist in the diagnosis and medical management of PD patients.

  3. Decreased RECQL5 correlated with disease progression of osteosarcoma

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Junlong; Zhi, Liqiang; Dai, Xin; Cai, Qingchun; Ma, Wei, E-mail: doctormawei@163.com

    2015-11-27

    Human RecQ helicase family, consisting of RECQL, RECQL4, RECQL5, BLM and WRN, has critical roles in genetic stability and tumorigenesis. Although RECQL5 has been reported to correlate with the susceptibility to malignances including osteosarcoma, the specific effect on tumor genesis and progression is not yet clarified. Here we focused on the relationship between RECQL5 expression and osteosarcoma disease progression, and further investigated the function of RECQL5 on MG-63 cell proliferation and apoptosis. By immunohistochemical analysis, qRT-PCR and western blot, we found that RECQL5 expression was downregulated in osteosarcoma tissues and cells. Patients with advanced tumor stage and low grade expressed lower RECQL5. To construct a stable RECQL5 overexpression osteosarcoma cell line (MG-63-RECQL5), RECQL5 gene was inserted into the human AAVS1 safe harbor by CRISPR/Cas9 system. The overexpression of RECQL5 was verified by qRT-PCR and western blot. Cell proliferation, cell cycle and apoptosis assay revealed that RECQL5 overexpression inhibited proliferation, induced G1-phase arrest and promoted apoptosis in MG-63 cells. Collectively, our results suggested RECQL5 as a tumor suppressor in osteosarcoma and may be a potential therapeutic target for osteosarcoma treatment. - Highlights: • The expression of RECQL5 was downregulated in osteosarcoma tissues and cells. • Decreased RECQL5 correlated with osteosarcoma Enneking surgical classification. • We constructed a stable RECQL5 overexpression cell line by CRISPR/Cas9 system. • RECQL5 overexpression inhibited proliferation of MG-63 cells. • RECQL5 overexpression promoted apoptosis of MG-63 cells.

  4. Greater loss of axons in primary progressive multiple sclerosis plaques compared to secondary progressive disease.

    Science.gov (United States)

    Tallantyre, E C; Bø, L; Al-Rawashdeh, O; Owens, T; Polman, C H; Lowe, J; Evangelou, N

    2009-05-01

    The pathological substrate of progressive disability in multiple sclerosis is hypothesized to be axonal loss. Differences in the demographic, pathological and radiological features of patients with primary progressive compared with secondary progressive multiple sclerosis raise the question as to whether they actually represent separate clinical entities. So far, large pathological studies comparing axonal damage between primary progressive and secondary progressive multiple sclerosis have not been reported. In this clinico-pathological study we examined the cervical spinal cord in patients with primary and secondary progressive multiple sclerosis. Human cervical spinal cord was derived at autopsy from 54 patients (17 primary progressive, 30 secondary progressive and 7 controls). Tissue was stained immunohistochemically and examined to determine: (i) the number of surviving corticospinal tract axons; (ii) the extent of grey and white matter demyelination; (iii) the degree of inflammation inside and outside of lesions; and (iv) the relationship between demyelination and axonal loss. Associated clinical data was used to calculate expanded disability status scale for each patient preceding death. Motor disability in the primary progressive and secondary progressive groups was similar preceding death. Secondary progressive multiple sclerosis patients showed considerably more extensive demyelination of both the white and grey matter of the cervical spinal cord. The total number of corticospinal axons was equally low in primary progressive and secondary progressive multiple sclerosis groups versus controls. The reduction of axonal density in demyelinated regions compared to normal appearing white matter was significantly more extensive in primary progressive versus secondary progressive patients (33% reduction versus 16% reduction, P progressive multiple sclerosis with a common plaque-centred mechanism. More extensive axonal loss within areas of demyelination in primary

  5. The senescence hypothesis of disease progression in Alzheimer disease: an integrated matrix of disease pathways for FAD and SAD.

    Science.gov (United States)

    Hunter, Sally; Arendt, Thomas; Brayne, Carol

    2013-12-01

    Alzheimer disease (AD) is a progressive, neurodegenerative disease characterised in life by cognitive decline and behavioural symptoms and post-mortem by the neuropathological hallmarks including the microtubule-associated protein tau-reactive tangles and neuritic plaques and amyloid-beta-protein-reactive senile plaques. Greater than 95 % of AD cases are sporadic (SAD) with a late onset and FAD) with an early onset. FAD is associated with various genetic mutations in the amyloid precursor protein (APP) and the presenilins (PS)1 and PS2. As yet, no disease pathway has been fully accepted and there are no treatments that prevent, stop or reverse the cognitive decline associated with AD. Here, we review and integrate available environmental and genetic evidence associated with all forms of AD. We present the senescence hypothesis of AD progression, suggesting that factors associated with AD can be seen as partial stressors within the matrix of signalling pathways that underlie cell survival and function. Senescence pathways are triggered when stressors exceed the cells ability to compensate for them. The APP proteolytic system has many interactions with pathways involved in programmed senescence and APP proteolysis can both respond to and be driven by senescence-associated signalling. Disease pathways associated with sporadic disease may be different to those involving familial genetic mutations. The interpretation we provide strongly points to senescence as an additional underlying causal process in dementia progression in both SAD and FAD via multiple disease pathways.

  6. Haematuria as a risk factor for chronic kidney disease progression in glomerular diseases: A review.

    Science.gov (United States)

    Moreno, Juan Antonio; Yuste, Claudia; Gutiérrez, Eduardo; Sevillano, Ángel M; Rubio-Navarro, Alfonso; Amaro-Villalobos, Juan Manuel; Praga, Manuel; Egido, Jesús

    2016-04-01

    Haematuria has long been considered to be a benign condition associated with glomerular diseases. However, new evidences suggest that haematuria has a pathogenic role in promoting kidney disease progression. An increased risk for end-stage renal disease has been reported in adolescents and young adults with persistent microscopic haematuria. A persistent impairment of renal function has been also reported following macroscopic haematuria-associated acute kidney injury in immunoglobulin A nephropathy. Haematuria-induced renal damage has been related to oxidant, cytotoxic and inflammatory effects induced by haemoglobin or haem released from red blood cells. The pathophysiological origin of haematuria may be due to a more fragile and easily ruptured glomerular filtration barrier, as reported in several glomerular diseases. In this review we describe a number of the key issues associated with the epidemiology and pathogenesis of haematuria-associated diseases, provide an update of recent knowledge on the role of haematuria on renal function outcome and discuss specific therapeutic approaches in this setting. KEY SUMMARY POINTS: 1. Glomerular haematuria is a common observation in a number of renal diseases that may lead to persistent renal injury. 2. Haematuria in children differs from that in adults in specific aspects, particularly in the frequency of glomerular diseases and renal disease outcome. 3. Regular follow-up of renal function in children with isolated microhaematuria may be recommended.

  7. Metabolic Syndrome and Periodontal Disease Progression in Men.

    Science.gov (United States)

    Kaye, E K; Chen, N; Cabral, H J; Vokonas, P; Garcia, R I

    2016-07-01

    Metabolic syndrome, a cluster of 3 or more risk factors for cardiovascular disease, is associated with periodontal disease, but few studies have been prospective in design. This study's aim was to determine whether metabolic syndrome predicts tooth loss and worsening of periodontal disease in a cohort of 760 men in the Department of Veterans Affairs Dental Longitudinal Study and Normative Aging Study who were followed up to 33 y from 1981 to 2013. Systolic and diastolic blood pressures were measured with a standard mercury sphygmomanometer. Waist circumference was measured in units of 0.1 cm following a normal expiration. Fasting blood samples were measured in duplicate for glucose, triglyceride, and high-density lipoprotein. Calibrated periodontists served as dental examiners. Periodontal outcome events on each tooth were defined as progression to predefined threshold levels of probing pocket depth (≥5 mm), clinical attachment loss (≥5 mm), mobility (≥0.5 mm), and alveolar bone loss (≥40% of the distance from the cementoenamel junction to the root apex, on radiographs). Hazards ratios (95% confidence intervals) of tooth loss or a periodontitis event were estimated from tooth-level extended Cox proportional hazards regression models that accounted for clustering of teeth within individuals and used time-dependent status of metabolic syndrome. Covariates included age, education, smoking status, plaque level, and initial level of the appropriate periodontal disease measure. Metabolic syndrome as defined by the International Diabetes Federation increased the hazards of tooth loss (1.39; 1.08 to 1.79), pocket depth ≥5 mm (1.37; 1.14 to 1.65), clinical attachment loss ≥5 mm (1.19; 1.00 to 1.41), alveolar bone loss ≥40% (1.25; 1.00 to 1.56), and tooth mobility ≥0.5 mm (1.43; 1.07 to 1.89). The number of positive metabolic syndrome conditions was also associated with each of these outcomes. These findings suggest that the metabolic disturbances that

  8. A novel biomarker of laminin turnover is associated with mortality and disease progression in chronic kidney disease

    DEFF Research Database (Denmark)

    Nielsen, Signe Holm; Guldager Kring Rasmussen, Daniel; Fenton, Anthony

    2017-01-01

    INTRODUCTION AND AIMS: Patients with chronic kidney disease (CKD) have increased risk of progressing to end-stage renal disease (ESRD) and a high mortality rate. One of the major underlying causes of progression of renal failure is renal fibrosis, which is caused by dysregulated extracellular...

  9. Haematuria increases progression of advanced proteinuric kidney disease.

    Directory of Open Access Journals (Sweden)

    Claudia Yuste

    Full Text Available Haematuria has been traditionally considered as a benign hallmark of some glomerular diseases; however new studies show that haematuria may decrease renal function.To determine the influence of haematuria on the rate of chronic kidney disease (CKD progression in 71 proteinuric patients with advanced CKD (baseline eGFR 65 years (-1.2±6.8 (HP vs. 1.5±7.7 (P mL/min/1.73 m2/year. Furthermore, the harmful effect of haematuria on eGFR slope was found patients with proteinuria >0.5 g/24 h (-5.8±6.4 (HP vs. -1.37± 7.9 (P mL/min/1.73 m2/year, p<0.05, whereas no significant differences were found in patients with proteinuria < 0.5 g/24 h (-0.62±7.4 (HP vs. 3.4±11.1 (P mL/min/1.73 m2/year. Multivariate analysis reported that presence of haematuria was significantly and independently associated with eGFR deterioration after adjusting for traditional risk factors, including age, serum phosphate, mean proteinuria and mean serum PTH (β=-4.316, p=0.025.The presence of haematuria is closely associated with a faster decrease in renal function in advanced proteinuric CKD patients, especially in younger CKD patients with high proteinuria levels; therefore this high risk subgroup of patients would benefit of intensive medical surveillance and treatment.

  10. Surgery for Crohn's disease in the era of biologicals:A reduced need or delayed verdict?

    Institute of Scientific and Technical Information of China (English)

    Anthony de Buck van Overstraeten; Albert Wolthuis; André D'Hoore

    2012-01-01

    Crohn's disease (CD) is a chronic inflammatory bowel disease that can affect the entire gastrointestinal tract.Ultimately,up to 70% of all patients will need surgery,despite optimized medical therapy.Moreover,about half of the patients will need redo-surgery because of disease recurrence.The introduction of anti-tumor necrosis factor (TNF) drugs (Infliximab in 1998) revolutionized the treatment of CD.Different randomized trials assessed the efficacy of anti-TNF treatment not only to induce,but also to maintain,steroid-free remission.Furthermore,these agents can rapidly lead to mucosal healing.This aspect is important,as it is a major predictor for long-term disease control.Subgroup analyses of responding patients seemed to suggest a reduction in the need for surgery at median-term follow up (1-3 years).However if one looks at population surveys,one does not observe any decline in the need for surgery since the introduction of Infliximab in 1998.The short follow-up term and the exclusion of patients with imminent surgical need in the randomized trials could bias the results.Only 60% of patients respond to induction of anti-TNF therapy,moreover,some patients will actually develop resistance to biologicals.Many patients are diagnosed when stenosing disease has already occurred,obviating the need for biological therapy.In a further attempt to change the actual course of the disease,top down strategies have been progressively implemented.Whether this will indeed obviate surgery for a substantial group of patients remains unclear.For the time being,surgery will still play a pivotal role in the treatment of CD.

  11. Homoarginine and progression of chronic kidney disease: results from the Mild to Moderate Kidney Disease Study.

    Directory of Open Access Journals (Sweden)

    Christiane Drechsler

    Full Text Available BACKGROUND: Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD. METHODS: We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years (median 4.45 years, interquartile range 2.54-5.19 using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease. RESULTS: Study participants were at baseline on average 47±13 years old and 65% were male. Mean±standard deviation of homoarginine concentrations were 2.5±1.1 µmol/L and concentrations were incrementally lower at lower levels of GFR with mean concentrations of 2.90±1.02 µmol/L (GFR>90 ml/min, 2.64±1.06 µmol/L (GFR 60-90 ml/min, 2.52±1.24 µmol/L (GFR 30-60 ml/min and 2.05±0.78 µmol/L (GFR<30 ml/min, respectively (p = 0.002. The age- and sex-adjusted risk to reach the renal endpoint was significantly higher by 62% with each decrease by one standard deviation (1.1 µmol/L of homoarginine (HR 1.62, 95% CI 1.16-2.27, p = 0.005. This association was independent of proteinuria (HR 1.56, 95% CI 1.11-2.20, p = 0.01, and was slightly attenuated when adjusting for GFR (HR 1.40 (95% CI 0.98-1.98, p = 0.06. CONCLUSIONS: Homoarginine concentrations are directly correlated with kidney function and are significantly

  12. Tubular atrophy in the pathogenesis of chronic kidney disease progression.

    Science.gov (United States)

    Schelling, Jeffrey R

    2016-05-01

    The longstanding focus in chronic kidney disease (CKD) research has been on the glomerulus, which is sensible because this is where glomerular filtration occurs, and a large proportion of progressive CKD is associated with significant glomerular pathology. However, it has been known for decades that tubular atrophy is also a hallmark of CKD and that it is superior to glomerular pathology as a predictor of glomerular filtration rate decline in CKD. Nevertheless, there are vastly fewer studies that investigate the causes of tubular atrophy, and fewer still that identify potential therapeutic targets. The purpose of this review is to discuss plausible mechanisms of tubular atrophy, including tubular epithelial cell apoptosis, cell senescence, peritubular capillary rarefaction and downstream tubule ischemia, oxidative stress, atubular glomeruli, epithelial-to-mesenchymal transition, interstitial inflammation, lipotoxicity and Na(+)/H(+) exchanger-1 inactivation. Once a a better understanding of tubular atrophy (and interstitial fibrosis) pathophysiology has been obtained, it might then be possible to consider tandem glomerular and tubular therapeutic strategies, in a manner similar to cancer chemotherapy regimens, which employ multiple drugs to simultaneously target different mechanistic pathways.

  13. Progress on Complications of Direct Bypass for Moyamoya Disease

    Science.gov (United States)

    Yu, Jinlu; Shi, Lei; Guo, Yunbao; Xu, Baofeng; Xu, Kan

    2016-01-01

    Moyamoya disease (MMD) involves progressive occlusion of the intracranial internal carotid artery resulting in formation of moyamoya-like vessels at the base of the brain. It can be characterized by hemorrhage or ischemia. Direct vascular bypass is the main and most effective treatment of MMD. However, patients with MMD differ from those with normal cerebral vessels. MMD patients have unstable intracranial artery hemodynamics and a poor blood flow reserve; therefore, during the direct bypass of superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis, perioperative risk factors and anesthesia can affect the hemodynamics of these patients. When brain tissue cannot tolerate a high blood flow rate, it becomes prone to hyperperfusion syndrome, which leads to neurological function defects and can even cause intracranial hemorrhage in severe cases. The brain tissue is prone to infarction when hemodynamic equilibrium is affected. In addition, bypass vessels become susceptible to occlusion or atrophy when blood resistance increases. Even compression of the temporalis affects bypass vessels. Because the STA is used in MMD surgery, the scalp becomes ischemic and is likely to develop necrosis and infection. These complications of MMD surgery are difficult to manage and are not well understood. To date, no systematic studies of the complications that occur after direct bypass in MMD have been performed, and reported complications are hidden among various case studies; therefore, this paper presents a review and summary of the literature in PubMed on the complications of direct bypass in MMD. PMID:27499690

  14. Progress on Complications of Direct Bypass for Moyamoya Disease.

    Science.gov (United States)

    Yu, Jinlu; Shi, Lei; Guo, Yunbao; Xu, Baofeng; Xu, Kan

    2016-01-01

    Moyamoya disease (MMD) involves progressive occlusion of the intracranial internal carotid artery resulting in formation of moyamoya-like vessels at the base of the brain. It can be characterized by hemorrhage or ischemia. Direct vascular bypass is the main and most effective treatment of MMD. However, patients with MMD differ from those with normal cerebral vessels. MMD patients have unstable intracranial artery hemodynamics and a poor blood flow reserve; therefore, during the direct bypass of superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis, perioperative risk factors and anesthesia can affect the hemodynamics of these patients. When brain tissue cannot tolerate a high blood flow rate, it becomes prone to hyperperfusion syndrome, which leads to neurological function defects and can even cause intracranial hemorrhage in severe cases. The brain tissue is prone to infarction when hemodynamic equilibrium is affected. In addition, bypass vessels become susceptible to occlusion or atrophy when blood resistance increases. Even compression of the temporalis affects bypass vessels. Because the STA is used in MMD surgery, the scalp becomes ischemic and is likely to develop necrosis and infection. These complications of MMD surgery are difficult to manage and are not well understood. To date, no systematic studies of the complications that occur after direct bypass in MMD have been performed, and reported complications are hidden among various case studies; therefore, this paper presents a review and summary of the literature in PubMed on the complications of direct bypass in MMD.

  15. Early versus delayed erythropoietin for the anaemia of end-stage kidney disease.

    Science.gov (United States)

    Coronado Daza, Jorge; Martí-Carvajal, Arturo J; Ariza García, Amaury; Rodelo Ceballos, Joaquín; Yomayusa González, Nancy; Páez-Canro, Carol; Loza Munárriz, César; Urrútia, Gerard

    2015-12-16

    Anaemia is a common complication in people with chronic kidney disease (CKD) and mainly develops as a consequence of relative erythropoietin (EPO) deficiency. Anaemia develops early in the course of disease and peaks among people with end-stage kidney disease (ESKD). Many types of EPO - also called erythropoiesis-stimulating agents (ESAs) - are used to treat anaemia in people with ESKD.ESAs have changed treatment of severe anaemia among people with CKD by relieving symptoms and avoiding complications associated with blood transfusion. However, no benefits have been found in relation to mortality rates and non-cardiac fatal events, except quality of life. Moreover, a relationship between ESA use and increased cardiovascular morbidity and mortality in patients with CKD has been reported in studies with fully correcting anaemia comparing with partial anaemia correction. Until 2012, guidelines recommended commencing ESA treatment when haemoglobin was less than 11 g/dL; the current recommendation is EPO commencement when haemoglobin is between 9 and 10 g/dL. However, advantages in commencing therapy when haemoglobin levels are greater than 10 g/dL but less than 11 g/dL remain unknown, especially among older people whose life expectancy is limited, but in whom EPO therapy may improve quality of life. To assess the clinical benefits and harms of early versus delayed EPO for anaemia in patients with ESKD undergoing haemodialysis or peritoneal dialysis We searched the Cochrane Kidney and Transplant Specialised Register to 8 July 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. We planned to include randomised controlled trials (RCTs) and quasi-RCTs evaluating at the clinical benefits and harms of early versus delayed EPO for anaemia in patients with ESKD undergoing haemodialysis or peritoneal dialysis. Studies comparing EPO with another EPO, placebo or no treatment were eligible for inclusion. It was planned that two

  16. Optical coherence tomography findings in Huntington's disease: a potential biomarker of disease progression.

    Science.gov (United States)

    Kersten, Hannah M; Danesh-Meyer, Helen V; Kilfoyle, Dean H; Roxburgh, Richard H

    2015-11-01

    Previous reports of ocular abnormalities in Huntington's disease (HD) have detailed eye movement disorders. The objective of this case-control study was to investigate optic nerve and macular morphology in HD using optical coherence tomography (OCT). A total of 26 HD patients and 29 controls underwent a thorough ophthalmic examination including spectral domain OCT scans of the macula and peripapillary retinal nerve fibre layer (RNFL). Genetic testing results, disease duration, HD disease burden scores and Unified HD Rating Scale motor scores were acquired for HD patients. Temporal RNFL thickness was significantly reduced in the HD group (62.3 vs. 69.8 μm, p = 0.005), and there was a significant negative correlation between temporal RNFL thickness and disease duration (R (2) = -0.51, p = 0.04). Average peripapillary RNFL thickness was not significantly different between the HD and control groups. There was a significant negative correlation between macular volume and disease duration (R (2) = -0.71, p = 0.002), and motor scores (R (2) = -0.56, p = 0.01). Colour vision was significantly poorer in the HD group. Temporal RNFL is preferentially thinned in HD patients, possibly implicating mitochondrial dysfunction as the temporal RNFL is reduced in the patients with some mitochondrial disorders, including Leber's hereditary optic neuropathy. The correlation between the decrease in macular volume and temporal RNFL, and increasing disease severity suggests that OCT may be a useful biomarker for disease progression in HD. Larger, longitudinal studies are required.

  17. Delayed gastric emptying does not normalize after gluten withdrawal in adult celiac disease.

    Science.gov (United States)

    Usai-Satta, Paolo; Oppia, Francesco; Scarpa, Mariella; Giannetti, Cristiana; Cabras, Francesco

    2016-08-01

    Objective Delayed gastric emptying has been frequently detected in patients with untreated celiac disease. According to several studies, gluten withdrawal showed to be effective in normalizing the gastric emptying rate. The aim of this study was to evaluate the gastric emptying rate of solids in patients with celiac disease before and after a gluten-free diet. Methods Twelve adult patients with celiac disease (age range 20-57 years) and 30 healthy controls (age range 30-54 years) underwent a (13)C-octanoic acid breath test to measure gastric emptying. Half emptying time (t1/2) and lag phase (tlag) were calculated. After at least 12 months of a gluten-free diet, celiac patients underwent a new (13)C-octanoic acid breath test. A symptom score was utilized to detect dyspeptic and malabsorption symptoms in all the patients. Results The gastric motility parameters, t1/2 and tlag, were significantly longer in patients than in controls. On a gluten-free diet, surprisingly, the gastric emptying did not normalize despite an improvement of symptom score. No significant correlation between abnormal gastric emptying and specific symptom patterns, anthropometric parameters or severity of histological damage was found. Conclusions This finding supports the hypothesis that gluten-driven mucosal inflammation might determine motor abnormalities by affecting smooth muscle contractility or impairing gut hormone function. The persistence of these abnormalities on a gluten free diet suggests the presence of a persistent low-grade mucosal inflammation with a permanent perturbation of the neuro-immunomodulatory regulation.

  18. Progression of autosomal dominant kidney disease: measurement of the stage transitions of chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Christopher M Blanchette

    2015-04-01

    Full Text Available Background: Autosomal dominant polycystic kidney disease (ADPKD is a progressive genetic disorder characterized by the development of numerous kidney cysts that result in kidney failure. Little is known regarding the key patient characteristics and utilization of healthcare resources for ADPKD patients along the continuum of disease progression. This observational study was designed to describe the characteristics of ADPKD patients and compare them with those of patients with other chronic kidney diseases. Methods: This retrospective cohort study involved patients with a claim for ADPKD or PKD unspecified from 1/1/2000–2/28/2013 and ≥6 months of previous continuous enrollment (baseline within a large database of administrative claims in the USA. A random sample of chronic kidney disease (CKD patients served as comparators. For a subset of ADPKD patients who had only a diagnosis code of unspecified PKD, abstraction of medical records was undertaken to estimate the proportion of patients who had medical chart-confirmed ADPKD. In patients with linked electronic laboratory data, the estimated glomerular filtration rate was calculated via serum creatinine values to determine CKD stage at baseline and during follow-up. Proportions of patients transitioning to another stage and the mean age at transition were calculated. Results: ADPKD patients were, in general, younger and had fewer physician visits, but had more specific comorbidities at observation start compared with CKD patients. ADPKD patients had a longer time in the milder stages and longer duration before recorded transition to a more severe stage compared with CKD patients. Patients with ADPKD at risk of rapid progression had a shorter time-to-end-stage renal disease than patients with CKD and ADPKD patients not at risk, but stage duration was similar between ADPKD patients at risk and those not at risk. Conclusions: These results suggest that distribution of patients by age at transition

  19. A high-fat diet delays age-related hearing loss progression in C57BL/6J mice.

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    Takeshi Fujita

    Full Text Available Age-related hearing loss (AHL, or presbycusis, is the most common sensory disorder among the elderly. We used C57BL/6J mice as an AHL model to determine a possible association between AHL and a high-fat diet (HFD.Forty C57BL/6J mice were randomly assigned to a control or HFD group. Each group was divided into the following subgroups: 1-, 3-, 5- and 12-month groups (HFD, n = 5/subgroup; control, n = 5/subgroup. Nine CBA/N-slc mice were also used as a 12-month control (n = 5 or 12-month HFD (n = 4 group. The mice were fed a HFD or normal (control diet throughout this study. Hearing function was evaluated at 1, 3, 5 and 12 months using auditory evoked brainstem responses (ABRs. Spiral ganglion cells (SGCs were also counted.The elevation of ABR thresholds (at 4 and 32 kHz at 3 and 5 months was significantly suppressed in the HFD group compared with the control groups for C57BL/6J mice. After 12 months, the elevation of ABR thresholds was significantly suppressed in the HFD group at all frequencies for C57BL/6J mice. In contrast, CBA/N-slc mice displayed opposite outcomes, as ABR thresholds at all frequencies at 12 months were significantly elevated in the HFD group compared with the control group. For the C57BL/6J mice at 12 months, SGC numbers significantly decreased in all parts of the cochleae in the control group compared with the HFD groups. In contrast, for the CBA/N-slc mice, SGC numbers significantly decreased, particularly in the upper parts of the cochleae in the HFD group compared with the control groups.The elevation in ABR thresholds and SGC loss associated with aging in the HFD-fed C57BL/6J mice were significantly suppressed compared with those in the normal diet-fed mice. These results suggest that HFD delays AHL progression in the C57B/6J mice.

  20. Delayed Diagnosis, Leprosy Reactions, and Nerve Injury Among Individuals With Hansen's Disease Seen at a United States Clinic.

    Science.gov (United States)

    Leon, Kristoffer E; Jacob, Jesse T; Franco-Paredes, Carlos; Kozarsky, Phyllis E; Wu, Henry M; Fairley, Jessica K

    2016-03-01

    Background.  Hansen's disease (HD), or leprosy, is uncommon in the United States. We sought to describe the characteristics of patients with HD in a US clinic, including an assessment of delays in diagnosis and HD reactions, which have both been associated with nerve damage. Methods.  A retrospective chart review was conducted on patients seen at an HD clinic in the southern United States between January 1, 2002 and January 31, 2014. Demographic and clinical characteristics were summarized, including delays in diagnosis, frequency of reactions, and other complications including peripheral neuropathy. Results.  Thirty patients were seen during the study time period. The majority of patients were male (73%) and had multibacillary disease (70%). Brazil, Mexico, and the United States were the most frequent of the 14 countries of origin. Hansen's disease "reactions", severe inflammatory complications, were identified among 75% of patients, and nerve damage was present at diagnosis in 36% of patients. The median length of time between symptom onset and diagnosis was long at 12 months (range, 1-96), but no single factor was associated with a delay in diagnosis. Conclusions.  The diagnosis of HD was frequently delayed among patients referred to our US clinic. The high frequency of reactions and neuropathy at diagnosis suggests that further efforts at timely diagnosis and management of this often unrecognized disease is needed to prevent the long-term sequelae associated with irreversible nerve damage.

  1. Altered aiming movements in Parkinson's disease patients and elderly adults as a function of delays in movement onset

    NARCIS (Netherlands)

    Romero, D.H.; Gemmert, A.W.A. van; Adler, C.H.; Bekkering, H.; Stelmach, G.E.

    2003-01-01

    This study investigated the effect of lengthening the time the hand remains immobilized on an aiming movement performed by Parkinson's disease (PD) patients and elderly adults, and whether visual information could compensate for the effects of delay. In Experiment One, PD patients and elderly adults

  2. [Responsiveness of the Expanded Disability Status Scale (EDSS) to disease progression and therapeutic intervention in progressive forms of multiple sclerosis].

    Science.gov (United States)

    Cadavid, Diego; Tang, Yongqiang; O'Neill, Gilmore

    2010-09-16

    The standard approach in relapsing forms of multiple sclerosis (MS) has been to measure therapeutic effects on clinical exacerbations and physical disability as determined by the Expanded Disability Status Scale (EDSS). However, measuring clinical relapses is not a viable option in the progressive forms of MS because of their low frequency. Therefore, the standard approach in clinical trials of progressive forms of MS has been to use the EDSS as primary outcome measure. We examined the responsiveness of the EDSS to disease progression and treatment effects in the context of clinical trials of secondary progressive (SPMS) and primary progressive (PPMS) MS and compared it to the three functional tasks of the Multiple Sclerosis Functional Composite (MSFC): the Timed 25 Foot Walk (T25FW), the 9 Hole PEG (9HP), and the Paced Auditory Serial Attention Test (PASAT). The effect size of the EDSS after two years on placebo was only 0.2-0.3 in both SPMS and PPMS, similar to the 9HP and the PASAT. In contrast, the effect size of the T25FW was much greater and driven to a large extent by subjects who could not complete the task. The EDSS shows poor responsiveness to both disease progression and treatment effects in SPMS and PPMS. The use of alternative primary outcome measures is recommended for therapeutic trials of progressive MS.

  3. The Economic Promise of Delayed Aging.

    Science.gov (United States)

    Goldman, Dana

    2015-12-18

    Biomedicine has made enormous progress in the last half century in treating common diseases. However, we are becoming victims of our own success. Causes of death strongly associated with biological aging, such as heart disease, cancer, Alzheimer's disease, and stroke-cluster within individuals as they grow older. These conditions increase frailty and limit the benefits of continued, disease-specific improvements. Here, we show that a "delayed-aging" scenario, modeled on the biological benefits observed in the most promising animal models, could solve this problem of competing risks. The economic value of delayed aging is estimated to be $7.1 trillion over 50 years. Total government costs, including Social Security, rise substantially with delayed aging--mainly caused by longevity increases--but we show that these can be offset by modest policy changes. Expanded biomedical research to delay aging appears to be a highly efficient way to forestall disease and extend healthy life.

  4. Identification of unstable network modules reveals disease modules associated with the progression of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Masataka Kikuchi

    Full Text Available Alzheimer's disease (AD, the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs, we identified the PINs expressed in three brain regions: the entorhinal cortex (EC, hippocampus (HIP and superior frontal gyrus (SFG. Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system.

  5. Early energy deficit in Huntington disease: identification of a plasma biomarker traceable during disease progression.

    Directory of Open Access Journals (Sweden)

    Fanny Mochel

    Full Text Available Huntington disease (HD is a fatal neurodegenerative disorder, with no effective treatment. The pathogenic mechanisms underlying HD has not been elucidated, but weight loss, associated with chorea and cognitive decline, is a characteristic feature of the disease that is accessible to investigation. We, therefore, performed a multiparametric study exploring body weight and the mechanisms of its loss in 32 presymptomatic carriers and HD patients in the early stages of the disease, compared to 21 controls. We combined this study with a multivariate statistical analysis of plasma components quantified by proton nuclear magnetic resonance ((1H NMR spectroscopy. We report evidence of an early hypermetabolic state in HD. Weight loss was observed in the HD group even in presymptomatic carriers, although their caloric intake was higher than that of controls. Inflammatory processes and primary hormonal dysfunction were excluded. (1H NMR spectroscopy on plasma did, however, distinguish HD patients at different stages of the disease and presymptomatic carriers from controls. This distinction was attributable to low levels of the branched chain amino acids (BCAA, valine, leucine and isoleucine. BCAA levels were correlated with weight loss and, importantly, with disease progression and abnormal triplet repeat expansion size in the HD1 gene. Levels of IGF1, which is regulated by BCAA, were also significantly lower in the HD group. Therefore, early weight loss in HD is associated with a systemic metabolic defect, and BCAA levels may be used as a biomarker, indicative of disease onset and early progression. The decreased plasma levels of BCAA may correspond to a critical need for Krebs cycle energy substrates in the brain that increased metabolism in the periphery is trying to provide.

  6. High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer's Disease in Human Cerebrospinal Fluid.

    Directory of Open Access Journals (Sweden)

    Ronald C Hendrickson

    Full Text Available Disease modifying treatments for Alzheimer's disease (AD constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001 and SME-2 (p = 0.0004 for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR, in AD were 21% (p = 0.039 and 17% (p = 0.026 lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic.

  7. Therapeutic induction of autophagy to modulate neurodegenerative disease progression

    Institute of Scientific and Technical Information of China (English)

    Warren E HOCHFELD; Shirley LEE; David C RUBINSZTEIN

    2013-01-01

    There is accumulating evidence that aggregating,misfolded proteins may have an impact on autophagic function,suggesting that this could be a secondary pathological mechanism in many diseases.In this review,we focus on the role of autophagy in four major neurodegenerative diseases:Alzheimer disease (AD),Huntington's disease (HD),Parkinson's disease (PD) and amyotropic lateral sclerosis.

  8. Excisional wound healing is delayed in a murine model of chronic kidney disease.

    Directory of Open Access Journals (Sweden)

    Akhil K Seth

    Full Text Available BACKGROUND: Approximately 15% of the United States population suffers from chronic kidney disease (CKD, often demonstrating an associated impairment in wound healing. This study outlines the development of a surgical murine model of CKD in order to investigate the mechanisms underlying this impairment. METHODS: CKD was induced in mice by partial cauterization of one kidney cortex and contralateral nephrectomy, modifying a previously published technique. After a minimum of 6-weeks, splinted, dorsal excisional wounds were created to permit assessment of wound healing parameters. Wounds were harvested on postoperative days (POD 0, 3, 7, and 14 for histological, immunofluorescent, and quantitative PCR (qPCR. RESULTS: CKD mice exhibited deranged blood chemistry and hematology profiles, including profound uremia and anemia. Significant decreases in re-epithelialization and granulation tissue deposition rates were found in uremic mice wounds relative to controls. On immunofluorescent analysis, uremic mice demonstrated significant reductions in cellular proliferation (BrdU and angiogenesis (CD31, with a concurrent increase in inflammation (CD45 as compared to controls. CKD mice also displayed differential expression of wound healing-related genes (VEGF, IL-1β, eNOS, iNOS on qPCR. CONCLUSIONS: These findings represent the first reported investigation of cutaneous healing in a CKD animal model. Ongoing studies of this significantly delayed wound healing phenotype include the establishment of renal failure model in diabetic strains to study the combined effects of CKD and diabetes.

  9. Delay in maturation of the submandibular gland in Chagas disease correlates with lower DNA synthesis

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    José B Alves

    2008-09-01

    Full Text Available It has been demonstrated that the acute phase of Trypanosoma cruzi infection promotes several changes in the oral glands. The present study examined whether T. cruzi modulates the expression of host cell apoptotic or mitotic pathway genes. Rats were infected with T. cruzi then sacrificed after 18, 32, 64 or 97 days, after which the submandibular glands were analyzed by immunohistochemistry. Immunohistochemical analyses using an anti-bromodeoxyuridine antibody showed that, during acute T. cruzi infection, DNA synthesizing cells in rat submandibular glands were lower than in non-infected animals (p < 0.05. However, after 64 days of infection (chronic phase, the number of immunolabeled cells are similar in both groups. However, immunohistochemical analysis of Fas and Bcl-2 expression did not find any difference between infected and non-infected animals in both the acute and chronic stages. These findings suggest that the delay in ductal maturation observed at the acute phase of Chagas disease is correlated with lower expression of DNA synthesis genes, but not apoptotic genes.

  10. Ezrin Is Associated with Disease Progression in Ovarian Carcinoma

    Science.gov (United States)

    Horwitz, Vered; Davidson, Ben; Stern, Dganit; Tropé, Claes G.; Tavor Re’em, Tali; Reich, Reuven

    2016-01-01

    Objective Ezrin and p130Cas are structural proteins with an important role in signaling pathways and have been shown to promote cancer dissemination. We previously reported on overexpression of both ezrin and p130Cas in breast carcinoma effusions compared to primary carcinomas. Since ovarian and breast carcinomas share the ability to disseminate by forming malignant effusions, we sought to study the role of these molecules in ovarian carcinoma (OC). Methods OC cell lines were cultured in two different 3-dimensional conditions, on alginate scaffolds and as spheroids, which served as models for solid tumor and malignant effusions, respectively. shRNA was used to reduce protein expression in the cells. The malignant potential was evaluated by chemo-invasion assay, branching capacity on Matrigel and rate of proliferation. Subsequently, clinical specimens of high-grade serous carcinoma effusions, ovarian tumors and solid metastases were analyzed for ezrin and p130Cas expression. Results Higher ezrin expression was found in cells composing the spheroids compared to their counterparts cultured on alginate scaffold and in clinical samples of malignant effusions compared to solid tumors. In addition, reduced Ezrin expression impaired the invasion ability and the branching capacity of OC cells to a greater extent than reduced p130Cas expression. However, ezrin and p130Cas expression in effusions was unrelated to clinical outcome. Conclusions The 3-dimensional cell cultures were found to mimic the different tumor sites and be applicable as a model. The in vitro results concur with the clinical specimen analysis, suggesting that in OC, the role of ezrin in disease progression is more pronounced than that of p130Cas. PMID:27622508

  11. Quantitative muscle MRI as an assessment tool for monitoring disease progression in LGMD2I

    DEFF Research Database (Denmark)

    Willis, Tracey A; Hollingsworth, Kieren G; Coombs, Anna;

    2013-01-01

    Outcome measures for clinical trials in neuromuscular diseases are typically based on physical assessments which are dependent on patient effort, combine the effort of different muscle groups, and may not be sensitive to progression over short trial periods in slow-progressing diseases. We hypoth...

  12. Improving caregiver well-being delays nursing home placement of patients with Alzheimer disease.

    Science.gov (United States)

    Mittelman, Mary S; Haley, William E; Clay, Olivio J; Roth, David L

    2006-11-14

    To determine the effectiveness of a counseling and support intervention for spouse caregivers in delaying time to nursing home placement of patients with Alzheimer disease (AD), and identify the mechanisms through which the intervention accomplished this goal. We conducted a randomized controlled trial of an enhanced counseling and support intervention compared to usual care. Participants were a referred volunteer sample of 406 spouse caregivers of community-dwelling patients who had enrolled in the study over a 9.5-year period. The intervention consisted of six sessions of individual and family counseling, support group participation, and continuous availability of ad hoc telephone counseling. Structured questionnaires were administered at baseline and at regular follow-up intervals, every 4 months for the first year and every 6 months thereafter. Cox proportional hazard models were used to test the effects of the intervention on the time to nursing home placement for the patients after controlling for multiple time-invariant and time-dependent predictors of placement. Patients whose spouses received the intervention experienced a 28.3% reduction in the rate of nursing home placement compared with usual care controls (hazard ratio = 0.717 after covariate adjustment, p = 0.025). The difference in model-predicted median time to placement was 557 days. Improvements in caregivers' satisfaction with social support, response to patient behavior problems, and symptoms of depression collectively accounted for 61.2% of the intervention's beneficial impact on placement. Greater access to effective programs of counseling and support could yield considerable benefits for caregivers, patients with Alzheimer disease, and society.

  13. Role of rasagiline in treating Parkinson’s disease: effect on disease progression

    Directory of Open Access Journals (Sweden)

    Irene A Malaty

    2009-05-01

    Full Text Available Irene A Malaty, Hubert H FernandezUniversity of Florida Movement Disorders Center, Gainesville, FL, USAAbstract: Rasagiline is a second generation, selective, irreversible monoamine oxidase type B (MAO-B inhibitor. It has demonstrated efficacy in monotherapy for early Parkinson’s disease (PD patients in one large randomized, placebo-controlled trial (TVP-1012 in Early Monotherapy for Parkinson’s Disease Outpatients, and has shown ability to reduce off time in more advanced PD patients with motor fluctuations in two large placebo-controlled trials (Parkinson’s Rasagiline: Efficacy and Safety in the Treatment of “Off”, and Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily. Preclinical data abound to suggest potential for neuroprotection by this compound against a variety of neurotoxic insults in cell cultures and in animals. The lack of amphetamine metabolites provides an advantage over the first generation MAO-B inhibitor selegiline. One large trial has investigated the potential for disease modification in PD patients (Attenuation of Disease progression with Azilect Given Once-daily and preliminary results maintain some possible advantage to earlier initiation of the 1 mg/day dose. The clinical significance of the difference detected remains a consideration.Keywords: rasagiline, Parkinson’s disease, neuroprotection, selegiline

  14. The Y-Box Binding Protein 1 Suppresses Alzheimer's Disease Progression in Two Animal Models.

    Directory of Open Access Journals (Sweden)

    N V Bobkova

    Full Text Available The Y-box binding protein 1 (YB-1 is a member of the family of DNA- and RNA binding proteins. It is involved in a wide variety of DNA/RNA-dependent events including cell proliferation and differentiation, stress response, and malignant cell transformation. Previously, YB-1 was detected in neurons of the neocortex and hippocampus, but its precise role in the brain remains undefined. Here we show that subchronic intranasal injections of recombinant YB-1, as well as its fragment YB-11-219, suppress impairment of spatial memory in olfactory bulbectomized (OBX mice with Alzheimer's type degeneration and improve learning in transgenic 5XFAD mice used as a model of cerebral amyloidosis. YB-1-treated OBX and 5XFAD mice showed a decreased level of brain β-amyloid. In OBX animals, an improved morphological state of neurons was revealed in the neocortex and hippocampus; in 5XFAD mice, a delay in amyloid plaque progression was observed. Intranasally administered YB-1 penetrated into the brain and could enter neurons. In vitro co-incubation of YB-1 with monomeric β-amyloid (1-42 inhibited formation of β-amyloid fibrils, as confirmed by electron microscopy. This suggests that YB-1 interaction with β-amyloid prevents formation of filaments that are responsible for neurotoxicity and neuronal death. Our data are the first evidence for a potential therapeutic benefit of YB-1 for treatment of Alzheimer's disease.

  15. [Top ten progressions of clinical research in fundus diseases in China].

    Science.gov (United States)

    2014-11-01

    Ten research items in the past five years representing the progression of clinical research in fundus diseases in China were voted by specialists from the Ocular Fundus Disease Group of Ophthalmology Society of Chinese Medical Association. Choroidal neovascular disease, pediatric retinal disease, polypoidal choroidal vasculopathy, intraocular malignant tumor, and intraocular infection caused by specific pathogens are covered. Novel treatment, like anti-VEGF medication, PDT, minimally invasive vitrectomy, and intraocular injection, establishment of the Clinical Research Center of New Drug Development, and the epidemiologic study of fundus diseases are also included. These landmark research progressions represent the power and influence of Chinese fundus disease scholars in the world.

  16. Occupational therapy for patients with chronic diseases: CVA, rheumatoid arthritis and progressive diseases of the central nervous system.

    NARCIS (Netherlands)

    Driessen, M.J.; Dekker, J.; Lankhorst, G.; Zee, J. van der

    1997-01-01

    A substantial proportion of the patients treated by occupational therapists have a chronic disease. The aim of this study was to describe the outlines of occupational therapy treatment for three specific groups of chronic diseases: progressive neurological diseases, cerebrovascular accident and rh

  17. Occupational therapy for patients with chronic diseases: CVA, rheumatoid arthritis and progressive diseases of the central nervous system.

    NARCIS (Netherlands)

    Driessen, M.J.; Dekker, J.; Lankhorst, G.; Zee, J. van der

    1997-01-01

    A substantial proportion of the patients treated by occupational therapists have a chronic disease. The aim of this study was to describe the outlines of occupational therapy treatment for three specific groups of chronic diseases: progressive neurological diseases, cerebrovascular accident and

  18. Kidney disease in China: recent progress and prospects

    Institute of Scientific and Technical Information of China (English)

    YU Xue-qing; WEI Jia-li

    2009-01-01

    a. Glomerulonephritis is still the most common cause of ESRD in China. However, the prevalence of diabetes and hypertension are increasing dramatically. There are modifiable risk factors for the development of progressive renal dysfunction.

  19. A small molecule polyamine oxidase inhibitor blocks androgen-induced oxidative stress and delays prostate cancer progression in the transgenic adenocarcinoma of the mouse prostate model.

    Science.gov (United States)

    Basu, Hirak S; Thompson, Todd A; Church, Dawn R; Clower, Cynthia C; Mehraein-Ghomi, Farideh; Amlong, Corey A; Martin, Christopher T; Woster, Patrick M; Lindstrom, Mary J; Wilding, George

    2009-10-01

    High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiologic factor in prostate cancer (CaP) occurrence, recurrence, and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase, the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells, as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data show that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays CaP progression.

  20. A Small Molecule Polyamine Oxidase Inhibitor Blocks Androgen-Induced Oxidative Stress and Delays Prostate Cancer Progression in the TRAMP Mouse Model

    Science.gov (United States)

    Basu, Hirak S.; Thompson, Todd A.; Church, Dawn R.; Clower, Cynthia C.; Mehraein-Ghomi, Farideh; Amlong, Corey A.; Martin, Christopher T.; Woster, Patrick M.; Lindstrom, Mary J.; Wilding, George

    2009-01-01

    High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiological factor in prostate cancer (CaP) occurrence, recurrence and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase (SSAT), the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data demonstrate that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays prostate cancer progression. PMID:19773450

  1. A conserved transcriptional signature of delayed aging and reduced disease vulnerability is partially mediated by SIRT3.

    Directory of Open Access Journals (Sweden)

    Jamie L Barger

    Full Text Available Aging is the most significant risk factor for a range of diseases, including many cancers, neurodegeneration, cardiovascular disease, and diabetes. Caloric restriction (CR without malnutrition delays aging in diverse species, and therefore offers unique insights into age-related disease vulnerability. Previous studies suggest that there are shared mechanisms of disease resistance associated with delayed aging, however quantitative support is lacking. We therefore sought to identify a common response to CR in diverse tissues and species and determine whether this signature would reflect health status independent of aging. We analyzed gene expression datasets from eight tissues of mice subjected to CR and identified a common transcriptional signature that includes functional categories of mitochondrial energy metabolism, inflammation and ribosomal structure. This signature is detected in flies, rats, and rhesus monkeys on CR, indicating aspects of CR that are evolutionarily conserved. Detection of the signature in mouse genetic models of slowed aging indicates that it is not unique to CR but rather a common aspect of extended longevity. Mice lacking the NAD-dependent deacetylase SIRT3 fail to induce mitochondrial and anti-inflammatory elements of the signature in response to CR, suggesting a potential mechanism involving SIRT3. The inverse of this transcriptional signature is detected with consumption of a high fat diet, obesity and metabolic disease, and is reversed in response to interventions that decrease disease risk. We propose that this evolutionarily conserved, tissue-independent, transcriptional signature of delayed aging and reduced disease vulnerability is a promising target for developing therapies for age-related diseases.

  2. Discontinuing disease-modifying therapy in progressive multiple sclerosis: can we stop what we have started?

    LENUS (Irish Health Repository)

    Lonergan, Roisin

    2012-02-01

    Disease-modifying therapy is ineffective in disabled patients (Expanded Disability Status Scale [EDSS] > 6.5) with secondary progressive multiple sclerosis (MS) without relapses, or in primary progressive MS. Many patients with secondary progressive MS who initially had relapsing MS continue to use disease-modifying therapies. The enormous associated costs are a burden to health services. Regular assessment is recommended to guide discontinuation of disease-modifying therapies when no longer beneficial, but this is unavailable to many patients, particularly in rural areas. The objectives of this study are as follows: 1. To observe use of disease-modifying therapies in patients with progressive multiple sclerosis and EDSS > 6.5. 2. To examine approaches used by a group of international MS experts to stopping-disease modifying therapies in patients with secondary progressive MS without relapses. During an epidemiological study in three regions of Ireland (southeast Dublin city, and Wexford and Donegal Counties), we recorded details of disease-modifying therapies in patients with progressive MS and EDSS > 6.5. An e-questionnaire was sent to 26 neurologists with expert knowledge of MS, asking them to share their approach to stopping disease-modifying therapies in patients with secondary progressive MS. Three hundred and thirty-six patients were studied: 88 from southeast Dublin, 99 from Wexford and 149 from Donegal. Forty-four had EDSS > 6.5: 12 were still using disease-modifying therapies. Of the surveyed neurologists, 15 made efforts to stop disease-modifying therapies in progressive multiple sclerosis, but most did not insist. A significant proportion (12 of 44 patients with progressive MS and EDSS > 6.5) was considered to be receiving therapy without benefit. Eleven of the 12 were from rural counties, reflecting poorer access to neurology services. The costs of disease-modifying therapies in this group (>170,000 euro yearly) could be re-directed towards development

  3. Total Kidney Volume in Autosomal Dominant Polycystic Kidney Disease: A Biomarker of Disease Progression and Therapeutic Efficacy.

    Science.gov (United States)

    Alam, Ahsan; Dahl, Neera K; Lipschutz, Joshua H; Rossetti, Sandro; Smith, Patricia; Sapir, Daniel; Weinstein, Jordan; McFarlane, Philip; Bichet, Daniel G

    2015-10-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially life-threatening monogenic disorder in humans, characterized by progressive development and expansion of fluid-filled cysts in the kidneys and other organs. Ongoing cyst growth leads to progressive kidney enlargement, whereas kidney function remains stable for decades as a result of hyperfiltration and compensation by unaffected nephrons. Kidney function irreversibly declines only in the late stages of the disease, when most of the parenchyma is lost to cystic and fibrotic tissue and the remaining compensatory capacity is overwhelmed. Hence, conventional kidney function measures, such as glomerular filtration rate, do not adequately assess disease progression in ADPKD, especially in its early stages. Given the recent development of potential targeted therapies in ADPKD, it has become critically important to identify relevant biomarkers that can be used to determine the degree of disease progression and evaluate the effects of therapeutic interventions on the course of the disease. We review the current evidence to provide an informed perspective on whether total kidney volume (TKV) is a suitable biomarker for disease progression and whether TKV can be used as an efficacy end point in clinical trials. We conclude that because cystogenesis is the central factor leading to kidney enlargement, TKV appears to be an appropriate biomarker and is gaining wider acceptance. Several studies have identified TKV as a relevant imaging biomarker for monitoring and predicting disease progression and support its use as a prognostic end point in clinical trials.

  4. Research Progression of Cellular Autophagy in Liver System Diseases

    Directory of Open Access Journals (Sweden)

    Chunyun Liu

    2013-09-01

    Full Text Available Autophagy is a basic biological phenomenon widely existed in eukaryotic cells and an important mechanism for cells to adjust to the surrounding environment, prevent invasion of pathogenic micro-organisms and maintain homeostasis, whose activity changes evidently in multiple liver system diseases, suggesting that there is close association between autophagy and the generation and development of liver system diseases. It is also reported that autophagy develops and exerts an important function in many liver-related diseases, such as hepatic carcinoma, non-alcoholic fatty liver disease, alcoholic liver disease, viral liver disease and acute liver injury. Therefore, this study aimed to summarize the relationship between autophagy and multiple liver diseases, hoping to explore the effect of autophagy in liver system diseases and further study the regulative effect of autophagy so as to provide new thoughts for their treatment.

  5. Research Progression of Cellular Autophagy in Liver System Diseases

    Institute of Scientific and Technical Information of China (English)

    Liu Chunyun; Gong Xiangwen; Xiao Xinfa; Yuan Xiangying

    2013-01-01

    Autophagy is a basic biological phenomenon widely existed in eukaryotic cells and an important mechanism for cells to adjust to the surrounding environment, prevent invasion of pathogenic micro-organisms and maintain homeostasis, whose activity changes evidently in multiple liver system diseases, suggesting that there is close association between autophagy and the generation and development of liver system diseases. It is also reported that autophagy develops and exerts an important function in many liver-related diseases, such as hepatic carcinoma, non-alcoholic fatty liver disease, alcoholic liver disease, viral liver disease and acute liver injury. Therefore, this study aimed to summarize the relationship between autophagy and multiple liver diseases, hoping to explore the effect of autophagy in liver system diseases and further study the regulative effect of autophagy so as to provide new thoughts for their treatment.

  6. New progress in brain aging and its related neurological diseases

    Directory of Open Access Journals (Sweden)

    Ming-wei ZHU

    2014-03-01

    Full Text Available Brain aging-related neurological diseases including Alzheimer's disease (AD, Parkinson's disease (PD and cerebral amyloid angiopathy (CAA have become one of the major diseases endangering the health of old people in China. Although the mechanism of brain aging and pathogenesis of its related neurodegenerative diseases remain unclear, protein pathological studies such as tau, α-synuclein (α-Syn, TDP-43 and amyloid-β protein (Aβ based on brain tissue bank and case registration database are opening the door to solve the mystery in the brain aging process and unlock pathogenesis of aging-related neurodegenerative diseases. Research on functional neuroimaging including 11C-PIB PET and 18F-FDDNP PET in Alzheimer's disease and 18F-FDG PET in Parkinson's disease, and biomarkers such as total-tau, phosphorylated-tau, and the 42 amino acid fragment of β-amyloid in cerebrospinal fluid (CSF in the preclinical stages of Alzheimer's disease now become hot topics in the field of elderly dementia and movement disorders. Clinicopathological correlation research of Alzheimer's disease, Parkinson's disease and cerebral amyloid angiopathy is also one of focuses in the geriatric neurological diseases. doi: 10.3969/j.issn.1672-6731.2014.03.004

  7. Activation delay-induced mechanical dyssynchrony in single-ventricle heart disease

    DEFF Research Database (Denmark)

    Forsha, Daniel; Risum, Niels; Barker, Piers

    2017-01-01

    We present the case of an infant with a single functional ventricle who developed ventricular dysfunction and heart failure due to an electrical activation delay and dyssynchrony. Earlier recognition of this potentially reversible aetiology may have changed her poor outcome.......We present the case of an infant with a single functional ventricle who developed ventricular dysfunction and heart failure due to an electrical activation delay and dyssynchrony. Earlier recognition of this potentially reversible aetiology may have changed her poor outcome....

  8. Anosognosia in Alzheimer disease: Prevalence, associated factors, and influence on disease progression.

    Science.gov (United States)

    Castrillo Sanz, A; Andrés Calvo, M; Repiso Gento, I; Izquierdo Delgado, E; Gutierrez Ríos, R; Rodríguez Herrero, R; Rodríguez Sanz, F; Tola-Arribas, M A

    2016-06-01

    Anosognosia is a frequent symptom in Alzheimer disease (AD). The objective of this article is to describe prevalence of this condition at time of diagnosis and analyse any predisposing factors and their influence on disease progression. Observational, prospective, and analytical multi-centre study in an outpatient setting. Patients recently diagnosed with AD (NINCDS-ADRDA criteria) were included. Each patient underwent two cognitive, functional, and neuropsychiatric assessments separated by an interval of 18 months. The Clinical Insight Rating Scale was employed as a measure of anosognosia (CIR, scored 0-8). Progression was defined as an increase in the Clinical Dementia Rating Scale-sum of boxes of more than 2.5 points. The predictor variables were analysed using binary logistic regression. The study included 127 patients, and 94 completed both assessments. Of the total, 31.5% displayed severe anosognosia (CIR 7-8); 39.4%, altered level of consciousness (CIR 3-6); and 29.1%, normal awareness (CIR 0-2). The median baseline CIR in this cohort was 4 (Q1-Q3: 1-7), and at 18 months, 6 (Q1-Q3: 3-8), P<.001. Advanced age (odds ratio (OR) 2.43; CI 95%:1.14-5.19), lower educational level (OR 2.15; CI 95%:1.01-4.58), and more marked neuropsychiatric symptoms (OR 2.66; CI 95%:1.23-5.74) were predictor variables of anosognosia. Baseline CIR was similar in the groups with and without significant clinical progression. The large majority of patients with AD at the time of diagnosis showed significant anosognosia, and this condition was associated with advanced age, lower educational level, and more marked behavioural symptoms. Our results did not show that anosognosia had an effect on the initial clinical progression of AD after diagnosis. Copyright © 2014 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  9. Characterization of annual disease progression of multiple sclerosis patients: A population-based study

    DEFF Research Database (Denmark)

    Freilich, Jonatan; Manouchehrinia, Ali; Trusheim, Mark

    2017-01-01

    the milestone. To characterize clinical factors influencing MS disease progression as annual transitions from each Expanded Disability Status Scale (EDSS). The annual progression of 11,964 patients from the Swedish MS Registry was analysed with 10 multinomial logistic regressions, that is, one for transition......Previous research characterizing factors influencing multiple sclerosis (MS) disease progression has typically been based on time to disease milestones (Kaplan-Meier, Cox hazard regression, etc.). A limitation of these methods is the handling of the often large groups of patients not reaching...

  10. New Strategy That Delays Progression of Amyotrophic Lateral Sclerosis in G1H-G93A Transgenic Mice: Oral Administration of Xanthine Oxidoreductase Inhibitors That Are Not Substrates for the Purine Salvage Pathway.

    Science.gov (United States)

    Kato, Shinsuke; Kato, Masako; Kusano, Teruo; Nishino, Takeshi

    2016-12-01

    Amyotrophic lateral sclerosis (ALS), Lou Gehrig's disease, is a progressive fatal neurodegenerative disease that involves both upper and lower motor neurons. We orally administered 4 xanthine oxidoreductase (XOR) inhibitors to G1H-G93A mice carrying 25 transgene copy numbers of human mutant G93A superoxide dismutase 1, from 80 days of age. Three nonpurine-analogue inhibitors (TEI-6720: Febuxostat, Y-700 and FYX-051), but not allopurinol with a purine analogue ring (pyrazolo pyrimidine ring), significantly delayed disease onset, prolonged survival and the duration of disease stages, improved clinical signs, and alleviated weight loss. Exercise testing (extension reflex, inclined plane, footprint, rotarod, and beam balance tests) showed significantly improved motor function in the G1H-G93A mice treated with these 3 inhibitors. Significant amelioration of disease was seen even when TEI-6720 or Y-700 was administered after the appearance of early signs. Histopathological evaluation in the late stage revealed that G1H-G93A mice treated with TEI-6720 had well-preserved motor neurons and fewer inclusion bodies, compared with mice treated with placebo or with allopurinol. Our results indicate that these 3 nonpurine-analogue XOR inhibitors might increase the supply of high-energy compounds via the purine salvage pathway, thereby protecting motor neurons against death. This strategy may be applicable for oral therapy of ALS patients. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

  11. Exploration of Anaemia as a Progression Factor in African Americans with Cardiovascular Disease

    Science.gov (United States)

    Despite the higher incidence of end stage renal disease (ESRD) among African Americans, whites in the United States population have a higher prevalence of chronic kidney disease. This may be due, in part, to a faster rate of progression to ESRD among African Americans with kidney disease. Anemia i...

  12. The stability analysis of a general viral infection model with distributed delays and multi-staged infected progression

    Science.gov (United States)

    Wang, Jinliang; Liu, Shengqiang

    2015-01-01

    We investigate an in-host model with general incidence and removal rate, as well as distributed delays in virus infections and in productions. By employing Lyapunov functionals and LaSalle's invariance principle, we define and prove the basic reproductive number R0 as a threshold quantity for stability of equilibria. It is shown that if R0 > 1 , then the infected equilibrium is globally asymptotically stable, while if R0 ⩽ 1 , then the infection free equilibrium is globally asymptotically stable under some reasonable assumptions. Moreover, n + 1 distributed delays describe (i) the time between viral entry and the transcription of viral RNA, (ii) the n - 1 -stage time needed for activated infected cells between viral RNA transcription and viral release, and (iii) the time necessary for the newly produced viruses to be infectious (maturation), respectively. The model can describe the viral infection dynamics of many viruses such as HIV-1, HCV and HBV.

  13. Strategies and resources for coping with fear of disease progression in women with reproductive system cancer

    Directory of Open Access Journals (Sweden)

    Moskovchenko, Denis V.

    2016-06-01

    Full Text Available Fear of disease progression is one of the most common sources of psychological distress in patients suffering from chronic diseases. Fear of disease progression is a situationspecific and fully discernible (reportable emotion based on personal experience of a life-threatening disease. This article presents the results of a study of cancer patients’ coping behavior according to the levels of fear of disease progression experienced. The presence of pronounced fear of disease progression reflects a negative cognitive-affective response to one’s expectations for one’s own future; this response is related to a decrease in adaptive capacity. To determine the particular characteristics of coping strategies and coping resources in women with reproductive-system cancers according to the level of fear of disease progression. A total of 177 women with reproductive-system cancers were examined, among them 59 with breast cancer and 118 with gynecological cancers. Women with reproductive-system cancers have varying sets of coping strategies and coping resources according to their level of fear of disease progression. For each of the differentiated groups, specific characteristics of the strategies of coping with difficult life situations are described, along with cognitive self-regulation strategies specific to the illness and to coping resources. The women exhibiting moderate fear of disease progression significantly more often adhered to problem-oriented strategies of coping with difficult life situations and illness and had an internal locus of control regarding treatment. Patients with a low level of fear of disease progression tended to use strategies of positive reinterpretation of difficult life situations and illness; an external locus of control regarding treatment prevailed in this group. Patients found to have a dysfunctional level of fear of disease progression displayed significantly higher rates of using cognitive-regulation strategies

  14. Hepatitis C virus: risk factors and disease progression

    NARCIS (Netherlands)

    Grady, B.P.X.

    2015-01-01

    Hepatitis C virus (HCV) is a single-stranded RNA virus and was first identified in 1989 as a cause for transfusion-associated non-A, non-B hepatitis. Transmission of HCV occurs predominantly via blood-to-blood contact. After acute infection about 75% of those infected progress to a persistent infect

  15. Ultraviolet-Visible and Fluorescence Spectroscopy Techniques Are Important Diagnostic Tools during the Progression of Atherosclerosis: Diet Zinc Supplementation Retarded or Delayed Atherosclerosis

    Science.gov (United States)

    Abdelhalim, Mohamed Anwar K.; Moussa, Sherif A. Abdelmottaleb; AL-Mohy, Yanallah Hussain

    2013-01-01

    Background. In this study, we examined whether UV-visible and fluorescence spectroscopy techniques detect the progression of atherosclerosis in serum of rabbits fed on high-cholesterol diet (HCD) and HCD supplemented with zinc (HCD + Zn) compared with the control. Methods. The control rabbits group was fed on 100 g/day of normal diet. The HCD group was fed on Purina Certified Rabbit Chow supplemented with 1.0% cholesterol plus 1.0% olive oil (100 g/day) for the same period. The HCD + Zn group was fed on normal Purina Certified Rabbit Chow plus 1.0% cholesterol and 1.0% olive oil supplemented with 470 ppm Zn for the same feeding period. UV-visible and fluorescence spectroscopy and biochemistry in Rabbit's blood serum and blood hematology were measured in Rabbit's blood. Results. We found that the fluorescent peak of HCD shifted toward UV-visible wavelength compared with the control using fluorescent excitation of serum at 192 nm. In addition, they showed that supplementation of zinc (350 ppm) restored the fluorescent peak closely to the control. By using UV-visible spectroscopy approach, we found that the peak absorbance of HCD (about 280 nm) was higher than that of control and that zinc supplementation seemed to decrease the absorbance. Conclusions. This study demonstrates that ultraviolet-visible and fluorescence spectroscopy techniques can be applied as noninvasive techniques on a sample blood serum for diagnosing or detecting the progression of atherosclerosis. The Zn supplementation to rabbits fed on HCD delays or retards the progression of atherosclerosis. Inducing anemia in rabbits fed on HCD delays the progression of atherosclerosis. PMID:24350281

  16. Ultraviolet-visible and fluorescence spectroscopy techniques are important diagnostic tools during the progression of atherosclerosis: diet zinc supplementation retarded or delayed atherosclerosis.

    Science.gov (United States)

    Abdelhalim, Mohamed Anwar K; Moussa, Sherif A Abdelmottaleb; Al-Mohy, Yanallah Hussain

    2013-01-01

    In this study, we examined whether UV-visible and fluorescence spectroscopy techniques detect the progression of atherosclerosis in serum of rabbits fed on high-cholesterol diet (HCD) and HCD supplemented with zinc (HCD + Zn) compared with the control. The control rabbits group was fed on 100 g/day of normal diet. The HCD group was fed on Purina Certified Rabbit Chow supplemented with 1.0% cholesterol plus 1.0% olive oil (100 g/day) for the same period. The HCD + Zn group was fed on normal Purina Certified Rabbit Chow plus 1.0% cholesterol and 1.0% olive oil supplemented with 470 ppm Zn for the same feeding period. UV-visible and fluorescence spectroscopy and biochemistry in Rabbit's blood serum and blood hematology were measured in Rabbit's blood. We found that the fluorescent peak of HCD shifted toward UV-visible wavelength compared with the control using fluorescent excitation of serum at 192 nm. In addition, they showed that supplementation of zinc (350 ppm) restored the fluorescent peak closely to the control. By using UV-visible spectroscopy approach, we found that the peak absorbance of HCD (about 280 nm) was higher than that of control and that zinc supplementation seemed to decrease the absorbance. This study demonstrates that ultraviolet-visible and fluorescence spectroscopy techniques can be applied as noninvasive techniques on a sample blood serum for diagnosing or detecting the progression of atherosclerosis. The Zn supplementation to rabbits fed on HCD delays or retards the progression of atherosclerosis. Inducing anemia in rabbits fed on HCD delays the progression of atherosclerosis.

  17. CDC Periodontal Disease Surveillance Project: background, objectives, and progress report.

    Science.gov (United States)

    Eke, Paul I; Genco, Robert J

    2007-07-01

    This supplement contains papers presented at the 2006 International Association of Dental Research (IADR) symposium entitled "Development of Self-Reported Measures for Population-Based Surveillance of Periodontitis." These papers highlight activities of an independent periodontal disease surveillance workgroup convened by the Division of Oral Health (DOH), Centers for Disease Control and Prevention (CDC), in collaboration with the American Academy of Periodontology, to examine the feasibility of using self-reported measures for population-based surveillance of periodontal disease in the United States. This workgroup was convened in 2003 as part of a CDC periodontal disease surveillance project.

  18. Inhibition of Aerobic Glycolysis Attenuates Disease Progression in Polycystic Kidney Disease.

    Directory of Open Access Journals (Sweden)

    Meliana Riwanto

    Full Text Available Dysregulated signaling cascades alter energy metabolism and promote cell proliferation and cyst expansion in polycystic kidney disease (PKD. Here we tested whether metabolic reprogramming towards aerobic glycolysis ("Warburg effect" plays a pathogenic role in male heterozygous Han:SPRD rats (Cy/+, a chronic progressive model of PKD. Using microarray analysis and qPCR, we found an upregulation of genes involved in glycolysis (Hk1, Hk2, Ldha and a downregulation of genes involved in gluconeogenesis (G6pc, Lbp1 in cystic kidneys of Cy/+ rats compared with wild-type (+/+ rats. We then tested the effect of inhibiting glycolysis with 2-deoxyglucose (2DG on renal functional loss and cyst progression in 5-week-old male Cy/+ rats. Treatment with 2DG (500 mg/kg/day for 5 weeks resulted in significantly lower kidney weights (-27% and 2-kidney/total-body-weight ratios (-20% and decreased renal cyst index (-48% compared with vehicle treatment. Cy/+ rats treated with 2DG also showed higher clearances of creatinine (1.98±0.67 vs 1.41±0.37 ml/min, BUN (0.69±0.26 vs 0.40±0.10 ml/min and uric acid (0.38±0.20 vs 0.21±0.10 ml/min, and reduced albuminuria. Immunoblotting analysis of kidney tissues harvested from 2DG-treated Cy/+ rats showed increased phosphorylation of AMPK-α, a negative regulator of mTOR, and restoration of ERK signaling. Assessment of Ki-67 staining indicated that 2DG limits cyst progression through inhibition of epithelial cell proliferation. Taken together, our results show that targeting the glycolytic pathway may represent a promising therapeutic strategy to control cyst growth in PKD.

  19. Modelling Alcoholism as a Contagious Disease: A Mathematical Model with Awareness Programs and Time Delay

    Directory of Open Access Journals (Sweden)

    Shuang-Hong Ma

    2015-01-01

    Full Text Available A dynamic alcohol consumption model with awareness programs and time delay is formulated and analyzed. The aim of this model is to capture the effects of awareness programs and time delay in controlling the alcohol problems. We introduce awareness programs by media in the model as a separate class with growth rate of the cumulative density of them being proportional to the number of mortalities induced by heavy drinking. Susceptible population will isolate themselves and avoid contact with the heavy drinkers or become aware of risk of heavy drinking and decline to drink due to such programs. In particular, we incorporate time delay because the nonconsumer population will take a period of time to become an alcohol consumer. We find that the model has two equilibria: one without alcohol problems and one where alcohol problems are endemic in population. The model analysis shows that though awareness programs cannot eradicate alcohol problems, they are effective measures in controlling the alcohol problems. Further, we conclude that the time delay in alcohol consumption habit which develops in susceptible population may result in Hopf bifurcation by increasing the value of time delay. Some numerical simulation results are also given to support our theoretical predictions.

  20. Periodontal disease's contribution to Alzheimer's disease progression in Down syndrome.

    Science.gov (United States)

    Kamer, Angela R; Fortea, Juan O; Videla, Sebastià; Mayoral, Angela; Janal, Malvin; Carmona-Iragui, Maria; Benejam, Bessy; Craig, Ronald G; Saxena, Deepak; Corby, Patricia; Glodzik, Lidia; Annam, Kumar Raghava Chowdary; Robbins, Miriam; de Leon, Mony J

    2016-01-01

    People with Down syndrome (DS) are at an increased risk for Alzheimer's disease (AD). After 60 years of age, >50% of DS subjects acquire dementia. Nevertheless, the age of onset is highly variable possibly because of both genetic and environmental factors. Genetics cannot be modified, but environmental risk factors present a potentially relevant intervention for DS persons at risk for AD. Among them, inflammation, important in AD of DS type, is potential target. Consistent with this hypothesis, chronic peripheral inflammation and infections may contribute to AD pathogenesis in DS. People with DS have an aggressive form of periodontitis characterized by rapid progression, significant bacterial and inflammatory burden, and an onset as early as 6 years of age. This review offers a hypothetical mechanistic link between periodontitis and AD in the DS population. Because periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.

  1. Clinical value of nutritional status in neurodegenerative diseases: What is its impact and how it affects disease progression and management?

    Science.gov (United States)

    Tsagalioti, Eftyhia; Trifonos, Christina; Morari, Aggeliki; Vadikolias, Konstantinos; Giaginis, Constantinos

    2016-11-30

    Neurodegenerative diseases constitute a major problem of public health that is associated with an increased risk of mortality and poor quality of life. Malnutrition is considered as a major problem that worsens the prognosis of patients suffering from neurodegenerative diseases. In this aspect, the present review is aimed to critically collect and summarize all the available existing clinical data regarding the clinical impact of nutritional assessment in neurodegenerative diseases, highlighting on the crucial role of nutritional status in disease progression and management. According to the currently available clinical data, the nutritional status of patients seems to play a very important role in the development and progression of neurodegenerative diseases. A correct nutritional evaluation of neurodegenerative disease patients and a right nutrition intervention is essential in monitoring their disease.

  2. CSF biomarkers associated with disease heterogeneity in early Parkinson's disease: the Parkinson's Progression Markers Initiative study.

    Science.gov (United States)

    Kang, Ju-Hee; Mollenhauer, Brit; Coffey, Christopher S; Toledo, Jon B; Weintraub, Daniel; Galasko, Douglas R; Irwin, David J; Van Deerlin, Vivianna; Chen-Plotkin, Alice S; Caspell-Garcia, Chelsea; Waligórska, Teresa; Taylor, Peggy; Shah, Nirali; Pan, Sarah; Zero, Pawel; Frasier, Mark; Marek, Kenneth; Kieburtz, Karl; Jennings, Danna; Tanner, Caroline M; Simuni, Tanya; Singleton, Andrew; Toga, Arthur W; Chowdhury, Sohini; Trojanowski, John Q; Shaw, Leslie M

    2016-06-01

    The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aβ1-42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aβ1-42, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aβ1-42, or highest t-tau/Aβ1-42 and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance. APOE ε4 genotype was associated with lower levels of Aβ1-42, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance.

  3. In vivo parahippocampal white matter pathology as a biomarker of disease progression to Alzheimer's disease.

    Science.gov (United States)

    Solodkin, Ana; Chen, E Elinor; Van Hoesen, Gary W; Heimer, Lennart; Shereen, Ahmed; Kruggel, Frithjof; Mastrianni, James

    2013-12-15

    Noninvasive diagnostic tests for Alzheimer's disease (AD) are limited. Postmortem diagnosis is based on density and distribution of neurofibrillary tangles (NFTs) and amyloid-rich neuritic plaques. In preclinical stages of AD, the cells of origin for the perforant pathway within the entorhinal cortex are among the first to display NFTs, indicating its compromise in early stages of AD. We used diffusion tensor imaging (DTI) to assess the integrity of the parahippocampal white matter in mild cognitive impairment (MCI) and AD, as a first step in developing a noninvasive tool for early diagnosis. Subjects with AD (N = 9), MCI (N = 8), or no cognitive impairment (NCI; N = 20) underwent DTI-MRI. Fractional anisotropy (FA) and mean (MD) and radial (RD) diffusivity measured from the parahippocampal white matter in AD and NCI subjects differed greatly. Discriminant analysis in the MCI cases assigned statistical membership of 38% of MCI subjects to the AD group. Preliminary data 1 year later showed that all MCI cases assigned to the AD group either met the diagnostic criteria for probable AD or showed significant cognitive decline. Voxelwise analysis in the parahippocampal white matter revealed a progressive change in the DTI patterns in MCI and AD subjects: whereas converted MCI cases showed structural changes restricted to the anterior portions of this region, in AD the pathology was generalized along the entire anterior-posterior axis. The use of DTI for in vivo assessment of the parahippocampal white matter may be useful for identifying individuals with MCI at highest risk for conversion to AD and for assessing disease progression.

  4. Dietary manipulation and social isolation alter disease progression in a murine model of coronary heart disease.

    Directory of Open Access Journals (Sweden)

    Yumiko Nakagawa-Toyama

    Full Text Available BACKGROUND: Mice with a deficiency in the HDL receptor SR-BI and low expression of a modified apolipoprotein E gene (SR-BI KO/ApoeR61(h/h called 'HypoE' when fed an atherogenic, 'Paigen' diet develop occlusive, atherosclerotic coronary arterial disease (CHD, myocardial infarctions (MI, and heart dysfunction and die prematurely (50% mortality ~40 days after initiation of this diet. Because few murine models share with HypoE mice these cardinal, human-like, features of CHD, HypoE mice represent a novel, small animal, diet-inducible and genetically tractable model for CHD. To better describe the properties of this model, we have explored the effects of varying the composition and timing of administration of atherogenic diets, as well as social isolation vs. group housing, on these animals. METHODOLOGY/PRINCIPAL FINDINGS: HypoE mice were maintained on a standard lab chow diet (control until two months of age. Subsequently they received one of three atherogenic diets (Paigen, Paigen without cholate, Western or control diet for varying times and were housed in groups or singly, and we determined the plasma cholesterol levels, extent of cardiomegaly and/or survival. The rate of disease progression could be reduced by lowering the severity of the atherogenic diet and accelerated by social isolation. Disease could be induced by Paigen diets either containing or free of cholate. We also established conditions under which CHD could be initiated by an atherogenic diet and then subsequently, by replacing this diet with standard lab chow, hypercholesterolemia could be reduced and progression to early death prevented. CONCLUSIONS/SIGNIFICANCE: HypoE mice provide a powerful, surgery-free, diet-'titratable' small animal model that can be used to study the onset of recovery from occlusive, atherosclerotic CHD and heart failure due to MI. HypoE mice can be used for the analysis of the effects of environment (diet, social isolation on a variety of features of

  5. Bile Acids in Polycystic Liver Diseases: Triggers of Disease Progression and Potential Solution for Treatment.

    Science.gov (United States)

    Perugorria, Maria J; Labiano, Ibone; Esparza-Baquer, Aitor; Marzioni, Marco; Marin, Jose J G; Bujanda, Luis; Banales, Jesús M

    2017-01-01

    Polycystic liver diseases (PLDs) are a group of genetic hereditary cholangiopathies characterized by the development and progressive growth of cysts in the liver, which are the main cause of morbidity. Current therapies are based on surgical procedures and pharmacological strategies, which show short-term and modest beneficial effects. Therefore, the determination of the molecular mechanisms of pathogenesis appears to be crucial in order to find new potential targets for pharmacological therapy. Ductal plate malformation during embryogenesis and abnormal cystic cholangiocyte growth and secretion are some of the key mechanisms involved in the pathogenesis of PLDs. However, the discovery of the presence of bile acids in the fluid collected from human cysts and the intrahepatic accumulation of cytotoxic bile acids in an animal model of PLD (i.e. polycystic kidney (PCK) rat) suggest a potential role of impaired bile acid homeostasis in the pathogenesis of these diseases. On the other hand, ursodeoxycholic acid (UDCA) has emerged as a new potential therapeutic tool for PLDs by promoting the inhibition of cystic cholangiocyte growth in both PCK rats and highly symptomatic patients with autosomal dominant polycystic kidney disease (ADPKD: most common type of PLD), and improving symptoms. Chronic treatment with UDCA normalizes the decreased intracellular calcium levels in ADPKD human cholangiocytes in vitro, which results in the reduction of their baseline-stimulated proliferation. Moreover, UDCA decreases the liver concentration of cytotoxic bile acids in PCK rats and the bile acid-dependent enhanced proliferation of cystic cholangiocytes. Here, the role of bile acids in the pathogenesis of PLDs and the potential therapeutic value of UDCA for the treatment of these diseases are reviewed and future lines of investigation in this field are proposed.

  6. Early low-frequency stimulation of the pudendal nerve can inhibit detrusor overactivity and delay progress of bladder fibrosis in dogs with spinal cord injuries.

    Science.gov (United States)

    Li, P; Liao, L; Chen, G; Zhang, F; Tian, Y

    2013-09-01

    To determine the inhibitory effects of pudendal nerve stimulation (5 Hz) on bladder overactivity at the early stage of spinal cord injury (SCI) in dogs, and to explore the possible effects on delayed progression of bladder fibrosis after SCI. The study was performed using six dogs with spinal cord transection at the T9–T10 level. Group 1 (three dogs) under went low-frequency electrical stimulation of the pudendal nerve 1 day after spinal cord transection. Group 2 (three dogs) underwent only spinal cord transection. All dogs underwent urodynamic examination at 1 and 3 months after SCI. The bladders were removed for histological examination of fibrosis at 3 months after SCI. Bladder capacity and compliance were significantly increased (Pstimulation in group 1 when compared with group 2 at 1 and 3 months after SCI. Non-voiding contractions (NVCs) were inhibited in group 1 compared with group 2. Collagen fibers were significantly increased and elastic fibers were significantly decreased (PEarly low-frequency pudendal nerve stimulation can inhibit detrusor overactivity (DO), increase bladder capacity and delay the progression of bladder fibrosis.

  7. DNA topoisomerase 2 mutant allele mildly delays the mitotic progression and activates the checkpoint protein kinase Chk1 in fission yeast Schizosaccharomyces pombe.

    Science.gov (United States)

    Yadav, Sudhanshu; Verma, Sumit Kumar; Ahmed, Shakil

    2011-08-01

    DNA topoisomerases are specialized nuclear enzymes that perform topological modifications on double-stranded DNA (dsDNA) and hence are essential for DNA metabolism such as replication, transcription, recombination, condensation and segregation. In a genetic screen, we identified a temperature-sensitive mutant allele of topoisomerase 2 that exhibits conditional synthetic lethality with a chk1 knockout strain. The mutant allele of topoisomerase 2 is defective in chromosome segregation at a non-permissive temperature and there was increase in chromosome segregation defects in the double mutant of top2-10 and chk1 delete at a non-permissive temperature. More importantly, topoisomearse 2 mutant cells mildly delay the mitotic progression at non-permissive temperature that is mediated by checkpoint protein kinase Chk1. Additionally, top2-10 mutant cells also activate the Chk1 at a non-permissive temperature and this activation of Chk1 takes place at the time of mitosis. Interestingly, top2-10 mutant cells retain their viability at a non-permissive temperature if the cells are not allowed to enter into mitosis. Taking together our results, we speculate that in the top2-10 mutant, the segregation of entangled chromatids during mitosis could result in delaying the mitotic progression through the activation of Chk1 kinase.

  8. Association between IgG4-related disease and progressively transformed germinal centers of lymph nodes.

    Science.gov (United States)

    Sato, Yasuharu; Inoue, Dai; Asano, Naoko; Takata, Katsuyoshi; Asaoku, Hideki; Maeda, Yoshinobu; Morito, Toshiaki; Okumura, Hirokazu; Ishizawa, Shin; Matsui, Shoko; Miyazono, Takayoshi; Takeuchi, Tamotsu; Kuroda, Naoto; Orita, Yorihisa; Takagawa, Kiyoshi; Kojima, Masaru; Yoshino, Tadashi

    2012-07-01

    Progressively transformed germinal centers is a benign condition of unknown pathogenesis characterized by a distinctive variant form of reactive follicular hyperplasia in lymph nodes. We recently reported Ig G4-related disease in progressively transformed germinal centers. However, no large case series has been reported and clinicopathologic findings remain unclear. Here, we report 40 Japanese patients (28 men, 12 women; median age, 56 years) with progressively transformed germinal centers of the lymph nodes who fulfilled the histological diagnostic criteria for IgG4-related disease (IgG4(+) progressively transformed germinal centers), with asymptomatic localized lymphadenopathy involving the submandibular nodes in 24, submandibular and cervical nodes in 14, cervical nodes only in 1, and cervical and supraclavicular nodes in 1. In all, 16 (52%) of 31 examined patients had allergic disease. Histologically, the lymph nodes demonstrated uniform histological findings, namely marked follicular hyperplasia with progressively transformed germinal centers, and localization of the majority of IgG4(+) plasma cells in the germinal centers. Serum IgG4, serum IgE and peripheral blood eosinophils were elevated in 87%, 92% and 53% of examined patients, respectively. Eighteen patients subsequently developed extranodal lesions (including five who developed systemic disease), which on histological examination were consistent with IgG4-related disease. IgG4(+) progressively transformed germinal centers presents with uniform clinicopathological features of asymptomatic localized submandibular lymphadenopathy, which persists and/or relapses, and sometimes progresses to extranodal lesions or systemic disease. Nine patients were administered steroid therapy when the lesions progressed, to which all responded well. We suggest that IgG4(+) progressively transformed germinal centers should be included in the IgG4-related disease spectrum.

  9. Disease progresses more quickly in introverts. Shy, inhibited personalities may fare worse.

    Science.gov (United States)

    2004-03-01

    Los Angeles researchers recently have discovered clinical evidence that HIV-positive people with shy and introverted personalities tend to have a faster disease progression and less optimal outcomes under antiretroviral treatment than do people with extroverted personalities.

  10. Progress and potential of nanomedicine to address infectious diseases of poverty

    CSIR Research Space (South Africa)

    Hayeshi, R

    2013-11-01

    Full Text Available Nanomedical Device and Systems Design: Challenges, Possibilities, Visions Chapter 13, pp 483-508 Progress and Potential of Nanomedicine to Address Infectious Diseases of Poverty Rose Hayeshi, Boitumelo Semete, Lonji Kalombo, Yolandy Lemmer, Lebogang...

  11. Skeletal Plasmacytoma: Progression of disease and impact of local treatment; an analysis of SEER database

    Directory of Open Access Journals (Sweden)

    Scully Sean P

    2009-09-01

    Full Text Available Abstract Background Previous reports suggest an as yet unidentifiable subset of patients with plasmacytoma will progress to myeloma. The current study sought to establish the risk of developing myeloma and determine the prognostic factors affecting the progression of disease. Methods Patients with plasmacytoma diagnosed between 1973 and 2005 were identified in the SEER database(1164 patients. Patient demographics and clinical characteristics, treatment(s, cause of death, and survival were extracted. Kaplan-Meier, log-rank, and Cox regression were used to analyze prognostic factors. Results The five year survival among patients initially diagnosed with plasmacytoma that later progressed to multiple myeloma and those initially diagnosed with multiple myeloma were almost identical (25% and 23%; respectively. Five year survival for patients with plasmacytoma that did not progress to multiple myeloma was significantly better (72%. Age > 60 years was the only factor that correlated with progression of disease (p = 0.027. Discussion Plasmacytoma consists of two cohorts of patients with different overall survival; those patients that do not progress to systemic disease and those that develop myeloma. Age > 60 years is associated with disease progression. Identifying patients with systemic disease early in the treatment will permit aggressive and novel treatment strategies to be implemented.

  12. Prognostic Indicators of Renal Disease Progression in Adults with Fabry Disease: Natural History Data from the Fabry Registry

    NARCIS (Netherlands)

    C. Wanner; J.P. Oliveira; A. Ortiz; M. Mauer; D.P. Germain; G.E. Linthorst; A.L. Serra; L. Marodi; R. Mignani; B. Cianciaruso; B. Vujkovac; R. Lemay; D. Beitner-Johnson; S. Waldek; D.G. Warnock

    2010-01-01

    Background and objectives: These analyses were designed to characterize renal disease progression in untreated adults with Fabry disease. Design, setting, participants, & measurements: Data from the Fabry Registry for 462 untreated adults (121 men and 341 women) who had at least two estimated GFR (e

  13. Rate of disease progression during long-term follow-up of patients with late-onset Pompe disease

    NARCIS (Netherlands)

    Van der Beek, N. A. M. E.; Hagemans, M. L. C.; Reuser, A. J. J.; Hop, W. C. J.; Van der Ploeg, A. T.; Van Doorn, P. A.; Wokke, J. H. J.

    To determine the rate of disease progression in patients with late-onset Pompe disease, we collected longitudinal data on pulmonary function and skeletal muscle strength in 16 patients whose symptoms had started in childhood or adulthood. The mean duration of follow-up was 16 years (range 4-29

  14. Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease

    DEFF Research Database (Denmark)

    Aziz, N A; Jurgens, C K; Landwehrmeyer, G B;

    2009-01-01

    OBJECTIVE: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). We aimed to assess whether interaction between CAG repeat sizes in the mutant and normal allele could affect disease severity and progression. METHODS: Using...... with less severe symptoms and pathology. CONCLUSIONS: Increasing CAG repeat size in normal HTT diminishes the association between mutant CAG repeat size and disease severity and progression in Huntington disease. The underlying mechanism may involve interaction of the polyglutamine domains of normal...

  15. Assessment of Definitions of Sustained Disease Progression in Relapsing-Remitting Multiple Sclerosis

    Science.gov (United States)

    Healy, Brian C.; Engler, David; Glanz, Bonnie; Musallam, Alexander; Chitnis, Tanuja

    2013-01-01

    Sustained progression on the expanded disability status scale (EDSS) is a common outcome measure of disease progression in clinical studies of MS. Unfortunately, this outcome may not accurately measure long-term and irreversible disease progression. To assess the performance of definitions of sustained progression, patients with relapsing-remitting MS (RRMS) or a clinically isolated syndrome with evidence of lesions on a brain MRI were included in our study. Fifteen definitions of sustained progression using both the EDSS and the functional system (FS) scales were investigated. The impact of both relapses and changes in provider on the probability of maintaining progression was also evaluated. Although the provider scoring the EDSS sometimes changed during followup, the provider had access to previous EDSS scores. Between 15.8% and 42.2% of patients experienced sustained progression based on the definitions using EDSS as the outcome, but nearly 50% of these patients failed to maintain sustained progression for the duration of followup. When FS scales were used, progression was most common on the pyramidal and sensory scales. Unfortunately, progression on specific FS scales failed to be more sensitive to irreversible disability. Relapses or changes in provider did not explain the poor performance of the measures. Short-term changes in the EDSS or FS scores may not be an accurate marker of irreversible change in RRMS. PMID:23555057

  16. Progress Delayed Onset Muscle Soreness%延迟性肌肉酸痛研究进展

    Institute of Scientific and Technical Information of China (English)

    刘志锋

    2015-01-01

    机体大强度或不习惯的运动,尤其是离心运动,常常会引起肌肉的延迟性酸痛,并在运动后的2-3天达到高峰,伴有一系列的肌肉结构、组织学及生物化学的改变,严重时会影响到人们健身及训练的效果。延迟性肌肉酸痛是体育运动中一种常见的现象。有关其研究已有百年的历史,但其产生的机制至今仍不清楚,也没有找到真正有效地清除延迟性肌肉酸痛的方法。文章运用文献资料法对国内有关延迟性肌肉酸痛的发生机制及治疗方法进行综述,并提出一些研究的不足和展望,为延迟性肌肉酸痛的进一步研究提供参考。%Intensive body strength exercise and unaccustomed exercise especially centrifugal movement will inevitably lead to delayed muscle soreness which will go at peak after 2 to 3 days. The symptom also appears as the muscle structure and biochemistry changes happens. It will leave harmful consequences in people’s training. Delayed onset muscle soreness is a common sports phenomenon. As for the research, it has lasts for centuries but the mechanism is still unclear as to what produces the harmful body reaction and how to find a truly effective way to remove DOMS . In this paper, by appliance of literature reviews on the mechanisms and treatment of delayed onset muscle soreness related to the occurrence of domestic reviewed, hatefully it will make up a number of shortcomings and deliver outlook studies providing a reference for further study of delayed onset muscle soreness.

  17. Calcium Carbonate versus Sevelamer Hydrochloride as Phosphate Binders after Long-Term Disease Progression in 5/6 Nephrectomized Rats

    Directory of Open Access Journals (Sweden)

    Suvi Törmänen

    2014-01-01

    Full Text Available Our aim was to compare the effects of calcium carbonate and sevelamer-HCl treatments on calcium-phosphate metabolism and renal function in 5/6 nephrectomized (NX rats so that long-term disease progression preceded the treatment. After 15-week progression, calcium carbonate (3.0%, sevelamer-HCl (3.0%, or control diets (0.3% calcium were given for 9 weeks. Subtotal nephrectomy reduced creatinine clearance (−40%, plasma calcidiol (−25%, and calcitriol (−70% and increased phosphate (+37%, parathyroid hormone (PTH (11-fold, and fibroblast growth factor-23 (FGF-23 (4-fold. In NX rats, calcium carbonate diet increased plasma (+20% and urinary calcium (6-fold, reduced plasma phosphate (−50% and calcidiol (−30%, decreased creatinine clearance (−35% and FGF 23 (−85%, and suppressed PTH without influencing blood pH. In NX rats, sevelamer-HCl increased urinary calcium (4-fold and decreased creatinine clearance (−45%, PTH (−75%, blood pH (by 0.20 units, plasma calcidiol (−40%, and calcitriol (−65%. Plasma phosphate and FGF-23 were unchanged. In conclusion, when initiated after long-term progression of experimental renal insufficiency, calcium carbonate diet reduced plasma phosphate and FGF-23 while sevelamer-HCl did not. The former induced hypercalcemia, the latter induced acidosis, while both treatments reduced vitamin D metabolites and deteriorated renal function. Thus, delayed initiation influences the effects of these phosphate binders in remnant kidney rats.

  18. Optical Assessment of Vascular Disease Progression and Treatment

    Science.gov (United States)

    Samuels, Joshua A.

    Vascular disease manifests itself in many different forms, including chronic ulcers which do not heal, impaired blood flow to the limbs, or damage to the natural reperfusion process. The current forms of assessing vascular disease are often subjective and provide incomplete knowledge about the tissue of interest. This work focused on developing non-invasive techniques to quantitatively evaluate three specific elements of vascular disease: diabetic ulcers, venous ulcers, and peripheral arterial disease. Diffuse Near Infrared Spectroscopy (DNIRS) was used to predict healing (82% positive predictive value) in diabetic ulcers after 4 weeks of assessment (sensitivity of 0.9 and specificity of 0.86; pulcers, using a low-frequency (20kHz), low intensity (ulcers compared to wounds which do not heal (p30 seconds) belonging to patients with PAD (pvascular health and the results obtained promise to develop new clinically relevant and quantitative techniques using non-invasive optical modalities.

  19. Immune Evasion Mechanisms of Entamoeba histolytica: Progression to Disease

    OpenAIRE

    2015-01-01

    Entamoeba histolytica (Eh) is a protozoan parasite that infects 10% of the world's population and results in 100,000 deaths/year from amebic dysentery and/or liver abscess. In most cases, this extracellular parasite colonizes the colon by high affinity binding to MUC2 mucin without disease symptoms, whereas in some cases, Eh triggers an aggressive inflammatory response upon invasion of the colonic mucosa. The specific host-parasite factors critical for disease pathogenesis are still not well ...

  20. Immune evasion mechanisms of Entamoeba histolytica: progression to disease

    OpenAIRE

    2015-01-01

    Entamoeba histolytica (Eh) is a protozoan parasite that infects 10% of the world’s population and results in 100,000 deaths/year from amebic dysentery and/or liver abscess. In most cases, this extracellular parasite colonizes the colon by high affinity binding to MUC2 mucin without disease symptoms, whereas in some cases, Eh triggers an aggressive inflammatory response upon invasion of the colonic mucosa. The specific host-parasite factors critical for disease pathogenesis are still not well ...

  1. Research progress on animal models of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Wen DONG

    2015-08-01

    Full Text Available Alzheimer's disease (AD is a degenerative disease of the central nervous system, and its pathogenesis is complex. Animal models play an important role in study on pathogenesis and treatment of AD. This paper summarized methods of building models, observation on animal models and evaluation index in recent years, so as to provide related evidence for basic and clinical research in future. DOI: 10.3969/j.issn.1672-6731.2015.08.003

  2. Application of Stem Cells in Oral Disease Therapy: Progresses and Perspectives

    Science.gov (United States)

    Yang, Bo; Qiu, Yi; Zhou, Niu; Ouyang, Hong; Ding, Junjun; Cheng, Bin; Sun, Jianbo

    2017-01-01

    Stem cells are undifferentiated and pluripotent cells that can differentiate into specialized cells with a more specific function. Stem cell therapies become preferred methods for the treatment of multiple diseases. Oral and maxillofacial defect is one kind of the diseases that could be most possibly cured by stem cell therapies. Here we discussed oral diseases, oral adult stem cells, iPS cells, and the progresses/challenges/perspectives of application of stem cells for oral disease treatment. PMID:28421002

  3. Sudden death in noncoronary heart disease is associated with delayed paced ventricular activation

    NARCIS (Netherlands)

    Saumarez, RC; Chojnowska, L; Derksen, R; Pytkowski, M; Sterlinski, M; Huang, CLH; Sadoul, N; Hauer, RNW; Ruzyllo, W; Grace, AA

    2003-01-01

    Background-Slowed or delayed myocardial activation and dispersed refractoriness predispose to reentrant excitation that may lead to ventricular fibrillation (VF). Increased ventricular electrogram duration (DeltaED) in response to extrastimuli and increased S1S2 coupling intervals at which electrogr

  4. Soluble beta-amyloid precursor protein is related to disease progression in amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Petra Steinacker

    Full Text Available BACKGROUND: Biomarkers of disease progression in amyotrophic lateral sclerosis (ALS could support the identification of beneficial drugs in clinical trials. We aimed to test whether soluble fragments of beta-amyloid precursor protein (sAPPα and sAPPß correlated with clinical subtypes of ALS and were of prognostic value. METHODOLOGY/PRINCIPAL FINDINGS: In a cross-sectional study including patients with ALS (N = 68 with clinical follow-up data over 6 months, Parkinson's disease (PD, N = 20, and age-matched controls (N = 40, cerebrospinal fluid (CSF levels of sAPPα a, sAPPß and neurofilaments (NfH(SMI35 were measured by multiplex assay, Progranulin by ELISA. CSF sAPPα and sAPPß levels were lower in ALS with a rapidly-progressive disease course (p = 0.03, and p = 0.02 and with longer disease duration (p = 0.01 and p = 0.01, respectively. CSF NfH(SMI35 was elevated in ALS compared to PD and controls, with highest concentrations found in patients with rapid disease progression (p<0.01. High CSF NfH(SMI3 was linked to low CSF sAPPα and sAPPß (p = 0.001, and p = 0.007, respectively. The ratios CSF NfH(SMI35/CSF sAPPα,-ß were elevated in patients with fast progression of disease (p = 0.002 each. CSF Progranulin decreased with ongoing disease (p = 0.04. CONCLUSIONS: This study provides new CSF candidate markers associated with progression of disease in ALS. The data suggest that a deficiency of cellular neuroprotective mechanisms (decrease of sAPP is linked to progressive neuro-axonal damage (increase of NfH(SMI35 and to progression of disease.

  5. Intractable episodic bradycardia resulting from progressive lead traction in an epileptic child with a vagus nerve stimulator: a delayed complication.

    Science.gov (United States)

    Clark, Aaron J; Kuperman, Rachel A; Auguste, Kurtis I; Sun, Peter P

    2012-04-01

    Vagus nerve stimulation (VNS) is used as palliation for adult and pediatric patients with intractable epilepsy who are not candidates for curative resection. Although the treatment is generally safe, complications can occur intraoperatively, perioperatively, and in a delayed time frame. In the literature, there are 2 reports of pediatric patients with implanted VNS units who had refractory bradycardia that resolved after the stimulation was turned off. The authors report the case of a 13-year-old boy with a history of vagus nerve stimulator placement at 2 years of age, who developed intractable episodic bradycardia that persisted despite the cessation of VNS and whose imaging results suggested vagus nerve tethering by the leads. He was subsequently taken to the operating room for exploration, where it was confirmed that the stimulator lead was exerting traction on the vagus nerve, which was displaced from the carotid sheath. After the vagus nerve was untethered and the leads were replaced, the bradycardia eventually resolved with continual effective VNS therapy. When placing a VNS unit in a very young child, accommodations must be made for years of expected growth. Delayed intractable bradycardia can result from a vagus nerve under traction by tethered stimulator leads.

  6. Shoulder activity level and progression of degenerative cuff disease.

    Science.gov (United States)

    Keener, Jay D; Skelley, Nathan W; Stobbs-Cucchi, Georgia; Steger-May, Karen; Chamberlain, Aaron M; Aleem, Alex W; Brophy, Robert H

    2017-09-01

    This study prospectively examined the relationship of direct and indirect measures of shoulder activity with the risks of tear progression and pain development in subjects with an asymptomatic degenerative rotator cuff tear. A cohort of asymptomatic degenerative rotator cuff tears was prospectively monitored annually, documenting tear size progression with ultrasound imaging and potential shoulder pain development. Shoulder activity level, self-reported occupational and physical demand level, and hand dominance were compared with risks of tear enlargement and future pain development. The study monitored 346 individuals with a mean age of 62.1 years for a median duration of 4.1 years (interquartile range [IQR], 2.4-7.9 years). Tear enlargement was seen in 177 shoulders (51.2%), and pain developed in 161 shoulders (46.5%) over time. Tear presence in the dominant shoulder was associated with a greater risk of tear enlargement (hazard ratio, 1.40; P = .03) and pain development (hazard ratio, 1.63; P = .002). Shoulder activity level (P = .37) and occupational demand level (P = .62) were not predictive of tear enlargement. Occupational demand categories of manual labor (P = .047) and "in between" (P = .045) had greater risks of pain development than sedentary demands. The median shoulder activity score for shoulders that became painful was lower than for shoulders that remained asymptomatic (10.0 [IQR, 7.0-13.0] vs. 11.0 [IQR, 8.0-14.0], P = .02). Tear enlargement and pain development in asymptomatic tears are more common with involvement of the dominant shoulder. Shoulder activity level is not related to tear progression risks. Pain development is associated with a lower shoulder activity level even though patients with higher occupational demands are more likely to develop pain. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

  7. Podoplanin Expression Correlates with Disease Progression in Mycosis Fungoides.

    Science.gov (United States)

    Jankowska-Konsur, Alina; Kobierzycki, Christopher; Grzegrzółka, Jędrzej; Piotrowska, Aleksandra; Gomulkiewicz, Agnieszka; Glatzel-Plucinska, Natalia; Reich, Adam; Podhorska-Okołów, Marzenna; Dzięgiel, Piotr; Szepietowski, Jacek C

    2017-02-08

    The aim of this study was to investigate the role of lymphangiogenesis in the clinical progression and outcome of mycosis fungoides. Immunohistochemistry and Western blot techniques were used to assess the expression of podoplanin and vascular endothelial growth factor C in mycosis fungoides. Expression of vascular endothelial growth factor C measured by immunohistochemistry was significantly higher in mycosis fungoides samples in comparison with control cases (chronic benign dermatoses) (p = 0.0012). Increased expression of podoplanin was found in advanced vs. early mycosis fungoides (p mycosis fungoides.

  8. Oxidative stress: Lipid peroxidation products as predictors in disease progression

    Directory of Open Access Journals (Sweden)

    Suranjana Ray Halder

    2014-09-01

    Full Text Available Oxidative stress is implicated in the pathogenesis of numerous disease processes, including diabetes mellitus, atherosclerosis, ischemia reperfusion injury, rheumatoid arthritis, neurodegenerative diseases as well as in the aging process. Chemical modification of amino acids in protein during lipid peroxidation (LPO results in the formation of lipoxidation products, which may serve as indicators of oxidative stress in vivo. The various types of aldehydes such as 4-hydroxynonenal, malondialdehyde, acrolein and others produced during LPO may serve as potent oxidative stress biomarkers. Their activation in different signaling cascades lead to apoptosis, differentiation, proliferation, etc., Increased amount of these aldehydes in aging or with metabolic complications or in other diseases indicate their pathophysiological significance. Thus, LPO products or other oxidative stress biomarkers may open the way for the development of early detection, prevention, and therapeutic strategies for stress associated human diseases. Now-a-days, antioxidant supplementation has become an increasingly popular practice to restore the redox homeostatic condition of the cell. Disease specific, target directed, bioavailable antioxidants may be beneficial for sustenance of the quality-of-life in future days. [J Exp Integr Med 2014; 4(3.000: 151-164

  9. Periodontal Pocket Depth, Hyperglycemia, and Progression of Chronic Kidney Disease: A Population-Based Longitudinal Study.

    Science.gov (United States)

    Chang, Jia-Feng; Yeh, Jih-Chen; Chiu, Ya-Lin; Liou, Jian-Chiun; Hsiung, Jing-Ru; Tung, Tao-Hsin

    2017-01-01

    No large epidemiological study has been conducted to investigate the interaction and joint effects of periodontal pocket depth and hyperglycemia on progression of chronic kidney disease in patients with periodontal diseases. Periodontal pocket depth was utilized for the grading severity of periodontal disease in 2831 patients from January 2002 to June 2013. Progression of chronic kidney disease was defined as progression of color intensity in glomerular filtration rate and albuminuria grid of updated Kidney Disease-Improving Global Outcomes guidelines. Multivariable-adjusted hazard ratios (aHR) in various models were presented across different levels of periodontal pocket depth and hemoglobin A1c (HbA1c) in forest plots and 3-dimensional histograms. During 7621 person-years of follow-up, periodontal pocket depth and HbA1C levels were robustly associated with incremental risks for progression of chronic kidney disease (aHR 3.1; 95% confidence interval [CI], 2.0-4.6 for periodontal pocket depth >4.5 mm, and 2.5; 95% CI, 1.1-5.4 for HbA1C >6.5%, respectively). The interaction between periodontal pocket depth and HbA1C on progression of chronic kidney disease was strong (P periodontal pocket depth (>4.5 mm) and higher HbA1C (>6.5%) had the greatest risk (aHR 4.2; 95% CI, 1.7-6.8) compared with the lowest aHR group (periodontal pocket depth ≤3.8 mm and HbA1C ≤6%). Our study identified combined periodontal pocket depth and HbA1C as a valuable predictor of progression of chronic kidney disease in patients with periodontal diseases. While considering the interaction between periodontal diseases and hyperglycemia, periodontal survey and optimizing glycemic control are warranted to minimize the risk of worsening renal function. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Progression of postural changes in Parkinson's disease: quantitative assessment.

    Science.gov (United States)

    Khlebtovsky, Alexander; Djaldetti, Ruth; Rodity, Yaniv; Keret, Ofir; Tsvetov, Gloria; Slutzcki-Shraga, Ilana; Benninger, Felix

    2017-02-02

    Previous studies of posture in Parkinson's disease (PD) patients focused on the pathophysiology of severe deformities, using mainly subjective estimations or goniometric measures. The aim of this study was to investigate risk factors associated with flexed posture in PD and their effects on the course of posture variations. One hundred-ninety patients with definite PD were prospectively evaluated for angles of spinal inclination in upright position, extension, and flexion using a mechanical computer-assisted, hand-held device (SpinalMouse). Patients underwent clinical examination, including background data and bone mineral density. Motor function was evaluated with the UPDRS, and back pain with the RMDQ. Physical activity data were collected by self-report. Postural measurements were repeated after 10-17 months. Angle of upright inclination correlated with age (p = 0.0004), older age at disease onset (p = 0.0085), longer disease duration (p = 0.003), higher UPDRS motor and posture score (p = 0.0005 and 0.0001), the presence of back-pain (p = 0.0097), and osteoporosis (p = 0.027). There was no correlation between upright angle of inclination and gender, disease type, or side of disease onset. Re-evaluation of posture in 124 patients at 13.77 ± 4.4 months after the initial evaluation showed significant deterioration in forward bending (p physical activity (p = 0.0327). Older age, disease severity and duration, presence of back-pain and osteoporosis are associated with postural abnormalities in PD. Physical activity might slow the worsening of postural abnormalities in PD.

  11. Progression of experimental chronic Aleutian mink disease virus infection

    DEFF Research Database (Denmark)

    Jensen, Trine Hammer; Chriél, Mariann; Hansen, Mette Sif

    2016-01-01

    Aleutian mink disease virus (AMDV) is found world-wide and has a major impact on mink health and welfare by decreasing reproduction and fur quality. In the majority of mink, the infection is subclinical and the diagnosis must be confirmed by serology or polymerase chain reaction (PCR). Increased ...

  12. Multimodal imaging of the disease progression of birdshot chorioretinopathy

    NARCIS (Netherlands)

    Teussink, M.M.; Veld, P.I. Huis In Het; Vries, L.A.M. de; Hoyng, C.B.; Klevering, B.J.; Theelen, T.

    2016-01-01

    PURPOSE: To study outer retinal deterioration in relation to clinical disease activity in patients with birdshot chorioretinopathy using fundus autofluorescence and spectral-domain optical coherence tomography (OCT). METHODS: A single-centre retrospective cohort study was carried out on 42 eyes of 2

  13. Quantitative and qualitative progression of peripheral arterial disease by non-invasive testing.

    Science.gov (United States)

    Bird, C E; Criqui, M H; Fronek, A; Denenberg, J O; Klauber, M R; Langer, R D

    1999-01-01

    There is little information on the progression of peripheral arterial disease (PAD) over time. A series of 508 patients with a prior examination for PAD were contacted and brought in for follow-up to evaluate the natural history of PAD. A total of 85 patients were excluded because they had interventions in both limbs prior to their return visit. Progression was assessed in the remaining 423 patients for a total of 755 limbs, both quantitatively and qualitatively using six categories of PAD severity. There was a modest overall categorical progression of disease: 228 limbs (30.2%) displayed categorical progression, while 172 limbs (22.8%) improved over a 4.6-year average follow-up. Through analysis of quantitative change, it was determined that more quantitative progression occurred than was evident from categorical progression. Two of the three non-invasive tests employed, the ankle/brachial index (ABI) and posterior tibial peak forward flow velocity (peak PT), showed statistically significant progression during follow-up: mean ABI change = -0.019, 95% confidence interval (CI)= -0.031 to -0.007; mean peak PT change = -2.32 cm/s, 95% CI = -3.20 to -1.44. The toe/brachial index (TBI) also suggested progression: mean change= -0.013, but the 95% CI included no change. Standard scores (sum of the Z-scores for ABI, peak PT and TBI) were calculated. The standard score progressed approximately 0.34 units (standard deviations), p-value amputation status. Thus, in this cohort of PAD patients, PAD on average progressed significantly over 4.6 years. This progression was independently related to age, diabetes and several markers of disease severity.

  14. Direct comparison between regional cerebral metabolism in progressive supranuclear palsy and Parkinson's disease

    NARCIS (Netherlands)

    Klein, RC; de Jong, BM; de Vries, JJ; Leenders, KL

    2005-01-01

    The differentiation between progressive supranuclear palsy (PSP) and Parkinson's disease (PD) may be difficult, especially in the early stages of disease. Positron emission tomography potentially provides a tool for making such a distinction. To identify key features in the spatial distributions of

  15. Serum microRNA-125a-5p, a useful biomarker in liver diseases, correlates with disease progression.

    Science.gov (United States)

    Zheng, Jianjian; Zhou, Zhenxu; Xu, Ziqiang; Li, Guojun; Dong, Peihong; Chen, Zhanguo; Lin, Dezhao; Chen, Bicheng; Yu, Fujun

    2015-07-01

    It has been demonstrated that liver microRNA-125a-5p (miR-125a-5p) is correlated with disease progression in different liver diseases, including liver fibrosis and hepatocellular carcinoma (HCC). The present study investigated whether serum miR-125a-5p correlated with the progression of different liver diseases. Serum samples were obtained from healthy individuals, patients with chronic hepatitis B who had undergone a liver biopsy, and patients with HCC and were analyzed for the levels of miR-125a-5p. Compared with the healthy controls, the serum levels of miR-125a-5p were significantly higher in the liver fibrosis serum, and were reduced in HCC. With the development of liver fibrosis, there was a significant increase in the expression of miR-125a-5p (Pserum miR-125a-5p and viral replication (Pserum levels of miR-125a-5p were correlated with a poor prognosis, determined by Kaplan-Meier curve analysis (P=0.009). In the liver fibrosis and HCC groups, different expression levels of serum miR-125a-5p were observed, and were correlated with disease progression. The results of the present study suggested that serum miR-125a-5p may be used as a non-invasive biomarker for monitoring disease progression in liver diseases.

  16. miR-181b is a biomarker of disease progression in chronic lymphocytic leukemia.

    Science.gov (United States)

    Visone, Rosa; Veronese, Angelo; Rassenti, Laura Z; Balatti, Veronica; Pearl, Dennis K; Acunzo, Mario; Volinia, Stefano; Taccioli, Cristian; Kipps, Thomas J; Croce, Carlo M

    2011-09-15

    MicroRNAs play a crucial role in chronic lymphocytic leukemia. We investigated whether microRNAs can discriminate patients with a progressive disease from patients with a stable disease. We analyzed microRNA expression on leukemic cells isolated from 358 sequential samples of 114 patients with either stable or progressive disease. We found that during the course of the disease the expression values of miR-181b, the most dysregulated microRNA, decreased in samples of patients with a progressive (P miR-181b value ≤ 0.005 at the starting time point were significant to differentiate progressive from stable disease (P = .004, training set; P miR-181b targets Mcl-1 protein and that the decrease of its expression inversely correlated with increased protein levels of MCL1 and BCL2 target genes. We conclude that parameters defined on the basis of the miR-181b expression values specify disease progression in chronic lymphocytic leukemia and are associated with clinical outcome.

  17. Disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural disease: case report.

    Science.gov (United States)

    Kessler, Brice A; Bookhout, Christine; Jaikumar, Sivakumar; Hipps, John; Lee, Yueh Z

    2015-01-01

    We report the neuroimaging and histopathologic findings of a 12-year-old female patient with a disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural metastatic disease. These tumors may represent distinct pathology primarily seen in pediatric patients. Neuroimaging demonstrates diffuse, progressive enhancement of the leptomeninges often with interval development of intraparenchymal lesions on follow-up. Disease is typically confined to the central nervous system, though diffuse peritoneal disease was seen in our case, possibly through metastatic seeding of the abdomen via ventriculoperitoneal shunt.

  18. Disease Progression and Resolution in Rodent Models of Clostridium difficile Infection and Impact of Antitoxin Antibodies and Vancomycin.

    Science.gov (United States)

    Warn, Peter; Thommes, Pia; Sattar, Abdul; Corbett, David; Flattery, Amy; Zhang, Zuo; Black, Todd; Hernandez, Lorraine D; Therien, Alex G

    2016-11-01

    Clostridium difficile causes infections of the colon in susceptible patients. Specifically, gut dysbiosis induced by treatment with broad-spectrum antibiotics facilitates germination of ingested C. difficile spores, expansion of vegetative cells, and production of symptom-causing toxins TcdA and TcdB. The current standard of care for C. difficile infections (CDI) consists of administration of antibiotics such as vancomycin that target the bacterium but also perpetuate gut dysbiosis, often leading to disease recurrence. The monoclonal antitoxin antibodies actoxumab (anti-TcdA) and bezlotoxumab (anti-TcdB) are currently in development for the prevention of recurrent CDI. In this study, the effects of vancomycin or actoxumab/bezlotoxumab treatment on progression and resolution of CDI were assessed in mice and hamsters. Rodent models of CDI are characterized by an early severe phase of symptomatic disease, associated with high rates of morbidity and mortality; high intestinal C. difficile burden; and a disrupted intestinal microbiota. This is followed in surviving animals by gradual recovery of the gut microbiota, associated with clearance of C. difficile and resolution of disease symptoms over time. Treatment with vancomycin prevents disease initially by inhibiting outgrowth of C. difficile but also delays microbiota recovery, leading to disease relapse following discontinuation of therapy. In contrast, actoxumab/bezlotoxumab treatment does not impact the C. difficile burden but rather prevents the appearance of toxin-dependent symptoms during the early severe phase of disease, effectively preventing disease until the microbiota (the body's natural defense against C. difficile) has fully recovered. These data provide insight into the mechanism of recurrence following vancomycin administration and into the mechanism of recurrence prevention observed clinically with actoxumab/bezlotoxumab. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  19. 20 YEARS OF PROGRESS IN DIARRHEAL DISEASE RESEARCH

    Directory of Open Access Journals (Sweden)

    Narain H. Punjabi

    2012-09-01

    Full Text Available When NAMRU started its collaboration work with the National Institute of Health, Research and Development (NIHRD, it became apparent that diarrheal disease was one of the most important causes of morbidity and mortality in Indonesia, especially in children. Many of the most important etiologic agents of diarrhea were not known and the percentage of diarrheas with an identifiable etiologic agent was very low. Since these early times NAMRU and NIHRD have worked together in all aspects of diarrheal disease research. Increased capabilities for the identification of bac­tériologie, parasitic and viral enteropathogens, new vaccines, and better treatment via oral rehydration solutions are some of the results of this collaboration.

  20. Epidemic progression on networks based on disease generation time

    Science.gov (United States)

    Davoudi, Bahman; Moser, Flavia; Brauer, Fred; Pourbohloul, Babak

    2013-01-01

    We investigate the time evolution of disease spread on a network and present an analytical framework using the concept of disease generation time. Assuming a susceptible–infected–recovered epidemic process, this network-based framework enables us to calculate in detail the number of links (edges) within the network that are capable of producing new infectious nodes (individuals), the number of links that are not transmitting the infection further (non-transmitting links), as well as the number of contacts that individuals have with their neighbours (also known as degree distribution) within each epidemiological class, for each generation period. Using several examples, we demonstrate very good agreement between our analytical calculations and the results of computer simulations. PMID:23889499

  1. Smoking and Progression of Alzheimers Disease: Connecting Edges

    Directory of Open Access Journals (Sweden)

    Vivek Sharma

    2014-06-01

    Full Text Available Smoking is a practice to burn and inhale the smoke and is primarily a route of administration for recreational drugs. The combustion releases the active substances in drugs such as nicotine and make them available for absorption through the lungs.The most common form of smoking is ciggarate smoking and is associated with life threatening complications like heart diseases, lung cancer, atherosclerosis, rheumatoid arthritis, osteoporosios, immune system dysfunction, hypertension, chronic obstructive pulmonary diseases, miscarriage, premature birth and dysfunctions of reproductive system as well. Smoking affet almost every organ of the body however, compared to the volume of research on the cardiovascular, pulmonary and cancer related health consequences of chronic smoking, lesser attention has been devoted to investigation of its effects on human neurocognition and brain neurobiology. In central nervous system, it leads to deficiencies in auditory verbal learning and/or memory, general intellectual abilities, visual search speeds, processing speed, cognitive flexibility, working memory and executive functions across a wide age range. The present work makes an effort to compile the evidence to challenge the notion/myth that smoking may be neuroprotective in cases of Alzheimers disease. The neuroprotective effects of smoking may be accredited only to nicotinic content of cigarrate smoke that too in part, but smoke is a deadly mixture of thousands of chemicals that must have disastrous effect on central nervous system. The various effets of cigarrate smoke and its ingredients on pathological markers of Alzheimers disease as oxidative stress, senile plaques, tau hyperphosphorylation, neuroinflammation, synapse loss and effects on blood brain barrier are disussed. [Archives Medical Review Journal 2014; 23(3.000: 534-561

  2. Study progress of berberine for treating cardiovascular disease

    Institute of Scientific and Technical Information of China (English)

    Le-Min Xia; Mei-Hong Luo

    2015-01-01

    Berberine (BBR) is a natural alkaloid isolated from the Coptis chinensis.While this plant has been used in Chinese medicine for more than 2500 years,interest in its effects in treating cardiovascular disease has been growing in the last decade.Recent researches showed that BBR had the effect of anti-heart failure,anti-hypertension,anti-hyperlipidemia,anti-insulin resistance,anti-arrhythmias,and anti-platelet aggregation.

  3. History and progression of Fat cadherins in health and disease

    Science.gov (United States)

    Zhang, Xiaofeng; Liu, Jinghua; Liang, Xiao; Chen, Jiang; Hong, Junjie; Li, Libo; He, Qiang; Cai, Xiujun

    2016-01-01

    Intercellular adhesions are vital hubs for signaling pathways during multicellular development and animal morphogenesis. In eukaryotes, under aberrant intracellular conditions, cadherins are abnormally regulated, which can result in cellular pathologies such as carcinoma, kidney disease, and autoimmune diseases. As a member of the Ca2+-dependent adhesion super-family, Fat proteins were first described in the 1920s as an inheritable lethal mutant phenotype in Drosophila, consisting of four member proteins, FAT1, FAT2, FAT3, and FAT4, all of which are highly conserved in structure. Functionally, FAT1 was found to regulate cell migration and growth control through specific protein–protein interactions of its cytoplasmic tail. FAT2 and FAT3 are relatively less studied and are thought to participate in the development of human cancer through a pathway similar to that of the Ena/VASP proteins. In contrast, FAT4 has been widely studied in the context of biological functions and tumor mechanisms and has been shown to regulate the planar cell polarity pathway, the Hippo signaling pathway, the canonical Wnt signaling cascade, and the expression of YAP1. Overall, Fat cadherins may be useful as emerging disease biomarkers and as novel therapeutic targets. PMID:27942226

  4. Calprotectin as a Biomarker for Melioidosis Disease Progression and Management.

    Science.gov (United States)

    Natesan, Mohan; Corea, Enoka; Krishnananthasivam, Shivankari; Sathkumara, Harindra Darshana; Dankmeyer, Jennifer L; Dyas, Beverly K; Amemiya, Kei; De Silva, Aruna Dharshan; Ulrich, Robert G

    2017-04-01

    Melioidosis is a neglected tropical disease that is caused by the bacterium Burkholderia pseudomallei and is underreported in many countries where the disease is endemic. A long and costly administration of antibiotics is needed to clear infections, and there is an unmet need for biomarkers to guide antibiotic treatment and increase the number of patients that complete therapy. We identified calprotectin as a lead biomarker of B. pseudomallei infections and examined correlations between this serum protein and the antibiotic treatment outcomes of patients with melioidosis. Serum levels of calprotectin and C-reactive protein were significantly higher in patients with melioidosis and nonmelioidosis sepsis than in healthy controls. Median calprotectin levels were higher in patients with melioidosis than in those with nonmelioidosis sepsis, whereas C-reactive protein levels were similar in both groups. Notably, intensive intravenous antibiotic treatment of patients with melioidosis resulted in lower levels of calprotectin and C-reactive protein (P < 0.0001), coinciding with recovery. The median percent reduction of calprotectin and C-reactive protein was 71% for both biomarkers after antibacterial therapy. In contrast, we found no significant differences in calreticulin levels between the two melioidosis treatment phases. Thus, reductions in serum calprotectin levels were linked to therapeutic responses to antibiotics. Our results suggest that calprotectin may be a sensitive indicator of melioidosis disease activity and illustrate the potential utility of this biomarker in guiding the duration of antibiotic therapy.

  5. Progress in studies of gene therapy for Huntington's disease

    Directory of Open Access Journals (Sweden)

    JIN Fan-ying

    2012-06-01

    Full Text Available Huntington's disease (HD is a kind of inherited neurodegenerative disorder characterized by movement problems, cognitive decline and psychiatry disturbance. HD is caused by mutation in gene IT -15 involving the expansion of a trinucleotide (CAG repeat encoding glutamine, which leads to abnormal conformation of huntingtin (Htt protein and finally emerge cytotoxic functions. Currently, HD remains a fatal untreatable disease. Gene therapy for HD discussed in this review is under preclinical studies. Silencing of mutant IT-15 via RNA interference (RNAi or antisense oligonucleotide (ASO has shown some effectiveness in mouse model studies. Increasing the clearance of mutant Htt protein could be achieved by viral-mediated delivery of anti-Htt intrabodies (iAbs or induction of autophagy, and beneficial results have been observed. Ectopic expression of neurotrophic factors, such as nerve growth factor (NGF and brain-derived neurotrophic factor (BDNF, mediated either by viral vectors or transplantation of genetically modified cells, has also been proved to be effective. Other gene-modifying methods aiming at correction of transcriptional dysregulation by histone modification, activation of endogenous neural stem cells, and normalization of calcium signaling and mitochondrial function, are also under intensive research. Gene therapy for Huntington's disease is promising, yet a long way remains from preclinical studies to clinical trials.

  6. The rate of progression of renal disease may not be slower in women compared with men

    DEFF Research Database (Denmark)

    Jafar, Tazeen H; Schmid, Christopher H; Stark, Paul C

    2003-01-01

    of renal disease progression with gender. METHODS: We analysed a pooled database of patients with non-diabetic renal disease enrolled in 11 randomized controlled trials evaluating the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) for slowing renal disease progression. The primary end point...... patient characteristics, and changes from baseline to follow-up systolic blood pressure (SBP) and urine protein (UP) excretion. RESULTS: The total number of patients was 1860: 645 (35%) females and 1215 (65%) males. Mean duration of follow-up was 2.2 years. The proportions randomized to ACEI (51%), mean...... ACEIs and baseline UP, and 1.36 (1.06-1.75) after adjusting for baseline variables and changes in SBP and UP during follow-up. Similar results were found for the outcome of ESRD. CONCLUSIONS: Our findings suggest that the rate of renal disease progression may not be slower, and may even be faster...

  7. The relationship between CAG repeat length and clinical progression in Huntington's disease.

    Science.gov (United States)

    Ravina, Bernard; Romer, Megan; Constantinescu, Radu; Biglan, Kevin; Brocht, Alicia; Kieburtz, Karl; Shoulson, Ira; McDermott, Michael P

    2008-07-15

    The objective of this study was to examine the relationship between CAG repeat length (CAGn) and clinical progression in patients with Huntington's disease (HD). There are conflicting reports about the relationship between CAGn and clinical progression of HD. We conducted an analysis of data from the Coenzyme Q10 and Remacemide Evaluation in Huntington's Disease (CARE-HD) clinical trial. We modeled progression over 30 months on the Unified Huntington's Disease Rating Scale (UHDRS) and supplemental neuropsychological and behavioral tests using multiple linear regression. Mean subject age was 47.9 +/- 10.5 years and mean CAGn was 45.0 +/- 4.1. Multiple linear regression revealed statistically significant associations between CAGn and worsening on several motor, cognitive, and functional outcomes, but not behavioral outcomes. Many effects were clinically important; 10 additional CAG repeats were associated with an 81% increase in progression on the Independence Scale. These associations were not observed in the absence of age adjustment. Age at the time of assessment confounds the association between CAGn and progression. Adjusting for age shows that longer CAGn is associated with greater clinical progression of HD. This finding may account for the variable results from previous studies examining CAGn and progression. Adjusting for CAGn may be important for clinical trials.

  8. The combination of lanthanum chloride and the calcimimetic calindol delays the progression of vascular smooth muscle cells calcification

    Energy Technology Data Exchange (ETDEWEB)

    Ciceri, Paola; Volpi, Elisa; Brenna, Irene; Elli, Francesca [Renal Division and Laboratory of Experimental Nephrology, Dipartimento di Medicina e Chirurgia, Universita di Milano, Milan (Italy); Borghi, Elisa [Dipartimento di Salute Pubblica, Microbiologia e Virologia, Universita di Milano, Milan (Italy); Brancaccio, Diego [Renal Division and Laboratory of Experimental Nephrology, Dipartimento di Medicina e Chirurgia, Universita di Milano, Milan (Italy); Cozzolino, Mario, E-mail: mario.cozzolino@unimi.it [Renal Division and Laboratory of Experimental Nephrology, Dipartimento di Medicina e Chirurgia, Universita di Milano, Milan (Italy)

    2012-02-24

    Highlights: Black-Right-Pointing-Pointer Lanthanum reduces the progression of high phosphate-induced calcium deposition. Black-Right-Pointing-Pointer Calcium receptor agonists and the calcimimetic calindol reduce calcium deposition. Black-Right-Pointing-Pointer Lanthanum and calindol cooperate on reducing calcium deposition. Black-Right-Pointing-Pointer Lanthanum and calindol may interact with the same receptor. -- Abstract: Phosphate (Pi)-binders are commonly used in dialysis patients to control high Pi levels, that associated with vascular calcification (VC). The aim of this study was to investigate the effects of lanthanum chloride (LaCl{sub 3}) on the progression of high Pi-induced VC, in rat vascular smooth muscle cells (VSMCs). Pi-induced Ca deposition was inhibited by LaCl{sub 3}, with a maximal effect at 100 {mu}M (59.0 {+-} 2.5% inhibition). Furthermore, we studied the effects on VC of calcium sensing receptor (CaSR) agonists. Gadolinium chloride, neomycin, spermine, and the calcimimetic calindol significantly inhibited Pi-induced VC (55.9 {+-} 2.2%, 37.3 {+-} 4.7%, 30.2 {+-} 5.7%, and 63.8 {+-} 5.7%, respectively). To investigate the hypothesis that LaCl{sub 3} reduces the progression of VC by interacting with the CaSR, we performed a concentration-response curve of LaCl{sub 3} in presence of a sub-effective concentration of calindol (10 nM). Interestingly, this curve was shifted to the left (IC{sub 50} 9.6 {+-} 2.6 {mu}M), compared to the curve in the presence of LaCl{sub 3} alone (IC{sub 50} 19.0 {+-} 4.8 {mu}M). In conclusion, we demonstrated that lanthanum chloride effectively reduces the progression of high phosphate-induced vascular calcification. In addition, LaCl{sub 3} cooperates with the calcimimetic calindol in decreasing Ca deposition in this in vitro model. These results suggest the potential role of lanthanum in the treatment of VC induced by high Pi.

  9. Association of serum uric acid levels with the progression of Parkinson's disease in Chinese patients

    Institute of Scientific and Technical Information of China (English)

    SUN Cong-cong; LUO Fei-fei; WEI Lei; LEI Mi; LI Guo-fei; LIU Zhuo-lin; LE Wei-dong; XU Ping-yi

    2012-01-01

    Background Uric acid (UA) is suspected to play a neuro-protective role in Parkinson's disease (PD).This study aimed to evaluate whether the serum UA level was associated with the disease progression of PD in a relatively large population of Chinese patients.Methods Serum UA levels were measured from 411 Chinese PD patients and 396 age-matched controls; following the uric acid colorimetric method,the serum creatinine (Scr) levels were also measured to reduce the bias caused by possible differences in renal excretion function.The disease progression was scored by Hoehn and Yahr (H&Y) scales and disease durations; PD group was divided into 3 subgroups according to H&Y scales.Independent-samples ttest was performed to analyze the differences between PD group and control group.Multiple analysis of covariance was performed to analyze the differences between PD subgroups.Spearman rank-correlation was performed to evaluate the associations between serum UA or Scr level and disease progression.Results PD patients were found to have significantly lower levels of serum UA than controls ((243.38±78.91) vs.(282.97±90.80) pmol/L,P<0.01).As the disease progression,the serum UA levels were gradually reduced.There was a significantly inverse correlation of UA levels with H&Y scales (Rs=-0.429,P <0.01) and disease duration (Rs=-0.284,P <0.01) in PD patients of both females and males.No significant difference of the Scr level between PD patients and controls was found ((70.01±14.70) vs.(69.84±16.46) μmol/L),and the Scr level was not involved in disease progression.Conclusion Lower serum UA levels may possess a higher risk of PD,which may be a potential useful biomarker to indicate the progression of PD.

  10. Serum metabolomics of slow vs. rapid motor progression Parkinson's disease: a pilot study.

    Directory of Open Access Journals (Sweden)

    James R Roede

    Full Text Available Progression of Parkinson's disease (PD is highly variable, indicating that differences between slow and rapid progression forms could provide valuable information for improved early detection and management. Unfortunately, this represents a complex problem due to the heterogeneous nature of humans in regards to demographic characteristics, genetics, diet, environmental exposures and health behaviors. In this pilot study, we employed high resolution mass spectrometry-based metabolic profiling to investigate the metabolic signatures of slow versus rapidly progressing PD present in human serum. Archival serum samples from PD patients obtained within 3 years of disease onset were analyzed via dual chromatography-high resolution mass spectrometry, with data extraction by xMSanalyzer and used to predict rapid or slow motor progression of these patients during follow-up. Statistical analyses, such as false discovery rate analysis and partial least squares discriminant analysis, yielded a list of statistically significant metabolic features and further investigation revealed potential biomarkers. In particular, N8-acetyl spermidine was found to be significantly elevated in the rapid progressors compared to both control subjects and slow progressors. Our exploratory data indicate that a fast motor progression disease phenotype can be distinguished early in disease using high resolution mass spectrometry-based metabolic profiling and that altered polyamine metabolism may be a predictive marker of rapidly progressing PD.

  11. Disease severity and progression in progressive supranuclear palsy and multiple system atrophy: validation of the NNIPPS--Parkinson Plus Scale.

    Directory of Open Access Journals (Sweden)

    Christine A M Payan

    Full Text Available BACKGROUND: The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362 and Multiple System Atrophy (MSA, n = 398. To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study. METHODS AND FINDINGS: Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116, validity (n = 760, and responsiveness (n = 642. Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α ≥ 0.70. Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94 and 9 dimensions (Intra-class coefficient = 0.80-0.93, and moderate (Intra-class coefficient = 0.54-0.77 for 6. Correlations of the total score with other clinical measures of severity were good (rho ≥ 0.70. The total score was significantly and linearly related to survival (p<0.0001. Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10, though higher in PSP (SRM = 1.25 than in MSA (SRM = 1.0, indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall severity and progression was similar

  12. A Case of Immunotactoid Glomerulopathy with Rapid Progression to End-Stage Renal Disease

    Directory of Open Access Journals (Sweden)

    Shikha Jain

    2009-01-01

    Full Text Available Immunotactoid glomerulopathy (IGN is a rare immunoglobulin deposition disease. It is often mistaken for cryoglobulinemia or amyloidosis due to the similarities on biopsy findings. The disease progresses to end-stage renal disease (ESRD within 7 months to 10 years. This is the first case reported of a patient with a diagnosis of IGN who developed acute kidney injury (AKI and ESRD within 1 week of initial presentation.

  13. Uraemia progression in chronic kidney disease stages 3-5 is not constant

    DEFF Research Database (Denmark)

    Heaf, James Goya; Mortensen, Leif Spange

    2011-01-01

    Chronic kidney disease (CKD) is a progressive disease leading to loss of glomerular filtration rate (ΔGFR, measured in ml/min/1.73 m(2)/year). ΔGFR is usually assumed to be constant, but the hyperfiltration theory suggests that it accelerates in severe uraemia. A retrospective analysis of estimat...... GFR (eGFR) calculated from the Modification of Diet in Renal Disease equation was performed to evaluate whether ΔGFR is constant or accelerating....

  14. Dietary Energy Density, Renal Function, and Progression of Chronic Kidney Disease

    OpenAIRE

    2016-01-01

    Background. There is evidence of the association between dietary energy density and chronic diseases. However, no report exists regarding the relation between DED and chronic kidney disease (CKD). Objective. To examine the association between dietary energy density (DED), renal function, and progression of chronic kidney disease (CKD). Design. Cross-sectional. Setting. Three nephrology clinics. Subjects. Two hundred twenty-one subjects with diagnosed CKD. Main Outcome Measure. Dietary intake ...

  15. Heart transplantation in rapidly progressive end-stage heart failure associated with celiac disease

    Science.gov (United States)

    Barrio, Juan P; Cura, Geraldine; Ramallo, German; Diez, Mirta; Vigliano, Carlos A; Katus, Hugo A; Mereles, Derliz

    2011-01-01

    Celiac disease is characterised by chronic immune-mediated malabsorption in genetically susceptible individuals induced by gluten proteins present in wheat, barley and rye. It occurs in adults and children at rates approaching 1% of the population. Cardiomyopathy associated with celiac disease is infrequent. The authors present here a first case of a severe progressive dilated cardiomyopathy that required heart transplantation in young woman with celiac disease. PMID:22696747

  16. Electrostimulation to reduce synaptic scaling driven progression of Alzheimer's disease.

    Science.gov (United States)

    Rowan, Mark S; Neymotin, Samuel A; Lytton, William W

    2014-01-01

    Cell death and synapse dysfunction are two likely causes of cognitive decline in AD. As cells die and synapses lose their drive, remaining cells suffer an initial decrease in activity. Neuronal homeostatic synaptic scaling then provides a feedback mechanism to restore activity. This homeostatic mechanism is believed to sense levels of activity-dependent cytosolic calcium within the cell and to adjust neuronal firing activity by increasing the density of AMPA synapses at remaining synapses to achieve balance. The scaling mechanism increases the firing rates of remaining cells in the network to compensate for decreases in network activity. However, this effect can itself become a pathology, as it produces increased imbalance between excitatory and inhibitory circuits, leading to greater susceptibility to further cell loss via calcium-mediated excitotoxicity. Here, we present a mechanistic explanation of how directed brain stimulation might be expected to slow AD progression based on computational simulations in a 470-neuron biomimetic model of a neocortical column. The simulations demonstrate that the addition of low-intensity electrostimulation (neuroprosthesis) to a network undergoing AD-like cell death can raise global activity and break this homeostatic-excitotoxic cascade. The increase in activity within the remaining cells in the column results in lower scaling-driven AMPAR upregulation, reduced imbalances in excitatory and inhibitory circuits, and lower susceptibility to ongoing damage.

  17. Electrostimulation to reduce synaptic scaling driven progression of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Mark eRowan

    2014-04-01

    Full Text Available Cell death and synapse dysfunction are two likely causes of cognitive decline in AD. As cells die and synapses lose their drive, remaining cells suffer an initial decrease in activity. Neuronal homeostatic synaptic scaling then provides a feedback mechanism to restore activity. This homeostatic mechanism is believed to sense levels of activity-dependent cytosolic calcium within the cell and to adjust neuronal firing activity by increasing the density of AMPA synapses at remaining synapses to achieve balance. The scaling mechanism increases the firing rates of remaining cells in the network to compensate for decreases in network activity. However, this effect can itself become a pathology, as it produces increased imbalance between excitatory and inhibitory circuits, leading to greater susceptibility to further cell loss via calcium-mediated excitotoxicity.Here, we present a mechanistic explanation of how directed brain stimulation might be expected to slow AD progression based on computational simulations in a 470-neuron biomimetic model of a neocortical column. The simulations demonstrate that the addition of low-intensity electrostimulation (neuroprosthesis to a network undergoing AD-like cell death can raise global activity and break this homeostatic-excitotoxic cascade. The increase in activity within the remaining cells in the column results in lower scaling-driven AMPAR upregulation, reduced imbalances in excitatory and inhibitory circuits, and lower susceptibility to ongoing damage.

  18. A review and synthesis of late Pleistocene extinction modeling: progress delayed by mismatches between ecological realism, interpretation, and methodological transparency.

    Science.gov (United States)

    Yule, Jeffrey V; Fournier, Robert J; Jensen, Christopher X J; Yang, Jinyan

    2014-06-01

    Late Pleistocene extinctions occurred globally over a period of about 50,000 years, primarily affecting mammals of > or = 44 kg body mass (i.e., megafauna) first in Australia, continuing in Eurasia and, finally, in the Americas. Polarized debate about the cause(s) of the extinctions centers on the role of climate change and anthropogenic factors (especially hunting). Since the late 1960s, investigators have developed mathematical models to simulate the ecological interactions that might have contributed to the extinctions. Here, we provide an overview of the various methodologies used and conclusions reached in the modeling literature, addressing both the strengths and weaknesses of modeling as an explanatory tool. Although late Pleistocene extinction models now provide a solid foundation for viable future work, we conclude, first, that single models offer less compelling support for their respective explanatory hypotheses than many realize; second, that disparities in methodology (both in terms of model parameterization and design) prevent meaningful comparison between models and, more generally, progress from model to model in increasing our understanding of these extinctions; and third, that recent models have been presented and possibly developed without sufficient regard for the transparency of design that facilitates scientific progress.

  19. History and progression of Fat cadherins in health and disease

    Directory of Open Access Journals (Sweden)

    Zhang X

    2016-12-01

    Full Text Available Xiaofeng Zhang,1,2,* Jinghua Liu,3,* Xiao Liang,1,2 Jiang Chen,1,2 Junjie Hong,1,2 Libo Li,1 Qiang He,3 Xiujun Cai1,2 1Department of General Surgery, 2Key Laboratory of Surgery of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, 3Department of Hepatobiliary Surgery, Linyi People’s Hospital, Linyi, Shandong, People’s Republic of China *These authors contribute equally to this work Abstract: Intercellular adhesions are vital hubs for signaling pathways during multicellular development and animal morphogenesis. In eukaryotes, under aberrant intracellular conditions, cadherins are abnormally regulated, which can result in cellular pathologies such as carcinoma, kidney disease, and autoimmune diseases. As a member of the Ca2+-dependent adhesion superfamily, Fat proteins were first described in the 1920s as an inheritable lethal mutant phenotype in Drosophila, consisting of four member proteins, FAT1, FAT2, FAT3, and FAT4, all of which are highly conserved in structure. Functionally, FAT1 was found to regulate cell migration and growth control through specific protein–protein interactions of its cytoplasmic tail. FAT2 and FAT3 are relatively less studied and are thought to participate in the development of human cancer through a pathway similar to that of the Ena/VASP proteins. In contrast, FAT4 has been widely studied in the context of biological functions and tumor mechanisms and has been shown to regulate the planar cell polarity pathway, the Hippo signaling pathway, the canonical Wnt signaling cascade, and the expression of YAP1. Overall, Fat cadherins may be useful as emerging disease biomarkers and as novel therapeutic targets. Keywords: Fat cadherins, FAT1, FAT2, FAT3, FAT4, CpG island, Hippo pathway, WNT signaling

  20. [Progress of experimental research on treating Alzheimer's disease by acupuncture].

    Science.gov (United States)

    Liu, Yu-Jing; Fu, Yu

    2014-03-01

    To discuss the pathogenesis of Alzheimer's disease (AD), we summarized the mechanisms of treating AD animal models by acupuncture from literatures in recent years as follows. Senile dementia rats' cognitive capabilities and memory could be improved by reduction of beta-amyloid protein, attenuation of excessive phosphorylation of tau protein, regulation of center neurotransmitter dysmetabolism, oxidation of anti-free radicals, reduction of neuron apoptosis in the cortex and the hippocampus, inhibition of glial cells' differentiation, adjustment of G protein signaling transduction, and improvement of the mitochondrial dysfunction, thus providing experimental evidence for treating AD by acupuncture.

  1. Research progress of pathophysiological concepts in cerebral small vessel disease

    Directory of Open Access Journals (Sweden)

    Zai-qiang ZHANG

    2016-11-01

    Full Text Available The current definition of cerebral small vessels refers to all vascular structures ranging from 5 μ m to 2 mm in diameter in the brain parenchyma and they encompass small arteries, arterioles, capillaries, venules and small veins. Different diameters of cerebral small vessels have different distribution, and predilection to different types of pathophysiological process. Cerebral small vessel disease (cSVD, including lacunar infarct (LACI, white matter hyperintensity (WMH and cerebral microbleeds (CMBs, have different pathophysiological mechanisms and risk factors. Arterial stiffness is independently associated with all components of cSVD. DOI: 10.3969/j.issn.1672-6731.2016.11.007

  2. Characterization of annual disease progression of multiple sclerosis patients: A population-based study.

    Science.gov (United States)

    Freilich, Jonatan; Manouchehrinia, Ali; Trusheim, Mark; Baird, Lynn G; Desbiens, Sophie; Berndt, Ernst; Hillert, Jan

    2017-05-01

    Previous research characterizing factors influencing multiple sclerosis (MS) disease progression has typically been based on time to disease milestones (Kaplan-Meier, Cox hazard regression, etc.). A limitation of these methods is the handling of the often large groups of patients not reaching the milestone. To characterize clinical factors influencing MS disease progression as annual transitions from each Expanded Disability Status Scale (EDSS). The annual progression of 11,964 patients from the Swedish MS Registry was analysed with 10 multinomial logistic regressions, that is, one for transition from each full EDSS with explanatory variables age, sex, age at onset, time in current EDSS, highest prior EDSS, MS course and treatment. All factors (except sex) investigated had statistically significant impacts on transitions from at least one EDSS. However, significance and size of the effect are dependent on the EDSS state of the patient. Greater age, longer time in a state, highest prior EDSS, having progressive MS and treatment had significant impacts, whereas age at onset had minor impact. Our study confirms that established factors associated with MS disease worsening in time to disease milestones also have impacts on annual progression. This approach adds granularity to what EDSS these factors have an influence.

  3. Prion protein polymorphisms affect chronic wasting disease progression.

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    Chad J Johnson

    Full Text Available Analysis of the PRNP gene in cervids naturally infected with chronic wasting disease (CWD suggested that PRNP polymorphisms affect the susceptibility of deer to infection. To test this effect, we orally inoculated 12 white-tailed deer with CWD agent. Three different PRNP alleles, wild-type (wt; glutamine at amino acid 95 and glycine at 96, Q95H (glutamine to histidine at amino acid position 95 and G96S (glycine to serine at position 96 were represented in the study cohort with 5 wt/wt, 3 wt/G96S, and 1 each wt/Q95H and Q95H/G96S. Two animals were lost to follow-up due to intercurrent disease. The inoculum was prepared from Wisconsin hunter-harvested homozygous wt/wt animals. All infected deer presented with clinical signs of CWD; the orally infected wt/wt had an average survival period of 693 days post inoculation (dpi and G96S/wt deer had an average survival period of 956 dpi. The Q95H/wt and Q95H/G96S deer succumbed to CWD at 1,508 and 1,596 dpi respectively. These data show that polymorphisms in the PRNP gene affect CWD incubation period. Deer heterozygous for the PRNP alleles had extended incubation periods with the Q95H allele having the greatest effect.

  4. Prion protein polymorphisms affect chronic wasting disease progression.

    Science.gov (United States)

    Johnson, Chad J; Herbst, Allen; Duque-Velasquez, Camilo; Vanderloo, Joshua P; Bochsler, Phil; Chappell, Rick; McKenzie, Debbie

    2011-01-01

    Analysis of the PRNP gene in cervids naturally infected with chronic wasting disease (CWD) suggested that PRNP polymorphisms affect the susceptibility of deer to infection. To test this effect, we orally inoculated 12 white-tailed deer with CWD agent. Three different PRNP alleles, wild-type (wt; glutamine at amino acid 95 and glycine at 96), Q95H (glutamine to histidine at amino acid position 95) and G96S (glycine to serine at position 96) were represented in the study cohort with 5 wt/wt, 3 wt/G96S, and 1 each wt/Q95H and Q95H/G96S. Two animals were lost to follow-up due to intercurrent disease. The inoculum was prepared from Wisconsin hunter-harvested homozygous wt/wt animals. All infected deer presented with clinical signs of CWD; the orally infected wt/wt had an average survival period of 693 days post inoculation (dpi) and G96S/wt deer had an average survival period of 956 dpi. The Q95H/wt and Q95H/G96S deer succumbed to CWD at 1,508 and 1,596 dpi respectively. These data show that polymorphisms in the PRNP gene affect CWD incubation period. Deer heterozygous for the PRNP alleles had extended incubation periods with the Q95H allele having the greatest effect.

  5. Role of salivary leukocyte protease inhibitor in periodontal disease progression

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    Pateel Deepak

    2010-01-01

    Full Text Available Context: Proteases play a major role in the tissue destruction involved in periodontal disease. It is known that the balance between proteases and their inhibitors is a major determinant in maintaining tissue integrity. The association between the proteases and periodontitis is well established, but not many studies have been carried out to know the role played by a protease inhibitor like salivary leukocyte protease inhibitor (SLPI in periodontitis. Aim: The aim of the present study was to correlate SLPI with periodontitis. Settings and Design: Case-control study. Materials and Methods: Seventy-five clinically confirmed cases of periodontitis and 20 controls were included in the study. A detailed case history and periodontal index (PI were recorded. Two milliliters of unstimulated saliva samples was obtained and subjected to quantification of SLPI leaves using SLPI in enzyme-linked immunosorbent assay (ELISA kit. Based on the periodontal index score of the individuals, the cases and controls were divided into groups A, B and C, and the obtained SLPI levels were compared among the groups. Statistical Analysis: Mann-Whitney U test and correlation coefficient test. Results: The results showed that in the initial stages of periodontitis there is a tendency of SLPI levels to be raised. The SLPI levels were found to be reduced in the terminal stages of periodontitis. Conclusion: It appears that SLPI accumulates in the local environment, at least in the initial stages of the periodontal disease, probably to inhibit the action of increased elastic activity.

  6. Development assistance for neglected tropical diseases: progress since 2009.

    Science.gov (United States)

    Liese, Bernhard H; Houghton, Natalia; Teplitskaya, Lyubov

    2014-09-01

    Neglected tropical diseases (NTDs) is an umbrella term for a diverse group of debilitating infections that represent the most common afflictions for 2.7 billion people living on less than US$2 per day. Major efforts have recently re-focused attention on NTDs, including structured advocacy by the Bill and Melinda Gates Foundation, technical and political support by WHO and large-scale drug donation programs by pharmaceutical companies. An analysis of the Official Development Assistance (ODA) for NTDs in 2009 showed that Development Assistance Committee members and multilateral donors had largely ignored funding NTD control projects. This study reviews the changes since 2009 and finds an increased engagement by pharmaceutical manufacturers through drug donation programs substantially increased by the 'London Declaration' in 2012, a focused effort of 77 public and private partners on control or elimination of the 10 most common NTDs, but no increase in ODA for NTDs between 2008 and 2012. The allocation of ODA still does not reflect the respective importance of these diseases.

  7. Body mass index, weight change, and clinical progression in mild cognitive impairment and Alzheimer disease.

    Science.gov (United States)

    Besser, Lilah M; Gill, Dawn P; Monsell, Sarah E; Brenowitz, Willa; Meranus, Dana H; Kukull, Walter; Gustafson, Deborah R

    2014-01-01

    The speed and severity of clinical progression after Alzheimer disease (AD) diagnosis varies and depends on multiple factors, most not well elucidated. We assessed whether body mass index (BMI) and 1-year weight change (WC) are associated with clinical progression in amnestic mild cognitive impairment (aMCI) and early-stage AD. Longitudinal data comprising 2268 aMCI and 1506 AD participants in the National Alzheimer's Coordinating Center's Uniform Data Set were used to examine nuances of clinical progression by BMI and WC, as well as potential variations in associations by age, sex, BMI (WC model), or apolipoprotein E genotype. In aMCI, high BMI (vs. moderate BMI) was associated with slower progression; weight loss (vs. no WC) was associated with faster progression. In AD, no significant differences were observed in clinical progression by BMI or WC. The association between BMI and clinical progression varied significantly by apolipoprotein E genotype in AD, and the association between WC and clinical progression varied significantly by sex and BMI in aMCI. Baseline BMI and 1-year WC in late life may serve as early prognostic indicators in aMCI and early-stage AD. If replicated, these results may help in counseling patients on anticipated clinical progression and suggest windows of opportunity for intervention.

  8. PHD2: from hypoxia regulation to disease progression.

    Science.gov (United States)

    Meneses, Ana M; Wielockx, Ben

    2016-01-01

    Oxygen represents one of the major molecules required for the development and maintenance of life. An adequate response to hypoxia is therefore required for the functioning of the majority of living organisms and relies on the activation of the hypoxia-inducible factor (HIF) pathway. HIF prolyl hydroxylase domain-2 (PHD2) has long been recognized as the major regulator of this response, controlling a myriad of outcomes that range from cell death to proliferation. However, this enzyme has been associated with more pathways, making the role of this protein remarkably complex under distinct pathologies. While a protective role seems to exist in physiological conditions such as erythropoiesis; the picture is more complex during pathologies such as cancer. Since the regulation of this enzyme and its closest family members is currently considered as a possible therapy for various diseases, understanding the different particular roles of this protein is essential.

  9. Caregiver-recipient closeness and symptom progression in Alzheimer disease. The Cache County Dementia Progression Study.

    Science.gov (United States)

    Norton, Maria C; Piercy, Kathleen W; Rabins, Peter V; Green, Robert C; Breitner, John C S; Ostbye, Truls; Corcoran, Christopher; Welsh-Bohmer, Kathleen A; Lyketsos, Constantine G; Tschanz, Joann T

    2009-09-01

    Applying Rusbult's investment model of dyadic relationships, we examined the effect of caregiver-care recipient relationship closeness (RC) on cognitive and functional decline in Alzheimer's disease. After diagnosis, 167 participants completed up to six visits, observed over an average of 20 months. Participants were 64% women, had a mean age of 86 years, and mean dementia duration of 4 years. Caregiver-rated closeness was measured using a six-item scale. In mixed models adjusted for dementia severity, dyads with higher levels of closeness (p Alzheimer's dementia (AD) decline with closer relationships, particularly with spouse caregivers, are consistent with investment theory. Future interventions designed to enhance the caregiving dyadic relationship may help slow decline in AD.

  10. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis.

    Science.gov (United States)

    Sharma, Mithun; Mitnala, Shasikala; Vishnubhotla, Ravi K; Mukherjee, Rathin; Reddy, Duvvur N; Rao, Padaki N

    2015-06-01

    Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed.

  11. DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease

    OpenAIRE

    Zeybel, Müjdat; Karahüseyinoğlu, Serçin; Vatansever, Sezgin; Hardy, Timothy; Sarı, Aysegül Akder; Çakalağaoğlu, Fulya; Avcı, Arzu; Zeybel, Gemma Louise; Bashton, Matthew; Mathers, John C.; Ünsal, Belkis; Mann, Jelena

    2016-01-01

    Background: Chronic hepatitis B infection is characterized by hepatic immune and inflammatory response with considerable variation in the rates of progression to cirrhosis. Genetic variants and environmental cues influence predisposition to the development of chronic liver disease; however, it remains unknown if aberrant DNA methylation is associated with fibrosis progression in chronic hepatitis B. Results: To identify epigenetic marks associated with inflammatory and fibrotic processes of t...

  12. HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8(+ T Cell Response against HIV-1.

    Directory of Open Access Journals (Sweden)

    Marcus Altfeld

    2006-10-01

    Full Text Available Very little is known about the immunodominance patterns of HIV-1-specific T cell responses during primary HIV-1 infection and the reasons for human lymphocyte antigen (HLA modulation of disease progression.In a cohort of 104 individuals with primary HIV-1 infection, we demonstrate that a subset of CD8(+ T cell epitopes within HIV-1 are consistently targeted early after infection, while other epitopes subsequently targeted through the same HLA class I alleles are rarely recognized. Certain HLA alleles consistently contributed more than others to the total virus-specific CD8(+ T cell response during primary infection, and also reduced the absolute magnitude of responses restricted by other alleles if coexpressed in the same individual, consistent with immunodomination. Furthermore, individual HLA class I alleles that have been associated with slower HIV-1 disease progression contributed strongly to the total HIV-1-specific CD8(+ T cell response during primary infection.These data demonstrate consistent immunodominance patterns of HIV-1-specific CD8(+ T cell responses during primary infection and provide a mechanistic explanation for the protective effect of specific HLA class I alleles on HIV-1 disease progression.

  13. Genomic aberrations of myeloproliferative and myelodysplastic/myeloproliferative neoplasms in chronic phase and during disease progression.

    Science.gov (United States)

    Hahm, C; Huh, H J; Mun, Y C; Seong, C M; Chung, W S; Huh, J

    2015-04-01

    Myeloproliferative neoplasms (MPN) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) may transform into secondary myelofibrosis (MF) or evolve into acute myeloid leukemia (AML). The genetic mechanisms underlying disease progression in MPN and MDS/MPN patients remain unclear. The purpose of this study was to investigate sequential genomic aberrations identified by single nucleotide polymorphism array (SNP-A)-based karyotyping that can detect cryptic aberrations or copy neutral loss of heterozygosity (CN-LOH) in the chronic phase and during disease progression of MPN and MDS/MPN patients. The study group included 13 MPN and four MDS/MPN patients (seven polycythemia vera (PV); four essential thrombocythemia (ET); two MPN-unclassifiable (MPN-U); one chronic myelomonocytic leukemia (CMML); one atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML); and two MDS/MPN-unclassifiable (MDS/MPN-U)). Among them, five patients (two PV, two MPN-U, and one MDS/MPN-U) progressed to MF and three patients (one CMML, one aCML, and one MDS/MPN-U) transformed to AML. The median follow-up period was 70 months (range, 7-152). Whole-genome SNP-A (SNP 6.0; Affymetrix, Santa Clara, CA, USA)-based karyotyping and JAK2 mutation analysis were performed according to the manufacturer's instructions. SNP-A showed 19 kinds of genomic aberrations, including seven gains, eight deletions, and four CN-LOH. CN-LOH of 9p involving JAK2 was the most common aberration, followed by 5q deletion and 9p gain. The incidence of genomic changes identified by SNP was not different in patients with disease progression (75%), compared with those without disease progression (56%) (P = 0.4). However, when excluding 9p CN-LOH, the incidence of genomic changes was significantly higher in patients with disease progression than in patients without disease progression (63% and 0%, respectively, P = 0.01). Among eight patients with disease progression, two patients (two MPN-U) showed abnormal SNP-A results

  14. Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function.

    Science.gov (United States)

    Ontaneda, Daniel; Thompson, Alan J; Fox, Robert J; Cohen, Jeffrey A

    2016-11-23

    Multiple sclerosis is a major cause of neurological disability, which accrues predominantly during progressive forms of the disease. Although development of multifocal inflammatory lesions is the underlying pathological process in relapsing-remitting multiple sclerosis, the gradual accumulation of disability that characterises progressive multiple sclerosis seems to result more from diffuse immune mechanisms and neurodegeneration. As a result, the 14 anti-inflammatory drugs that have regulatory approval for treatment of relapsing-remitting multiple sclerosis have little or no efficacy in progressive multiple sclerosis without inflammatory lesion activity. Effective therapies for progressive multiple sclerosis that prevent worsening, reverse damage, and restore function are a major unmet need. In this Series paper we summarise the current status of therapy for progressive multiple sclerosis and outline prospects for the future.

  15. Research progress on natural products from traditional Chinese medicine in treatment of Alzheimer's disease.

    Science.gov (United States)

    Gao, Jianjun; Inagaki, Yoshinori; Li, Xuan; Kokudo, Norihiro; Tang, Wei

    2013-04-01

    Alzheimer's disease (AD) is a severe condition in aging societies. Although research on this disease is advancing rapidly, thus far few very effective drugs are available for AD patients. The currently widely used medicines such as donepezil and galantamine transiently improve the symptoms of patients with mild to moderate AD. They are hardly capable of preventing, halting or reversing the progression of this disease. In the long history of development of traditional Chinese medicine, many herbs have been discovered and employed to treat dementia diseases in clinics in China. In recent decades, a number of agents were isolated from these herbs and their efficacies against AD were tested. Some flavonoids, alkaloids, phenylpropanoids, triterpenoid saponins, and polysaccharides were demonstrated to have potential efficacies against AD via targeting multiple pathological changes of this disease. In this article, we reviewed research progress on the efficacies and underlying mechanisms of these agents.

  16. Ketogenic Diet Prevents Epileptogenesis and Disease Progression in Adult Mice and Rats

    Science.gov (United States)

    Lusardi, Theresa A.; Akula, Kiran K.; Coffman, Shayla Q.; Ruskin, David; Masino, Susan A.; Boison, Detlev

    2015-01-01

    Epilepsy is a highly prevalent seizure disorder which tends to progress in severity and become refractory to treatment. Yet no therapy is proven to halt disease progression or to prevent the development of epilepsy. Because a high fat low carbohydrate ketogenic diet (KD) augments adenosine signaling in the brain and because adenosine not only suppresses seizures but also affects epileptogenesis, we hypothesized that a ketogenic diet might prevent epileptogenesis through similar mechanisms. Here, we tested this hypothesis in two independent rodent models of epileptogenesis. Using a pentylenetetrazole kindling paradigm in mice, we first show that a KD, but not a conventional antiepileptic drug (valproic acid), suppressed kindling-epileptogenesis. Importantly, after treatment reversal, increased seizure thresholds were maintained in those animals kindled in the presence of a KD, but not in those kindled in the presence of valproic acid. Next, we tested whether a KD can halt disease progression in a clinically relevant model of progressive epilepsy. Epileptic rats that developed spontaneous recurrent seizures after a pilocarpine-induced status epilepticus were treated with a KD or control diet (CD). Whereas seizures progressed in severity and frequency in the CD-fed animals, KD-fed animals showed a prolonged reduction of seizures, which persisted after diet reversal. KD-treatment was associated with increased adenosine and decreased DNA methylation, the latter being maintained after diet discontinuation. Our findings demonstrate that a KD prevented disease progression in two mechanistically different models of epilepsy, and suggest an epigenetic mechanism underlying the therapeutic effects. PMID:26256422

  17. Ketogenic diet prevents epileptogenesis and disease progression in adult mice and rats.

    Science.gov (United States)

    Lusardi, Theresa A; Akula, Kiran K; Coffman, Shayla Q; Ruskin, David N; Masino, Susan A; Boison, Detlev

    2015-12-01

    Epilepsy is a highly prevalent seizure disorder which tends to progress in severity and become refractory to treatment. Yet no therapy is proven to halt disease progression or to prevent the development of epilepsy. Because a high fat low carbohydrate ketogenic diet (KD) augments adenosine signaling in the brain and because adenosine not only suppresses seizures but also affects epileptogenesis, we hypothesized that a ketogenic diet might prevent epileptogenesis through similar mechanisms. Here, we tested this hypothesis in two independent rodent models of epileptogenesis. Using a pentylenetetrazole kindling paradigm in mice, we first show that a KD, but not a conventional antiepileptic drug (valproic acid), suppressed kindling-epileptogenesis. Importantly, after treatment reversal, increased seizure thresholds were maintained in those animals kindled in the presence of a KD, but not in those kindled in the presence of valproic acid. Next, we tested whether a KD can halt disease progression in a clinically relevant model of progressive epilepsy. Epileptic rats that developed spontaneous recurrent seizures after a pilocarpine-induced status epilepticus were treated with a KD or control diet (CD). Whereas seizures progressed in severity and frequency in the CD-fed animals, KD-fed animals showed a prolonged reduction of seizures, which persisted after diet reversal. KD-treatment was associated with increased adenosine and decreased DNA methylation, the latter being maintained after diet discontinuation. Our findings demonstrate that a KD prevented disease progression in two mechanistically different models of epilepsy, and suggest an epigenetic mechanism underlying the therapeutic effects.

  18. Pregnancy and HIV Disease Progression in an Early Infection Cohort from Five African Countries.

    Science.gov (United States)

    Wall, Kristin M; Rida, Wasima; Haddad, Lisa B; Kamali, Anatoli; Karita, Etienne; Lakhi, Shabir; Kilembe, William; Allen, Susan; Inambao, Mubiana; Yang, Annie H; Latka, Mary H; Anzala, Omu; Sanders, Eduard J; Bekker, Linda-Gail; Edward, Vinodh A; Price, Matt A

    2017-03-01

    Understanding associations between pregnancy and HIV disease progression is critical to provide appropriate counseling and care to HIV-positive women. From 2006 to 2011, women less than age 40 with incident HIV infection were enrolled in an early HIV infection cohort in Kenya, Rwanda, South Africa, Uganda, and Zambia. Time-dependent Cox models evaluated associations between pregnancy and HIV disease progression. Clinical progression was defined as a single CD4 measurement <200 cells/μl, percent CD4 <14%, or category C event, with censoring at antiretroviral (ART) initiation for reasons other than prevention of mother-to-child transmission (PMTCT). Immunologic progression was defined as two consecutive CD4s ≤350 cells/μl or a single CD4 ≤350 cells/μl followed by non-PMTCT ART initiation. Generalized estimating equations assessed changes in CD4 before and after pregnancy. Among 222 women, 63 experienced clinical progression during 783.5 person-years at risk (8.0/100). Among 205 women, 87 experienced immunologic progression during 680.1 person-years at risk (12.8/100). The association between pregnancy and clinical progression was adjusted hazard ratio [aHR] = 0.7; 95% confidence interval (CI): 0.2, 1.8. The association between pregnancy and immunologic progression was aHR = 1.7; 95% CI: 0.9, 3.3. Models controlled for age; human leukocyte antigen alleles A*03:01, B*45, B*57; CD4 set point; and HIV-1 subtype. CD4 measurements before versus after pregnancies were not different. In this cohort, pregnancy was not associated with increased clinical or immunologic HIV progression. Similarly, we did not observe meaningful deleterious associations of pregnancy with CD4s. Our findings suggest that HIV-positive women may become pregnant without harmful health effects occurring during the pregnancy. Evaluation of longer-term impact of pregnancy on progression is warranted.

  19. Ebolavirus Vaccines: Progress in the Fight Against Ebola Virus Disease.

    Science.gov (United States)

    Wu, Xiao-Xin; Yao, Hang-Ping; Wu, Nan-Ping; Gao, Hai-Nv; Wu, Hai-Bo; Jin, Chang-Zhong; Lu, Xiang-Yun; Xie, Tian-Shen; Li, Lan-Juan

    2015-01-01

    Ebolaviruses are highly infectious pathogens that cause lethal Ebola virus disease (EVD) in humans and non-human primates (NHPs). Due to their high pathogenicity and transmissibility, as well as the potential to be misused as a bioterrorism agent, ebolaviruses would threaten the health of global populations if not controlled. In this review, we describe the origin and structure of ebolaviruses and the development of vaccines from the beginning of the 1980s, including conventional ebolavirus vaccines, DNA vaccines, Ebola virus-like particles (VLPs), vaccinia virus-based vaccines, Venezuelan equine encephalitis virus (VEEV)-like replicon particles, Kunjin virus-based vaccine, recombinant Zaire Ebolavirusx2206;VP30, recombinant cytomegalovirus (CMV)-based vaccines, recombinant rabies virus (RABV)-based vaccines, recombinant paramyxovirus-based vaccines, adenovirus-based vaccines and vesicular stomatitis virus (VSV)-based vaccines. No licensed vaccine or specific treatment is currently available to counteract ebolavirus infection, although DNA plasmids and several viral vector approaches have been evaluated as promising vaccine platforms. These vaccine candidates have been confirmed to be successful in protecting NHPs against lethal infection. Moreover, these vaccine candidates were successfully advanced to clinical trials. The present review provides an update of the current research on Ebola vaccines, with the aim of providing an overview on current prospects in the fight against EVD.

  20. Ebolavirus Vaccines: Progress in the Fight Against Ebola Virus Disease

    Directory of Open Access Journals (Sweden)

    Xiao-Xin Wu

    2015-11-01

    Full Text Available Ebolaviruses are highly infectious pathogens that cause lethal Ebola virus disease (EVD in humans and non-human primates (NHPs. Due to their high pathogenicity and transmissibility, as well as the potential to be misused as a bioterrorism agent, ebolaviruses would threaten the health of global populations if not controlled. In this review, we describe the origin and structure of ebolaviruses and the development of vaccines from the beginning of the 1980s, including conventional ebolavirus vaccines, DNA vaccines, Ebola virus-like particles (VLPs, vaccinia virus-based vaccines, Venezuelan equine encephalitis virus (VEEV-like replicon particles, Kunjin virus-based vaccine, recombinant Zaire Ebolavirus∆VP30, recombinant cytomegalovirus (CMV-based vaccines, recombinant rabies virus (RABV-based vaccines, recombinant paramyxovirus-based vaccines, adenovirus-based vaccines and vesicular stomatitis virus (VSV-based vaccines. No licensed vaccine or specific treatment is currently available to counteract ebolavirus infection, although DNA plasmids and several viral vector approaches have been evaluated as promising vaccine platforms. These vaccine candidates have been confirmed to be successful in protecting NHPs against lethal infection. Moreover, these vaccine candidates were successfully advanced to clinical trials. The present review provides an update of the current research on Ebola vaccines, with the aim of providing an overview on current prospects in the fight against EVD.

  1. Control of diabetes and fibrinogen levels as well as improvement in health care might delay low cognitive performance in societies aging progressively

    Directory of Open Access Journals (Sweden)

    Daniele Almeida Lopes

    2015-01-01

    Full Text Available Objective To know the prevalence and factors associated to low cognitive performance in a representative sample of the adult population in a society aging progressively. Method Cross-sectional population-based study carried out in a three-stage sampling: 81 census tracts (primary sampling unity were randomly selected, followed by 1,672 households and 2,471 participants (weighted sample corresponding to the second and third stages, respectively. The outcome prevalence was calculated according sociodemographic, behavioral and health related variables. Crude and adjusted prevalence ratios were estimated using Poisson regression. Results The prevalence of low cognitive performance was high, mainly among females, and indicated linear trends into categories of age, schooling, income, plasma fibrinogen and self-reported health status. In multivariate models, gender, diabetes, fibrinogen and self-reported health status presented positive associations, while schooling, employment and sitting time presented negative associations with the outcome. Conclusion Interventions related to diabetes and fibrinogen levels control as well as improvement in health care might delay low cognitive performance in societies aging progressively as such the study population.

  2. Neurophysiological assessment of neural network plasticity and connectivity: Progress towards early functional biomarkers for disease interception therapies in Alzheimer's disease.

    Science.gov (United States)

    Walsh, C; Drinkenburg, W H I M; Ahnaou, A

    2017-02-01

    Despite a great deal of research into Alzheimer's disease (AD) over the last 20 years, an effective treatment to halt or slow its progression has yet to be developed. With many aspects of the disease progression still to be elucidated, focus has shifted from reducing levels of amyloid β (Aβ) in the brains of AD patients towards tau, another pathology, which initiates much earlier in deeper brainstem networks and is thought to propagate via cell-to-cell processes prior to the onset of amyloid pathology and cognitive impairments. In-vitro, ex-vivo molecular biology/biochemistry read-outs, and various transgenic animal models have been developed, yet clinical failures have highlighted a clear disconnect and inadequate use of such animal models in translational research across species. AD pathology is now estimated to begin at least 10-20 years before clinical symptoms, and imaging and cerebrospinal fluid biomarkers are leading the way in assessing the disease progression at a stage where neuronal damage has already occurred. Here, we emphasize the relevance of assessing early disruptions in network connectivity and plasticity that occur before neuropathological damage and progressive memory dysfunction, which can have high translational value for discovery of pre-symptomatic AD biomarkers and early mechanism-based disease interception therapeutics.

  3. Progressive disease in glioblastoma: Benefits and limitations of semi-automated volumetry

    Science.gov (United States)

    Alber, Georgina; Bette, Stefanie; Kaesmacher, Johannes; Boeckh-Behrens, Tobias; Gempt, Jens; Ringel, Florian; Specht, Hanno M.; Meyer, Bernhard; Zimmer, Claus

    2017-01-01

    Purpose Unambiguous evaluation of glioblastoma (GB) progression is crucial, both for clinical trials as well as day by day routine management of GB patients. 3D-volumetry in the follow-up of GB provides quantitative data on tumor extent and growth, and therefore has the potential to facilitate objective disease assessment. The present study investigated the utility of absolute changes in volume (delta) or regional, segmentation-based subtractions for detecting disease progression in longitudinal MRI follow-ups. Methods 165 high resolution 3-Tesla MRIs of 30 GB patients (23m, mean age 60.2y) were retrospectively included in this single center study. Contrast enhancement (CV) and tumor-related signal alterations in FLAIR images (FV) were semi-automatically segmented. Delta volume (dCV, dFV) and regional subtractions (sCV, sFV) were calculated. Disease progression was classified for every follow-up according to histopathologic results, decisions of the local multidisciplinary CNS tumor board and a consensus rating of the neuro-radiologic report. Results A generalized logistic mixed model for disease progression (yes / no) with dCV, dFV, sCV and sFV as input variables revealed that only dCV was significantly associated with prediction of disease progression (P = .005). Delta volume had a better accuracy than regional, segmentation-based subtractions (79% versus 72%) and a higher area under the curve by trend in ROC curves (.83 versus .75). Conclusion Absolute volume changes of the contrast enhancing tumor part were the most accurate volumetric determinant to detect progressive disease in assessment of GB and outweighed FLAIR changes as well as regional, segmentation-based image subtractions. This parameter might be useful in upcoming objective response criteria for glioblastoma. PMID:28245291

  4. A clinical index to predict progression from mild cognitive impairment to dementia due to Alzheimer's disease.

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    Sei J Lee

    Full Text Available BACKGROUND: Mild cognitive impairment is often a precursor to dementia due to Alzheimer's disease, but many patients with mild cognitive impairment never develop dementia. New diagnostic criteria may lead to more patients receiving a diagnosis of mild cognitive impairment. OBJECTIVE: To develop a prediction index for the 3-year risk of progression from mild cognitive impairment to dementia relying only on information that can be readily obtained in most clinical settings. DESIGN AND PARTICIPANTS: 382 participants diagnosed with amnestic mild cognitive impairment enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI, a multi-site, longitudinal, observational study. MAIN PREDICTORS MEASURES: Demographics, comorbid conditions, caregiver report of participant symptoms and function, and participant performance on individual items from basic neuropsychological scales. MAIN OUTCOME MEASURE: Progression to probable Alzheimer's disease. KEY RESULTS: Subjects had a mean (SD age of 75 (7 years and 43% progressed to probable Alzheimer's disease within 3 years. Important independent predictors of progression included being female, resisting help, becoming upset when separated from caregiver, difficulty shopping alone, forgetting appointments, number of words recalled from a 10-word list, orientation and difficulty drawing a clock. The final point score could range from 0 to 16 (mean [SD]: 4.2 [2.9]. The optimism-corrected Harrell's c-statistic was 0.71(95% CI: 0.68-0.75. Fourteen percent of subjects with low risk scores (0-2 points, n = 124 converted to probable Alzheimer's disease over 3 years, compared to 51% of those with moderate risk scores (3-8 points, n = 223 and 91% of those with high risk scores (9-16 points, n = 35. CONCLUSIONS: An index using factors that can be obtained in most clinical settings can predict progression from amnestic mild cognitive impairment to probable Alzheimer's disease and may help clinicians

  5. Multivariate clustering of progression profiles reveals different depression patterns in prodromal Huntington disease.

    Science.gov (United States)

    Kim, Ji-in; Long, Jeffrey D; Mills, James A; McCusker, Elizabeth; Paulsen, Jane S

    2015-11-01

    Although Huntington disease (HD) is caused by an autosomal dominant mutation, its phenotypic presentation differs widely. Variability in clinical phenotypes of HD may reflect the existence of disease subtypes. This hypothesis was tested in prodromal participants from the longitudinal Neurobiological Predictors of Huntington Disease (PREDICT-HD) study. We performed clustering using longitudinal data assessing motor, cognitive, and depression symptoms. Using data from 521 participants with 2,716 data points, we fit growth mixture models (GMM) that identify groups based on multivariate trajectories. In various GMM, different phases of disease progression were partitioned by progression trajectories of motor and cognitive signs, and by overall level of depression symptoms. More progressed motor signs were accompanied by more progressed cognitive signs, but not always by higher levels of depressive symptoms. In several models, there were at least 2 groups with similar trajectories for motor and cognitive signs that showed different levels for depression symptoms-one with a very low level of depression and the other with a higher level of depression. Findings indicate that at least intermediate HD progression might be associated with different levels of depression. Depression is one of the few symptoms that is treatable in HD and has implications for clinical care. Identification of potential depression subtypes may also help to select appropriate patients for clinical trials. (c) 2015 APA, all rights reserved).

  6. Microcephaly disease gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size.

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    Chen, Jian-Fu; Zhang, Ying; Wilde, Jonathan; Hansen, Kirk C; Lai, Fan; Niswander, Lee

    2014-05-30

    Human genetic studies have established a link between a class of centrosome proteins and microcephaly. Current studies of microcephaly focus on defective centrosome/spindle orientation. Mutations in WDR62 are associated with microcephaly and other cortical abnormalities in humans. Here we create a mouse model of Wdr62 deficiency and find that the mice exhibit reduced brain size due to decreased neural progenitor cells (NPCs). Wdr62 depleted cells show spindle instability, spindle assembly checkpoint (SAC) activation, mitotic arrest and cell death. Mechanistically, Wdr62 associates and genetically interacts with Aurora A to regulate spindle formation, mitotic progression and brain size. Our results suggest that Wdr62 interacts with Aurora A to control mitotic progression, and loss of these interactions leads to mitotic delay and cell death of NPCs, which could be a potential cause of human microcephaly.

  7. Poverty, disease progression and employment among people living with HIV/AIDS in Australia.

    Science.gov (United States)

    Ezzy, D; de Visser, R; Bartos, M

    1999-08-01

    A national survey of 925 people living with HIV/AIDS (PLWHA) in Australia is used to examine the relationship between disease progression, employment status, poverty and economic hardship. While disease progression has some impact on economic hardship, employment status is found to be the strongest determinant of both poverty and economic hardship. The most commonly cited reasons for leaving work were psychosocial (71%), with declining health cited by half of respondents. It is therefore argued that psychosocial issues are at least as important as changes in health in causing unemployment and therefore poverty and economic hardship among PLWHA in Australia.

  8. Delayed post-hypoxic leukoencephalopathy: case report with a review of disease pathophysiology

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    Michael Andrew Meyer

    2013-07-01

    Full Text Available Delayed post-hypoxic leukoencephalopathy is a rare clinical phenomenon usually observed in a small number of carbon monoxide poisoning survivors. A similar phenomenon is reported here in a patient who successfully recovered from a large overdose of diazepam and methadone, but then abruptly declined 3 weeks after the initial event. Magnetic resnance revealed confluent white matter hyperintensity on fluid-attenuated inversion recovery and T2 weighted sequences, and spectroscopy revealed elevated peaks in choline, creatinine, and lactate. Analysis and review of the literature suggests this phenomenon occurs on average about 19 days after the initial event. Although the pathophysiology remains obscure, it is noted here that the mean lucid interval coincides approximately with the replacement half-life for myelin related lipids and proteins.

  9. Quantitative EEG parameters correlate with the progression of human prion diseases

    Science.gov (United States)

    Wehner, Tim; Lowe, Jessica; Porter, Marie-Claire; Kenny, Joanna; Thompson, Andrew; Rudge, Peter; Collinge, John; Mead, Simon

    2016-01-01

    Background Prion diseases are universally fatal and often rapidly progressive neurodegenerative diseases. EEG has long been used in the diagnosis of sporadic Creutzfeldt-Jakob disease; however, the characteristic waveforms do not occur in all types of prion diseases. Here, we re-evaluate the utility of EEG by focusing on the development of biomarkers. We test whether abnormal quantitative EEG parameters can be used to measure disease progression in prion diseases or predict disease onset in healthy individuals at risk of disease. Methods In the National Prion Monitoring Cohort study, we did quantitative encephalography on 301 occasions in 29 healthy controls and 67 patients with prion disease. The patients had either inherited prion disease or sporadic Creutzfeldt-Jakob disease. We computed the main background frequency, the α and θ power and the α/θ power ratio, then averaged these within 5 electrode groups. These measurements were then compared among participant groups and correlated with functional and cognitive scores cross-sectionally and longitudinally. Results We found lower main background frequency, α power and α/θ power ratio and higher θ power in patients compared to control participants. The main background frequency, the power in the α band and the α/θ power ratio also differed in a consistent way among the patient groups. Moreover, the main background frequency and the α/θ power ratio correlated significantly with functional and cognitive scores. Longitudinally, change in these parameters also showed significant correlation with the change in clinical and cognitive scores. Conclusions Our findings support the use of quantitative EEG to follow the progression of prion disease, with potential to help evaluate the treatment effects in future clinical-trials. PMID:27413165

  10. Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression.

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    Cristin D Davidson

    Full Text Available Niemann-Pick type C (NPC disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs. While current treatment therapies are limited, a few drugs tested in Npc1(-/- mice have shown partial benefit. During a combination treatment trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ and allopregnanolone, we noted increased lifespan for Npc1(-/- mice receiving only 2-hydroxypropyl-beta-cyclodextrin (CD, the vehicle for allopregnanolone. This finding suggested that administration of CD alone, but with greater frequency, might provide additional benefit.Administration of CD to Npc1(-/- mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS type IIIA, might likewise benefit from CD treatment. Treated Npc2(-/- mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage.Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1(-/- and Npc2(-/- mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis.

  11. Two cases of cervical disc disease with intramedullary pathological changes, which are responsible for their neurological syndromes, on delayed CT myelography

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    Isu, Toyohiko; Iwasaki, Yoshinobu; Abe, Hiroshi; Tashiro, Kunio; Murai, Hiroshi; Miyasaka, Kazuo

    1987-08-01

    We report two cases of cervical disc disease with myelopathy classified as of motor system syndrome type showing small contrast accumulation within the spinal cord on delayed CT myelography. In our two cases, high density spots on delayed CT myelography were bilaterally localized within the spinal cord, and believed represent pathological changes of the spinal cord, such as collection of microcavities or cystic necrosis. In case 1, the high density areas seemed to be localized in the anterior horn and corticospinal tract, and in case 2, they seemed to be localized in the corticospinal tract. The patient in case 1 produced signs and symptoms resembling motor neurone disease and lesion could not be differentiated from the latter. Delayed CT myelography showed that the cause of the upper limb amyotrophy was attributed to an anterior horn disorder and that of pyramidal tract sign to a corticospinal tract disorder. Therefore, we could differentiate the lesion from motor neurone disease on delayed CT myelography in case 1. In conclusion, we emphasize that delayed CT myelography can demonstrate the intramedullary pathological changes in the cervical disc disease and is useful in distinguishing between cervical disc disease simulating motor neurone disease and the latter.

  12. Disease progression in pre-dialysis patients : renal function, symptoms, and health-related quality of life

    NARCIS (Netherlands)

    Goeij, Moniek Cornelia Maria de

    2013-01-01

    This thesis investigated the effect of several risk factors on objectively assessed disease progression (renal function decline and time until the start of renal replacement therapy) and subjectively assessed disease progression (disease-related symptoms and health-related quality of life) in patien

  13. White matter disease correlates with lexical retrieval deficits in primary progressive aphasia

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    John P. Powers

    2013-12-01

    Full Text Available Objective: To relate fractional anisotropy changes associated with the semantic and logopenic variants of primary progressive aphasia to measures of lexical retrieval.Methods: We collected neuropsychological testing, volumetric MRI, and diffusion-weighted imaging on semantic variant primary progressive aphasia (n=11 and logopenic variant primary progressive aphasia (n=13 patients diagnosed using published criteria. We also acquired neuroimaging data on a group of demographically comparable healthy seniors (n=34. Fractional anisotropy was calculated and analyzed using a white matter tract-specific analysis approach. This approach utilizes anatomically guided data reduction to increase sensitivity and localizes results within canonically defined tracts. We used non-parametric, cluster-based statistical analysis to relate language performance to fractional anisotropy and determine regions of reduced fractional anisotropy in patients. Results: We found widespread fractional anisotropy reductions in white matter for both variants of primary progressive aphasia. Fractional anisotropy was related to both confrontation naming and category naming fluency performance in left uncinate fasciculus and corpus callosum in semantic variant primary progressive aphasia and left superior and inferior longitudinal fasciculi in logopenic variant primary progressive aphasia. Conclusions: Semantic variant primary progressive aphasia and logopenic variant primary progressive aphasia are associated with distinct disruptions of a large-scale network implicated in lexical retrieval, and the white matter disease in each phenotype may contribute to language impairments including lexical retrieval.

  14. Diagnostic delay in clinical practice: A case report of Coeliac disease

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    Ahmedul Kabir

    2016-08-01

    Full Text Available Once considered a gastrointestinal disease of childhood affecting mainly whites, Coeliac Disease is now recognized as a systemic disease that may affect persons of any age and many races and ethnic groups. In this paper we present a case of a 60-year-old woman presented with protein-losing enteropathy associated with partial villous atrophy on distal duodenal biopsy. In Coeliac enteropathy the changes in intestinal permeability is sufficient to cause excessive loss of protein into the gut leading to hypoproteinaemia. The patient had presented with peripheral oedema without liver or renal impairment. The case emphasizes that clinicians should have a heightened suspicion about the disease that may be present at any age in both sexes and in a wide variety of clinical circumstances.

  15. Delayed Newcastle disease virus replication using RNA interference to target the nucleoprotein

    Science.gov (United States)

    Each year millions of chickens die from Newcastle disease virus (NDV) worldwide, leading to economic and food losses. Current vaccination campaigns have limitations including cost, administration, and thermostability. These problems are heightened in the developing world where constraints are more...

  16. Progressive Neuronal Degeneration of Childhood with Liver's Disease (Alpers' Disease) Clinical Features and Neuropathological Studies of 4 Sibling

    Institute of Scientific and Technical Information of China (English)

    Yupu Guo; Zhong Guo; Haowen Liu; Mingwe Wang; Hongwei Duan; Shufang Gao; Haitao Ren

    2000-01-01

    We report four siblings of a family with Alpers' disease. Three of four siblings occurred diarrhea and myoclonus at the ages of 7 to 8 years old. During the disease evolution, symptoms of subacute encephalopathy such as headache, visual disturbance, cortical blindness, progressive seizures and mental retardation were presented at the ages of 15 to 20 years old. Downhill progression led them to death in multiple organ failure within six to eight months of onset. CT showed hypodensity lesions in the bilateral oc cipital and temporal lobes. Spongiform changes, which characterized by diffuse neuronal degeneration or loss and astrocytosis, were most severe in the gray matter. White matter was slightly involved, while basal ganglia, pons, brain stem and cerebellum were not involved. Physical examination of the only live brother of the four siblings showed short status (165 cm), arched feet and improper nose-pointed test of the left side. Muscle biopsy of him showed a large amount of Red-Ragged (RR) fibers and abnormal mitochondria. Clinical features and pathological findings of autopsy in all the four siblings were consistent with progressive neuronal degeneration of childhood with liver disease (PNDC) - Alpers' disease. The muscle biopsy showed the characteristic findings of mitochondrial myopathy. Our report confirmed the classification of late onset Alpers' disease as a mitochondrial disorders.

  17. Estimating Premorbid Functioning in Huntington's Disease: The Relationship between Disease Progression and the Wide Range Achievement Test Reading Subtest

    Science.gov (United States)

    O'Rourke, Justin J.F.; Adams, William H.; Duff, Kevin; Byars, Joanne; Nopoulos, Peg; Paulsen, Jane S.; Beglinger, Leigh J.

    2011-01-01

    The estimation of premorbid abilities is an essential part of a neuropsychological evaluation, especially in neurodegenerative conditions. Although word pronunciation tests are one standard method for estimating the premorbid level, research suggests that these tests may not be valid in neurodegenerative diseases. Therefore, the current study sought to examine two estimates of premorbid intellect, the Wide Range Achievement Test (WRAT) Reading subtest and the Barona formula, in 93 patients with mild to moderate Huntington's disease (HD) to determine their utility and to investigate how these measures relate to signs and symptoms of disease progression. In 89% of participants, WRAT estimates were below the Barona estimates. WRAT estimates were related to worsening memory and motor functioning, whereas the Barona estimates had weaker relationships. Neither estimate was related to depression or functional capacity. Irregular word reading tests appear to decline with HD progression, whereas estimation methods based on demographic factors may be more robust but overestimate premorbid functioning. PMID:21147861

  18. The progress of cerebrospinal fluid biomarkers in patients with neurodegenerative diseases

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    WANG Wei-zhi

    2013-02-01

    Full Text Available Neurodegenerative diseases include a heterogeneous group of diseases with complicated and overlapped clinical phenotypes. It is difficult to diagnose or identify this kind of disease due to insidious onset and chronic and progressive development. Since processes in the brain can be monitored by analysis of cerebrospinal fluid (CSF, abundant research efforts focus on the efficacy of biomarkers in CSF to indicate specific neurodegenerative lesions and to assist the diagnosis process, assessing whether one biomarker or several biomarkers together could be the reliable tools for diagnosis of specific neurodegenerative diseases. This article mainly reviews the research status and supplementary value in diagnosis and differentiation of CSF biomarkers in common degenerative diseases [e.g. multiple sclerosis (MS, Alzheimer's disease (AD, Parkinson's disease (PD, amyotrophic lateral sclerosis (ALS].

  19. Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease

    DEFF Research Database (Denmark)

    Currie, Gemma; Taylor, Alison H M; Fujita, Toshiro

    2016-01-01

    BACKGROUND: Hypertension and proteinuria are critically involved in the progression of chronic kidney disease. Despite treatment with renin angiotensin system inhibition, kidney function declines in many patients. Aldosterone excess is a risk factor for progression of kidney disease. Hyperkalaemia...... is a concern with the use of mineralocorticoid receptor antagonists. We aimed to determine whether the renal protective benefits of mineralocorticoid antagonists outweigh the risk of hyperkalaemia associated with this treatment in patients with chronic kidney disease. METHODS: We conducted a meta......-analysis investigating renoprotective effects and risk of hyperkalaemia in trials of mineralocorticoid receptor antagonists in chronic kidney disease. Trials were identified from MEDLINE (1966-2014), EMBASE (1947-2014) and the Cochrane Clinical Trials Database. Unpublished summary data were obtained from investigators...

  20. Natural history of periodontitis: Disease progression and tooth loss over 40 years.

    Science.gov (United States)

    Ramseier, C A; Ånerud, Å; Dulac, M; Lulic, M; Cullinan, M P; Seymour, G J; Faddy, M J; Büergin, W; Schätzle, M; Lang, N P

    2017-07-22

    To assess long-term attachment and periodontitis-related tooth loss (PTL) in untreated periodontal disease over 40 years. Data originated from the natural history of periodontitis study in Sri Lankan tea labourers first examined in 1970. In 2010, 75 subjects (15.6%) of the original cohort were re-examined. PTL over 40 years varied between 0 and 28 teeth (mean 13.1). Four subjects presented with no PTL while 12 were edentulous. Logistic regression revealed attachment loss as a statistically significant covariate for PTL (pcalculus were associated with disease initiation and that calculus, plaque and gingivitis were associated with loss of attachment and progression to advanced disease. Mean attachment loss calculus removal, plaque control and the control of gingivitis are essential in preventing disease progression, further loss of attachment and ultimately tooth loss. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  1. Progression of Alport Kidney Disease in Col4a3 Knock Out Mice Is Independent of Sex or Macrophage Depletion by Clodronate Treatment.

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    Munkyung Kim

    Full Text Available Alport syndrome is a genetic disease of collagen IV (α3, 4, 5 resulting in renal failure. This study was designed to investigate sex-phenotype correlations and evaluate the contribution of macrophage infiltration to disease progression using Col4a3 knock out (Col4a3KO mice, an established genetic model of autosomal recessive Alport syndrome. No sex differences in the evolution of body mass loss, renal pathology, biomarkers of tubular damage KIM-1 and NGAL, or deterioration of kidney function were observed during the life span of Col4a3KO mice. These findings confirm that, similar to human autosomal recessive Alport syndrome, female and male Col4a3KO mice develop renal failure at the same age and with similar severity. The specific contribution of macrophage infiltration to Alport disease, one of the prominent features of the disease in human and Col4a3KO mice, remains unknown. This study shows that depletion of kidney macrophages in Col4a3KO male mice by administration of clodronate liposomes, prior to clinical onset of disease and throughout the study period, does not protect the mice from renal failure and interstitial fibrosis, nor delay disease progression. These results suggest that therapy targeting macrophage recruitment to kidney is unlikely to be effective as treatment of Alport syndrome.

  2. The Three Gorges Dam: Does it accelerate or delay the progress towards eliminating transmission of schistosomiasis in China?

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    Zhou, Yi-Biao; Liang, Song; Chen, Yue; Jiang, Qing-Wu

    2016-07-05

    The Three Gorges Dam, located in the largest endemic area of schistosomiasis in China, is one of the world's largest hydroelectric projects to date. Some large-scale hydro projects have resulted in schistosomiasis emergence or re-emergence. Therefore, the dam's potential impact on the transmission of Schistosoma japonicum has raised concerns from medical researchers worldwide. A systematic literature review, coupled with an analysis of data on the water level and snail density in the Yangtze River was conducted to assess the impact of the dam on schistosomiasis transmission after more than 10 years of operation. The dam has significantly altered the water levels in the Yangtze River according to different seasons. These changes directly impact the ecology of the schistosome snail host. Due to the dam, there has been a reduction in the density of Oncomelania snails and/or changes in the distribution of snails. The prevalence of infection with S. japonicum has decreased in the downstream areas of the dam, including in the Dongting and Poyang Lakes. The prevalence of infection with S. japonicum in humans has decreased from 6.80 % in 2002 (before the dam began operating) to 0.50 % in 2012, and the number of people infected with S. japonicum have decreased from 94 208 in 2002 to 59 200 in 2011 in the Poyang Lake region. The presence of the dam does not seem to affect snail breeding or the prevalence of schistosomiasis in the Three Gorges Reservoir. Overall, the Three Gorges Dam has significantly contributed to changes in hydrology after more than 10 years of the dam operating. The changes caused by the dam, together with integrated control of schistosomiasis, might be accelerating the progress towards eliminating the transmission of S. japonicum in the middle and lower reaches of the Yangtze River. Despite the positive effect the dam is having in controlling S. japonicum transmission, continued surveillance is required to monitor the future ecological impacts of the

  3. Dietary flax oil during pregnancy and lactation retards disease progression in rat offspring with inherited kidney disease.

    Science.gov (United States)

    Sankaran, Deepa; Bankovic-Calic, Neda; Peng, Claudia Yu-Chen; Ogborn, Malcolm R; Aukema, Harold M

    2006-12-01

    Dietary flax oil (FO) retards disease progression in growing or adult animal models of kidney disease. To determine whether dietary flax oil during the perinatal period would alter renal disease progression in offspring, Han-SPRD-cy rats with inherited cystic kidney disease were given diets with either 7% FO or corn oil (CO), throughout pregnancy and lactation. At 3 wk of age, offspring were then given either the same or the alternate diet for 7 wk. Rats given FO during the maternal period had 15% less renal cyst growth compared with rats given FO only in the postweaning period. Dietary FO, compared with CO, in the maternal period also resulted in 12% lower cell proliferation and 15% less oxidant injury in diseased kidneys of offspring. Including FO in both the maternal and postweaning period resulted in 29-34% less renal interstitial fibrosis and 22-23% lower glomerular hypertrophy. Along with improved histology, these rats exhibited 13% less proteinuria and 30% lower creatinine clearance when dietary FO was given in the maternal period. The potential for dietary FO during pregnancy and lactation to positively modulate adult renal disease has significant implications for the 1 in 1000 individuals with congenital cystic kidney disease.

  4. Deletion of the BDNF truncated receptor TrkB.T1 delays disease onset in a mouse model of amyotrophic lateral sclerosis.

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    Sudhirkumar U Yanpallewar

    Full Text Available Brain Derived Neurotrophic Factor (BDNF exerts strong pro-survival effects on developing and injured motoneurons. However, in clinical trials, BDNF has failed to benefit patients with amyotrophic lateral sclerosis (ALS. To date, the cause of this failure remains unclear. Motoneurons express the TrkB kinase receptor but also high levels of the truncated TrkB.T1 receptor isoform. Thus, we investigated whether the presence of this receptor may affect the response of diseased motoneurons to endogenous BDNF. We deleted TrkB.T1 in the hSOD1(G93A ALS mouse model and evaluated the impact of this mutation on motoneuron death, muscle weakness and disease progression. We found that TrkB.T1 deletion significantly slowed the onset of motor neuron degeneration. Moreover, it delayed the development of muscle weakness by 33 days. Although the life span of the animals was not affected we observed an overall improvement in the neurological score at the late stage of the disease. To investigate the effectiveness of strategies aimed at bypassing the TrkB.T1 limit to BDNF signaling we treated SOD1 mutant mice with the adenosine A2A receptor agonist CGS21680, which can activate motoneuron TrkB receptor signaling independent of neurotrophins. We found that CGS21680 treatment slowed the onset of motor neuron degeneration and muscle weakness similarly to TrkB.T1 removal. Together, our data provide evidence that endogenous TrkB.T1 limits motoneuron responsiveness to BDNF in vivo and suggest that new strategies such as Trk receptor transactivation may be used for therapeutic intervention in ALS or other neurodegenerative disorders.

  5. Improving power to detect disease progression in multiple sclerosis through alternative analysis strategies.

    Science.gov (United States)

    Healy, Brian; Chitnis, Tanuja; Engler, David

    2011-10-01

    In patients with multiple sclerosis, investigation of a treatment effect on disease progression in clinical trials and observational studies often uses sustained progression on the expanded disability status scale (EDSS) as an outcome. It is not clear whether this outcome is the most powerful to detect a treatment effect on clinical disease progression. Assessment of EDSS modeling choice on the detection of treatment effect was of interest. This assessment was separately conducted under three potential treatment effects: treatment reducing the chance of higher future EDSS, treatment increasing the chance of lower future EDSS, and treatment leading to both effects. To assess the effect of modeling choice, nine modeling strategies were applied to the data to determine the most powerful approach. EDSS measurements were simulated at 6 month intervals for 24 months. Each patient's initial EDSS value ranged between 0 and 3, and probabilities of transitioning from one EDSS state to another were based on the empirical probabilities of transition obtained from available clinical data. Modeling approaches based on sustained progression had less power than approaches which modeled the EDSS score directly, regardless of treatment effect. This difference was especially pronounced when the treatment effect corresponded to an increase in the probability of improvement. Sustained progression on the EDSS is a less powerful outcome measure for clinical progression than approaches based on the actual EDSS values.

  6. Prospects for the use of celecoxib in patients with ankylosing spondylitis: impact on retarding disease progression

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    Yulia Leonidovna Korsakova

    2012-01-01

    Full Text Available Ankylosing spondylitis (AS is one of the major inflammatory diseases that affect the vertebral column and joints. The first-line drugs for the treatment of this disease are now nonsteroidal anti-inflammatory drugs (NSAIDs that not only reduce painful sensations and rigidity, but also retard the radiological progression of AS. Celecoxib is one of the effective and safe NDAIDs that are promising for the treatment of AS.

  7. Progress of foliar diseases in wheat crops at Passo Fundo, RS, Brazil

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    Felipe Rafael Garcés Fiallos

    2011-12-01

    Full Text Available The aim was to study the progress of the yellow spot, brown spot and leaf rust in wheat cultivar FUNDACEP 50 in Passo Fundo. Was evaluated the incidence of yellow spot [Drechslera tritici-repentis (Died Drechs.] brown spot [Bipolaris sorokiniana (Sacc.] and leaf rust [Puccinia triticina (Eriks]. Values obtained were integralized as Area Under the Disease Incidence Progress Curve (AUDIPC and to analyze the progress of the disease was considered the disease progress rate (r, which was obtained with the Logistic and Gompertz. Determination coefficients were high (0.93 to 0.98, as well as the mean square error (4.0706 to 7.6831. The r were 0.02 to 0.22 units, while the accumulated AUDIPC 787.5, 1216.3 and 1338.8 units for yellow spot, brown spot and leaf rust, respectively. The two models used satisfactorily explain the progress of yellow spot and brown spot, while the Gompertz explains better leaf rust.

  8. Papular pruritic eruptions: A marker of progressive HIV disease in children: Experience from eastern India

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    Samanta Moumita

    2009-01-01

    Full Text Available Context: Papular pruritic eruptions (PPEs are a commonly seen dermatological manifestation in children with Human Immunodeficiency Virus (HIV stage 2 disease, whereas recurrent upper respiratory tract infection (URTI (>2 episodes in 6 months is the most common presenting illness in this category. Papular pruritic eruptions has been associated with progressive HIV disease in adults though it is categorized in early stage. Aim: To evaluate PPE as a clinical marker for progressive pediatric HIV. Setting and Design: In Pediatric HIV/AIDS clinic, Medical College, Kolkata, a prospective longitudinal hospital-based observational study was carried out. Materials and Methods: A total of 108 children in WHO stage 2 HIV disease aged between 2 and 12 years were selected, of which 58 had recurrent URTI without PPE and another 50 had PPE with or without secondary bacterial infection. Clinico-immunological deterioration was compared between the groups in terms of progression to undernutrition, WHO clinical stage 4 disease, severe immunodeficiency, need for initiation of Highly Active Anti Retroviral Therapy (HAART and mortality over a period of 2 years. Statistical Analysis: SPSS statistical software version 10 was used. P value, relative risk (RR with 95% Confidence Interval (CI, sensitivity and specificity was estimated. P < 0.05 was considered significant. Results: Significantly higher incidence (P < 0.001 of clinico-immunological progression of disease at a significantly shorter time period (P < 0.05 was found in those with PPE in comparison to those without PPE. Papular pruritic eruption has high sensitivity, specificity and positive predictive value as a clinical marker for severe immunodeficiency. Conclusion: Papular pruritic eruption could be a useful clinical marker of progressive HIV disease in children.

  9. [Correlation study of HIV/AIDS abnormal immune activation and disease progression].

    Science.gov (United States)

    Wang, Jie; Wu, Xin-Fang; Li, Yong; Zeng, Yi

    2013-08-01

    To learn the levels of immune function and immune activation of HIV/AIDS patients in China and find the correlation between the immune activation and CD4+ T lymphocyte and disease progression. And discuss the relevance of immune activation with HIV/AIDS pathogenesis. Two hundred and eighty seven cases of HIV/AIDS patients in different disease stages who never accept HAART before and 40 healthy HIV negative donors have been involved in the research. Their immune function and abnormal immune activation markers are detected by flow cytometry counts, and the immune activation markers include CD8 CD38+ T cells and CD8+ HLA-DR+ T cell. Compare the difference of abnormal immune activation between patients of various disease stages. And by Pearson correlation test analysis, the correlation between the immune activation levels and abnormal CD4+ T lymphocyte count and disease progression will be found. The immune abnormal activation levels were significantly different between patients of different disease stages (P HIV infection may lead to decreased CD4+ T cell count and disease progression.

  10. Delayed focal involvement of upper motor neurons in the Madras pattern of motor neuron disease.

    Science.gov (United States)

    Massa, R; Scalise, A; Iani, C; Palmieri, M G; Bernardi, G

    1998-12-01

    We report the case of a young man from the south of India, initially presenting the typical signs of benign monomelic amyotrophy (BMA) in the left upper limb. After several years, the involvement of other limbs and the appearance of bulbar signs suggested the possible diagnosis of the Madras pattern of motor neuron disease (MMND). Serial motor evoked potential (MEP) recordings allowed detection of the onset of a focal involvement of upper motor neurons (UMN) controlling innervation in the originally amyotrophic limb. Therefore, serial MEP recordings can be useful for the early detection of sub-clinical UMN damage in motor neuron disease presenting with pure lower motor neuron (LMN) signs.

  11. Attenuation of Rhes activity significantly delays the appearance of behavioral symptoms in a mouse model of Huntington's disease.

    Directory of Open Access Journals (Sweden)

    Brandon A Baiamonte

    Full Text Available Huntington's disease (HD is a neuropsychiatric disorder characterized by choreiform movement of the limbs, cognitive disability, psychosis and dementia. It is invariably associated with an abnormally long CAG expansion within the IT15 gene on human chromosome 4. Although the mutant huntingtin protein is ubiquitously expressed in HD patients, cellular degeneration occurs predominantly in neurons within the corpus striatum and cerebral cortex. The Ras homolog Rhes is expressed very selectively in the precise brain areas affected by HD. Recent in vitro work suggests that Rhes may be a co-factor with mutant huntingtin in cell death. The objective of the present study was to examine whether the inhibition of Rhes would attenuate or delay the symptoms of HD in vivo. We used a transgenic mouse model of HD crossed with Rhes knockout mice to show that the behavioral symptoms of HD are regulated by Rhes. HD(+/Rhes(-/- mice showed significantly delayed expression of HD-like symptoms in this in vivo model. Drugs that block or inhibit the actions of Rhes may be useful as the first treatments for HD.

  12. The use of anti-TNF therapy for ankylosing spondylitis in everyday rheumatology practice and the relationship to disease activity, work disability and diagnostic delay.

    Science.gov (United States)

    Sullivan, C; Quinn, K; Harney, S; Ryan, J G

    2014-12-01

    Ankylosing spondylitis (AS) is characterised by insidious onset lower back pain. Poor symptom recognition results in delays in diagnosis of up to 11 years. Despite the widespread use of anti-tumour necrosis factor alpha (anti-TNFα) therapy, work disability remains a challenging problem in AS. A retrospective review of AS patients attending our physiotherapy service was carried out. Data regarding patient demographics, delay in diagnosis, treatment and disease activity were recorded. Ninety-two patients were identified of which 80 % were male. Just over 60 % of patients were on treatment with a TNF inhibitor and the average delay in diagnosis was 6 years. Clinically relevant changes in disease activity after 3 months of anti-TNFα therapy were demonstrated with a reduction in Bath AS Metrology Index, Bath AS Functional Index and Bath AS Disease Activity Index of 1, 1.99 and 2.39, respectively. In patients under the age of 65 years only 55.4 % of patients were employed. There was no relationship identified between diagnostic delay, employment status and treatment with an anti-TNF agent. Delays in diagnosis of AS remain unacceptably high; however, delays of 6 years compare favourably to reported data. Despite this and the appropriate use of anti-TNFα agents, we continue to see high rates of unemployment in this patient group which can impact both on the person and society and bears further consideration.

  13. Patterns of disease progression in the rheumatoid wrist : A longterm followup

    NARCIS (Netherlands)

    van Vugt, RM; van Jaarsveld, CHM; Hofman, DM; Helders, PJM; Bijlsma, JWJ

    1999-01-01

    Objective, To identify different patterns of disease manifestation and changes in the rate of progression of rheumatoid arthritis (RA) in the wrist.Methods. Forty wrists, with normal baseline radiographs, of 20 patients with RA were evaluated by means of a retrospective radiographic review for a per

  14. Progression of Alzheimer Disease in Europe: Data from the European ICTUS Study

    NARCIS (Netherlands)

    Vellas, B.; Hausner, L.; Frolich, L.; Cantet, C.; Gardette, V.; Reynish, E.; Gillette, S.; Aguera-Morales, E.; Auriacombe, S.; Boada, M.; Bullock, R.; Byrne, J.; Camus, V.; Cherubini, A.; Eriksdotter-Jonhagen, M.; Frisoni, G.B.; Hasselbalch, S.; Jones, R.W.; Martinez-Lage, P.; Olde Rikkert, M.G.; Tsolaki, M.; Ousset, P.J.; Pasquier, F.; Ribera-Casado, J.M.; Rigaud, A.S.; Robert, P.; Rodriguez, G.; Salmon, E.; Salva, A.; Scheltens, P.; Schneider, A.; Sinclair, A.; Spiru, L.; Touchon, J.; Zekry, D.; Winblad, B.; Andrieu, S.

    2012-01-01

    The clinical progression of Alzheimer disease (AD) was studied in European subjects under treatment with AChE inhibitors (AChE-I) in relation to geographical location over a 2-years period. One thousand three hundred and six subjects from 11 European countries were clustered into 3 regions (North,

  15. White matter lesions are associated with progression of medial temporal lobe atrophy in Alzheimer disease.

    NARCIS (Netherlands)

    Leeuw, F.E. de; Korf, E.; Barkhof, F.; Scheltens, P.

    2006-01-01

    BACKGROUND AND PURPOSE: Medial temporal lobe atrophy (MTA) is a hallmark of Alzheimer disease (AD). Its progression is often seen during the course of AD, but its frequency and risk factors remain unclear. METHODS: We investigated MTA in 35 patients with AD from whom sequential magnetic resonance

  16. Brain Substrates of Learning and Retention in Mild Cognitive Impairment Diagnosis and Progression to Alzheimer's Disease

    Science.gov (United States)

    Chang, Yu-Ling; Bondi, Mark W.; Fennema-Notestine, Christine; McEvoy, Linda K.; Hagler, Donald J., Jr.; Jacobson, Mark W.; Dale, Anders M.

    2010-01-01

    Understanding the underlying qualitative features of memory deficits in mild cognitive impairment (MCI) can provide critical information for early detection of Alzheimer's disease (AD). This study sought to investigate the utility of both learning and retention measures in (a) the diagnosis of MCI, (b) predicting progression to AD, and (c)…

  17. Untreated periodontal disease in Indonesian adolescents : Subgingival microbiota in relation to experienced progression of periodontitis

    NARCIS (Netherlands)

    Timmerman, MF; Van der Weijden, GA; Arief, EM; Armand, S; Abbas, F; Winkel, EG; Van Winkelhoff, AJ; Van der Velden, U

    2001-01-01

    Background/aims: In an Indonesian population deprived of regular dental care, the experienced progression of disease between baseline (1987) and follow-up (1994) was investigated in relation to the composition of the subgingival microbiota at follow-up. At baseline the age ranged from 15 to 25 years

  18. Urine liver fatty acid binding protein and chronic kidney disease progression

    DEFF Research Database (Denmark)

    Khatir, Dinah S; Bendtsen, Mette D; Birn, Henrik

    2017-01-01

    , regarding progression of chronic kidney disease (CKD). In a prospective study design a cohort of 74 stage 3-4 CKD patients (age 61 ± 13 years) were included. Glomerular filtration ratio (GFR, (51)Cr-EDTA-clearance), 24-hour ambulatory BP, 24-hour urinary albumin/creatinine ratio (UAC) and urinary L...

  19. Familial progressive neuronal disease and chronic idiopathic intestinal pseudo-obstruction.

    Science.gov (United States)

    Steiner, I; Steinberg, A; Argov, Z; Faber, J; Fich, A; Gilai, A

    1987-06-01

    Chronic idiopathic intestinal pseudo-obstruction (CIIP) is characterized by recurrent episodes of bowel obstruction without mechanical cause. In five members of two Jewish-Iranian families, CIIP was associated with progressive neuronal disease, starting before age 30, with ophthalmoplegia, sensorimotor peripheral neuropathy, and hearing loss. There was no evidence of CNS involvement. The pattern suggested autosomal recessive inheritance.

  20. Accuracy of MR markers for differentiating Progressive Supranuclear Palsy from Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Stefano Zanigni

    2016-01-01

    Conclusion: Although several quantitative brain MR markers provided high diagnostic accuracy in differentiating Progressive Supranuclear Palsy-Richardson's Syndrome from Parkinson's disease, the morphometric assessment of midbrain area is the best single diagnostic marker and should be routinely included in the neuroradiological work-up of parkinsonian patients.

  1. Bacterial toxins fuel disease progression in cutaneous T-cell lymphoma

    DEFF Research Database (Denmark)

    Willerslev-Olsen, Andreas; Krejsgaard, Thorbjørn; Lindahl, Lise M

    2013-01-01

    In patients with cutaneous T-cell lymphoma (CTCL) bacterial infections constitute a major clinical problem caused by compromised skin barrier and a progressive immunodeficiency. Indeed, the majority of patients with advanced disease die from infections with bacteria, e.g., Staphylococcus aureus...

  2. Serum matrix metalloproteinase 3 in early rheumatoid arthritis is correlated with disease activity and radiological progression

    NARCIS (Netherlands)

    Posthumus, MD; Limburg, PC; Westra, J; van Leeuwen, MA; van Rijswijk, MH

    2000-01-01

    Objective. To analyze the clinical significance of serial measurements of serum matrix metalloproteinase 3 (MMP-3) levels in relation to markers of disease activity and radiological progression in early rheumatoid arthritis (RA). Methods. In a 3 year prospective study of 33 patients with early RA (s

  3. Accelerating regional atrophy rates in the progression from normal aging to Alzheimer's disease

    NARCIS (Netherlands)

    Sluimer, J.D.; van der Flier, W.M.; Karas, G.B.; van Schijndel, R.; Barnes, J.; Boyes, R.G.; Cover, K.S.; Olabarriaga, S.D.; Fox, N.C.; Scheltens, P.; Vrenken, H.; Barkhof, F.

    2009-01-01

    We investigated progression of atrophy in vivo, in Alzheimer's disease (AD), and mild cognitive impairment (MCI). We included 64 patients with AD, 44 with MCI and 34 controls with serial MRI examinations (interval 1.8 +/- 0.7 years). A nonlinear registration algorithm (fluid) was used to calculate a

  4. Raptor/mTORC1 loss in adipocytes causes progressive lipodystrophy and fatty liver disease

    Directory of Open Access Journals (Sweden)

    Peter L. Lee

    2016-06-01

    Conclusions: mTORC1 activity in mature adipocytes is essential for maintaining normal adipose tissue growth and its selective loss in mature adipocytes leads to a progressive lipodystrophy disorder and systemic metabolic disease that shares many of the hallmarks of human congenital generalized lipodystrophy.

  5. Partial External Biliary Diversion in Children With Progressive Familial Intrahepatic Cholestasis and Alagille Disease

    NARCIS (Netherlands)

    Yang, Huiqi; Porte, Robert J.; Verkade, Henkjan J.; De Langen, Zacharias J.; Hulscher, Jan B. F.

    2009-01-01

    Background: Partial external biliary diversion (PEBD) is a promising treatment for children with progressive familial intrahepatic cholestasis (PFIC) and Alagille disease. Little is known about long-term Outcomes. Patients and Methods: A retrospective chart review of all patients undergoing PEBD in

  6. Potential biomarkers to follow the progression and treatment response of Huntington's disease.

    Science.gov (United States)

    Disatnik, Marie-Hélène; Joshi, Amit U; Saw, Nay L; Shamloo, Mehrdad; Leavitt, Blair R; Qi, Xin; Mochly-Rosen, Daria

    2016-11-14

    Huntington's disease (HD) is a rare genetic disease caused by expanded polyglutamine repeats in the huntingtin protein resulting in selective neuronal loss. Although genetic testing readily identifies those who will be affected, current pharmacological treatments do not prevent or slow down disease progression. A major challenge is the slow clinical progression and the inability to biopsy the affected tissue, the brain, making it difficult to design short and effective proof of concept clinical trials to assess treatment benefit. In this study, we focus on identifying peripheral biomarkers that correlate with the progression of the disease and treatment benefit. We recently developed an inhibitor of pathological mitochondrial fragmentation, P110, to inhibit neurotoxicity in HD. Changes in levels of mitochondrial DNA (mtDNA) and inflammation markers in plasma, a product of DNA oxidation in urine, mutant huntingtin aggregates, and 4-hydroxynonenal adducts in muscle and skin tissues were all noted in HD R6/2 mice relative to wild-type mice. Importantly, P110 treatment effectively reduced the levels of these biomarkers. Finally, abnormal levels of mtDNA were also found in plasma of HD patients relative to control subjects. Therefore, we identified several potential peripheral biomarkers as candidates to assess HD progression and the benefit of intervention for future clinical trials.

  7. Automated estimation of progression of interstitial lung disease in CT images.

    NARCIS (Netherlands)

    Arzhaeva, Y.; Prokop, M.; Murphy, K.; Rikxoort, E.M. van; Jong, P.A. de; Gietema, H.A.; Viergever, M.A.; Ginneken, B. van

    2010-01-01

    PURPOSE: A system is presented for automated estimation of progression of interstitial lung disease in serial thoracic CT scans. METHODS: The system compares corresponding 2D axial sections from baseline and follow-up scans and concludes whether this pair of sections represents regression,

  8. The effect of angiotensin-converting-enzyme inhibitors on progression of advanced polycystic kidney disease

    DEFF Research Database (Denmark)

    Jafar, Tazeen H; Stark, Paul C; Schmid, Christopher H

    2005-01-01

    BACKGROUND: It is not known whether angiotensin-converting-enzyme (ACE) inhibitors slow the progression of polycystic kidney disease (PKD). We performed a patient-level meta-analysis to compare the effect of antihypertensive regimens, including ACE inhibitors, to those without ACE inhibitors (con...

  9. Automated estimation of progression of interstitial lung disease in CT images.

    NARCIS (Netherlands)

    Arzhaeva, Y.; Prokop, M.; Murphy, K.; Rikxoort, E.M. van; Jong, P.A. de; Gietema, H.A.; Viergever, M.A.; Ginneken, B. van

    2010-01-01

    PURPOSE: A system is presented for automated estimation of progression of interstitial lung disease in serial thoracic CT scans. METHODS: The system compares corresponding 2D axial sections from baseline and follow-up scans and concludes whether this pair of sections represents regression, progressi

  10. Accelerating regional atrophy rates in the progression from normal aging to Alzheimer's disease

    NARCIS (Netherlands)

    Sluimer, J.D.; van der Flier, W.M.; Karas, G.B.; van Schijndel, R.; Barnes, J.; Boyes, R.G.; Cover, K.S.; Olabarriaga, S.D.; Fox, N.C.; Scheltens, P.; Vrenken, H.; Barkhof, F.

    2009-01-01

    We investigated progression of atrophy in vivo, in Alzheimer's disease (AD), and mild cognitive impairment (MCI). We included 64 patients with AD, 44 with MCI and 34 controls with serial MRI examinations (interval 1.8 +/- 0.7 years). A nonlinear registration algorithm (fluid) was used to calculate a

  11. Clinical marker for Alzheimer disease pathology in logopenic primary progressive aphasia

    NARCIS (Netherlands)

    Giannini, Lucia A. A.; Irwin, David J.; McMillan, Corey T.; Ash, Sharon; Rascovsky, Katya; Wolk, David A.; Van Deerlin, Vivianna M.; Lee, Edward B.; Trojanowski, John Q.; Grossman, Murray

    2017-01-01

    Objective: To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA). Methods: We performed a retrospective case-control study of 34 patients with PPA with available autopsy tissue. We compared baseline a

  12. Accelerating regional atrophy rates in the progression from normal aging to Alzheimer's disease

    NARCIS (Netherlands)

    Sluimer, J.D.; van der Flier, W.M.; Karas, G.B.; van Schijndel, R.; Barnes, J.; Boyes, R.G.; Cover, K.S.; Olabarriaga, S.D.; Fox, N.C.; Scheltens, P.; Vrenken, H.; Barkhof, F.

    2009-01-01

    We investigated progression of atrophy in vivo, in Alzheimer's disease (AD), and mild cognitive impairment (MCI). We included 64 patients with AD, 44 with MCI and 34 controls with serial MRI examinations (interval 1.8 +/- 0.7 years). A nonlinear registration algorithm (fluid) was used to calculate

  13. White matter lesions are associated with progression of medial temporal lobe atrophy in Alzheimer disease.

    NARCIS (Netherlands)

    Leeuw, F.E. de; Korf, E.; Barkhof, F.; Scheltens, P.

    2006-01-01

    BACKGROUND AND PURPOSE: Medial temporal lobe atrophy (MTA) is a hallmark of Alzheimer disease (AD). Its progression is often seen during the course of AD, but its frequency and risk factors remain unclear. METHODS: We investigated MTA in 35 patients with AD from whom sequential magnetic resonance im

  14. RIPK3-Mediated Necroptosis and Apoptosis Contributes to Renal Tubular Cell Progressive Loss and Chronic Kidney Disease Progression in Rats.

    Science.gov (United States)

    Zhu, Yongjun; Cui, Hongwang; Xia, Yunfeng; Gan, Hua

    2016-01-01

    Tubulointerstitial fibrosis (TIF) is caused by the progressive loss of renal tubular cells and the consequent replacement of the extracellular matrix. The progressive depletion of renal tubular cells results from apoptosis and necroptosis; however, the relative significance of each of these cell death mechanisms at different stages during the progression of chronic kidney disease (CKD) remains unclear. We sought to explore the mechanisms of renal tubular cell death during the early and intermediate stages of chronic renal damage of subtotal nephrectomied (SNx) rats. The results of tissue histological assays indicated that the numbers of necrotic dying cells and apoptotic cells were significantly higher in kidney tissues derived from a rat model of CKD. In addition, there was a significant increase in necroptosis observed by transmission electron microscopy (TEM) and an increase in the proportion of TUNEL-positive cells in kidney tissues from SNx rats compared with control rats, and necrostatin-1 (Nec-1) could inhibit necroptosis and reduce the proportion of TUNEL-positive cells. More importantly, we observed a significant increase in the incidence of necroptosis compared with apoptosis by TEM in vivo and in vitro and a significant increase in the proportion of TUNEL-positive tubular epithelial cells that did not express caspase-3 compared with those expressing cleaved caspase-3 in vitro. Furthermore, treatment with Nec-1 and zVAD strongly reduced necroptosis- and apoptosis-mediated renal tubular cell death and decreased the levels of blood urea nitrogen and serum creatinine and tubular damage scores of SNx rats. These results suggest that necroptotic cell death plays a more significant role than apoptosis in mediating the loss of renal tubular cells in SNx rats and that effectively blocking both necroptosis and apoptosis improves renal function and tubular damage at early and intermediate stages of CKD.

  15. Citicoline oral solution in glaucoma: is there a role in slowing disease progression?

    Science.gov (United States)

    Ottobelli, L; Manni, G L; Centofanti, M; Iester, M; Allevena, F; Rossetti, L

    2013-01-01

    To assess the effect of citicoline on visual field rates of progression in patients with progressing glaucoma. Forty-one patients with a diagnosis of progressing glaucoma received citicoline in oral solution for 2 years. Included were patients with a disease progression of at least -1 dB/year (at MD, mean deviation) for at least 3 years before entering the study despite controlled intraocular pressure (IOP). Patients were followed with 4 visual field examinations per year for 2 years. At baseline, the mean rate of progression was -1.1 (±0.7) dB/year despite the fact that the IOP had been below 18 mm Hg for at least 3 years. At study inclusion, the mean IOP was 15.5 (±2.6) mm Hg and the mean MD was -9.2 (±6.7) dB in the worst eye. Starting from the first cycle of treatment with citicoline, the mean rate of progression significantly changed to -0.15 (±0.3) dB/year at the end of the study (p = 0.01). This study seems to indicate that supplementation with citicoline might significantly slow down glaucomatous rates of progression. Copyright © 2013 S. Karger AG, Basel.

  16. SEEKING MEDICAL-CARE FOR A SEXUALLY-TRANSMITTED DISEASE - DETERMINANTS OF DELAY-BEHAVIOR

    NARCIS (Netherlands)

    LEENAARS, PEM; ROMBOUTS, R; KOK, G

    1993-01-01

    Control of Sexually Transmitted Diseases (STD) is important considering the high incidence of acute infections, complications and sequelae, their social and economic impact and their role in increasing transmission of the Human Immunodeficiency Virus. Unfortunately, a common response to illness is

  17. Treatment with interferon-alpha delays disease in swine infected with a highly virulent CSFV strain

    Science.gov (United States)

    Classical swine fever (CSF) is an economically significant, highly contagious swine disease. The etiological agent, CSF virus (CSFV), is an enveloped virus with a positive-sense, single-stranded RNA genome, classified as a member of the genus Pestivirus within the family Flaviviridae (Becher et al.,...

  18. SEEKING MEDICAL-CARE FOR A SEXUALLY-TRANSMITTED DISEASE - DETERMINANTS OF DELAY-BEHAVIOR

    NARCIS (Netherlands)

    LEENAARS, PEM; ROMBOUTS, R; KOK, G

    1993-01-01

    Control of Sexually Transmitted Diseases (STD) is important considering the high incidence of acute infections, complications and sequelae, their social and economic impact and their role in increasing transmission of the Human Immunodeficiency Virus. Unfortunately, a common response to illness is t

  19. An alpha-synuclein MRM assay with diagnostic potential for Parkinson's disease and monitoring disease progression

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Li [Department of Pathology, University of Washington, Seattle WA USA; Stewart, Tessandra [Department of Pathology, University of Washington, Seattle WA USA; Shi, Min [Department of Pathology, University of Washington, Seattle WA USA; Pottiez, Gwenael [Department of Pathology, University of Washington, Seattle WA USA; Dator, Romel [Department of Pathology, University of Washington, Seattle WA USA; Wu, Rui [Department of Pathology, University of Washington, Seattle WA USA; Department of Pathology, No. 3 Hospital of Beijing University, Beijing China; Aro, Patrick [Department of Pathology, University of Washington, Seattle WA USA; Schuster, Robert J. [Department of Pathology, University of Washington, Seattle WA USA; Ginghina, Carmen [Department of Pathology, University of Washington, Seattle WA USA; Pan, Catherine [Department of Pathology, University of Washington, Seattle WA USA; Gao, Yuqian [Pacific Northwest National Laboratory, Richland WA USA; Qian, Weijun [Pacific Northwest National Laboratory, Richland WA USA; Zabetian, Cyrus P. [Parkinson' s Disease Research and Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle WA USA; Department of Neurology, University of Washington School of Medicine, Seattle WA USA; Hu, Shu-Ching [Department of Neurology, University of Washington School of Medicine, Seattle WA USA; Quinn, Joseph F. [Department of Neurology, Oregon Health and Science University, Portland OR USA; Zhang, Jing [Department of Pathology, University of Washington, Seattle WA USA; Department of Pathology, Peking University Health Science Centre and Third Hospital, Beijing 100083 China

    2017-04-19

    Aim: The alpha-synuclein (α-syn) level in human cerebrospinal fluid (CSF), as measured by immunoassays, is promising as a Parkinson’s disease (PD) biomarker. However, the levels of total α-syn are inconsistent among studies with large cohorts and different measurement platforms. Total α-syn level also does not correlate with disease severity or progression. Here, we developed a highly sensitive Multiple Reaction Monitoring (MRM) method to measure absolute CSF α-syn peptide concentrations without prior enrichment or fractionation, aiming to discover new candidate biomarkers. Results: Six peptides covering 73% of protein sequence were reliably identified, and two were consistently quantified in cross-sectional and longitudinal cohorts. Absolute concentration of α-syn in human CSF was determined to be 2.1ng/mL. A unique α-syn peptide, TVEGAGSIAAATGFVK (81-96), displayed excellent correlation with previous immunoassay results in two independent PD cohorts (p < 0.001), correlated with disease severity, and its changes significantly tracked the disease progression longitudinally. Conclusions: An MRM assay to quantify human CSF α-syn was developed and optimized. Sixty clinical samples from cross-sectional and longitudinal PD cohorts were analyzed with this approach. Although further larger-scale validation is needed, the results suggest that α-syn peptide could serve as a promising biomarker in PD diagnosis and progression.

  20. Neurofilament Light Chain in Blood and CSF as Marker of Disease Progression in Mouse Models and in Neurodegenerative Diseases.

    Science.gov (United States)

    Bacioglu, Mehtap; Maia, Luis F; Preische, Oliver; Schelle, Juliane; Apel, Anja; Kaeser, Stephan A; Schweighauser, Manuel; Eninger, Timo; Lambert, Marius; Pilotto, Andrea; Shimshek, Derya R; Neumann, Ulf; Kahle, Philipp J; Staufenbiel, Matthias; Neumann, Manuela; Maetzler, Walter; Kuhle, Jens; Jucker, Mathias

    2016-07-01

    A majority of current disease-modifying therapeutic approaches for age-related neurodegenerative diseases target their characteristic proteopathic lesions (α-synuclein, Tau, Aβ). To monitor such treatments, fluid biomarkers reflecting the underlying disease process are crucial. We found robust increases of neurofilament light chain (NfL) in CSF and blood in murine models of α-synucleinopathies, tauopathy, and β-amyloidosis. Blood and CSF NfL levels were strongly correlated, and NfL increases coincided with the onset and progression of the corresponding proteopathic lesions in brain. Experimental induction of α-synuclein lesions increased CSF and blood NfL levels, while blocking Aβ lesions attenuated the NfL increase. Consistently, we also found NfL increases in CSF and blood of human α-synucleinopathies, tauopathies, and Alzheimer's disease. Our results suggest that CSF and particularly blood NfL can serve as a reliable and easily accessible biomarker to monitor disease progression and treatment response in mouse models and potentially in human proteopathic neurodegenerative diseases.

  1. Apomorphine Penject – Emerging Evidence and Treatment Strategies for Delayed on and off Periods in Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Olivier Rascol

    2014-07-01

    Full Text Available This educational symposium was held during the Joint Congress of European Neurology (EFNS–ENS, which took place from 31st May to 3rd June 2014 in Istanbul, Turkey, and was sponsored by Britannia Pharmaceuticals Limited. The symposium debated the problem of delayed ON and OFF periods in Parkinson’s disease that can occur even in patients optimised on oral medication. Emerging evidence for the rapid and effective resolution of such complications using apomorphine intermittent injection (penject was reviewed with particular reference to the positive results of the recent AM IMPAKT trial in patients with morning akinaesia. The discussions were illustrated with examples of ‘real life’ patient case studies to help determine which patients might be best suited for treatment with apomorphine injection.

  2. End-stage renal disease due to delayed diagnosis of renal tuberculosis: a fatal case report

    Directory of Open Access Journals (Sweden)

    Elizabeth De Francesco Daher

    Full Text Available Renal TB is difficult to diagnose, because many patients present themselves with lower urinary symptoms which are typical of bacterial cystitis. We report a case of a young woman with renal TB and ESRD. She was admitted with complaints of adynamia, anorexia, fever, weight loss, dysuria and generalized edema for 10 months. At physical examination she was febrile (39ºC, and her abdomen had increased volume and was painful at palpation. Laboratorial tests showed serum urea=220mg/dL, creatinine=6.6mg/dL, hemoglobin=7.9g/dL, hematocrit=24.3%, leukocytes=33,600/mm³ and platelets=664,000/mm³. Urinalysis showed an acid urine (pH=5.0, leukocyturia (2+/4+ and mild proteinuria (1+/4+. She was also oliguric (urinary volume <400mL/day. Abdominal echography showed thick and contracted bladder walls and heterogeneous liquid collection in the left pelvic region. Two laparotomies were performed, in which abscess in pelvic region was found. Anti-peritoneal tuberculosis treatment with rifampin, isoniazid and pyrazinamide was started. During the follow-up, the urine culture was found to be positive for M. tuberculosis. Six months later the patient had complaints of abdominal pain and dysuria. New laboratorial tests showed serum urea=187mg/dL, creatinine=8.0mg/dL, potassium=6.5mEq/L. Hemodialysis was then started. The CT scan showed signs of chronic nephropathy, dilated calyces and thinning of renal cortex in both kidneys and severe dilation of ureter. The patient developed neurologic symptoms, suggesting tuberculous meningoencephalitis, and died despite of support measures adopted. The patient had ESRD due to secondary uropathy to prolonged tuberculosis of urinary tract that was caused by delayed clinical and laboratorial diagnosis, and probably also due to inadequate antituberculous drugs administration.

  3. The Natural Progression of Parkinson's Disease in a Small Cohort with 15 Drug-naive Patients

    Institute of Scientific and Technical Information of China (English)

    Ying Liu; Jin-Hu Fan; Xiang Gao; Li Ma; You-Lin Qiao; Lin Zhang

    2015-01-01

    Background:The studies of the natural progression of Parkinson's disease (PD) in Chinese populations have been lacking.To address this issue and obtain a preliminary data,we conducted a PD progression assessment in 15 adults with de novo PD from a nutritional intervention trial (NIT) cohort in Lin County China.Methods:Using the Copiah County screening questionnaire and United Kingdom Parkinson's Disease Society Brain Bank diagnostic criteria,we surveyed the available NIT cohort members in 2000 and diagnosed 86 patients as PD.In 2010,we resurveyed all PD patients and confirmed definite PD diagnosis in 15 cases with the rest of them being dead (54);having probable (10) PD or vascular Parkinsonism (3);refusing to participate (2);or being away (2).In both surveys,we used Hoehn and Yahr (HY) scale and assessed the disease progression.Unified Parkinson's Disease Rating Scale (UPDRS) was added to the second survey.Results:In 2010,the average disease duration for 15 definite PD patients was 13.6 ± 7.3 years.Over a 10-year time span,9 out of 15 patients remained at the same HY stage while the remaining 6 progressed.Rigidity (47% vs.100%;P =0.002) and postural instability (7% vs.47%;P =0.005) worsened significantly.The mean UPDRS motor scores in 2010 were 39.4 ± 23.7.Conclusions:Overall worsening of motor function in PD seems to be the rule in this untreated cohort,and their rate of progression seemed to be slower than those reported in the western populations.

  4. Quantitative evaluation of disease progression in a longitudinal mild cognitive impairment cohort.

    Science.gov (United States)

    Runtti, Hilkka; Mattila, Jussi; van Gils, Mark; Koikkalainen, Juha; Soininen, Hilkka; Lötjönen, Jyrki

    2014-01-01

    Several neuropsychological tests and biomarkers of Alzheimer's disease (AD) have been validated and their evolution over time has been explored. In this study, multiple heterogeneous predictors of AD were combined using a supervised learning method called Disease State Index (DSI). The behavior of DSI values over time was examined to study disease progression quantitatively in a mild cognitive impairment (MCI) cohort. The DSI method was applied to longitudinal data from 140 MCI cases that progressed to AD and 149 MCI cases that did not progress to AD during the follow-up. The data included neuropsychological tests, brain volumes from magnetic resonance imaging, cerebrospinal fluid samples, and apolipoprotein E from the Alzheimer's Disease Neuroimaging Initiative database. Linear regression of the longitudinal DSI values (including the DSI value at the point of MCI to AD conversion) was performed for each subject having at least three DSI values available (147 non-converters, 126 converters). Converters had five times higher slopes and almost three times higher intercepts than non-converters. Two subgroups were found in the group of non-converters: one group with stable DSI values over time and another group with clearly increasing DSI values suggesting possible progression to AD in the future. The regression parameters differentiated between the converters and the non-converters with classification accuracy of 76.9% for the slopes and 74.6% for the intercepts. In conclusion, this study demonstrated that quantifying longitudinal patient data using the DSI method provides valid information for follow-up of disease progression and support for decision making.

  5. Treatment with a non-toxic, self-replicating anti-prion delays or prevents prion disease in vivo.

    Science.gov (United States)

    Diaz-Espinoza, R; Morales, R; Concha-Marambio, L; Moreno-Gonzalez, I; Moda, F; Soto, C

    2017-06-20

    Transmissible spongiform encephalopathies (TSEs) are fatal neurological disorders caused by prions, which are composed of a misfolded protein (PrP(Sc)) that self-propagates in the brain of infected individuals by converting the normal prion protein (PrP(C)) into the pathological isoform. Here, we report a novel experimental strategy for preventing prion disease based on producing a self-replicating, but innocuous PrP(Sc)-like form, termed anti-prion, which can compete with the replication of pathogenic prions. Our results show that a prophylactic inoculation of prion-infected animals with an anti-prion delays the onset of the disease and in some animals completely prevents the development of clinical symptoms and brain damage. The data indicate that a single injection of the anti-prion eliminated ~99% of the infectivity associated to pathogenic prions. Furthermore, this treatment caused significant changes in the profile of regional PrP(Sc) deposition in the brains of animals that were treated, but still succumbed to the disease. Our findings provide new insights for a mechanistic understanding of prion replication and support the concept that prion replication can be separated from toxicity, providing a novel target for therapeutic intervention.Molecular Psychiatry advance online publication, 20 June 2017; doi:10.1038/mp.2017.84.

  6. Delayed cerebral ischemia associated with reversible cerebral vasoconstriction in a patient with Moyamoya disease with intraventricular hemorrhage: Case report.

    Science.gov (United States)

    Matsuoka, Go; Kubota, Yuichi; Okada, Yoshikazu

    2015-06-01

    We describe a case of cerebral infarctions caused by transient vasoconstrictions in the posterior circulation 2 weeks after intraventricular hemorrhage without subarachnoid hemorrhage in a 35-year-old patient with Moyamoya disease. To our knowledge, this is the first case report where diffuse segmental vasoconstrictions of the basilar and posterior cerebral arteries were recognized after intraventricular hemorrhage in Moyamoya disease. The patient complained of severe and acute-onset headache 14 days after the intraventricular hemorrhage, which had a different character and severity from the one she complained of at the onset of intraventricular hemorrhage. Finally, headache disappeared within 1 month and vasoconstriction resolved in 2 months. Reversible cerebral vasoconstriction syndrome was under consideration for the etiology of her condition because of the "thunderclap" characteristics of the headache and the delayed timing of occurrence of the vasoconstriction. This case report informs and alerts neurologists, neurosurgeons and neuroradiologists who observe and treat patients with Moyamoya disease that vasoconstriction in the posterior circulation may occur after intraventricular hemorrhage in these patients.

  7. HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells.

    Science.gov (United States)

    Dasgupta, Tanushree; Antony, Jisha; Braithwaite, Antony W; Horsfield, Julia A

    2016-06-10

    Cohesin, a multi-subunit protein complex involved in chromosome organization, is frequently mutated or aberrantly expressed in cancer. Multiple functions of cohesin, including cell division and gene expression, highlight its potential as a novel therapeutic target. The SMC3 subunit of cohesin is acetylated (ac) during S phase to establish cohesion between replicated chromosomes. Following anaphase, ac-SMC3 is deacetylated by HDAC8. Reversal of SMC3 acetylation is imperative for recycling cohesin so that it can be reloaded in interphase for both non-mitotic and mitotic functions. We blocked deacetylation of ac-SMC3 using an HDAC8-specific inhibitor PCI-34051 in MCF7 breast cancer cells, and examined the effects on transcription of cohesin-dependent genes that respond to estrogen. HDAC8 inhibition led to accumulation of ac-SMC3 as expected, but surprisingly, had no influence on the transcription of estrogen-responsive genes that are altered by siRNA targeting of RAD21 or SMC3. Knockdown of RAD21 altered estrogen receptor α (ER) recruitment at SOX4 and IL20, and affected transcription of these genes, while HDAC8 inhibition did not. Rather, inhibition of HDAC8 delayed cell cycle progression, suppressed proliferation and induced apoptosis in a concentration-dependent manner. We conclude that HDAC8 inhibition does not change the estrogen-specific transcriptional role of cohesin in MCF7 cells, but instead, compromises cell cycle progression and cell survival. Our results argue that candidate inhibitors of cohesin function may differ in their effects depending on the cellular genotype and should be thoroughly tested for predicted effects on cohesin's mechanistic roles.

  8. Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy.

    Science.gov (United States)

    Waddington Cruz, Márcia; Amass, Leslie; Keohane, Denis; Schwartz, Jeffrey; Li, Huihua; Gundapaneni, Balarama

    2016-09-01

    Transthyretin hereditary amyloid polyneuropathy, also traditionally known as transthyretin familial amyloid polyneuropathy (ATTR-FAP), is a rare, relentless, fatal hereditary disorder. Tafamidis, an oral, non-NSAID, highly specific transthyretin stabilizer, demonstrated safety and efficacy in slowing neuropathy progression in early-stage ATTRV30M-FAP in a 1.5-year, randomized, double-blind, placebo-controlled trial, and 1-year open-label extension study, with a second long-term open-label extension study ongoing. Subgroup analysis of the effectiveness of tafamidis in the pivotal study and its open-label extensions revealed a relatively cohesive cohort of patients with mild neuropathy (i.e. Neuropathy Impairment Score for Lower Limbs [NIS-LL] ≤ 10) at the start of active treatment. Early treatment with tafamidis for up to 5.5 years (≥1 dose of tafamidis meglumine 20 mg once daily during the original trial or after switching from placebo in its extension) resulted in sustained delay in neurologic progression and long-term preservation of nutritional status in this cohort. Mean (95% CI) changes from baseline in NIS-LL and mBMI were 5.3 (1.6, 9.1) points and -7.8 (-44.3, 28.8) kg/m(2) × g/L at 5.5 years, respectively. No new safety issues or side effects were identified. These data represent the longest prospective evaluation of tafamidis to date, confirm a favorable safety profile, and underscore the long-term benefits of early intervention with tafamidis.

  9. Animal models for retinitis pigmentosa induced by MNU; disease progression, mechanisms and therapeutic trials.

    Science.gov (United States)

    Tsubura, A; Yoshizawa, K; Kuwata, M; Uehara, N

    2010-07-01

    Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases in humans characterized by loss of photoreceptor cells leading to visual disturbance and eventually to blindness. A single systemic administration of N-methyl-N-nitrosourea (MNU) causes retinal degeneration in various animal species. The retinal degeneration is highly reproducible, and the photoreceptor cell loss occurs within seven days after MNU administration via apoptosis resembling human RP. Here, we describe the disease progression, disease mechanisms, and therapeutic trials of MNU-induced retinal degeneration.

  10. Assembly and interrogation of Alzheimer's disease genetic networks reveal novel regulators of progression.

    Directory of Open Access Journals (Sweden)

    Soline Aubry

    Full Text Available Alzheimer's disease (AD is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe, yielded an interactome consisting of 488,353 transcription-factor/target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa, identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsy-derived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3 are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression.

  11. Towards an expert system for accurate diagnosis and progress monitoring of Parkinson's disease.

    Science.gov (United States)

    Alexiou, Athanasios; Psiha, Maria; Vlamos, Panayiotis

    2015-01-01

    While Parkinson's disease is a chronic and progressive movement disorder, no one can predict which symptoms will affect an individual patient. At the present time there is no cure for Parkinson's disease but instead a variety of alternative treatments provide relief from the symptoms. Due to these unpromising factors, we propose a new multi-scale ontology-based modeling technology for the accurate diagnosis of Parkinson's disease and its progress monitoring. The proposed model will be used to assess the status of the patient with PD corresponding treatments using a multilayer neural network. The proposed tool also aims to identify new associated physical and biological biomarkers from heterogeneous patients' data. The architecture of this expert system and its implementation in Protégé is presented in this paper.

  12. Rationale and Design of the DIPAK 1 Study : A Randomized Controlled Clinical Trial Assessing the Efficacy of Lanreotide to Halt Disease Progression in Autosomal Dominant Polycystic Kidney Disease

    NARCIS (Netherlands)

    Meijer, Esther; Drenth, Joost P. H.; d'Agnolo, Hedwig; Casteleijn, Niek F.; de Fijter, Johan W.; Gevers, Tom J.; Kappert, Peter; Peters, Dorien J. M.; Salih, Mahdi; Soonawala, Darius; Spithoven, Edwin M.; Torres, Vicente E.; Visser, Folkert W.; Wetzels, Jack F. M.; Zietse, Robert; Gansevoort, Ron T.

    Background: There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney phenotype. We report

  13. Rationale and Design of the DIPAK 1 Study: A Randomized Controlled Clinical Trial Assessing the Efficacy of Lanreotide to Halt Disease Progression in Autosomal Dominant Polycystic Kidney Disease

    NARCIS (Netherlands)

    Meijer, E.; Drenth, J.P.H.; d'Agnolo, H.; Casteleijn, N.F.; Fijter, J.W. de; Gevers, T.J.G.; Kappert, P.; Peters, D.J.; Salih, M.; Soonawala, D.; Spithoven, E.M.; Torres, V.E.; Visser, F.W.; Wetzels, J.F.M.; Zietse, R.; Gansevoort, R.T.

    2014-01-01

    BACKGROUND: There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney phenotype. We report

  14. Rationale and design of the DIPAK 1 study: A randomized controlled clinical trial assessing the efficacy of lanreotide to halt disease progression in autosomal dominant polycystic kidney disease

    NARCIS (Netherlands)

    E. Meijer (Esther); J.P.H. Drenth (Joost); H. D'Agnolo (Hedwig); E. Casteleijn (Eric); J.W. de Fijter (Johan); T.J.G. Gevers (Tom); P. Kappert (Peter); D. Peters (Dorien); M. Salih (Mahdi); D. Soonawala (Darius); E.M. Spithoven (Edwin); V.E. Torres (Vicente); F.W. Visser (Folkert); J.F.M. Wetzels (Jack); R. Zietse (Bob); R.T. Gansevoort (Ron)

    2014-01-01

    textabstractBackground There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney

  15. Transcranial magnetic stimulation follow-up study in early Parkinson's disease: A decline in compensation with disease progression?

    Science.gov (United States)

    Kojovic, Maja; Kassavetis, Panagiotis; Bologna, Matteo; Pareés, Isabel; Rubio-Agusti, Ignacio; Berardelli, Alfredo; Beraredelli, Alfredo; Edwards, Mark J; Rothwell, John C; Bhatia, Kailash P

    2015-07-01

    A number of neurophysiological abnormalities have been described in patients with Parkinson's disease, but very few longitudinal studies of how these change with disease progression have been reported. We describe measures of motor cortex inhibition and plasticity at 6 and 12 mo in 12 patients that we previously reported at initial diagnosis. Given the well-known interindividual variation in these measures, we were particularly concerned with the within-subject changes over time. Patients were assessed clinically, and transcranial magnetic stimulation (TMS) was used to measure motor cortical excitability, inhibition (short interval intracortical inhibition, cortical silent period), and plasticity (response to excitatory paired associative stimulation protocol) in both hemispheres. All measurements were performed 6 mo and 12 mo after the baseline experiments. Asymmetry in clinical motor symptoms was reflected in asymmetry of plasticity and inhibition. In the group as a whole, little change was seen in any of the parameters over 12 mo. However, analysis of within-individual data showed clear correlations between changes in clinical asymmetry and asymmetry of response to paired associative stimulation protocol and cortical silent period. Longitudinal changes in cortical silent period and response to paired associative stimulation protocol in Parkinson's disease reflect dynamic effects on motor cortex that are related to progression of motor signs. They are useful objective markers of early disease progression that could be used to detect effects of disease-modifying therapies. The decline in heightened plasticity that was present at disease onset may reflect failure of compensatory mechanisms that maintained function in the preclinical state. © 2015 International Parkinson and Movement Disorder Society.

  16. The impact of food assistance on weight gain and disease progression among HIV-infected individuals accessing AIDS care and treatment services in Uganda

    Directory of Open Access Journals (Sweden)

    McNamara Paul E

    2010-06-01

    Full Text Available Abstract Background The evidence evaluating the benefits of programmatic nutrition interventions to HIV-infected individuals in developing countries, where there is a large overlap between HIV prevalence and malnutrition, is limited. This study evaluates the impact of food assistance (FA on change in weight and disease progression as measured by WHO staging. Methods We utilize program data from The AIDS Support Organization (TASO in Uganda to compare outcomes among FA recipients to a control group, using propensity score matching (PSM methods among 14,481 HIV-infected TASO clients. Results FA resulted in a significant mean weight gain of 0.36 kg over one year period. This impact was conditional on anti-retroviral therapy (ART receipt and disease stage at baseline. FA resulted in mean weight gain of 0.36 kg among individuals not receiving ART compared to their matched controls. HIV-infected individuals receiving FA with baseline WHO stage II and III had a significant weight gain (0.26 kg and 0.2 kg respectively compared to their matched controls. Individuals with the most advanced disease at baseline (WHO stage IV had the highest weight gain of 1.9 kg. The impact on disease progression was minimal. Individuals receiving FA were 2 percentage points less likely to progress by one or more WHO stage compared to their matched controls. There were no significant impacts on either outcome among individuals receiving ART. Conclusions Given the widespread overlap of HIV and malnutrition in sub-Saharan Africa, FA programs have the potential to improve weight and delay disease progression, especially among HIV-infected individuals not yet on ART. Additional well designed prospective studies evaluating the impact of FA are urgently needed.

  17. An Unrecognized Rash Progressing to Lyme Carditis: Important Features and Recommendations Regarding Lyme Disease.

    Science.gov (United States)

    Lee, Shawn; Singla, Montish

    2016-01-01

    We present a case report of 46-year-old man with no medical history, who complained of extreme fatigue, near-syncope, and palpitations. He initially presented in complete heart block. A transvenous pacemaker was placed in the emergency department, and he was started empirically on Ceftriaxone for Lyme disease. He was admitted and over the course of the next few days, his rhythm regressed to Mobitz type I first-degree atrioventricular block and then to normal sinus rhythm. This case report highlights some important features regarding Lyme carditis, a rare presentation of early disseminated Lyme disease (seen in a few weeks to months after the initial tick bite). In 25%-30% of patients, the characteristic targetoid rash may not be seen, a likely culprit of the disease not being detected early and progressing to disseminated disease. The most common cardiac complaint of Lyme disease is palpitations, occurring in 6.6% of patients, which may not accurately reflect progression into disseminated Lyme disease because it is a nonspecific finding. Conduction abnormality, occurring in 1.8% of patients, is a more specific finding of Borrelia invading cardiac tissue. Finally, this case report highlights a recommendation that patients with confirmed Lyme disease or those presenting with cardiac abnormalities or symptoms who have an atypical profile for a cardiac event should be screened with a 12-lead electrocardiogram, Lyme serology, and be considered for antibiotic therapy with the possibility of temporary pacing.

  18. Effect of post-mortem delay on N-terminal huntingtin protein fragments in human control and Huntington disease brain lysates.

    Science.gov (United States)

    Schut, Menno H; Patassini, Stefano; Kim, Eric H; Bullock, Jocelyn; Waldvogel, Henry J; Faull, Richard L M; Pepers, Barry A; den Dunnen, Johan T; van Ommen, Gert-Jan B; van Roon-Mom, Willeke M C

    2017-01-01

    Huntington disease is associated with elongation of a CAG repeat in the HTT gene that results in a mutant huntingtin protein. Several studies have implicated N-terminal huntingtin protein fragments in Huntington disease pathogenesis. Ideally, these fragments are studied in human brain tissue. However, the use of human brain tissue comes with certain unavoidable variables such as post mortem delay, artefacts from freeze-thaw cycles and subject-to-subject variation. Knowledge on how these variables might affect N-terminal huntingtin protein fragments in post mortem human brain is important for a proper interpretation of study results. The effect of post mortem delay on protein in human brain is known to vary depending on the protein of interest. In the present study, we have assessed the effect of post mortem delay on N-terminal huntingtin protein fragments using western blot. We mimicked post mortem delay in one individual control case and one individual Huntington disease case with low initial post mortem delay. The influence of subject-to-subject variation on N-terminal huntingtin fragments was assessed in human cortex and human striatum using two cohorts of control and Huntington disease subjects. Our results show that effects of post mortem delay on N-terminal huntingtin protein fragments are minor in our individual subjects. Additionally, one freeze-thaw cycle decreases the huntingtin western blot signal intensity in the cortex control subject, but does not introduce additional N-terminal huntingtin fragments. Our results suggest that subject-to-subject variation contributes more to variability in N-terminal huntingtin fragments than post mortem delay.

  19. Heterogeneity of neuroanatomical patterns in prodromal Alzheimer's disease: links to cognition, progression and biomarkers.

    Science.gov (United States)

    Dong, Aoyan; Toledo, Jon B; Honnorat, Nicolas; Doshi, Jimit; Varol, Erdem; Sotiras, Aristeidis; Wolk, David; Trojanowski, John Q; Davatzikos, Christos

    2016-12-20

    Individuals with mild cognitive impairment and Alzheimer's disease clinical diagnoses can display significant phenotypic heterogeneity. This variability likely reflects underlying genetic, environmental and neuropathological differences. Characterizing this heterogeneity is important for precision diagnostics, personalized predictions, and recruitment of relatively homogeneous sets of patients into clinical trials. In this study, we apply state-of-the-art semi-supervised machine learning methods to the Alzheimer's disease Neuroimaging cohort (ADNI) to elucidate the heterogeneity of neuroanatomical differences between subjects with mild cognitive impairment (n = 530) and Alzheimer's disease (n = 314) and cognitively normal individuals (n = 399), thereby adding to an increasing literature aiming to establish neuroanatomical and neuropathological (e.g. amyloid and tau deposition) dimensions in Alzheimer's disease and its prodromal stages. These dimensional approaches aim to provide surrogate measures of heterogeneous underlying pathologic processes leading to cognitive impairment. We relate these neuroimaging patterns to cerebrospinal fluid biomarkers, white matter hyperintensities, cognitive and clinical measures, and longitudinal trajectories. We identified four such atrophy patterns: (i) individuals with largely normal neuroanatomical profiles, who also turned out to have the least abnormal cognitive and cerebrospinal fluid biomarker profiles and the slowest clinical progression during follow-up; (ii) individuals with classical Alzheimer's disease neuroanatomical, cognitive, cerebrospinal fluid biomarkers and clinical profile, who presented the fastest clinical progression; (iii) individuals with a diffuse pattern of atrophy with relatively less pronounced involvement of the medial temporal lobe, abnormal cerebrospinal fluid amyloid-β1-42 values, and proportionally greater executive impairment; and (iv) individuals with notably focal involvement of the medial

  20. Basal values and changes of liver stiffness predict the risk of disease progression in compensated advanced chronic liver disease.

    Science.gov (United States)

    Pons, Mònica; Simón-Talero, Macarena; Millán, Laura; Ventura-Cots, Meritxell; Santos, Begoña; Augustin, Salvador; Genescà, Joan

    2016-10-01

    Transient elastography has been proposed as a tool to predict the risk of decompensation in patients with chronic liver disease. We aimed to identify risk groups of disease progression, using a combination of baseline liver stiffness measurement (LSM) and its change over time (delta-LSM) in patients with compensated advanced chronic liver disease (cACLD). Ninety-four patients with baseline LSM ≥10kPa, Child-Pugh score 5 and without previous decompensation were included. A second LSM was performed during follow-up and data on liver function and liver-related events were collected. The primary endpoint was a composite that included death, liver decompensation and impairment in at least 1 point in Child-Pugh score. After a median follow-up of 43.6 months, 15% of patients presented the primary endpoint. Multivariate analysis identified baseline LSM (OR 1.12, P=0.002) and delta-LSM (OR 1.02, P=0.048) as independent predictors of the primary endpoint. A high risk group represented by patients with baseline LSM ≥21kPa and delta-LSM ≥10% (risk of progression 47.1%, 95% CI: 23-71%) was identified, while patients with LSM <21kPa and delta-LSM <10% presented zero risk of progression (P=0.03). Simple classification rules using baseline LSM and delta-LSM identify cACLD patients at low or high risk of disease progression. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  1. Subjective cognitive concerns and neuropsychiatric predictors of progression to the early clinical stages of Alzheimer disease.

    Science.gov (United States)

    Donovan, Nancy J; Amariglio, Rebecca E; Zoller, Amy S; Rudel, Rebecca K; Gomez-Isla, Teresa; Blacker, Deborah; Hyman, Bradley T; Locascio, Joseph J; Johnson, Keith A; Sperling, Reisa A; Marshall, Gad A; Rentz, Dorene M

    2014-12-01

    To examine neuropsychiatric and neuropsychological predictors of progression from normal to early clinical stages of Alzheimer disease (AD). From a total sample of 559 older adults from the Massachusetts Alzheimer's Disease Research Center longitudinal cohort, 454 were included in the primary analysis: 283 with clinically normal cognition (CN), 115 with mild cognitive impairment (MCI), and 56 with subjective cognitive concerns (SCC) but no objective impairment, a proposed transitional group between CN and MCI. Two latent cognitive factors (memory-semantic, attention-executive) and two neuropsychiatric factors (affective, psychotic) were derived from the Alzheimer's Disease Centers' Uniform Data Set neuropsychological battery and Neuropsychiatric Inventory brief questionnaire. Factors were analyzed as predictors of time to progression to a worse diagnosis using a Cox proportional hazards regression model with backward elimination. Covariates included baseline diagnosis, gender, age, education, prior depression, antidepressant medication, symptom duration, and interaction terms. Higher/better memory-semantic factor score predicted lower hazard of progression (hazard ratio [HR] = 0.4 for 1 standard deviation [SD] increase, p <0.0001), and higher/worse affective factor score predicted higher hazard (HR = 1.3 for one SD increase, p = 0.01). No other predictors were significant in adjusted analyses. Using diagnosis as a sole predictor of transition to MCI, the SCC diagnosis carried a fourfold risk of progression compared with CN (HR = 4.1, p <0.0001). These results identify affective and memory-semantic factors as significant predictors of more rapid progression from normal to early stages of cognitive decline and highlight the subgroup of cognitively normal elderly with SCC as those with elevated risk of progression to MCI. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  2. High resolution radiographic and fine immunologic definition of TB disease progression in the rhesus macaque.

    Science.gov (United States)

    Lewinsohn, David M; Tydeman, Ian S; Frieder, Marisa; Grotzke, Jeff E; Lines, Rebecca A; Ahmed, Sheela; Prongay, Kamm D; Primack, Steven L; Colgin, Lois M A; Lewis, Anne D; Lewinsohn, Deborah A

    2006-09-01

    Mycobacterium tuberculosis infection in non-human primates parallels human tuberculosis, and provides a valuable vaccine evaluation model. However, this model is limited by the availability of real-time, non-invasive information regarding disease progression. Consequently, we have combined computed tomography scanning with enumeration of antigen-specific T cell responses. Four rhesus monkeys were infected with M. tuberculosis strain H37Rv (1000 cfu) in the right lower lobe via a bronchoscope. All uniformly developed progressive tuberculosis, and required euthanasia at 12 weeks. Computed tomography scanning provided detailed real-time imaging of disease progression. At necropsy, computed tomography and pathohistologic findings were tightly correlated, and characteristic of human disease. Immunologic monitoring demonstrated progressive evolution of high frequency M. tuberculosis-specific CD4(+) and CD8(+) T cell responses. Peripheral blood effector cell frequencies were similar to those observed in tissues. In summary, computed tomography scanning in conjunction with immunologic monitoring provides a non-invasive, accurate, and rapid assessment of tuberculosis in the non-human primate.

  3. Progress on stem cell research towards the treatment of Parkinson's disease.

    Science.gov (United States)

    Gibson, Stuart A J; Gao, Guo-Dong; McDonagh, Katya; Shen, Sanbing

    2012-04-03

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of Lewy body inclusions along with selective destruction of dopaminergic (DA) neurons in the nigrostriatal tract of the brain. Genetic studies have revealed much about the pathophysiology of PD, enabling the identification of both biomarkers for diagnosis and genetic targets for therapeutic treatment, which are evolved in tandem with the development of stem cell technologies. The discovery of induced pluripotent stem (iPS) cells facilitates the derivation of stem cells from adult somatic cells for personalized treatment and thus overcomes not only the limited availability of human embryonic stem cells but also ethical concerns surrounding their use. Non-viral, non-integration, or non-DNA-mediated reprogramming technologies are being developed. Protocols for generating midbrain DA neurons are undergoing constant refinement. The iPS cell-derived DA neurons provide cellular models for investigating disease progression in vitro and for screening molecules of novel therapeutic potential and have beneficial effects on improving the behavior of parkinsonian animals. Further progress in the development of safer non-viral/non-biased reprogramming strategies and the subsequent generation of homogenous midbrain DA neurons shall pave the way for clinical trials. A combined approach of drugs, cell replacement, and gene therapy to stop disease progression and to improve treatment may soon be within our reach.

  4. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease.

    OpenAIRE

    Zeybel, Müjdat; Hardy, Timothy; Robinson, Stuart M.; Fox, Christopher; Anstee, Quentin M.; Ness, Thomas; Masson, Steven; Masson, Steven; French, Jeremy; White, Steve; Mann, Jelena

    2015-01-01

    RESEARCH Open Access Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease Müjdat Zeybel1, Timothy Hardy1, Stuart M Robinson1, Christopher Fox1, Quentin M Anstee1, Thomas Ness2, Steven Masson1, John C Mathers1, Jeremy French1, Steve White1 and Jelena Mann1* Abstract Background: Chronic liver injury can lead to the development of liver fibrosis and cirrhosis but only in a minority of patie...

  5. [Delayed diagnosis in a patient with Creutzfeldt-Jakob disease in a psychiatric hospital].

    Science.gov (United States)

    Roest, S; Mestdagh, I; de Grave, C; Pals, P

    2016-01-01

    A 51-year-old female teacher of dance was referred to the diagnostic unit of our psychiatric hospital with symptoms of anxiety and depression. The clinical image was suggestive of organic pathology, but this could not be determined with certainty until a late stage. We discuss the course of the patient's illness. Her symptoms appeared to be psychiatric and closely resembled those of Creutzfeldt-Jakob disease. We comment on some of the signs that could have led to an earlier diagnosis and we discuss the tools that are needed.

  6. Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment.

    Science.gov (United States)

    Clapper, Jason R; Hendricks, Michelle D; Gu, Guibao; Wittmer, Carrie; Dolman, Carrie S; Herich, John; Athanacio, Jennifer; Villescaz, Christiane; Ghosh, Soumitra S; Heilig, Joseph S; Lowe, Carolyn; Roth, Jonathan D

    2013-10-01

    Shortcomings of previously reported preclinical models of nonalcoholic steatohepatitis (NASH) include inadequate methods used to induce disease and assess liver pathology. We have developed a dietary model of NASH displaying features observed clinically and methods for objectively assessing disease progression. Mice fed a diet containing 40% fat (of which ∼18% was trans fat), 22% fructose, and 2% cholesterol developed three stages of nonalcoholic fatty liver disease (steatosis, steatohepatitis with fibrosis, and cirrhosis) as assessed by histological and biochemical methods. Using digital pathology to reconstruct the left lateral and right medial lobes of the liver, we made comparisons between and within lobes to determine the uniformity of collagen deposition, which in turn informed experimental sampling methods for histological, biochemical, and gene expression analyses. Gene expression analyses conducted with animals stratified by disease severity led to the identification of several genes for which expression highly correlated with the histological assessment of fibrosis. Importantly, we have established a biopsy method allowing assessment of disease progression. Mice subjected to liver biopsy recovered well from the procedure compared with sham-operated controls with no apparent effect on liver function. Tissue obtained by biopsy was sufficient for gene and protein expression analyses, providing the opportunity to establish an objective method of assessing liver pathology before subjecting animals to treatment. The improved assessment techniques and the observation that mice fed the high-fat diet exhibit many clinically relevant characteristics of NASH establish a preclinical model for identifying pharmacological interventions with greater likelihood of translating to the clinic.

  7. The Progressive BSSG Rat Model of Parkinson's: Recapitulating Multiple Key Features of the Human Disease.

    Science.gov (United States)

    Van Kampen, Jackalina M; Baranowski, David C; Robertson, Harold A; Shaw, Christopher A; Kay, Denis G

    2015-01-01

    The development of effective neuroprotective therapies for Parkinson's disease (PD) has been severely hindered by the notable lack of an appropriate animal model for preclinical screening. Indeed, most models currently available are either acute in nature or fail to recapitulate all characteristic features of the disease. Here, we present a novel progressive model of PD, with behavioural and cellular features that closely approximate those observed in patients. Chronic exposure to dietary phytosterol glucosides has been found to be neurotoxic. When fed to rats, β-sitosterol β-d-glucoside (BSSG) triggers the progressive development of parkinsonism, with clinical signs and histopathology beginning to appear following cessation of exposure to the neurotoxic insult and continuing to develop over several months. Here, we characterize the progressive nature of this model, its non-motor features, the anatomical spread of synucleinopathy, and response to levodopa administration. In Sprague Dawley rats, chronic BSSG feeding for 4 months triggered the progressive development of a parkinsonian phenotype and pathological events that evolved slowly over time, with neuronal loss beginning only after toxin exposure was terminated. At approximately 3 months following initiation of BSSG exposure, animals displayed the early emergence of an olfactory deficit, in the absence of significant dopaminergic nigral cell loss or locomotor deficits. Locomotor deficits developed gradually over time, initially appearing as locomotor asymmetry and developing into akinesia/bradykinesia, which was reversed by levodopa treatment. Late-stage cognitive impairment was observed in the form of spatial working memory deficits, as assessed by the radial arm maze. In addition to the progressive loss of TH+ cells in the substantia nigra, the appearance of proteinase K-resistant intracellular α-synuclein aggregates was also observed to develop progressively, appearing first in the olfactory bulb, then

  8. A case of biopsy-proven chronic kidney disease on progression from acute phosphate nephropathy

    Directory of Open Access Journals (Sweden)

    Woo Chul Joo

    2012-06-01

    Full Text Available Acute phosphate nephropathy (APhN following oral sodium phosphate solution (OSP ingestion as a bowel purgative has been frequently reported. It was recently suggested that APhN could progress to chronic kidney disease (CKD and a history of APhN might be considered as one of the causes of CKD. However, there are few reports proving APhN as a cause of CKD. Here, we report a case of APhN that progressed to CKD, as proven by renal biopsy.

  9. Weight preserving image registration for monitoring disease progression in lung CT

    DEFF Research Database (Denmark)

    Gorbunova, Vladlena; Lo, Pechin Chien Pau; Haseem, Ashraf

    2008-01-01

    the density of lung tissue with respect to local expansion or compression such that the total weight of the lungs is preserved during deformation. Our method provides a good estimation of regional destruction of lung tissue for subjects with a significant difference in inspiration level between CT scans...... compared with intensities in the deformed baseline image indicate local loss of lung tissue that is associated with progression of emphysema. To account for differences in lung intensity owing to differences in the inspiration level in the two scans rather than disease progression, we propose to adjust...

  10. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Lake, April D. [University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721 (United States); Novak, Petr [Biology Centre ASCR, Institute of Plant Molecular Biology, Ceske Budejovice 37001 (Czech Republic); Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D. [Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543 (United States); Lu, Zhenqiang [The Arizona Statistical Consulting Laboratory, University of Arizona, Tucson, AZ 85721 (United States); Lehman-McKeeman, Lois D. [Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543 (United States); Cherrington, Nathan J., E-mail: cherrington@pharmacy.arizona.edu [University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721 (United States)

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  11. Mapping the Progression of Atrophy in Early- and Late-Onset Alzheimer's Disease.

    Science.gov (United States)

    Migliaccio, Raffaella; Agosta, Federica; Possin, Katherine L; Canu, Elisa; Filippi, Massimo; Rabinovici, Gil D; Rosen, Howard J; Miller, Bruce L; Gorno-Tempini, Maria Luisa

    2015-01-01

    The term early-onset Alzheimer's disease (EOAD) identifies patients who meet criteria for AD, but show onset of symptoms before the age of 65. We map progression of gray matter atrophy in EOAD patients compared to late-onset AD (LOAD). T1-weighted MRI scans were obtained at diagnosis and one-year follow-up from 15 EOAD, 10 LOAD, and 38 age-matched controls. Voxel-based and tensor-based morphometry were used, respectively, to assess the baseline and progression of atrophy. At baseline, EOAD patients already showed a widespread atrophy in temporal, parietal, occipital, and frontal cortices. After one year, EOAD had atrophy progression in medial temporal and medial parietal cortices. At baseline, LOAD patients showed atrophy in the medial temporal regions only, and, after one year, an extensive pattern of atrophy progression in the same neocortical cortices of EOAD. Although atrophy mainly involved different lateral neocortical or medial temporal hubs at baseline, it eventually progressed along the same brain default-network regions in both groups. The cortical region showing a significant progression in both groups was the medial precuneus/posterior cingulate.

  12. Disease Progression/Clinical Outcome Model for Castration-Resistant Prostate Cancer in Patients Treated with Eribulin

    NARCIS (Netherlands)

    Van Hasselt, J. G C; Gupta, A.; Hussein, Z.; Beijnen, J. H.; Schellens, J. H M; Huitema, A. D R

    2015-01-01

    Frameworks that associate cancer dynamic disease progression models with parametric survival models for clinical outcome have recently been proposed to support decision making in early clinical development. Here we developed such a disease progression clinical outcome model for castration-resistant

  13. Disease Progression/Clinical Outcome Model for Castration-Resistant Prostate Cancer in Patients Treated with Eribulin

    NARCIS (Netherlands)

    Van Hasselt, J. G C; Gupta, A.; Hussein, Z.; Beijnen, J. H.; Schellens, J. H M; Huitema, A. D R

    2015-01-01

    Frameworks that associate cancer dynamic disease progression models with parametric survival models for clinical outcome have recently been proposed to support decision making in early clinical development. Here we developed such a disease progression clinical outcome model for castration-resistant

  14. Do Intraindividual Variation in Disease Progression and the Ensuing Tight Window of Opportunity Affect Estimation of Screening Benefits?

    NARCIS (Netherlands)

    Koffijberg, Hendrik; Rinkel, Gabriel; Buskens, Erik

    2009-01-01

    Background. The effects of variation in disease progression between individuals on the effectiveness of screening have been assessed extensively in the literature. For several diseases, progression may also vary within individuals over time. The authors study the effects of intraindividual variation

  15. Management of almond leaf scorch disease: long term data on yield, tree vitality, and disease progress

    Science.gov (United States)

    Almond leaf scorch (ALS) disease has been a chronic problem for California almond growers. This disease is caused by the bacterial pathogen Xylella fastidiosa and is transmitted by xylem-feeding insects. Previous research suggested that retaining, rather than roguing, ALS-affected trees may be more ...

  16. Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

    Science.gov (United States)

    Ishibashi, Hidetoshi; Minakawa, Eiko N.; Motohashi, Hideyuki H.; Takayama, Osamu; Popiel, H. Akiko; Puentes, Sandra; Owari, Kensuke; Nakatani, Terumi; Nogami, Naotake; Yamamoto, Kazuhiro; Yonekawa, Takahiro; Tanaka, Yoko; Fujita, Naoko; Suzuki, Hikaru; Aizawa, Shu; Nagano, Seiichi; Yamada, Daisuke; Wada, Keiji; Kohsaka, Shinichi

    2017-01-01

    Abstract Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases. PMID:28374014

  17. Exosomes-associated neurodegeneration and progression of Parkinson’s disease

    Science.gov (United States)

    Russo, Isabella; Bubacco, Luigi; Greggio, Elisa

    2012-01-01

    Growing evidence indicates the role of exosomes in a variety of physiological pathways as conveyors of biological materials from cell-to-cell. However the molecular mechanism(s) of secretion and their interaction with receiving cells are yet unclear. Recently, it is emerging that exosomes are involved in pathological processes as potential carriers in the progression of neurodegenerative pathologies associated with misfolded proteins. In the current review we will discuss some recent findings on the key role of exosomes in the spreading of the aggregated products of α-synuclein from neuron-to-neuron and of inflammatory response propagation from immune cell-to-cell; we will highlight the implication of exosomes in the neurodegeneration and progression of the disease and the their potential interplay with genes related to Parkinson’s disease. Increasing our knowledge on the cell-to-cell transmissions might provide new insights into mechanism of disease onset and progression and identify novel strategies for diagnosis and therapeutic intervention in Parkinson and other neurodegenerative diseases. PMID:23383394

  18. Kinetics of disease progression and host response in a rat model of bubonic plague.

    Science.gov (United States)

    Sebbane, Florent; Gardner, Donald; Long, Daniel; Gowen, Brian B; Hinnebusch, B Joseph

    2005-05-01

    Plague, caused by the gram-negative bacterium Yersinia pestis, primarily affects rodents but is also an important zoonotic disease of humans. Bubonic plague in humans follows transmission by infected fleas and is characterized by an acute, necrotizing lymphadenitis in the regional lymph nodes that drain the intradermal flea bite site. Septicemia rapidly follows with spread to spleen, liver, and other organs. We developed a model of bubonic plague using the inbred Brown Norway strain of Rattus norvegicus to characterize the progression and kinetics of infection and the host immune response after intradermal inoculation of Y. pestis. The clinical signs and pathology in the rat closely resembled descriptions of human bubonic plague. The bacteriology; histopathology; host cellular response in infected lymph nodes, blood, and spleen; and serum cytokine levels were analyzed at various times after infection to determine the kinetics and route of disease progression and to evaluate hypothesized Y. pestis pathogenic mechanisms. Understanding disease progression in this rat infection model should facilitate further investigations into the molecular pathogenesis of bubonic plague and the immune response to Y. pestis at different stages of the disease.

  19. View of God as benevolent and forgiving or punishing and judgmental predicts HIV disease progression.

    Science.gov (United States)

    Ironson, Gail; Stuetzle, Rick; Ironson, Dale; Balbin, Elizabeth; Kremer, Heidemarie; George, Annie; Schneiderman, Neil; Fletcher, Mary Ann

    2011-12-01

    This study assessed the predictive relationship between View of God beliefs and change in CD4-cell and Viral Load (VL) in HIV positive people over an extended period. A diverse sample of HIVseropositive participants (N = 101) undergoing comprehensive psychological assessment and blood draws over the course of 4 years completed the View of God Inventory with subscales measuring Positive View (benevolent/forgiving) and Negative View of God (harsh/judgmental/punishing). Adjusting for initial disease status, age, gender, ethnicity, education, and antiretroviral medication (at every 6-month visit), a Positive View of God predicted significantly slower disease-progression (better preservation of CD4-cells, better control of VL), whereas a Negative View of God predicted faster disease-progression over 4 years. Effect sizes were greater than those previously demonstrated for psychosocial variables known to predict HIV-disease-progression, such as depression and coping. Results remained significant even after adjusting for church attendance and psychosocial variables (health behaviors, mood, and coping). These results provide good initial evidence that spiritual beliefs may predict health outcomes.

  20. Serum Resistin Level and Progression of Atherosclerosis during Glucocorticoid Therapy for Systemic Autoimmune Diseases.

    Science.gov (United States)

    Tanaka, Nahoko; Masuoka, Shotaro; Kusunoki, Natsuko; Nanki, Toshihiro; Kawai, Shinichi

    2016-09-16

    Adipokines are important regulators of several processes, including inflammation and atherosclerosis. In patients with systemic autoimmune diseases, atherosclerosis is accelerated with higher cardiovascular morbidity and mortality. We prospectively investigated the association of adipokines and glucocorticoid therapy with progression of premature atherosclerosis in 38 patients starting glucocorticoid therapy for systemic autoimmune diseases. To detect premature atherosclerosis, carotid ultrasonography was performed at initiation of glucocorticoid therapy and after a mean three-year follow-up period. The ankle-brachial pressure index and cardio-ankle vascular index (CAVI) were measured. Serum adipokine levels were determined with enzyme-linked immunosorbent assay kits. Twenty-three patients (60.5%) had carotid artery plaque at baseline. The carotid artery intima-media thickness (IMT) increased significantly during follow-up. Glucocorticoids reduced the serum resistin level, while increasing serum leptin and high molecular weight-adiponectin. There was slower progression of atherosclerosis (carotid IMT and CAVI) at follow-up in patients with greater reduction of serum resistin and with higher cumulative prednisolone dose. In conclusion, progression of premature atherosclerosis occurred at an early stage of systemic autoimmune diseases before initiation of glucocorticoid therapy. Since resistin, an inflammation and atherosclerosis related adipokine, is reduced by glucocorticoids, glucocortidoid therapy may not accelerate atherosclerosis in patients with systemic autoimmune diseases.

  1. Chronic Progressive Neurodegeneration in a transgenic mouse model of Prion disease

    Directory of Open Access Journals (Sweden)

    Nina Fainstein

    2016-11-01

    Full Text Available Neurodegenerative diseases present pathologically with progressive structural destruction of neurons and accumulation of mis-folded proteins specific for each condition leading to brain atrophy and functional disability. Many animal models exert deposition of pathogenic protein without accompanying neurodegeneration pattern. The lack of a comprehensive model hinders the efforts to develop treatment. We performed longitudinal quantification of cellular, neuronal and synaptic density, as well as of neurogenesis in brains of mice, mimicking for genetic Creutzfeldt-Jacob disease as compared to age matched wild type mice. Mice exhibited a neurodegenerative process indicated by progressive reduction in cortical neurons and synapses, starting at age of 4-6 months, in accordance with neurologic disability. This was accompanied by significant decrease in subventricular/subependymal zone neurogenesis. Although increased hippocampal neurogenesis was detected in mice, a neurodegenerative process of CA1 and CA3 regions associated with impaired hippocampal-dependent memory function was observed. In conclusion, mice exhibit pathological neurodegeneration concomitant with progressive neurological disease, indicating these mice can serve as a model for neurodegenerative diseases.

  2. Expression of Muscle-Specific MiRNA 206 in the Progression of Disease in a Murine SMA Model.

    Science.gov (United States)

    Valsecchi, Valeria; Boido, Marina; De Amicis, Elena; Piras, Antonio; Vercelli, Alessandro

    2015-01-01

    Spinal muscular atrophy (SMA) is a severe neuromuscular disease, the most common in infancy, and the third one among young people under 18 years. The major pathological landmark of SMA is a selective degeneration of lower motor neurons, resulting in progressive skeletal muscle denervation, atrophy, and paralysis. Recently, it has been shown that specific or general changes in the activity of ribonucleoprotein containing micro RNAs (miRNAs) play a role in the development of SMA. Additionally miRNA-206 has been shown to be required for efficient regeneration of neuromuscular synapses after acute nerve injury in an ALS mouse model. Therefore, we correlated the morphology and the architecture of the neuromuscular junctions (NMJs) of quadriceps, a muscle affected in the early stage of the disease, with the expression levels of miRNA-206 in a mouse model of intermediate SMA (SMAII), one of the most frequently used experimental model. Our results showed a decrease in the percentage of type II fibers, an increase in atrophic muscle fibers and a remarkable accumulation of neurofilament (NF) in the pre-synaptic terminal of the NMJs in the quadriceps of SMAII mice. Furthermore, molecular investigation showed a direct link between miRNA-206-HDAC4-FGFBP1, and in particular, a strong up-regulation of this pathway in the late phase of the disease. We propose that miRNA-206 is activated as survival endogenous mechanism, although not sufficient to rescue the integrity of motor neurons. We speculate that early modulation of miRNA-206 expression might delay SMA neurodegenerative pathway and that miRNA-206 could be an innovative, still relatively unexplored, therapeutic target for SMA.

  3. Cyclooxygenase product inhibition with acetylsalicylic acid slows disease progression in the Han:SPRD-Cy rat model of polycystic kidney disease.

    Science.gov (United States)

    Ibrahim, Naser H M; Gregoire, Melanie; Devassy, Jessay G; Wu, Yinhong; Yoshihara, Daisuke; Yamaguchi, Tamio; Nagao, Shizuko; Aukema, Harold M

    2015-01-01

    Renal cyclooxygenase (COX) derived eicosanoids are elevated and lipoxygenase (LOX) products are reduced in the Han:SPRD-Cy rat model of polycystic kidney disease (PKD). Selective COX2 inhibition reduces kidney disease progression, but COX1 levels also are elevated in this model. Since the effect of reducing the products of both COX isoforms and the role of LOX products is not known, weanling normal and diseased Han:SPRD-cy littermates were given either low dose acetylsalicylic acid (ASA), nordihydroguaiaretic (NDGA) or no treatment for eight weeks. Renal eicosanoids were altered in the diseased compared to normal cortex, with COX products being higher and LOX products being lower. ASA reduced COX products, cyst growth and kidney water content, while NDGA reduced LOX products without altering disease progression or kidney function. Hence, a human equivalent ASA dose equal to less than one regular strength aspirin per day slowed disease progression, while further reduction of LOX products did not worsen disease progression.

  4. Can focusing on UPDRS Part II make assessments of Parkinson disease progression more efficient?

    Science.gov (United States)

    Sampaio, Cristina

    2009-03-01

    Harrison et al. have attempted to validate Part II of the Unified Parkinson's Disease Rating Scale (UPDRS II) as a medication-independent measure of disease progression. The authors collected cross-sectional data from a cohort of 888 patients with idiopathic Parkinson disease, and they found a robust association between UPDRS II scores and disease duration. Other variables considered were the patients' levodopa status, age at disease onset, and scores on UPDRS I, II and III. The results suggest that a single UPDRS II measurement might be a good indicator of progression at a given time point, irrespective of the current disease-related circumstances. This concept is attractive in its simplicity and patient-centeredness. However, this evidence came from a single-center, retrospective study, the statistical model was constructed using a nonvalidated surrogate as an independent variable, and no external replication was conducted. Until further confirmation, therefore, Harrison et al.'s proposal can only be considered to be a working hypothesis.

  5. HIV-1 Disease Progression and Survival in an Adult Population in Zimbabwe

    DEFF Research Database (Denmark)

    Zinyama-Gutsire, Rutendo B L; Chasela, Charles; Kallestrup, Per

    2015-01-01

    plasma deficiency or MBL2 genetic variants from baseline to 3 years follow up period in this adult population. We suggest the need for global OMICS research and that the present findings attest to the large between-population variability in a host of factors that can predispose individuals susceptible......HIV infection remains a major global health burden since its discovery in 1983. Sub-Saharan Africa is the region hardest hit by the HIV/AIDS pandemic where 63% of the 33 million infected people live. While there is marked person-to-person variability in susceptibility, progression, and survival...... here the first study on the putative role of MBL deficiency on HIV progression and survival in an African adult population. We hypothesized that MBL deficiency has a role to play in HIV infection by increasing HIV disease progression and decreasing survival. We assessed the role of MBL deficiency...

  6. Delaying the onset of Alzheimer disease: bilingualism as a form of cognitive reserve.

    Science.gov (United States)

    Craik, Fergus I M; Bialystok, Ellen; Freedman, Morris

    2010-11-09

    There is strong epidemiologic evidence to suggest that older adults who maintain an active lifestyle in terms of social, mental, and physical engagement are protected to some degree against the onset of dementia. Such factors are said to contribute to cognitive reserve, which acts to compensate for the accumulation of amyloid and other brain pathologies. We present evidence that lifelong bilingualism is a further factor contributing to cognitive reserve. Data were collected from 211 consecutive patients diagnosed with probable Alzheimer disease (AD). Patients' age at onset of cognitive impairment was recorded, as was information on occupational history, education, and language history, including fluency in English and any other languages. Following this procedure, 102 patients were classified as bilingual and 109 as monolingual. We found that the bilingual patients had been diagnosed 4.3 years later and had reported the onset of symptoms 5.1 years later than the monolingual patients. The groups were equivalent on measures of cognitive and occupational level, there was no apparent effect of immigration status, and the monolingual patients had received more formal education. There were no gender differences. The present data confirm results from an earlier study, and thus we conclude that lifelong bilingualism confers protection against the onset of AD. The effect does not appear to be attributable to such possible confounding factors as education, occupational status, or immigration. Bilingualism thus appears to contribute to cognitive reserve, which acts to compensate for the effects of accumulated neuropathology.

  7. Presymptomatic diagnosis of delayed-onset disease with linked DNA markers: The experience in Huntington's disease

    Energy Technology Data Exchange (ETDEWEB)

    Brandt, J.; Quaid, K.A.; Folstein, S.E.; Garber, P.; Maestri, N.E.; Abbott, M.H.; Slavney, P.R.; Franz, M.L.; Kasch, L.; Kazazian, H.H. Jr. (Johns Hopkins Univ. School of Medicine, Baltimore, MD (USA))

    1989-06-02

    Clinical medicine in the 21st century is almost certain to include wide-scale use of molecular genetic diagnostic tests. In September 1986, The Johns Hopkins University School of Medicine initiated a voluntary program of presymptomatic genetic testing for Huntington's disease for persons at 50% risk. DNA analyses using the D4S10 (G8), D4S43, and D4S95 locus probes have been performed for 55 people. Twelve of the tests have yielded positive results, 30 were negative, and 13 were uninformative. Initial reactions ranged from joy and relief to disappointment, sadness, and demoralization. Thus far, there have been no severe depressive reactions. Although the sample size is small, the data suggest that people who receive genetic test results cope well, at least over the short term, when the testing is performed in a clinical context that includes education, pretest counselling, psychological support, and regular follow-up.

  8. Pregnancy and HIV disease progression: a systematic review and meta-analysis.

    Science.gov (United States)

    Calvert, Clara; Ronsmans, Carine

    2015-02-01

    To assess whether pregnancy accelerates HIV disease progression. Studies comparing progression to HIV-related illness, low CD4 count, AIDS-defining illness, HIV-related death, or any death in HIV-infected pregnant and non-pregnant women were included. Relative risks (RR) for each outcome were combined using random effects meta-analysis and were stratified by antiretroviral therapy (ART) availability. 15 studies met the inclusion criteria. Pregnancy was not associated with progression to HIV-related illness [summary RR: 1.32, 95% confidence interval (CI): 0.66-2.61], AIDS-defining illness (summary RR: 0.97, 95% CI: 0.74-1.25) or mortality (summary RR: 0.97, 95% CI: 0.62-1.53), but there was an association with low CD4 counts (summary RR: 1.41, 95% CI: 0.99-2.02) and HIV-related death (summary RR: 1.65, 95% CI: 1.06-2.57). In settings where ART was available, there was no evidence that pregnancy accelerated progress to HIV/AIDS-defining illnesses, death and drop in CD4 count. In settings without ART availability, effect estimates were consistent with pregnancy increasing the risk of progression to HIV/AIDS-defining illnesses and HIV-related or all-cause mortality, but there were too few studies to draw meaningful conclusions. In the absence of ART, pregnancy is associated with small but appreciable increases in the risk of several negative HIV outcomes, but the evidence is too weak to draw firm conclusions. When ART is available, the effects of pregnancy on HIV disease progression are attenuated and there is little reason to discourage healthy HIV-infected women who desire to become pregnant from doing so. © 2014 John Wiley & Sons Ltd.

  9. Validating predictors of disease progression in a large cohort of primary-progressive multiple sclerosis based on a systematic literature review.

    Science.gov (United States)

    Stellmann, Jan-Patrick; Neuhaus, Anneke; Lederer, Christian; Daumer, Martin; Heesen, Christoph

    2014-01-01

    New agents with neuroprotective or neuroregenerative potential might be explored in primary-progressive Multiple Sclerosis (PPMS)--the MS disease course with leading neurodegenerative pathology. Identification of patients with a high short-term risk for progression may minimize study duration and sample size. Cohort studies reported several variables as predictors of EDSS disability progression but findings were partially contradictory. To analyse the impact of published predictors on EDSS disease progression in a large cohort of PPMS patients. A systematic literature research was performed to identify predictors for disease progression in PPMS. Individual case data from the Sylvia Lawry Centre (SLC) and the Hamburg MS patient database (HAPIMS) was pooled for a retrospective validation of these predictors on the annualized EDSS change. The systematic literature analysis revealed heterogeneous data from 3 prospective and 5 retrospective natural history cohort studies. Age at onset, gender, type of first symptoms and early EDSS changes were available for validation. Our pooled cohort of 597 PPMS patients (54% female) had a mean follow-up of 4.4 years and mean change of EDSS of 0.35 per year based on 2503 EDSS assessments. There was no significant association between the investigated variables and the EDSS-change. None of the analysed variables were predictive for the disease progression measured by the annualized EDSS change. Whether PPMS is still unpredictable or our results may be due to limitations of cohort assessments or selection of predictors cannot be answered. Large systematic prospective studies with new endpoints are needed.

  10. Connected speech as a marker of disease progression in autopsy-proven Alzheimer's disease

    National Research Council Canada - National Science Library

    Ahmed, Samrah; Haigh, Anne-Marie F; de Jager, Celeste A; Garrard, Peter

    2013-01-01

    ... cognitive domains, including language. Previous studies from our group have shown that language changes may be reflected in connected speech production in the earliest stages of typical Alzheimer's disease...

  11. Gut Microbiota in HIV Infection: Implication for Disease Progression and Management

    Directory of Open Access Journals (Sweden)

    Felix Chinweije Nwosu

    2014-01-01

    Full Text Available Survival rates among HIV patients have significantly improved since the introduction of antiretroviral therapy (ART in HIV management. However, persistent disease progression and clinical complications in virally suppressed individuals point to additional contributing factors other than HIV replication; microbial translocation is one such factor. The role of underlying commensal microbes and microbial products that traverse the intestinal lumen into systemic circulation in the absence of overt bacteraemia is under current investigation. This review focuses on current knowledge of the complex microbial communities and microbial markers involved in the disruption of mucosal immune T-cells in the promotion of inflammatory processes in HIV infections. Unanswered questions and aims for future studies are addressed. We provide perspective for discussing potential future therapeutic strategies focused on modulating the gut microbiota to abate HIV disease progression.

  12. ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity

    Science.gov (United States)

    Beers, David R.; Zhao, Weihua; Wang, Jinghong; Zhang, Xiujun; Wen, Shixiang; Neal, Dan; Thonhoff, Jason R.; Alsuliman, Abdullah S.; Shpall, Elizabeth J.; Rezvani, Katy

    2017-01-01

    Neuroinflammation is a pathological hallmark of ALS in both transgenic rodent models and patients, and is characterized by proinflammatory T lymphocytes and activated macrophages/microglia. In ALS mouse models, decreased regulatory T lymphocytes (Tregs) exacerbate the neuroinflammatory process, leading to accelerated motoneuron death and shortened survival; passive transfer of Tregs suppresses the neuroinflammation and prolongs survival. Treg numbers and FOXP3 expression are also decreased in rapidly progressing ALS patients. A key question is whether the marked neuroinflammation in ALS can be attributed to the impaired suppressive function of ALS Tregs in addition to their decreased numbers. To address this question, T lymphocyte proliferation assays were performed. Compared with control Tregs, ALS Tregs were less effective in suppressing responder T lymphocyte proliferation. Although both slowly and rapidly progressing ALS patients had dysfunctional Tregs, the greater the clinically assessed disease burden or the more rapidly progressing the patient, the greater the Treg dysfunction. Epigenetically, the percentage methylation of the Treg-specific demethylated region was greater in ALS Tregs. After in vitro expansion, ALS Tregs regained suppressive abilities to the levels of control Tregs, suggesting that autologous passive transfer of expanded Tregs might offer a novel cellular therapy to slow disease progression. PMID:28289705

  13. Pazopanib treatment slows progression and stabilizes disease in patients with taxane-resistant cutaneous angiosarcoma.

    Science.gov (United States)

    Ogata, Dai; Yanagisawa, Hiroto; Suzuki, Kenji; Oashi, Kohei; Yamazaki, Naoya; Tsuchida, Tetsuya

    2016-10-01

    Although cutaneous angiosarcoma (cAS) has one of the worst prognoses among malignant skin tumors, few effective drug options for secondary treatment have been discovered to date because of the limited number of cases. Therefore, this study was aimed at determining pazopanib's potential as a new cAS treatment option. We retrospectively evaluated five patients with taxane-resistant unresectable cAS treated with pazopanib at a university hospital. Their characteristics and treatment outcomes were retrieved from their records. Progression-free survival (PFS), overall survival (OS), disease progression, and toxicity were evaluated; furthermore, the response to pazopanib was assessed in relation to the expression of vascular endothelial growth factor receptor 2 (VEGFR-2). The median PFS from the time of pazopanib initiation was 94 days. Two patients showed partial response, two showed stable disease, and one had progressive disease in the case of the best overall response. VEGFR-2 expression was positive in all cases, and patients with high expression had improved median OS compared to that in those with low expression. VEGFR-2 expression was correlated with a longer OS. The most common toxicities were hypertension and anorexia followed by myelosuppression. This is the largest case series reported wherein pazopanib was used for taxane-resistant cAS. Although the cytoreductive effect and survival benefits were not significant in this small sample, we consider pazopanib a valid treatment option for preserving patients' quality of life. Our results suggest pazopanib treatment slows the progression of disease and stabilizes it in patients with taxane-resistant cAS.

  14. Serum Cholesterol and the Progression of Parkinson's Disease: Results from DATATOP

    OpenAIRE

    Xuemei Huang; Peggy Auinger; Shirley Eberly; David Oakes; Michael Schwarzschild; Alberto Ascherio; Richard Mailman; Honglei Chen

    2011-01-01

    BACKGROUND: Recent studies have suggested that higher serum cholesterol may be associated with lower occurrence of Parkinson's disease (PD). This study is to test the hypothesis that higher serum cholesterol correlates with slower PD progression. METHODS: Baseline non-fasting serum total cholesterol was measured in 774 of the 800 subjects with early PD enrolled between 1987 and 1988 in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. Participants were followe...

  15. Hypoxia,angiogenesis and liver fibrogenesis in the progression of chronic liver diseases

    Institute of Scientific and Technical Information of China (English)

    Claudia; Paternostro; Ezio; David; Erica; Novo; Maurizio; Parola

    2010-01-01

    Angiogenesis is a dynamic,hypoxia-stimulated and growth factor-dependent process,and is currently referred to as the formation of new vessels from preexisting blood vessels.Experimental and clinical studies have unequivocally reported that hepatic angiogenesis,irrespective of aetiology,occurs in conditions of chronic liver diseases(CLDs) characterized by perpetuation of cell injury and death,inflammatory response and progressive fibrogenesis.Angiogenesis and related changes in liver vascular architecture,th...

  16. Genetic Risk Score Modelling for Disease Progression in New-Onset Type 1 Diabetes Patients

    DEFF Research Database (Denmark)

    Brorsson, Caroline A.; Nielsen, Lotte B.; Andersen, Marie Louise;

    2016-01-01

    1 diabetes (T1D). As gene expression may represent an intermediate phenotype between genetic variation and disease, we hypothesized that genes within T1D loci which are expressed in islets and transcriptionally regulated by proinflammatory cytokines would be the best predictors of disease...... progression. Two-thirds of 46 GWAS candidate genes examined were expressed in human islets, and 11 of these significantly changed expression levels following exposure to proinflammatory cytokines (IL-1β + IFNγ + TNFα) for 48 h. Using the GWAS single nucleotide polymorphisms (SNPs) from each locus, we...

  17. Rapid progression to cardiac tamponade in Erdheim-Chester disease despite treatment with interferon alpha.

    Science.gov (United States)

    Nakhleh, Afif; Slobodin, Gleb; Elias, Nizar; Bejar, Jacob; Odeh, Majed

    2016-07-01

    Erdheim-Chester disease (ECD) is a rare form of non-Langerhans histiocytosis with heterogeneous clinical manifestations. The most common presentation is bone pains typically involving the long bones. Approximately 75% of the patients develop extraskeletal involvement. Cardiac involvement is seen in up to 45% of the patients, and although, pericardial involvement is the most common cardiac pathology of this rare disease, cardiac tamponade due to ECD has been very rarely reported. We describe a case of a patient found to have ECD with multi-organ involvement and small pericardial effusion, which progressed to cardiac tamponade despite treatment with interferon alpha.

  18. Oral health information systems--towards measuring progress in oral health promotion and disease prevention

    DEFF Research Database (Denmark)

    Petersen, Poul Erik; Bourgeois, Denis; Bratthall, Douglas

    2005-01-01

    programmes oriented towards disease prevention and health promotion. The WHO Oral Health Country/Area Profile Programme (CAPP) provides data on oral health from countries, as well as programme experiences and ideas targeted to oral health professionals, policy-makers, health planners, researchers...... systems are being developed within the framework of the WHO STEPwise approach to surveillance of noncommunicable, chronic disease, and data stored in the WHO Global InfoBase may allow advanced health systems research. Sound knowledge about progress made in prevention of oral and chronic disease......This article describes the essential components of oral health information systems for the analysis of trends in oral disease and the evaluation of oral health programmes at the country, regional and global levels. Standard methodology for the collection of epidemiological data on oral health has...

  19. Progress toward an integrated understanding of Parkinson's disease [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Maxime W.C. Rousseaux

    2017-07-01

    Full Text Available Parkinson's disease (PD is the second most common neurodegenerative disorder after Alzheimer's disease, affecting over 10 million individuals worldwide. While numerous effective symptomatic treatments are currently available, no curative or disease-modifying therapies exist. An integrated, comprehensive understanding of PD pathogenic mechanisms will likely address this unmet clinical need. Here, we highlight recent progress in PD research with an emphasis on promising translational findings, including (i advances in our understanding of disease susceptibility, (ii improved knowledge of cellular dysfunction, and (iii insights into mechanisms of spread and propagation of PD pathology. We emphasize connections between these previously disparate strands of PD research and the development of an emerging systems-level understanding that will enable the next generation of PD therapeutics.

  20. Longitudinal deformation models, spatial regularizations and learning strategies to quantify Alzheimer's disease progression.

    Science.gov (United States)

    Fiot, Jean-Baptiste; Raguet, Hugo; Risser, Laurent; Cohen, Laurent D; Fripp, Jurgen; Vialard, François-Xavier

    2014-01-01

    In the context of Alzheimer's disease, two challenging issues are (1) the characterization of local hippocampal shape changes specific to disease progression and (2) the identification of mild-cognitive impairment patients likely to convert. In the literature, (1) is usually solved first to detect areas potentially related to the disease. These areas are then considered as an input to solve (2). As an alternative to this sequential strategy, we investigate the use of a classification model using logistic regression to address both issues (1) and (2) simultaneously. The classification of the patients therefore does not require any a priori definition of the most representative hippocampal areas potentially related to the disease, as they are automatically detected. We first quantify deformations of patients' hippocampi between two time points using the large deformations by diffeomorphisms framework and transport these deformations to a common template. Since the deformations are expected to be spatially structured, we perform classification combining logistic loss and spatial regularization techniques, which have not been explored so far in this context, as far as we know. The main contribution of this paper is the comparison of regularization techniques enforcing the coefficient maps to be spatially smooth (Sobolev), piecewise constant (total variation) or sparse (fused LASSO) with standard regularization techniques which do not take into account the spatial structure (LASSO, ridge and ElasticNet). On a dataset of 103 patients out of ADNI, the techniques using spatial regularizations lead to the best classification rates. They also find coherent areas related to the disease progression.

  1. Inferring biomarkers for Mycobacterium avium subsp. paratuberculosis infection and disease progression in cattle using experimental data

    Science.gov (United States)

    Magombedze, Gesham; Shiri, Tinevimbo; Eda, Shigetoshi; Stabel, Judy R.

    2017-03-01

    Available diagnostic assays for Mycobacterium avium subsp. paratuberculosis (MAP) have poor sensitivities and cannot detect early stages of infection, therefore, there is need to find new diagnostic markers for early infection detection and disease stages. We analyzed longitudinal IFN-γ, ELISA-antibody and fecal shedding experimental sensitivity scores for MAP infection detection and disease progression. We used both statistical methods and dynamic mathematical models to (i) evaluate the empirical assays (ii) infer and explain biological mechanisms that affect the time evolution of the biomarkers, and (iii) predict disease stages of 57 animals that were naturally infected with MAP. This analysis confirms that the fecal test is the best marker for disease progression and illustrates that Th1/Th2 (IFN-γ/ELISA antibodies) assays are important for infection detection, but cannot reliably predict persistent infections. Our results show that the theoretical simulated macrophage-based assay is a potential good diagnostic marker for MAP persistent infections and predictor of disease specific stages. We therefore recommend specifically designed experiments to test the use of a based assay in the diagnosis of MAP infections.

  2. Real-time progressive hyperspectral remote sensing detection methods for crop pest and diseases

    Science.gov (United States)

    Wu, Taixia; Zhang, Lifu; Peng, Bo; Zhang, Hongming; Chen, Zhengfu; Gao, Min

    2016-05-01

    Crop pests and diseases is one of major agricultural disasters, which have caused heavy losses in agricultural production each year. Hyperspectral remote sensing technology is one of the most advanced and effective method for monitoring crop pests and diseases. However, Hyperspectral facing serial problems such as low degree of automation of data processing and poor timeliness of information extraction. It resulting we cannot respond quickly to crop pests and diseases in a critical period, and missed the best time for quantitative spraying control on a fixed point. In this study, we take the crop pests and diseases as research point and breakthrough, using a self-development line scanning VNIR field imaging spectrometer. Take the advantage of the progressive obtain image characteristics of the push-broom hyperspectral remote sensor, a synchronous real-time progressive hyperspectral algorithms and models will development. Namely, the object's information will get row by row just after the data obtained. It will greatly improve operating time and efficiency under the same detection accuracy. This may solve the poor timeliness problem when we using hyperspectral remote sensing for crop pests and diseases detection. Furthermore, this method will provide a common way for time-sensitive industrial applications, such as environment, disaster. It may providing methods and technical reserves for the development of real-time detection satellite technology.

  3. Effects of HMG-CoA reductase inhibitors (statins) on progression of kidney disease.

    Science.gov (United States)

    Fried, Linda F

    2008-09-01

    Chronic kidney disease, especially in the setting of proteinuria, is characterized by hyperlipidemia. In animal models, hyperlipidemia causes glomerular foam cells and glomerulosclerosis. Treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) ameliorates kidney disease in these models. The data of the role of hyperlipidemia in progression of human kidney disease are less clear. Data from small studies in glomerular disease suggest that statins decrease proteinuria. Data mainly from cardiovascular studies suggest that statins decrease the loss of glomerular filtration. The benefit of statins may derive from their lipid lowering effects. More recently, data suggest that the benefit of statins is greater than lipid lowering alone. The pleiotropic effects of statins may derive from inhibition of other downstream targets (isoprenoids) of the mevalonic acid pathway that are separate from cholesterol synthesis. Statins inhibits isoprenylation of Ras and Rho GTPases. These effects may lead to decreased monocyte/macrophage infiltration in the glomerulus, decreased mesangial proliferation and decreased accumulation of extracellular matrix and fibrosis. In addition, inhibition of RhoA and Ras may decrease inflammation and increase eNOS activity. These effects could lead to improvement in the progression of kidney disease.

  4. The genetics of human autoimmune disease: A perspective on progress in the field and future directions.

    Science.gov (United States)

    Seldin, Michael F

    2015-11-01

    Progress in defining the genetics of autoimmune disease has been dramatically enhanced by large scale genetic studies. Genome-wide approaches, examining hundreds or for some diseases thousands of cases and controls, have been implemented using high throughput genotyping and appropriate algorithms to provide a wealth of data over the last decade. These studies have identified hundreds of non-HLA loci as well as further defining HLA variations that predispose to different autoimmune diseases. These studies to identify genetic risk loci are also complemented by progress in gene expression studies including definition of expression quantitative trait loci (eQTL), various alterations in chromatin structure including histone marks, DNase I sensitivity, repressed chromatin regions as well as transcript factor binding sites. Integration of this information can partially explain why particular variations can alter proclivity to autoimmune phenotypes. Despite our incomplete knowledge base with only partial definition of hereditary factors and possible functional connections, this progress has and will continue to facilitate a better understanding of critical pathways and critical changes in immunoregulation. Advances in defining and understanding functional variants potentially can lead to both novel therapeutics and personalized medicine in which therapeutic approaches are chosen based on particular molecular phenotypes and genomic alterations. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Tempol, a Superoxide Dismutase-Mimetic Drug, Ameliorates Progression of Renal Disease in CKD Mice

    Directory of Open Access Journals (Sweden)

    Wei Ding

    2015-07-01

    Full Text Available Background: Oxidative stress has been implicated in the pathogenesis of chronic kidney disease (CKD and antioxidants may ameliorate disease progression. We investigate the beneficial effect of Tempol, a superoxide dismutase-mimetic drug, on progression of disease in a mouse model of CKD. Methods: CKD was surgically induced in c57BL/6 mice by 5/6 nephrectomy. Mice were randomly divided into 3 groups: sham group, 5/6 nephrectomized group (Nx and Nx+Tempol (2 mmol/l in drinking water. Mice were sacrificed at the end of 12 weeks. Renal function, structure as well as expression of key molecules involved in the pathogenesis of inflammation, fibrosis and progression in mice were measured. Results: Reduced body weight and impaired renal function (elevation on serum creatinine, blood urea nitrogen, urine albumin, segmental sclerosis and tubulointerstitial damage was demonstrated in Nx mice but was significantly improved by Tempol administration. Nx animals exhibited significantly elevated proinflammatory and profibrotic factors, activation of NF-κB, increased expression of NADPH oxidase related subunits (p47phox, p67phox, gp91phox, and elevated activation of TGF-ß/Smad3, EGFR, MAPK signaling pathway. Tempol inhibited NF-κB mediated inflammation, TGF-ß/Smad3-induced renal fibrosis as well as EGFR and MAPK signaling pathway activation. Conclusions: Tempol administration attenuated renal injury in CKD mice through NF-κB, TGF-ß/Smad3, redox-senstive EGFR activation and c-Raf/MEK/ERK pathways.

  6. Tumour necrosis factor-α inhibition can stabilize disease in progressive vitiligo.

    Science.gov (United States)

    Webb, K C; Tung, R; Winterfield, L S; Gottlieb, A B; Eby, J M; Henning, S W; Le Poole, I C

    2015-09-01

    Tumour necrosis factor (TNF)-α, a proinflammatory cytokine central to many autoimmune diseases, has been implicated in the depigmentation process in vitiligo. We review its role in vitiligo by exploring its pro- and anti-inflammatory properties and examine the effects of blocking its actions with TNF-α antagonist therapeutics in reports available in the literature. We found that TNF-α inhibition halts disease progression in patients with progressive vitiligo but that, paradoxically, treatment can be associated with de novo vitiligo development in some patients when used for other autoimmune conditions, particularly when using adalimumab and infliximab. These studies reinforce the importance of stating appropriate outcomes measures, as most pilot trials propose to measure repigmentation, whereas halting depigmentation is commonly overlooked as a measure of success. We conclude that TNF-α inhibition has proven useful for patients with progressive vitiligo, where TNF-α inhibition is able to quash cytotoxic T-cell-mediated melanocyte destruction. However, a lingering concern for initiating de novo disease will likely prevent more widespread application of TNF inhibitors to treat vitiligo.

  7. UPDRS activity of daily living score as a marker of Parkinson's disease progression.

    Science.gov (United States)

    Harrison, Madaline B; Wylie, Scott A; Frysinger, Robert C; Patrie, James T; Huss, Diane S; Currie, Lillian J; Wooten, G Frederick

    2009-01-30

    The activities of daily living (ADL) subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) captures the impact of Parkinson's disease (PD) on daily function and may be less affected than other subsections by variability associated with drug cycle and motor fluctuations. We examined UPDRS mentation, ADL and motor subscores in 888 patients with idiopathic PD. Multiple linear regression analyses determined the association between disease duration and UPDRS subscores as a function of medication status at examination and in a subset of patients with multiple examinations. Independent of medication status and across cross-sectional and longitudinal analyses, ADL subscores showed a stronger and more stable association with disease duration than other UPDRS subscores after adjusting for age of disease onset. The association between disease duration and the motor subscore depended on medication status. The strong association between ADL subscore and disease duration in PD suggests that this measure may serve as a better marker of disease progression than signs and symptoms assessed in other UPDRS sections.

  8. 18F-AV-1451 positron emission tomography in Alzheimer's disease and progressive supranuclear palsy.

    Science.gov (United States)

    Passamonti, Luca; Vázquez Rodríguez, Patricia; Hong, Young T; Allinson, Kieren S J; Williamson, David; Borchert, Robin J; Sami, Saber; Cope, Thomas E; Bevan-Jones, W Richard; Jones, P Simon; Arnold, Robert; Surendranathan, Ajenthan; Mak, Elijah; Su, Li; Fryer, Tim D; Aigbirhio, Franklin I; O'Brien, John T; Rowe, James B

    2017-03-01

    The ability to assess the distribution and extent of tau pathology in Alzheimer's disease and progressive supranuclear palsy in vivo would help to develop biomarkers for these tauopathies and clinical trials of disease-modifying therapies. New radioligands for positron emission tomography have generated considerable interest, and controversy, in their potential as tau biomarkers. We assessed the radiotracer 18F-AV-1451 with positron emission tomography imaging to compare the distribution and intensity of tau pathology in 15 patients with Alzheimer's pathology (including amyloid-positive mild cognitive impairment), 19 patients with progressive supranuclear palsy, and 13 age- and sex-matched controls. Regional analysis of variance and a support vector machine were used to compare and discriminate the clinical groups, respectively. We also examined the 18F-AV-1451 autoradiographic binding in post-mortem tissue from patients with Alzheimer's disease, progressive supranuclear palsy, and a control case to assess the 18F-AV-1451 binding specificity to Alzheimer's and non-Alzheimer's tau pathology. There was increased 18F-AV-1451 binding in multiple regions in living patients with Alzheimer's disease and progressive supranuclear palsy relative to controls [main effect of group, F(2,41) = 17.5, P AV-1451 binding was significantly increased in patients with Alzheimer's disease, relative to patients with progressive supranuclear palsy and with control subjects, in the hippocampus and in occipital, parietal, temporal, and frontal cortices (t's > 2.2, P's AV-1451 binding was elevated in the midbrain (t = 2.1, P AV-1451 uptake in the putamen, pallidum, thalamus, midbrain, and in the dentate nucleus of the cerebellum (t's > 2.7, P's AV-1451 strongly bound to Alzheimer-related tau pathology, but less specifically in progressive supranuclear palsy. 18F-AV-1451 binding to the basal ganglia was strong in all groups in vivo. Postmortem histochemical staining showed absence of

  9. Chitosan-Hyaluronate Hybrid Gel Intraarticular Injection Delays Osteoarthritis Progression and Reduces Pain in a Rat Meniscectomy Model as Compared to Saline and Hyaluronate Treatment

    Directory of Open Access Journals (Sweden)

    Shachar Patchornik

    2012-01-01

    Full Text Available Chitosan-Hyaluronate hybrid gel (CHHG is a self-forming thermo-responsive hydrogel. The current study was undertaken in order to assess the effect of CHHG on rat's surgically induced osteoarthritis. Methods. Thirteen rats were included in the study. In all rats weight-bearing was assessed using a Linton Incapacitance tester. All rats underwent bilateral medial partial meniscectomy. Four rats received a saline injection in the control knee and a 200-microliter injection of CHHG in the experimental knee. Five rats received a high-molecular weight hyaluronate injection to the control knee and a 200-microliter injection of CHHG in the experimental knee. Four rats underwent the same surgical procedure, allowed to recuperate for seven days and then CHHG and hyaluronate were injected. The animals were followed for 6 weeks. Two weeks after injection of a therapeutic substance the amount of weight-bearing on each knee was evaluated using a Linton Incapacitance meter. Results. Two weeks after induction of osteoarthritis there is less pain in the CHHG-treated knee than in the control-treated knee, as determined using a Lintron Incapacitance meter. After six-weeks the histological appearance of the CHHG-treated knee was superior to that of the controls. This is indicated by thicker cartilage remaining on the medial femoral condyle as well as less cyst formation in the CHHG-treated kn