"Cherry red spot" in a patient with Tay-Sachs disease: case report "Mácula em cereja" em paciente com doença de Tay-Sachs: relato de caso

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Ricardo Evangelista Marrocos de Aragão

2009-08-01

Full Text Available Tay-Sachs disease is an autosomal recessive disorder of sphingolipid metabolism, caused by enzime hexosaminidase A deficiency that leads to an accumulation of GM2 in neurocytes which results in progressive loss of neurological function. The accumulation of lipid in retinal ganglion cells that leads to a chalk-white appearance of the fundus called "cherry red spot" is the hallmark of Tay-Sachs disease. It is also seen in others neurometabolic diseases as well as in central retinal artery occlusion. This case reports a child with Tay-Sachs disease in a family with four previous similar deaths without diagnostic.Tay-Sachs é uma doença autossômica recessiva, caracterizada pela deficiência da enzima hexosaminidase A levando ao acúmulo de esfingolipídios (GM2 em células neuronais que resulta em uma perda progressiva da função neurológica. O acúmulo de lipídios em células ganglionais da retina leva a uma aparência de mácula em cereja, característica do fundo de olho de pessoas acometidas. "Mácula em cereja" também pode ser vista em outras doenças neurometabólicas e em oclusão da artéria central da retina. Este trabalho relata o caso de um paciente com doença de Tay-Sachs em uma família com história de quatro óbitos por causas semelhantes sem diagnóstico.

Tay-Sach disease with "cherry-red spot"--first reported case in Malaysia.

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Chan, L Y; Balasubramaniam, S; Sunder, R; Jamalia, R; Karunakar, T V N; Alagaratnam, J

2011-12-01

We present a rare case of Tay-Sachs disease with retinal 'cherry-red spots' in a 19-month-old Malay child. Molecular genetic studies confirmed the diagnosis. The case highlights that 'cherry-red spot' is a useful clinical clue in Tay-Sachs disease and several other lysosomal storage disorders. It serves as an ideal illustration of the eye as a window to inborn error of metabolism.

[Sandhoff's and Tay-Sachs disease--based on our own cases].

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Kokot, Witold; Raczyńska, Krystyna; Krajka-Lauer, Jarosława; Iwaszkiewicz-Bilikiewicz, Barbara; Wierzba, Jolanta

2004-01-01

The authors described two infant with Sandhoff's and Tay-Sachs disease. Tay-Sachs disease is well-known inherited disease leading to an accumulation of gangliosides in the brain and retina. Sandhoffs disease (GM2 gangliosidosis type 0) was diagnosed in an infant, in whom a progressive neurological disorder and cherry-red foveal spots were developed. In addition, to the general clinical examination, indirect ophthalnoscopy, blood white cells enzymatic examination are used to make definitive diagnosis. In this cases, the early eye fundus examination allowed us to make the proper diagnosis. The fundus change is characterized by the "cherry-red spot" in the central area.

Tay Sachs and Related Storage Diseases: Family Planning

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Schneiderman, Gerald; And Others

1978-01-01

Based on interviews with 24 families, the article discusses family planning and the choices available to those families in which a child has previously died from Tay-Sachs or related lipid storage diseases. (IM)

Lyso-GM2 ganglioside: a possible biomarker of Tay-Sachs disease and Sandhoff disease.

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Kodama, Takashi; Togawa, Tadayasu; Tsukimura, Takahiro; Kawashima, Ikuo; Matsuoka, Kazuhiko; Kitakaze, Keisuke; Tsuji, Daisuke; Itoh, Kohji; Ishida, Yo-Ichi; Suzuki, Minoru; Suzuki, Toshihiro; Sakuraba, Hitoshi

2011-01-01

To find a new biomarker of Tay-Sachs disease and Sandhoff disease. The lyso-GM2 ganglioside (lyso-GM2) levels in the brain and plasma in Sandhoff mice were measured by means of high performance liquid chromatography and the effect of a modified hexosaminidase (Hex) B exhibiting Hex A-like activity was examined. Then, the lyso-GM2 concentrations in human plasma samples were determined. The lyso-GM2 levels in the brain and plasma in Sandhoff mice were apparently increased compared with those in wild-type mice, and they decreased on intracerebroventricular administration of the modified Hex B. The lyso-GM2 levels in plasma of patients with Tay-Sachs disease and Sandhoff disease were increased, and the increase in lyso-GM2 was associated with a decrease in Hex A activity. Lyso-GM2 is expected to be a potential biomarker of Tay-Sachs disease and Sandhoff disease.

Lyso-GM2 ganglioside: a possible biomarker of Tay-Sachs disease and Sandhoff disease.

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Takashi Kodama

Full Text Available To find a new biomarker of Tay-Sachs disease and Sandhoff disease. The lyso-GM2 ganglioside (lyso-GM2 levels in the brain and plasma in Sandhoff mice were measured by means of high performance liquid chromatography and the effect of a modified hexosaminidase (Hex B exhibiting Hex A-like activity was examined. Then, the lyso-GM2 concentrations in human plasma samples were determined. The lyso-GM2 levels in the brain and plasma in Sandhoff mice were apparently increased compared with those in wild-type mice, and they decreased on intracerebroventricular administration of the modified Hex B. The lyso-GM2 levels in plasma of patients with Tay-Sachs disease and Sandhoff disease were increased, and the increase in lyso-GM2 was associated with a decrease in Hex A activity. Lyso-GM2 is expected to be a potential biomarker of Tay-Sachs disease and Sandhoff disease.

Temporary Efficacy of Pyrimethamine in Juvenile-Onset Tay-Sachs Disease Caused by 2 Unreported HEXA Mutations in the Indian Population.

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Udwadia-Hegde, Anaita; Hajirnis, Omkar

2017-01-01

Juvenile Tay-Sachs disease is rarer than other forms of Tay-Sachs disease and is usually seen in children between the age of 2 and 10 years. Pyrimethamine as a pharmacological chaperone was used to increase β-hexosaminidase A activity in this patient. We describe a patient with Tay-Sachs disease from the Indian population, a juvenile case who presented with developmental regression starting at the age of three, initially with motor followed by language regression. She is currently incapacitated with severe behavioral issues. This brief communication gives an insight into the efficacy of pharmacological chaperones. It also describes two unreported mutations in hexosaminidase A gene from the Indian population. After commencing Pyrimethamine, though initial benefits with increase in levels corresponded with briefly halting the motor regression, the observed increase was only transient and not associated with discernible beneficial neurological or psychiatric effects.

Temporary Efficacy of Pyrimethamine in Juvenile-Onset Tay-Sachs Disease Caused by 2 Unreported HEXA Mutations in the Indian Population

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Anaita Udwadia-Hegde MD, DCH, MRCPCH

2017-01-01

Full Text Available Background: Juvenile Tay-Sachs disease is rarer than other forms of Tay-Sachs disease and is usually seen in children between the age of 2 and 10 years. Pyrimethamine as a pharmacological chaperone was used to increase β-hexosaminidase A activity in this patient. Patient: We describe a patient with Tay-Sachs disease from the Indian population, a juvenile case who presented with developmental regression starting at the age of three, initially with motor followed by language regression. She is currently incapacitated with severe behavioral issues. Conclusion: This brief communication gives an insight into the efficacy of pharmacological chaperones. It also describes two unreported mutations in hexosaminidase A gene from the Indian population. After commencing Pyrimethamine, though initial benefits with increase in levels corresponded with briefly halting the motor regression, the observed increase was only transient and not associated with discernible beneficial neurological or psychiatric effects.

Tay-Sachs and Sandhoff diseases: enzymatic diagnosis in dried blood spots on filter paper: retrospective diagnoses in newborn-screening cards.

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Chamoles, Néstor A; Blanco, Mariana; Gaggioli, Daniela; Casentini, Carina

2002-04-01

Tay-Sachs disease (TSD), Sandhoff disease (SD) and variants are caused by deficient activity of the lysosomal enzymes hexosaminidase A (HA) and total hexosaminidase (TH) (hexosaminidase A plus B), respectively. For diagnosis, these enzymes are usually measured in plasma or extracts of leukocytes. We describe methods for the assay of hexosaminidase A and total hexosaminidase activities in dried blood spots (DBSs) on filter paper. We studied 163 healthy controls, 9 Tay-Sachs patients, 4 Sandhoff patients, 18 obligate carriers and the newborn-screening cards from two patients with Tay-Sachs and one patient with Sandhoff disease. To tubes containing a 3-mm-diameter blood spot, we added elution liquid and substrate solution. After incubation at 37 degrees C, the amount of hydrolyzed product was compared with a calibrator to allow the quantification of enzyme activity. The described methodology is useful to distinguish patients with Tay-Sachs disease or Sandhoff disease from carriers and controls using samples that are sufficiently stable to be transported to the testing laboratory by mail. The diagnosis of both diseases from a newborn-screening card (NSC) was clearly demonstrated, even after storage for up to 38 months at room temperature. The newborn-screening card has been added to the biological materials that allow the identification of patients with Tay-Sachs disease and Sandhoff disease.

Preconception risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease.

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Hussein, Norita; Weng, Stephen F; Kai, Joe; Kleijnen, Jos; Qureshi, Nadeem

2018-03-14

Globally, about five per cent of children are born with congenital or genetic disorders. The most common autosomal recessive conditions are thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease, with higher carrier rates in specific patient populations. Identifying and counselling couples at genetic risk of the conditions before pregnancy enables them to make fully informed reproductive decisions, with some of these choices not being available if genetic counselling is only offered in an antenatal setting. This is an update of a previously published review. To assess the effectiveness of systematic preconception genetic risk assessment to improve reproductive outcomes in women and their partners who are identified as carriers of thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease in healthcare settings when compared to usual care. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Registers. In addition, we searched for all relevant trials from 1970 (or the date at which the database was first available if after 1970) to date using electronic databases (MEDLINE, Embase, CINAHL, PsycINFO), clinical trial databases (National Institutes of Health, Clinical Trials Search portal of the World Health Organization, metaRegister of controlled clinical trials), and hand searching of key journals and conference abstract books from 1998 to date (European Journal of Human Genetics, Genetics in Medicine, Journal of Community Genetics). We also searched the reference lists of relevant articles, reviews and guidelines and also contacted subject experts in the field to request any unpublished or other published trials.Date of latest search of the registers: 20 June 2017.Date of latest search of all other sources: 16 November 2017. Any randomised or quasi-randomised controlled trials (published or unpublished) comparing reproductive outcomes of systematic preconception genetic risk assessment for thalassaemia, sickle

Tay Sachs disease: an autopsy case report.

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Jadhav, Meenal Vitthal; Landge, Meenal P; Sawaimoon, Satyakam K; Harke, Arun B; Deshmukh, Sanjay D

2005-10-01

This report describes a case report of a postmortem performed on a 5-year old patient of Tay-Sachs disease, presenting with failure to thrive, muscular flaccidity, and cherry-red spots on macula on fundoscopy. There was no history of similarly affected sibling or any other family member. The diagnosis was confirmed by enzyme studies. At postmortem, there was no organomegaly. The brain, on microscopy, showed vacuolated swollen neurons.

ACOG committee opinion. Number 318, October 2005. Screening for Tay-Sachs disease.

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2005-10-01

Tay-Sachs disease (TSD) is a severe progressive neurologic disease that causes death in early childhood. Carrier screening, should be offered before pregnancy to individuals and couples at high-risk, including those of Ashkenazi Jewish, French-Canadian, or Cajun descent and those with a family history consistent with TSD. If both partners are determined to be carriers of TSD, genetic counseling and prenatal diagnosis should be offered.

A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: Implications for carrier screening

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Triggs-Raine, B.L.; Akerman, B.R.; Gravel, R.A. (McGill Univ.-Montreal Children' s Hospital Research Institute, Montreal, Quebec (Canada)); Mules, E.H.; Thomas, G.H.; Dowling, C.E. (Johns Hopkins School of Medicine, Baltimore, MD (United States)); Kaback, M.M.; Lim-Steele, J.S.T. (Univ. of California, San Diego, CA (United States)); Natowicz, M.R. (Eunice Kennedy Shriver Center for Mental Retardation, Waltham, MA (United States)); Grebner, E.E. (Thomas Jefferson Univ., Philadelphia, PA (United States)); Navon, R.R. (Tel-Aviv Univ., Kfar-Sava (Israel)); Welch, J.P. (Dalhousie Univ., Halifax, Nova, Scotia (Canada)); Greenberg, C.R. (Univ. of Manitoba, Winnipeg (Canada))

1992-10-01

Deficiency of [beta]-hexosaminidase A (Hex A) activity typically results in Tay-Sachs disease. However, healthy subjects found to be deficient in Hex A activity (i.e., pseudodeficient) by means of in vitro biochemical tests have been described. The authors analyzed the HEXA gene of one pseudodeficient subject and identified both a C[sub 739]-to-T substitution that changes Arg[sub 247][yields]Trp on one allele and a previously identified Tay-Sachs disease mutation of the second allele. Six additional pseudodeficient subjects were found to have the C[sub 739]-to-T but for none of 36 Jewish enzyme-defined carries who did not have one of three known mutations common to this group. The C[sub 739]-to-T allele, together with a [open quotes]true[close quotes] Tay-Sachs disease allele, causes Hex A pseudodeficiency. Given both the large proportion of non-Jewish carriers with this allele and that standard biochemical screening cannot differentiate between heterozygotes for the C[sub 739]-to-T mutations and Tay-Sachs disease carriers, DNA testing for this mutation in at-risk couples is essential. This could prevent unnecessary or incorrect prenatal diagnoses. 40 refs., 3 figs., 4 tabs.

Correlation of augmented startle reflex with brainstem electrophysiological responses in Tay-Sachs disease.

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Nakamura, Sadao; Saito, Yoshiaki; Ishiyama, Akihiko; Sugai, Kenji; Iso, Takashi; Inagaki, Masumi; Sasaki, Masayuki

2015-01-01

To clarify the evolution of an augmented startle reflex in Tay-Sachs disease and compare the temporal relationship between this reflex and brainstem evoked potentials. Clinical and electrophysiological data from 3 patients with Tay-Sachs disease were retrospectively collected. The augmented startle reflex appeared between the age of 3 and 17 months and disappeared between the age of 4 and 6 years. Analysis of brainstem auditory evoked potentials revealed that poor segregation of peak I, but not peak III, coincided with the disappearance of the augmented startle reflex. A blink reflex with markedly high amplitude was observed in a patient with an augmented startle reflex. The correlation between the augmented startle reflex and the preservation of peak I but not peak III supports the theory that the superior olivary nucleus is dispensable for this reflex. The blink reflex with high amplitudes may represent augmented excitability of reticular formation at the pontine tegmentum in Tay-Sachs disease, where the pattern generators for the augmented startle and blink reflexes may functionally overlap. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Distribution of a pseudodeficiency allele among Tay-Sachs carriers

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Tomczak, J.; Grebner, E.E. (Thomas Jefferson Univ., Philadelphia, PA (United States)); Boogen, C. (Univ. of Essen Medical School (Germany))

1993-08-01

Recently Triggs-Raine et al. (1992) identified a new mutation in the gene coding for the [alpha]-subunit of [beta]-hexosaminidase A (hex A), the enzyme whose deficiency causes Tay-Sachs disease. This mutation, a C[sub 739]-to-T transition in exon 7, results in an altered enzyme that is active (albeit at reduced levels) in cells but that has essentially no activity in serum. This so-called pseudodeficient allele was first detected in compound heterozygotes who also carried a Tay-Sachs disease allele and therefore had no detectable hex A in their serum but who were in good health. Carriers of this apparently benign mutation are generally indistinguishable from carriers of a lethal mutation by means of routine enzyme-based screening tests, because the product of the pseudodeficient allele is not detectable in serum and has decreased activity in cells. This suggests that some individuals who have been classified as Tay-Sachs carriers are actually carriers of the pseudodeficient allele and are not at risk to have a child affected with Tay-Sachs disease. The pseudodeficient allele may also be responsible for some inconclusive diagnoses, where leukocyte values fall below the normal range but are still above the carrier range. The fact that there are now two mutant alleles (the psuedodeficient and the adult) that are indistinguishable from the lethal infantile mutations by means of enzyme assay yet that are phenotypically very different and that together may account for as much as 12% of enzyme-defined carriers on the basis of the data here suggests that DNA analysis should be part of a comprehensive screening program. It will be particularly useful to identify the mutations in couples at risk, before they undergo prenatal diagnosis. DNA analysis will also resolve some inconclusive diagnoses.

Atypical presentation of late-onset Tay-Sachs disease.

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Deik, Andres; Saunders-Pullman, Rachel

2014-05-01

Late-onset Tay-Sachs disease (LOTS) is a lysosomal storage disease caused by deficient Beta-hexosaminidase A activity. We describe a 53-year-old woman who presented with adult-onset leg weakness, and whose initial diagnosis was progressive muscular atrophy without identifiable etiology. Development of cerebellar ataxia in mid-life prompted reassessment. Beta-hexosaminidase A quantification assay demonstrated absence of the isozyme. Genetic testing identified compound heterozygous mutations in the HEXA gene, confirming the diagnosis of LOTS. The phenotypic spectrum of LOTS includes motor neuronopathy, ataxia, choreoathetosis, neuropathy, and psychiatric symptoms in various combinations. This patient highlights the emergence of different clinical features over many years and emphasizes the need to consider LOTS in the differential diagnosis of progressive muscular atrophy. Copyright © 2013 Wiley Periodicals, Inc.

Neurocognitive testing in late-onset Tay-Sachs disease: a pilot study.

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Elstein, D; Doniger, G M; Simon, E; Korn-Lubetzki, I; Navon, R; Zimran, A

2008-08-01

To test neurocognitive function in patients with late-onset Tay-Sachs disease (LOTS) using a computerized system to assess whether cognition is a clinically relevant outcome measure of possible therapeutic intervention in LOTS. Ten adults with Tay-Sachs disease were administered at least one battery of the Mindstreams Neurotrax system for evaluation of cognitive function. Six sub-scores and a Global Cognitive Score (GCS) were tabulated. A disease specific severity score was also devised with six domains. Despite identical genotypes, all patients but the two oldest had > or = 3/6 sub-scores one standard deviation below normal mean (100); verbal and executive functions were most affected. The severity score measured other functions. Because of provocative findings on re-testing in patients exposed to miglustat, and despite the very small cohort, cognitive function may be an appropriate and clinically relevant outcome measure for future therapeutic interventions in LOTS.

Expanding the spectrum of HEXA mutations in Indian patients with Tay-Sachs disease.

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Sheth, Jayesh; Mistri, Mehul; Datar, Chaitanya; Kalane, Umesh; Patil, Shekhar; Kamate, Mahesh; Shah, Harshuti; Nampoothiri, Sheela; Gupta, Sarita; Sheth, Frenny

2014-01-01

Tay-Sachs disease is an autosomal recessive neurodegenerative disorder occurring due to impaired activity of β-hexosaminidase-A (EC 3.2.1.52), resulting from the mutation in HEXA gene. Very little is known about the molecular pathology of TSD in Indian children except for a few mutations identified by us. The present study is aimed to determine additional mutations leading to Tay-Sachs disease in nine patients confirmed by the deficiency of β-hexosaminidase-A (C (D175A) and c.805G>C (p.G269R) in one case; and one small 1 bp deletion c.426delT (p.F142LfsX57) and one splice site mutation c.459+4A>C in the other two cases respectively. None of these mutations were detected in 100 chromosomes from healthy individuals of the same ethnic group. Three previously reported missense mutations, (i) c.532C>T (p.R178C), (ii) c.964G>T (p.D322Y), and (iii) c.1385A>T (p.E462V); two nonsense mutations (i) c.709C>T (p.Q237X) and (ii) c.1528C>T (p.R510X), one 4 bp insertion c.1277_1278insTATC (p.Y427IfsX5) and one splice site mutation c.459+5G>A were also identified in six cases. We observe from this study that novel mutations are more frequently observed in Indian patients with Tay-Sachs disease with clustering of ~ 73% of disease causing mutations in exons 5 to 12. This database can be used for a carrier rate screening in the larger population of the country.

Tay-Sachs disease with conspicuous cranial computerized tomographic appearances

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Watanabe, Kishichiro; Mukawa, Akio; Muto, Kazuhiko; Nishikawa, Jiro; Takahashi, Shigeko.

1985-01-01

An autopsy case of a 3-year-old female infant with Tay-Sachs disease was presented. A cherry red spot in the fundus and a deficiency of N-acetyl-β-hexosaminidase A in the white blood cells were revealed soon after admission at the age of one year. Her parents and sister were found to be healthy carriers. The patient showed a typical clinical course with marked cranial swelling. In addition to the marked ballooning of neurons on light microscope, membranous cytoplasmic body (MCB) on electron microscope and abnormal accumulation of GM 2 ganglioside in the cerebral cortex by thin layer chromatography were confirmed in the autopsy specimens. In the late stage of her clinical course, the cranial computerized tomography (CT) demonstrated symmetric and deep-wavy hyperdense cerebral cortical zones, diffuse hypodensity and diminished volume of cerebral white matter, mild to moderate ventricular dilatation, and a small cerebellum and brainstem. These conspicuous appearances of the cranial CT seem to be characteristic of Tay-Sachs disease in the late stage, and they are derived from abnormal accumulation of GM 2 ganglioside in the cerebral cortex, and diffuse intense demyelination (dysmyelinating demyelination) of the cerebral white matter. (author)

Segregation of Tay-Sachs and Sandhoff alleles in a non-Jewish family.

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Lane, A B; Young, E; Jenkins, T

1980-01-01

A non-Jewish family is presented in which the genes for Tay-Sachs disease and Sandhoff disease are segregating. Individuals heterozygous for both alleles have low serum and white cell total hexosaminidase levels together with a proportion of heat-labile hexosaminidase A (HEX A) which falls in the normal range. The individuals would not be detected as carriers of Tay-Sachs disease or Sandhoff disease in a population screening program.

Choroidal Coloboma in a Case of Tay-Sachs Disease

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Ahmed, Nasreen Raees; Tripathy, Koushik; Kumar, Vivek; Gogia, Varun

2014-01-01

Coloboma as an ocular finding has been documented in various syndromes. Here we have a case of infantile Tay-Sachs disease associated with unilateral choroidal coloboma. To the best of our knowledge, such an association has not been documented in the literature. Whether such an association is a matter of chance or signifies the involvement of ganglioside metabolism in ocular embryogenesis remains to be elucidated.

Choroidal coloboma in a case of tay-sachs disease.

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Ahmed, Nasreen Raees; Tripathy, Koushik; Kumar, Vivek; Gogia, Varun

2014-01-01

Coloboma as an ocular finding has been documented in various syndromes. Here we have a case of infantile Tay-Sachs disease associated with unilateral choroidal coloboma. To the best of our knowledge, such an association has not been documented in the literature. Whether such an association is a matter of chance or signifies the involvement of ganglioside metabolism in ocular embryogenesis remains to be elucidated.

Impact of gene patents and licensing practices on access to genetic testing and carrier screening for Tay-Sachs and Canavan disease.

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Colaianni, Alessandra; Chandrasekharan, Subhashini; Cook-Deegan, Robert

2010-04-01

Genetic testing for Tay-Sachs and Canavan disease is particularly important for Ashkenazi Jews, because both conditions are more frequent in that population. This comparative case study was possible because of different patenting and licensing practices. The role of DNA testing differs between Tay-Sachs and Canavan diseases. The first-line screening test for Tay-Sachs remains an enzyme activity test rather than genotyping. Genotyping is used for preimplantation diagnosis and confirmatory testing. In contrast, DNA-based testing is the basis for Canavan screening and diagnosis. The HEXA gene for Tay-Sachs was cloned at the National Institutes of Health, and the gene was patented but has not been licensed. The ASPA gene for Canavan disease was cloned and patented by Miami Children's Hospital. Miami Children's Hospital did not inform family members and patient groups that had contributed to the gene discovery that it was applying for a patent, and pursued restrictive licensing practices when a patent issued in 1997. This led to intense controversy, litigation, and a sealed, nonpublic 2003 settlement that apparently allowed for nonexclusive licensing. A survey of laboratories revealed a possible price premium for ASPA testing, with per-unit costs higher than for other genetic tests in the Secretary's Advisory Committee on Genetics, Health, and Society case studies. The main conclusion from comparing genetic testing for Tay-Sachs and Canavan diseases, however, is that patenting and licensing conducted without communication with patients and advocates cause mistrust and can lead to controversy and litigation, a negative model to contrast with the positive model of patenting and licensing for genetic testing of cystic fibrosis.

Segregation of Tay-Sachs and Sandhoff alleles in a non-Jewish family.

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Lane, A B; Young, E; Jenkins, T

1980-01-01

A non-Jewish family is presented in which the genes for Tay-Sachs disease and Sandhoff disease are segregating. Individuals heterozygous for both alleles have low serum and white cell total hexosaminidase levels together with a proportion of heat-labile hexosaminidase A (HEX A) which falls in the normal range. The individuals would not be detected as carriers of Tay-Sachs disease or Sandhoff disease in a population screening program. PMID:7446530

Diagnosis and molecular characterization of non-classic forms of Tay-Sachs disease in Brazil.

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Rozenberg, R; Kok, F; Burin, M G; Sá Miranda, M C; Vasques, C; Henriques-Souza, A M M; Giugliani, R; Vainzof, Mariz; Pereira, L V

2006-06-01

Molecular analysis of five Brazilian families, including eight patients presenting with nonclassic Tay-Sachs disease, was performed to identify frequent causative mutations and their correlation with clinical course. Three patients were affected by the B1 subacute variant and were shown to carry the R178H mutation (the DN allele), which is also common among Portuguese patients. Two of them were compound heterozygotes, whereas the third presented with the mutation in both alleles. Since Brazil was a Portuguese colony for over two centuries, common ancestry might be the probable explanation. The fourth patient presented with a juvenile phenotype and carries the R499H mutation, which has been reported only once worldwide and is associated with residual enzyme activity, responsible for a slower clinical course. The fifth family, of an Ashkenazi Jewish background, showed an extensive intrafamilial clinical variability among three affected sibs presenting with muscle atrophy, ataxia, and psychiatric symptoms. They were first diagnosed as having atypical spinal muscular atrophy and, subsequently, spinocerebellar ataxia, but, recently, the diagnosis of late-onset Tay-Sachs disease was confirmed based on reduced plasma hexosaminidase A activity and the G269S/InsTATC1278 genotype. It is therefore highly recommended to test patients with a similar clinical history for Tay-Sachs disease. In the same family, one first cousin committed suicide at the age of 24 years, presenting with a clinical phenotype that suggested an undiagnosed case and highlighting the effect of the intrafamilial clinical variability in delaying a prompt diagnosis. It is now recognized that his parents are, in fact, a carrier couple. Additionally, another relative had been previously identified as a heterozygote in a Tay-Sachs disease screening program, but the information was not shared among the family. Since this information might anticipate diagnosis and genetic counseling, it is advisable that

Choroidal Coloboma in a Case of Tay-Sachs Disease

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Nasreen Raees Ahmed

2014-01-01

Full Text Available Coloboma as an ocular finding has been documented in various syndromes. Here we have a case of infantile Tay-Sachs disease associated with unilateral choroidal coloboma. To the best of our knowledge, such an association has not been documented in the literature. Whether such an association is a matter of chance or signifies the involvement of ganglioside metabolism in ocular embryogenesis remains to be elucidated.

GM2-Gangliosidosis (Sandhoff and Tay Sachs disease): Diagnosis and Neuroimaging Findings (An Iranian Pediatric Case Series).

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Karimzadeh, Parvaneh; Jafari, Narjes; Nejad Biglari, Habibeh; Jabbeh Dari, Sayena; Ahmad Abadi, Farzad; Alaee, Mohammad-Reza; Nemati, Hamid; Saket, Sasan; Tonekaboni, Seyed Hasan; Taghdiri, Mohammad-Mahdi; Ghofrani, Mohammad

2014-01-01

GM2-Gangliosidosis disease is a rare autosomal recessive genetic disorder that includes two disorders (Tay-Sachs and Sandhoff disease).These disorders cause a progressive deterioration of nerve cells and inherited deficiency in creating hexosaminidases A, B, and AB. Patients who were diagnosed withGM2-Gangliosidosis in the Neurology Department of Mofid Children's Hospital in Tehran, Iran from October 2009 to February 2014were included in our study. The disorder was confirmed by neurometabolic and enzyme level detection of hexosaminidases A, B, and AB in reference to Wagnester Laboratory in Germany. We assessed age, gender, past medical history, developmental status, clinical manifestations, and neuroimaging findings of 9 patients with Sandhoff disease and 9 with Tay Sachs disease. 83% of our patients were the offspring of consanguineous marriages. All of them had a developmental disorder as a chief complaint. 38%of patients had a history of developmental delay or regression and 22% had seizures. The patients with Sandhoff and Tay Sachs disease were followed for approximately 5 years and the follow-up showed all patients were bedridden or had expired due to refractory seizures, pneumonia aspiration, or swallowing disorders. Neuro-imaging findings included bilateral thalamic involvement, brain atrophy, and hypo myelination in near half of our patients (48%). According to the results of this study, we suggest that cherry-red spots, hyperacusis, refractory seizures, and relative parents in children with developmental delay and/or regression should be considered for assessment of GM2-Gangliosidosis disease.

Splice junction mutation in some Ashkenazi Jews with Tay-Sachs disease: Evidence against a single defect within this ethnic group

International Nuclear Information System (INIS)

Myerowitz, R.

1988-01-01

Tay-Sachs disease is an inherited disorder in which the α chain of the lysosomal enzyme β-N-acetylhexosaminidase A bears the mutation. Ashkenazi Jews are found to be carriers for a severe type of Tay-Sachs disease, the classic form, 10 times more frequently than the general population. Ashkenazi Jewish patients with classic Tay-Sachs disease have appeared to be clinically and biochemically identical, and the usual assumption has been that they harbor the same α-chain mutation. The author has isolated the α-chain gene from an Ashkenazi Jewish patient, GM2968, with classic Tay-Sachs disease and compared its nucleotide sequences with that of the normal α-chain gene in the promoter region, exon and splice junction regions, and polyadenylylation signal area. Only one difference was observed between these sequences. The alteration is presumed to be functionally significant and to result in aberrant mRNA splicing. Utilizing the polymerase chain reaction to amplify the region encompassing the mutation, the author developed an assay to screen patients and heterozygote carriers for this mutation. Surprisingly, in each of two Ashkenazi patients, only one α-chain allele harbored the splice junction mutation. Only one parent of each of these patients was positive for the defect. Another Ashkenazi patient did not bear this mutation at all nor did either of the subject's parents. The data are consistent with the presence of more than one mutation underlying the classic form of Tay-Sachs disease in the Ashkenazi Jewish population

Mechanism of interrupted saccades in patients with late-onset Tay-Sachs disease.

Science.gov (United States)

Optican, Lance M; Rucker, Janet C; Keller, Edward L; Leigh, R John

2008-01-01

In late-onset Tay-Sachs disease (LOTS), saccades are interrupted by one or more transient decelerations. Some saccades reaccelerate and continue on before eye velocity reaches zero, even in darkness. Intervals between successive decelerations are not regularly spaced. Peak decelerations of horizontal and vertical components of oblique saccades in LOTS is more synchronous than those in control subjects. We hypothesize that these decelerations are caused by dysregulation of the fastigial nuclei (FN) of the cerebellum, which fire brain stem inhibitory burst neurons (IBNs).

Targeted disruption of the Hexa gene results in mice with biochemical and pathologic features of Tay-Sachs disease

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Proia, R.L.; Yamanaka, S.; Johnson, M.D. [and others

1994-09-01

Tay-Sachs disease, the prototype of the G{sub M2} gangliosidoses, is a catastrophic neurodegenerative disorder of infancy. The disease is caused by mutations in the HEXA gene resulting in an absence of the lysosomal enzyme, {beta}-hexosaminidase A. As consequence of the enzyme deficiency, G{sub M2} ganglioside accumulates progressively, beginning early in fetal life, to excessive amounts in the central nervous system (CNS). Rapid mental and motor deterioration starting in the first year of life leads to death by 2 to 4 years of age. Through the targeted disruption of the Hexa gene in embryonic stem cells, we have produced mice with biochemical and neuropathologic features of Tay-Sachs disease. The mutant mice exhibited less than 1% of normal {beta}-hexosaminidase A activity and accumulated G{sub M2} ganglioside in their CNS in an age-dependent manner. The accumulated ganglioside was stored in neurons as membranous cytoplasmic bodies characteristically found in the neurons of Tay-Sachs disease patients. At three to five months of age the mutant mice showed no apparent defects in motor or memory function. These {beta}-hexosaminidase A deficient mice should be useful for devising strategies to introduce functional enzymes and genes into the CNS. This model may also be valuable for studying the biochemical and pathologic changes occurring during the course of the disease.

Molecular characterization of a novel HEXA mutation at the +3 position of intron 8 in a Tay-Sachs disease patient

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Richard, M.; Triggs-Raine, B. [Univ. of Manitoba, Winnipeg (Canada); Natowicz, M. [E.K. Shriver Center, Waltham, MA (United States)

1994-09-01

Tay-Sachs disease is an autosomal recessive lysosomal storage disorder resulting from mutations in the HEXA gene that cause a deficiency in the activity of that enzyme {beta}-hexosaminidase A (Hex A). This deficiency leads to the build-up of G{sub M2} ganglioside, resulting in neurodegeneration and death. Biochemical analysis of a non-Jewish patient with a late-infantile form of Tay-Sachs disease revealed a substantial level of Hex A activity (38.4%) when 4-MUG was used as the substrate. However, when a substrate (4-MUGS) specific for the {alpha}-subunit of Hex A ({alpha}{beta}) was used, almost no activity was detected in the HEXA gene of the patient using SSCP analysis followed by sequencing. The first mutation, a G533A substitution in exon 5, is previously described and associated with the B1 form of Tay-Sachs disease. The second mutation is a novel a-to-g base change at the +3 position of intron 8. This was confirmed using the AIRS method, whereby a MaeIII site was created in the presence of the mutation. Normal and patient mRNA was reverse transcribed and exons 7 to 9 were PCR-amplified from the cDNA. An abnormally sized amplification product detected only in the patient cDNA was sequenced; exon 8 had been deleted and exons 7 and 9 were spliced together. A substantial level of normally-sized PCR product was also detected in the patient`s cDNA. Experiments are in progress to determine if this is produced from the allele harboring the G533A mutation. Given that previous mutations of this type have been associated with 97-100% abnormal splicing, this mutation is likely to be the cause, together with the G533A mutation, of Tay-Sachs disease in this patient.

Tay-Sachs disease: current perspectives from Australia

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Lew RM

2015-01-01

Full Text Available Raelia M Lew,1,7 Leslie Burnett,2,3,4 Anné L Proos,2 Martin B Delatycki5,6 1Department of Obstetrics and Gynecology, QEII Research Institute for Mothers and Infants, The University of Sydney, Australia; 2NSW Health Pathology North, Royal North Shore Hospital, St Leonards, Australia; 3SEALS, Prince of Wales Hospital, Randwick, Australia; 4Sydney Medical School-Northern, Royal North Shore Hospital E25, University of Sydney, Sydney, Australia; 5Department of Clinical Genetics, Austin Health, Heidelberg, Australia; 6Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Australia; 7Department of Obstetrics and Gynaecology, Dentistry and Health Sciences, Faculty of Medicine, The University of Melbourne, Melbourne, Australia Abstract: Tay-Sachs disease (TSD is a fatal, recessively inherited neurodegenerative condition of infancy and early childhood. Although rare in most other populations, the carrier frequency is one in 25 in Ashkenazi Jews. Australian high-school-based TSD preconception genetic screening programs aim to screen, educate, and optimize reproductive choice for participants. These programs have demonstrated high uptake, low psychological morbidity, and have been shown to result in fewer than expected Jewish TSD-affected births over 18 years of operation. The majority of Jewish individuals of reproductive age outside of the high school screening program setting in Australia have not accessed screening. Recent recommendations advocate supplementing the community high school screening programs with general practitioner- and obstetrician-led genetic screening of Ashkenazi Jewish individuals for TSD and other severe recessive diseases for which this group is at risk. Massively parallel DNA sequencing is expected to become the testing modality of choice over the coming years. Keywords: Tay-Sachs disease, genetic screening, Australia

Role of the physician in screening for carriers of Tay-Sachs disease.

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Lowden, J. A.

1978-01-01

A screening test for carriers of Tay-Sachs disease has been available in Toronto for more than 6 years. In that time more than 11 000 Jewish residents have been tested. Most had requested testing after hearing about the screening program from friends or the media; few had been advised by their physicians to be tested. To sample the attitudes of physicians in Toronto towards carrier screening, we studied questionnaire responses of 42 physicians whose practices were composed largely of Jewish patients. Only 31% regularly advised their young adult Jewish patients to have a carrier screening test but 76% said they had patients who asked if they should be tested. Of the 14 (33%) who had had one or more patients with Tay-Sachs disease 6 did not advise carrier testing. There was a positive correlation between specialty training and support for the screening program. Methods for increasing physician advocacy of these programs are discussed. PMID:709448

Splice junction mutation in some Ashkenazi Jews with Tay-Sachs disease: Evidence against a single defect within this ethnic group

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Myerowitz, R. (National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, MD (USA))

1988-06-01

Tay-Sachs disease is an inherited disorder in which the {alpha} chain of the lysosomal enzyme {beta}-N-acetylhexosaminidase A bears the mutation. Ashkenazi Jews are found to be carriers for a severe type of Tay-Sachs disease, the classic form, 10 times more frequently than the general population. Ashkenazi Jewish patients with classic Tay-Sachs disease have appeared to be clinically and biochemically identical, and the usual assumption has been that they harbor the same {alpha}-chain mutation. The author has isolated the {alpha}-chain gene from an Ashkenazi Jewish patient, GM2968, with classic Tay-Sachs disease and compared its nucleotide sequences with that of the normal {alpha}-chain gene in the promoter region, exon and splice junction regions, and polyadenylylation signal area. Only one difference was observed between these sequences. The alteration is presumed to be functionally significant and to result in aberrant mRNA splicing. Utilizing the polymerase chain reaction to amplify the region encompassing the mutation, the author developed an assay to screen patients and heterozygote carriers for this mutation. Surprisingly, in each of two Ashkenazi patients, only one {alpha}-chain allele harbored the splice junction mutation. Only one parent of each of these patients was positive for the defect. Another Ashkenazi patient did not bear this mutation at all nor did either of the subject's parents. The data are consistent with the presence of more than one mutation underlying the classic form of Tay-Sachs disease in the Ashkenazi Jewish population.

Late-onset Tay-Sachs disease: adverse effects of medications and implications for treatment.

Science.gov (United States)

Shapiro, B E; Hatters-Friedman, S; Fernandes-Filho, J A; Anthony, K; Natowicz, M R

2006-09-12

The authors conducted a retrospective and brief prospective study of adverse effects of approximately 350 medications in 44 adults with late-onset Tay-Sachs disease (LOTS). Some medications were relatively safe, whereas others, particularly haloperidol, risperidone, and chlorpromazine, were associated with neurologic worsening.

Haematopoietic Stem Cell Transplantation Arrests the Progression of Neurodegenerative Disease in Late-Onset Tay-Sachs Disease.

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Stepien, Karolina M; Lum, Su Han; Wraith, J Edmond; Hendriksz, Christian J; Church, Heather J; Priestman, David; Platt, Frances M; Jones, Simon; Jovanovic, Ana; Wynn, Robert

2017-12-07

Tay-Sachs disease is a rare metabolic disease caused by a deficiency of hexosaminidase A that leads to accumulation of GM2 gangliosides predominantly in neural tissue. Late-onset Tay-Sachs disease variant is associated with a higher level of residual HexA activity. Treatment options are limited, and there are a few described cases who have undergone haematopoietic stem cell transplantation (HSCT) with variable outcome.We describe a case of a 23-year-old male patient who presented with a long-standing tremor since 7 years of age. He had gait ataxia, a speech stammer and swallowing problems. His condition had had a static course apart from his tremor that had been gradually deteriorating. Because of the deterioration in his neurological function, the patient had an uneventful, matched-sibling donor bone marrow transplant at the age of 15 years. Eight years post-HSCT, at the age of 23, he retains full donor engraftment, and his white cell beta-HexA of 191 nmol/mg/h is comparable to normal controls (in-assay control = 187). He continues to experience some intentional tremor that is tolerable for daily life and nonprogressive since HSCT. HSCT is a potential treatment option which might arrest neurodegeneration in patients with LOTS.

Late-onset Tay-Sachs disease.

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Barritt, Andrew W; Anderson, Stuart J; Leigh, P Nigel; Ridha, Basil H

2017-10-01

We discuss the assessment and differential diagnoses of a young adult Hungarian man with a 1-year history of a progressive and symmetric amyotrophic lateral sclerosis-like syndrome, along with irregular action tremor and stimulus-sensitive myoclonus of the arms. MR scan of the brain showed isolated cerebellar atrophy and formal neuropsychometric testing identified significant subclinical deficits in attention, processing speed and memory. We suspected a form of GM 2 gangliosidosis, and white cell enzyme analysis showed markedly reduced enzymatic activity of β-hexosaminidase A. Genetic testing subsequently revealed two heterozygous pathogenic mutations in the HEXA gene (c.1499delT p.(Leu500fs) and c.805G>A p.(Gly269Ser)), confirming the very rare diagnosis of adult-onset Tay-Sachs disease. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Late onset Tay-Sachs disease in mice with targeted disruption of the Hexa gene: behavioral changes and pathology of the central nervous system.

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Miklyaeva, Elena I; Dong, Weijia; Bureau, Alexandre; Fattahie, Roya; Xu, Yongqin; Su, Meng; Fick, Gordon H; Huang, Jing-Qi; Igdoura, Suleiman; Hanai, Nobuo; Gravel, Roy A

2004-03-19

Tay-Sachs disease is an autosomal recessive neurodegenerative disease resulting from a block in the hydrolysis of GM2 ganglioside, an intermediate in ganglioside catabolism. The mouse model of Tay-Sachs disease (Hexa -/-) has been described as behaviorally indistinguishable from wild type until at least 1 year of age due to a sialidase-mediated bypass of the metabolic defect that reduces the rate of GM2 ganglioside accumulation. In this study, we have followed our mouse model to over 2 years of age and have documented a significant disease phenotype that is reminiscent of the late onset, chronic form of human Tay-Sachs disease. Onset occurs at 11-12 months of age and progresses slowly, in parallel with increasing storage of GM2 ganglioside. The disease is characterized by hind limb spasticity, weight loss, tremors, abnormal posture with lordosis, possible visual impairment, and, late in the disease, muscle weakness, clasping of the limbs, and myoclonic twitches of the head. Immunodetection of GM2 ganglioside showed that storage varies widely in different regions, but is most intense in pyriform cortex, hippocampus (CA3 field, subiculum), amygdala, hypothalamus (paraventricular supraoptic, ventromedial and arcuate nuclei, and mammilary body), and the somatosensory cortex (layer V) in 1- to 2-year-old mutant mice. We suggest that the Tay-Sachs mouse model is a phenotypically valid model of disease and may provide for a reliable indicator of the impact of therapeutic strategies, in particular geared to the late onset, chronic form of human Tay-Sachs disease.

Substrate reduction therapy in the infantile form of Tay-Sachs disease.

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Bembi, B; Marchetti, F; Guerci, V I; Ciana, G; Addobbati, R; Grasso, D; Barone, R; Cariati, R; Fernandez-Guillen, L; Butters, T; Pittis, M G

2006-01-24

Substrate reduction therapy (SRT) with miglustat has been proposed for treatment of some lysosomal storage disorders. Based on the positive experience in Gaucher disease and experimental data in Tay-Sachs (TSD) and Sandhoff animal models, the authors investigated the clinical efficacy of SRT in two patients with infantile TSD. SRT could not arrest the patients' neurologic deterioration. However, a significant drug concentration in CSF as well as macrocephaly prevention were observed.

Three novel mutations in Iranian patients with Tay-Sachs disease.

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Jamali, Solmaz; Eskandari, Nasim; Aryani, Omid; Salehpour, Shadab; Zaman, Talieh; Kamalidehghan, Behnam; Houshmand, Massoud

2014-01-01

Tay-Sachs disease (TSD), or GM2 gangliosidosis, is a lethal autosomal recessive neurodegenerative disorder, which is caused by a deficiency of beta-hexosaminidase A (HEXA), resulting in lysosomal accumulation of GM2 ganglioside. The aim of this study was to identify the TSD-causing mutations in an Iranian population. In this study, we examined 31 patients for TSD-causing mutations using PCR, followed by restriction enzyme digestion. Molecular genetics analysis of DNA from 23 patients of TSD revealed mutations that has been previously reported, including four-base duplications c.1274_1277dupTATC in exon 11 and IVS2+1G>A, deletion TTAGGCAAGGGC in exon 10 as well as a few novel mutations, including C331G, which altered Gln>Glu in HEXB, A>G, T>C, and p.R510X in exon 14, which predicted a termination codon or nonsense mutation. In conclusion, with the discovery of these novel mutations, the genotypic spectrum of Iranian patients with TSD disease has been extended and could facilitate definition of disease-related mutations.

Unilaterally and rapidly progressing white matter lesion and elevated cytokines in a patient with Tay-Sachs disease.

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Hayase, Tomomi; Shimizu, Jun; Goto, Tamako; Nozaki, Yasuyuki; Mori, Masato; Takahashi, Naoto; Namba, Eiji; Yamagata, Takanori; Momoi, Mariko Y

2010-03-01

We report the case of a girl with Tay-Sachs disease who had convulsions and deteriorated rapidly after an upper respiratory infection at the age of 11 months. At the age of 16 months, her seizures became intractable and magnetic resonance imaging of the brain showed high signal intensity on T2-weighted images and marked swelling in the white matter and basal nucelei of the right hemisphere. Her seizures and right hemisphere lesion improved with glycerol and dexamethasone treatment. When dexamethasone was discontinued, her symptoms worsened and lesions later appeared in the left hemisphere. Her cerebrospinal fluid showed elevated levels of the cytokines TNF-alpha and IL-5. It is considered that inflammation contributes to disease progression in Tay-Sachs disease.

Neuro-ophthalmology of late-onset Tay-Sachs disease (LOTS).

Science.gov (United States)

Rucker, J C; Shapiro, B E; Han, Y H; Kumar, A N; Garbutt, S; Keller, E L; Leigh, R J

2004-11-23

Late-onset Tay-Sachs disease (LOTS) is an adult-onset, autosomal recessive, progressive variant of GM2 gangliosidosis, characterized by involvement of the cerebellum and anterior horn cells. To determine the range of visual and ocular motor abnormalities in LOTS, as a prelude to evaluating the effectiveness of novel therapies. Fourteen patients with biochemically confirmed LOTS (8 men; age range 24 to 53 years; disease duration 5 to 30 years) and 10 age-matched control subjects were studied. Snellen visual acuity, contrast sensitivity, color vision, stereopsis, and visual fields were measured, and optic fundi were photographed. Horizontal and vertical eye movements (search coil) were recorded, and saccades, pursuit, vestibulo-ocular reflex (VOR), vergence, and optokinetic (OK) responses were measured. All patients showed normal visual functions and optic fundi. The main eye movement abnormality concerned saccades, which were "multistep," consisting of a series of small saccades and larger movements that showed transient decelerations. Larger saccades ended earlier and more abruptly (greater peak deceleration) in LOTS patients than in control subjects; these changes can be attributed to premature termination of the saccadic pulse. Smooth-pursuit and slow-phase OK gains were reduced, but VOR, vergence, and gaze holding were normal. Patients with late-onset Tay-Sachs disease (LOTS) show characteristic abnormalities of saccades but normal afferent visual systems. Hypometria, transient decelerations, and premature termination of saccades suggest disruption of a "latch circuit" that normally inhibits pontine omnipause neurons, permitting burst neurons to discharge until the eye movement is completed. These measurable abnormalities of saccades provide a means to evaluate the effects of novel treatments for LOTS.

Enfermedad de Tay-Sachs

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Albia Josefina Pozo Alonso

Full Text Available La enfermedad de Tay-Sachs es un trastorno neurodegenerativo progresivo de herencia autosómica recesiva. Se debe a la deficiencia de la enzima β-hexosaminidasa A, que provoca una acumulación de gangliósidos GM2 en los lisosomas. Se incluye dentro de las esfingolipidosis. De las esfingolipidosis que presentan mancha rojo cereza en la mácula, la enfermedad de Tay-Sachs es la única en la que no se evidencia hepatoesplenomegalia. La variante más frecuente se inicia en la lactancia. Se presenta un lactante del sexo masculino al que se le realizó el diagnóstico de esta entidad a los 8 meses de edad. A partir de los 4 meses comenzó a presentar una reacción de sobresalto. A los 6 meses comenzó a perder habilidades previamente adquiridas y crisis epilépticas mioclónicas. Se constató una disminución de la actividad específica de la enzima hexosaminidasa A en leucocitos.

Identification of two HEXA mutations causing infantile-onset Tay-Sachs disease in the Persian population.

Science.gov (United States)

Haghighi, Alireza; Rezazadeh, Jamileh; Shadmehri, Azam Ahmadi; Haghighi, Amirreza; Kornreich, Ruth; Desnick, Robert J

2011-09-01

The β-hexosaminidase A (HEXA) mutations in the first reported cases of infantile Tay-Sachs disease in the Persian population were identified in two unrelated consanguineous families. The clinical diagnoses of the affected infants were confirmed by their markedly deficient levels of HEXA activity in plasma or peripheral leukocytes. The specific causative mutation in each family was determined by sequencing the HEXA alleles in both sets of related parents. Two mutations were identified: c.1A>G (p.MIV), which obliterated the initiating methionine in codon 1, and c.1177C>T (p.R393X), which predicted a termination codon or nonsense mutation.

Tay-Sachs disease: current perspectives from Australia.

Science.gov (United States)

Lew, Raelia M; Burnett, Leslie; Proos, Anné L; Delatycki, Martin B

2015-01-01

Tay-Sachs disease (TSD) is a fatal, recessively inherited neurodegenerative condition of infancy and early childhood. Although rare in most other populations, the carrier frequency is one in 25 in Ashkenazi Jews. Australian high-school-based TSD preconception genetic screening programs aim to screen, educate, and optimize reproductive choice for participants. These programs have demonstrated high uptake, low psychological morbidity, and have been shown to result in fewer than expected Jewish TSD-affected births over 18 years of operation. The majority of Jewish individuals of reproductive age outside of the high school screening program setting in Australia have not accessed screening. Recent recommendations advocate supplementing the community high school screening programs with general practitioner- and obstetrician-led genetic screening of Ashkenazi Jewish individuals for TSD and other severe recessive diseases for which this group is at risk. Massively parallel DNA sequencing is expected to become the testing modality of choice over the coming years.

Rapid identification of HEXA mutations in Tay-Sachs patients.

Science.gov (United States)

Giraud, Carole; Dussau, Jeanne; Azouguene, Emilie; Feillet, François; Puech, Jean-Philippe; Caillaud, Catherine

2010-02-19

Tay-Sachs disease (TSD) is a recessively inherited neurodegenerative disorder due to mutations in the HEXA gene resulting in a beta-hexosaminidase A (Hex A) deficiency. The purpose of this study was to characterize the molecular abnormalities in patients with infantile or later-onset forms of the disease. The complete sequencing of the 14 exons and flanking regions of the HEXA gene was performed with a unique technical condition in 10 unrelated TSD patients. Eleven mutations were identified, including five splice mutations, one insertion, two deletions and three single-base substitutions. Four mutations were novel: two splice mutations (IVS8+5G>A, IVS2+4delAGTA), one missense mutation in exon 6 (c.621T>G (p.D207E)) and one small deletion (c.1211-1212delTG) in exon 11 resulting in a premature stop codon at residue 429. The c.621T>G missense mutation was found in a patient presenting an infantile form. Its putative role in the pathogenesis of TSD is suspected as residue 207 is highly conserved in human, mouse and rat. Moreover, structural modelling predicted changes likely to affect substrate binding and catalytic activity of the enzyme. The time-saving procedure reported here could be useful for the characterization of Tay-Sachs-causing mutations, in particular in non-Ashkenazi patients mainly exhibiting rare mutations. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Tay-Sachs disease in Jacob sheep.

Science.gov (United States)

Torres, Paola A; Zeng, Bai Jin; Porter, Brian F; Alroy, Joseph; Horak, Fred; Horak, Joan; Kolodny, Edwin H

2010-12-01

Autopsy studies of four Jacob sheep dying within their first 6-8 months of a progressive neurodegenerative disorder suggested the presence of a neuronal storage disease. Lysosomal enzyme studies of brain and liver from an affected animal revealed diminished activity of hexosaminidase A (Hex A) measured with an artificial substrate specific for this component of β-hexosaminidase. Absence of Hex A activity was confirmed by cellulose acetate electrophoresis. Brain lipid analyses demonstrated the presence of increased concentrations of G(M2)-ganglioside and asialo-G(M2)-ganglioside. The hexa cDNA of Jacob sheep was cloned and sequenced revealing an identical number of nucleotides and exons as in human HexA and 86% homology in nucleotide sequence. A missense mutation was found in the hexa cDNA of the affected sheep caused by a single nucleotide change at the end of exon 11 resulting in skipping of exon 11. Transfection of normal sheep hexa cDNA into COS1 cells and human Hex A-deficient cells led to expression of Hex S but no increase in Hex A indicating absence of cross-species dimerization of sheep Hex α-subunit with human Hex β-subunits. Using restriction site analysis, the heterozygote frequency of this mutation in Jacob sheep was determined in three geographically separate flocks to average 14%. This large naturally occurring animal model of Tay-Sachs disease is the first to offer promise as a means for trials of gene therapy applicable to human infants. Copyright © 2010 Elsevier Inc. All rights reserved.

Tay-Sachs disease: high gene frequency in a non-Jewish population.

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Kelly, T E; Chase, G A; Kaback, M M; Kumor, K; McKusick, V A

1975-01-01

A non-Amish "Pennsylvania Dutch" semi-isolate was found to have a high frequency of Tay-Sachs gene. This high frequency could be ascribed to founder effect and may represent, in microcosm, how this mechanism could have produced the high gene frequency among Ashkenazi Jews. PMID:803011

Doença de Tay-Sachs em criança de raça negra Tay-Sachs disease in a Negro child

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Sérgio Rosemberg

1970-12-01

Full Text Available É relatado um caso de doença de Tay-Sachs em criança da raça negra. O encontro desta entidade em indivíduos não judeus é bastante raro, sendo este o quinto caso descrito em criança negra. Os autores estudam alguns aspectos genéticos, chegando à conclusão de que o cálculo da freqüência do gene mutante é impossível devido ao pequeno número de casos e ao fato de que não há estimativas seguras quanto à taxa de nascimento de indivíduos negros na população, Em que pese o fato de o diagnóstico se assentar em bases puramente clínicas e anatômicas, prescindindo os autores de exames bioquímicos específicos, os dados apresentados são congruentes com os casos clássicos descritos na literatura.A case of Tay-Sachs diseases in a Negro child is reported. The occurrence of this disease in non-Jewish individuals is very rare and this is the fifth case of a Negro-child reported in the litterature. Some genetical aspects are studied and the authors conclude that the frequency calculation of the mutant gene is impossible due to the small number of cases and to the fact that there is reliable information regarding the rate of birth of Negro individuals in the general population. The diagnosis was based on ophtalmological and clinical data. No specific biochemical tests were performed but the data obtained are congruent with other cases reported in the litterature.

Crystal Structure of Human [Beta]-Hexosaminidase B: Understanding the Molecular Basis of Sandhoff and Tay-Sachs Disease

Energy Technology Data Exchange (ETDEWEB)

Mark, Brian L.; Mahuran, Don J.; Cherney, Maia M.; Zhao, Dalian; Knapp, Spencer; James, Michael N.G.

2010-12-01

In humans, two major {beta}-hexosaminidase isoenzymes exist: Hex A and Hex B. Hex A is a heterodimer of subunits {alpha} and {beta} (60% identity), whereas Hex B is a homodimer of {beta}-subunits. Interest in human {beta}-hexosaminidase stems from its association with Tay-Sachs and Sandhoff disease; these are prototypical lysosomal storage disorders resulting from the abnormal accumulation of G{sub M2}-ganglioside (G{sub M2}). Hex A degrades G{sub M2} by removing a terminal N-acetyl-D-galactosamine ({beta}-GalNAc) residue, and this activity requires the G{sub M2}-activator, a protein which solubilizes the ganglioside for presentation to Hex A. We present here the crystal structure of human Hex B, alone (2.4 {angstrom}) and in complex with the mechanistic inhibitors GalNAc-isofagomine (2.2 {angstrom}) or NAG-thiazoline (2.5 {angstrom}). From these, and the known X-ray structure of the G{sub M2}-activator, we have modeled Hex A in complex with the activator and ganglioside. Together, our crystallographic and modeling data demonstrate how {alpha} and {beta}-subunits dimerize to form either Hex A or Hex B, how these isoenzymes hydrolyze diverse substrates, and how many documented point mutations cause Sandhoff disease ({beta}-subunit mutations) and Tay-Sachs disease ({alpha}-subunit mutations).

Tay-Sachs disease: progression of changes on neuroimaging in four cases

International Nuclear Information System (INIS)

Fukumizu, M.; Yoshikawa, H.; Kurokawa, T.; Takashima, S.; Sakuragawa, N.

1992-01-01

The neuroradiological findings in four patients with Tay-Sachs disease are described in three phases of the clinical course. The basal ganglia and cerebral white matter show low density on computed tomography and high signal intensity on T2-weighted magnetic resonance imaging in the initial phase. The caudate nuclei are characteristically enlarged and protrude into the lateral ventricles in the first and second phases. The cerebral white matter shows low density on the CT which varies in extent from the second to third phases, and the whole brain becomes atrophic in the last phase. Thus, central nervous system involvement in the disease may begin in basal ganglia as well as in cerebral white matter. (orig.)

Tay-Sachs disease: progression of changes on neuroimaging in four cases

Energy Technology Data Exchange (ETDEWEB)

Fukumizu, M; Yoshikawa, H; Kurokawa, T [National Center Hospital for Mental, Nervous, and Muscular Disorders, Tokyo (Japan). Div. of Child Neurology; Takashima, S [National Inst. of Neuroscience, National Center of Neurology and Psychiatry, Tokyo (Japan). Div. of Mental Retardation and Birth Defect Research; Sakuragawa, N [National Inst. of Neuroscience, National Center of Neurology and Psychiatry, Tokyo (Japan). Div. of Inherited Metabolic Disease

1992-11-01

The neuroradiological findings in four patients with Tay-Sachs disease are described in three phases of the clinical course. The basal ganglia and cerebral white matter show low density on computed tomography and high signal intensity on T2-weighted magnetic resonance imaging in the initial phase. The caudate nuclei are characteristically enlarged and protrude into the lateral ventricles in the first and second phases. The cerebral white matter shows low density on the CT which varies in extent from the second to third phases, and the whole brain becomes atrophic in the last phase. Thus, central nervous system involvement in the disease may begin in basal ganglia as well as in cerebral white matter. (orig.).

Late-onset Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients.

Science.gov (United States)

Neudorfer, Orit; Pastores, Gregory M; Zeng, Bai J; Gianutsos, John; Zaroff, Charles M; Kolodny, Edwin H

2005-02-01

The purpose of this study was to describe the phenotype (and corresponding genotype) of adult patients with late-onset Tay-Sachs disease, a clinical variant of the GM2-gangliosidoses. A comprehensive physical examination, including neurological assessments, was performed to establish the current disease pattern and severity. In addition, the patients' past medical histories were reviewed. The patients' alpha-subunit mutations (beta-Hexosaminidase A genotype) were determined and correlated with their corresponding clinical findings and disease course. Twenty-one patients (current mean age: 27.0 years; range: 14-47 years) were identified. The pedigree revealed a relative with the "classic" infantile or late-onset form of Tay-Sachs disease in four (out of 18) unrelated families. The patients were predominantly male (15/21 individuals) and of Ashkenazi Jewish ancestry (15/18 families). Mean age at onset was 18.1 years; balance problems and difficulty climbing stairs were the most frequent presenting complaints. In several cases, the diagnosis was delayed (mean age at diagnosis: 27.0 years). Analysis of the beta-hex A gene revealed the G269S mutation as the most common disease allele; found in homozygosity (N = 1) or heterozygosity (N = 18; including 2 sib pairs). Disease onset (age 36 years) was delayed and progression relatively slower in the homozygous G269S patient. Two siblings (ages 28 and 31 years), of non-Jewish ancestry, were compound heterozygotes (TATC1278/W474C); their clinical course is dominated by psychiatric problems. Brain imaging studies revealed marked cerebellar atrophy in all patients (N = 18) tested, regardless of disease stage. Late-onset Tay-Sachs disease is an infrequent disorder and the diagnosis is often missed or delayed (by approximately 8 years). Early on, the majority of patients develop signs of either cerebellar or anterior motor neuron involvement. Affected individuals may also develop psychotic episodes. In most cases, the later

Serial MR imaging and 1H-MR spectroscopy in monozygotic twins with Tay-Sachs disease.

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Imamura, A; Miyajima, H; Ito, R; Orii, K O

2008-10-01

Four-year-old monozygotic female twins with early onset Tay-Sachs disease are described. The sisters showed similar slowly progressive clinical symptoms and deterioration, however the younger sister also demonstrated intractable myoclonus in the right leg. The serial MR images and (1)H-MR spectroscopy of the brain were obtained in both twins. MR images showed high intensity on T (2)-weighted image in the bilateral white matter, however there were no signal changes in the basal ganglia and thalamus during any of the phases. The ratio of N-acetylaspartate (NAA)/creatine (Cr) was decreased in the both white matter lesions and the corpus striatum, and that of myoinositol (mI)/Cr was increased in the damaged white matter on MR spectroscopy. The elevation of the lactate peak was clearly demonstrated in the left basal ganglia of the younger sister; however it was not shown in cerebral lesions of the elder sister. Changes in metabolites on MR spectroscopy were closely linked to the respective clinical features of each twin. Follow-up examination by (1)H-MR spectroscopy is useful for the evaluation of neuronal changes in children with Tay-Sachs disease.

İki Kardeşte Görülen Tay-Sachs Hastalığı

OpenAIRE

KÜÇÜKÖDÜK, Ş.

2010-01-01

In view of two cases of autosomal recessive Tay-Sachs disease which affected two siblings, genetic consultation has been once more emphasized. The clinical features of this entity has been reviewed under the information obtained from recent literature. Otozomal resesif geçiş gösteren ve iki kardeşide etkiliyen Tay-Sachs hastalığında, genetik danışmanın önemi bir kez daha vurgulandı. Bu hastalığın klinik özellikleri literatür bilgilerinin ışığı altında gözden geçirildi....

Multimedia messages in genetics: design, development, and evaluation of a computer-based instructional resource for secondary school students in a Tay Sachs disease carrier screening program.

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Gason, Alexandra A; Aitken, MaryAnne; Delatycki, Martin B; Sheffield, Edith; Metcalfe, Sylvia A

2004-01-01

Tay Sachs disease is a recessively inherited neurodegenerative disorder, for which carrier screening programs exist worldwide. Education for those offered a screening test is essential in facilitating informed decision-making. In Melbourne, Australia, we have designed, developed, and evaluated a computer-based instructional resource for use in the Tay Sachs disease carrier screening program for secondary school students attending Jewish schools. The resource entitled "Genetics in the Community: Tay Sachs disease" was designed on a platform of educational learning theory. The development of the resource included formative evaluation using qualitative data analysis supported by descriptive quantitative data. The final resource was evaluated within the screening program and compared with the standard oral presentation using a questionnaire. Knowledge outcomes were measured both before and after either of the educational formats. Data from the formative evaluation were used to refine the content and functionality of the final resource. The questionnaire evaluation of 302 students over two years showed the multimedia resource to be equally effective as an oral educational presentation in facilitating participants' knowledge construction. The resource offers a large number of potential benefits, which are not limited to the Tay Sachs disease carrier screening program setting, such as delivery of a consistent educational message, short delivery time, and minimum financial and resource commitment. This article outlines the value of considering educational theory and describes the process of multimedia development providing a framework that may be of value when designing genetics multimedia resources in general.

Late-onset Tay-Sachs disease: the spectrum of peripheral neuropathy in 30 affected patients.

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Shapiro, Barbara E; Logigian, Eric L; Kolodny, Edwin H; Pastores, Gregory M

2008-08-01

Late-onset Tay-Sachs (LOTS) disease is a chronic, progressive, lysosomal storage disorder caused by a partial deficiency of beta-hexosaminidase A (HEXA) activity. Deficient levels of HEXA result in the intracellular accumulation of GM2-ganglioside, resulting in toxicity to nerve cells. Clinical manifestations primarily involve the central nervous system (CNS) and lower motor neurons, and include ataxia, weakness, spasticity, dysarthria, dysphagia, dystonia, seizures, psychosis, mania, depression, and cognitive decline. The prevalence of peripheral nervous system (PNS) involvement in LOTS has not been well documented, but it has traditionally been thought to be very low. We examined a cohort of 30 patients with LOTS who underwent clinical and electrophysiologic examination, and found evidence of a predominantly axon loss polyneuropathy affecting distal nerve segments in the lower and upper extremities in eight patients (27%).

The first family with Tay-Sachs disease in Cyprus: Genetic analysis reveals a nonsense (c.78G>A) and a silent (c.1305C>T) mutation and allows preimplantation genetic diagnosis.

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Georgiou, Theodoros; Christopoulos, George; Anastasiadou, Violetta; Hadjiloizou, Stavros; Cregeen, David; Jackson, Marie; Mavrikiou, Gavriella; Kleanthous, Marina; Drousiotou, Anthi

2014-12-01

Tay-Sachs disease (TSD) is a recessively inherited neurodegenerative disorder caused by mutations in the HEXA gene resulting in β-hexosaminidase A (HEX A) deficiency and neuronal accumulation of GM2 ganglioside. We describe the first patient with Tay-Sachs disease in the Cypriot population, a juvenile case which presented with developmental regression at the age of five. The diagnosis was confirmed by measurement of HEXA activity in plasma, peripheral leucocytes and fibroblasts. Sequencing the HEXA gene resulted in the identification of two previously described mutations: the nonsense mutation c.78G>A (p.Trp26X) and the silent mutation c.1305C>T (p.=). The silent mutation was reported once before in a juvenile TSD patient of West Indian origin with an unusually mild phenotype. The presence of this mutation in another juvenile TSD patient provides further evidence that it is a disease-causing mutation. Successful preimplantation genetic diagnosis (PGD) and prenatal follow-up were provided to the couple.

Pathological alterations typical of human Tay-Sachs disease, in the retina of a deep-sea fish

Science.gov (United States)

Fishelson, L.; Delarea, Yacov; Galil, Bella S.

Micrographs of retinas from the deep-sea fish Cataetyx laticeps revealed visual cells containing membranous whorls in the ellipsoids of the inner segments resulting from stretching and modifications of the mitochondria membranes and their cristae. These pathological structures seem to be homologous to the whorls observed in retinas of human carriers of Tay-Sachs disease. This disease, a genetic disorder, is found in humans and some mammals. Our findings in fish suggest that the gene responsible can be found throughout the vertebrate evolutionary tree, possibly dormant in most taxa.

Spontaneous appearance of Tay-Sachs disease in an animal model.

Science.gov (United States)

Zeng, B J; Torres, P A; Viner, T C; Wang, Z H; Raghavan, S S; Alroy, J; Pastores, G M; Kolodny, E H

2008-01-01

Tay-Sachs disease (TSD) is a progressive neurodegenerative disorder due to an autosomal recessively inherited deficiency of beta-hexosaminidase A (Hex A). Deficiency of Hex A in TSD is caused by a defect of the alpha-subunit resulting from mutations of the HEXA gene. To date, there is no effective treatment for TSD. Animal models of genetic diseases, similar to those known to exist in humans, are valuable and essential research tools for the study of potentially effective therapies. However, there is no ideal animal model of TSD available for use in therapeutic trials. In the present study, we report an animal model (American flamingo; Phoenicopterus ruber) of TSD with Hex A deficiency occurring spontaneously in nature, with accumulation of G(M2)-ganglioside, deficiency of Hex A enzymatic activity, and a homozygous P469L mutation in exon 12 of the hexa gene. In addition, we have isolated the full-length cDNA sequence of the flamingo, which consists of 1581 nucleotides encoding a protein of 527 amino acids. Its coding sequence indicates approximately 71% identity at the nucleotide level and about 72.5% identity at the amino acid level with the encoding region of the human HEXA gene. This animal model, with many of the same features as TSD in humans, could represent a valuable resource for investigating therapy of TSD.

Simultaneous preimplantation genetic diagnosis for Tay-Sachs and Gaucher disease.

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Altarescu, Gheona; Brooks, Barry; Margalioth, Ehud; Eldar Geva, Talia; Levy-Lahad, Ephrat; Renbaum, Paul

2007-07-01

Preimplantation genetic diagnosis (PGD) for single gene defects is described for a family in which each parent is a carrier of both Tay-Sachs (TS) and Gaucher disease (GD). A multiplex fluorescent polymerase chain reaction protocol was developed that simultaneously amplified all four familial mutations and 10 informative microsatellite markers. In one PGD cycle, seven blastomeres were analysed, reaching a conclusive diagnosis in six out of seven embryos for TS and in five out of seven embryos for GD. Of the six diagnosed embryos, one was wild type for both TS and GD, and three were wild type for GD and carriers of TS. Two remaining embryos were compound heterozygotes for TS. Two transferable embryos developed into blastocysts (wt/wt and wt GD/carrier TS) and both were transferred on day 5. This single cycle of PGD resulted in a healthy live child. Allele drop-out (ADO) was observed in three of 34 reactions, yielding an 8% ADO rate. The occurrence of ADO in single cell analysis and undetected recombination events are primary causes of misdiagnosis in PGD and emphasize the need to use multiple polymorphic markers. So far as is known, this is the first report of concomitant PGD for two frequent Ashkenazi Jewish recessive disorders.

Generation of HEXA-deficient hiPSCs from fibroblasts of a Tay-Sachs disease patient

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Zhong Liu

2016-09-01

Full Text Available Human iPSC line TSD-01-hiPSC was generated from fibroblasts of a patient with infantile Tay-Sachs disease (TSD. The patient is compound heterozygous at the HEXA gene by carrying a 1278insTATC allele and an IVS12+1G>C allele. STEMCCA lentivirus, which expresses OCT4, SOX2, KLF4, and c-MYC from a polycistronic transcript, were used for reprogramming. TSD-01-hiPSC express pluripotency markers such as OCT4, SOX2, NANOG, Tra-1-60, and alkaline phosphatase, and can differentiate into tissues from all the three embryonic germ layers. This TSD patient-derived hiPSC line may serve as a valuable in vitro tool for disease modeling and drug test.

Generation of HEXA-deficient hiPSCs from fibroblasts of a Tay-Sachs disease patient.

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Liu, Zhong; Zhao, Rui

2016-09-01

Human iPSC line TSD-01-hiPSC was generated from fibroblasts of a patient with infantile Tay-Sachs disease (TSD). The patient is compound heterozygous at the HEXA gene by carrying a 1278insTATC allele and an IVS12+1G>C allele. STEMCCA lentivirus, which expresses OCT4, SOX2, KLF4, and c-MYC from a polycistronic transcript, were used for reprogramming. TSD-01-hiPSC express pluripotency markers such as OCT4, SOX2, NANOG, Tra-1-60, and alkaline phosphatase, and can differentiate into tissues from all the three embryonic germ layers. This TSD patient-derived hiPSC line may serve as a valuable in vitro tool for disease modeling and drug test. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.

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Mehul Mistri

Full Text Available Tay Sachs disease (TSD is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients. Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K, c.964 G>A (p.D322N, c.964 G>T (p.D322Y, c.1178C>G (p.R393P and c.1385A>T (p.E462V, c.1432 G>A (p.G478R and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W. The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.

Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.

Science.gov (United States)

Mistri, Mehul; Tamhankar, Parag M; Sheth, Frenny; Sanghavi, Daksha; Kondurkar, Pratima; Patil, Swapnil; Idicula-Thomas, Susan; Gupta, Sarita; Sheth, Jayesh

2012-01-01

Tay Sachs disease (TSD) is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients). Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K), c.964 G>A (p.D322N), c.964 G>T (p.D322Y), c.1178C>G (p.R393P) and c.1385A>T (p.E462V), c.1432 G>A (p.G478R) and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W). The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.

Miglustat in late-onset Tay-Sachs disease: a 12-month, randomized, controlled clinical study with 24 months of extended treatment.

Science.gov (United States)

Shapiro, Barbara E; Pastores, Gregory M; Gianutsos, John; Luzy, Cécile; Kolodny, Edwin H

2009-06-01

To evaluate the safety and efficacy of miglustat in patients with GM2 gangliosidosis. A randomized, multicenter, open-label, 12-month study involving patients aged 18 years or older, randomized 2:1 to miglustat (200 mg TID) or "no miglustat treatment." This study was followed by 24 months of extended treatment during which all patients received miglustat. Primary efficacy endpoints were change in eight measures of isometric muscle strength in the limbs and isometric grip strength, evaluated at baseline, and months 12 and 36. Secondary efficacy endpoints included gait, balance, disability, and other neurological assessments. Safety evaluations included adverse event reporting. Thirty patients (67% male, age range 18-56 years) with late-onset Tay-Sachs disease were enrolled; 20 were randomized to miglustat and 10 to "no miglustat treatment." Muscle and grip strength generally decreased over the study period. No differences were observed between the two groups in any efficacy measure, either during the 12-month randomized phase or the full 36 months. The most common treatment-related adverse events were decrease in weight and diarrhea. Miglustat treatment was not shown to lead to measurable benefits in this cohort of patients with late-onset Tay-Sachs disease. The observed safety profile was consistent with that of the approved dose (100 mg TID) in type 1 Gaucher disease.

Murine Sialidase Neu3 facilitates GM2 degradation and bypass in mouse model of Tay-Sachs disease.

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Seyrantepe, Volkan; Demir, Secil Akyildiz; Timur, Zehra Kevser; Von Gerichten, Johanna; Marsching, Christian; Erdemli, Esra; Oztas, Emin; Takahashi, Kohta; Yamaguchi, Kazunori; Ates, Nurselin; Dönmez Demir, Buket; Dalkara, Turgay; Erich, Katrin; Hopf, Carsten; Sandhoff, Roger; Miyagi, Taeko

2018-01-01

Tay-Sachs disease is a severe lysosomal storage disorder caused by mutations in Hexa, the gene that encodes for the α subunit of lysosomal β-hexosaminidase A (HEXA), which converts GM2 to GM3 ganglioside. Unexpectedly, Hexa -/- mice have a normal lifespan and show no obvious neurological impairment until at least one year of age. These mice catabolize stored GM2 ganglioside using sialidase(s) to remove sialic acid and form the glycolipid GA2, which is further processed by β-hexosaminidase B. Therefore, the presence of the sialidase (s) allows the consequences of the Hexa defect to be bypassed. To determine if the sialidase NEU3 contributes to GM2 ganglioside degradation, we generated a mouse model with combined deficiencies of HEXA and NEU3. The Hexa -/- Neu3 -/- mice were healthy at birth, but died at 1.5 to 4.5months of age. Thin-layer chromatography and mass spectrometric analysis of the brains of Hexa -/- Neu3 -/- mice revealed the abnormal accumulation of GM2 ganglioside. Histological and immunohistochemical analysis demonstrated cytoplasmic vacuolation in the neurons. Electron microscopic examination of the brain, kidneys and testes revealed pleomorphic inclusions of many small vesicles and complex lamellar structures. The Hexa -/- Neu3 -/- mice exhibited progressive neurodegeneration with neuronal loss, Purkinje cell depletion, and astrogliosis. Slow movement, ataxia, and tremors were the prominent neurological abnormalities observed in these mice. Furthermore, radiographs revealed abnormalities in the skeletal bones of the Hexa -/- Neu3 -/- mice. Thus, the Hexa -/- Neu3 -/- mice mimic the neuropathological and clinical abnormalities of the classical early-onset Tay-Sachs patients, and provide a suitable model for the future pre-clinical testing of potential treatments for this condition. Copyright © 2017 Elsevier Inc. All rights reserved.

Design, synthesis, and biological evaluation of enantiomeric beta-N-acetylhexosaminidase inhibitors LABNAc and DABNAc as potential agents against Tay-Sachs and Sandhoff disease.

Science.gov (United States)

Rountree, J S Shane; Butters, Terry D; Wormald, Mark R; Boomkamp, Stephanie D; Dwek, Raymond A; Asano, Naoki; Ikeda, Kyoko; Evinson, Emma L; Nash, Robert J; Fleet, George W J

2009-03-01

N-Acetylhexosaminidases are of considerable importance in mammals and are involved in various significant biological processes. In humans, deficiencies of these enzymes in the lysosome, resulting from inherited genetic defects, cause the glycolipid storage disorders Tay-Sachs and Sandhoff diseases. One promising therapy for these diseases involves the use of beta-N-acetylhexosaminidase inhibitors as chemical chaperones to enhance the enzyme activity above sub-critical levels. Herein we describe the synthesis and biological evaluation of a potent inhibitor, 2-acetamido-1,4-imino-1,2,4-trideoxy-L-arabinitol (LABNAc), in a high-yielding 11-step procedure from D-lyxonolactone. The N-benzyl and N-butyl analogues were also prepared and found to be potent inhibitors. The enantiomers DABNAc and NBn-DABNAc were synthesised from L-lyxonolactone, and were also evaluated. The L-iminosugar LABNAc and its derivatives were found to be potent noncompetitive inhibitors of some beta-N-acetylhexosaminidases, while the D-iminosugar DABNAc and its derivatives were found to be weaker competitive inhibitors. These results support previous work postulating that D-iminosugar mimics inhibit D-glycohydrolases competitively, and that their corresponding L-enantiomers show noncompetitive inhibition of these enzymes. Molecular modelling studies confirm that the spatial organisation in enantiomeric inhibitors leads to a different overlay with the monosaccharide substrate. Initial cell-based studies suggest that NBn-LABNAc can act as a chemical chaperone to enhance the deficient enzyme's activity to levels that may cause a positive pharmacological effect. LABNAc, NBn-LABNAc, and NBu-LABNAc are potent and selective inhibitors of beta-N-acetylhexosaminidase and may be useful as therapeutic agents for treating adult Tay-Sachs and Sandhoff diseases.

Regional neuro axonal injury detected by 1H 3 Tesla spectroscopic imaging in late onset Tay sachs

International Nuclear Information System (INIS)

Gagoski, Borjan Aleksandar; Eichler, Florian S.

2010-01-01

Late-onset Tay Sachs (LOTS) is a rare lysosomal storage disorder resulting from mutations of the subunit of the lysosomal enzyme β-hexosaminidase A, which catalyzes the degradation of GM2 ganglioside. We have applied the fast encoding spectroscopic imaging technique to LOTS patients to further investigate the neuro degenerative consequences of this disease.(Author)

Adeno-Associated Virus Gene Therapy in a Sheep Model of Tay-Sachs Disease.

Science.gov (United States)

Gray-Edwards, Heather L; Randle, Ashley N; Maitland, Stacy A; Benatti, Hector R; Hubbard, Spencer M; Canning, Peter F; Vogel, Matthew B; Brunson, Brandon L; Hwang, Misako; Ellis, Lauren E; Bradbury, Allison M; Gentry, Atoska S; Taylor, Amanda R; Wooldridge, Anne A; Wilhite, Dewey R; Winter, Randolph L; Whitlock, Brian K; Johnson, Jacob A; Holland, Merilee; Salibi, Nouha; Beyers, Ronald J; Sartin, James L; Denney, Thomas S; Cox, Nancy R; Sena-Esteves, Miguel; Martin, Douglas R

2018-03-01

Tay-Sachs disease (TSD) is a fatal neurodegenerative disorder caused by a deficiency of the enzyme hexosaminidase A (HexA). TSD also occurs in sheep, the only experimental model of TSD that has clinical signs of disease. The natural history of sheep TSD was characterized using serial neurological evaluations, 7 Tesla magnetic resonance imaging, echocardiograms, electrodiagnostics, and cerebrospinal fluid biomarkers. Intracranial gene therapy was also tested using AAVrh8 monocistronic vectors encoding the α-subunit of Hex (TSD α) or a mixture of two vectors encoding both the α and β subunits separately (TSD α + β) injected at high (1.3 × 10 13 vector genomes) or low (4.2 × 10 12 vector genomes) dose. Delay of symptom onset and/or reduction of acquired symptoms were noted in all adeno-associated virus-treated sheep. Postmortem evaluation showed superior HexA and vector genome distribution in the brain of TSD α + β sheep compared to TSD α sheep, but spinal cord distribution was low in all groups. Isozyme analysis showed superior HexA formation after treatment with both vectors (TSD α + β), and ganglioside clearance was most widespread in the TSD α + β high-dose sheep. Microglial activation and proliferation in TSD sheep-most prominent in the cerebrum-were attenuated after gene therapy. This report demonstrates therapeutic efficacy for TSD in the sheep brain, which is on the same order of magnitude as a child's brain.

The Val{sup 192}Leu mutation in the {alpha}-subunit of {beta}-hexosaminidase A is not associated with the B1-variant form of Tay-Sachs disease

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Hou, Y.; Vavougios, G.; Hinek, A. [Univ. of Toronto (Canada)] [and others

1996-07-01

Substitution mutations adversely affecting the {alpha}-subunit of {beta}-hexosaminidase A ({alpha}{beta}) (EC 3.2.1.52) result in Tay-Sachs disease. The majority affect the initial folding of the pro-{alpha} chain in the endoplasmic reticulum, resulting in its retention and degradation. A much less common occurrence is a mutation that specifically affects an {open_quotes}active-site{close_quotes} residue necessary for substrate binding and/or catalysis. In this case, hexosaminidase A is present in the lysosome, but it lacks all {alpha}-specific activity. This biochemical phenotype is referred to as the {open_quotes}B1-variant form{close_quotes} of Tay-Sachs disease. Kinetic analysis of suspected B1-variant mutations is complex because hexosaminidase A is heterodimeric and both subunits possess similar active sites. In this report, we examine a previously identified B1-variant mutation, {alpha}-Val{sup 192}Leu. Chinese hamster ovary cells were permanently cotransfected with an {alpha}-cDNA-construct encoding the substitution and a mutant {beta}-cDNA ({beta}-Arg{sup 211}Lys), encoding a {beta}-subunit that is inactive but normal in all other respects. We were surprised to find that the Val{sup 192}Leu substitution produced a pro-{alpha} chain that did not form {alpha}-{beta} dimers and was not transported to the lysosome. Finally, we reexamined the hexosaminidase activity and protein levels in the fibroblasts from the original patient. These data were also not consistent with the biochemical phenotype of the B1 variant of Tay-Sachs disease previously reported to be present. Thus, we conclude that the Val{sup 192}Leu substitution does not specifically affect the {alpha}-active site. 23 refs., 4 figs., 2 tabs.

Characterization of inducible models of Tay-Sachs and related disease.

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Sargeant, Timothy J; Drage, Deborah J; Wang, Susan; Apostolakis, Apostolos A; Cox, Timothy M; Cachón-González, M Begoña

2012-09-01

Tay-Sachs and Sandhoff diseases are lethal inborn errors of acid β-N-acetylhexosaminidase activity, characterized by lysosomal storage of GM2 ganglioside and related glycoconjugates in the nervous system. The molecular events that lead to irreversible neuronal injury accompanied by gliosis are unknown; but gene transfer, when undertaken before neurological signs are manifest, effectively rescues the acute neurodegenerative illness in Hexb-/- (Sandhoff) mice that lack β-hexosaminidases A and B. To define determinants of therapeutic efficacy and establish a dynamic experimental platform to systematically investigate cellular pathogenesis of GM2 gangliosidosis, we generated two inducible experimental models. Reversible transgenic expression of β-hexosaminidase directed by two promoters, mouse Hexb and human Synapsin 1 promoters, permitted progression of GM2 gangliosidosis in Sandhoff mice to be modified at pre-defined ages. A single auto-regulatory tetracycline-sensitive expression cassette controlled expression of transgenic Hexb in the brain of Hexb-/- mice and provided long-term rescue from the acute neuronopathic disorder, as well as the accompanying pathological storage of glycoconjugates and gliosis in most parts of the brain. Ultimately, late-onset brainstem and ventral spinal cord pathology occurred and was associated with increased tone in the limbs. Silencing transgenic Hexb expression in five-week-old mice induced stereotypic signs and progression of Sandhoff disease, including tremor, bradykinesia, and hind-limb paralysis. As in germline Hexb-/- mice, these neurodegenerative manifestations advanced rapidly, indicating that the pathogenesis and progression of GM2 gangliosidosis is not influenced by developmental events in the maturing nervous system.

Characterization of inducible models of Tay-Sachs and related disease.

Directory of Open Access Journals (Sweden)

Timothy J Sargeant

2012-09-01

Full Text Available Tay-Sachs and Sandhoff diseases are lethal inborn errors of acid β-N-acetylhexosaminidase activity, characterized by lysosomal storage of GM2 ganglioside and related glycoconjugates in the nervous system. The molecular events that lead to irreversible neuronal injury accompanied by gliosis are unknown; but gene transfer, when undertaken before neurological signs are manifest, effectively rescues the acute neurodegenerative illness in Hexb-/- (Sandhoff mice that lack β-hexosaminidases A and B. To define determinants of therapeutic efficacy and establish a dynamic experimental platform to systematically investigate cellular pathogenesis of GM2 gangliosidosis, we generated two inducible experimental models. Reversible transgenic expression of β-hexosaminidase directed by two promoters, mouse Hexb and human Synapsin 1 promoters, permitted progression of GM2 gangliosidosis in Sandhoff mice to be modified at pre-defined ages. A single auto-regulatory tetracycline-sensitive expression cassette controlled expression of transgenic Hexb in the brain of Hexb-/- mice and provided long-term rescue from the acute neuronopathic disorder, as well as the accompanying pathological storage of glycoconjugates and gliosis in most parts of the brain. Ultimately, late-onset brainstem and ventral spinal cord pathology occurred and was associated with increased tone in the limbs. Silencing transgenic Hexb expression in five-week-old mice induced stereotypic signs and progression of Sandhoff disease, including tremor, bradykinesia, and hind-limb paralysis. As in germline Hexb-/- mice, these neurodegenerative manifestations advanced rapidly, indicating that the pathogenesis and progression of GM2 gangliosidosis is not influenced by developmental events in the maturing nervous system.

A direct gene transfer strategy via brain internal capsule reverses the biochemical defect in Tay-Sachs disease.

Science.gov (United States)

Martino, S; Marconi, P; Tancini, B; Dolcetta, D; De Angelis, M G Cusella; Montanucci, P; Bregola, G; Sandhoff, K; Bordignon, C; Emiliani, C; Manservigi, R; Orlacchio, A

2005-08-01

Therapy for neurodegenerative lysosomal Tay-Sachs (TS) disease requires active hexosaminidase (Hex) A production in the central nervous system and an efficient therapeutic approach that can act faster than human disease progression. We combined the efficacy of a non-replicating Herpes simplex vector encoding for the Hex A alpha-subunit (HSV-T0alphaHex) and the anatomic structure of the brain internal capsule to distribute the missing enzyme optimally. With this gene transfer strategy, for the first time, we re-established the Hex A activity and totally removed the GM2 ganglioside storage in both injected and controlateral hemispheres, in the cerebellum and spinal cord of TS animal model in the span of one month's treatment. In our studies, no adverse effects were observed due to the viral vector, injection site or gene expression and on the basis of these results, we feel confident that the same approach could be applied to similar diseases involving an enzyme defect.

GM2 gangliosidoses in Spain: analysis of the HEXA and HEXB genes in 34 Tay-Sachs and 14 Sandhoff patients.

Science.gov (United States)

Gort, Laura; de Olano, Natalia; Macías-Vidal, Judit; Coll, M A Josep

2012-09-10

The GM2 gangliosidoses are autosomal recessive lysosomal storage diseases caused by a deficiency of the β-hexosaminidase A enzyme. This enzyme is composed of two polypeptide chains designated the α- and β- subunits and it interacts with the GM2 activator protein. The HEXA and HEXB genes encode the α-subunit and the β-subunit, respectively. Mutations in these genes are causative of Tay-Sachs disease (HEXA) and Sandhoff disease (HEXB). We analyzed the complete HEXA gene in 34 Spanish patients with Tay-Sachs disease and the HEXB gene in 14 Spanish patients with Sandhoff disease. We identified 27 different mutations, 14 of which were novel, in the HEXA gene and 14 different mutations, 8 of which unreported until now, in the HEXB gene, and we attempted to correlate these mutations with the clinical presentation of the patients. We found a high frequency of c.459+5G>A (IVS4+5G>A) mutation in HEXA affected patients, 22 of 68 alleles, which represent the 32.4%. This is the highest percentage found of this mutation in a population. All patients homozygous for mutation c.459+5G>A presented with the infantile form of the disease and, as previously reported, patients carrying mutation p.R178H in at least one of the alleles presented with a milder form. In HEXB affected patients, the novel deletion c.171delG accounts for 21.4% of the mutant alleles (6/28). All patients with this deletion showed the infantile form of the disease. The Spanish GM2 gangliosidoses affected patients show a great mutational heterogeneity as seen in other inherited lisosomal diseases in this country. Copyright © 2012. Published by Elsevier B.V.

In silico analyses of essential interactions of iminosugars with the Hex A active site and evaluation of their pharmacological chaperone effects for Tay-Sachs disease.

Science.gov (United States)

Kato, Atsushi; Nakagome, Izumi; Nakagawa, Shinpei; Kinami, Kyoko; Adachi, Isao; Jenkinson, Sarah F; Désiré, Jérôme; Blériot, Yves; Nash, Robert J; Fleet, George W J; Hirono, Shuichi

2017-11-15

The affinity of a series of iminosugar-based inhibitors exhibiting various ring sizes toward Hex A and their essential interactions with the enzyme active site were investigated. All the Hex A-inhibiting iminosugars tested formed hydrogen bonds with Arg178, Asp322, Tyr421 and Glu462 and had the favorable cation-π interaction with Trp460. Among them, DMDP amide (6) proved to be the most potent competitive inhibitor with a K i value of 0.041 μM. We analyzed the dynamic properties of both DMDP amide (6) and DNJNAc (1) in aqueous solution using molecular dynamics (MD) calculations; the distance of the interaction between Asp322 and 3-OH and Glu323 and 6-OH was important for stable interactions with Hex A, reducing fluctuations in the plasticity of the active site. DMDP amide (6) dose-dependently increased intracellular Hex A activity in the G269S mutant cells and restored Hex A activity up to approximately 43% of the wild type level; this effect clearly exceeded the border line treatment for Tay-Sachs disease, which is regarded as 10-15% of the wild type level. This is a significantly greater effect than that of pyrimethamine, which is currently in Phase 2 clinical trials. DMDP amide (6), therefore, represents a new promising pharmacological chaperone candidate for the treatment of Tay-Sachs disease.

Tay-Sachs disease in an Arab family due to c.78G>A HEXA nonsense mutation encoding a p.W26X early truncation enzyme peptide.

Science.gov (United States)

Haghighi, Alireza; Masri, Amira; Kornreich, Ruth; Desnick, Robert J

2011-12-01

Tay-Sachs disease (TSD), a pan-ethnic, autosomal recessive, neurodegenerative, lysosomal disease, results from deficient β-hexosaminidase A activity due to β-hexosaminidase α-subunit (HEXA) mutations. Prenatal/premarital carrier screening programs in the Ashkenazi Jewish community have markedly reduced disease occurrence. We report the first Jordanian Arab TSD patient diagnosed by deficient β-hexosaminidase A activity. HEXA mutation analysis revealed homozygosity for a nonsense mutation, c.78G>A (p.W26X). Previously reported in Arab patients, this mutation is a candidate for TSD screening in Arab populations. Copyright © 2011 Elsevier Inc. All rights reserved.

High school Tay-Sachs disease carrier screening: 5 to 11-year follow-up.

Science.gov (United States)

Curd, Helen; Lewis, Sharon; Macciocca, Ivan; Sahhar, Margaret; Petrou, Vicki; Bankier, Agnes; Lieberman, Sari; Levy-Lahad, Ephrat; Delatycki, Martin B

2014-04-01

The Melbourne high school Tay-Sachs disease (TSD) carrier screening program began in 1997. The aim of this study was to assess the outcomes of this screening program among those who had testing more than 5 years ago, to evaluate the long-term impact of screening. A questionnaire was used for data collection and consisted of validated scales and purposively designed questions. Questionnaires were sent to all carriers and two non-carriers for each carrier who were screened in the program between 1999 and 2005. Twenty-four out of 69 (34.8 %) carriers and 30/138 (21.7 %) non-carriers completed the questionnaire. Most participants (82 %) retained good knowledge of TSD and there was no evidence of a difference in knowledge between carriers and non-carriers. Most participants (83 %) were happy with the timing and setting of screening and thought that education and screening for TSD should be offered during high school. There was no difference between carriers and non-carriers in mean scores for the State Trait Anxiety Inventory and Decision Regret Scale. This evaluation indicated that 5-11 years post high school screening, those who were screened are supportive of the program and that negative consequences are rare.

Ashkenazi Jewish population screening for Tay-Sachs disease: the international and Australian experience.

Science.gov (United States)

Lew, Raelia M; Burnett, Leslie; Proos, Anné L; Barlow-Stewart, Kristine; Delatycki, Martin B; Bankier, Agnes; Aizenberg, Harry; Field, Michael J; Berman, Yemima; Fleischer, Ronald; Fietz, Michael

2015-03-01

Internationally, Tay-Sachs disease (TSD) preconception screening of Ashkenazi Jewish (AJ) individuals and couples has led to effective primary prevention of TSD. In Australia, adolescent preconception genetic screening programs operate mainly in Jewish community high schools. These existing programs offer an effective means of primary prevention of TSD, are cost effective and safe. However, in the broader Australian community TSD screening is not systematically performed and cases still occur in unscreened AJ individuals. In order to improve the effectiveness of Australian screening, there is a need for definitive guidelines for healthcare professionals to facilitate extension of the proven benefits of preconception TSD screening to all AJ individuals at risk. We performed a systematic review of the relevant literature relating to AJ pre-conception and antenatal screening for TSD. The evidence was assessed using an established National Health and Medical Research Council evidence grading system. Evaluations of efficacy of TSD screening programs design and execution, cost-benefit and cost-utility health economic evaluation, and population outcomes were undertaken. The results have been used to propose a model for universal AJ TSD preconception and antenatal screening for the primary care setting. © 2014 The Authors. Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

The presence of two different infantile Tay-Sachs disease mutations in a Cajun population

Energy Technology Data Exchange (ETDEWEB)

McDowell, G.A.; Blitzer, M.G. (Univ. of Maryland School of Medicine, Baltimore, MD (United States)); Mules, E.H. (Kennedy Krieger Institute, Baltimore, MD (United States)); Fabacher, P. (Office of Public Health, Shreveport, LA (United States)); Shapira, E. (Tulane Univ. of School of Medicine, New Orleans, LA (United States))

1992-11-01

A study was undertaken to characterize the mutation(s) responsible for Tay-Sachs disease (TSD) in a Cajun population in southwest Louisiana and to identify the origins of these mutations. Eleven of 12 infantile TSD alleles examined in six families had the [beta]-hexosaminidase A (Hex A) [alpha]-subunit exon 11 insertion mutation that is present in approximately 70% of Ashkenazi Jewish TSD heterozygotes. The mutation in the remaining allele was a single-base transition in the donor splice site of the [alpha]-subunit intron 9. To determine the origins of these two mutations in the Cajun population, the TSD carrier status was enzymatically determined for 90 members of four of the six families, and extensive pedigrees were constructed for all carriers. A single ancestral couple from France was found to be common to most of the carriers of the exon 11 insertion. Pedigree data suggest that this mutation has been in the Cajun population since its founding over 2 centuries ago and that it may be widely distributed within the population. In contrast, the intron 9 mutation apparently was introduced within the last century and probably is limited to a few Louisiana families. 29 refs., 4 figs.

Serial CT scans and MRI scans of Tay-Sachs disease

International Nuclear Information System (INIS)

Shimoizumi, Hideo; Miyao, Masutomo; Ichihashi, Koh; Sawa, Rituko; Yamamoto, Yoshifumi; Tanaka, Osamu; Yanagisawa, Masayoshi; Kamoshita, Shigehiko.

1986-01-01

Serial X-ray CT and MRI were performed on 2 cases of Tay-Sachs disease. Case 1 : a 3-year-10-month-old girl. Her developmental milestones were normal until the age of 6 months. At the age of 10 months, hypotonia and unduly sensitiveness to sounds were noticed. She had cherry red spots in both fundi, and the serum hexosaminidase A activity was low. Significant clinical features during the next 3 years included regression of developmental milestones to the level of one month, and myoclonic and generalised seizures. After 3 years she showed megalencephaly, unstable body temperature, and respiratory disorders. Case 2 : a 2-year-6-month-old boy. His developmental milestones were normal until the age of 5 months. Then he manifested hyperreaction to noises and further developments ceased. He started to deteriorate from the age of 1 year and 2 months, and had no head control at the age of 1 year and 6 months. Cherry red spots were detected and the serum hexsosaminidase A activity was low, too. X-ray CT at the early stage of cases 1 and 2 showed mild cerebral atrophy and high density areas in bilateral thalami and basal ganglia. At the late stage of Case 1, high density areas appeared in occipital and frontal white matters. MRI in both patients were strikingly similar. In their grey matters, linear light areas were demonstrated on IR images. Their white matters showed extensive dark (long T 1 ) areas on IR images, and extensive light (long T 2 ) areas on SE images. Bilateral thalami and basal ganglia were light on IR images and dark on SE images. The findings of MRI in our patients seemed to correlate well with pathological and biochemical changes in their brains. (author)

Origin and spread of the 1278insTATC mutation causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a robust and parsimonious hypothesis.

Science.gov (United States)

Frisch, Amos; Colombo, Roberto; Michaelovsky, Elena; Karpati, Mazal; Goldman, Boleslaw; Peleg, Leah

2004-03-01

The 1278insTATC is the most prevalent beta-hexosaminidase A ( HEXA) gene mutation causing Tay-Sachs disease (TSD), one of the four lysosomal storage diseases (LSDs) occurring at elevated frequencies among Ashkenazi Jews (AJs). To investigate the genetic history of this mutation in the AJ population, a conserved haplotype (D15S981:175-D15S131:240-D15S1050:284-D15S197:144-D15S188:418) was identified in 1278insTATC chromosomes from 55 unrelated AJ individuals (15 homozygotes and 40 heterozygotes for the TSD mutation), suggesting the occurrence of a common founder. When two methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the insertion was found to be 40+/-12 generations (95% confidence interval: 30-50 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 8th-9th century. This corresponds with the demographic expansion of AJs in central Europe, following the founding of the Ashkenaz settlement in the early Middle Ages. The results are consistent with the geographic distribution of the main TSD mutation, 1278insTATC being more common in central Europe, and with the coalescent times of mutations causing two other LSDs, Gaucher disease and mucolipidosis type IV. Evidence for the absence of a determinant positive selection (heterozygote advantage) over the mutation is provided by a comparison between the estimated age of 1278insTATC and the probability of the current AJ frequency of the mutant allele as a function of its age, calculated by use of a branching-process model. Therefore, the founder effect in a rapidly expanding population arising from a bottleneck provides a robust parsimonious hypothesis explaining the spread of 1278insTATC-linked TSD in AJ individuals.

Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation.

Science.gov (United States)

Zampieri, Stefania; Montalvo, Annalisa; Blanco, Mariana; Zanin, Irene; Amartino, Hernan; Vlahovicek, Kristian; Szlago, Marina; Schenone, Andrea; Pittis, Gabriela; Bembi, Bruno; Dardis, Andrea

2012-05-15

Tay-Sachs disease (TSD) is a recessively inherited disorder caused by the deficient activity of hexosaminidase A due to mutations in the HEXA gene. Up to date there is no information regarding the molecular genetics of TSD in Argentinean patients. In the present study we have studied 17 Argentinean families affected by TSD, including 20 patients with the acute infantile form and 3 with the sub-acute form. Overall, we identified 14 different mutations accounting for 100% of the studied alleles. Eight mutations were novel: 5 were single base changes leading to drastic residue changes or truncated proteins, 2 were small deletions and one was an intronic mutation that may cause a splicing defect. Although the spectrum of mutations was highly heterogeneous, a high frequency of the c.459+5G>A mutation, previously described in different populations was found among the studied cohort. Haplotype analysis suggested that in these families the c.459+5G>A mutation might have arisen by a single mutational event. Copyright © 2012 Elsevier B.V. All rights reserved.

Crystallographic Structure of Human β-Hexosaminidase A: Interpretation of Tay-Sachs Mutations and Loss of GM2 Ganglioside Hydrolysis

Science.gov (United States)

Lemieux, M. Joanne; Mark, Brian L.; Cherney, Maia M.; Withers, Stephen G.; Mahuran, Don J.; James, Michael N. G.

2010-01-01

Lysosomal β-hexosaminidase A (Hex A) is essential for the degradation of GM2 gangliosides in the central and peripheral nervous system. Accumulation of GM2 leads to severely debilitating neurodegeneration associated with Tay-Sachs disease (TSD), Sandoff disease (SD) and AB variant. Here, we present the X-ray crystallographic structure of Hex A to 2.8 Å resolution and the structure of Hex A in complex with NAG-thiazoline, (NGT) to 3.25 Å resolution. NGT, a mechanism-based inhibitor, has been shown to act as a chemical chaperone that, to some extent, prevents misfolding of a Hex A mutant associated with adult onset Tay Sachs disease and, as a result, increases the residual activity of Hex A to a level above the critical threshold for disease. The crystal structure of Hex A reveals an αβ heterodimer, with each subunit having a functional active site. Only the α-subunit active site can hydrolyze GM2 gangliosides due to a flexible loop structure that is removed post-translationally from β, and to the presence of αAsn423 and αArg424. The loop structure is involved in binding the GM2 activator protein, while αArg424 is critical for binding the carboxylate group of the N-acetyl-neuraminic acid residue of GM2. The β-subunit lacks these key residues and has βAsp452 and βLeu453 in their place; the β-subunit therefore cleaves only neutral substrates efficiently. Mutations in the α-subunit, associated with TSD, and those in the β-subunit, associated with SD are discussed. The effect of NGT binding in the active site of a mutant Hex A and its effect on protein function is discussed. PMID:16698036

Evaluation of the risk for Tay-Sachs disease in individuals of French Canadian ancestry living in new England.

Science.gov (United States)

Martin, Dianna C; Mark, Brian L; Triggs-Raine, Barbara L; Natowicz, Marvin R

2007-03-01

The assessment of risk for Tay-Sachs disease (TSD) in individuals of French Canadian background living in New England is an important health issue. In preliminary studies of the enzyme-defined carrier frequency for TSD among Franco-Americans in New England, we found frequencies (1:53) higher than predicted from the incidence of infantile TSD in this region. We have now further evaluated the risk for TSD in the Franco-American population of New England. Using a fluorescence-based assay for beta-hexosaminidase activity, we determined the carrier frequencies for TSD in 2783 Franco-Americans. DNA analysis was used to identify mutations causing enzyme deficiency in TSD carriers. We determined the enzyme-defined carrier frequency for TSD as 1:65 (95% confidence interval 1:49 to 1:90). DNA-based analysis of 24 of the enzyme-defined carriers revealed 21 with sequence changes: 9 disease-causing, 4 benign, and 8 of unknown significance. Six of the unknowns were identified as c.748G>A p.G250S, a mutation we show by expression analysis to behave similarly to the previously described c.805G>A p.G269S adult-onset TSD mutation. This putative adult-onset TSD c.748G>A p.G250S mutation has a population frequency similar to the common 7.6 kb deletion mutation that occurs in persons of French Canadian ancestry. We estimate the frequency of deleterious TSD alleles in Franco-Americans to be 1:73 (95% confidence interval 1:55 to 1:107). These data provide a more complete data base from which to formulate policy recommendations regarding TSD heterozygosity screening in individuals of French Canadian background.

Assessing the potential success of cystic fibrosis carrier screening: lessons learned from Tay-Sachs disease and beta-thalassemia.

Science.gov (United States)

Laberge, A-M; Watts, C; Porter, K; Burke, W

2010-01-01

The objective of this study was to identify factors involved in the success of 2 well-established population-based carrier screening programs - Tay-Sachs disease (TSD) in Ashkenazi Jews and beta-thalassemia in Sardinia and Cyprus - and to assess the potential for success of a population-based cystic fibrosis (CF) carrier screening strategy using these factors. We performed a literature review and key informant interviews. Factors involved in the success of TSD and beta-thalassemia carrier screening programs include disease characteristics (well-defined population at risk, severe disease with predictable course, availability of effective treatment), test characteristics (high sensitivity, straightforward interpretation of results), and community characteristics (involvement of community, support of families and advocacy groups, consensus in favor of avoiding affected births). Current CF screening strategies include few of the factors listed above. Unlike TSD and beta-thalassemia, the purpose of current CF carrier screening strategies is informed reproductive decision-making, without an explicit goal of reducing disease incidence. When compared to TSD and beta-thalassemia, CF is a less favorable candidate for population-based carrier screening. Because of its different purpose, CF carrier screening will require different measures of success than those used for TSD and beta-thalassemia carrier screening, and a consensus on the value or success of CF carrier screening may be difficult to achieve.

Transient HEXA expression in a transformed human fetal Tay-Sachs disease neuroglial cell line

Energy Technology Data Exchange (ETDEWEB)

Fernandes, M.J.; Hechtman, P.; Kaplan, F. [McGill Univ., Quebec (Canada)] [and others

1994-09-01

Tay-Sachs disease (TSD) is a severe neurodegenerative disorder characterized by the accumulation of GM{sub 2} ganglioside in the neurons of the central cortex. The recessively inherited disorder results from deficiency of hexosaminidase A (Hex A), a heterodimer of an {alpha} and {beta} subunit encoded by the HEXA and HEXB genes. Expression of HEXA mutations in COS cells has several disadvantages including high endogenous hexosaminidase activity. We report a new transient expression system with very low endogenous Hex A activity. An SV40-transformed fetal TSD neuroglial cell line was assessed for transient expression of the HEXA gene. pCMV{alpha}, a vector incorporating the cytomegalovirus promoter with the human {alpha}-subunit cDNA insert, proved to be the most efficient expression vector. Transfection of 4x10{sup 6} cells with 5-20 {mu}g of plasmid resulted in 100 to 500-fold Hex A activity (4MUGS hydrolysis) relative to mock-transfected cells. Use of pCMV{beta}-Gal as a control for transfection efficiency indicated that 10-20% of cells were transfected. Hex A specific activity increased for at least 72 h post-transfection. This new transient expression system should greatly improve the characterization of mutations in which low levels of HEXA expression result in milder clinical phenotypes and permit studies on enzymatic properties of mutant forms of Hex A. Since the cells used are of CNS origin and synthesize gangliosides, it should also be possible to study, in culture, the metabolic phenotype associated with TSD.

Tay Sachs disease in Australia: reduced disease incidence despite stable carrier frequency in Australian Jews.

Science.gov (United States)

Lew, Raelia M; Proos, Anne L; Burnett, Leslie; Delatycki, Martin; Bankier, Agnes; Fietz, Michael J

2012-12-10

To evaluate the outcomes of preconception screening of Jewish Australians for Tay Sachs disease (TSD) carrier status on Jewish TSD-affected births. Epidemiological observational study involving a complete retrospective audit of infantile and intermediate TSD cases diagnosed in Sydney and Melbourne between 1 January 1995 and 31 December 2011 (Royal Children's Hospital Melbourne; Pacific Laboratory Medicine Services, Pathology North, NSW Health Pathology, Sydney; Victorian Clinical Genetics Services, Melbourne; and SA Pathology, Adelaide), and carrier frequency among Jewish high school students attending schools participating in TSD screening programs over the same period. Jewish TSD carrier frequency; and expected versus observed Jewish TSD-affected births. The 2006 Census indicated that most of the total 88,826 Jewish Australians live in Melbourne (46%) and Sydney (40%). The 7,756 Jewish high school students screened for TSD in Sydney and Melbourne during the study period had a carrier frequency of one in 31 (3.26%; 95% CI, 2.89%-3.68%).The estimated expected number of TSD-affected births in Melbourne and Sydney in 1995-2011 was 4.1 for Jewish births and 7.4 for other births (a ratio of Jewish to non-Jewish births of 1:2). The actual number was 12 (four in Sydney and eight in Melbourne), of which two were Jewish (a ratio of Jewish to non-Jewish births of 1:5). This finding of fewer than expected Jewish TSD cases coincided with a period during which screening programs were operating. There have been no Jewish TSD-affected children born to parents who were screened previously. Community education, appreciation of autosomal recessive inheritance and genetic carrier screening before pregnancy are the likely factors in our finding of fewer than expected Jewish babies with TSD. Ongoing outcome monitoring must continue.

Radioimmunoassay and heat denaturation enzyme assay for the detection of Tay-Sachs heterozygotes during pregnancy

International Nuclear Information System (INIS)

Nguyen, C.; Gold, R.J.M.; Mahuran, D.; Lowden, J.A.

1981-01-01

Tay-Sachs disease results from a loss of activity of hexosaminidase A (HEX A) in body tissues and fluids. Heterozygotes for the disease are usually identified by their relatively low ratio of heat-labile HEX A to total hexosaminidase. During pregnancy an intermediate isoenzyme (HEX I) increases in activity in serum and obscures the heterozygote status. HEX I does not increase in leucocytes, tears and other body tissues but because of technical difficulties in these assays the authors examined the feasibility of using a radioimmunoassay for HEX A. By univariate analysis, the heat denaturation assay gave a lower cost of misclassification for non-pregnant normals while RIA did so for pregnant normals. A combination of both tests led to reduced cost of misclassification compared to either alone. Bayesian analysis of bivariate gaussian density functions for heat denaturation and for radioimmunoassays of HEX isoenzymes was employed to calculate misclassification frequencies. Among the parameters examined, HEX A measured by RIA and % HEX A by heat-denaturation assay were the two having the best discriminatory power. (Auth.)

Molecular characterization of both alleles in an unusual Tay-Sachs disease BI variant

Energy Technology Data Exchange (ETDEWEB)

Coulter-Mackie, M.B. (Univ. of Western Ontario, London (Canada) Child Health Research Institute, Children' s Hospital of Western Ontario, London (Canada) Child Parent Resource Institute, London, Ontario (Canada))

1994-06-01

In a recent report, the authors described an exon 6 mutation in a Tay-Sachs B1 variant patient, first reported by Gordon et al. (1988), who displayed a typical B1 variant biochemical phenotype - i.e., (a) significant levels of hexosaminidase A (Hex A) activity in an assay with a neutral synthetic substrate, 4-methylumbelliferyl-[beta]-N-acetylglucosamide, and (b) <2% of control Hex A in a test on the sulfated substrate, 4-methylumbelliferyl-[beta]-N-acetylglucosamide-6-sulfate. The patient was found to carry a double mutation (G[sub 574][yields]C [val[sub 192][yields]leu] and G[sub 598][yields]A [val[sub 200][yields]met]) inherited from her mother. Only the 574 mutation produced a deleterious effect on Hex A activity in transfected COS0-1 cells, producing a B1 variant biochemical phenotype. The paternal allele apparently caused decreased abundance of mRNA, since no candidate paternal mutations were found in cloned reverse transcription-PCR (RT-PCR) products in the reported study. The biochemical phenotype of the original patient and the properties of the cDNA carrying the G[sub 574] [yields] C mutation in transient expression studies were compatible with a B1 variant mutation. The possibility remained that there might be some contribution from the paternal allele to the patient's phenotype. However, the paternal allele produces relatively low yields of a largely mis-spliced mRNA whose product would not be functional. Therefore, the G[sub 574] [yields] C (val[yields]leu) mutation in the maternal allele is clearly confirmed as a B1 variant mutation with all the ramifications for the substrate binding site and/or catalytic center that this implies.

[beta]-hexosaminidase isozymes from cells cotransfected with [alpha] and [beta] cDNA constructs: Analysis of the [alpha]-subunit missense mutation associated with the adult form of Tay-Sachs disease

Energy Technology Data Exchange (ETDEWEB)

Brown, C.A.; Mahuran, D.J. (Univ. of Toronto (Canada))

1993-08-01

In vitro mutagenesis and transient expression in COS cells has been used to associate a missense mutation with a clinical or biochemical phenotype. Mutations affecting the [alpha]-subunit of [beta]-hexosaminidase A ([alpha][beta]) (E.C.3.2.1.52) result in Tay-Sachs disease. Because hexosaminidase A is heterodimeric, analysis of [alpha]-chain mutations is not straightforward. The authors examine three approaches utilizing previously identified mutations affecting [alpha]-chain folding. These involve transfection of (1) the [alpha] cDNA alone; (2) a [beta] cDNA construct encoding a [beta]-subunit substituted at a position homologous to that of the [alpha]-subunit, and (3) both [alpha] and [beta] cDNAs. The latter two procedures amplified residual activity levels over that of patient samples, an effect not previously found with mutations affecting an [open quotes]active[close quotes] [alpha]Arg residue. This effect may help to discriminate between protein-folding and active-site mutations. The authors conclude that, with proper controls, the latter method of cotransfection can be used to evaluate the effects and perhaps to predict the clinical course of some [alpha]-chain mutations. Using this technique, they demonstrate that the adult-onset Tay-Sachs mutation, [alpha]Gly[yields]Ser[sup 269], does not directly affect [alpha][beta] dimerization but exerts an indirect effect on the dimer through destabilizing the folded [alpha]-subunit at physiological temperatures. Two other [alpha] mutations linked to more severe phenotypes appear to inhibit the initial folding of the subunit. 36 refs., 2 figs., 5 tabs.

Mortality incidence estimation using federal death certificate and natality data with an application to Tay-Sachs disease.

Science.gov (United States)

Jalal, Kabir; Carter, Randy L

2015-09-01

For confidentiality reasons, US federal death certificate data are incomplete with regards to the dates of birth and death for the decedents, making calculation of total lifetime of a decedent impossible and thus estimation of mortality incidence difficult. This paper proposes the use of natality data and an imputation-based method to estimate age-specific mortality incidence rates in the face of this missing information. By utilizing previously determined probabilities of birth, a birth date and death date are imputed for every decedent in the dataset. Thus, the birth cohort of each individual is imputed, and the total on-study time can be calculated. This idea is implemented in two approaches for estimation of mortality incidence rates. The first is an extension of a person-time approach, while the second is an extension of a life table approach. Monte Carlo simulations showed that both approaches perform well in comparison to the ideal complete data methods, but that the person-time method is preferred. An application to Tay-Sachs disease is demonstrated. It is concluded that the imputation methods proposed provide valid estimates of the incidence of death from death certificate data without the need for additional assumptions under which usual mortality rates provide valid estimates. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Tay-Sachs disease mutations in HEXA target the α chain of hexosaminidase A to endoplasmic reticulum-associated degradation.

Science.gov (United States)

Dersh, Devin; Iwamoto, Yuichiro; Argon, Yair

2016-12-01

Loss of function of the enzyme β-hexosaminidase A (HexA) causes the lysosomal storage disorder Tay-Sachs disease (TSD). It has been proposed that mutations in the α chain of HexA can impair folding, enzyme assembly, and/or trafficking, yet there is surprisingly little known about the mechanisms of these potential routes of pathogenesis. We therefore investigated the biosynthesis and trafficking of TSD-associated HexA α mutants, seeking to identify relevant cellular quality control mechanisms. The α mutants E482K and G269S are defective in enzymatic activity, unprocessed by lysosomal proteases, and exhibit altered folding pathways compared with wild-type α. E482K is more severely misfolded than G269S, as observed by its aggregation and inability to associate with the HexA β chain. Importantly, both mutants are retrotranslocated from the endoplasmic reticulum (ER) to the cytosol and are degraded by the proteasome, indicating that they are cleared via ER-associated degradation (ERAD). Leveraging these discoveries, we observed that manipulating the cellular folding environment or ERAD pathways can alter the kinetics of mutant α degradation. Additionally, growth of patient fibroblasts at a permissive temperature or with chemical chaperones increases cellular Hex activity by improving mutant α folding. Therefore modulation of the ER quality control systems may be a potential therapeutic route for improving some forms of TSD. © 2016 Dersh et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Novel Vector Design and Hexosaminidase Variant Enabling Self-Complementary Adeno-Associated Virus for the Treatment of Tay-Sachs Disease.

Science.gov (United States)

Karumuthil-Melethil, Subha; Nagabhushan Kalburgi, Sahana; Thompson, Patrick; Tropak, Michael; Kaytor, Michael D; Keimel, John G; Mark, Brian L; Mahuran, Don; Walia, Jagdeep S; Gray, Steven J

2016-07-01

GM2 gangliosidosis is a family of three genetic neurodegenerative disorders caused by the accumulation of GM2 ganglioside (GM2) in neuronal tissue. Two of these are due to the deficiency of the heterodimeric (α-β), "A" isoenzyme of lysosomal β-hexosaminidase (HexA). Mutations in the α-subunit (encoded by HEXA) lead to Tay-Sachs disease (TSD), whereas mutations in the β-subunit (encoded by HEXB) lead to Sandhoff disease (SD). The third form results from a deficiency of the GM2 activator protein (GM2AP), a substrate-specific cofactor for HexA. In their infantile, acute forms, these diseases rapidly progress with mental and psychomotor deterioration resulting in death by approximately 4 years of age. After gene transfer that overexpresses one of the deficient subunits, the amount of HexA heterodimer formed would empirically be limited by the availability of the other endogenous Hex subunit. The present study used a new variant of the human HexA α-subunit, μ, incorporating critical sequences from the β-subunit that produce a stable homodimer (HexM) and promote functional interactions with the GM2AP- GM2 complex. We report the design of a compact adeno-associated viral (AAV) genome using a synthetic promoter-intron combination to allow self-complementary (sc) packaging of the HEXM gene. Also, a previously published capsid mutant, AAV9.47, was used to deliver the gene to brain and spinal cord while having restricted biodistribution to the liver. The novel capsid and cassette design combination was characterized in vivo in TSD mice for its ability to efficiently transduce cells in the central nervous system when delivered intravenously in both adult and neonatal mice. This study demonstrates that the modified HexM is capable of degrading long-standing GM2 storage in mice, and it further demonstrates the potential of this novel scAAV vector design to facilitate widespread distribution of the HEXM gene or potentially other similar-sized genes to the nervous system.

A double mutation in exon 6 of the [beta]-hexosaminidase [alpha] subunit in a patient with the B1 variant of Tay-Sachs disease

Energy Technology Data Exchange (ETDEWEB)

Ainsworth, P.J. (Univ. of Western Ontario, Ontario (Canada) Child Health Research Institute, London, Ontario (Canada)); Coulter-Mackie, M.B. (Univ. of Western Ontario, Ontario (Canada) Child Health Research Institute, London, Ontario (Canada) Children' s Psychiatric Research Institute, London, Ontario (Canada))

1992-10-01

The B1 variant form of Tay-Sachs disease is enzymologically unique in that the causative mutation(s) appear to affect the active site in the [alpha] subunit of [beta]-hexosaminidase A without altering its ability to associate with the [beta] subunit. Most previously reported B1 variant mutations were found in exon 5 within codon 178. The coding sequence of the [alpha] subunit gene of a patient with the B1 variant form was examined with a combination of reverse transcription of mRNA to cDNA, PCR, and dideoxy sequencing. A double mutation in exon 6 has been identified: a G[sub 574][yields]C transversion causing a val[sub 192][yields]leu change and a G[sub 598][yields] A transition resulting in a val[sub 200][yields]met alteration. The amplified cDNAs were otherwise normal throughout their sequence. The 574 and 598 alterations have been confirmed by amplification directly from genomic DNA from the patient and her mother. Transient-expression studies of the two exon 6 mutations (singly or together) in COS-1 cells show that the G[sub 574][yields]C change is sufficient to cause the loss of enzyme activity. The biochemical phenotype of the 574 alteration in transfection studies is consistent with that expected for a B1 variant mutation. As such, this mutation differs from previously reported B1 variant mutations, all of which occur in exon 5. 31 refs., 2 figs., 2 tabs.

Prader-Willi syndrome and Tay-Sachs disease in association with mixed maternal uniparental isodisomy and heterodisomy 15 in a girl who also had isochromosome Xq.

Science.gov (United States)

Zeesman, Susan; McCready, Elizabeth; Sadikovic, Bekim; Nowaczyk, Małgorzata Jm

2015-01-01

Malsegregation of chromosomes during reproduction can result in uniparental disomy when associated with trisomy rescue, monosomy rescue or gamete complementation. Pathogenicity stemming from uniparental disomy in liveborns results from imprinting disorders or autozygosity for autosomal recessive disorders. We report on a girl with Prader-Willi syndrome and Tay-Sachs disease resulting from maternal uniparental disomy of chromosome 15. The child also had an isochromosome Xq. To further characterize the etiology of the aberrant chromosome 15 and the isochromosome Xq, SNP loci from both chromosomes were assessed in the proband and parents, and genome-wide DNA methylation analysis was performed. SNP and DNA methylation analysis confirmed maternal uniparental heterodisomy around the Prader-Willi locus, while the region around the HEXA locus showed maternal uniparental isodisomy. This result is consistent with trisomy rescue of a maternal meiosis l error in a chromosome 15 with two meiotic recombinations. SNP analysis of the X chromosomes is consistent with a maternal origin for the isochromosome. © 2014 Wiley Periodicals, Inc.

Tay-Sachs Disease

Science.gov (United States)

... better understanding of how neurological deficits arise in lipid storage diseases and on the development of new treatments targeting disease mechanisms. Specific research on the gangliodisoses including expanding the use of ...

Imaging MALDI mass spectrometry using an oscillating capillary nebulizer matrix coating system and its application to analysis of lipids in brain from a mouse model of Tay-Sachs/Sandhoff disease.

Science.gov (United States)

Chen, Yanfeng; Allegood, Jeremy; Liu, Ying; Wang, Elaine; Cachón-Gonzalez, Begoña; Cox, Timothy M; Merrill, Alfred H; Sullards, M Cameron

2008-04-15

The quality of tissue imaging by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) depends on the effectiveness of the matrix deposition, especially for lipids that may dissolve in the solvent used for the matrix application. This article describes the use of an oscillating capillary nebulizer (OCN) to spray small droplets of matrix aerosol onto the sample surface for improved matrix homogeneity, reduced crystal size, and controlled solvent effects. This system was then applied to the analysis of histological slices of brains from mice with homozygous disruption of the hexb gene (hexb-/-), a model of Tay-Sachs and Sandhoff disease, versus the functionally normal heterozygote (hexb+/-) by imaging MALDI-MS. This allowed profiling and localization of many different lipid species, and of particular interest, ganglioside GM2, asialo-GM2 (GA2), and sulfatides (ST). The presence of these compounds was confirmed by analysis of brain extracts using electrospray ionization in conjunction with tandem mass spectrometry (MS/MS). The major fatty acid of the ceramide backbone of both GM2 and GA2 was identified as stearic acid (18:0) versus nervonic acid (24:1) for ST by both tissue-imaging MS and ESI-MS/MS. GM2 and GA2 were highly elevated in hexb-/- and were both localized in the granular cell region of the cerebellum. ST, however, was localized mainly in myelinated fiber (white matter) region of the cerebellum as well as in the brain stem with a relatively uniform distribution and had similar relative signal intensity for both hexb+/- and hexb-/- brain. It was also observed that there were distinct localizations for numerous other lipid subclasses; hence, imaging MALDI-MS could be used for "lipidomic" studies. These results illustrate the usefulness of tissue-imaging MALDI-MS with matrix deposition by OCN for histologic comparison of lipids in tissues such as brains from this mouse model of Tay-Sachs and Sandhoff disease.

Tay-Sachs disease preconception screening in Australia: self-knowledge of being an Ashkenazi Jew predicts carrier state better than does ancestral origin, although there is an increased risk for c.1421 + 1G > C mutation in individuals with South African heritage

OpenAIRE

Lew, Raelia; Burnett, Leslie; Proos, Anné

2011-01-01

The Australasian Community Genetics Program provided a preconception screening for Tay-Sachs disease (TSD) to 4,105 Jewish high school students in Sydney and Melbourne over the 12-year period 1995–2007. By correlating the frequencies of mutant HEXA, MIM *606869 (gene map locus 15q23-q24) alleles with subjects’ nominated ethnicity (Ashkenazi/Sephardi/Mixed) and grandparental birthplaces, we established that Ashkenazi ethnicity is a better predictor of TSD carrier status than grandparental ance...

Tay-Sachs Carrier Screening by Enzyme and Molecular Analyses in the New York City Minority Population.

Science.gov (United States)

Mehta, Nikita; Lazarin, Gabriel A; Spiegel, Erica; Berentsen, Kathleen; Brennan, Kelly; Giordano, Jessica; Haque, Imran S; Wapner, Ronald

2016-09-01

Carrier screening for Tay-Sachs disease is performed by sequence analysis of the HEXA gene and/or hexosaminidase A enzymatic activity testing. Enzymatic analysis (EA) has been suggested as the optimal carrier screening method, especially in non-Ashkenazi Jewish (non-AJ) individuals, but its utilization and efficacy have not been fully evaluated in the general population. This study assesses the reliability of EA in comparison with HEXA sequence analysis in non-AJ populations. Five hundred eight Hispanic and African American patients (516 samples) had EA of their leukocytes performed and 12 of these patients who tested positive by EA ("carriers") had subsequent HEXA gene sequencing performed. Of the 508 patients, 25 (4.9%) were EA positive and 40 (7.9%) were inconclusive. Of the 12 patients who were sequenced, 11 did not carry a pathogenic variant and one carried a likely deleterious mutation (NM_000520.4(HEXA):c.1510C>T). High inconclusive rates and poor correlation between positive/inconclusive enzyme results and identification of pathogenic mutations suggest that ethnic-specific recalibration of reference ranges for EA may be necessary. Alternatively, HEXA gene sequencing could be performed.

Common HEXB polymorphisms reduce serum HexA and HexB enzymatic activities, potentially masking Tay-Sachs disease carrier identification.

Science.gov (United States)

Vallance, Hilary; Morris, Tara J; Coulter-Mackie, Marion; Lim-Steele, Joyce; Kaback, Michael

2006-02-01

A DNA-proven Tay-Sachs disease (TSD) carrier and his brother were found to have serum percent Hexosaminidase A (%HexA) enzymatic activities in the non-carrier range, while the leukocyte %HexA profiles clearly identified them as TSD heterozygotes. Both their serum HexA and HexB enzymatic activities were below reference range, suggesting inheritance of mutations in both the HEXA (alpha-subunit) and HEXB (beta-subunit) genes. DNA sequencing revealed that both individuals, carried the common HEXA 1277_1278insTATC mutation, and two common HEXB polymorphisms: [619A>G (+) delTG]. To determine if these HEXB polymorphisms reduce HexA and HexB enzymatic activities, 69 DNA samples from subjects previously screened enzymatically in both serum and leukocytes for TSD carrier status were selected for either high, mid-range or low serum Total Hex (defined as the sum of HexA and HexB) activities and were tested for the HEXB mutations. Further, three additional TSD carriers ascertained by the atypical pattern of normal serum %HexA but carrier leukocyte %HexA, were found to have the [delTG (+) 619A>G] genotype. In addition, the frequency of the [delTG (+) 619A>G] genotype was significantly higher (P G] haplotype in the Ashkenazi Jewish population (approximately 10%), up to 10% of TSD carriers may have normal serum %HexA values with low total Hex. Accordingly, serum %HexA should not be the sole criterion used for carrier status determination. Where total Hex activity is reduced, further testing with leukocyte Hex profiles is indicated.

Improving accuracy of Tay Sachs carrier screening of the non-Jewish population: analysis of 34 carriers and six late-onset patients with HEXA enzyme and DNA sequence analysis.

Science.gov (United States)

Park, Noh Jin; Morgan, Craig; Sharma, Rajesh; Li, Yuanyin; Lobo, Raynah M; Redman, Joy B; Salazar, Denise; Sun, Weimin; Neidich, Julie A; Strom, Charles M

2010-02-01

The purpose of this study was to determine whether combining different testing modalities namely beta-hexosaminidase A (HEXA) enzyme analysis, HEXA DNA common mutation assay, and HEXA gene sequencing could improve the sensitivity for carrier detection in non-Ashkenazi (AJ) individuals. We performed a HEXA gene sequencing assay, a HEXA DNA common mutation assay, and a HEXA enzyme assay on 34 self-reported Tay-Sachs disease (TSD) carriers, six late-onset patients with TSD, and one pseudodeficiency allele carrier. Sensitivity of TSD carrier detection was 91% for gene sequencing compared with 91% for the enzyme assay and 52% for the DNA mutation assay. Gene sequencing combined with enzyme testing had the highest sensitivity (100%) for carrier detection. Gene sequencing detected four novel mutations, three of which are predicted to be disease causing [118.delT, 965A-->T (D322V), and 775A-->G (T259A)]. Gene sequencing is useful in identifying rare mutations in patients with TSD and their families, in evaluating spouses of known carriers for TSD who have indeterminate enzyme analysis and negative for common mutation analysis, and in resolving ambiguous enzyme testing results.

UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells

Science.gov (United States)

2018-03-15

Adrenoleukodystrophy; Batten Disease; Mucopolysaccharidosis II; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Neimann Pick Disease; Pelizaeus-Merzbacher Disease; Sandhoff Disease; Tay-Sachs Disease; Brain Diseases, Metabolic, Inborn; Alpha-Mannosidosis; Sanfilippo Mucopolysaccharidoses

Genetics Home Reference: GM2-gangliosidosis, AB variant

Science.gov (United States)

... Resources Genetic Testing (1 link) Genetic Testing Registry: Tay-Sachs disease, variant AB General Information from MedlinePlus (5 links) ... AB variant Activator Deficiency/GM2 Gangliosidosis Activator-deficient Tay-Sachs disease GM2 Activator Deficiency Disease GM2 gangliosidosis, type AB ...

Reversibility of neuropathology in Tay-Sachs-related diseases.

Science.gov (United States)

Cachón-González, María-Begoña; Wang, Susan Z; Ziegler, Robin; Cheng, Seng H; Cox, Timothy M

2014-02-01

The GM2 gangliosidoses are progressive neurodegenerative disorders due to defects in the lysosomal β-N-acetylhexosaminidase system. Accumulation of β-hexosaminidases A and B substrates is presumed to cause this fatal condition. An authentic mouse model of Sandhoff disease (SD) with pathological characteristics resembling those noted in infantile GM2 gangliosidosis has been described. We have shown that expression of β-hexosaminidase by intracranial delivery of recombinant adeno-associated viral vectors to young adult SD mice can prevent many features of the disease and extends lifespan. To investigate the nature of the neurological injury in GM2 gangliosidosis and the extent of its reversibility, we have examined the evolution of disease in the SD mouse; we have moreover explored the effects of gene transfer delivered at key times during the course of the illness. Here we report greatly increased survival only when the therapeutic genes are expressed either before the disease is apparent or during its early manifestations. However, irrespective of when treatment was administered, widespread and abundant expression of β-hexosaminidase with consequent clearance of glycoconjugates, α-synuclein and ubiquitinated proteins, and abrogation of inflammatory responses and neuronal loss was observed. We also show that defects in myelination occur in early life and cannot be easily resolved when treatment is given to the adult brain. These results indicate that there is a limited temporal opportunity in which function and survival can be improved-but regardless of resolution of the cardinal pathological features of GM2 gangliosidosis, a point is reached when functional deterioration and death cannot be prevented.

Tay-Sachs Disease

Science.gov (United States)

... During the next months — or even years — the baby will progressively lose the ability to see, hear, and move. A red spot will develop in the back of the child's eyes. The child will stop smiling, crawling, turning over, and reaching out for things. By ...

Genetics Home Reference: Tay-Sachs disease

Science.gov (United States)

... NIH Resources (4 links) GeneEd National Human Genome Research Institute National Institute of Neurological Disorders and Stroke: Lipid Storage Diseases Fact Sheet National Institute of Neurological ...

Effect of cyclic, low dose pyrimethamine treatment in patients with Late Onset Tay Sachs: an open label, extended pilot study.

Science.gov (United States)

Osher, Etty; Fattal-Valevski, Aviva; Sagie, Liora; Urshanski, Nataly; Sagiv, Nadav; Peleg, Leah; Lerman-Sagie, Tally; Zimran, Ari; Elstein, Deborah; Navon, Ruth; Valevski, Avi; Stern, Naftali

2015-04-17

Late Onset Tay- Sachs disease (LOTS) is a rare neurodegenerative lysosomal storage disease which results from mutations in the gene encoding the α subunit (HEXA) of β-hexosaminidase enzyme (HexA). At the present time, no effective treatment exists for LOTS and other neurodegenerative diseases involving the central nerve system (CNS). Pyrimethamine (PMT) was previously shown to act as a HexA chaperone in human fibroblasts in vitro carrying some (e.g., αG269S), but not all LOTS-related mutations. The present study assessed the effect of cyclic, low dose and long term pyrimethamine treatment on HexA in subjects with LOTS. In an open label trial in 4 LOTS patients, PMT was initiated at an average daily dose of ~2.7 mg and administered cyclically guided by blood lymphocyte HexA activity for a mean duration of 82.8 (±22.5; SD) weeks (~1.5 year). HexA activity rose in all subjects, with a mean peak increase of 2.24 folds (±0.52; SD) over baseline activity (range 1.87-3). The mean treatment time required to attain this peak was of 15.7 (±4.8; SD) weeks. Following increase in activity, HexA gradually declined with the continued use of PMT, which was then stopped, resulting in the return of HexA activity to baseline. A second cycle of PMT treatment was then initiated, resulting again in an increase in HexA activity. Three of the patients experienced a measurable neuropsychiatric deterioration whereas one subject remained entirely stable. Cyclic low dose of PMT can increase HexA activity in LOTS patients. However, the observed increase is repeatedly transient and not associated with discernible beneficial neurological or psychiatric effects.

A Drosophila protein family implicated in pheromone perception is related to Tay-Sachs GM2-activator protein.

Science.gov (United States)

Starostina, Elena; Xu, Aiguo; Lin, Heping; Pikielny, Claudio W

2009-01-02

Low volatility, lipid-like cuticular hydrocarbon pheromones produced by Drosophila melanogaster females play an essential role in triggering and modulating mating behavior, but the chemosensory mechanisms involved remain poorly understood. Recently, we showed that the CheB42a protein, which is expressed in only 10 pheromone-sensing taste hairs on the front legs of males, modulates progression to late stages of male courtship behavior in response to female-specific cuticular hydrocarbons. Here we report that expression of all 12 genes in the CheB gene family is predominantly or exclusively gustatory-specific, and occurs in many different, often non-overlapping patterns. Only the Gr family of gustatory receptor genes displays a comparable variety of gustatory-specific expression patterns. Unlike Grs, however, expression of all but one CheB gene is sexually dimorphic. Like CheB42a, other CheBs may therefore function specifically in gustatory perception of pheromones. We also show that CheBs belong to the ML superfamily of lipid-binding proteins, and are most similar to human GM2-activator protein (GM2-AP). In particular, GM2-AP residues involved in ligand binding are conserved in CheBs but not in other ML proteins. Finally, CheB42a is specifically secreted into the inner lumen of pheromone-sensing taste hairs, where pheromones interact with membrane-bound receptors. We propose that CheB proteins interact directly with lipid-like Drosophila pheromones and modulate their detection by the gustatory signal transduction machinery. Furthermore, as loss of GM2-AP in Tay-Sachs disease prevents degradation of GM2 gangliosides and results in neurodegeneration, the function of CheBs in pheromone response may involve biochemical mechanisms critical for lipid metabolism in human neurons.

A Drosophila Protein Family Implicated in Pheromone Perception Is Related to Tay-Sachs GM2-Activator Protein*

Science.gov (United States)

Starostina, Elena; Xu, Aiguo; Lin, Heping; Pikielny, Claudio W.

2009-01-01

Low volatility, lipid-like cuticular hydrocarbon pheromones produced by Drosophila melanogaster females play an essential role in triggering and modulating mating behavior, but the chemosensory mechanisms involved remain poorly understood. Recently, we showed that the CheB42a protein, which is expressed in only 10 pheromone-sensing taste hairs on the front legs of males, modulates progression to late stages of male courtship behavior in response to female-specific cuticular hydrocarbons. Here we report that expression of all 12 genes in the CheB gene family is predominantly or exclusively gustatory-specific, and occurs in many different, often non-overlapping patterns. Only the Gr family of gustatory receptor genes displays a comparable variety of gustatory-specific expression patterns. Unlike Grs, however, expression of all but one CheB gene is sexually dimorphic. Like CheB42a, other CheBs may therefore function specifically in gustatory perception of pheromones. We also show that CheBs belong to the ML superfamily of lipid-binding proteins, and are most similar to human GM2-activator protein (GM2-AP). In particular, GM2-AP residues involved in ligand binding are conserved in CheBs but not in other ML proteins. Finally, CheB42a is specifically secreted into the inner lumen of pheromone-sensing taste hairs, where pheromones interact with membrane-bound receptors. We propose that CheB proteins interact directly with lipid-like Drosophila pheromones and modulate their detection by the gustatory signal transduction machinery. Furthermore, as loss of GM2-AP in Tay-Sachs disease prevents degradation of GM2 gangliosides and results in neurodegeneration, the function of CheBs in pheromone response may involve biochemical mechanisms critical for lipid metabolism in human neurons. PMID:18952610

Population-based Tay-Sachs screening among Ashkenazi Jewish young adults in the 21st century: Hexosaminidase A enzyme assay is essential for accurate testing.

Science.gov (United States)

Schneider, Adele; Nakagawa, Sachiko; Keep, Rosanne; Dorsainville, Darnelle; Charrow, Joel; Aleck, Kirk; Hoffman, Jodi; Minkoff, Sherman; Finegold, David; Sun, Wei; Spencer, Andrew; Lebow, Johannah; Zhan, Jie; Apfelroth, Stephen; Schreiber-Agus, Nicole; Gross, Susan

2009-11-01

Tay-Sachs disease (TSD) carrier screening, initiated in the 1970s, has reduced the birth-rate of Ashkenazi Jews with TSD worldwide by 90%. Recently, several nationwide programs have been established that provide carrier screening for the updated panel of Jewish genetic diseases on college campuses and in Jewish community settings. The goals of this study were to determine the performance characteristics of clinical TSD testing in college- and community-based screening programs and to determine if molecular testing alone is adequate in those settings. Clinical data for TSD testing were retrospectively anonymized and subsequently analyzed for 1,036 individuals who participated in these programs. The performance characteristics of the serum and the platelet Hexosaminidase assays were compared, and also correlated with the results of targeted DNA analysis. The serum assay identified 29 carriers and the platelet assay identified 35 carriers for carrier rates of 1/36 and 1/29, respectively. One hundred sixty-nine samples (16.3%) were inconclusive by serum assay in marked contrast to four inconclusive samples (0.4%) by the platelet assay. Molecular analysis alone would have missed four of the 35 carriers detected by the platelet assay, yielding a false negative rate of 11.4% with a sensitivity of 88.6%. Based on the results of this study, platelet assay was superior to serum with a minimal inconclusive rate. Due to changing demographics of the Ashkenazi Jewish population, molecular testing alone in the setting of broad-based population screening programs is not sufficient, and biochemical analysis should be the assay of choice. Copyright 2009 Wiley-Liss, Inc.

A G {r_arrow} A transition at position IVS-11 +1 of the HEX A {alpha}-chain gene in a non-Ashkenazic Mexican Tay-Sachs infant

Energy Technology Data Exchange (ETDEWEB)

Miranda, S.R.P.; Gwon, S.; DeGasperi, R. [New York Univ. Medical Center, NY (United States)] [and others

1994-09-01

Tay-Sachs disease (TSD) is an autosomal recessive storage disorder caused by a deficiency of the lysosomal enzyme, {beta}-N-acetylhexosaminidase A (Hex A), a heteropolymer composed of two polypeptides, {alpha} and {beta}. Mutations in the {alpha}-chain gene render the enzyme defective, resulting in the accumulation of g{sub m2} ganglioside in the nervous system. Deficiency of Hex A was detected in a non-Ashkenazic girl of Mexican origin indicating infantile onset of TSD. Molecular investigation of the {alpha}-chain gene excluded the typical Ashkenazic 4 bp insertion in the exon 11 and the intron 12 splice-junction mutations by Hae III and Dde I restriction analysis, respectively. Single strand conformation polymorphism (SSCP) analysis showed a different pattern in the sample where exon 11 and flanking regions were amplified in the patient DNA as compared to the migration of control DNA. Sequencing of PCR amplified genomic DNA containing exon 11 and flanking intronic regions showed a single base substitution (G {r_arrow} A) at position IVS-11 +1. This mutation creates a recognition site for the restriction enzyme Mbo II. Digestion of exon 11 and flanking regions with Mbo II demonstrated homozygosity of the patient for this mutation and heterozygosity in the mother. mRNA from cultured fibroblasts obtained from a normal control and from the propositus was reverse transcribed. The cDNAs coding for Hex A {alpha}-chain were amplified in four overlapping fragments. In the patient sample it was not possible to amplify the fragment containing the exon 11/intron 11 junction, indicating that this mutation alters normal RNA processing of the Hex A pre-mRNA resulting in the deficiency of Hex A activity.

The Natural History of Juvenile or Subacute GM2 Gangliosidosis: 21 New Cases and Literature Review of 134 Previously Reported

Science.gov (United States)

Maegawa, Gustavo H. B.; Stockley, Tracy; Tropak, Michael; Banwell, Brenda; Blaser, Susan; Kok, Fernando; Giugliani, Roberto; Mahuran, Don; Clarke, Joe T. R.

2010-01-01

OBJECTIVE Juvenile GM2 gangliosidosis is a group of inherited neurodegenerative diseases caused by deficiency of lysosomal β-hexosaminidase resulting in GM2 ganglioside accumulation in brain. The purpose of this study was to delineate the natural history of the condition and identify genotype-phenotype correlations that might be helpful in predicting the course of the disease in individual patients. METHODS A cohort of 21 patients with juvenile GM2 gangliosidosis, 15 with the Tay-Sachs variant and 6 with the Sandhoff variant, was studied prospectively in 2 centers. Our experience was compared with previously published reports on 134 patients. Information about clinical features, β-hexosaminidase enzyme activity, and mutation analysis was collected. RESULTS In our cohort of patients, the mean (±SD) age of onset of symptoms was 5.3 ± 4.1 years, with a mean follow-up time of 8.4 years. The most common symptoms at onset were gait disturbances (66.7%), incoordination (52.4%), speech problems (28.6%), and developmental delay (28.6%). The age of onset of gait disturbances was 7.1 ± 5.6 years. The mean time for progression to becoming wheelchair-bound was 6.2 ± 5.5 years. The mean age of onset of speech problems was 7.0 ± 5.6 years, with a mean time of progression to anarthria of 5.6 ± 5.3 years. Muscle wasting (10.6 ± 7.4 years), proximal weakness (11.1 ± 7.7 years), and incontinence of sphincters (14.6 ± 9.7 years) appeared later in the course of the disease. Psychiatric disturbances and neuropathy were more prevalent in patients with the Sandhoff variant than in those with the Tay-Sachs variant. However, dysphagia, sphincter incontinence, and sleep problems occurred earlier in those with the Tay-Sachs variant. Cerebellar atrophy was the most common finding on brain MRI (52.9%). The median survival time among the studied and reviewed patients was 14.5 years. The genotype-phenotype correlation revealed that in patients with the Tay-Sachs variant, the presence

Stem Cell Transplant for Inborn Errors of Metabolism

Science.gov (United States)

2017-12-03

Adrenoleukodystrophy; Metachromatic Leukodystrophy; Globoid Cell Leukodystrophy; Gaucher's Disease; Fucosidosis; Wolman Disease; Niemann-Pick Disease; Batten Disease; GM1 Gangliosidosis; Tay Sachs Disease; Sandhoff Disease

Análise da Incidência de Mutações no Gene HEXA na População Judaica Brasileira - Avaliação da Importância de um Programa Preventivo da Doença de Tay-Sachs

OpenAIRE

Roberto Rozenberg

2000-01-01

A doença de Tay-Sachs (DTS) é uma doença neurodegenerativa, de herança autossômica recessiva, que se manifesta a partir do sexto mês de vida. Crianças afetadas desenvolvem degeneração física e mental intensa, levando à morte até os 5 anos de idade. Não há atualmente cura ou tratamento disponível. Na população judaica, 1 em cada 31 indivíduos é portador da DTS, e a incidência da doença (aproximadamente 1 em cada 4.000 nascimentos) é cerca de 100 vezes maior nesta do que em outras populações. O...

Genetic Counseling in Mental Retardation.

Science.gov (United States)

Bowen, Peter

The task of the genetic counselor who identifies genetic causes of mental retardation and assists families to understand risk of recurrence is described. Considered are chromosomal genetic disorders such as Down's syndrome, inherited disorders such as Tay-Sachs disease, identification by testing the amniotic fluid cells (amniocentresis) in time…

MR imaging of white-matter diseases in children

International Nuclear Information System (INIS)

Sato, Y.; Yuh, W.T.C.; Mathews, K.; Wiese, J.; Kao, S.; Schreiber, A.; Farner, R.; Smith, W.

1987-01-01

MR imaging has become a valuable tool in the investigation of central nervous system abnormalities in children. This exhibit displays the MR imaging patterns in 30 children with diseases involving the white matter. Clinical, CT, and pathologic findings will be presented for comparison. The white matter disease entities studies include acquired white matter diseases, metabolic diseases, and phycomatoses. Specific examples include acute dissemination encephalomyelitis, anoxic encephalopathy, disseminated necrotizing leukoencephalopathy, demyelinating adrenoleukodystrophy, Krabbe disease, metachromatic leukodystrophy, Tay-Sachs disease, Gaucher disease, neurofibromatosis, and Sturge-Weber syndrome

Two novel exonic point mutations in HEXA identified in a juvenile Tay-Sachs patient: role of alternative splicing and nonsense-mediated mRNA decay.

Science.gov (United States)

Levit, A; Nutman, D; Osher, E; Kamhi, E; Navon, R

2010-06-01

We have identified three mutations in the beta-hexoseaminidase A (HEXA) gene in a juvenile Tay-Sachs disease (TSD) patient, which exhibited a reduced level of HEXA mRNA. Two mutations are novel, c.814G>A (p.Gly272Arg) and c.1305C>T (p.=), located in exon 8 and in exon 11, respectively. The third mutation, c.1195A>G (p.Asn399Asp) in exon 11, has been previously characterized as a common polymorphism in African-Americans. Hex A activity measured in TSD Glial cells, transfected with HEXA cDNA constructs bearing these mutations, was unaltered from the activity level measured in normal HEXA cDNA. Analysis of RT-PCR products revealed three aberrant transcripts in the patient, one where exon 8 was absent, one where exon 11 was absent and a third lacking both exons 10 and 11. All three novel transcripts contain frameshifts resulting in premature termination codons (PTCs). Transfection of mini-gene constructs carrying the c.814G>A and c.1305C>T mutations proved that the two mutations result in exon skipping. mRNAs that harbor a PTC are detected and degraded by the nonsense-mediated mRNA decay (NMD) pathway to prevent synthesis of abnormal proteins. However, although NMD is functional in the patient's fibroblasts, aberrant transcripts are still present. We suggest that the level of correctly spliced transcripts as well as the efficiency in which NMD degrade the PTC-containing transcripts, apparently plays an important role in the phenotype severity of the unique patient and thus should be considered as a potential target for drug therapy.

Learning about Tay-Sachs Disease

Science.gov (United States)

... Care Genomic Medicine Working Group New Horizons and Research Patient Management Policy and Ethics Issues Quick Links for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for ...

Expanding the spectrum of HEXA mutations in Indian patients with Tay–Sachs disease

Directory of Open Access Journals (Sweden)

Jayesh Sheth

2014-01-01

Full Text Available Tay–Sachs disease is an autosomal recessive neurodegenerative disorder occurring due to impaired activity of β-hexosaminidase-A (EC 3.2.1.52, resulting from the mutation in HEXA gene. Very little is known about the molecular pathology of TSD in Indian children except for a few mutations identified by us. The present study is aimed to determine additional mutations leading to Tay–Sachs disease in nine patients confirmed by the deficiency of β-hexosaminidase-A (C (D175A and c.805G>C (p.G269R in one case; and one small 1 bp deletion c.426delT (p.F142LfsX57 and one splice site mutation c.459+4A>C in the other two cases respectively. None of these mutations were detected in 100 chromosomes from healthy individuals of the same ethnic group. Three previously reported missense mutations, (i c.532C>T (p.R178C, (ii c.964G>T (p.D322Y, and (iii c.1385A>T (p.E462V; two nonsense mutations (i c.709C>T (p.Q237X and (ii c.1528C>T (p.R510X, one 4 bp insertion c.1277_1278insTATC (p.Y427IfsX5 and one splice site mutation c.459+5G>A were also identified in six cases. We observe from this study that novel mutations are more frequently observed in Indian patients with Tay–Sachs disease with clustering of ~73% of disease causing mutations in exons 5 to 12. This database can be used for a carrier rate screening in the larger population of the country.

Mice doubly-deficient in lysosomal hexosaminidase A and neuraminidase 4 show epileptic crises and rapid neuronal loss.

Directory of Open Access Journals (Sweden)

Volkan Seyrantepe

2010-09-01

Full Text Available Tay-Sachs disease is a severe lysosomal disorder caused by mutations in the HexA gene coding for the α-subunit of lysosomal β-hexosaminidase A, which converts G(M2 to G(M3 ganglioside. Hexa(-/- mice, depleted of β-hexosaminidase A, remain asymptomatic to 1 year of age, because they catabolise G(M2 ganglioside via a lysosomal sialidase into glycolipid G(A2, which is further processed by β-hexosaminidase B to lactosyl-ceramide, thereby bypassing the β-hexosaminidase A defect. Since this bypass is not effective in humans, infantile Tay-Sachs disease is fatal in the first years of life. Previously, we identified a novel ganglioside metabolizing sialidase, Neu4, abundantly expressed in mouse brain neurons. Now we demonstrate that mice with targeted disruption of both Neu4 and Hexa genes (Neu4(-/-;Hexa(-/- show epileptic seizures with 40% penetrance correlating with polyspike discharges on the cortical electrodes of the electroencephalogram. Single knockout Hexa(-/- or Neu4(-/- siblings do not show such symptoms. Further, double-knockout but not single-knockout mice have multiple degenerating neurons in the cortex and hippocampus and multiple layers of cortical neurons accumulating G(M2 ganglioside. Together, our data suggest that the Neu4 block exacerbates the disease in Hexa(-/- mice, indicating that Neu4 is a modifier gene in the mouse model of Tay-Sachs disease, reducing the disease severity through the metabolic bypass. However, while disease severity in the double mutant is increased, it is not profound suggesting that Neu4 is not the only sialidase contributing to the metabolic bypass in Hexa(-/- mice.

SAChES: Scalable Adaptive Chain-Ensemble Sampling.

Energy Technology Data Exchange (ETDEWEB)

Swiler, Laura Painton [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Ray, Jaideep [Sandia National Lab. (SNL-CA), Livermore, CA (United States); Ebeida, Mohamed Salah [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Huang, Maoyi [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Hou, Zhangshuan [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Bao, Jie [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Ren, Huiying [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

2017-08-01

We present the development of a parallel Markov Chain Monte Carlo (MCMC) method called SAChES, Scalable Adaptive Chain-Ensemble Sampling. This capability is targed to Bayesian calibration of com- putationally expensive simulation models. SAChES involves a hybrid of two methods: Differential Evo- lution Monte Carlo followed by Adaptive Metropolis. Both methods involve parallel chains. Differential evolution allows one to explore high-dimensional parameter spaces using loosely coupled (i.e., largely asynchronous) chains. Loose coupling allows the use of large chain ensembles, with far more chains than the number of parameters to explore. This reduces per-chain sampling burden, enables high-dimensional inversions and the use of computationally expensive forward models. The large number of chains can also ameliorate the impact of silent-errors, which may affect only a few chains. The chain ensemble can also be sampled to provide an initial condition when an aberrant chain is re-spawned. Adaptive Metropolis takes the best points from the differential evolution and efficiently hones in on the poste- rior density. The multitude of chains in SAChES is leveraged to (1) enable efficient exploration of the parameter space; and (2) ensure robustness to silent errors which may be unavoidable in extreme-scale computational platforms of the future. This report outlines SAChES, describes four papers that are the result of the project, and discusses some additional results.

Tay-Sachs disease preconception screening in Australia: self-knowledge of being an Ashkenazi Jew predicts carrier state better than does ancestral origin, although there is an increased risk for c.1421 + 1G > C mutation in individuals with South African heritage.

Science.gov (United States)

Lew, Raelia; Burnett, Leslie; Proos, Anné

2011-12-01

The Australasian Community Genetics Program provided a preconception screening for Tay-Sachs disease (TSD) to 4,105 Jewish high school students in Sydney and Melbourne over the 12-year period 1995-2007. By correlating the frequencies of mutant HEXA, MIM *606869 (gene map locus 15q23-q24) alleles with subjects' nominated ethnicity (Ashkenazi/Sephardi/Mixed) and grandparental birthplaces, we established that Ashkenazi ethnicity is a better predictor of TSD carrier status than grandparental ancestral origins. Screening self-identified Ashkenazi subjects detected 95% of TSD carriers (carrier frequency 1:25). Having mixed Ashkenazi and non-Ashkenazi heritage reduced the carrier frequency (1:97). South African heritage conveyed a fourfold risk of c.1421 + 1G > C mutation compared with other AJ subjects (odds ratio (OR), 4.19; 95% confidence interval (CI), 1.83-9.62, p = 0.001), but this was the only specific case of ancestral origin improving diagnostic sensitivity over that based on determining Ashkenazi ethnicity. Carriers of c.1278insTATC mutations were more likely to have heritage from Western Europe (OR, 1.65 (95% CI, 1.04-2.60), p = 0.032) and South Eastern Europe (OR, 1.77 (95% CI, 1.14-2.73), p = 0.010). However, heritage from specific European countries investigated did not significantly alter the overall odds of TSD carrier status.

Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: studies of lysosomal storage diseases and channelopathy

Science.gov (United States)

Kano, Shin-ichi; Yuan, Ming; Cardarelli, Ross A.; Maegawa, Gustavo; Higurashi, Norimichi; Gaval-Cruz, Meriem; Wilson, Ashley M.; Tristan, Carlos; Kondo, Mari A.; Chen, Yian; Koga, Minori; Obie, Cassandra; Ishizuka, Koko; Seshadri, Saurav; Srivastava, Rupali; Kato, Takahiro A.; Horiuchi, Yasue; Sedlak, Thomas W.; Lee, Yohan; Rapoport, Judith L.; Hirose, Shinichi; Okano, Hideyuki; Valle, David; O'Donnell, Patricio; Sawa, Akira; Kai, Mihoko

2015-01-01

Methodologies for generating functional neuronal cells directly from human fibroblasts [induced neuronal (iN) cells] have been recently developed, but the research so far has only focused on technical refinements or recapitulation of known pathological phenotypes. A critical question is whether this novel technology will contribute to elucidation of novel disease mechanisms or evaluation of therapeutic strategies. Here we have addressed this question by studying Tay-Sachs disease, a representative lysosomal storage disease, and Dravet syndrome, a form of severe myoclonic epilepsy in infancy, using human iN cells with feature of immature postmitotic glutamatergic neuronal cells. In Tay-Sachs disease, we have successfully characterized canonical neuronal pathology, massive accumulation of GM2 ganglioside, and demonstrated the suitability of this novel cell culture for future drug screening. In Dravet syndrome, we have identified a novel functional phenotype that was not suggested by studies of classical mouse models and human autopsied brains. Taken together, the present study demonstrates that human iN cells are useful for translational neuroscience research to explore novel disease mechanisms and evaluate therapeutic compounds. In the future, research using human iN cells with well-characterized genomic landscape can be integrated into multidisciplinary patient-oriented research on neuropsychiatric disorders to address novel disease mechanisms and evaluate therapeutic strategies. PMID:25732146

An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay-Sachs or Sandhoff variants).

Science.gov (United States)

Clarke, Joe T R; Mahuran, Don J; Sathe, Swati; Kolodny, Edwin H; Rigat, Brigitte A; Raiman, Julian A; Tropak, Michael B

2011-01-01

Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of ß-hexosaminidase A (Hex A), resulting from mutations in the HEXA (Tay-Sachs variant) or the HEXB (Sandhoff variant) genes. The enzyme deficiency in many patients with juvenile or adult onset forms of the disease results from the production of an unstable protein, which becomes targeted for premature degradation by the quality control system of the smooth endoplasmic reticulum and is not transported to lysosomes. In vitro studies have shown that many mutations in either the α or β subunit of Hex A can be partially rescued, i.e. enhanced levels of both enzyme protein and activity in lysosomes, following the growth of patient cells in the presence of the drug, pyrimethamine. The objectives of the present clinical trial were to establish the tolerability and efficacy of the treatment of late-onset GM2 gangliosidosis patients with escalating doses of pyrimethamine, to a maximum of 100 mg per day, administered orally in a single daily dose, over a 16-week period . The primary objective, tolerability, was assessed by regular clinical examinations, along with a panel of hematologic and biochemical studies. Although clinical efficacy could not be assessed in this short trial, treatment efficacy was evaluated by repeated measurements of leukocyte Hex A activity, expressed relative to the activity of lysosomal ß-glucuronidase. A total of 11 patients were enrolled, 8 males and 3 females, aged 23 to 50 years. One subject failed the initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events which were not drug-related. For the remaining 8 subjects, up to a 4-fold enhancement of Hex A activity at doses of 50 mg per day or less was observed. Additionally marked individual variations in the pharmacokinetics of the drug among the patients were

Mucopolysaccharidoses

Science.gov (United States)

... Hunter's Hope Foundation[A Leukodystrophy Resource] National MPS Society, Inc. National Tay-Sachs and Allied Diseases ... Definition The mucopolysaccharidoses are a group of inherited metabolic ...

Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders

Science.gov (United States)

2017-11-15

Hurler Syndrome (MPS I); Hurler-Scheie Syndrome; Hunter Syndrome (MPS II); Sanfilippo Syndrome (MPS III); Krabbe Disease (Globoid Leukodystrophy); Metachromatic Leukodystrophy (MLD); Adrenoleukodystrophy (ALD and AMN); Sandhoff Disease; Tay Sachs Disease; Pelizaeus Merzbacher (PMD); Niemann-Pick Disease; Alpha-mannosidosis

Penerapankonsep Taysîrdalam Sistem Ekonomi Islam

OpenAIRE

Iswandi, Andi

2014-01-01

Application of Taysîrin The Islamic Economic System. Studies about the taysîrconcept are still minimal but taysîrhas a significant function in addressing issues of Islamic law, particularly in the field of mu'âmalah. In the field of mu'âmalah, the taysîrconcept is not only needed, moreover it is a ‘cure' in necessity to heal the morbidity of heretical behaviour in business and economics. Taysîrhas also become the answer for groups of people who are contradictory when addressing the Shari'a la...

Hypotonia

Science.gov (United States)

... damage include: Down syndrome Spinal muscular atrophy Prader-Willi syndrome Tay-Sachs disease Trisomy 13 Other disorders ... commercial use must be authorized in writing by ADAM Health Solutions. About MedlinePlus Site Map FAQs Customer ...

A Trp474Cys mutation in the alpha-subunit of beta-hexosaminidase causes a subacute encephalopathic form of G{sub M2} gangliosidosis, type 1

Energy Technology Data Exchange (ETDEWEB)

Petroulakis, E.; Cao, Z.; Salo, T. [Univ. of Manitoba, Winnipeg (Canada)] [and others

1994-09-01

Mutations in the HEXA gene that encodes the {alpha}-subunit of the heterodimeric lysosomal enzyme {beta}-hexosaminidase A, or Hex A ({alpha}{beta}), cause G{sub M2} gangliosidosis, type 1. The infantile form (Tay-Sachs disease) results when there is no residual Hex A activity, while less severe and more variable clinical phenotypes result when residual Hex A activity is present. A non-Jewish male who presented with an acute psychotic episode at age 16 was diagnosed with a subacute encephalopathic form of G{sub M2} gangliosidosis. At age 19, chronic psychosis with intermittent acute exacerbations remains the most disabling symptom in this patient and his affected brother although both exhibit some ataxia and moderately severe dysarthria. We have found a 4 bp insertion (+TATC 1278) associated with infantile Tay-Sachs disease on one allele; no previously identified mutation was found on the second allele. SSCP analysis detected a shift in exon 13 and sequencing revealed a G1422C mutation in the second allele that results in a Trp474Cys substitution. The presence of the mutation was confirmed by the loss of HaeIII and ScrFI sites in exon 13 PCR products from the subjects and their father. The mutation was introduced into the {alpha}-subunit cDNA and Hex S ({alpha}{alpha}) and Hex A ({alpha}{beta}) were transiently expressed in monkey COS-7 cells. The Trp474Cys mutant protein had approximately 5% and 12% of wild-type Hex S and Hex A activity, respectively. Western blot analysis revealed a small amount of residual mature {alpha}-subunit and a normal level of precursor protein. We conclude that the Trp474Cys mutation is the cause of the Hex A deficiency associated with a subacute (juvenile-onset) phenotype in this patient. Like other mutations in exon 13 of HEXA, it appears to affect intracellular processing. Studies of the defect in intracellular processing are in progress.

Longitudinal Study of Neurodegenerative Disorders

Science.gov (United States)

2018-01-31

MLD; Krabbe Disease; ALD; MPS I; MPS II; MPS III; Vanishing White Matter Disease; GM3 Gangliosidosis; PKAN; Tay-Sachs Disease; NP Deficiency; Osteopetrosis; Alpha-Mannosidosis; Sandhoff Disease; Niemann-Pick Diseases; MPS IV; Gaucher Disease; GAN; GM1 Gangliosidoses; Morquio Disease; S-Adenosylhomocysteine Hydrolase Deficiency; Batten Disease; Pelizaeus-Merzbacher Disease; Leukodystrophy; Lysosomal Storage Diseases; Purine Nucleoside Phosphorylase Deficiency; Multiple Sulfatase Deficiency Disease

Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease

Science.gov (United States)

Bradbury, Allison M; Gray-Edwards, Heather L; Shirley, Jamie L; McCurdy, Victoria J; Colaco, Alexandria N; Randle, Ashley N; Christopherson, Pete W; Bird, Allison C; Johnson, Aime K; Wilson, Diane U; Hudson, Judith A; De Pompa, Nicholas L; Sorjonen, Donald C; Brunson, Brandon L; Jeyakumar, Mylvaganam; Platt, Frances M; Baker, Henry J; Cox, Nancy R; Sena-Esteves, Miguel; Martin, Douglas R

2014-01-01

The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are progressive neurodegenerative disorders that are caused by a mutation in the enzyme β-N-acetylhexosaminidase (Hex). Due to the recent emergence of novel experimental treatments, biomarker development has become particularly relevant in GM2 gangliosidosis as an objective means to measure therapeutic efficacy. Here we describe blood, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electrodiagnostic methods for evaluating disease progression in the feline SD model and application of these approaches to assess AAV-mediated gene therapy. SD cats were treated by intracranial injections of the thalami combined with either the deep cerebellar nuclei or a single lateral ventricle using AAVrh8 vectors encoding feline Hex. Significantly altered in untreated SD cats, blood and CSF based biomarkers were normalized after AAV gene therapy. Also reduced after treatment were expansion of the lysosomal compartment in peripheral blood mononuclear cells and elevated activity of secondary lysosomal enzymes. MRI changes characteristic of the gangliosidoses were documented in SD cats and normalized after AAV gene therapy. The minimally invasive biomarkers reported herein should be useful to assess disease progression of untreated GM2 patients and those in future clinical trials. PMID:25284324

Human genetics in Johannesburg, South Africa: Past, present and ...

African Journals Online (AJOL)

Genetic screening was then initiated for the Jewish community because of their high carrier rate for Tay-Sachs disease. Educational courses in human genetics were offered at Wits Medical School, and medical as well as other health professionals began to be trained. Research, supported by national and international ...

Survey on serum acetylecholinesterase (SAChE activity in selected farming communities at risk of organophosphate exposure, Southern Ghana

Directory of Open Access Journals (Sweden)

Ato Kwamena Tetteh

2017-12-01

Material and Methods ― The study was cross-sectional, involving 963 participants who consented to being screened for serum acetylcholinesterase (SAChE activity, using the dry chemistry test strips. The SAChE activity was then categorized into normal, low or high risk of developing symptoms associated with OP poisoning. Results ― The total group included 54.5% females and 45.5% males. Majority were crop farmers (46.3% and students/pupils (30.8%. The remaining 22.9% consisted mainly of traders, teachers, fishermen/fish processors, drivers and dressmakers. Very low SAChE activity unit of 30 U/ml. By this, a significant majority had either low or high risk of developing OP poisoning (χ2=4.43, 95%CI: 4.12–4.65, p=0.014 compared with those with normal activity. Most of the participants were in the 10–19 years age group of which 15.6% were in the high risk category, while 13.6% had low risk of OP poisoning. Reduced SAChE activity was predominant among all age groups compared with those with normal activity of the enzyme. As well, 27.3% who were females had reduced SAChE activity rate <30 U/ml (high risk of OP poisoning. Similarly, 23.4% of males were also at high risk of OP poisoning. There was however no statistical significance between the sex with regards to the numbers at risk of OP poisoning (χ2=4.80, 95% CI: 4.25–4.75, p=0.160. Conclusion ― This study provides some evidence of exposure, deduced from reduced SAChE activity, which potentially puts participants at a high risk of developing symptoms associated with OP poisoning. A follow-up study might be able to suggest to physicians in Ghana considering diagnostics of OP poisoning, especially for clients from farming communities where pesticides are used extensively.

75 FR 14379 - Airworthiness Directives; Rolls-Royce Deutschland Ltd & Co KG (RRD) Models Tay 620-15, Tay 650-15...

Science.gov (United States)

2010-03-25

...: Following a review of operational data of the Tay 651-54 engine, it has been found that the actual stress... any written relevant data, views, or arguments about this proposed AD. Send your comments to an... found that the actual stress levels in the Tay 651-54 engine High Pressure Compressor (HPC) stages 1, 3...

Tectonic Evolution of Jabal Tays Ophiolite Complex, Eastern Arabian Shield, Saudi Arabia

Science.gov (United States)

AlHumidan, Saad; Kassem, Osama; Almutairi, Majed; Al-Faifi, Hussain; Kahal, Ali

2017-04-01

Microstructural analysis is important for investigation of tectonic evaluation of Jable Tays area. Furthermore, the Jable Tays ophiolite complex is effected by Al Amar -Idsas fault. The nature of the Al Amar-Idsas fault is a part of the Eastern Arabian Shield, which was subjected to multiple interpretations. Through fieldwork investigation, microscopic examination, and microstructural analysis, we aim to understand the evolution and tectonic setting of the Jable Tays area. Finite-strain data displays that the Abt schist, the metavolcanics and the metagranites are highly to moderately deformed. The axial ratios in the XZ section range from 1.40 to 2.20. The long axes of the finite-strain ellipsoids trend NW- SE and W-E in the Jable Tays area while, their short axes are subvertical to subhorizontal foliations. The strain magnitude does not increase towards the tectonic contacts between the Abt schist and metavolcano-sedimentary. While majority of the obtained data indicate a dominant oblate with minor prolate strain symmetries in the Abt schist, metavolcano-sedimentary and metagranites. The strain data also indicate flattening with some constriction. We assume that the Abt schist and the metavolcano-sedimentry rocks have similar deformation behavior. The finite strain in the studied rocks accumulated during the metamorphism that effected by thrusting activity. Based on these results, we finally concluded that the contact between Abt schist and metavolcano-sedimentary rocks were formed during the progressive thrusting under brittle to semi-ductile deformation conditions by simple shear that also involved a component of vertical shortening, causing subhorizontal foliation in Jable Tays area.

A second mutation associated with apparent [beta]-hexosaminidase A pseudodeficiency: Identification and frequency estimation

Energy Technology Data Exchange (ETDEWEB)

Cao, Z.; Chabot, T.; Triggs-Raine, B.L. (Univ. of Manitoba, Winnepeg (Canada)); Natowicz, M.R.; Prence, E.M. (Shriver Center for Mental Retardation, Waltham, MA (United States) Harvard Medical School, Boston, MA (United States)); Kaback, M.M.; Lim-Steele, S.T.; Brown, D. (Children' s Hospital, San Diego, CA (United States) Univ. of California, San Diego, CA (United States))

1993-12-01

Deficient activity of [beta]-hexosaminidase A (Hex A), resulting from mutations in the HEXA gene, typically causes Tay-Sachs disease. However, healthy individuals lacking Hex A activity against synthetic substrates (i.e., individuals who are pseudodeficient) have been described. Recently, an apparently benign C[sub 739]-to-T (Arg247Trp) mutation was found among individuals with Hex A levels indistinguishable from those of carriers of Tay-Sachs disease. This allele, when in compound heterozygosity with a second [open quotes]disease-causing[close quotes] allele, results in Hex A pseudodeficiency. The authors examined the HEXA gene of a healthy 42-year-old who was Hex A deficient but did not have the C[sub 739]-to-T mutation. The HEXA exons were PCR amplified, and the products were analyzed for mutations by using restriction-enzyme digestion or single-strand gel electrophoresis. A G[sub 805]-to-A (Gly269Ser) mutation associated with adult-onset G[sub m2] gangliosidosis was found on one chromosome. A new mutation, C[sub 745]-to-T (Arg 249Trp), was identified on the second chromosome. This mutation was detected in an additional 4/63 (6%) non-Jewish and 0/218 Ashkenazi Jewish enzyme-defined carriers. Although the Arg249Trp change may result in a late-onset form of G[sub M2] gangliosidosis, any phenotype must be very mild. This new mutation and the benign C[sub 739]-to-T mutation together account for [approximately]38% of non-Jewish enzyme-defined carriers. Because carriers of the C[sub 739]-to-T and C[sub 745]-to-T mutations cannot be differentiated from carriers of disease-causing alleles by using the classical biochemical screening approaches, DNA-based analyses for these mutations should be offered for non-Jewish enzyme-defined heterozygotes, before definitive counseling is provided. 46 refs., 5 figs., 2 tabs.

Lysosomal storage diseases

Science.gov (United States)

Ferreira, Carlos R.; Gahl, William A.

2016-01-01

Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency of an activator protein, as occurs in the AB variant of GM2 gangliosidosis. Still other times, the accumulated lysosomal material results from failed egress of a small molecule as a consequence of a deficient transporter, as in cystinosis or Salla disease. In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases. Examples include imiglucerase, taliglucerase and velaglucerase for Gaucher disease, laronidase for Hurler disease, idursulfase for Hunter disease, elosulfase for Morquio disease, galsulfase for Maroteaux-Lamy disease, alglucosidase alfa for Pompe disease, and agalsidase alfa and beta for Fabry disease. In addition, substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease. The advent of treatment options for some of these disorders has led to newborn screening pilot studies, and ultimately to the addition of Pompe disease and Hurler disease to the Recommended Uniform Screening Panel (RUSP) in 2015 and 2016, respectively. PMID:29152458

GM2 gangliosidosis in a UK study of children with progressive neurodegeneration: 73 cases reviewed.

Science.gov (United States)

Smith, Nicholas J; Winstone, Anne Marie; Stellitano, Lesley; Cox, Timothy M; Verity, Christopher M

2012-02-01

To report the demographic, phenotypic, and time-to-diagnosis characteristics of children with GM2 gangliosidosis referred to the UK study of Progressive Intellectual and Neurological Deterioration. Case notification is made via monthly surveillance card, administered by the British Paediatric Surveillance Unit to all UK-based paediatricians; children with GM2 gangliosidosis were identified from cases satisfying inclusion in the UK study of Progressive Intellectual and Neurological Deterioration and analysed according to phenotypic and biochemical categories. Between May 1997 and January 2010, 73 individuals with GM2 gangliosidoses were reported: 40 with Tay-Sachs disease, 31 with Sandhoff disease, and two with GM2 activator protein deficiency. Together they account for 6% (73/1164) of all diagnosed cases of progressive intellectual and neurological deterioration. The majority (62/73) were sporadic index cases with no family history. Children of Pakistani ancestry were overrepresented in all subtypes, particularly juvenile Sandhoff disease, accounting for 10 of 11 notified cases. Infantile-onset variants predominated (55/73); the mean age at onset of symptoms was 6.2 and 4.7 months for infantile-onset Tay-Sachs and Sandhoff disease respectively, and 26.2 and 34.7 months for the corresponding juvenile-onset variants. Time to diagnosis averaged 7.4 months and 28.0 months in infantile- and juvenile-onset disease respectively. GM2 gangliosidosis is a significant cause of childhood neurodegenerative disease; timely diagnosis relies upon improved clinical recognition, which may be increasingly important as specific therapies become available. There is a potential benefit from the introduction of screening programmes for high-risk ethnic groups. © The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.

In cellulo examination of a beta-alpha hybrid construct of beta-hexosaminidase A subunits, reported to interact with the GM2 activator protein and hydrolyze GM2 ganglioside.

Directory of Open Access Journals (Sweden)

Incilay Sinici

Full Text Available The hydrolysis in lysosomes of GM2 ganglioside to GM3 ganglioside requires the correct synthesis, intracellular assembly and transport of three separate gene products; i.e., the alpha and beta subunits of heterodimeric beta-hexosaminidase A, E.C. # 3.2.1.52 (encoded by the HEXA and HEXB genes, respectively, and the GM2-activator protein (GM2AP, encoded by the GM2A gene. Mutations in any one of these genes can result in one of three neurodegenerative diseases collectively known as GM2 gangliosidosis (HEXA, Tay-Sachs disease, MIM # 272800; HEXB, Sandhoff disease, MIM # 268800; and GM2A, AB-variant form, MIM # 272750. Elements of both of the hexosaminidase A subunits are needed to productively interact with the GM2 ganglioside-GM2AP complex in the lysosome. Some of these elements have been predicted from the crystal structures of hexosaminidase and the activator. Recently a hybrid of the two subunits has been constructed and reported to be capable of forming homodimers that can perform this reaction in vivo, which could greatly simplify vector-mediated gene transfer approaches for Tay-Sachs or Sandhoff diseases. A cDNA encoding a hybrid hexosaminidase subunit capable of dimerizing and hydrolyzing GM2 ganglioside could be incorporated into a single vector, whereas packaging both subunits of hexosaminidase A into vectors, such as adeno-associated virus, would be impractical due to size constraints. In this report we examine the previously published hybrid construct (H1 and a new more extensive hybrid (H2, with our documented in cellulo (live cell- based assay utilizing a fluorescent GM2 ganglioside derivative. Unfortunately when Tay-Sachs cells were transfected with either the H1 or H2 hybrid construct and then were fed the GM2 derivative, no significant increase in its turnover was detected. In vitro assays with the isolated H1 or H2 homodimers confirmed that neither was capable of human GM2AP-dependent hydrolysis of GM2 ganglioside.

III. Ulusal Sosyoloji Çalıştayı

OpenAIRE

Hür Mahmut YÜCER; Sami Şener; Beğlü Dikeçligil; Ümit Tatlıcan; Muammer Tuna; Zeki Arslantürk; Müzeyyen Güler; Aylin Görgün Baran; Yahya Mustafa Keskin; Vehbi Bayhan; Ali Öztürk

2012-01-01

III. Ulusal Sosyoloji Çalıştayı 26 Mayıs 2012 tarihinde Karabük Üniversitesi Sosyoloji bölümünün ev sahipliğinde gerçekleştirildi. Çalıştayın I. Oturumunda Sosyolojinin Temel sorunları ele alındı. II. Oturumda ise Sosyolojinin istihdam sorunları üzerinde duruldu. Burada yer alan metin, Karabük Üniversitesi Sosyoloji Bölümü yüksek lisans öğrencilerinin, çalıştayın görüntü ve ses kayıtlarını çözümlemeleriyle oluşturulmuştur.

Planck 2015 results: XXI. The integrated Sachs-Wolfe effect

DEFF Research Database (Denmark)

Ade, P. A R; Aghanim, N.; Arnaud, M.

2016-01-01

This paper presents a study of the integrated Sachs-Wolfe (ISW) effect from the Planck 2015 temperature and polarization data release. This secondary cosmic microwave background (CMB) anisotropy caused by the large-scale time-evolving gravitational potential is probed from different perspectives....

Energy in the Kantowski–Sachs space-time using teleparallel ...

Indian Academy of Sciences (India)

Energy in the Kantowski–Sachs space-time using teleparallel geometry ... Kantowski–Sachs metric; teleparallelism; gravitational energy. Abstract. The purpose of this paper is to examine the energy content of the inflationary Universe described by Kantowski–Sachs space-time in quasilocal approach of teleparallel gravity ...

Expression of the benign HEXA mutations, Arg247Trp and Arg249Trp, associated with beta-hexosaminidase A pseudodeficiency

Energy Technology Data Exchange (ETDEWEB)

Cao, Z.; Petroulakis, E.; Salo, T. [Univ. of Manitoba (Canada)] [and others

1994-09-01

{beta}-Hexosaminidase (Hex A) is a heterodimer of {alpha} and {beta} subunits encoded by the HEXA and HEXB genes, respectively. Mutations in the HEXA gene typically cause Tay-Sachs disease or less severe forms of G{sub M2} gangliosidosis. However, two benign mutations (Arg247Trp and Arg249Trp) in the {alpha}-subunit of Hex A account for Hex A deficiency in {approximately}36% of non-Jewish enzyme-defined Tay-Sachs disease carriers. These mutations do not result in any apparent clinical phenotype in individuals who are genetic compounds with a second disease-causing mutation. We expressed the {alpha}-subunit harboring each of the benign mutations separately to study activity toward the synthetic substrate, 4-MUGS, for comparison to activity from enzymes containing mutations associated with other forms of G{sub M2} gangliosidosis. The C739T (Arg247Trp;benign), C745T (Arg 249Trp; benign), G805A (Gly269Ser; adult-onset), G749A (Gly250Asp; juvenile), and C508T (Arg170Trp; infantile) mutations were introduced into the {alpha}-subunit cDNA. These were transfected alone, or with the {beta}-subunit cDNA, to generate Hex S ({alpha}{alpha}) or Hex A ({alpha}{beta}), respectively. The activities were monitored using 4-MUGS, and the levels of {alpha}-subunit protein were assessed by Western blotting. Repeated experiments show that the benign mutations produce approximately 35% of normal Hex S and 40% of normal Hex A activity. This level is much higher than that of Hex A harbouring the Gly169Ser adult-onset mutation (12%). A sequential decrease in expressed Hex A activity is observed as mutations associated with more severe phenotypes are expressed. The benign mutations also result in lower levels of mature {alpha}-subunit protein compared to normal, and slightly reduced levels of {alpha}-subunit precursor protein. The Hex A deficiency resulting from benign mutations is not as great as that associated with disease-causing mutations.

Evolutionary explanations in medical and health profession courses: are you answering your students' "why" questions?

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Malyango Avelin A

2005-05-01

Full Text Available Abstract Background Medical and pre-professional health students ask questions about human health that can be answered in two ways, by giving proximate and evolutionary explanations. Proximate explanations, most common in textbooks and classes, describe the immediate scientifically known biological mechanisms of anatomical characteristics or physiological processes. These explanations are necessary but insufficient. They can be complemented with evolutionary explanations that describe the evolutionary processes and principles that have resulted in human biology we study today. The main goal of the science of Darwinian Medicine is to investigate human disease, disorders, and medical complications from an evolutionary perspective. Discussion This paper contrasts the differences between these two types of explanations by describing principles of natural selection that underlie medical questions. Thus, why is human birth complicated? Why does sickle cell anemia exist? Why do we show symptoms like fever, diarrhea, and coughing when we have infection? Why do we suffer from ubiquitous age-related diseases like arteriosclerosis, Alzheimer's and others? Why are chronic diseases like type II diabetes and obesity so prevalent in modern society? Why hasn't natural selection eliminated the genes that cause common genetic diseases like hemochromatosis, cystic fibrosis, Tay sachs, PKU and others? Summary In giving students evolutionary explanations professors should underscore principles of natural selection, since these can be generalized for the analysis of many medical questions. From a research perspective, natural selection seems central to leading hypotheses of obesity and type II diabetes and might very well explain the occurrence of certain common genetic diseases like cystic fibrosis, hemochromatosis, Tay sachs, Fragile X syndrome, G6PD and others because of their compensating advantages. Furthermore, armed with evolutionary explanations, health care

Computed tomography of neurodegenerative disease in childhood

International Nuclear Information System (INIS)

Kataoka, Kenkichi; Nakagawa, Yoshihiro; Hojo, Hiroatsu

1984-01-01

Serial computed tomographic scans were performed on seven children with neurodegenerative disorders. In two cases of white-matter diseases (Krabbe's disease and metachromatic leukodystrophy), diffuse, low-density lesions of white matter were visible in the early stage of the diseases. In one case of adrenoleukodystrophy, regional low-density lesions of the white matter around the posterior horns and peculiar high-density strip lesions were visible in the early stage. In two cases of storage-type gray-matter diseases (Tay-Sachs' and infantile Gaucher's disease), there were no abnormalities in the early stage, but diffuse cortical atrophies in the late stage. In one case of Leigh's disease, there were small, low-density lesions of the basal ganglia and multiple low-density lesions of the gray matter in the early stage. In one case of subacute sclerosing panencephalitis, there were no abnormalities in the early stage, but small, low-density lesions of the basal ganglia and diffuse cerebral atrophies in the late stage. Diagnostic values were recognized dominantly in two cases of adrenoleukodystrophy and Leigh's disease. In the other cases, however, serial CT scans were useful in the diagnostic process. (author)

CO2 Storage Potential of the Eocene Tay Sandstone, Central North Sea, UK

Science.gov (United States)

Gent, Christopher; Williams, John

2017-04-01

Carbon Capture and Storage (CCS) is crucial for low-carbon industry, climate mitigation and a sustainable energy future. The offshore capacity of the UK is substantial and has been estimated at 78 Gt of CO2 in saline aquifers and hydrocarbon fields. The early-mid Eocene Tay Sandstone Member of the Central North Sea (CNS) is a submarine-fan system and potential storage reservoir with a theoretical capacity of 123 Mt of CO2. The Tay Sandstone comprises of 4 sequences, amalgamating into a fan complex 125km long and 40 km at a minimum of 1500 m depth striking NW-SE, hosting several hydrocarbon fields including Gannett A, B, D and Pict. In order to better understand the storage potential and characteristics, the Tay Sandstone over Quadrant 21 has been interpreted using log correlation and 3D seismic. Understanding the internal and external geometry of the sandstone as well as the lateral extent of the unit is essential when considering CO2 vertical and horizontal fluid flow pathways and storage security. 3D seismic mapping of a clear mounded feature has revealed the youngest sequence of the Tay complex; a homogenous sand-rich channel 12 km long, 1.5 km wide and on average 100 m thick. The sandstone has porosity >35%, permeability >5 D and a net to gross of 0.8, giving a total pore volume of 927x106 m3. The remaining three sequences are a series of stacked channels and interbedded mudstones which are more quiescent on the seismic, however, well logs indicate each subsequent sequence reduce in net to gross with age as mud has a greater influence in the early fan system. Nevertheless, the sandstone properties remain relatively consistent and are far more laterally extensive than the youngest sequence. The Tay Sandstone spatially overlaps several other potential storage sites including the older Tertiary sandstones of the Cromarty, Forties and Mey Members and deeper Jurassic reservoirs. This favours the Tay Sandstone to be considered in a secondary or multiple stacked

Outcomes of arthroscopic "Remplissage": capsulotenodesis of the engaging large Hill-Sachs lesion

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Mayo Lee

2011-06-01

Full Text Available Abstract Background A Hill-Sachs lesion of the humeral head after a shoulder dislocation is clinically insignificant in most cases. However, a sizable defect will engage with the anterior rim of the glenoid and cause instability even after anterior glenoid reconstruction. The purpose of this study was to evaluate the outcome of arthroscopic capsulotenodesis of the posterior capsule and infraspinatus tendon ("remplissage" to seal a large engaging Hill-Sachs lesion in an unstable shoulder. Methods This was a prospective follow-up study of patients who underwent arthroscopic surgery for recurrent shoulder instability with a large engaging Hill-Sachs lesion from 2007 to 2009. The clinical results were measured preoperatively and postoperatively with the Simple Shoulder test (SST and the Rowe score for instability. Results Eleven patients met the inclusion criteria of this study. The mean follow-up time was 30 months (range 24 to 35 months. At the last follow-up, significant improvement was observed in both scores with no recurrent dislocations. The mean SST improved from 6.6 to 11 (p Conclusions Arthroscopic remplissage for shoulder instability is an effective soft tissue technique to seal a large engaging Hill-Sachs lesion with respect to recurrence rate, range of motion and shoulder function.

Natural History of Infantile GM2 Gangliosidosis

Science.gov (United States)

Bley, Annette E.; Giannikopoulos, Ourania A.; Hayden, Doug; Kubilus, Kim; Tifft, Cynthia J.

2011-01-01

OBJECTIVE: GM2 gangliosidoses are caused by an inherited deficiency of lysosomal β-hexosaminidase and result in ganglioside accumulation in the brain. Onset during infancy leads to rapid neurodegeneration and death before 4 years of age. We set out to quantify the rate of functional decline in infantile GM2 gangliosidosis on the basis of patient surveys and a comprehensive review of existing literature. METHODS: Patients with infantile GM2 gangliosidosis (N = 237) were surveyed via questionnaire by the National Tay Sachs & Allied Diseases Association (NTSAD). These data were supplemented by survival data from the NTSAD database and a literature survey. Detailed retrospective surveys from 97 patients were available. Five patients who had received hematopoietic stem cell transplantation were evaluated separately. The mortality rate of the remaining 92 patients was comparable to that of the 103 patients from the NTSAD database and 121 patients reported in the literature. RESULTS: Common symptoms at onset were developmental arrest (83%), startling (65%), and hypotonia (60%). All 55 patients who had learned to sit without support lost that ability within 1 year. Individual functional measures correlated with each other but not with survival. Gastric tube placement was associated with prolonged survival. Tay Sachs and Sandhoff variants did not differ. Hematopoietic stem cell transplantation was not associated with prolonged survival. CONCLUSIONS: We studied the timing of regression in 97 cases of infantile GM2 gangliosidosis and conclude that clinical disease progression does not correlate with survival, likely because of the impact of improved supportive care over time. However, functional measures are quantifiable and can inform power calculations and study design of future interventions. PMID:22025593

Personalized medicine and human genetic diversity.

Science.gov (United States)

Lu, Yi-Fan; Goldstein, David B; Angrist, Misha; Cavalleri, Gianpiero

2014-07-24

Human genetic diversity has long been studied both to understand how genetic variation influences risk of disease and infer aspects of human evolutionary history. In this article, we review historical and contemporary views of human genetic diversity, the rare and common mutations implicated in human disease susceptibility, and the relevance of genetic diversity to personalized medicine. First, we describe the development of thought about diversity through the 20th century and through more modern studies including genome-wide association studies (GWAS) and next-generation sequencing. We introduce several examples, such as sickle cell anemia and Tay-Sachs disease that are caused by rare mutations and are more frequent in certain geographical populations, and common treatment responses that are caused by common variants, such as hepatitis C infection. We conclude with comments about the continued relevance of human genetic diversity in medical genetics and personalized medicine more generally. Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

78 FR 24447 - Goldman Sachs Trust, et al.; Notice of Application

Science.gov (United States)

2013-04-25

... SECURITIES AND EXCHANGE COMMISSION [Investment Company Act Release No. 30471; 812-14075] Goldman Sachs Trust, et al.; Notice of Application April 19, 2013. AGENCY: Securities and Exchange Commission..., or cause more than 10% of the acquired company's voting stock to be owned by investment companies and...

Fingerprinting of bed sediment in the Tay Estuary, Scotland: an environmental magnetism approach

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P. A. Jenkins

2002-01-01

Full Text Available Sediment fingerprinting is commonly used for sediment provenance studies in lakes, rivers and reservoirs and on hillslopes and floodplains. This investigation explores the mixing of terrestrial and marine-derived sediment in the Tay Estuary, Scotland, using mineral magnetic attributes for fingerprinting. Samples representative of the estuary sediments and of four sources (end-members were subjected to a suite of magnetic susceptibility and remanence measurements. Sediment samples from the beds of the Rivers Tay and Earn represented fluvial inputs while samples from the Angus and Fife coasts represented marine input. Multivariate discriminant and factor analysis showed that the sources could be separated on the basis of six magnetic parameters in a simple multivariate unmixing model to identify source contributions to estuarine bed sediments. Multi-domain magnetite signatures, characteristic of unweathered bedrock, dominate the magnetic measurements. Overall contributions of 3% from the River Earn, 17% from the River Tay, 29% from the Angus coast and 51% from the Fife coast source end-members, demonstrated the present-day regime of marine sediment derivation in the Tay Estuary. However, this conceals considerable spatial variability both along-estuary and in terms of sub-environments, with small-scale variations in sediment provenance reflecting local morphology, particularly areas of channel convergence. Keywords: bed sediment, environmental magnetism, fingerprinting, Tay Estuary, Scotland

Stemcell Information: SKIP000247 [SKIP Stemcell Database[Archive

Lifescience Database Archive (English)

Full Text Available M2-1TKB). Same patient as iTS1. iTS3. RikenBRC HPS0150| Tay-Sachs病患者由来iPS細胞。iPS1, iPS3と同じ患者（RCB0697 GM2-1TKB... disease 272800 ... 0-9 Female ... No No iPS cell line derived from Tay-Sachs' disease patient (RCB0697 G...S-SOX2/TSdeltaF, SeV18+HS-KLF4/TSdeltaF, SeV18(HNL)c-MYCQC/TSdeltaF ... Yes MEF (X-rays:5000R or MMC) 3-5x10^(5) cell...able Riken Bio Resource Center 理研BRC http://www2.brc.riken.jp/lab/cell/detail.cgi?cell_no=HPS0150&type=1&lang=en ... 遺伝子診断実施の有無不明。|HPS10150

Computed tomography of neurodegenerative disease in childhood. Serial CT findings and their diagnostic values

Energy Technology Data Exchange (ETDEWEB)

Kataoka, Kenkichi; Nakagawa, Yoshihiro; Hojo, Hiroatsu

1984-12-01

Serial computed tomographic scans were performed on seven children with neurodegenerative disorders. In two cases of white-matter diseases (Krabbe's disease and metachromatic leukodystrophy), diffuse, low-density lesions of white matter were visible in the early stage of the diseases. In one case of adrenoleukodystrophy, regional low-density lesions of the white matter around the posterior horns and peculiar high-density strip lesions were visible in the early stage. In two cases of storage-type gray-matter diseases (Tay-Sachs' and infantile Gaucher's disease), there were no abnormalities in the early stage, but diffuse cortical atrophies in the late stage. In one case of Leigh's disease, there were small, low-density lesions of the basal ganglia and multiple low-density lesions of the gray matter in the early stage. In one case of subacute sclerosing panencephalitis, there were no abnormalities in the early stage, but small, low-density lesions of the basal ganglia and diffuse cerebral atrophies in the late stage. Diagnostic values were recognized dominantly in two cases of adrenoleukodystrophy and Leigh's disease. In the other cases, however, serial CT scans were useful in the diagnostic process. (author).

Tay's syndrome: MRI

Energy Technology Data Exchange (ETDEWEB)

Porto, L.; Reichel, P.; Lanfermann, H.; Zanella, F.E. [Institut of Neuroradiology, Johann Wolfgang Goethe-University, Frankfurt/Main (Germany); Weis, R. [Neuropediatric Department, Johann Wolfgang Goethe-University, Frankfurt/Main (Germany); Schulz, C. [Dermatology Department, Johann Wolfgang Goethe-University, Frankfurt/Main (Germany)

2000-11-01

Tay's syndrome is a trichothiodystrophy associated with congenital ichthyosis. We report the findings on MRI and spectroscopy in a young girl with sparse, short, ruffled hair, dry skin and delayed milestones. T2-weighted images showed prominent diffuse confluent increase in signal symmetrically in all the supratentorial white matter. These findings are similar to those in a previously described case, and consistent with dysmyelination. Spectroscopy showed increased myoinositol and decreased choline. (orig.)

Cloning, characterization and targeting of the mouse HEXA gene

Energy Technology Data Exchange (ETDEWEB)

Wakamatsu, N.; Trasler, J.M.; Gravel, R.A. [McGill Univ., Quebec (Canada)] [and others

1994-09-01

The HEXA gene, encoding the {alpha} subunit of {beta}-hexosaminidase A, is essential for the metabolism of ganglioside G{sub M2}, and defects in this gene cause Tay-Sachs disease in humans. To elucidate the role of the gene in the nervous system of the mouse and to establish a mouse model of Tay-Sachs disease, we have cloned and characterized the HEXA gene and targeted a disruption of the gene in mouse ES cells. The mouse HEXA gene spans {approximately}26 kb and consists of 14 exons, similar to the human gene. A heterogeneous transcription initiation site was identified 21-42 bp 5{prime} of the initiator ATG, with two of the sites fitting the consensus CTCA (A = start) as seen for some weak initiator systems. Promoter analysis showed that the first 150 bp 5{prime} of the ATG contained 85% of promoter activity observed in constructs containing up to 1050 bp of 5{prime} sequence. The active region contained a sequence matching that of the adenovirus major late promoter upstream element factor. A survey of mouse tissues showed that the highest mRNA levels were in (max to min): testis (5.5 x brain cortex), adrenal, epididymis, heart, brain, lung, kidney, and liver (0.3 x brain cortex). A 12 kb BstI/SalI fragment containing nine exons was disrupted with the insertion of the bacterial neo{sup r} gene in exon 11 and was targeted into 129/Sv ES cells by homologous recombination. Nine of 153 G418 resistant clones were correctly targeted as confirmed by Southern blotting. The heterozygous ES cells were microinjected into mouse blastocysts and implanted into pseudo-pregnant mice. Nine male chimeric mice, showing that 40-95% chimerism for the 129/Sv agouti coat color marker, are being bred in an effort to generate germline transmission of the disrupted HEXA gene.

Construction of a hybrid β-hexosaminidase subunit capable of forming stable homodimers that hydrolyze GM2 ganglioside in vivo

Directory of Open Access Journals (Sweden)

Michael B Tropak

2016-01-01

Full Text Available Tay-Sachs or Sandhoff disease result from mutations in either the evolutionarily related HEXA or HEXB genes encoding respectively, the α- or β-subunits of β-hexosaminidase A (HexA. Of the three Hex isozymes, only HexA can interact with its cofactor, the GM2 activator protein (GM2AP, and hydrolyze GM2 ganglioside. A major impediment to establishing gene or enzyme replacement therapy based on HexA is the need to synthesize both subunits. Thus, we combined the critical features of both α- and β-subunits into a single hybrid µ-subunit that contains the α-subunit active site, the stable β-subunit interface and unique areas in each subunit needed to interact with GM2AP. To facilitate intracellular analysis and the purification of the µ-homodimer (HexM, CRISPR-based genome editing was used to disrupt the HEXA and HEXB genes in a Human Embryonic Kidney 293 cell line stably expressing the µ-subunit. In association with GM2AP, HexM was shown to hydrolyze a fluorescent GM2 ganglioside derivative both in cellulo and in vitro. Gene transfer studies in both Tay-Sachs and Sandhoff mouse models demonstrated that HexM expression reduced brain GM2 ganglioside levels.

Construction of a hybrid β-hexosaminidase subunit capable of forming stable homodimers that hydrolyze GM2 ganglioside in vivo

Science.gov (United States)

Tropak, Michael B; Yonekawa, Sayuri; Karumuthil-Melethil, Subha; Thompson, Patrick; Wakarchuk, Warren; Gray, Steven J; Walia, Jagdeep S; Mark, Brian L; Mahuran, Don

2016-01-01

Tay-Sachs or Sandhoff disease result from mutations in either the evolutionarily related HEXA or HEXB genes encoding respectively, the α- or β-subunits of β-hexosaminidase A (HexA). Of the three Hex isozymes, only HexA can interact with its cofactor, the GM2 activator protein (GM2AP), and hydrolyze GM2 ganglioside. A major impediment to establishing gene or enzyme replacement therapy based on HexA is the need to synthesize both subunits. Thus, we combined the critical features of both α- and β-subunits into a single hybrid µ-subunit that contains the α-subunit active site, the stable β-subunit interface and unique areas in each subunit needed to interact with GM2AP. To facilitate intracellular analysis and the purification of the µ-homodimer (HexM), CRISPR-based genome editing was used to disrupt the HEXA and HEXB genes in a Human Embryonic Kidney 293 cell line stably expressing the µ-subunit. In association with GM2AP, HexM was shown to hydrolyze a fluorescent GM2 ganglioside derivative both in cellulo and in vitro. Gene transfer studies in both Tay-Sachs and Sandhoff mouse models demonstrated that HexM expression reduced brain GM2 ganglioside levels. PMID:26966698

GM2 gangliosidosis associated with a HEXA missense mutation in Japanese Chin dogs: a potential model for Tay Sachs disease.

Science.gov (United States)

Sanders, Douglas N; Zeng, Rong; Wenger, David A; Johnson, Gary S; Johnson, Gayle C; Decker, Jared E; Katz, Martin L; Platt, Simon R; O'Brien, Dennis P

2013-01-01

GM2 gangliosidosis is a fatal lysosomal storage disease caused by a deficiency of β-hexosaminidase (EC 3.2.1.52). There are two major isoforms of the enzyme: hexosaminidase A composed of an α and a β subunit (encoded by HEXA and HEXB genes, respectively); and, hexosaminidase B composed of two β subunits. Hexosaminidase A requires an activator protein encoded by GM2A to catabolize GM2 ganglioside, but even in the absence of the activator protein, it can hydrolyze the synthetic substrates commonly used to assess enzyme activity. GM2 gangliosidosis has been reported in Japanese Chin dogs, and we identified the disease in two related Japanese Chin dogs based on clinical signs, histopathology and elevated brain GM2 gangliosides. As in previous reports, we found normal or elevated hexosaminidase activity when measured with the synthetic substrates. This suggested that the canine disease is analogous to human AB variant of G(M2) gangliosidosis, which results from mutations in GM2A. However, only common neutral single nucleotide polymorphisms were found upon sequence analysis of the canine ortholog of GM2A from the affected Japanese Chins. When the same DNA samples were used to sequence HEXA, we identified a homozygous HEXA:c967G>A transition which predicts a p.E323K substitution. The glutamyl moiety at 323 is known to make an essential contribution to the active site of hexosaminidase A, and none of the 128 normal Japanese Chins and 92 normal dogs of other breeds that we tested was homozygous for HEXA:c967A. Thus it appears that the HEXA:c967G>A transition is responsible for the GM2 gangliosidosis in Japanese Chins. Copyright © 2012 Elsevier Inc. All rights reserved.

Next-generation DNA sequencing of HEXA: a step in the right direction for carrier screening

OpenAIRE

Hoffman, Jodi D; Greger, Valerie; Strovel, Erin T; Blitzer, Miriam G; Umbarger, Mark A; Kennedy, Caleb; Bishop, Brian; Saunders, Patrick; Porreca, Gregory J; Schienda, Jaclyn; Davie, Jocelyn; Hallam, Stephanie; Towne, Charles

2013-01-01

Tay-Sachs disease (TSD) is the prototype for ethnic-based carrier screening, with a carrier rate of ∼1/27 in Ashkenazi Jews and French Canadians. HexA enzyme analysis is the current gold standard for TSD carrier screening (detection rate ∼98%), but has technical limitations. We compared DNA analysis by next-generation DNA sequencing (NGS) plus an assay for the 7.6 kb deletion to enzyme analysis for TSD carrier screening using 74 samples collected from participants at a TSD family conference. ...

J-GLOBAL MeSH Dictionary: AB変異型Tay‐Sachs病 [MeCab user dictionary for science technology term[Archive

Lifescience Database Archive (English)

Full Text Available MeCab user dictionary for science technology term AB変異型Tay‐Sachs病 名詞 一般 * * * * AB変異...型Tay‐Sachs病 ... MeSH D049290 200906052904481110 C LS51 UNKNOWN_2 A B 変異 型 Tay ‐ Sachs 病

17 CFR 249.619 - Form TA-Y2K, information required of transfer agents pursuant to section 17 of the Securities...

Science.gov (United States)

2010-04-01

... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Form TA-Y2K, information... Certain Exchange Members, Brokers, and Dealers § 249.619 Form TA-Y2K, information required of transfer... affecting Form TA-Y2K, see the List of CFR Sections Affected, which appears in the Finding Aids section of...

A critique of Jeffrey D. Sachs's The end of poverty.

Science.gov (United States)

Henwood, Doug

2006-01-01

Jeffrey Sachs's The End of Poverty is a manifesto and how-to guide on ending extreme poverty around the world; it promotes the U.N. Millennium Development Goals. Sachs achieved fame with his policy package for the "stabilization" of Bolivia (which did nothing to relieve Bolivia's poverty), and became advisor to the Yeltsin government in Russia and to Poland, Slovenia, and Estonia as they began their transitions to capitalism (the last three mixed successes; Russia a thorough disaster). Sachs later became more prominent as a critic of development orthodoxy, and was economic advisor to the Jubilee 2000 movement. The End of Poverty is full of sharp critiques of Western imperialism, but his views on the rest of the development business are more conventional.

Next-generation DNA sequencing of HEXA: a step in the right direction for carrier screening

Science.gov (United States)

Hoffman, Jodi D; Greger, Valerie; Strovel, Erin T; Blitzer, Miriam G; Umbarger, Mark A; Kennedy, Caleb; Bishop, Brian; Saunders, Patrick; Porreca, Gregory J; Schienda, Jaclyn; Davie, Jocelyn; Hallam, Stephanie; Towne, Charles

2013-01-01

Tay-Sachs disease (TSD) is the prototype for ethnic-based carrier screening, with a carrier rate of ∼1/27 in Ashkenazi Jews and French Canadians. HexA enzyme analysis is the current gold standard for TSD carrier screening (detection rate ∼98%), but has technical limitations. We compared DNA analysis by next-generation DNA sequencing (NGS) plus an assay for the 7.6 kb deletion to enzyme analysis for TSD carrier screening using 74 samples collected from participants at a TSD family conference. Fifty-one of 74 participants had positive enzyme results (46 carriers, five late-onset Tay-Sachs [LOTS]), 16 had negative, and seven had inconclusive results. NGS + 7.6 kb del screening of HEXA found a pathogenic mutation, pseudoallele, or variant of unknown significance (VUS) in 100% of the enzyme-positive or obligate carrier/enzyme-inconclusive samples. NGS detected the B1 allele in two enzyme-negative obligate carriers. Our data indicate that NGS can be used as a TSD clinical carrier screening tool. We demonstrate that NGS can be superior in detecting TSD carriers compared to traditional enzyme and genotyping methodologies, which are limited by false-positive and false-negative results and ethnically focused, limited mutation panels, respectively, but is not ready for sole use due to lack of information regarding some VUS. PMID:24498621

Risks assessment - role of pre-existing genetic variation

International Nuclear Information System (INIS)

Unrau, P.; Doerffer, K.

1996-01-01

Previously published research on the epidemiology and molecular basis of genetic or congenital diseases and their occurrence in certain 'ethnic' or isolated populations is discussed to show the significance of consanguinity and 'ethnicity' as contributing factors. A statistical study aiming to correlate malformations with absolutely any environmental factor may miss the significance of defects in a gene pool. This consideration has an obvious significance for the nuclear industry. For example, carriers of Fanconi's anemia appear to have an increased tendency to develop acute myelogenous leukemia. The authors indicate the difficulty in finding a definite molecular basis even for simple Mendelian monogenic disorders such as Tay-Sachs disease. 12 refs., 4 tabs

Sachês antimicrobianos em pós-colheita de manga

Directory of Open Access Journals (Sweden)

Eber Antonio Alves Medeiros

2011-10-01

Full Text Available Objetivou-se com este trabalho desenvolver sachês incorporados com óleos essenciais avaliando as propriedades físico-químicas e microbiológicas de mangas armazenadas em saco de papel contendo estes sachês em seu interior. Os óleos essenciais de orégano (Origanum vulgaris e capim-limão (Cymbopogon citratus foram incorporados em saches, e sua atividade antimicrobiana foi testada nos fungos Colletotrichum gloeosporides, Lasiodiplodia theobromae, Xanthomonas campestris pv. mangiferae indica, Alternaria alternata. Frutos de manga 'Tommy Atkins' foram acondicionados individualmente em sacos de papel contendo em seu interior um sachê antimicrobiano e mantidos a 25 °C ± 2 °C e UR 80% ± 5% por nove dias. Os parâmetros cor da epiderme, firmeza de polpa, sólidos solúveis, acidez titulável e pH sofreram pouca influência dos óleos essenciais de orégano e capim limão, indicando que a presença do óleo essencial não altera as características físico-químicas da polpa de manga. Os sachês ativos incorporados com óleos essenciais de orégano e capim limão apresentaram controle no crescimento dos microrganismos testados, sendo o capim-limão mais eficiente, reduzindo em aproximadamente 2 ciclos Log a contagem de mesófilos aeróbios e fungos filamentosos e leveduras em relação ao tratamento controle empregado.

Lending a helping hand, screening chemical libraries for compounds that enhance β-hexosaminidase A activity in GM2 gangliosidosis cells

Science.gov (United States)

Tropak, Michael B.; Mahuran, Don

2010-01-01

Enzyme enhancement therapy is an emerging therapeutic approach that has the potential to treat many genetic diseases. Candidate diseases are those associated with a mutant protein that has difficulty folding and/or assembling into active oligomers in the endoplasmic reticulum. Many lysosomal storage diseases are candidates for enzyme enhancement therapy and have the additional advantage of requiring only 5–10% of normal enzyme levels to reduce and/or prevent substrate accumulation. Our long experience in working with the β-hexosaminidase (EC 3.2.1.52) isozymes system and its associated deficiencies (Tay-Sachs and Sandhoff disease) lead us to search for possible enzyme enhancement therapy-agents that could treat the chronic forms of these diseases which express 2–5% residual activity. Pharmacological chaperones are enzyme enhancement therapy-agents that are competitive inhibitors of the target enzyme. Each of the known β-hexosaminidase inhibitors (low μM IC50) increased mutant enzyme levels to ≥ 10% in chronic Tay-Sachs fibroblasts and also attenuated the thermo-denaturation of β-hexosaminidase. To expand the repertoire of pharmacological chaperones to more ‘drug-like’ compounds, we screened the Maybridge library of 50 000 compounds using a real-time assay for non-carbohydrate-based β-hexosaminidase inhibitors and identified several that functioned as pharmacological chaperones in patient cells. Two of these inhibitors had derivatives that had been tested in humans for other purposes. These observations lead us to screen the NINDS library of 1040 Food and Drug Administration approved compounds for pharmacological chaperones. Pyrimethamine, an antimalarial drug with well documented pharmacokinetics, was confirmed as a β-hexosaminidase pharmacological chaperone and compared favorably with our best carbohydrate-based pharmacological chaperone in patient cells with various mutant genotypes. PMID:17894780

Basic versus applied research: Julius Sachs (1832-1897) and the experimental physiology of plants.

Science.gov (United States)

Kutschera, Ulrich

2015-01-01

The German biologist Julius Sachs was the first to introduce controlled, accurate, quantitative experimentation into the botanical sciences, and is regarded as the founder of modern plant physiology. His seminal monograph Experimental-Physiologie der Pflanzen (Experimental Physiology of Plants) was published 150 y ago (1865), when Sachs was employed as a lecturer at the Agricultural Academy in Poppelsdorf/Bonn (now part of the University). This book marks the beginning of a new era of basic and applied plant science. In this contribution, I summarize the achievements of Sachs and outline his lasting legacy. In addition, I show that Sachs was one of the first biologists who integrated bacteria, which he considered to be descendants of fungi, into the botanical sciences and discussed their interaction with land plants (degradation of wood etc.). This "plant-microbe-view" of green organisms was extended and elaborated by the laboratory botanist Wilhelm Pfeffer (1845-1920), so that the term "Sachs-Pfeffer-Principle of Experimental Plant Research" appears to be appropriate to characterize this novel way of performing scientific studies on green, photoautotrophic organisms (embryophytes, algae, cyanobacteria).

Comparative study of non-premixed and partially-premixed combustion simulations in a realistic Tay model combustor

OpenAIRE

Zhang, K.; Ghobadian, A.; Nouri, J. M.

2017-01-01

A comparative study of two combustion models based on non-premixed assumption and partially premixed assumptions using the overall models of Zimont Turbulent Flame Speed Closure Method (ZTFSC) and Extended Coherent Flamelet Method (ECFM) are conducted through Reynolds stress turbulence modelling of Tay model gas turbine combustor for the first time. The Tay model combustor retains all essential features of a realistic gas turbine combustor. It is seen that the non-premixed combustion model fa...

Prevention of Lysosomal Storage Diseases and Derivation of Mutant Stem Cell Lines by Preimplantation Genetic Diagnosis

Science.gov (United States)

Altarescu, Gheona; Beeri, Rachel; Eiges, Rachel; Epsztejn-Litman, Silvina; Eldar-Geva, Talia; Elstein, Deborah; Zimran, Ari; Margalioth, Ehud J.; Levy-Lahad, Ephrat; Renbaum, Paul

2012-01-01

Preimplantation genetic diagnosis (PGD) allows birth of unaffected children for couples at risk for a genetic disorder. We present the strategy and outcome of PGD for four lysosomal storage disorders (LSD): Tay-Sachs disease (TSD), Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (HS), and subsequent development of stem cell lines. For each disease, we developed a family-specific fluorescent multiplex single-cell PCR protocol that included the familial mutation and informative markers surrounding the mutation. Embryo biopsy and PGD analysis were performed on either oocytes (polar bodies one and two) or on single blastomeres from a six-cell embryo. We treated twenty families carrying mutations in these lysosomal storage disorders, including 3 couples requiring simultaneous analysis for two disorders (TSD/GD, TSD/balanced Robertsonian translocation 45XYder(21;14), and HS/oculocutaneus albinism). These analyses led to an overall pregnancy rate/embryo transfer of 38% and the birth of 20 unaffected children from 17 families. We have found that PGD for lysosomal disorders is a safe and effective method to prevent birth of affected children. In addition, by using mutant embryos for the derivation of stem cell lines, we have successfully established GD and HS hESC lines for use as valuable models in LSD research. PMID:23320174

Tay–Sachs disease mutations in HEXA target the α chain of hexosaminidase A to endoplasmic reticulum–associated degradation

Science.gov (United States)

Dersh, Devin; Iwamoto, Yuichiro; Argon, Yair

2016-01-01

Loss of function of the enzyme β-hexosaminidase A (HexA) causes the lysosomal storage disorder Tay–Sachs disease (TSD). It has been proposed that mutations in the α chain of HexA can impair folding, enzyme assembly, and/or trafficking, yet there is surprisingly little known about the mechanisms of these potential routes of pathogenesis. We therefore investigated the biosynthesis and trafficking of TSD-associated HexA α mutants, seeking to identify relevant cellular quality control mechanisms. The α mutants E482K and G269S are defective in enzymatic activity, unprocessed by lysosomal proteases, and exhibit altered folding pathways compared with wild-type α. E482K is more severely misfolded than G269S, as observed by its aggregation and inability to associate with the HexA β chain. Importantly, both mutants are retrotranslocated from the endoplasmic reticulum (ER) to the cytosol and are degraded by the proteasome, indicating that they are cleared via ER-associated degradation (ERAD). Leveraging these discoveries, we observed that manipulating the cellular folding environment or ERAD pathways can alter the kinetics of mutant α degradation. Additionally, growth of patient fibroblasts at a permissive temperature or with chemical chaperones increases cellular Hex activity by improving mutant α folding. Therefore modulation of the ER quality control systems may be a potential therapeutic route for improving some forms of TSD. PMID:27682588

CMB anisotropies at all orders: the non-linear Sachs-Wolfe formula

OpenAIRE

Roldan, Omar

2017-01-01

We obtain the non-linear generalization of the Sachs-Wolfe + integrated Sachs-Wolfe (ISW) formula describing the CMB temperature anisotropies. Our formula is valid at all orders in perturbation theory, is also valid in all gauges and includes scalar, vector and tensor modes. A direct consequence of our results is that the maps of the logarithmic temperature anisotropies are much cleaner than the usual CMB maps, because they automatically remove many secondary anisotropies. This can for instan...

Determination of frequencies of alleles, associated with the pseudodeficiency of lysosomal hydrolases, in population of Ukraine

Directory of Open Access Journals (Sweden)

N. V. Olkhovych

2016-10-01

Full Text Available The pseudodeficiency of lysosomal hydrolases described as a significant reduction in enzyme activi­ty in vitro in clinically healthy individuals, can lead to diagnostic errors in the process of biochemical analysis of lysosomal storage disease in case of its combination with pathology of another origin. Pseudodeficiency is mostly caused by some non-pathogenic changes in the corresponding gene. These changes lead to the in vitro lability of the enzyme molecule, whereas in vivo the enzyme retains its functional activity. To assess the prevalence of the most common lysosomal hydrolases pseudodeficiency alleles in Ukraine, we have determined the frequency of alleles c.1055A>G and c.* 96A>G in the ARSA gene, substitutions c.739C>T (R247W and c.745C>T (R249W in the HEXA gene, c.1726G>A (G576S and c.2065G>A (E689K in the GAA gene, c.937G>T (D313Y in the GLA1 gene and c.898G>A (A300T in the IDUA gene in a group of 117 healthy individuals from different regions of the country and 14 heterozygous carriers of pathogenic mutations in the HEXA gene (parents of children with confirmed diagnosis of Tay-Sachs disease. The total frequency of haplotypes, associated with arylsulfatase A pseudodeficiency, in healthy people in Ukraine (c.1055G/c.*96G and c.1055G/c.*96A haplotypes was 10.3%. The frequency of c.739C>T (R247W allele, associated with hexo­saminidase A pseudodeficiency, among Tay-Sachs carriers from Ukraine was 7.1%. The total frequency of α-glucosidase pseudodeficiency haplotypes in healthy individuals in Ukraine (c.1726A/c.2065A and c.1726G/c.2065A haplotypes was 2.6%. No person among examined individuals with the substitution c.937G>T (D313Y in the GLA1 gene and c.898G>A (A300T in the IDUA gene was found. The differential diagnostics of lysosomal storage diseases requires obligatory determination of the presence of the pseudodeficiency alleles, particularly the ones with high incidence in the total population. Ignoring phenomenon of

Determination of frequencies of alleles, associated with the pseudodeficiency of lysosomal hydrolases, in population of Ukraine.

Science.gov (United States)

Olkhovych, N V; Gorovenko, N G

2016-01-01

The pseudodeficiency of lysosomal hydrolases described as a significant reduction in enzyme activi­ty in vitro in clinically healthy individuals, can lead to diagnostic errors in the process of biochemical analysis of lysosomal storage disease in case of its combination with pathology of another origin. Pseudodeficiency is mostly caused by some non-pathogenic changes in the corresponding gene. These changes lead to the in vitro lability of the enzyme molecule, whereas in vivo the enzyme retains its functional activity. To assess the prevalence of the most common lysosomal hydrolases pseudodeficiency alleles in Ukraine, we have determined the frequency of alleles c.1055A>G and c.* 96A>G in the ARSA gene, substitutions c.739C>T (R247W) and c.745C>T (R249W) in the HEXA gene, c.1726G>A (G576S) and c.2065G>A (E689K) in the GAA gene, c.937G>T (D313Y) in the GLA1 gene and c.898G>A (A300T) in the IDUA gene in a group of 117 healthy individuals from different regions of the country and 14 heterozygous carriers of pathogenic mutations in the HEXA gene (parents of children with confirmed diagnosis of Tay-Sachs disease). The total frequency of haplotypes, associated with arylsulfatase A pseudodeficiency, in healthy people in Ukraine (c.1055G/c.*96G and c.1055G/c.*96A haplotypes) was 10.3%. The frequency of c.739C>T (R247W) allele, associated with hexo­saminidase A pseudodeficiency, among Tay-Sachs carriers from Ukraine was 7.1%. The total frequency of α-glucosidase pseudodeficiency haplotypes in healthy individuals in Ukraine (c.1726A/c.2065A and c.1726G/c.2065A haplotypes) was 2.6%. No person among examined individuals with the substitution c.937G>T (D313Y) in the GLA1 gene and c.898G>A (A300T) in the IDUA gene was found. The differential diagnostics of lysosomal storage diseases requires obligatory determination of the presence of the pseudodeficiency alleles, particularly the ones with high incidence in the total population. Ignoring phenomenon of pseudodeficiency may

The white matter of the human cerebrum: Part I The occipital lobe by Heinrich Sachs

Science.gov (United States)

Forkel, Stephanie J.; Mahmood, Sajedha; Vergani, Francesco; Catani, Marco

2015-01-01

This is the first complete translation of Heinrich Sachs' outstanding white matter atlas dedicated to the occipital lobe. This work is accompanied by a prologue by Prof Carl Wernicke who for many years was Sachs' mentor in Breslau and enthusiastically supported his work. PMID:25527430

Three-dimensional computed tomography measurement accuracy of varying Hill-Sachs lesion size.

Science.gov (United States)

Ho, Anthony; Kurdziel, Michael D; Koueiter, Denise M; Wiater, J Michael

2018-02-01

The glenoid track concept has been proposed to correlate shoulder stability with bone loss. Accurate assessment of Hill-Sachs lesion size preoperatively may affect surgical planning and postoperative outcomes; however, no measurement method has been universally accepted. This study aimed to assess the accuracy and reliability of measuring Hill-Sachs lesion sizes using 3-dimensional (3D) computed tomography (CT). Nine polyurethane humerus bone substitutes were used to create Hill-Sachs lesions of varying sizes with a combination of lesion depth (shallow, intermediate, and deep) and width (small, medium, and large). Specimens were scanned with a clinical CT scanner for size measurements and a micro-CT scanner for measurement of true lesion size. Six evaluators repeated measurements twice in a 2-week interval. Scans were measured by use of 3D CT reconstructions for length, width, and Hill-Sachs interval and with use of 2D CT for depth. The interclass correlation coefficient evaluated interobserver and intraobserver variability and percentage error, and Student t-tests assessed measurement accuracy. Interclass correlation coefficient reliability demonstrated strong agreement for all variables measured (0.856-0.975). Percentage error between measured length and measured depth and the true measurement significantly varied with respect to both lesion depth (P = .003 and P = .005, respectively) and lesion size (P = .049 and P = .004, respectively). The 3D CT imaging is effective and reproducible in determining lesion size. Determination of Hill-Sachs interval width is also reliable when it is applied to the glenoid track concept. Measured values on 3D and 2-dimensional imaging using a conventional CT scanner may slightly underestimate true measurements. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Mercury in marine organisms of the Tay region

Energy Technology Data Exchange (ETDEWEB)

Jones, A M; Jones, Y; Stewart, W D.P.

1972-07-21

The problem of mercury pollution in the Tay region of the United Kingdom is discussed with emphasis on mercury concentration within marine algae and invertebrates. High levels of Hg were found in Broughty Ferry algae while there was no detectable mercury in any of the samples collected from north of Arbroath. Most was found in the thallose algae, Ulva lactuca and Porphyra umbilicalis, and in Ceramium rubrum. In studies carried out on molluscs, high levels were found in the lamellibranch, Mytilus edulis and in the gastropods Littorina littoralis and Nucella lapillus. 12 references, 3 tables.

The white matter of the human cerebrum: part I The occipital lobe by Heinrich Sachs.

Science.gov (United States)

Forkel, Stephanie J; Mahmood, Sajedha; Vergani, Francesco; Catani, Marco

2015-01-01

This is the first complete translation of Heinrich Sachs' outstanding white matter atlas dedicated to the occipital lobe. This work is accompanied by a prologue by Prof Carl Wernicke who for many years was Sachs' mentor in Breslau and enthusiastically supported his work. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

CMB anisotropies at all orders: the non-linear Sachs-Wolfe formula

International Nuclear Information System (INIS)

Roldan, Omar

2017-01-01

We obtain the non-linear generalization of the Sachs-Wolfe + integrated Sachs-Wolfe (ISW) formula describing the CMB temperature anisotropies. Our formula is valid at all orders in perturbation theory, is also valid in all gauges and includes scalar, vector and tensor modes. A direct consequence of our results is that the maps of the logarithmic temperature anisotropies are much cleaner than the usual CMB maps, because they automatically remove many secondary anisotropies. This can for instance, facilitate the search for primordial non-Gaussianity in future works. It also disentangles the non-linear ISW from other effects. Finally, we provide a method which can iteratively be used to obtain the lensing solution at the desired order.

CMB anisotropies at all orders: the non-linear Sachs-Wolfe formula

Energy Technology Data Exchange (ETDEWEB)

Roldan, Omar, E-mail: oaroldan@if.ufrj.br [Instituto de Física, Universidade Federal do Rio de Janeiro, 21941-972, Rio de Janeiro, RJ (Brazil)

2017-08-01

We obtain the non-linear generalization of the Sachs-Wolfe + integrated Sachs-Wolfe (ISW) formula describing the CMB temperature anisotropies. Our formula is valid at all orders in perturbation theory, is also valid in all gauges and includes scalar, vector and tensor modes. A direct consequence of our results is that the maps of the logarithmic temperature anisotropies are much cleaner than the usual CMB maps, because they automatically remove many secondary anisotropies. This can for instance, facilitate the search for primordial non-Gaussianity in future works. It also disentangles the non-linear ISW from other effects. Finally, we provide a method which can iteratively be used to obtain the lensing solution at the desired order.

Prenatal Genetic Screening Tests

Science.gov (United States)

... Inherited disorders include sickle cell disease , cystic fibrosis , Tay–Sachs disease , and many others. In most cases, both parents ... pain. It occurs most often in African Americans. Tay–Sachs Disease: An inherited birth defect that causes intellectual disability, ...

Quantum field theory of the universe in the Kantowski-Sachs space-time

International Nuclear Information System (INIS)

Shen, Y.; Tan, Z.

1996-01-01

In this paper, the quantum field theory of the universe in the Kantowski-Sachs space-time is studied. An analogue of proceedings in quantum field theory is applied in curved space-time to the Kantowski-Sachs space-time, obtaining the wave function of the universe satisfied the Wheeler-DeWitt equation. Regarding the wave function as a universe field in the minisuperspace, the authors can not only overcome the difficulty of the probabilistic interpretation in quantum cosmology, but also come to the conclusion that there is multiple production of universes. The average number of the produced universes from nothing is calculated. The distribution of created universe is given. It is the Planckian distribution

Energy in the Kantowski–Sachs space-time using teleparallel ...

Indian Academy of Sciences (India)

Inflation is again considered to be one of the early phases of the Universe [10]. For testing gravitational energy–momentum tensor of the teleparallel theory in quasilocal approach and also in the. Hamiltonian structure of TEGR, it is intended to calculate the total energy of inflationary. Kantowski–Sachs-type Universe. Again ...

Bianchi - I, II, VIII, IX and Kantowski-Sachs-like cosmological models with perfect fluid and electromagnetic fields with conductivity current

International Nuclear Information System (INIS)

Portugal, R.

1984-01-01

Three processes of solutions of the Einstein-Maxwell equations for Bianchi - I, II, VIII, IX and Kantowski-Sachs-like cosmological models with perfect fluid in magnetohydrolodynamical regimem are presented. Diagonal Bianchi-like models are considered with two anisotropy direction in the maximum. Solutions are found for Bianchi-II and IX-like models with energy conditions to be analyzed. Solutions are found for Bianchi-IX and Kantowski-Sachs-Like models with positive electric conductivity and satisfering to the predominant energy conditions. Solutions are formed for isotropic Kantowski-Sachs-Like models satisfering to the equation of state p=λρ, 0 0, admiting, in addition to the perfect fluid, electric field only. It is shown that a class of Bertotti-Robinson-like solutions is unstable by perturbations and it is carried in Kantowski-Sachs-like models with non-null electric conductivity. (L.C.) [pt

Gravitational, shear and matter waves in Kantowski-Sachs cosmologies

Energy Technology Data Exchange (ETDEWEB)

Keresztes, Zoltán; Gergely, László Á. [Department of Theoretical Physics, University of Szeged, Tisza Lajos krt 84-86, Szeged 6720 (Hungary); Forsberg, Mats; Bradley, Michael [Department of Physics, UmeåUniversity (Sweden); Dunsby, Peter K.S., E-mail: zkeresztes@titan.physx.u-szeged.hu, E-mail: forsberg.mats.a.b@gmail.com, E-mail: michael.bradley@physics.umu.se, E-mail: peter.dunsby@uct.ac.za, E-mail: gergely@physx.u-szeged.hu [Astrophysics, Cosmology and Gravity Centre (ACGC), University of Cape Town, Rondebosch 7701, Cape Town (South Africa)

2015-11-01

A general treatment of vorticity-free, perfect fluid perturbations of Kantowski-Sachs models with a positive cosmological constant are considered within the framework of the 1+1+2 covariant decomposition of spacetime. The dynamics is encompassed in six evolution equations for six harmonic coefficients, describing gravito-magnetic, kinematic and matter perturbations, while a set of algebraic expressions determine the rest of the variables. The six equations further decouple into a set of four equations sourced by the perfect fluid, representing forced oscillations and two uncoupled damped oscillator equations. The two gravitational degrees of freedom are represented by pairs of gravito-magnetic perturbations. In contrast with the Friedmann case one of them is coupled to the matter density perturbations, becoming decoupled only in the geometrical optics limit. In this approximation, the even and odd tensorial perturbations of the Weyl tensor evolve as gravitational waves on the anisotropic Kantowski-Sachs background, while the modes describing the shear and the matter density gradient are out of phase dephased by π /2 and share the same speed of sound.

Polymorphisms in the glucocerebrosidase gene and pseudogene urge caution in clinical analysis of Gaucher disease allele c.1448T>C (L444P

Directory of Open Access Journals (Sweden)

Lahey Cora

2006-08-01

Full Text Available Abstract Background Gaucher disease is a potentially severe lysosomal storage disorder caused by mutations in the human glucocerebrosidase gene (GBA. We have developed a multiplexed genetic assay for eight diseases prevalent in the Ashkenazi population: Tay-Sachs, Gaucher type I, Niemann-Pick types A and B, mucolipidosis type IV, familial dysautonomia, Canavan, Bloom syndrome, and Fanconi anemia type C. This assay includes an allelic determination for GBA allele c.1448T>C (L444P. The goal of this study was to clinically evaluate this assay. Methods Biotinylated, multiplex PCR products were directly hybridized to capture probes immobilized on fluorescently addressed microspheres. After incubation with streptavidin-conjugated fluorophore, the reactions were analyzed by Luminex IS100. Clinical evaluations were conducted using de-identified patient DNA samples. Results We evaluated a multiplexed suspension array assay that includes wild-type and mutant genetic determinations for Gaucher disease allele c.1448T>C. Two percent of samples reported to be wild-type by conventional methods were observed to be c.1448T>C heterozygous using our assay. Sequence analysis suggested that this phenomenon was due to co-amplification of the functional gene and a paralogous pseudogene (ΨGBA due to a polymorphism in the primer-binding site of the latter. Primers for the amplification of this allele were then repositioned to span an upstream deletion in the pseudogene, yielding a much longer amplicon. Although it is widely reported that long amplicons negatively impact amplification or detection efficiency in recently adopted multiplex techniques, this assay design functioned properly and resolved the occurrence of false heterozygosity. Conclusion Although previously available sequence information suggested GBA gene/pseudogene discrimination capabilities with a short amplified product, we identified common single-nucleotide polymorphisms in the pseudogene that

Stigmatization of carrier status: social implications of heterozygote genetic screening programs.

Science.gov (United States)

Kenen, R H; Schmidt, R M

1978-01-01

Possible latent psychological and social consequences ensuing from genetic screening programs need to be investigated during the planning phase of national genetic screening programs. The relatively few studies which have been performed to determine psychological, social, and economic consequences resulting from a genetic screening program are reviewed. Stigmatization of carrier-status, having major psychosocial implications in heterozygote genetic screening programs, is discussed and related to Erving Goffman's work in the area of stigmatization. Questions are raised regarding the relationship between such variables as religiosity and sex of the individual and acceptance of the status of newly identified carrier of a mutant gene. Severity of the deleterious gene and visibility of the carrier status are two important factors to consider in an estimation of potential stigma. Specific implications are discussed for four genetic diseases: Tay-Sachs, Sickle-Cell Anemia, Huntington's disease and Hemophilia. PMID:152585

Derivados de aminociclitoles, procedimiento de obtención y usos

OpenAIRE

Díaz Bueno, Lucía; Casas Brugulat, Josefina; Bujons Vilàs, Jordi; Egido Gabás, Meritxell; Delgado Cirilo, Antonio; Llebaria, Amadeu

2009-01-01

La presente invención se refiere a los compuestos de fórmula general (1) ya sus usos como composiciones farmacéuticas para el tratamiento de enfermedades relacionadas con la acumulación lisosomal de esfingolípidos, tales como la enfermedad de Gaucher, la enfermedad de TaySachs, la enfermedad de Sandhoff, la enfermedad de Fabry, la enfermedad de Niemann-Pick, leucodistrofia metacromática y la enfermedad de Krabbe. Además, la invención se refiere al procedimiento de obte...

Genetics Home Reference: Sandhoff disease

Science.gov (United States)

... Cooper A, Ferrie CD. Juvenile Sandhoff disease--nine new cases and a review of the literature. J Inherit Metab Dis. 2004;27(2):241-9. Review. Citation on PubMed Tay SK, Low PS, Ong HT, Loke KY. Sandhoff disease--a case report of 3 siblings and a review of potential therapies. Ann Acad ...

Kantowski--Sachs cosmological models as big-bang models

International Nuclear Information System (INIS)

Weber, E.

1985-01-01

In the presence of a nonzero cosmological constant Λ, we classify the anisotropic cosmological models of the Kantowski--Sachs type by means of the quantities epsilon 2 0 , q 0 , summation 0 corresponding, respectively, to the relative root-mean-square deviation from isotropy, the deceleration parameter, and the density parameter of the perfect fluid at a given time t = t 0 . We obtain for Λ>0 a set of big-bang models of zero measure as well as a set of cosmological models of nonzero measure evolving toward the de Sitter solution

Black Hole Entropy from Bondi-Metzner-Sachs Symmetry at the Horizon.

Science.gov (United States)

Carlip, S

2018-03-09

Near the horizon, the obvious symmetries of a black hole spacetime-the horizon-preserving diffeomorphisms-are enhanced to a larger symmetry group with a three-dimensional Bondi-Metzner-Sachs algebra. Using dimensional reduction and covariant phase space techniques, I investigate this augmented symmetry and show that it is strong enough to determine the black hole entropy in any dimension.

Integrated Sachs-Wolfe effect versus redshift test for the cosmological parameters

Science.gov (United States)

Kantowski, R.; Chen, B.; Dai, X.

2015-04-01

We describe a method using the integrated Sachs-Wolfe (ISW) effect caused by individual inhomogeneities to determine the cosmological parameters H0, Ωm , and ΩΛ, etc. This ISW-redshift test requires detailed knowledge of the internal kinematics of a set of individual density perturbations, e.g., galaxy clusters and/or cosmic voids, in particular their density and velocity profiles, and their mass accretion rates. It assumes the density perturbations are isolated and embedded (equivalently compensated) and makes use of the newly found relation between the ISW temperature perturbation of the cosmic microwave background (CMB) and the Fermat potential of the lens. Given measurements of the amplitudes of the temperature variations in the CMB caused by such clusters or voids at various redshifts and estimates of their angular sizes or masses, one can constrain the cosmological parameters. More realistically, the converse is more likely, i.e., if the background cosmology is sufficiently constrained, measurement of ISW profiles of clusters and voids (e.g., hot and cold spots and rings) can constrain dynamical properties of the dark matter, including accretion, associated with such lenses and thus constrain the evolution of these objects with redshift.

Application of DNA Machineries for the Barcode Patterned Detection of Genes or Proteins.

Science.gov (United States)

Zhou, Zhixin; Luo, Guofeng; Wulf, Verena; Willner, Itamar

2018-06-05

The study introduces an analytical platform for the detection of genes or aptamer-ligand complexes by nucleic acid barcode patterns generated by DNA machineries. The DNA machineries consist of nucleic acid scaffolds that include specific recognition sites for the different genes or aptamer-ligand analytes. The binding of the analytes to the scaffolds initiate, in the presence of the nucleotide mixture, a cyclic polymerization/nicking machinery that yields displaced strands of variable lengths. The electrophoretic separation of the resulting strands provides barcode patterns for the specific detection of the different analytes. Mixtures of DNA machineries that yield, upon sensing of different genes (or aptamer ligands), one-, two-, or three-band barcode patterns are described. The combination of nucleic acid scaffolds acting, in the presence of polymerase/nicking enzyme and nucleotide mixture, as DNA machineries, that generate multiband barcode patterns provide an analytical platform for the detection of an individual gene out of many possible genes. The diversity of genes (or other analytes) that can be analyzed by the DNA machineries and the barcode patterned imaging is given by the Pascal's triangle. As a proof-of-concept, the detection of one of six genes, that is, TP53, Werner syndrome, Tay-Sachs normal gene, BRCA1, Tay-Sachs mutant gene, and cystic fibrosis disorder gene by six two-band barcode patterns is demonstrated. The advantages and limitations of the detection of analytes by polymerase/nicking DNA machineries that yield barcode patterns as imaging readout signals are discussed.

Derivatives of aminocyclitols, obtainment procedure and uses

OpenAIRE

Llebaria, Amadeu; Casas Brugulat, Josefina; Egido Gabás, Meritxell; Díaz Bueno, Lucía; Bujons Vilàs, Jordi

2009-01-01

[ES] La presente invención se refiere a los compuestos de fórmula general (I) y a sus usos como composiciones farmacéuticas para el tratamiento de enfermedades relacionadas con la acumulación lisosomal de esfingolípidos, tales como la enfermedad de Gaucher, la enfermedad de Tay-Sachs, la enfermedad de Sandhoff, la enfermedad de Fabry, la enfermedad de Niemann- Pick, leucodistrofia metacromática y la enfermedad de Krabbe. Además, la invención se refiere al procedimiento de obtenció...

The effect of a combined glenoid and Hill-Sachs defect on glenohumeral stability: a biomechanical cadaveric study using 3-dimensional modeling of 142 patients.

Science.gov (United States)

Arciero, Robert A; Parrino, Anthony; Bernhardson, Andrew S; Diaz-Doran, Vilmaris; Obopilwe, Elifho; Cote, Mark P; Golijanin, Petr; Mazzocca, Augustus D; Provencher, Matthew T

2015-06-01

Bone loss in anterior glenohumeral instability occurs on both the glenoid and the humerus; however, existing biomechanical studies have evaluated glenoid and humeral head defects in isolation. Thus, little is known about the combined effect of these bony lesions in a clinically relevant model on glenohumeral stability. The purpose of this study was to determine the biomechanical efficacy of a Bankart repair in the setting of bipolar (glenoid and humeral head) bone defects determined via computer-generated 3-dimensional (3D) modeling of 142 patients with recurrent anterior shoulder instability. The null hypothesis was that adding a bipolar bone defect will have no effect on glenohumeral stability after soft tissue Bankart repair. Controlled laboratory study. A total of 142 consecutive patients with recurrent anterior instability were analyzed with 3D computed tomography scans. Two Hill-Sachs lesions were selected on the basis of volumetric size representing the 25th percentile (0.87 cm(3); small) and 50th percentile (1.47 cm(3); medium) and printed in plastic resin with a 3D printer. A total of 21 cadaveric shoulders were evaluated on a custom shoulder-testing device permitting 6 degrees of freedom, and the force required to translate the humeral head anteriorly 10 mm at a rate of 2.0 mm/s with a compressive load of 50 N was determined at 60° of glenohumeral abduction and 60° of external rotation. All Bankart lesions were made sharply from the 2- to 6-o'clock positions for a right shoulder. Subsequent Bankart repair with transosseous tunnels using high-strength suture was performed. Hill-Sachs lesions were made in the cadaver utilizing a plastic mold from the exact replica off the 3D printer. Testing was conducted in the following sequence for each specimen: (1) intact, (2) posterior capsulotomy, (3) Bankart lesion, (4) Bankart repair, (5) Bankart lesion with 2-mm glenoid defect, (6) Bankart repair, (7) Bankart lesion with 2-mm glenoid defect and Hill-Sachs lesion

Probing the integrated Sachs-Wolfe effect using embedded lens models

Science.gov (United States)

Chen, B.; Kantowski, R.

2015-04-01

The photometry profile of the integrated Sachs-Wolfe (ISW) effect, recently obtained by the Planck consortium by stacking patches of cosmic microwave background (CMB) sky maps around a large number of cosmic voids, contains a cold ring at about half the void's effective radius surrounded by a hot ring near the void's boundary. The source of the temperature structure is assumed to be the ISW effect but the exact cause of the ringed structure is not currently well understood, particularly the outer hot ring. Numerical simulations have suggested that hot/cold ring structures can be produced by motions associated with nonlinear growths of cosmic structures whose gravitational potentials produce the ISW effect. We have recently developed the embedded lens theory and the Fermat potential formalism which can be used to model the ISW effect caused by intervening individual lens inhomogeneities evolving arbitrarily. This theory only requires knowledge of the void's projected mass profile as a function of the passing CMB photons' impact radius and the rate of change of that mass distribution at passage. We present two simple embedded void lens models with evolving mass densities and investigate the ISW effect caused by these lenses. Both models possess expanding mass shells which produce hot rings around central cold regions, consistent with the recent observations. By adding a small overdensity at the void's center we can produce the slight positive temperature excess hinted at in Planck's photometric results. We conclude that the embedded lens theory and the Fermat potential formalism is well suited for modeling the ISW effect.

Translational Aspects of Sphingolipid Metabolism in Renal Disorders

Directory of Open Access Journals (Sweden)

Alaa Abou Daher

2017-11-01

Full Text Available Sphingolipids, long thought to be passive components of biological membranes with merely a structural role, have proved throughout the past decade to be major players in the pathogenesis of many human diseases. The study and characterization of several genetic disorders like Fabry’s and Tay Sachs, where sphingolipid metabolism is disrupted, leading to a systemic array of clinical symptoms, have indeed helped elucidate and appreciate the importance of sphingolipids and their metabolites as active signaling molecules. In addition to being involved in dynamic cellular processes like apoptosis, senescence and differentiation, sphingolipids are implicated in critical physiological functions such as immune responses and pathophysiological conditions like inflammation and insulin resistance. Interestingly, the kidneys are among the most sensitive organ systems to sphingolipid alterations, rendering these molecules and the enzymes involved in their metabolism, promising therapeutic targets for numerous nephropathic complications that stand behind podocyte injury and renal failure.

Molecular basis of adult-onset and chronic G sub M2 gangliosidoses in patients of Ashkenazi Jewish origin: Substitution of serine for glycine at position 269 of the. alpha. -subunit of. beta. -hexosaminidase

Energy Technology Data Exchange (ETDEWEB)

Paw, B.H.; Kaback, M.M.; Neufeld, E.F. (Univ. of California, Los Angeles (USA))

1989-04-01

Chronic and adult-onset G{sub M2} gangliosidoses are neurological disorders caused by marked deficiency of the A isoenzyme of {beta}-hexosaminidase; they occur in the Ashkenazi Jewish population, though less frequently than classic (infantile) Tay-Sachs disease. Earlier biosynthetic studies had identified a defective {alpha}-subunit that failed to associate with the {beta}-subunit. The authors have now found a guanosine to adenosine transition at the 3{prime} end of exon 7, which causes substitution of serine for glycine at position 269 of the {alpha}-subunit. An RNase protection assay was used to localize the mutation to a segment of mRNA from fibroblasts of a patient with the adult-onset disorder. That segment of mRNA (after reverse transcription) and a corresponding segment of genomic DNA were amplified by the polymerase chain reaction and sequenced by the dideoxy method. The sequence analysis, together with an assay based on the loss of a ScrFI restriction site, showed that the patient was a compound heterozygote who had inherited the 269 (Gly {yields} Ser) mutation from his father and an allelic null mutation from his mother. The 269 (Gly {yields} Ser) mutation, in compound heterozygosity with a presumed null allele, was also found in fetal fibroblasts with an association-defective phenotype and in cells from five patients with chronic G{sub M2} gangliosidosis.

Molecular basis of adult-onset and chronic GM2 gangliosidoses in patients of Ashkenazi Jewish origin: Substitution of serine for glycine at position 269 of the α-subunit of β-hexosaminidase

International Nuclear Information System (INIS)

Paw, B.H.; Kaback, M.M.; Neufeld, E.F.

1989-01-01

Chronic and adult-onset G M2 gangliosidoses are neurological disorders caused by marked deficiency of the A isoenzyme of β-hexosaminidase; they occur in the Ashkenazi Jewish population, though less frequently than classic (infantile) Tay-Sachs disease. Earlier biosynthetic studies had identified a defective α-subunit that failed to associate with the β-subunit. The authors have now found a guanosine to adenosine transition at the 3' end of exon 7, which causes substitution of serine for glycine at position 269 of the α-subunit. An RNase protection assay was used to localize the mutation to a segment of mRNA from fibroblasts of a patient with the adult-onset disorder. That segment of mRNA (after reverse transcription) and a corresponding segment of genomic DNA were amplified by the polymerase chain reaction and sequenced by the dideoxy method. The sequence analysis, together with an assay based on the loss of a ScrFI restriction site, showed that the patient was a compound heterozygote who had inherited the 269 (Gly → Ser) mutation from his father and an allelic null mutation from his mother. The 269 (Gly → Ser) mutation, in compound heterozygosity with a presumed null allele, was also found in fetal fibroblasts with an association-defective phenotype and in cells from five patients with chronic G M2 gangliosidosis

A Deceptive Initiation: An Ecological Paradigm in Howard O’Hagan’s Tay John

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Sergiy Yakovenko

2017-11-01

Full Text Available Howard O’Hagan’s novel Tay John has been widely discussed as a modernist work of deconstruction that undermines the established concepts of broadly understood mythology, narrative, and gender. In this article, I focus on one of the previously neglected aspects of the novel’s mythological drama – the clash of the pre-modern and modern ecological epistemai, which unfolds as an originary event of entering into modernity. I argue that the dramatic irony of a recoded indigenous myth introduces the aboriginal Shuswaps to the colonialist perception of the environment, deceptively making them hostages of their own beliefs and thereby drastically changing their temporal-spatial continuum.

Generalized Bondi-Sachs equations for characteristic formalism of numerical relativity

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Cao, Zhoujian; He, Xiaokai

2013-11-01

The Cauchy formalism of numerical relativity has been successfully applied to simulate various dynamical spacetimes without any symmetry assumption. But discovering how to set a mathematically consistent and physically realistic boundary condition is still an open problem for Cauchy formalism. In addition, the numerical truncation error and finite region ambiguity affect the accuracy of gravitational wave form calculation. As to the finite region ambiguity issue, the characteristic extraction method helps much. But it does not solve all of the above issues. Besides the above problems for Cauchy formalism, the computational efficiency is another problem. Although characteristic formalism of numerical relativity suffers the difficulty from caustics in the inner near zone, it has advantages in relation to all of the issues listed above. Cauchy-characteristic matching (CCM) is a possible way to take advantage of characteristic formalism regarding these issues and treat the inner caustics at the same time. CCM has difficulty treating the gauge difference between the Cauchy part and the characteristic part. We propose generalized Bondi-Sachs equations for characteristic formalism for the Cauchy-characteristic matching end. Our proposal gives out a possible same numerical evolution scheme for both the Cauchy part and the characteristic part. And our generalized Bondi-Sachs equations have one adjustable gauge freedom which can be used to relate the gauge used in the Cauchy part. Then these equations can make the Cauchy part and the characteristic part share a consistent gauge condition. So our proposal gives a possible new starting point for Cauchy-characteristic matching.

Accuracy of preimplantation genetic diagnosis (PGD) of single gene and chromosomal disorders

Energy Technology Data Exchange (ETDEWEB)

Verlinsky, Y.; Strom, C.; Rechitsky, S. [Reproductive Genetics Institute, Chicage, IL (United States)] [and others

1994-09-01

We have developed a polar body inferred approach for preconception diagnosis of single gene and chromosomal disorders. Preconception PCR or FISH analysis was performed in a total of 310 first polar bodies for the following genetic conditions: cystic fibrosis, hemophilia A, alpha-1-antitrypsin deficiency, Tay Sachs disease, retinitis pigmentosa and common chromosomal trisomies. An important advantage of this approach is the avoidance of sperm (DNA) contamination, which is the major problem of PGD. We are currently applying FISH analysis of biopsied blastomeres, in combination with PCR or separately, and have demonstrated a significant improvement of the accuracy of PGD of X-linked disorders at this stage. Our data have also demonstrated feasibility of the application of FISH technique for PGD of chromosomal disorders. It was possible to detect chromosomal non-disjunctions and chromatid malsegregations in the first meiotic division, as well as to evaluate chromosomal mutations originating from the second meiotic nondisjunction.

Shock absorption of below-knee prostheses : A comparison between the SACH and the Multiflex foot

NARCIS (Netherlands)

van Leeuwen, J. L.; Speth, L. A W M; Daanen, H. A M

1990-01-01

Shock waves were measured during walking on a treadmill on the metal tube of a below-knee KBM prosthesis, provided either with a SACH foot or with a Multiflex foot. Accelerations were measured in the axial direction and the dorso-ventral direction, about 160 mm proximal to the sole of the shoe. The

Kantowski-Sachs multidimensional cosmological models and dynamical dimensional reduction

International Nuclear Information System (INIS)

Demianski, M.; Rome Univ.; Golda, Z.A.; Heller, M.; Szydlowski, M.

1988-01-01

Einstein's field equations are solved for a multidimensional spacetime (KS) x Tsup(m), where (KS) is a four-dimensional Kantowski-Sachs spacetime and Tsup(m) is an m-dimensional torus. Among all possible vacuum solutions there is a large class of spacetimes in which the macroscopic space expands and the microscopic space contracts to a finite volume. We also consider a non-vacuum case and we explicitly solve the field equations for the matter satisfying the Zel'dovich equation of state. In non-vacuum models, with matter satisfying an equation of state p = γρ, O ≤ γ < 1, at a sufficiently late stage of evolution the microspace always expands and the dynamical dimensional reduction does not occur. (author)

Integrated Sachs-Wolfe effect in a quintessence cosmological model: Including anisotropic stress of dark energy

International Nuclear Information System (INIS)

Wang, Y. T.; Xu, L. X.; Gui, Y. X.

2010-01-01

In this paper, we investigate the integrated Sachs-Wolfe effect in the quintessence cold dark matter model with constant equation of state and constant speed of sound in dark energy rest frame, including dark energy perturbation and its anisotropic stress. Comparing with the ΛCDM model, we find that the integrated Sachs-Wolfe (ISW)-power spectrums are affected by different background evolutions and dark energy perturbation. As we change the speed of sound from 1 to 0 in the quintessence cold dark matter model with given state parameters, it is found that the inclusion of dark energy anisotropic stress makes the variation of magnitude of the ISW source uncertain due to the anticorrelation between the speed of sound and the ratio of dark energy density perturbation contrast to dark matter density perturbation contrast in the ISW-source term. Thus, the magnitude of the ISW-source term is governed by the competition between the alterant multiple of (1+3/2xc-circumflex s 2 ) and that of δ de /δ m with the variation of c-circumflex s 2 .

Hill-Sachs lesion location: does it play a role in engagement?

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Gyftopoulos, Soterios; Wang, Annie; Babb, James [NYU Langone Medical Center, Department of Radiology, New York, NY (United States)

2015-08-15

To see if there is an association between engagement on physical examination (PE) and the location of the Hill-Sachs lesion (HSL) as assessed by the modified biceps angle. Sixty-two patients with a history of anterior shoulder dislocation, who underwent preoperative MRI and arthroscopy at our institution and were tested for engagement on PE, were collected. Two musculoskeletal radiologists reviewed the MR studies, noting the presence of an HSL and documenting the location of the HSL with the modified biceps angle. Statistical analysis included the Mann-Whitney (MW) test and ROC (receiver-operating characteristic) curve. Of 62 patients, there were 58 males and 4 females with a mean age of 30 (range 18-59 years). Twenty patients demonstrated engagement on PE, while 42 did not. All patients had evidence of an HSL on MRI and arthroscopy. The mean biceps angle for the engaging group was 151.5 ± 13.9 , and 142.4 ± 17.3 for the non-engaging group. The biceps angle was statistically significantly higher among patients who had engagement compared to those who did not (p = 0.027). Overall, diagnostic accuracy was highest for a biceps angle >149 , which resulted in a sensitivity of 70 % and specificity of 67 %. The modified biceps angle, as measured on MRI, was significantly higher in patients who demonstrated engagement on physical examination than in those who did not. This supports the theory that the location of the Hill-Sachs lesion may play a role in engagement and may be its most important characteristic when determining its significance. (orig.)

Characterization of recombinant human lysosomal beta-hexosaminidases produced in the methylotrophic yeast Pichia pastoris

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Angela Johana Espejo Mojica

2016-08-01

Full Text Available β-hexosaminidases (Hex are dimeric enzymes involved in the lysosomal degradation of glycolipids and glycans. They are formed by α- and/or β-subunits encoded byHEXA and HEXB genes, respectively. Mutations in these genes lead to Tay Sachs or Sandhoff diseases, which are neurodegenerative disorders caused by the accumulation of non-degraded glycolipids. Although tissue-derived Hex have been widely characterized, limited information is available for recombinant β-hexosaminidases. In this study, human lysosomal recombinant Hex (rhHex-A, rhHex-B, and rhHex-S were produced in the methylotrophic yeast Pichia pastoris GS115. The highest specific enzyme activities were 13,124 for rhHexA; 12,779 for rhHex-B; and 14,606 U .mg-1 for rhHex-S. These results were 25- to 50-fold higher than those obtained from normal human leukocytes. Proteins were purified and characterized at different pH and temperature conditions. All proteins were stable at acidic pH, and at 4 °C and 37 °C. At 45 °C rhHex-S was completely inactivated, while rhHex-A and rhHex-B showed high stability. This study demonstrates P. pastoris GS115 potential for polymeric lysosomal enzyme production, and describes the characterization of recombinant β-hexosaminidases produced within the same host.

Neuronal ceroid-lipofuscinosis, a type of amaurotic family idiocy: clinical and pathological study of four cases

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Luciano de Souza Queiroz

1974-03-01

Full Text Available Neuronal ceroid-lipofuscinosis (NCL is a recent term, proposed for acurate designation of the late-onset types of Amaurotic Family Idiocy (AFI. Histopathology shows ubiquitous intraneuronal accumulation of lipopigments, being the most important factor for characterization of the entity at present time. Biochemical changes and pathogenesis are obscure. NCL is in contrast to the infantile type of AFI (Tay-Sachs disease, in which intraneuronal accumulation of gangliosides (sphingolipids is due to the well known deficiency of a lysosomal enzyme. The authors report on four cases of NCL, two brothers of the late infantile (Jansky-Bielschowsky type and a brother and a sister of the juvenile (Spielmeyer-Sjögren type. One autopsy and three cortical biopsies revealed moderate to severe distention of the neurons by lipopigment, with nerve cell loss, gliosis and cerebral atrophy. Lipopigment was also increased in liver, heart and spleen. The patients were the first in Brazilian literature in whom the storage material was identified as lipopigment by histochemical methods. A brief summary of the clinical features of NCL is presented, and relevant problems are discussed, concerning interpretation of the nature of the storage material, and significance of the disease for gerontological research.

[Dr Mavro Sachs (1817-1888): the first lecturer of Zagreb University].

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Dugacki, Vladimir

2010-01-01

Mavro Sachs (Jánosháza, Hungary, 1817 % emdash; Rijeka, 1888.) was a Zagreb student since 1828. In 1846 he graduated in medicine from the University of Vienna and returned to Zagreb to be the city physician. In 1849, he started to teach forensic medicine at the School of Law of the Royal Academy of Sciences in Zagreb and continued teaching the same subject at the Zagreb University Faculty of Law in the capacity of docent (corresponds to lecturer in the British system). He also taught medical law at pharmaceutical studies of Zagreb University. From 1855 to 1860, he presided over the Jewish Community of Zagreb.

Kantowski-Sachs Einstein-æther perfect fluid models

Energy Technology Data Exchange (ETDEWEB)

Latta, Joey [Department of Mathematics and Statistics, Dalhousie University, Halifax, Nova Scotia, B3H 3J5 (Canada); Leon, Genly [Instituto de Física, Pontificia Universidad de Católica de Valparaíso, Casilla 4950, Valparaíso (Chile); Paliathanasis, Andronikos, E-mail: lattaj@mathstat.dal.ca, E-mail: genly.leon@pucv.cl, E-mail: anpaliat@phys.uoa.gr [Instituto de Ciencias Físicas y Matemáticas, Universidad Austral de Chile, Valdivia (Chile)

2016-11-01

We investigate Kantowski-Sachs models in Einstein-æ ther theory with a perfect fluid source using the singularity analysis to prove the integrability of the field equations and dynamical system tools to study the evolution. We find an inflationary source at early times, and an inflationary sink at late times, for a wide region in the parameter space. The results by A.A. Coley, G. Leon, P. Sandin and J. Latta ( JCAP 12 (2015) 010), are then re-obtained as particular cases. Additionally, we select other values for the non-GR parameters which are consistent with current constraints, getting a very rich phenomenology. In particular, we find solutions with infinite shear, zero curvature, and infinite matter energy density in comparison with the Hubble scalar. We also have stiff-like future attractors, anisotropic late-time attractors, or both, in some special cases. Such results are developed analytically, and then verified by numerics. Finally, the physical interpretation of the new critical points is discussed.

Molecular analysis of beta-hexosaminidase A (Hex A) deficiency among persons of French Canadian background living in New England

Energy Technology Data Exchange (ETDEWEB)

Triggs-Raine, B.; Richard, M.; Wasel, N. [Univ. of Manitoba, Winnepeg (Canada)] [and others

1994-09-01

Tay-Sachs disease (TSD) results from mutations in the HEXA gene that cause Hex A deficiency. Enzyme screening for disease prevention has been applied in the Ashkenazi Jewish and French Canadian populations which have an elevated disease incidence. However, benign mutations that cause Hex A deficiency, but not TSD, complicate enzyme screening programs. While benign mutations account for only about 2% of Jewish carriers, they account for about 36% of non-Jewish enzyme-defined carriers. We have found a carrier frequency of 1/72 (n=1300) among persons of French Canadian background living in New England using an enzyme-based assay. The HEXA gene of these carriers and others was analyzed to determine the molecular basis of Hex A deficiency in this group. DNA samples were tested for common previously identified mutations; samples in which no change was found were screened for uncommon or novel mutations using SSCP analysis. Exons showing mobility shifts were sequenced and most mutations were confirmed by restriction enzyme digestion. Known disease-causing mutations were found in 8 samples (4 had a 7.6 kb deletion found in 80% of French Canadian TSD alleles) and known benign mutations were found in 4 samples. Seven novel mutations (G748A; +18 IVS-10 G-to-A; T1338C; +94 IVS-14 T-to-G; C1164G; +30 IVS-6 T-to-G) were identified; the G748A (Gly250Ser) change was found in 3 samples. The effects of the novel mutations on Hex A is unknown; some are likely polymorphisms. The molecular basis of this carrier population is clearly different from that of French Canadian TSD patients. Screening centers should be aware of the presence of benign mutations in the French Canadian population. Given the frequency of the Gly250Ser mutation, and the fact that it has been detected in a TSD patient, it too may be benign.

Exact Kantowski-Sachs and Bianchi types I and III cosmological models with a conformally invariant scalar field

International Nuclear Information System (INIS)

Accioly, A.J.

1985-01-01

Exact solutions of the Einstein-Conformally Invariant Scalar Field Equations are obtained for Kantowski-Sachs and Bianchi types I and III cosmologies. The presence of the conformally invariant scalar field is responsible for some interesting features of the solutions. In particular it is found that the Bianchi I model is consistent with the big-bang theory of cosmology. (Author) [pt

Symptoms and Causes of Celiac Disease

Science.gov (United States)

... Symptoms & Causes of Celiac Disease What are the symptoms of celiac disease? Most people with celiac disease have one or ... the rash and no other symptoms. Why are celiac disease symptoms so varied? Symptoms of celiac disease vary from ...

Memory effects of transformation textures in steel and its prediction by the double Kurdjumov–Sachs relation

International Nuclear Information System (INIS)

Tomida, T.; Wakita, M.; Yasuyama, M.; Sugaya, S.; Tomota, Y.; Vogel, S.C.

2013-01-01

The phenomenon that the transformation texture near the initial texture reproduces after the phase transformation cycle such as ferrite (α, body-centered cubic) → austenite (γ, face-centered cubic) → α is called a texture memory. In this study, the texture change in a 0.1% C–1% Mn hot-rolled steel sheet during the α → γ → α transformation cycle was studied via neutron diffraction and the transformation texture prediction based on a variant selection rule that we call the double Kurdjumov–Sachs (K–S) relation. The texture change observed by neutron diffraction, which clearly showed the texture memory, could be quantitatively reproduced by the proposed variant selection rule adopted into the calculation method based on the spherical harmonics expansion of orientation distribution functions. Therefore, it is most likely that the texture memory in steel is caused by the preferential selection of those K–S variants that reduce the interfacial energy between a precipitate and two adjoining parent phase grains at the same time, which we call the double K–S relation

Planck 2015 results: XXI. The integrated Sachs-Wolfe effect

International Nuclear Information System (INIS)

Ade, P. A. R.; Aghanim, N.; Arnaud, M.; Ashdown, M.; Aumont, J.

2016-01-01

Here, this paper presents a study of the integrated Sachs-Wolfe (ISW) effect from the Planck 2015 temperature and polarization data release. This secondary cosmic microwave background (CMB) anisotropy caused by the large-scale time-evolving gravitational potential is probed from different perspectives. The CMB is cross-correlated with different large-scale structure (LSS) tracers: radio sources from the NVSS catalogue; galaxies from the optical SDSS and the infrared WISE surveys; and the Planck 2015 convergence lensing map. The joint cross-correlation of the CMB with the tracers yields a detection at 4σ where most of the signal-to-noise is due to the Planck lensing and the NVSS radio catalogue. In fact, the ISW effect is detected from the Planck data only at ≈3σ (through the ISW-lensing bispectrum), which is similar to the detection level achieved by combining the cross-correlation signal coming from all the galaxy catalogues mentioned above. We study the ability of the ISW effect to place constraints on the dark-energy parameters; in particular, we show that Ω Λ is detected at more than 3σ. This cross-correlation analysis is performed only with the Planck temperature data, since the polarization scales available in the 2015 release do not permit significant improvement of the CMB-LSS cross-correlation detectability. Nevertheless, the Planck polarization data are used to study the anomalously large ISW signal previously reported through the aperture photometry on stacked CMB features at the locations of known superclusters and supervoids, which is in conflict with ΛCDM expectations. We find that the current Planck polarization data do not exclude that this signal could be caused by the ISW effect. In addition, the stacking of the Planck lensing map on the locations of superstructures exhibits a positive cross-correlation with these large-scale structures. Finally, we have improved our previous reconstruction of the ISW temperature fluctuations by combining

On the structure and applications of the Bondi-Metzner-Sachs group

Science.gov (United States)

Alessio, Francesco; Esposito, Giampiero

This work is a pedagogical review dedicated to a modern description of the Bondi-Metzner-Sachs (BMS) group. Minkowski space-time has an interesting and useful group of isometries, but, for a generic space-time, the isometry group is simply the identity and hence provides no significant informations. Yet symmetry groups have important role to play in physics; in particular, the Poincaré group describing the isometries of Minkowski space-time plays a role in the standard definitions of energy-momentum and angular-momentum. For this reason alone it would seem to be important to look for a generalization of the concept of isometry group that can apply in a useful way to suitable curved space-times. The curved space-times that will be taken into account are the ones that suitably approach, at infinity, Minkowski space-time. In particular we will focus on asymptotically flat space-times. In this work, the concept of asymptotic symmetry group of those space-times will be studied. In the first two sections we derive the asymptotic group following the classical approach which was basically developed by Bondi, van den Burg, Metzner and Sachs. This is essentially the group of transformations between coordinate systems of a certain type in asymptotically flat space-times. In the third section the conformal method and the notion of “asymptotic simplicity” are introduced, following mainly the works of Penrose. This section prepares us for another derivation of the BMS group which will involve the conformal structure, and is thus more geometrical and fundamental. In the subsequent sections we discuss the properties of the BMS group, e.g. its algebra and the possibility to obtain as its subgroup the Poincaré group, as we may expect. The paper ends with a review of the BMS invariance properties of classical gravitational scattering discovered by Strominger, that are finding application to black hole physics and quantum gravity in the literature.

Endocrine causes of nonalcoholic fatty liver disease.

Science.gov (United States)

Marino, Laura; Jornayvaz, François R

2015-10-21

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. The prevalence of NAFLD is increasing, becoming a substantial public health burden. NAFLD includes a broad spectrum of disorders, from simple conditions such as steatosis to severe manifestations such as fibrosis and cirrhosis. The relationship of NAFLD with metabolic alterations such as type 2 diabetes is well described and related to insulin resistance, with NAFLD being recognized as the hepatic manifestation of metabolic syndrome. However, NAFLD may also coincide with endocrine diseases such as polycystic ovary syndrome, hypothyroidism, growth hormone deficiency or hypercortisolism. It is therefore essential to remember, when discovering altered liver enzymes or hepatic steatosis on radiological exams, that endocrine diseases can cause NAFLD. Indeed, the overall prognosis of NAFLD may be modified by treatment of the underlying endocrine pathology. In this review, we will discuss endocrine diseases that can cause NALFD. Underlying pathophysiological mechanisms will be presented and specific treatments will be reviewed.

Phenomenological dynamics of loop quantum cosmology in Kantowski-Sachs spacetime

International Nuclear Information System (INIS)

Chiou, D.-W.

2008-01-01

The fundamental theory and the semiclassical description of loop quantum cosmology (LQC) have been studied in the Friedmann-Robertson-Walker and Bianchi I models. As an extension to include both anisotropy and intrinsic curvature, this paper investigates the cosmological model of Kantowski-Sachs spacetime with a free massless scalar field at the level of phenomenological dynamics with the LQC discreteness corrections. The LQC corrections are implemented in two different improved quantization schemes. In both schemes, the big bang and big crunch singularities of the classical solution are resolved and replaced by the big bounces when the area or volume scale factor approaches the critical values in the Planck regime measured by the reference of the scalar field momentum. Symmetries of scaling are also noted and suggest that the fundamental spatial scale (area gap) may give rise to a temporal scale. The bouncing scenarios are in an analogous fashion of the Bianchi I model, naturally extending the observations obtained previously.

Challenges of Pre- and Post-Test Counseling for Orthodox Jewish Individuals in the Premarital Phase.

Science.gov (United States)

Rose, E; Schreiber-Agus, N; Bajaj, K; Klugman, S; Goldwaser, T

2016-02-01

The Jewish community has traditionally taken ownership of its health, and has taken great strides to raise awareness about genetic issues that affect the community, such as Tay-Sachs disease and Hereditary Breast and Ovarian Cancer syndrome. Thanks in part to these heightened awareness efforts, many Orthodox Jewish individuals are now using genetics services as they begin to plan their families. Due to unique cultural and religious beliefs and perceptions, the Orthodox Jewish patients who seek genetic counseling face many barriers to a successful counseling session, and often seek the guidance of programs such as the Program for Jewish Genetic Health (PJGH). In this article, we present clinical vignettes from the PJGH's clinical affiliate, the Reproductive Genetics practice at the Montefiore Medical Center. These cases highlight unique features of contemporary premarital counseling and screening within the Orthodox Jewish Community, including concerns surrounding stigma, disclosure, "marriageability," the use of reproductive technologies, and the desire to include a third party in decision making. Our vignettes demonstrate the importance of culturally-sensitive counseling. We provide strategies and points to consider when addressing the challenges of pre- and post-test counseling as it relates to genetic testing in this population.

Area density of localization-entropy II: double cone-localization and quantum origin of the Bondi-Metzner-Sachs symmetry

Energy Technology Data Exchange (ETDEWEB)

Schroer, Bert

2006-04-15

The holographic encoding is generalized to subalgebras of QFT localized in double cones. It is shown that as a result of this radically different spacetime encoding the modular group acts geometrically on the holographic image. As a result we obtain a formula for localization entropy which is identical to the previously derived formula for the wedge-localized subalgebra. The symmetry group in the holographic encoding turns out to be the Bondi-Metzner-Sachs group. (author)

Corals diseases are a major cause of coral death

Science.gov (United States)

Corals, like humans, are susceptible to diseases. Some coral diseases are associated with pathogenic bacteria; however, the causes of most remain unknown. Some diseases trigger rapid and extensive mortality, while others slowly cause localized color changes or injure coral tiss...

8th European Conference on Rare Diseases & Orphan Products (ECRD 2016

Directory of Open Access Journals (Sweden)

Michael Schlander

2016-11-01

Full Text Available Table of contents O1 The European Social Preferences Measurement (ESPM study project: social cost value analysis, budget impact, commercial life cycle revenue management, and the economics of biopharmaceutical Research & Development (R&D Michael Schlander, Søren Holm, Erik Nord, Jeff Richardson, Silvio Garattini, Peter Kolominsky-Rabas, Deborah Marshall, Ulf Persson, Maarten Postma, Steven Simoens, Oriol de Solà Morales, Keith Tolley, Mondher Toumi, Harry Telser O2 Newborn Screening: the potential and the challenges James R Bonham O3 Untreatable disease outcomes - how would we measure them? Helmut Hintner, Anja Diem, Martin Laimer O4 Taking Integrated Care Forward: Experiences from Canada to inspire service provision for people living with rare disease in Europe Réjean Hébert O5 Listening to the patient’s voice: social media listening for safety and benefits in rare diseases Nabarun Dasgupta, Carrie E. Pierce, Melissa Jordan O6 Via Opta: Mobile apps making visually impaired patients’ lives easier Barbara Bori, Mohanad Fors, Emilie Prazakova O7 A report of the IRDiRC “Small Population Clinical Trial” Task Force Simon Day O8 HAE patient identification and diagnosis: An innovative, ‘game changing’ collaboration Thomas J. Croce Jr. O9 Co-creating with the community: primary packaging & administration for people with haemophilia Jonas Fransson, Philip Wood O10 Go with Gaucher, taking forward the next generation. How to involve young people to create a new generation of patient advocates Anne-Grethe Lauridsen, Joanne Higgs, Vesna Stojmirova Aleksovska P1 ODAK – Orphan Drug for Acanthamoeba Keratitis Christina Olsen, Ritchie Head, Antonio Asero, Vincenzo Papa, Christa van Kan, Loic Favennec, Silvana Venturella, Michela Salvador, Alan Krol P5 Rare Navigators help people living with rare diseases to manage the social – and healthcare systems Stephanie J. Nielsen, Birthe B. Holm P6 The eAcademy for Tay-Sachs & Sandhoff disease app

Animal models of GM2 gangliosidosis: utility and limitations

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Lawson CA

2016-07-01

Full Text Available Cheryl A Lawson,1,2 Douglas R Martin2,3 1Department of Pathobiology, 2Scott-Ritchey Research Center, 3Department of Anatomy, Physiology and Pharmacology, Auburn University College of Veterinary Medicine, Auburn, AL, USA Abstract: GM2 gangliosidosis, a subset of lysosomal storage disorders, is caused by a deficiency of the glycohydrolase, β-N-acetylhexosaminidase, and includes the closely related Tay–Sachs and Sandhoff diseases. The enzyme deficiency prevents the normal, stepwise degradation of ganglioside, which accumulates unchecked within the cellular lysosome, particularly in neurons. As a result, individuals with GM2 gangliosidosis experience progressive neurological diseases including motor deficits, progressive weakness and hypotonia, decreased responsiveness, vision deterioration, and seizures. Mice and cats are well-established animal models for Sandhoff disease, whereas Jacob sheep are the only known laboratory animal model of Tay–Sachs disease to exhibit clinical symptoms. Since the human diseases are relatively rare, animal models are indispensable tools for further study of pathogenesis and for development of potential treatments. Though no effective treatments for gangliosidoses currently exist, animal models have been used to test promising experimental therapies. Herein, the utility and limitations of gangliosidosis animal models and how they have contributed to the development of potential new treatments are described. Keywords: GM2 gangliosidosis, Tay–Sachs disease, Sandhoff disease, lysosomal storage disorder, sphingolipidosis, brain disease

Neuronal ceroid-lipofuscinosis, a type of amaurotic family idiocy: clinical and pathological study of four cases Ceróide-lipofuscinose neuronal, um tipo de idiotia amaurótica familiar: estudo clínico-patológico de quatro casos

Directory of Open Access Journals (Sweden)

Luciano de Souza Queiroz

1974-03-01

Full Text Available Neuronal ceroid-lipofuscinosis (NCL is a recent term, proposed for acurate designation of the late-onset types of Amaurotic Family Idiocy (AFI. Histopathology shows ubiquitous intraneuronal accumulation of lipopigments, being the most important factor for characterization of the entity at present time. Biochemical changes and pathogenesis are obscure. NCL is in contrast to the infantile type of AFI (Tay-Sachs disease, in which intraneuronal accumulation of gangliosides (sphingolipids is due to the well known deficiency of a lysosomal enzyme. The authors report on four cases of NCL, two brothers of the late infantile (Jansky-Bielschowsky type and a brother and a sister of the juvenile (Spielmeyer-Sjögren type. One autopsy and three cortical biopsies revealed moderate to severe distention of the neurons by lipopigment, with nerve cell loss, gliosis and cerebral atrophy. Lipopigment was also increased in liver, heart and spleen. The patients were the first in Brazilian literature in whom the storage material was identified as lipopigment by histochemical methods. A brief summary of the clinical features of NCL is presented, and relevant problems are discussed, concerning interpretation of the nature of the storage material, and significance of the disease for gerontological research.Estudos histoquímicos, bioquímicos e ultraestruturais permitiram recentemente distinguir dois tipos de entidades nosológicas dentre as doenças conhecidas como "Idiotia amaurótica familiar" (IAF. O primeiro, que inclue a doença de Tay-Sachs, ou tipo infantil de IAF, é constituido por doenças de armazenamento de gangliósides. Sua patogenia é conhecida, baseando-se em deficiências de enzimas lisossômicos. O segundo grupo, cuja patogenia é desconhecida, foi recentemente designado "Ceróide-lipofuscinose neuronal" (CLN por Zeman e colaboradores. Corresponde aos tipos infantil tardio, juvenil e adulto de IAF, caracterizando-se histopatologicamente pelo ac

Symptoms and Causes of Peptic Ulcer Disease

Science.gov (United States)

... ulcer. How do H. pylori cause a peptic ulcer and peptic ulcer disease? H. pylori are spiral-shaped bacteria that ... peptic ulcer. How do tumors from ZES cause peptic ulcers? Zollinger-Ellison syndrome is a rare disorder that ...

Magnification-temperature correlation: The dark side of integrated Sachs-Wolfe measurements

International Nuclear Information System (INIS)

LoVerde, Marilena; Hui, Lam; Gaztanaga, Enrique

2007-01-01

Integrated Sachs-Wolfe (ISW) measurements, which involve cross-correlating the microwave background anisotropies with the foreground large-scale structure (e.g. traced by galaxies/quasars), have proven to be an interesting probe of dark energy. We show that magnification bias, which is the inevitable modulation of the foreground number counts by gravitational lensing, alters both the scale dependence and amplitude of the observed ISW signal. This is true especially at high redshifts because (1) the intrinsic galaxy-temperature signal diminishes greatly back in the matter-dominated era, (2) the lensing efficiency increases with redshift and (3) the number count slope generally steepens with redshift in a magnitude limited sample. At z > or approx. 2, the magnification-temperature correlation dominates over the intrinsic galaxy-temperature correlation and causes the observed ISW signal to increase with redshift, despite dark energy subdominance--a result of the fact that magnification probes structures all the way from the observer to the sources. Ignoring magnification bias therefore can lead to (significantly) erroneous conclusions about dark energy. While the lensing modulation opens up an interesting high z window for ISW measurements, high redshift measurements are not expected to add much new information to low redshift ones if dark energy is indeed the cosmological constant. This is because lensing introduces significant covariance across redshifts. The most compelling reasons for pursuing high redshift ISW measurements are to look for potential surprises such as early dark energy domination or signatures of modified gravity. We conclude with a discussion of existing measurements, the highest redshift of which is at the margin of being sensitive to the magnification effect. We also develop a formalism which might be of more general interest: to predict biases in estimating parameters when certain physical effects are ignored in interpreting observations

Traumatic glenohumeral bone defects and their relationship to failure of arthroscopic Bankart repairs: significance of the inverted-pear glenoid and the humeral engaging Hill-Sachs lesion.

Science.gov (United States)

Burkhart, S S; De Beer, J F

2000-10-01

Our goal was to analyze the results of 194 consecutive arthroscopic Bankart repairs (performed by 2 surgeons with an identical suture anchor technique) in order to identify specific factors related to recurrence of instability. Case series. We analyzed 194 consecutive arthroscopic Bankart repairs by suture anchor technique performed for traumatic anterior-inferior instability. The average follow-up was 27 months (range, 14 to 79 months). There were 101 contact athletes (96 South African rugby players and 5 American football players). We identified significant bone defects on either the humerus or the glenoid as (1) "inverted-pear" glenoid, in which the normally pear-shaped glenoid had lost enough anterior-inferior bone to assume the shape of an inverted pear; or (2) "engaging" Hill-Sachs lesion of the humerus, in which the orientation of the Hill-Sachs lesion was such that it engaged the anterior glenoid with the shoulder in abduction and external rotation. There were 21 recurrent dislocations and subluxations (14 dislocations, 7 subluxations). Of those 21 shoulders with recurrent instability, 14 had significant bone defects (3 engaging Hill-Sachs and 11 inverted-pear Bankart lesions). For the group of patients without significant bone defects (173 shoulders), there were 7 recurrences (4% recurrence rate). For the group with significant bone defects (21 patients), there were 14 recurrences (67% recurrence rate). For contact athletes without significant bone defects, there was a 6.5% recurrence rate, whereas for contact athletes with significant bone defects, there was an 89% recurrence rate. (1) Arthroscopic Bankart repairs give results equal to open Bankart repairs if there are no significant structural bone deficits (engaging Hill-Sachs or inverted-pear Bankart lesions). (2) Patients with significant bone deficits as defined in this study are not candidates for arthroscopic Bankart repair. (3) Contact athletes without structural bone deficits may be treated by

Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides.

Science.gov (United States)

Pan, Xuefang; De Aragão, Camila De Britto Pará; Velasco-Martin, Juan P; Priestman, David A; Wu, Harry Y; Takahashi, Kohta; Yamaguchi, Kazunori; Sturiale, Luisella; Garozzo, Domenico; Platt, Frances M; Lamarche-Vane, Nathalie; Morales, Carlos R; Miyagi, Taeko; Pshezhetsky, Alexey V

2017-08-01

Gangliosides (sialylated glycolipids) play an essential role in the CNS by regulating recognition and signaling in neurons. Metabolic blocks in processing and catabolism of gangliosides result in the development of severe neurologic disorders, including gangliosidoses manifesting with neurodegeneration and neuroinflammation. We demonstrate that 2 mammalian enzymes, neuraminidases 3 and 4, play important roles in catabolic processing of brain gangliosides by cleaving terminal sialic acid residues in their glycan chains. In neuraminidase 3 and 4 double-knockout mice, G M3 ganglioside is stored in microglia, vascular pericytes, and neurons, causing micro- and astrogliosis, neuroinflammation, accumulation of lipofuscin bodies, and memory loss, whereas their cortical and hippocampal neurons have lower rate of neuritogenesis in vitro Double-knockout mice also have reduced levels of G M1 ganglioside and myelin in neuronal axons. Furthermore, neuraminidase 3 deficiency drastically increased storage of G M2 in the brain tissues of an asymptomatic mouse model of Tay-Sachs disease, a severe human gangliosidosis, indicating that this enzyme is responsible for the metabolic bypass of β-hexosaminidase A deficiency. Together, our results provide the first in vivo evidence that neuraminidases 3 and 4 have important roles in CNS function by catabolizing gangliosides and preventing their storage in lipofuscin bodies.-Pan, X., De Britto Pará De Aragão, C., Velasco-Martin, J. P., Priestman, D. A., Wu, H. Y., Takahashi, K., Yamaguchi, K., Sturiale, L., Garozzo, D., Platt, F. M., Lamarche-Vane, N., Morales, C. R., Miyagi, T., Pshezhetsky, A. V. Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides. © FASEB.

Chilli anthracnose disease caused by Colletotrichum species.

Science.gov (United States)

Than, Po Po; Prihastuti, Haryudian; Phoulivong, Sitthisack; Taylor, Paul W J; Hyde, Kevin D

2008-10-01

Anthracnose disease is one of the major economic constraints to chilli production worldwide, especially in tropical and subtropical regions. Accurate taxonomic information is necessary for effective disease control management. In the Colletotrichum patho-system, different Colletotrichum species can be associated with anthracnose of the same host. Little information is known concerning the interactions of the species associated with the chilli anthracnose although several Colletotrichum species have been reported as causal agents of chilli anthracnose disease worldwide. The ambiguous taxonomic status of Colletotrichum species has resulted in inaccurate identification which may cause practical problems in plant breeding and disease management. Although the management and control of anthracnose disease are still being extensively researched, commercial cultivars of Capsicum annuum that are resistant to the pathogens that cause chilli anthracnose have not yet been developed. This paper reviews the causal agents of chilli anthracnose, the disease cycle, conventional methods in identification of the pathogen and molecular approaches that have been used for the identification of Colletotrichum species. Pathogenetic variation and population structure of the causal agents of chilli anthracnose along with the current taxonomic status of Colletotrichum species are discussed. Future developments leading to the disease management strategies are suggested.

[Epidemiology and causes of Parkinson's disease].

Science.gov (United States)

Lill, C M; Klein, C

2017-04-01

Parkinson's disease (PD) is the second most common neurodegenerative disease and has a growing socioeconomic impact due to demographic changes in the industrial nations. There are several forms of PD, a fraction of which (parkinsonism including three autosomal dominantly (SNCA, LRRK2, VPS35) and three autosomal recessively inherited ones (Parkin, PINK1, DJ-1). In addition, there are a plethora of genes causing atypical forms of parkinsonism. In contrast, idiopathic PD is of a multifactorial nature. Genome-wide association studies have established a total of 26 genetic loci for this form of the disease; however, for most of these loci the underlying functional genetic variants have not yet been identified and the respective disease mechanisms remain unresolved. Furthermore, there are a number of environmental and life style factors that are associated with idiopathic PD. Exposure to pesticides and possibly a history of head trauma represent genuine risk factors. Other PD-associated factors, such as smoking and intake of coffee and alcohol may not represent risk factors per se and the cause-effect relationship has not yet been elucidated for most of these factors. A patient with a positive family history and/or an early age of disease onset should undergo counseling with respect to a possible monogenic form of the disease. Disease prediction based on genetic, environmental and life style factors is not yet possible for idiopathic PD and potential gene-specific therapies are currently in the development or early testing phase.

Root cause of waterborne diseases in Pakistan

International Nuclear Information System (INIS)

Hashml, H.N.; Ghumman, A.R.; Malik, N.E.

2005-01-01

The waterborne diseases are increasing rapidly at an alarming rate in Pakistan due to poor sanitation and unsafe drinking water supplies. This study shows that about 25 percent of all the illnesses in Lahore are due to severe cases of waterborne diseases. Unhygienic sanitation system is the root cause for this scenario. Drinking water, samples were collected from different zones of the city to find out the root cause of waterborne diseases. The samples from the distribution system serving 'Kachi Abbadies' (Underdeveloped areas) were much more contaminated, may be due to non-chlorination as compared to the water which is regularly chlorinated in posh areas of the city. Contribution of soakage pits in groundwater contamination is more significant at shallow depths. From the laboratory results it is clear that water distribution in underdeveloped areas of the city is highly contaminated and ground water available at shallow depth is also infected by microbial activities. Data collected from the different hospitals to investigate the problem shows that waterborne diseases vary their trend seasonally. Here in Pakistan, rainy season (July-August) reveals maximum number of cases of waterborne diseases. Proper sanitation and water supply systems are more essential to control the influence of waterborne diseases within the country. It is strongly recommended that reputable ways of communications are urgently required to highlight the diseases related to unsafe drinking water. (author)

Gumboro Disease Outbreaks Cause High Mortality Rates in ...

African Journals Online (AJOL)

Infectious bursal disease is a disease of economic importance which affects all types of chickens and causes variable mortality. To establish the importance of this disease in the indigenous chickens in Kenya a comparative study of natural outbreaks in flocks of layers, broilers and indigenous chickens was done. Thirty nine ...

Carrier screening in the era of expanding genetic technology.

Science.gov (United States)

Arjunan, Aishwarya; Litwack, Karen; Collins, Nick; Charrow, Joel

2016-12-01

The Center for Jewish Genetics provides genetic education and carrier screening to individuals of Jewish descent. Carrier screening has traditionally been performed by targeted mutation analysis for founder mutations with an enzyme assay for Tay-Sachs carrier detection. The development of next-generation sequencing (NGS) allows for higher detection rates regardless of ethnicity. Here, we explore differences in carrier detection rates between genotyping and NGS in a primarily Jewish population. Peripheral blood samples or saliva samples were obtained from 506 individuals. All samples were analyzed by sequencing, targeted genotyping, triplet-repeat detection, and copy-number analysis; the analyses were carried out at Counsyl. Of 506 individuals screened, 288 were identified as carriers of at least 1 condition and 8 couples were carriers for the same disorder. A total of 434 pathogenic variants were identified. Three hundred twelve variants would have been detected via genotyping alone. Although no additional mutations were detected by NGS in diseases routinely screened for in the Ashkenazi Jewish population, 26.5% of carrier results and 2 carrier couples would have been missed without NGS in the larger panel. In a primarily Jewish population, NGS reveals a larger number of pathogenic variants and provides individuals with valuable information for family planning.Genet Med 18 12, 1214-1217.

Inorganic arsenic causes fatty liver and interacts with ethanol to cause alcoholic liver disease in zebrafish

OpenAIRE

Kathryn Bambino; Chi Zhang; Christine Austin; Chitra Amarasiriwardena; Manish Arora; Jaime Chu; Kirsten C. Sadler

2018-01-01

The rapid increase in fatty liver disease (FLD) incidence is attributed largely to genetic and lifestyle factors; however, environmental toxicants are a frequently overlooked factor that can modify the effects of more common causes of FLD. Chronic exposure to inorganic arsenic (iAs) is associated with liver disease in humans and animal models, but neither the mechanism of action nor the combinatorial interaction with other disease-causing factors has been fully investigated. Here, we examined...

Embedded Lensing Time Delays, the Fermat Potential, and the Integrated Sachs-Wolfe Effect

Science.gov (United States)

Chen, Bin; Kantowski, Ronald; Dai, Xinyu

2015-05-01

We derive the Fermat potential for a spherically symmetric lens embedded in a Friedman-Lemaître-Robertson-Walker cosmology and use it to investigate the late-time integrated Sachs-Wolfe (ISW) effect, i.e., secondary temperature fluctuations in the cosmic microwave background (CMB) caused by individual large-scale clusters and voids. We present a simple analytical expression for the temperature fluctuation in the CMB across such a lens as a derivative of the lens’ Fermat potential. This formalism is applicable to both linear and nonlinear density evolution scenarios, to arbitrarily large density contrasts, and to all open and closed background cosmologies. It is much simpler to use and makes the same predictions as conventional approaches. In this approach the total temperature fluctuation can be split into a time-delay part and an evolutionary part. Both parts must be included for cosmic structures that evolve and both can be equally important. We present very simple ISW models for cosmic voids and galaxy clusters to illustrate the ease of use of our formalism. We use the Fermat potentials of simple cosmic void models to compare predicted ISW effects with those recently extracted from WMAP and Planck data by stacking large cosmic voids using the aperture photometry method. If voids in the local universe with large density contrasts are no longer evolving we find that the time delay contribution alone predicts values consistent with the measurements. However, we find that for voids still evolving linearly, the evolutionary contribution cancels a significant part of the time delay contribution and results in predicted signals that are much smaller than recently observed.

Prediction of disease causing non-synonymous SNPs by the Artificial Neural Network Predictor NetDiseaseSNP.

Directory of Open Access Journals (Sweden)

Morten Bo Johansen

Full Text Available We have developed a sequence conservation-based artificial neural network predictor called NetDiseaseSNP which classifies nsSNPs as disease-causing or neutral. Our method uses the excellent alignment generation algorithm of SIFT to identify related sequences and a combination of 31 features assessing sequence conservation and the predicted surface accessibility to produce a single score which can be used to rank nsSNPs based on their potential to cause disease. NetDiseaseSNP classifies successfully disease-causing and neutral mutations. In addition, we show that NetDiseaseSNP discriminates cancer driver and passenger mutations satisfactorily. Our method outperforms other state-of-the-art methods on several disease/neutral datasets as well as on cancer driver/passenger mutation datasets and can thus be used to pinpoint and prioritize plausible disease candidates among nsSNPs for further investigation. NetDiseaseSNP is publicly available as an online tool as well as a web service: http://www.cbs.dtu.dk/services/NetDiseaseSNP.

Chilli anthracnose disease caused by Colletotrichum species§

Science.gov (United States)

Than, Po Po; Prihastuti, Haryudian; Phoulivong, Sitthisack; Taylor, Paul W.J.; Hyde, Kevin D.

2008-01-01

Anthracnose disease is one of the major economic constraints to chilli production worldwide, especially in tropical and subtropical regions. Accurate taxonomic information is necessary for effective disease control management. In the Colletotrichum patho-system, different Colletotrichum species can be associated with anthracnose of the same host. Little information is known concerning the interactions of the species associated with the chilli anthracnose although several Colletotrichum species have been reported as causal agents of chilli anthracnose disease worldwide. The ambiguous taxonomic status of Colletotrichum species has resulted in inaccurate identification which may cause practical problems in plant breeding and disease management. Although the management and control of anthracnose disease are still being extensively researched, commercial cultivars of Capsicum annuum that are resistant to the pathogens that cause chilli anthracnose have not yet been developed. This paper reviews the causal agents of chilli anthracnose, the disease cycle, conventional methods in identification of the pathogen and molecular approaches that have been used for the identification of Colletotrichum species. Pathogenetic variation and population structure of the causal agents of chilli anthracnose along with the current taxonomic status of Colletotrichum species are discussed. Future developments leading to the disease management strategies are suggested. PMID:18837103

[A brief history of the natural causes of human disease].

Science.gov (United States)

Lips-Castro, Walter

2015-01-01

In the study of the causes of disease that have arisen during the development of humankind, one can distinguish three major perspectives: the natural, the supernatural, and the artificial. In this paper we distinguish the rational natural causes of disease from the irrational natural causes. Within the natural and rational causal approaches of disease, we can highlight the Egyptian theory of putrid intestinal materials called "wechdu", the humoral theory, the atomistic theory, the contagious theory, the cellular theory, the molecular (genetic) theory, and the ecogenetic theory. Regarding the irrational, esoteric, and mystic causal approaches to disease, we highlight the astrological, the alchemical, the iatrochemical, the iatromechanical, and others (irritability, solidism, brownism, and mesmerism).

Fermat Potentials of Embedded Lensing, the Integrated Sachs-Wolfe Effect, and Weak-Lensing of CMB by Cosmic Voids

Science.gov (United States)

Chen, Bin; Kantowski, R.; Dai, X.

2014-01-01

We have developed an accurate gravitational lens theory for an inhomogeneity embedded in an otherwise homogeneous universe, which to the lowest order is applicable to any mass distribution. We derive the Fermat potential for a spherically symmetric lens embedded in a FLRW cosmology and use it to investigate the late-time integrated Sachs-Wolfe effect (ISW) caused by individual large scale inhomogeneities, in particular, cosmic voids. We present a simple analytical expression for the CMB temperature fluctuation across such a lens as the derivative of the lens Fermat potential. Our formalism is applicable to both linear and nonlinear density evolution scenarios, to arbitrarily large density contrasts, and to all open and closed background cosmologies. Our results are particularly useful for modeling ISW effects extracted through stacking large numbers of cosmic voids and clusters (that is, the aperture photometry method). For structures co-expanding with the background cosmology, i.e., for time-independent density contrasts, we find that the gravitational lensing time delay alone can produce fluctuations of the order of seen in recent observations by WMAP and Planck. We revisit the possibility of explaining the non-Gaussian cold spot on the south hemisphere via the Rees-Sciama effect of a large cosmic void using constraints obtained from the most recent void catalogs and our new void-lensing formalism, and compare it with other explanations such as a collapsing cosmic texture. We also study the remapping of primordial CMB anisotropies, the weak-lensing shear, and magnification caused by void lensing.

Inorganic arsenic causes fatty liver and interacts with ethanol to cause alcoholic liver disease in zebrafish

Directory of Open Access Journals (Sweden)

Kathryn Bambino

2018-02-01

Full Text Available The rapid increase in fatty liver disease (FLD incidence is attributed largely to genetic and lifestyle factors; however, environmental toxicants are a frequently overlooked factor that can modify the effects of more common causes of FLD. Chronic exposure to inorganic arsenic (iAs is associated with liver disease in humans and animal models, but neither the mechanism of action nor the combinatorial interaction with other disease-causing factors has been fully investigated. Here, we examined the contribution of iAs to FLD using zebrafish and tested the interaction with ethanol to cause alcoholic liver disease (ALD. We report that zebrafish exposed to iAs throughout development developed specific phenotypes beginning at 4 days post-fertilization (dpf, including the development of FLD in over 50% of larvae by 5 dpf. Comparative transcriptomic analysis of livers from larvae exposed to either iAs or ethanol revealed the oxidative stress response and the unfolded protein response (UPR caused by endoplasmic reticulum (ER stress as common pathways in both these models of FLD, suggesting that they target similar cellular processes. This was confirmed by our finding that arsenic is synthetically lethal with both ethanol and a well-characterized ER-stress-inducing agent (tunicamycin, suggesting that these exposures work together through UPR activation to cause iAs toxicity. Most significantly, combined exposure to sub-toxic concentrations of iAs and ethanol potentiated the expression of UPR-associated genes, cooperated to induce FLD, reduced the expression of as3mt, which encodes an arsenic-metabolizing enzyme, and significantly increased the concentration of iAs in the liver. This demonstrates that iAs exposure is sufficient to cause FLD and that low doses of iAs can potentiate the effects of ethanol to cause liver disease. This article has an associated First Person interview with the first author of the paper.

Inorganic arsenic causes fatty liver and interacts with ethanol to cause alcoholic liver disease in zebrafish

Science.gov (United States)

Zhang, Chi; Austin, Christine; Amarasiriwardena, Chitra; Arora, Manish

2018-01-01

ABSTRACT The rapid increase in fatty liver disease (FLD) incidence is attributed largely to genetic and lifestyle factors; however, environmental toxicants are a frequently overlooked factor that can modify the effects of more common causes of FLD. Chronic exposure to inorganic arsenic (iAs) is associated with liver disease in humans and animal models, but neither the mechanism of action nor the combinatorial interaction with other disease-causing factors has been fully investigated. Here, we examined the contribution of iAs to FLD using zebrafish and tested the interaction with ethanol to cause alcoholic liver disease (ALD). We report that zebrafish exposed to iAs throughout development developed specific phenotypes beginning at 4 days post-fertilization (dpf), including the development of FLD in over 50% of larvae by 5 dpf. Comparative transcriptomic analysis of livers from larvae exposed to either iAs or ethanol revealed the oxidative stress response and the unfolded protein response (UPR) caused by endoplasmic reticulum (ER) stress as common pathways in both these models of FLD, suggesting that they target similar cellular processes. This was confirmed by our finding that arsenic is synthetically lethal with both ethanol and a well-characterized ER-stress-inducing agent (tunicamycin), suggesting that these exposures work together through UPR activation to cause iAs toxicity. Most significantly, combined exposure to sub-toxic concentrations of iAs and ethanol potentiated the expression of UPR-associated genes, cooperated to induce FLD, reduced the expression of as3mt, which encodes an arsenic-metabolizing enzyme, and significantly increased the concentration of iAs in the liver. This demonstrates that iAs exposure is sufficient to cause FLD and that low doses of iAs can potentiate the effects of ethanol to cause liver disease. This article has an associated First Person interview with the first author of the paper. PMID:29361514

Hereditary Causes of Kidney Stones and Chronic Kidney Disease

Science.gov (United States)

Edvardsson, Vidar O.; Goldfarb, David S.; Lieske, John C.; Beara-Lasic, Lada; Anglani, Franca; Milliner, Dawn S.; Palsson, Runolfur

2013-01-01

Adenine phosphoribosyltransferase (APRT) deficiency, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) and primary hyperoxaluria (PH) are rare but important causes of severe kidney stone disease and/or chronic kidney disease in children. Recurrent kidney stone disease and nephrocalcinosis, particularly in pre-pubertal children, should alert the physician to the possibility of an inborn error of metabolism as the underlying cause. Unfortunately, the lack of recognition and knowledge of the five disorders has frequently resulted in an unacceptable delay in diagnosis and treatment, sometimes with grave consequences. A high index of suspicion coupled with early diagnosis may reduce or even prevent the serious long-term complications of these diseases. In this paper, we review the epidemiology, clinical features, diagnosis, treatment and outcome of patients with APRT deficiency, cystinuria, Dent disease, FHHNC and PH with emphasis on childhood manifestations. PMID:23334384

Active packaging for fresh-cut broccoli using 1-methylcyclopropene in biodegradable sachet/ Embalagem ativa para brócolis minimamente processado utilizando 1-metilciclopropeno em sachê biodegradável

Directory of Open Access Journals (Sweden)

Marta de Toledo Benassi

2006-07-01

Full Text Available Fresh-cut broccoli florets were packed in polypropylene pots containing a sachet with 1- methylcyclopropene (1-MCP and sealed with biodegradable starch-based film. Broccoli was stored for 8 days at 12oC and after this time the color and the texture of the product were similar of the fresh broccoli, with no off-flavor development or decay. Active packaging with 1-MCP in a sachet was efficient to extent shelf life of broccoli florets retarding yellowing and vitamin C losses. It is an alternative of 1-MCP treatment for fresh-cut products and besides, the sachet can absorbs condensed water reducing spoilage and off-odor development.Brócolis minimamente processados foram embalados em bandejas de polipropileno com sachê contendo 1-metilciclopropeno (1-MCP e selado com filme biodegradável de amido. Os brócolis foram armazenados por 8 dias a 12oC e após este tempo a cor e a textura mantiveram-se similares às do produto fresco, sem desenvolvimento de odor não característico ou podridão. A embalagem ativa contendo 1-MCP na forma de sachê foi eficiente no aumento da vida de prateleira de brócolis, retardando o amarelecimento e a perda de vitamina C. Esta é uma alternativa para o tratamento com 1-MCP para produtos minimamente processados e além disso, o sachê pode absorver a água condensada, reduzindo a deterioração e o desenvolvimento de odor não característico.

Optical structures, algebraically special spacetimes, and the Goldberg-Sachs theorem in five dimensions

International Nuclear Information System (INIS)

Taghavi-Chabert, Arman

2011-01-01

Optical (or Robinson) structures are one generalization of four-dimensional shearfree congruences of null geodesics to higher dimensions. They are Lorentzian analogues of complex and CR structures. In this context, we extend the Goldberg-Sachs theorem to five dimensions. To be precise, we find a new algebraic condition on the Weyl tensor, which generalizes the Petrov type II condition, in the sense that it ensures the existence of such congruences on a five-dimensional spacetime, vacuum or under weaker assumptions on the Ricci tensor. This results in a significant simplification of the field equations. We discuss possible degenerate cases, including a five-dimensional generalization of the Petrov type D condition. We also show that the vacuum black ring solution is endowed with optical structures, yet fails to be algebraically special with respect to them. We finally explain the generalization of these ideas to higher dimensions, which has been checked in six and seven dimensions.

Danon’s disease as a cause of hypertrophic cardiomyopathy

Directory of Open Access Journals (Sweden)

I. V. Leontyeva

2015-01-01

Full Text Available Hypertrophic cardiomyopathy is the most common inherited disease of the myocardium. The causes of the disease are heterogeneous; its primary form results from mutations in the genes encoding cardiac sarcomeric proteins; its secondary (metabolic and syndromic forms develop due to mutations in the genes encoding non-sarcomeric proteins. Glycogenosis is the most common cause of the metabolic ones of hypertrophic cardiomyopathy. Danon’s disease (lysosome-associated membrane protein 2 (LAMP2-cardiomyopathy is a form of glycogenosis and it is characterized by a typical triad: hypertrophic cardiomyopathy, mental retardation, and skeletal myopathy. The disease occurs with mutations in the LAMP2 gene; X-linked dominant inheritance. LAMP2-cardiomyopathy does not virtually differ in its clinical manifestations from the severe form of hypertrophic cardiomyopathy, which results from mutations in the sarcomeric protein genes. The disease is characterized by a poor progressive course with the high probability of causing sudden death or with the progression of severe heart failure. Implantation of a cardioverter defibrillator is a main method to prevent sudden cardiac death. 

Factors Associated with Suicidal Thought and Help-Seeking Behaviour in Transition-Aged Youth versus Adults.

Science.gov (United States)

MacKinnon, Nathalie; Colman, Ian

2016-12-01

Suicide is a leading cause of death for transition-aged youth (TAY), and yet few studies examine correlates of suicidal ideation specifically in this age demographic (age 18-24 years). The transition to adulthood is a unique context, marked by novel stressors (e.g., joining the workforce) and increased independence, which may influence risk factors for suicidal ideation. This study examined correlates of suicidal ideation in TAY and adults and contrasted profiles across age. We used 4 biannual cycles (2005, 2007, 2009, 2011) of the Canadian Community Health Survey, a population-based cross-sectional survey on health. We used logistic regression to assess the association between suicidal ideation and depression, distress, alcohol use, smoking, exercise, sedentary behaviour, chronic illness, restrictions to daily living, perceived physical and mental health, and perceived social support independently in both TAY ( n = 4427) and adults ( n = 14,452). We subsequently assessed possible interactions with age (18-24 v. 25-44 years) and sex and differences in help-seeking behaviour in a combined model. TAY exhibited higher rates of suicidal ideation than adults did ( P suicidal ideation in TAY. Notably, alcohol abstinence was associated with decreased suicidal ideation in TAY but not for adults. Moreover, when depressed, TAY were significantly less likely to have received professional mental health help than adults (odds ratio = 0.64, 95% CI, 0.43 to 0.94). Suicidal ideation is more prevalent in TAY than adults, and its consequences may be aggravated by poor treatment-seeking behaviour in at-risk (i.e. depressed) individuals. These different risk profiles substantiate the recent shift toward clinical interventions focusing on transition-aged youth, rather than traditional child (18 years) services.

The bystander effect model of Brenner and Sachs fitted to lung cancer data in 11 cohorts of underground miners, and equivalence of fit of a linear relative risk model with adjustment for attained age and age at exposure

International Nuclear Information System (INIS)

Little, M P

2004-01-01

Bystander effects following exposure to α-particles have been observed in many experimental systems, and imply that linearly extrapolating low dose risks from high dose data might materially underestimate risk. Brenner and Sachs (2002 Int. J. Radiat. Biol. 78 593-604; 2003 Health Phys. 85 103-8) have recently proposed a model of the bystander effect which they use to explain the inverse dose rate effect observed for lung cancer in underground miners exposed to radon daughters. In this paper we fit the model of the bystander effect proposed by Brenner and Sachs to 11 cohorts of underground miners, taking account of the covariance structure of the data and the period of latency between the development of the first pre-malignant cell and clinically overt cancer. We also fitted a simple linear relative risk model, with adjustment for age at exposure and attained age. The methods that we use for fitting both models are different from those used by Brenner and Sachs, in particular taking account of the covariance structure, which they did not, and omitting certain unjustifiable adjustments to the miner data. The fit of the original model of Brenner and Sachs (with 0 y period of latency) is generally poor, although it is much improved by assuming a 5 or 6 y period of latency from the first appearance of a pre-malignant cell to cancer. The fit of this latter model is equivalent to that of a linear relative risk model with adjustment for age at exposure and attained age. In particular, both models are capable of describing the observed inverse dose rate effect in this data set

Podocyte Pathology and Nephropathy

Directory of Open Access Journals (Sweden)

Sandra eMerscher

2014-07-01

Full Text Available Sphingolipids are components of the lipid rafts in plasma membranes, which are important for proper function of podocytes, a key element of the glomerular filtration barrier. Research revealed an essential role of sphingolipids and sphingolipid metabolites in glomerular disorders of genetic and non-genetic origin. The discovery that glucocerebrosides accumulate in Gaucher disease in glomerular cells and are associated with clinical proteinuria initiated intensive research into the function of other sphingolipids in glomerular disorders. The accumulation of sphingolipids in other genetic diseases including Tay-Sachs, Sandhoff, Fabry, hereditary inclusion body myopathy 2, Niemann-Pick and nephrotic syndrome of the Finnish type and its implications with respect to glomerular pathology will be discussed. Similarily, sphingolipid accumulation occurs in glomerular diseases of non-genetic origin including diabetic kidney disease (DKD, HIV-associated nephropathy, focal segmental glomerulosclerosis (FSGS and lupus nephritis. Sphingomyelin metabolites, such as ceramide, sphingosine and sphingosine-1-phosphate have also gained tremendous interest. We recently described that sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b is expressed in podocytes where it modulates acid sphingomyelinase (ASMase activity and acts as a master modulator of danger signaling. Decreased SMPDL3b expression in post-reperfusion kidney biopsies from transplant recipients with idiopathic FSGS correlates with the recurrence of proteinuria in patients and in experimental models of xenotransplantation. Increased SMPDL3b expression is associated with DKD. The consequences of differential SMPDL3b expression in podocytes in these diseases with respect to their pathogenesis will be discussed. Finally, the role of sphingolipids in the formation of lipid rafts in podocytes and their contribution to the maintenance of a functional slit diaphragm in the glomerulus will be discussed.

Inorganic arsenic causes fatty liver and interacts with ethanol to cause alcoholic liver disease in zebrafish.

Science.gov (United States)

Bambino, Kathryn; Zhang, Chi; Austin, Christine; Amarasiriwardena, Chitra; Arora, Manish; Chu, Jaime; Sadler, Kirsten C

2018-02-26

The rapid increase in fatty liver disease (FLD) incidence is attributed largely to genetic and lifestyle factors; however, environmental toxicants are a frequently overlooked factor that can modify the effects of more common causes of FLD. Chronic exposure to inorganic arsenic (iAs) is associated with liver disease in humans and animal models, but neither the mechanism of action nor the combinatorial interaction with other disease-causing factors has been fully investigated. Here, we examined the contribution of iAs to FLD using zebrafish and tested the interaction with ethanol to cause alcoholic liver disease (ALD). We report that zebrafish exposed to iAs throughout development developed specific phenotypes beginning at 4 days post-fertilization (dpf), including the development of FLD in over 50% of larvae by 5 dpf. Comparative transcriptomic analysis of livers from larvae exposed to either iAs or ethanol revealed the oxidative stress response and the unfolded protein response (UPR) caused by endoplasmic reticulum (ER) stress as common pathways in both these models of FLD, suggesting that they target similar cellular processes. This was confirmed by our finding that arsenic is synthetically lethal with both ethanol and a well-characterized ER-stress-inducing agent (tunicamycin), suggesting that these exposures work together through UPR activation to cause iAs toxicity. Most significantly, combined exposure to sub-toxic concentrations of iAs and ethanol potentiated the expression of UPR-associated genes, cooperated to induce FLD, reduced the expression of as3mt , which encodes an arsenic-metabolizing enzyme, and significantly increased the concentration of iAs in the liver. This demonstrates that iAs exposure is sufficient to cause FLD and that low doses of iAs can potentiate the effects of ethanol to cause liver disease.This article has an associated First Person interview with the first author of the paper. © 2018. Published by The Company of Biologists Ltd.

Neuronal Ceroid-lipofuscinosis with prominent chorea and without visual manifestations: a case report

Directory of Open Access Journals (Sweden)

Luciano de Souza Queiroz

1979-03-01

Full Text Available A case of neuronal ceroid-lipofuscinosis (NCL is reported in a 11-year-old girl, whose main symptoms were progressive dementia since the age of 4 years and choreic movements since age 10. Seizures, myoclonus and visual deterioration were absent and optic fundi were normal. A cerebral biopsy disclosed two basic types of stored substance in the cytoplasm of neurons: a severely balloned nerve cells in cortical layers HI and V contained a non-autofluorescent material, which stained with PAS and Sudan Black B in frozen, but not in paraffin sections; ultrastructurally, these neurons showed abundant corpuscles similar to the membranous cytoplasmic bodies of Tay-Sachs disease and, in smaller amounts, also zebra bodies; b slightly distended or non-distended neurons in all layers contained lipopigment granules, which were autofluorescent, PAS-positive and sudanophil in both frozen and paraffin sections; their ultrastructure was closely comparable to that of lipofuscin. Similar bodies were found in the swollen segments of axons and in a few astrocytes and endothelial cells. The histochemical and ultrastructural demonstration of large amounts of lipopigments allows a presumptive classification of the case as NCL. However, the presence of involuntary movements, the absence of visual disturbances and the unusual ultrastructural features place the patient into a small heterogeneous group within the NCL. A better classification of such unique instances of the disease must await elucidation of the basic enzymatic defects.

The concept of wrongful life in the law.

Science.gov (United States)

Kasper, A S

1983-01-01

In the history of the law the concept of wrongful life is not new, but it has become of interest recently due to changing social attitudes and advances in contraceptive and genetic technologies. This discussion tries to assess the effects of wrongful life as a legal concept on the rights of childbearing women and their offspring. An unborn child had no rights under common law, which held that a fetus in utero had no existence separate from its mother. Consequently, a child had no right of action for personal harm brought upon it by another person. On occasion early courts disagreed with this view, but the majority of courts maintained that a child had no existence as a human being during gestation. The effect that this concept of common law would have on current abortion laws would be to make it considerably easier to argue for a woman's right to choose an abortion. The notion of wrongful life initially appeared in cases of illegitimate births. In Zepeda v. Zepeda, 1963, and Williams v. State of New York, 1966, the plaintiffs maintained that the children's births and existence were wrongful because they were unintended and illegitimate. In Williams the court ruled that birth under 1 set of circumstances and not another is not a recoverable injury. These cases failed to meet the requirements of tort law, and the court rejected the notion of children finding legal recourse for being born to a poor family or being born to a less desired race or class. A series of cases followed in which recovery for physical injury or birth deformities were claimed by parents for themselves and their children. In June 1980 a California appeals court reversed the decision of a lower court, addressing the fundamental principles of wrongful life as a legal concept. In Curlender v. Bio-Science Laboratories an infant brought suit alleging that the laboratories failed to correctly inform her parents of their status as carriers of Tay-Sachs disease during the mother's pregnancy. The infant

Hydatid disease: A rare cause of fracture nonunion

Directory of Open Access Journals (Sweden)

Divya Aggarwal

2017-01-01

Full Text Available Hydatid disease is an infrequent parasitic infestation caused by cestode, most commonly, Echinococcus granulosus. Bone involvement is distinctly uncommon. We would like to share our experience of a rare case of hydatid disease of femur in a 24-year-old male who presented with nonunion of subtrochanteric fracture. Histopathology showed typical lamellated wall and dagger-shaped hooklets. In view of its rarity, hydatid disease often remains an unsuspected infection of the bone.

Animal models of GM2 gangliosidosis: utility and limitations

Science.gov (United States)

Lawson, Cheryl A; Martin, Douglas R

2016-01-01

GM2 gangliosidosis, a subset of lysosomal storage disorders, is caused by a deficiency of the glycohydrolase, β-N-acetylhexosaminidase, and includes the closely related Tay–Sachs and Sandhoff diseases. The enzyme deficiency prevents the normal, stepwise degradation of ganglioside, which accumulates unchecked within the cellular lysosome, particularly in neurons. As a result, individuals with GM2 gangliosidosis experience progressive neurological diseases including motor deficits, progressive weakness and hypotonia, decreased responsiveness, vision deterioration, and seizures. Mice and cats are well-established animal models for Sandhoff disease, whereas Jacob sheep are the only known laboratory animal model of Tay–Sachs disease to exhibit clinical symptoms. Since the human diseases are relatively rare, animal models are indispensable tools for further study of pathogenesis and for development of potential treatments. Though no effective treatments for gangliosidoses currently exist, animal models have been used to test promising experimental therapies. Herein, the utility and limitations of gangliosidosis animal models and how they have contributed to the development of potential new treatments are described. PMID:27499644

Invasive Disease Caused by Nontypeable Haemophilus Influenzae

Centers for Disease Control (CDC) Podcasts

2015-11-12

Dr. Elizabeth Briere discusses Nontypeable Haemophilus influenzae which causes a variety of infections in children and adults.  Created: 11/12/2015 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 11/17/2015.

The unresolved puzzle why alanine extensions cause disease.

Science.gov (United States)

Winter, Reno; Liebold, Jens; Schwarz, Elisabeth

2013-08-01

The prospective increase in life expectancy will be accompanied by a rise in the number of elderly people who suffer from ill health caused by old age. Many diseases caused by aging are protein misfolding diseases. The molecular mechanisms underlying these disorders receive constant scientific interest. In addition to old age, mutations also cause congenital protein misfolding disorders. Chorea Huntington, one of the most well-known examples, is caused by triplet extensions that can lead to more than 100 glutamines in the N-terminal region of huntingtin, accompanied by huntingtin aggregation. So far, nine disease-associated triplet extensions have also been described for alanine codons. The extensions lead primarily to skeletal malformations. Eight of these proteins represent transcription factors, while the nuclear poly-adenylate binding protein 1, PABPN1, is an RNA binding protein. Additional alanines in PABPN1 lead to the disease oculopharyngeal muscular dystrophy (OPMD). The alanine extension affects the N-terminal domain of the protein, which has been shown to lack tertiary contacts. Biochemical analyses of the N-terminal domain revealed an alanine-dependent fibril formation. However, fibril formation of full-length protein did not recapitulate the findings of the N-terminal domain. Fibril formation of intact PABPN1 was independent of the alanine segment, and the fibrils displayed biochemical properties that were completely different from those of the N-terminal domain. Although intranuclear inclusions have been shown to represent the histochemical hallmark of OPMD, their role in pathogenesis is currently unclear. Several cell culture and animal models have been generated to study the molecular processes involved in OPMD. These studies revealed a number of promising future therapeutic strategies that could one day improve the quality of life for the patients.

Cause-Specific Mortality Among Spouses of Parkinson Disease Patients

DEFF Research Database (Denmark)

Nielsen, Malene; Hansen, Jonni; Ritz, Beate

2014-01-01

BACKGROUND: Caring for a chronically ill spouse is stressful, but the health effects of caregiving are not fully understood. We studied the effect on mortality of being married to a person with Parkinson disease. METHODS: All patients in Denmark with a first-time hospitalization for Parkinson...... disease between 1986 and 2009 were identified, and each case was matched to five population controls. We further identified all spouses of those with Parkinson disease (n = 8,515) and also the spouses of controls (n = 43,432). All spouses were followed in nationwide registries until 2011. RESULTS: Among...... men, being married to a Parkinson disease patient was associated with a slightly higher risk of all-cause mortality (hazard ratio = 1.06 [95% confidence interval = 1.00-1.11]). Mortality was particularly high for death due to external causes (1.42 [1.09-1.84]) including suicide (1.89 [1...

Genetic defect causing familial Alzheimer's disease maps on chromosome 21

Energy Technology Data Exchange (ETDEWEB)

St. George-Hyslop, P.H.; Tanzi, R.E.; Polinsky, R.J.; Haines, J.L.; Nee, L.; Watkins, P.C.; Myers, R.H.; Feldman, R.G.; Pollen, D.; Drachman, D.; Growdon, J.

1987-02-20

Alzheimer's disease is a leading cause of morbidity and mortality among the elderly. Several families have been described in which Alzheimer's disease is caused by an autosomal dominant gene defect. The chromosomal location of this defective gene has been discovered by using genetic linkage to DNA markers on chromosome 21. The localization on chromosome 21 provides an explanation for the occurrence of Alzheimer's disease-like pathology in Down syndrome. Isolation and characterization of the gene at this locus may yield new insights into the nature of the defect causing familial Alzheimer's disease and possibly, into the etiology of all forms of Alzheimer's disease.

Lack of exercise is a major cause of chronic diseases

Science.gov (United States)

Booth, Frank W.; Roberts, Christian K.; Laye, Matthew J.

2014-01-01

Chronic diseases are major killers in the modern era. Physical inactivity is a primary cause of most chronic diseases. The initial third of the article considers: activity and prevention definitions; historical evidence showing physical inactivity is detrimental to health and normal organ functional capacities; cause vs. treatment; physical activity and inactivity mechanisms differ; gene-environment interaction [including aerobic training adaptations, personalized medicine, and co-twin physical activity]; and specificity of adaptations to type of training. Next, physical activity/exercise is examined as primary prevention against 35 chronic conditions [Accelerated biological aging/premature death, low cardiorespiratory fitness (VO2max), sarcopenia, metabolic syndrome, obesity, insulin resistance, prediabetes, type 2 diabetes, non-alcoholic fatty liver disease, coronary heart disease, peripheral artery disease, hypertension, stroke, congestive heart failure, endothelial dysfunction, arterial dyslipidemia, hemostasis, deep vein thrombosis, cognitive dysfunction, depression and anxiety, osteoporosis, osteoarthritis, balance, bone fracture/falls, rheumatoid arthritis, colon cancer, breast cancer, endometrial cancer, gestational diabetes, preeclampsia, polycystic ovary syndrome, erectile dysfunction, pain, diverticulitis, constipation, and gallbladder diseases]. The article ends with consideration of deterioration of risk factors in longer-term sedentary groups; clinical consequences of inactive childhood/adolescence; and public policy. In summary, the body rapidly maladapts to insufficient physical activity, and if continued, results in substantial decreases in both total and quality years of life. Taken together, conclusive evidence exists that physical inactivity is one important cause of most chronic diseases. In addition, physical activity primarily prevents, or delays, chronic diseases, implying that chronic disease need not be an inevitable outcome during life

Congenital Heart Disease: Causes, Diagnosis, Symptoms, and Treatments.

Science.gov (United States)

Sun, RongRong; Liu, Min; Lu, Lei; Zheng, Yi; Zhang, Peiying

2015-07-01

The congenital heart disease includes abnormalities in heart structure that occur before birth. Such defects occur in the fetus while it is developing in the uterus during pregnancy. About 500,000 adults have congenital heart disease in USA (WebMD, Congenital heart defects medications, www.WebMD.com/heart-disease/tc/congenital-heart-defects-medications , 2014). 1 in every 100 children has defects in their heart due to genetic or chromosomal abnormalities, such as Down syndrome. The excessive alcohol consumption during pregnancy and use of medications, maternal viral infection, such as Rubella virus, measles (German), in the first trimester of pregnancy, all these are risk factors for congenital heart disease in children, and the risk increases if parent or sibling has a congenital heart defect. These are heart valves defects, atrial and ventricular septa defects, stenosis, the heart muscle abnormalities, and a hole inside wall of the heart which causes defect in blood circulation, heart failure, and eventual death. There are no particular symptoms of congenital heart disease, but shortness of breath and limited ability to do exercise, fatigue, abnormal sound of heart as heart murmur, which is diagnosed by a physician while listening to the heart beats. The echocardiogram or transesophageal echocardiogram, electrocardiogram, chest X-ray, cardiac catheterization, and MRI methods are used to detect congenital heart disease. Several medications are given depending on the severity of this disease, and catheter method and surgery are required for serious cases to repair heart valves or heart transplantation as in endocarditis. For genetic study, first DNA is extracted from blood followed by DNA sequence analysis and any defect in nucleotide sequence of DNA is determined. For congenital heart disease, genes in chromosome 1 show some defects in nucleotide sequence. In this review the causes, diagnosis, symptoms, and treatments of congenital heart disease are described.

Lipoprotein (a) as a cause of cardiovascular disease

DEFF Research Database (Denmark)

Nordestgaard, Børge G; Langsted, Anne

2016-01-01

Human epidemiologic and genetic evidence using the Mendelian randomization approach in large-scale studies now strongly supports that elevated lipoprotein (a) [Lp(a)] is a causal risk factor for cardiovascular disease, that is, for myocardial infarction, atherosclerotic stenosis, and aortic valve...... with very high concentrations to reduce cardiovascular disease are awaited. Recent genetic evidence documents elevated Lp(a) as a cause of myocardial infarction, atherosclerotic stenosis, and aortic valve stenosis....

Sleep duration and ischemic heart disease and all-cause mortality

DEFF Research Database (Denmark)

Garde, Anne Helene; Hansen, Åse Marie; Holtermann, Andreas

2013-01-01

This prospective study aimed to examine if sleep duration is a risk indicator for ischemic heart disease (IHD) and all-cause mortality, and how perceived stress during work and leisure time and use of tranquilizers/hypnotics modifies the association.......This prospective study aimed to examine if sleep duration is a risk indicator for ischemic heart disease (IHD) and all-cause mortality, and how perceived stress during work and leisure time and use of tranquilizers/hypnotics modifies the association....

Will chronic e-cigarette use cause lung disease?

OpenAIRE

Rowell, Temperance R.; Tarran, Robert

2015-01-01

Chronic tobacco smoking is a major cause of preventable morbidity and mortality worldwide. In the lung, tobacco smoking increases the risk of lung cancer, and also causes chronic obstructive pulmonary disease (COPD), which encompasses both emphysema and chronic bronchitis. E-cigarettes (E-Cigs), or electronic nicotine delivery systems, were developed over a decade ago and are designed to deliver nicotine without combusting tobacco. Although tobacco smoking has declined since the 1950s, E-Cig ...

Neuraminidase-1 contributes significantly to the degradation of neuronal B-series gangliosides but not to the bypass of the catabolic block in Tay–Sachs mouse models

Directory of Open Access Journals (Sweden)

Z.K. Timur

2015-09-01

Full Text Available Tay–Sachs disease is a severe lysosomal storage disorder caused by mutations in the HEXA gene coding for α subunit of lysosomal β-Hexosaminidase A enzyme, which converts GM2 to GM3 ganglioside. HexA−/− mice, depleted of the β-Hexosaminidase A iso-enzyme, remain asymptomatic up to 1 year of age because of a metabolic bypass by neuraminidase(s. These enzymes remove a sialic acid residue converting GM2 to GA2, which is further degraded by the still intact β-Hexosaminidase B iso-enzyme into lactosylceramide. A previously identified ganglioside metabolizing neuraminidase, Neu4, is abundantly expressed in the mouse brain and has activity against gangliosides like GM2 in vitro. Neu4−/− mice showed increased GD1a and decreased GM1 ganglioside in the brain suggesting the importance of the Neu4 in ganglioside catabolism. Mice with targeted disruption of both HexA and Neu4 genes showed accumulating GM2 ganglioside and epileptic seizures with 40% penetrance, indicating that the neuraminidase Neu4 is a modulatory gene, but may not be the only neuraminidase contributing to the metabolic bypass in HexA−/− mice. Therefore, we elucidated the biological role of neuraminidase-1 in ganglioside degradation in mouse. Analysis of HexA−/−Neu1−/− and HexA−/−Neu4−/−Neu1−/− mice models showed significant contribution of neuraminidase-1 on B-series ganglioside degradation in the brain. Therefore, we speculate that other neuraminidase/neuraminidases such as Neu2 and/or Neu3 might be also involved in the ganglioside degradation pathway in HexA−/− mice.

Initial-boundary-value problem of the self-gravitating scalar field in the Bondi-Sachs gauge

International Nuclear Information System (INIS)

Frittelli, Simonetta; Gomez, Roberto

2007-01-01

It is shown that, in the Bondi-Sachs gauge that fixes the speed of incoming light rays to the value 1, the Einstein equations coupled to a scalar field in spherical symmetry are cast into a symmetric-hyperbolic system of equations for the scalar field, lapse and shift as fundamental variables. In this system of equations, the lapse and shift are incoming characteristic fields, and the scalar field has three components: incoming, outgoing and static. A constraint-preserving boundary condition is prescribed by imposing the projection of the Einstein equation normal to the boundary at the outer value of the radial coordinate. The boundary condition specifies one of the two incoming metric fields. The remaining incoming metric field and the incoming scalar field component need to be specified arbitrarily. Numerical simulations of the scattering of the scalar field by a black hole in the nonlinear regime are presented that illustrate interesting facts about black-hole physics and the behavior of the characteristic variables of the problem

Controlling disease and creating disparities: a fundamental cause perspective.

Science.gov (United States)

Phelan, Jo C; Link, Bruce G

2005-10-01

The United States and other developed countries experienced enormous improvements in population health during the 20th century. In the context of this dramatic positive change, health disparities by race and socioeconomic status emerged for several potent killers. Any explanation for current health disparities must take these changing patterns into account. Any explanation that ignores large improvements in population health and fails to account for the emergence of disparities for specific diseases is an inadequate explanation of current disparities. We argue that genetic explanations and some prominent social causation explanations are incompatible with these facts. We propose that the theory of "fundamental causes" can account for both vast improvements in population health and the creation of large socioeconomic and racial disparities in mortality for specific causes of death over time. Specifically, we argue that it is our enormously expanded capacity to control disease and death in combination with existing social and economic inequalities that create health disparities by race and socioeconomic status: When we develop the ability to control disease and death, the benefits of this new-found ability are distributed according to resources of knowledge, money, power, prestige, and beneficial social connections. We present data on changing mortality patterns by race and socioeconomic status for two types of diseases: those for which our capacity to prevent death has increased significantly and those for which we remain largely unable to prevent death. Time trends in mortality patterns are consistent with the fundamental cause explanation.

Acute myeloid leukaemia as a cause of acute ischaemic heart disease

NARCIS (Netherlands)

van Haelst, P.L.; Schot, Bart; Hoendermis, E.S.; van den Berg, M.P.

2006-01-01

Ischaemic heart disease is almost invariably the result of atherosclerotic degeneration of the coronary arteries. However, other causes of ischaemic heart disease should always be considered. Here we describe two patients with a classic presentation of ischaemic heart disease resulting from acute

KMeyeDB: a graphical database of mutations in genes that cause eye diseases.

Science.gov (United States)

Kawamura, Takashi; Ohtsubo, Masafumi; Mitsuyama, Susumu; Ohno-Nakamura, Saho; Shimizu, Nobuyoshi; Minoshima, Shinsei

2010-06-01

KMeyeDB (http://mutview.dmb.med.keio.ac.jp/) is a database of human gene mutations that cause eye diseases. We have substantially enriched the amount of data in the database, which now contains information about the mutations of 167 human genes causing eye-related diseases including retinitis pigmentosa, cone-rod dystrophy, night blindness, Oguchi disease, Stargardt disease, macular degeneration, Leber congenital amaurosis, corneal dystrophy, cataract, glaucoma, retinoblastoma, Bardet-Biedl syndrome, and Usher syndrome. KMeyeDB is operated using the database software MutationView, which deals with various characters of mutations, gene structure, protein functional domains, and polymerase chain reaction (PCR) primers, as well as clinical data for each case. Users can access the database using an ordinary Internet browser with smooth user-interface, without user registration. The results are displayed on the graphical windows together with statistical calculations. All mutations and associated data have been collected from published articles. Careful data analysis with KMeyeDB revealed many interesting features regarding the mutations in 167 genes that cause 326 different types of eye diseases. Some genes are involved in multiple types of eye diseases, whereas several eye diseases are caused by different mutations in one gene.

Occupational disease caused by ionizing radiation

International Nuclear Information System (INIS)

Kluepfel, H.U.

1983-01-01

The study investigates the course of the disease of persons whose occupational exposure to radiation had resulted in impairment of their professional ability and entitled them to damages under the current regulations. 35 receivers of damages were found who by answering the question form and partly giving permission to study their file at the insurance institution under the conditions of data protection made is possible to carry through this investigation. 14 receivers of damages were occupied in the technical industry, 21 in the sector of medicine. The radiation disease acknowledged as professional concerned in 30 cases the skin, in two cases the lungs and in one case each the haematopoietic system, the eyes and the pelvic organs. In 8 indemnified, acute radiation exposure had caused the disease, in 25 the time of exposure had ranged from one year to several decades. The investigation describes when and under what professional circumstances the radiation exposure took place, the course of the disease, what kind of diagnostic and therapeutical measures were carried through and what personal and professional consequences the indemnified sustained. It gives suggestions to set up a future, more effective documentation system on the basis of the experience gathered on the occasion of this investigation with the currently valid registration system, which is unsuitable for further scientific studies, and with the currently practised methods of after-care. (orig./HP) [de

Spontaneous expulsive suprachoroidal hemorrhage caused by decompensated liver disease

Directory of Open Access Journals (Sweden)

Krishnagopal Srikanth

2013-01-01

Full Text Available Expulsive suprachoroidal hemorrhage can be surgical or spontaneous. Spontaneous expulsive suprachoroidal hemorrhage (SESCH is a rare entity. Most of the reported cases of SESCH were caused by a combination of corneal pathology and glaucoma. We are reporting a rare presentation of SESCH with no pre-existing glaucoma or corneal pathology and caused by massive intra- and peri-ocular hemorrhage due to decompensated liver disease.

Mycobacterium avium subspecies paratuberculosis causes Crohn's disease in some inflammatory bowel disease patients.

Science.gov (United States)

Naser, Saleh A; Sagramsingh, Sudesh R; Naser, Abed S; Thanigachalam, Saisathya

2014-06-21

Crohn's disease (CD) is a chronic inflammatory condition that plagues millions all over the world. This debilitating bowel disease can start in early childhood and continue into late adulthood. Signs and symptoms are usually many and multiple tests are often required for the diagnosis and confirmation of this disease. However, little is still understood about the cause(s) of CD. As a result, several theories have been proposed over the years. One theory in particular is that Mycobacterium avium subspecies paratuberculosis (MAP) is intimately linked to the etiology of CD. This fastidious bacterium also known to cause Johne's disease in cattle has infected the intestines of animals for years. It is believed that due to the thick, waxy cell wall of MAP it is able to survive the process of pasteurization as well as chemical processes seen in irrigation purification systems. Subsequently meat, dairy products and water serve as key vehicles in the transmission of MAP infection to humans (from farm to fork) who have a genetic predisposition, thus leading to the development of CD. The challenges faced in culturing this bacterium from CD are many. Examples include its extreme slow growth, lack of cell wall, low abundance, and its mycobactin dependency. In this review article, data from 60 studies showing the detection and isolation of MAP by PCR and culture techniques have been reviewed. Although this review may not be 100% comprehensive of all studies, clearly the majority of the studies overwhelmingly and definitively support the role of MAP in at least 30%-50% of CD patients. It is very possible that lack of detection of MAP from some CD patients may be due to the absence of MAP role in these patients. The latter statement is conditional on utilization of methodology appropriate for detection of human MAP strains. Ultimately, stratification of CD and inflammatory bowel disease patients for the presence or absence of MAP is necessary for appropriate and effective

Vascular pathology: Cause or effect in Alzheimer disease?

Science.gov (United States)

Rius-Pérez, S; Tormos, A M; Pérez, S; Taléns-Visconti, R

2018-03-01

Alzheimer disease (AD) is the main cortical neurodegenerative disease. The incidence of this disease increases with age, causing significant medical, social and economic problems, especially in countries with ageing populations. This review aims to highlight existing evidence of how vascular dysfunction may contribute to cognitive impairment in AD, as well as the therapeutic possibilities that might arise from this evidence. The vascular hypothesis emerged as an alternative to the amyloid cascade hypothesis as an explanation for the pathophysiology of AD. This hypothesis locates blood vessels as the origin for a variety of pathogenic pathways that lead to neuronal damage and dementia. Destruction of the organisation of the blood brain barrier, decreased cerebral blood flow, and the establishment of an inflammatory context would thus be responsible for any subsequent neuronal damage since these factors promote aggregation of β-amyloid peptide in the brain. The link between neurodegeneration and vascular dysfunction pathways has provided new drug targets and therapeutic approaches that will add to the treatments for AD. It is difficult to determine whether the vascular component in AD is the cause or the effect of the disease, but there is no doubt that vascular pathology has an important relationship with AD. Vascular dysfunction is likely to act synergistically with neurodegenerative changes in a cycle that exacerbates the cognitive impairment found in AD. Copyright © 2015 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

78 FR 71532 - Airworthiness Directives; Rolls-Royce Deutschland Ltd & Co KG Turbofan Engines

Science.gov (United States)

2013-11-29

... Deutschland Ltd & Co KG Turbofan Engines AGENCY: Federal Aviation Administration (FAA), DOT. [[Page 71533... (AD) 2007-03- 02 for all Rolls-Royce Deutschland (RRD) Tay 620-15, Tay 650-15, and Tay 651-54 turbofan..., January 29, 2007) (``AD 2007-03-02'') for certain RRD Tay 611-8 and Tay 620-15 turbofan engines with LP...

Time-dependent automorphism-inducing diffeomorphisms, open algebras and the generality of the Kantowski-Sachs vacuum geometry

Science.gov (United States)

Christodoulakis, T.; Papadopoulos, G. O.

2002-10-01

Following the spirit of a previous work of ours, we investigate the group of those general coordinate transformations (GCTs) which preserve manifest spatial homogeneity. In contrast to the case of Bianchi type models, here we permit an isometry group of motions G4 = SO(3) ⊗ Tr, where Tr is the translations group, along the radial direction, while SO(3) acts multiply transitively on each hypersurface of simultaneity Σt. The basis 1-forms cannot be invariant under the action of the entire isometry group and hence produce an open Lie algebra. In order for these GCTs to exist and have a nontrivial, well-defined action, certain integrability conditions have to be satisfied; their solutions, exhibiting the maximum expected 'gauge' freedom, can be used to simplify the generic, spatially homogeneous, line element. In this way an alternative proof of the generality of the Kantowski-Sachs (KS) vacuum is given, while its most general, manifestly homogeneous, form is explicitly presented.

Elevated C-reactive protein, depression, somatic diseases, and all-cause mortality

DEFF Research Database (Denmark)

Wium-Andersen, Marie Kim; Orsted, David Dynnes; Nordestgaard, Børge Grønne

2014-01-01

BACKGROUND: Elevated levels of plasma C-reactive protein (CRP) have been associated with many diseases including depression, but it remains unclear whether this association is causal. We tested the hypothesis that CRP is causally associated with depression, and compared these results to those...... for cancer, ischemic heart disease, chronic obstructive pulmonary disease, and all-cause mortality. METHODS: We performed prospective and instrumental variable analyses using plasma CRP levels and four CRP genotypes on 78,809 randomly selected 20- to 100-year-old men and women from the Danish general...... population. End points included hospitalization or death with depression and somatic diseases, prescription antidepressant medication use, and all-cause mortality. RESULTS: A doubling in plasma CRP yielded an observed odds ratio (OR) of 1.28 (95% confidence interval [CI]: 1.23-1.33) for hospitalization...

Will chronic e-cigarette use cause lung disease?

Science.gov (United States)

Rowell, Temperance R; Tarran, Robert

2015-12-15

Chronic tobacco smoking is a major cause of preventable morbidity and mortality worldwide. In the lung, tobacco smoking increases the risk of lung cancer, and also causes chronic obstructive pulmonary disease (COPD), which encompasses both emphysema and chronic bronchitis. E-cigarettes (E-Cigs), or electronic nicotine delivery systems, were developed over a decade ago and are designed to deliver nicotine without combusting tobacco. Although tobacco smoking has declined since the 1950s, E-Cig usage has increased, attracting both former tobacco smokers and never smokers. E-Cig liquids (e-liquids) contain nicotine in a glycerol/propylene glycol vehicle with flavorings, which are vaporized and inhaled. To date, neither E-Cig devices, nor e-liquids, are regulated by the Food and Drug Administration (FDA). The FDA has proposed a deeming rule, which aims to initiate legislation to regulate E-Cigs, but the timeline to take effect is uncertain. Proponents of E-Cigs say that they are safe and should not be regulated. Opposition is varied, with some opponents proposing that E-Cig usage will introduce a new generation to nicotine addiction, reversing the decline seen with tobacco smoking, or that E-Cigs generally may not be safe and will trigger diseases like tobacco. In this review, we shall discuss what is known about the effects of E-Cigs on the mammalian lung and isolated lung cells in vitro. We hope that collating this data will help illustrate gaps in the knowledge of this burgeoning field, directing researchers toward answering whether or not E-Cigs are capable of causing disease. Copyright © 2015 the American Physiological Society.

DIAGNOSIS OF ENDOCRINE DISEASE: Expanding the cause of hypopituitarism.

Science.gov (United States)

Pekic, Sandra; Popovic, Vera

2017-06-01

Hypopituitarism is defined as one or more pituitary hormone deficits due to a lesion in the hypothalamic-pituitary region. By far, the most common cause of hypopituitarism associated with a sellar mass is a pituitary adenoma. A high index of suspicion is required for diagnosing hypopituitarism in several other conditions such as other massess in the sellar and parasellar region, brain damage caused by radiation and by traumatic brain injury, vascular lesions, infiltrative/immunological/inflammatory diseases (lymphocytic hypophysitis, sarcoidosis and hemochromatosis), infectious diseases and genetic disorders. Hypopituitarism may be permanent and progressive with sequential pattern of hormone deficiencies (radiation-induced hypopituitarism) or transient after traumatic brain injury with possible recovery occurring years from the initial event. In recent years, there is increased reporting of less common and less reported causes of hypopituitarism with its delayed diagnosis. The aim of this review is to summarize the published data and to allow earlier identification of populations at risk of hypopituitarism as optimal hormonal replacement may significantly improve their quality of life and life expectancy. © 2017 European Society of Endocrinology.

Celiac disease causing severe osteomalacia: an association still present in Morocco!

OpenAIRE

Tahiri, Latifa; Azzouzi, Hamida; Squalli, Ghita; Abourazzak, Fatimazahra; Harzy, Taoufik

2014-01-01

Celiac disease (CD), a malabsorption syndrome caused by hypersensitivity to gliadin fraction of gluten. CD can manifest with classic symptoms; however, significant myopathy and multiple fractures are rarely the predominant presentation of untreated celiac disease. Osteomalacia complicating celiac disease had become more and more rare. We describe here a case of osteomalacia secondary to a longstanding untreated celiac disease. This patient complained about progressive bone and muscular pain, ...

Prediction of Disease Causing Non-Synonymous SNPs by the Artificial Neural Network Predictor NetDiseaseSNP

DEFF Research Database (Denmark)

Johansen, Morten Bo; Gonzalez-Izarzugaza, Jose Maria; Brunak, Søren

2013-01-01

We have developed a sequence conservation-based artificial neural network predictor called NetDiseaseSNP which classifies nsSNPs as disease-causing or neutral. Our method uses the excellent alignment generation algorithm of SIFT to identify related sequences and a combination of 31 features...

Ileitis caused by Yersinia enterocolitica - X-ray differential diagnosis of Crohn's disease

International Nuclear Information System (INIS)

Lingg, G.; Hering, L.; Tanneberger, D.

1981-01-01

The article gives a brief description of the characteristic features of the clinical and roentgenological course and the various stages of enteritis caused by Yersinia. Basing on three cases of ileitis caused by Yersinia, the far-reaching similarity with the early changes and even the advanced stages of Crohn's diseases are demonstrated. Attention is drawn to the possibilities of differentiating between the two disease patterns. (orig.) [de

Classification of Kantowski-Sachs and Bianchi Type III Space-Times According to Their Killing Vector Fields in Teleparallel Theory of Gravitation

International Nuclear Information System (INIS)

Shabbir, Ghulam; Khan, Suhail

2010-01-01

In this paper we classify Kantowski-Sachs and Bianchi type III space-times according to their teleparallel Killing vector fields using direct integration technique. It turns out that the dimension of the teleparallel Killing vector fields are 4 or 6, which are the same in numbers as in general relativity. In case of 4 the teleparallel Killing vector fields are multiple of the corresponding Killing vector fields in general relativity by some function of t. In the case of 6 Killing vector fields the metric functions become constants and the Killing vector fields in this case are exactly the same as in general relativity. Here we also discuss the Lie algebra in each case. (general)

Helicobacter pylori and autoimmune disease: Cause or bystander

Science.gov (United States)

Smyk, Daniel S; Koutsoumpas, Andreas L; Mytilinaiou, Maria G; Rigopoulou, Eirini I; Sakkas, Lazaros I; Bogdanos, Dimitrios P

2014-01-01

Helicobacter pylori (H. pylori) is the main cause of chronic gastritis and a major risk factor for gastric cancer. This pathogen has also been considered a potential trigger of gastric autoimmunity, and in particular of autoimmune gastritis. However, a considerable number of reports have attempted to link H. pylori infection with the development of extra-gastrointestinal autoimmune disorders, affecting organs not immediately relevant to the stomach. This review discusses the current evidence in support or against the role of H. pylori as a potential trigger of autoimmune rheumatic and skin diseases, as well as organ specific autoimmune diseases. We discuss epidemiological, serological, immunological and experimental evidence associating this pathogen with autoimmune diseases. Although over one hundred autoimmune diseases have been investigated in relation to H. pylori, we discuss a select number of papers with a larger literature base, and include Sjögrens syndrome, rheumatoid arthritis, systemic lupus erythematosus, vasculitides, autoimmune skin conditions, idiopathic thrombocytopenic purpura, autoimmune thyroid disease, multiple sclerosis, neuromyelitis optica and autoimmune liver diseases. Specific mention is given to those studies reporting an association of anti-H. pylori antibodies with the presence of autoimmune disease-specific clinical parameters, as well as those failing to find such associations. We also provide helpful hints for future research. PMID:24574735

Orientation relationship in various 9% Cr ferritic/martensitic steels-EBSD comparison between Nishiyama-Wassermann, Kurdjumov-Sachs and Greninger-Troiano

International Nuclear Information System (INIS)

Barcelo, F.; Bechade, J. L.; Fournier, B.

2010-01-01

EBSD measurements were carried out on four different martensitic steels (T91, P92, EM10 and Eurofer) in various metallurgical conditions (nine different microstructural states). The usual orientation relationships (ORs) between the parent austenitic phase and the resulting martensite in martensitic steels are those of Nishiyama-Wassermann (NW) and Kurjumov-Sachs (KS). The present study first proposes a methodology based on the combined analysis of the misorientation distribution, the pole figures (PFs) and the angle/axis pairs. This methodology leads to the conclusion that neither NW nor KS relationships are able to account for all the features observed whatever the material under study. A third OR proposed by Greninger and Troiano (GT) proves to describe the relationship between austenite and ferrite in all four different martensitic steels much more accurately. (authors)

38 CFR 3.815 - Monetary allowance under 38 U.S.C. chapter 18 for an individual with disability from covered...

Science.gov (United States)

2010-07-01

...) Osteogenesis imperfecta; (xiv) Pectus excavatum; (xv) Phenylketonuria; (xvi) Sickle cell disease; (xvii) Tay...) Stamina; (iv) Speech; (v) Hearing; (vi) Vision (other than correctable refraction errors); (vii) Memory...

Impact of a hospital-level intervention to reduce heart disease overreporting on leading causes of death.

Science.gov (United States)

Al-Samarrai, Teeb; Madsen, Ann; Zimmerman, Regina; Maduro, Gil; Li, Wenhui; Greene, Carolyn; Begier, Elizabeth

2013-05-16

The quality of cause-of-death reporting on death certificates affects the usefulness of vital statistics for public health action. Heart disease deaths are overreported in the United States. We evaluated the impact of an intervention to reduce heart disease overreporting on other leading causes of death. A multicomponent intervention comprising training and communication with hospital staff was implemented during July through December 2009 at 8 New York City hospitals reporting excessive heart disease deaths. We compared crude, age-adjusted, and race/ethnicity-adjusted proportions of leading, underlying causes of death reported during death certification by intervention and nonintervention hospitals during preintervention (January-June 2009) and postintervention (January-June 2010) periods. We also examined trends in leading causes of death for 2000 through 2010. At intervention hospitals, heart disease deaths declined by 54% postintervention; other leading causes of death (ie, malignant neoplasms, influenza and pneumonia, cerebrovascular disease, and chronic lower respiratory diseases) increased by 48% to 232%. Leading causes of death at nonintervention hospitals changed by 6% or less. In the preintervention period, differences in leading causes of death between intervention and nonintervention hospitals persisted after controlling for race/ethnicity and age; in the postintervention period, age accounted for most differences observed between intervention and nonintervention hospitals. Postintervention, malignant neoplasms became the leading cause of premature death (ie, deaths among patients aged 35-74 y) at intervention hospitals. A hospital-level intervention to reduce heart disease overreporting led to substantial changes to other leading causes of death, changing the leading cause of premature death. Heart disease overreporting is likely obscuring the true levels of cause-specific mortality.

Diseases caused by poxvirus - orf and milker's nodules: a review

Directory of Open Access Journals (Sweden)

S.R.C.S. Barraviera

2005-06-01

Full Text Available Sheep and cattle parapoxviruses cause in human beings diseases of very similar aspect, named orf and milker's nodules, respectively. These infections are generically called farmyard pox. In the present article, we show the epidemiological, clinical, and histopathological aspects, as well as the treatment of these two viral diseases that are very similar, being differentiated only by their epidemiological aspects.

Colletotrichum species causing anthracnose disease of chili in China.

Science.gov (United States)

Diao, Y-Z; Zhang, C; Liu, F; Wang, W-Z; Liu, L; Cai, L; Liu, X-L

2017-06-01

Anthracnose caused by Colletotrichum species is a serious disease of more than 30 plant genera. Several Colletotrichum species have been reported to infect chili in different countries. Although China is the largest chili-producing country, little is known about the species that have been infecting chili locally. Therefore, we collected samples of diseased chili from 29 provinces of China, from which 1285 strains were isolated. The morphological characters of all strains were observed and compared, and multi-locus phylogenetic analyses (ITS, ACT , CAL , CHS-1 , GAPDH , TUB2 , and HIS3 ) were performed on selected representative strains. Fifteen Colletotrichum species were identified, with C. fioriniae , C. fructicola , C. gloeosporioides , C. scovillei , and C. truncatum being prevalent. Three new species, C. conoides , C. grossum , and C. liaoningense , were recognised and described in this paper. Colletotrichum aenigma , C. cliviae , C. endophytica , C. hymenocallidis , C. incanum , C. karstii , and C. viniferum were reported for the first time from chili. Pathogenicity of all species isolated from chili was confirmed, except for C. endophytica . The current study improves the understanding of species causing anthracnose on chili and provides useful information for the effective control of the disease in China.

Diagnostics of vascular diseases as a cause for acute abdomen

International Nuclear Information System (INIS)

Juchems, M.S.; Aschoff, A.J.

2010-01-01

Vascular pathologies are rare causes of an acute abdomen. If the cause is a vascular disease a rapid diagnosis is desired as vascular pathologies are associated with high mortality. A differentiation must be made between arterial and venous diseases. An occlusion of the superior mesenteric artery is the most common reason for acute mesenteric ischemia but intra-abdominal arterial bleeding is also of great importance. Venous pathologies include thrombotic occlusion of the portal vein, the mesenteric vein and the vena cava. Multi-detector computed tomography (MDCT) is predestined for the diagnostics of vascular diseases of the abdomen. Using multiphasic contrast protocols enables reliable imaging of the arterial and venous vessel tree and detection of disorders with high sensitivity and specificity. Although conventional angiography has been almost completely replaced by MDCT as a diagnostic tool, it is still of high importance for minimally invasive interventions, for example in the management of gastrointestinal bleeding. (orig.) [de

Genetic screening in the Persian Jewish community: A pilot study.

Science.gov (United States)

Kaback, Michael; Lopatequi, Jean; Portuges, Amin Riley; Quindipan, Cathy; Pariani, Mitchel; Salimpour-Davidov, Nilou; Rimoin, David L

2010-10-01

Israeli investigators have identified several relatively frequent disorders due to founder point mutations in Persian (Iranian) Jews, who, for nearly three centuries up to the Islamic Revolution of 1979, were completely isolated reproductively. Using a community-based model previously employed with Tay-Sachs disease prevention, we developed a pilot program for the Persian Jewish community of greater Los Angeles. We screened for mutations responsible for four relatively frequent autosomal recessive conditions in Persian Jews in which effective interventions are available for each: Pseudocholinesterase deficiency (butyryl cholinesterase deficiency); Congenital hypoaldosteronism (corticosterone methyl oxidase II); Autoimmune polyendocrinopathy (autoimmune regulatory element); and Hereditary Inclusion Body myopathy. One thousand individuals volunteered. Mutations were assessed in saliva-derived DNA and were positive for 121/1000 butyryl cholinesterase deficiency; 92/1000 Hereditary Inclusion Body myopathy; 38/1000 corticosterone methyl oxidase II; and 37/1000 autoimmune regulatory element. Ten homozygous individuals (9 butyryl cholinesterase deficiency and 1 Hereditary Inclusion Body myopathy) and 10 "at-risk" couples (seven for butyryl cholinesterase deficiency and one each for the other three disorders) were identified. These frequencies are comparable with those in Israel and indicate an extraordinary level of inbreeding, as anticipated. A carefully planned effort can be delivered to an "increased risk" community if detailed attention is given to planning and organization. However, availability of an effective intervention for those found to be "at-risk" or possibly affected, is essential before embarking.

A novel sponge disease caused by a consortium of micro-organisms

Science.gov (United States)

Sweet, Michael; Bulling, Mark; Cerrano, Carlo

2015-09-01

In healthy sponges, microbes have been shown to account for up to 40 % of tissues. The majority of these are thought to originate from survivors evading digestion and immune responses of the sponge and growing and residing in the microenvironments of the mesophyll. Although a large percentage of these microbes are likely commensals, they may also include potentially pathogenic agents, which under specific conditions, such as temperature stress, may cause disease. Here we report a novel disease (sponge necrosis syndrome) that is severely affecting populations of the sponge Callyspongia ( Euplacella) aff biru. Both ITS fungal and 16S rDNA bacterial diversities were assessed in healthy and diseased individuals, highlighting six potential primary causal agents for this new disease: two bacteria, a Rhodobacteraceae sp. and a cyanobacterium, Hormoscilla spongeliae (formally identified as Oscillatoria spongeliae), and four fungi, a Ascomycota sp., a Pleosporales sp., a Rhabdocline sp., and a Clasosporium sp. Furthermore, histological analysis showed the dominance of fungal hyphae rather than bacteria throughout the disease lesion, which was absent or rare in healthy tissues. Inoculation trails showed that only a combination of one bacterium and one fungus could replicate the disease, fulfilling Henle-Koch's postulates and showing that this sponge disease is caused by a poly-microbial consortium.

[Disease burden caused by violence in the Chinese population, in 1990 and 2013].

Science.gov (United States)

Yang, L; Gao, X; Jin, Y; Ye, P P; Er, Y L; Deng, X; Wang, Y; Duan, L L

2017-10-10

Objective: To analyze the disease burden of violence in the Chinese population, in 1990 and 2013. Methods: Indicators including mortality rate, years of life lost due to premature mortality (YLL), years lived with disability (YLD), and disability-adjusted of life years (DALY) related to violence, were extracted from the Global Burden of Disease 2013 and used to describe the burden of disease caused by violence in the Chinese population. Data related to corresponding parameters on disease burden of violence in 1990 and 2013 were described. Results: In 2013, a total of 20 500 people died of violent events, with the death rate as 1.44 per 100 000, in China. DALY caused by violence was 1.08 million person years in 2013. DALY caused by sharp violence was 0.47 million person years, with 0.09 million person years lost due to firearm violence. Disease burden caused by violence appeared higher in males than in females. When comparing with data from the 1990s, reductions were seen by 67.35 % on the standardized death rate of violence, by 68.07 % on the DALY attributable to violence, and by 70.47 % on the standardized DALY rate attributable to violence, respectively, in 2013. Disease burden of violence among young adults and elderly was among the highest. When comparing with data from the 1990, DALY in 2013 decreased among all the age groups except for the 70-year-old showed an increase of 9.36 % . The standardized DALY rate in 2013 showed a declining trend in all the age groups, mostly in the 0-4-year-old group. The standardized DALY rates caused by sharp violence or firearm decreased by75.11 % and 83.20 % in the 0-4-year-old group. Conclusion: In recent years, the disease burden caused by violence showed a decreasing trend but appeared higher in males however with the increase of DALY in the elder population.

Diseases of comfort: primary cause of death in the 22nd century.

Science.gov (United States)

Choi, Bernard C K; Hunter, David J; Tsou, Walter; Sainsbury, Peter

2005-12-01

The world has started to feel the impact of a global chronic disease epidemic, which is putting pressure on our health care systems. If uncurbed, a new generation of "diseases of comfort" (such as those chronic diseases caused by obesity and physical inactivity) will become a major public health problem in this and the next century. To describe the concept, causes, and prevention and control strategies of diseases of comfort. Brokered by a senior research scientist specialised in knowledge translation, a chair, a president, and a past president of national public health associations contributed their views on the subject. Diseases of comfort have emerged as a price of living in a modern society. It is inevitable that these diseases will become more common and more disabling if human "progress" and civilisation continue toward better (more comfortable) living, without necessarily considering their effects on health. Modern technology must be combined with education, legislation, intersectoral action, and community involvement to create built and social environments that encourage, and make easy, walking, physical activity, and nutritious food choices, to reduce the health damaging effects of modern society for all citizens and not only the few. Public health needs to be more passionate about the health issues caused by human progress and adopt a health promotion stance, challenging the assumptions behind the notion of social "progress" that is giving rise to the burden of chronic disease and developing the skills to create more health promoting societies in which individual health thrives.

Integrated sequence analysis pipeline provides one-stop solution for identifying disease-causing mutations.

Science.gov (United States)

Hu, Hao; Wienker, Thomas F; Musante, Luciana; Kalscheuer, Vera M; Kahrizi, Kimia; Najmabadi, Hossein; Ropers, H Hilger

2014-12-01

Next-generation sequencing has greatly accelerated the search for disease-causing defects, but even for experts the data analysis can be a major challenge. To facilitate the data processing in a clinical setting, we have developed a novel medical resequencing analysis pipeline (MERAP). MERAP assesses the quality of sequencing, and has optimized capacity for calling variants, including single-nucleotide variants, insertions and deletions, copy-number variation, and other structural variants. MERAP identifies polymorphic and known causal variants by filtering against public domain databases, and flags nonsynonymous and splice-site changes. MERAP uses a logistic model to estimate the causal likelihood of a given missense variant. MERAP considers the relevant information such as phenotype and interaction with known disease-causing genes. MERAP compares favorably with GATK, one of the widely used tools, because of its higher sensitivity for detecting indels, its easy installation, and its economical use of computational resources. Upon testing more than 1,200 individuals with mutations in known and novel disease genes, MERAP proved highly reliable, as illustrated here for five families with disease-causing variants. We believe that the clinical implementation of MERAP will expedite the diagnostic process of many disease-causing defects. © 2014 WILEY PERIODICALS, INC.

Addison's Disease Caused by Tuberculosis with Atypical Hyperpigmentation and Active Pulmonary Tuberculosis.

Science.gov (United States)

Namikawa, Hiroki; Takemoto, Yasuhiko; Kainuma, Shigeto; Umeda, Sakurako; Makuuchi, Ayako; Fukumoto, Kazuo; Kobayashi, Masanori; Kinuhata, Shigeki; Isaka, Yoshihiro; Toyoda, Hiromitsu; Kamata, Noriko; Tochino, Yoshihiro; Hiura, Yoshikazu; Morimura, Mina; Shuto, Taichi

2017-01-01

We herein report a case of Addison's disease caused by tuberculosis characterized by atypical hyperpigmentation, noted as exacerbation of the pigmentation of freckles and the occurrence of new freckles, that was diagnosed in the presence of active pulmonary tuberculosis. The clinical condition of the patient was markedly ameliorated by the administration of hydrocortisone and anti-tuberculosis agents. When exacerbation of the pigmentation of the freckles and/or the occurrence of new freckles are noted, Addison's disease should be considered as part of the differential diagnosis. In addition, the presence of active tuberculosis needs to be assumed whenever we treat patients with Addison's disease caused by tuberculosis, despite its rarity.

Elevated Remnant Cholesterol Causes Both Low-Grade Inflammation and Ischemic Heart Disease, Whereas Elevated Low-Density Lipoprotein Cholesterol Causes Ischemic Heart Disease Without Inflammation

DEFF Research Database (Denmark)

Varbo, Anette; Benn, Marianne; Tybjærg-Hansen, Anne

2013-01-01

Elevated nonfasting remnant cholesterol and low-density lipoprotein (LDL) cholesterol are causally associated with ischemic heart disease (IHD), but whether elevated nonfasting remnant cholesterol and LDL cholesterol both cause low-grade inflammation is currently unknown....

Colletotrichum species causing anthracnose disease of chili in China

NARCIS (Netherlands)

Diao, Y.-Z.; Zhang, C.; Liu, F.; Wang, W.-Z.; Liu, L.; Cai, L.; Liu, X.-L.

2017-01-01

Anthracnose caused by Colletotrichum species is a serious disease of more than 30 plant genera. Several Colletotrichum species have been reported to infect chili in different countries. Although China is the largest chiliproducing country, little is known about the species that have been infecting

Apple Replant Disease: Role of microbial ecology in cause and control

Science.gov (United States)

1. Apple replant disease (ARD) has been reported from all major fruit-growing regions of the world, and is often caused by a consortium of biological agents. Development of non-fumigant alternatives for the control of this disease has been hindered by the absence of consensus concerning the etiology...

78 FR 17079 - Airworthiness Directives; Rolls-Royce Deutschland Ltd & Co KG Turbofan Engines

Science.gov (United States)

2013-03-20

... Airworthiness Directives; Rolls-Royce Deutschland Ltd & Co KG Turbofan Engines AGENCY: Federal Aviation... certain Rolls-Royce Deutschland Ltd & Co KG (RRD) models Tay 620-15 and Tay 650-15 turbofan engines. This... Tay 620-15 and Tay 650-15 turbofan engines with a low-pressure compressor (LPC) rotor disc assembly...

Mapping global potential risk of mango sudden decline disease caused by fungus Ceratocystis fimbriata

Science.gov (United States)

Mango Sudden Decline (MSD), sometimes referred to as mango wilt, is an important disease of mango caused by one of the most significant fungal species causing disease in woody plants, Ceratocystis fimbriata. This species is mainly disseminated by the mango bark beetle, Hypocryphalus mangiferae (Steb...

Chemical control of blossom blight disease of sarpagandha caused ...

African Journals Online (AJOL)

ONOS

2010-09-20

Sep 20, 2010 ... Chemical control of blossom blight disease of sarpagandha caused by Colletotrichum capsici. R. S. Shukla, Abdul-Khaliq and M. Alam*. Department of Plant Pathology, Central Institute of Medicinal and Aromatic Plants, Council of Scientific and Industrial. Research, P. O. CIMAP, Lucknow–226 015, India.

Dental erosion caused by gastroesophageal reflux disease: a case report

OpenAIRE

Cengiz, Seda; Cengiz, M ?nan?; Sara?, Y ?inasi

2009-01-01

Introduction Chronic regurgitation of gastric acids in patients with gastroesophageal reflux disease may cause dental erosion, which can lead in combination with attrition or bruxism to extensive loss of coronal tooth tissue. Case presentation This clinical report describes treatment of severe tooth wear of a gastroesophageal reflux disease patient who is 54-year-old Turkish male patient. After his medical treatment, severe tooth wear, bruxism and decreased vertical dimensions were determined...

Does radioiodine cause the ophthalmopathy of Graves' disease?

International Nuclear Information System (INIS)

McDougall, I.R.

1993-01-01

This editorial briefly reviews studies which might answer the question as to whether radioiodine treatment causes the ophthalmopathy of Graves' disease. However, the data do not allow any conclusion one way or the other. Other possible causal factors are discussed. Further studies are required to define whether treatment of hyperthyroidism aggravates the ophthalmopathy and whether one thereby is worse than the others and by how much. (UK)

Identification of a Disease on Cocoa Caused by Fusariumin Sulawesi

Directory of Open Access Journals (Sweden)

Ade Rosmana

2013-12-01

Full Text Available A disease presumed to be caused by Fusarium was observed in cocoa open fields with few or without shade trees. Within the population of cocoa trees in the field, some trees had died, some had yellowing leaves and dieback, and the others were apparently healthy. In order to demonstrate Fusarium species as the causal pathogen and to obtain information concerning the incidence of the disease, its distribution and its impact on sustainability of cocoa, isolation of the pathogen, inoculation of cocoa seedlings with isolates and a survey of disease has been conducted. Fusarium was isolated from roots and branches, and inoculated onto cocoa seedlings (one month old via soil. Symptoms appeared within 3-4 weeks after infection. These symptoms consisted of yellowing of leaves beginning from the bottom until the leaves falldown, and browning internal of vascular tissue. Darkened vascular traces in the petiole characteristic of vascularstreak dieback infection were absent. The occurrence of Fusarium in the field was characterized by the absence of obvious signs of fungal infestation on root of infected trees, yellowing of leaves on twigs, dieback, and tree mortality in severe infestations. Disease incidence could reach 77% and in this situation it was difficult for trees recover from heavy infections or to be regenerated in the farm. The study proves that Fusarium is a pathogen causing dieback and the disease is called as Fusarium vascular dieback (FVD. Its development is apparently enhanced by dry conditions in the field. Key words: Fusarium sp., vascular disease, dieback, FVD, Theobroma cacao L.

The Built Environment—A Missing “Cause of the Causes” of Non-Communicable Diseases

Directory of Open Access Journals (Sweden)

Kelvin L. Walls

2016-09-01

Full Text Available The United Nations “25 × 25 Strategy” of decreasing non-communicable diseases (NCDs, including cardiovascular diseases, diabetes, cancer and chronic respiratory diseases, by 25% by 2025 does not appear to take into account all causes of NCDs. Its focus is on a few diseases, which are often linked with life-style factors with “voluntary” “modifiable behavioral risk factors” causes tending towards an over-simplification of the issues. We propose to add some aspects of our built environment related to hazardous building materials, and detailed form of the construction of infrastructure and buildings, which we think are some of the missing causes of NCDs. Some of these could be termed “involuntary causes”, as they relate to factors that are beyond the control of the general public.

Low-density lipoproteins cause atherosclerotic cardiovascular disease

DEFF Research Database (Denmark)

Ference, Brian A.; Ginsberg, Henry N.; Graham, Ian

2017-01-01

Aims To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). Methods and results We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from...... proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects. Conclusion Consistent evidence from...

Can we control all-cause meningococcal disease in Europe?

Science.gov (United States)

Sadarangani, M; Pollard, A J

2016-12-01

Invasive disease caused by Neisseria meningitidis is potentially devastating, with a case fatality rate of 5-15% and high rates of significant sequelae among survivors after septicaemia or meningitis. Capsular group C (MenC) conjugate vaccines have been highly successful in achieving control of MenC disease across Europe, and some countries have also introduced quadrivalent MenACWY conjugate vaccines to reduce disease caused by groups A, W and Y in addition to C. These vaccines putatively elicit protective levels of bactericidal antibodies in all age groups, induce immunologic memory and reduce nasopharyngeal carriage, thereby leading to herd protection. Protein-based meningococcal vaccines based on subcapsular components, and designed primarily to target capsular group B (MenB) disease, have recently been licensed. These vaccines are highly immunogenic in infants and adolescents, inducing bactericidal antibodies against strains expressing high levels of vaccine antigens which are identical to the variants present in the vaccines. Effectiveness of these vaccines at a population level will be determined by whether vaccine-induced antibodies provide cross-protection against variants of the vaccine antigens present on the surface of the diverse collection of circulating invasive strains. The level of serum bactericidal activity induced against strains also seems to depend on the level of expression of the vaccine antigens. The duration of protection and the impact on carriage of meningococci will have a major bearing on the overall effectiveness of the programme. In September 2015 the UK became the first country to introduce the multicomponent meningococcal serogroup B vaccine (4CMenB) into a national routine immunization schedule, and data on the effectiveness of this programme are anticipated in the next few years. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Lost life years due to premature mortality caused by diseases of the respiratory system.

Science.gov (United States)

Maniecka-Bryła, Irena; Paciej-Gołębiowska, Paulina; Dziankowska-Zaborszczyk, Elżbieta; Bryła, Marek

2018-06-04

In Poland, as in most other European countries, diseases of the respiratory system are the 4th leading cause of mortality; they are responsible for about 8% of all deaths in the European Union (EU) annually. To assess the socio-economic aspects of mortality, it has become increasingly common to apply potential measures rather than conventionally used ratios. The aim of this study was to analyze years of life lost due to premature deaths caused by diseases of the respiratory system in Poland from 1999 to 2013. The study was based on a dataset of 5,606,516 records, obtained from the death certificates of Polish residents who died between 1999 and 2013. The information on deaths caused by diseases of the respiratory system, i.e., coded as J00-J99 according to the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10), was analyzed. The Standard Expected Years of Life Lost (SEYLL) indicator was used in the study. In the years 1999-2013, the Polish population suffered 280,519 deaths caused by diseases of the respiratory system (4.69% of all deaths). In the period analyzed, a gradual decrease in the standardized death rate was observed - from 46.31 per 100,000 inhabitants in 1999 to 41.02 in 2013. The dominant causes of death were influenza and pneumonia (J09-J18) and chronic lower respiratory diseases (J40-J47). Diseases of the respiratory system were the cause of 4,474,548.92 lost life years. The Standard Expected Years of Life Lost per person (SEYLLp) was 104.72 per 10,000 males and 52.85 per 10,000 females. The Standard Expected Years of Life Lost per death (SEYLLd) for people who died due to diseases of the respiratory system was 17.54 years of life on average for men and 13.65 years on average for women. The use of the SEYLL indicator provided significant information on premature mortality due to diseases of the respiratory system, indicating the fact that they play a large role in the health status of the Polish

Absenteeism due to Functional Limitations Caused by Seven Common Chronic Diseases in US Workers.

Science.gov (United States)

Vuong, Tam D; Wei, Feifei; Beverly, Claudia J

2015-07-01

The study examined the relationship between functional limitation due to chronic diseases and absenteeism among full-time workers. The studied chronic diseases include arthritis/rheumatism, cancer, diabetes, heart disease, hypertension, lung disease, and stroke. We analyzed data from the 2011 to 2013 National Health Interview Survey. Economic impact was determined by workdays lost and lost income. Increase in absenteeism was observed for each studied condition. Employees with multiple conditions also saw increase absenteeism. Employers lose 28.2 million workdays annually ($4.95 billion in lost income) due to functional limitation caused by chronic diseases. The results show a burden on society due to functional limitation caused by studied chronic diseases. Employers should look into implementing intervention/prevention programs, such as the Chronic Disease Self-Management Programs, to help reduce the cost associated with absenteeism.

Alterations and diseases of the gastrointestinal tract caused by old age

International Nuclear Information System (INIS)

Bayerl, F.

1981-01-01

The dissertation reviews the publications on 'The gastrointestinal tract in old age' since 1941. As in the 1941 publication by Heinrich, particular interest is taken in diagnostic radiology. The lower age limit of the cases described was set at 55 to 60 years. Oesophageal changes ranged from functional disturbances (e.g. atonia, changes in peristalsis, or dilatation) to chronic inflammation, displacement caused by the surrounding organs, and tumours (mainly carcinoma). Formation of diverticula takes an intermediate position. Of the gastric and duodenal changes, hiatal hermia and chronic atrophic gastritis were the most frequent. Ulcers caused by old age differ from 'common' ulcers in some respects, and the symptoms may be confused with those of gastric carcinoma. Early gastric carcinoma is another disease whose incidence increases with age. Thoracic and spinal changes may cause impressions on the stomach. The effects of old age on the time of passage of contrast media, on gastric tone, and on the shape of the stomach remain unclear. Changes caused by old age in the small and large intestine range from formation of diverticula and vascular diseases (e.g. ischaemic colitis and obstruction of the mesenteric vessels) to the frequent carcinoma of the large intestine and rectum. According to this study it has to be supposed that the degenerative atrophic processes of aging and previous diseases occurring increasingly in old age, favour the provocation of ratrogenic injuries. (orig./MG) [de

Detection of Secondary Causes and Coexisting Diseases in Hypertensive Patients: OSA and PA Are the Common Causes Associated with Hypertension.

Science.gov (United States)

Wang, Lei; Li, Nanfang; Yao, Xiaoguang; Chang, Guijuan; Zhang, Delian; Heizhati, Mulalibieke; Wang, Menghui; Luo, Qin; Kong, Jianqiong

2017-01-01

Since the control rate of blood pressure is lower in mainland China, the aim of this study is to investigate the proportion of secondary causes and coexisting diseases of hypertension in hypertensive patients. Data on consecutive patients with hypertension who visited the Hypertension Center. Diseases were detected using an established strict screening protocol. Detection rate of secondary causes and coexisting diseases of hypertension was 39.5% among 3003 hypertensive patients. Obstructive sleep apnea (OSA) was the most common, accounting for 24.7% of patients, followed by primary aldosteronism (PA) (5.8%) and PA + OSA (4.9%). Endocrine hypertension accounted for 12.1% of patients, including 10.7% of patients with PA, 1.1% with hypothyroidism, 0.1% with pheochromocytoma, 0.1% with Cushing's syndrome, and 0.1% with hyperthyroidism, respectively. Those who smoke, those who are obese, and those who have diabetes accounted for 31.3%, 27.5%, and 16.6% of total patients, respectively. There were overlapping conditions in secondary causes and coexisting diseases of hypertension. OSA was the most common in each age- and BMI-stratified group. Findings from the current study suggest an increasing frequency of secondary forms of hypertension, highlighting the burden of OSA and PA in hypertensive patients.

Detection of Secondary Causes and Coexisting Diseases in Hypertensive Patients: OSA and PA Are the Common Causes Associated with Hypertension

Directory of Open Access Journals (Sweden)

Lei Wang

2017-01-01

Full Text Available Background. Since the control rate of blood pressure is lower in mainland China, the aim of this study is to investigate the proportion of secondary causes and coexisting diseases of hypertension in hypertensive patients. Methods. Data on consecutive patients with hypertension who visited the Hypertension Center. Diseases were detected using an established strict screening protocol. Results. Detection rate of secondary causes and coexisting diseases of hypertension was 39.5% among 3003 hypertensive patients. Obstructive sleep apnea (OSA was the most common, accounting for 24.7% of patients, followed by primary aldosteronism (PA (5.8% and PA + OSA (4.9%. Endocrine hypertension accounted for 12.1% of patients, including 10.7% of patients with PA, 1.1% with hypothyroidism, 0.1% with pheochromocytoma, 0.1% with Cushing’s syndrome, and 0.1% with hyperthyroidism, respectively. Those who smoke, those who are obese, and those who have diabetes accounted for 31.3%, 27.5%, and 16.6% of total patients, respectively. There were overlapping conditions in secondary causes and coexisting diseases of hypertension. OSA was the most common in each age- and BMI-stratified group. Conclusion. Findings from the current study suggest an increasing frequency of secondary forms of hypertension, highlighting the burden of OSA and PA in hypertensive patients.

Update on chancroid: an important cause of genital ulcer disease.

Science.gov (United States)

Langley, C

1996-08-01

Chancroid is a major cause of genital ulcer disease worldwide, and occurred at epidemic rates in the United States in the late 1980s. Though the recent epidemic in the U.S. appears to be waning, a number of areas continue to report significant numbers of cases. Chancroid is a particular concern, because, like other diseases that cause genital ulceration, it is associated with an increased risk for transmission or acquisition of human immunodeficiency virus (HIV). Recent studies have advanced the understanding of chancroid epidemiology, and new diagnostic tests may improve the ability to recognize and appropriately treat chancroid. Increased awareness of chancroid, with appropriate treatment for suspected lesions, along with public health efforts to implement prevention in high-risk populations, will be critical to prevent ongoing transmission of chancroid, and potentially ongoing transmission of HIV.

How Do the Virulence Factors of Shigella Work Together to Cause Disease?

Science.gov (United States)

Mattock, Emily; Blocker, Ariel J

2017-01-01

Shigella is the major cause of bacillary dysentery world-wide. It is divided into four species, named S. flexneri, S. sonnei, S. dysenteriae , and S. boydii , which are distinct genomically and in their ability to cause disease. Shigellosis, the clinical presentation of Shigella infection, is characterized by watery diarrhea, abdominal cramps, and fever. Shigella 's ability to cause disease has been attributed to virulence factors, which are encoded on chromosomal pathogenicity islands and the virulence plasmid. However, information on these virulence factors is not often brought together to create a detailed picture of infection, and how this translates into shigellosis symptoms. Firstly, Shigella secretes virulence factors that induce severe inflammation and mediate enterotoxic effects on the colon, producing the classic watery diarrhea seen early in infection. Secondly, Shigella injects virulence effectors into epithelial cells via its Type III Secretion System to subvert the host cell structure and function. This allows invasion of epithelial cells, establishing a replicative niche, and causes erratic destruction of the colonic epithelium. Thirdly, Shigella produces effectors to down-regulate inflammation and the innate immune response. This promotes infection and limits the adaptive immune response, causing the host to remain partially susceptible to re-infection. Combinations of these virulence factors may contribute to the different symptoms and infection capabilities of the diverse Shigella species, in addition to distinct transmission patterns. Further investigation of the dominant species causing disease, using whole-genome sequencing and genotyping, will allow comparison and identification of crucial virulence factors and may contribute to the production of a pan- Shigella vaccine.

Modelling the economic impact of three lameness causing diseases using herd and cow level evidence

DEFF Research Database (Denmark)

Ettema, Jehan Frans; Østergaard, Søren; Kristensen, Anders Ringgaard

2010-01-01

Diseases to the cow's hoof, interdigital skin and legs are highly prevalent and of large economic impact in modern dairy farming. In order to support farmer's decisions on preventing and treating lameness and its underlying causes, decision support models can be used to predict the economic...... horn diseases. Secondly, the existing simulation model was set-up inwaythat it uses hyper-distributions describing diseases risk of the three lameness causing diseases. By combining information on herd level risk factors with prevalence of lameness or prevalence of underlying diseases among cows...

Influence of defect size and localization on the engagement of reverse Hill-Sachs lesions.

Science.gov (United States)

Moroder, Philipp; Runer, Armin; Kraemer, Manuel; Fierlbeck, Johann; Niederberger, Alfred; Cotofana, Sebastian; Vasvari, Imre; Hettegger, Bernhard; Tauber, Mark; Hurschler, Christof; Resch, Herbert

2015-03-01

Reverse Hill-Sachs (RHS) lesions can cause recurrent posterior shoulder instability because of engagement with the posterior glenoid rim; however, the effect of defect size and localization have yet to be determined. Both size and localization are critical for the engagement of an RHS defect with the posterior glenoid rim. Controlled laboratory study. Ten RHS defects with predefined extent and localization were created through an anterolateral rotator cuff sparing approach in 10 fresh-frozen cadaveric shoulder specimens using a custom-made saw guide. Computed tomography scans of all specimens were completed, and standardized measurements were performed to determine the size (alpha angle) and localization (beta angle) of the defect as well as a combination of both parameters (gamma angle). Internal rotation motions were imposed on the shoulder joint in different arm positions and with varying amount of posterior translation by means of a robot-assisted shoulder simulator. The association between engagement of the defects and the defined parameters (alpha, beta, and gamma angles) was analyzed. In 0° of abduction, a cutoff value between engaging and nonengaging defects of 37.5° for the alpha angle (100% sensitivity; 75% specificity; area under the curve [AUC], 0.875; P = .055) and 36.5° for the beta angle (100% sensitivity; 25% specificity; AUC, 0.708; P = .286) was determined. The gamma angle showed the highest discriminatory power (AUC, 0.938; P = .025) with a cutoff value of 85.5° rendering 100% sensitivity and 75% specificity in the prediction of engagement. An increase in the applied posterior translation force decreased the degrees of internal rotation necessary before engagement occurred. No engagement occurred during internal rotation with the arm in 60° of abduction or 60° of flexion. The size and localization of RHS defects are both critical factors for engagement. The combination of both parameters in terms of the gamma angle measurement might be a

Pelvic Hydatid Disease: CT and MRI Findings Causing Sciatica

Energy Technology Data Exchange (ETDEWEB)

Sanal, Hatice Tuba; Kocaoglu, Murat; Bulakbasi, Nail; Yildirim, Duzgun [Gulhane Military Medical School, Department of Radiology, 06018, Ankara (Turkmenistan)

2007-12-15

Pelvic masses, especially hydatid disease, rarely present with sciatica. We present the computed tomography (CT) and the magnetic resonance imaging (MRI) findings of a 49-year-old female patient with presacral hydatid disease, who was evaluated for her sciatica. We also want to emphasize the importance of assessing the pelvis of patients with symptoms and clinical findings that are inconsistent and that cannot be satisfactorily explained by the spinal imaging findings. isc herniation in the lumbar spine is a well-known etiology of back pains and sciatica, but whenever disc herniation of the lumbar spine is excluded by the employed imaging modalities, then the pelvis should be examined for other possible etiologies of nerve compression. We describe here a patient, who was complaining of sciatica, with no abnormal findings in her lumbar spinal magnetic resonance imaging (MRI). The cause of her sciatica was found to be associated with a pelvic hydatid cyst compressing the lumbosacral nerve plexus. In conclusion, if no pathology is evident for the lumbar discal structures, in connection with the cause of sciatica and lumbar back pains, then the pelvis should also be examined for the possible etiologies of compression of the lumbosacral nerve plexus. Whenever a multiseptated cyst is come across in a patient of an endemic origin with a positive history for hydatid disease like surgery, indicating recurrence, hydatid cyst is the most likely diagnosis.

Pelvic Hydatid Disease: CT and MRI Findings Causing Sciatica

International Nuclear Information System (INIS)

Sanal, Hatice Tuba; Kocaoglu, Murat; Bulakbasi, Nail; Yildirim, Duzgun

2007-01-01

Pelvic masses, especially hydatid disease, rarely present with sciatica. We present the computed tomography (CT) and the magnetic resonance imaging (MRI) findings of a 49-year-old female patient with presacral hydatid disease, who was evaluated for her sciatica. We also want to emphasize the importance of assessing the pelvis of patients with symptoms and clinical findings that are inconsistent and that cannot be satisfactorily explained by the spinal imaging findings. isc herniation in the lumbar spine is a well-known etiology of back pains and sciatica, but whenever disc herniation of the lumbar spine is excluded by the employed imaging modalities, then the pelvis should be examined for other possible etiologies of nerve compression. We describe here a patient, who was complaining of sciatica, with no abnormal findings in her lumbar spinal magnetic resonance imaging (MRI). The cause of her sciatica was found to be associated with a pelvic hydatid cyst compressing the lumbosacral nerve plexus. In conclusion, if no pathology is evident for the lumbar discal structures, in connection with the cause of sciatica and lumbar back pains, then the pelvis should also be examined for the possible etiologies of compression of the lumbosacral nerve plexus. Whenever a multiseptated cyst is come across in a patient of an endemic origin with a positive history for hydatid disease like surgery, indicating recurrence, hydatid cyst is the most likely diagnosis

The superior vena cava syndrome caused by malignant disease

International Nuclear Information System (INIS)

Eren, Suat; Karaman, Adem; Okur, Adnan

2006-01-01

Objective: The superior vena cava (SVC) obstruction by malignant diseases is either by direct invasion and compression or by tumour thrombus of the SVC. Whatever is its cause, obstruction of the SVC causes elevated pressure in the veins draining into the SVC and increased or reversed blood flow through collateral vessels. Severity of the syndrome depends on the collateral vascular system development. Therefore, imaging of the collateral veins with variable location and connection is important in determining the extension and management of the disease. Our aims are to describe collateral vessels of the superior vena cava syndrome (SVCS) related with the malignant diseases and to assess the ability of multi-detector row CT with multiplanar and 3D volume rendering techniques in determining and describing collateral circulations. Materials and methods: We present CT angiography findings of seven patients with small cell carcinoma of the lung (n = 2), squamous cell carcinoma of the lung (n = 3), Hodgkin disease of the thorax (n = 1), and squamous cell carcinoma of the oesophagus (n = 1). The patients received contrast-enhanced CT scans of the chest and abdomen on a multi-detector row CT during breath holding at suspended inspiration. Results: CT images revealed the cause and level of the SVC obstruction in all patients with axial and multiplanar reconstructed images. The SVC showed total obstruction in five patients and partial obstruction in two patients. The most common experienced collateral vessels were azygos vein (6), intercostal veins (6), mediastinal veins (6), paravertebral veins (5), hemiazygos vein (5), thoracoepigastric vein (5), internal mammary vein (5), thoracoacromioclavicular venous plexus (5), and anterior chest wall veins (5). While one case showed the portal-systemic shunt, V. cordis media and sinus coronarius with phrenic veins were enlarged in two cases, and the left adrenal vein was enlarged in a patient. In one case, the azygos vein with reversed

The superior vena cava syndrome caused by malignant disease

Energy Technology Data Exchange (ETDEWEB)

Eren, Suat [Department of Radiology, Faculty of Medicine, Atatuerk University, 25240 Erzurum (Turkey)]. E-mail: suateren@atauni.edu.tr; Karaman, Adem [Department of Radiology, Faculty of Medicine, Atatuerk University, 25240 Erzurum (Turkey); Okur, Adnan [Department of Radiology, Faculty of Medicine, Atatuerk University, 25240 Erzurum (Turkey)

2006-07-15

Objective: The superior vena cava (SVC) obstruction by malignant diseases is either by direct invasion and compression or by tumour thrombus of the SVC. Whatever is its cause, obstruction of the SVC causes elevated pressure in the veins draining into the SVC and increased or reversed blood flow through collateral vessels. Severity of the syndrome depends on the collateral vascular system development. Therefore, imaging of the collateral veins with variable location and connection is important in determining the extension and management of the disease. Our aims are to describe collateral vessels of the superior vena cava syndrome (SVCS) related with the malignant diseases and to assess the ability of multi-detector row CT with multiplanar and 3D volume rendering techniques in determining and describing collateral circulations. Materials and methods: We present CT angiography findings of seven patients with small cell carcinoma of the lung (n = 2), squamous cell carcinoma of the lung (n = 3), Hodgkin disease of the thorax (n = 1), and squamous cell carcinoma of the oesophagus (n = 1). The patients received contrast-enhanced CT scans of the chest and abdomen on a multi-detector row CT during breath holding at suspended inspiration. Results: CT images revealed the cause and level of the SVC obstruction in all patients with axial and multiplanar reconstructed images. The SVC showed total obstruction in five patients and partial obstruction in two patients. The most common experienced collateral vessels were azygos vein (6), intercostal veins (6), mediastinal veins (6), paravertebral veins (5), hemiazygos vein (5), thoracoepigastric vein (5), internal mammary vein (5), thoracoacromioclavicular venous plexus (5), and anterior chest wall veins (5). While one case showed the portal-systemic shunt, V. cordis media and sinus coronarius with phrenic veins were enlarged in two cases, and the left adrenal vein was enlarged in a patient. In one case, the azygos vein with reversed

Complete staghorn calculus in polycystic kidney disease: infection is still the cause.

Science.gov (United States)

Mao, Zhiguo; Xu, Jing; Ye, Chaoyang; Chen, Dongping; Mei, Changlin

2013-08-01

Kidney stones in patients with autosomal dominant polycystic kidney disease are common, regarded as the consequence of the combination of anatomic abnormality and metabolic risk factors. However, complete staghorn calculus is rare in polycystic kidney disease and predicts a gloomy prognosis of kidney. For general population, recent data showed metabolic factors were the dominant causes for staghorn calculus, but for polycystic kidney disease patients, the cause for staghorn calculus remained elusive. We report a case of complete staghorm calculus in a polycystic kidney disease patient induced by repeatedly urinary tract infections. This 37-year-old autosomal dominant polycystic kidney disease female with positive family history was admitted in this hospital for repeatedly upper urinary tract infection for 3 years. CT scan revealed the existence of a complete staghorn calculus in her right kidney, while there was no kidney stone 3 years before, and the urinary stone component analysis showed the composition of calculus was magnesium ammonium phosphate. UTI is an important complication for polycystic kidney disease and will facilitate the formation of staghorn calculi. As staghorn calculi are associated with kidney fibrosis and high long-term renal deterioration rate, prompt control of urinary tract infection in polycystic kidney disease patient will be beneficial in preventing staghorn calculus formation.

Hemolytic disease of the fetus and newborn caused by anti-E

Directory of Open Access Journals (Sweden)

Adiyyatu Sa′idu Usman

2013-01-01

Full Text Available Objective: Maternal allo-antibody production is stimulated when fetal red blood cells are positive for an antigen absent on the mother′s red cells. The maternal IgG antibodies produced will pass through the placenta and attack fetal red cells carrying the corresponding antigen. Allo-immune hemolytic disease of the fetus and newborn caused by anti-E rarely occurs. Case summary: We report two cases of anti-E hemolytic diseases in neonates. One of the neonates had severe hemolysis presenting with severe anemia, thrombocytopenia, and conjugated hyperbilirubinemia, while the other had moderate anemia and unconjugated hyperbilrubinemia. Although both the neonates were treated by phototherapy and intravenous immunoglobulin, one of them received double volume exchange transfusion. Conclusion: There appeared to be an increase in the occurrence of hemolytic disease of the fetus and newborn caused by Rh antibodies other than anti-D. In this case report, both patients presented with anemia and hyperbilirubinemia but were successfully treated, with a favorable outcome.

Micropropagation of Plectranthus edulis (Vatke) Agnew from ...

African Journals Online (AJOL)

SAM

2014-09-03

Sep 3, 2014 ... Key words: In vitro propagation, meristem culture, micropropagation, Plectranthus edulis (Vatke) Agnew, shoots multiplication. ... P. edulis showed the occurrence of diseases (Taye,. 2008). ..... Asian J. Plant Sci. 2:616-622.

ENPP1 Mutation Causes Recessive Cole Disease by Altering Melanogenesis.

Science.gov (United States)

Chourabi, Marwa; Liew, Mei Shan; Lim, Shawn; H'mida-Ben Brahim, Dorra; Boussofara, Lobna; Dai, Liang; Wong, Pui Mun; Foo, Jia Nee; Sriha, Badreddine; Robinson, Kim Samirah; Denil, Simon; Common, John Ea; Mamaï, Ons; Ben Khalifa, Youcef; Bollen, Mathieu; Liu, Jianjun; Denguezli, Mohamed; Bonnard, Carine; Saad, Ali; Reversade, Bruno

2018-02-01

Cole disease is a genodermatosis of pigmentation following a strict dominant mode of inheritance. In this study, we investigated eight patients affected with an overlapping genodermatosis after recessive inheritance. The patients presented with hypo- and hyperpigmented macules over the body, resembling dyschromatosis universalis hereditaria in addition to punctuate palmoplantar keratosis. By homozygosity mapping and whole-exome sequencing, a biallelic p.Cys120Arg mutation in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was identified in all patients. We found that this mutation, like those causing dominant Cole disease, impairs homodimerization of the ENPP1 enzyme that is mediated by its two somatomedin-B-like domains. Histological analysis revealed structural and molecular changes in affected skin that were likely to originate from defective melanocytes because keratinocytes do not express ENPP1. Consistently, RNA-sequencing analysis of patient-derived primary melanocytes revealed alterations in melanocyte development and in pigmentation signaling pathways. We therefore conclude that germline ENPP1 cysteine-specific mutations, primarily affecting the melanocyte lineage, cause a clinical spectrum of dyschromatosis, in which the p.Cys120Arg allele represents a recessive and more severe form of Cole disease. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Dracunculus medinensis (Guinea worm disease): a rare cause of calcification

Energy Technology Data Exchange (ETDEWEB)

Gospos, C.

1980-01-01

Tangled whorly calcifications were seen in the abdominal subcutaneous tissues of a negro patient from Africa. The differential diagnosis of such calcifications - rarely observed in Europe - includes a variety of parasites. In this patient, Dracunculus medinensis (guinea worm disease) was the cause.

First report of mango malformation disease caused by Fusarium pseudocircinatum in Mexico

Science.gov (United States)

Mango (Mangifera indica L.) malformation disease (MMD) is one of the most important diseases affecting this crop worldwide, causing severe economic loss due to reduction of yield. Subsequent to the first report in India in 1891 (3), MMD has spread worldwide to most mango-growing regions. Several spe...

Opinions in Denmark on the causes of peptic ulcer disease. A survey among Danish physicians and patients

DEFF Research Database (Denmark)

Christensen, A H; Gjørup, T; Andersen, I B

1994-01-01

The aim of the study was to investigate opinions among Danish patients and physicians on causes of peptic ulcer disease. Fifty-nine patients with an ulcer history and 77 physicians with a special interest in gastroenterology participated. They were given a questionnaire listing 16 possible causes...... of peptic ulcer and indicated for each whether they believed it was a contributory cause of the disease. The patients stated 0-10 causes each (median, 4), and the physicians 3-12 causes (median, 6) (p ... stated more causes than did their male colleagues (p peptic ulcer disease, whereas only around 40% believed that coffee/tea, alcohol, smoking, side effects...

Opinions in Denmark on the causes of peptic ulcer disease. A survey among Danish physicians and patients

DEFF Research Database (Denmark)

Christensen, A H; Gjørup, T; Andersen, I B

1994-01-01

stated more causes than did their male colleagues (p stress, were contributory causes of peptic ulcer disease, whereas only around 40% believed that coffee/tea, alcohol, smoking, side effects...... of medicine, and working conditions played a causal role. Around 95% of the physicians indicated that medical drugs and smoking were contributory causes of peptic ulcer disease, and around 80% that alcohol and psychologic factors were so. Only 30-40% of the physicians believed that coffee/tea, food habits......, infection, and working conditions could play a causal role in ulcer disease. It is concluded that the opinion on causal agents in peptic ulcer disease differ considerably among both patients and physicians. Opinions on causes of diseases may influence the way we treat and advise our patients, and attempts...

Celiac disease causing severe osteomalacia: an association still present in Morocco!

Science.gov (United States)

Tahiri, Latifa; Azzouzi, Hamida; Squalli, Ghita; Abourazzak, Fatimazahra; Harzy, Taoufik

2014-01-01

Celiac disease (CD), a malabsorption syndrome caused by hypersensitivity to gliadin fraction of gluten. CD can manifest with classic symptoms; however, significant myopathy and multiple fractures are rarely the predominant presentation of untreated celiac disease. Osteomalacia complicating celiac disease had become more and more rare. We describe here a case of osteomalacia secondary to a longstanding untreated celiac disease. This patient complained about progressive bone and muscular pain, weakness, fractures and skeletal deformities. Radiological and laboratory findings were all in favor of severe osteomalacia. Improvement of patient's weakness and laboratory abnormalities was obvious after treatment with gluten free diet, vitamin D, calcium and iron. This case affirms that chronic untreated celiac disease, can lead to an important bone loss and irreversible complications like skeletal deformities.

Unstable mutations: cause of some neurological hereditary diseases

International Nuclear Information System (INIS)

Cuenca Berger, P.; Morales Montero, F.

1999-01-01

Unstable mutations or amplification of triplets constitute a kind of genetic alteration discovered during the last decade. They had been found inside or near genes important for the normal neurological function of the human being. In some cases, the presence of the amplification causes the inactivation of the gene or the synthesis of a new product which functions different from the original protein. Some common characteristics of diseases caused by the amplification of triplets are that it affects the nervous system and are degenerative in nature. The expression of the manifestations varies according to age. Most of them show genetic anticipation in which the severity of the manifestations increases with each generation and appear at an earlier age. In most cases, the severity of the symptoms is correlated positively to the size of the amplification. The diagnosis of an affected individual in a family may indicate the presence of an altered gene in other relatives. These relatives may not present evident signs of the illness either because it is of late onset or because they carry premutations. The molecular diagnosis of these mutations is important to estimate the risk of developing the disease and/or of transmitting the illness to the descendants and to eliminate the fears of healthy relatives who have inherited normal copies of the gene. (Author) [es

Occupational diseases caused by ionizing radiation in medical personnel in the Czech Republic in 1974-1997

International Nuclear Information System (INIS)

Fenclova, Z.; Pelclova, D.; Lebedova, J.; Urban, P.; Petrova, K.

1999-01-01

During 1974-1997, the incidence of occupational diseases caused by ionizing radiation in medical personnel was low (0 to 0.4 % of all notified occupational diseases, with a decreasing tendency over this period of time). There have been 136 cases of occupational diseases caused by ionizing radiation; in this, 111 cases occurred in the health care sector. Radiation dermatitis was the most frequent disease (88 cases). Physicians constituted the most affected occupational group in the 1991 - 1997 period. The age of the affected physicians lay in the range of 45 to 77. The personnel affected by radiation dermatitis had the shortest (5 years) as well as longest (46 years) exposure. Lung cancer caused by radioactive chemicals was only diagnosed in two persons in the health care sector during 1974 - 1997. It should be noted that the occupational diseases were caused by elevated exposures experienced in previous years or developed as a consequence of radiation accidents. In view of the present advanced level of protection against ionizing radiation, the numbers of this kind of disease is not expected to grow any further

Ileitis caused by Yersinia enterocolitica - X-ray differential diagnosis of Crohn's disease

Energy Technology Data Exchange (ETDEWEB)

Lingg, G.; Hering, L.; Tanneberger, D.

1981-12-01

The article gives a brief description of the characteristic features of the clinical and roentgenological course and the various stages of enteritis caused by Yersinia. Basing on three cases of ileitis caused by Yersinia, the far-reaching similarity with the early changes and even the advanced stages of Crohn's diseases are demonstrated. Attention is drawn to the possibilities of differentiating between the two disease patterns.

Analysis of complications in thyroid arterial embolization for hyperthyroidism caused by Graves' disease

International Nuclear Information System (INIS)

Gao Bulang; Zhao Wei; Huang Jianqiang; Xiang Shutian; Li Liyuan; Li Minghua

2006-01-01

Objective: To investigate complications and causes of thyroid arterial embolization for hyperthyroidism caused by Graves' disease. Methods: Twenty-eight patients with hyperthyroidism caused by Graves' disease had been treated through transcathter arterial embolization with mid-term follow up. The thyroid angiography, interventional treatment, complications and causes were investigated. Results Followed up for over one year (12-24 months), mid-term rate of efficiency was 78.6% with recurrent rate of one year being 14.2%. Two patients (7.1%) had brain infarction with one partially recovered after proper therapy and the other died due to subsequent hyperthyroidism crisis. One case had temporary hypothyroidism, and another hypoparathyroidism but no permanent hypothyroidism or hypoparathyroidism occurred. One patient suffered relatively severe post-embolization syndrome. All the other complications disappeared after proper treatment. Followed up for more than a year, no other complications occurred. Conclusion: Misembolization due to regurgitation of embolized agent is one of the most important factors leading to complications of arterial embolization for Graves' disease. In order to reduce complications and improve therapeutic efficacy, it is essential to superselectively catheterize the thyroid, avoid dangerous anastomose, prevent regurgitation misembolization and strictly operate under fluoroscopy. (authors)

Seeking environmental causes of neurodegenerative disease and envisioning primary prevention.

Science.gov (United States)

Spencer, Peter S; Palmer, Valerie S; Kisby, Glen E

2016-09-01

Pathological changes of the aging brain are expressed in a range of neurodegenerative disorders that will impact increasing numbers of people across the globe. Research on the causes of these disorders has focused heavily on genetics, and strategies for prevention envision drug-induced slowing or arresting disease advance before its clinical appearance. We discuss a strategic shift that seeks to identify the environmental causes or contributions to neurodegeneration, and the vision of primary disease prevention by removing or controlling exposure to culpable agents. The plausibility of this approach is illustrated by the prototypical neurodegenerative disease amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS-PDC). This often-familial long-latency disease, once thought to be an inherited genetic disorder but now known to have a predominant or exclusive environmental origin, is in the process of disappearing from the three heavily affected populations, namely Chamorros of Guam and Rota, Japanese residents of Kii Peninsula, Honshu, and Auyu and Jaqai linguistic groups on the island of New Guinea in West Papua, Indonesia. Exposure via traditional food and/or medicine (the only common exposure in all three geographic isolates) to one or more neurotoxins in seed of cycad plants is the most plausible if yet unproven etiology. Neurotoxin dosage and/or subject age at exposure might explain the stratified epidemic of neurodegenerative disease on Guam in which high-incidence ALS peaked and declined before that of PD, only to be replaced today by a dementing disorder comparable to Alzheimer's disease. Exposure to the Guam environment is also linked to the delayed development of ALS among a subset of Chamorro and non-Chamorro Gulf War/Era veterans, a summary of which is reported here for the first time. Lessons learned from this study and from 65 years of research on ALS-PDC include the exceptional value of initial, field-based informal investigation of

Modelling the economic impact of three lameness causing diseases using herd and cow level evidence.

Science.gov (United States)

Ettema, Jehan; Østergaard, Søren; Kristensen, Anders Ringgaard

2010-06-01

Diseases to the cow's hoof, interdigital skin and legs are highly prevalent and of large economic impact in modern dairy farming. In order to support farmer's decisions on preventing and treating lameness and its underlying causes, decision support models can be used to predict the economic profitability of such actions. An existing approach of modelling lameness as one health disorder in a dynamic, stochastic and mechanistic simulation model has been improved in two ways. First of all, three underlying diseases causing lameness were modelled: digital dermatitis, interdigital hyperplasia and claw horn diseases. Secondly, the existing simulation model was set-up in way that it uses hyper-distributions describing diseases risk of the three lameness causing diseases. By combining information on herd level risk factors with prevalence of lameness or prevalence of underlying diseases among cows, marginal posterior probability distributions for disease prevalence in the specific herd are created in a Bayesian network. Random draws from these distributions are used by the simulation model to describe disease risk. Hereby field data on prevalence is used systematically and uncertainty around herd specific risk is represented. Besides the fact that estimated profitability of halving disease risk depended on the hyper-distributions used, the estimates differed for herds with different levels of diseases risk and reproductive efficiency. (c) 2010 Elsevier B.V. All rights reserved.

How tobacco smoke causes disease: the biology and behavioral basis for smoking-attributable disease : a report of the Surgeon General

National Research Council Canada - National Science Library

2010-01-01

.... This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke...

Mood and anxiety disorders in women with treated hyperthyroidism and ophthalmopathy caused by Graves' disease.

Science.gov (United States)

Bunevicius, Robertas; Velickiene, Dzilda; Prange, Arthur J

2005-01-01

To evaluate the prevalence of mood and anxiety disorders in women with treated hyperthyroidism caused by Graves' disease and to compare them with the prevalence of such findings in women without past or present thyroid disease. Thirty inpatient women with treated hyperthyroidism and ophthalmopathy caused by Graves' disease and 45 women hospitalized for treatment of gynecologic disorders such as abnormal vaginal bleeding, benign tumors or infertility were evaluated for the prevalence of mood and anxiety diagnoses using a standard Mini-International Neuropsychiatric Interview and for mood and anxiety ratings using the Profile of Mood States (POMS). At the time of assessment, it was discovered that 14 of 30 women with treated hyperthyroidism caused by Graves' disease were still hyperthyroid, while 16 women were euthyroid. Significantly greater prevalence of social anxiety disorder, generalized anxiety disorder, major depression and total mood and anxiety disorders, as well as higher symptom scores on the POMS, was found in hyperthyroid women with Graves' disease in comparison with the control group. A prevalence of total anxiety disorder, as well as history of mania or hypomania and lifetime bipolar disorder, but not lifetime unipolar depression, was more frequent in both the euthyroid and the hyperthyroid subgroups of study women in comparison with the control group. These results confirm a high prevalence of mood and anxiety disorders in women with treated hyperthyroidism and ophthalmopathy caused by Graves' disease. Hyperthyroidism plays a major role in psychiatric morbidity in Graves' disease.

The Disease Caused by Zika Virus: Current Clinical and Epidemiological Features

Directory of Open Access Journals (Sweden)

O.K. Duda

2016-04-01

Full Text Available The article deals with the topical issue of today — the disease caused by Zika virus. The etiology and pathogenesis of the disease were described, attention is paid to the examination of a patient with suspected Zika virus. Laboratory tests available in the Synevo laboratory are listed. Recommendations for the treatment are given taking into account the fact that today the causal antiviral treatment is not developed.

Association of Kidney Disease Measures with Cause-Specific Mortality: The Korean Heart Study.

Directory of Open Access Journals (Sweden)

Yejin Mok

Full Text Available The link of low estimated glomerular filtration rate (eGFR and high proteinuria to cardiovascular disease (CVD mortality is well known. However, its link to mortality due to other causes is less clear.We studied 367,932 adults (20-93 years old in the Korean Heart Study (baseline between 1996-2004 and follow-up until 2011 and assessed the associations of creatinine-based eGFR and dipstick proteinuria with mortality due to CVD (1,608 cases, cancer (4,035 cases, and other (non-CVD/non-cancer causes (3,152 cases after adjusting for potential confounders.Although cancer was overall the most common cause of mortality, in participants with chronic kidney disease (CKD, non-CVD/non-cancer mortality accounted for approximately half of cause of death (47.0%for eGFR <60 ml/min/1.73 m2 and 54.3% for proteinuria ≥1+. Lower eGFR (<60 vs. ≥60 ml/min/1.73 m2 was significantly associated with mortality due to CVD (adjusted hazard ratio 1.49 [95% CI, 1.24-1.78] and non-CVD/non-cancer causes (1.78 [1.54-2.05]. The risk of cancer mortality only reached significance at eGFR <45 ml/min/1.73 m2 when eGFR 45-59 ml/min/1.73 m2 was set as a reference (1.62 [1.10-2.39]. High proteinuria (dipstick ≥1+ vs. negative/trace was consistently associated with mortality due to CVD (1.93 [1.66-2.25], cancer (1.49 [1.32-1.68], and other causes (2.19 [1.96-2.45]. Examining finer mortality causes, low eGFR and high proteinuria were commonly associated with mortality due to coronary heart disease, any infectious disease, diabetes, and renal failure. In addition, proteinuria was also related to death from stroke, cancers of stomach, liver, pancreas, and lung, myeloma, pneumonia, and viral hepatitis.Low eGFR was associated with CVD and non-CVD/non-cancer mortality, whereas higher proteinuria was consistently related to mortality due to CVD, cancer, and other causes. These findings suggest the need for multidisciplinary prevention and management strategies in individuals with CKD

COMPOSITE PEPTIDE COMPOUNDS FOR DIAGNOSIS AND TREATMENT OF DISEASES CAUSED BY PRION PROTEINS

DEFF Research Database (Denmark)

2004-01-01

The present invention relates to diseases caused by prion proteins, Novel composite peptide compounds are disclosed which comprise two or more peptides or peptide fragments optionally linked to a backbone and the peptides or peptide fragments are spatially positioned relative to each other so tha....... Other uses of the composite peptide compounds are also disclosed, such as use in diagnostic assays, production of antibodies and uses as vaccine immunogens for the prophylactic protection and therapeutic treatment of subjects against transmissible prion disease.......The present invention relates to diseases caused by prion proteins, Novel composite peptide compounds are disclosed which comprise two or more peptides or peptide fragments optionally linked to a backbone and the peptides or peptide fragments are spatially positioned relative to each other so...

Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015

NARCIS (Netherlands)

Wang, Haidong; Naghavi, Mohsen; Allen, Christine; Barber, Ryan M.; Bhutta, Zulfiqar A.; Carter, Austin; Casey, Daniel C.; Charlson, Fiona J.; Chen, Alan Zian; Coates, Matthew M.; Coggeshall, Megan; Dandona, Lalit; Dicker, Daniel J.; Erskine, Holly E.; Ferrari, Alize J.; Fitzmaurice, Christina; Foreman, Kyle; Forouzanfar, Mohammad H.; Fraser, Maya S.; Pullman, Nancy; Gething, Peter W.; Goldberg, Ellen M.; Graetz, Nicholas; Haagsma, Juanita A.; Hay, Simon I.; Huynh, Chantal; Johnson, Catherine; Kassebaum, Nicholas J.; Kinfu, Yohannes; Kulikoff, Xie Rachel; Kutz, Michael; Kyu, Hmwe H.; Larson, Heidi J.; Leung, Janni; Liang, Xiaofeng; Lim, Stephen S.; Lind, Margaret; Lozano, Rafael; Marquez, Neal; Mensah, George A.; Mikesell, Joe; Mokdad, Ali H.; Mooney, Meghan D.; Nguyen, Grant; Nsoesie, Elaine; Pigott, David M.; Amare, Azmeraw T.; Hoek, Hans W.; Singh, Abhishek; Tura, Abera Kenay

2016-01-01

Background Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes

The causes of skin damage and leg ulceration in chronic venous disease.

Science.gov (United States)

Smith, Philip Coleridge

2006-09-01

Chronic venous disease with skin changes of the leg is a common condition affecting up to 1 in 20 people in westernized countries. The causes of this problem are not fully understood, although research in recent years has revealed a number of important mechanisms that contribute to the disease process. Patients with chronic venous disease suffer persistently raised pressures in their deep and superficial veins in the lower limb. Leucocytes become "trapped" in the circulation of the leg during periods of venous hyper-tension produced by sitting or standing. Studies of the plasma levels of neutrophil granule enzymes shows that these are increased during periods of venous hypertension, suggesting that this causes activation of the neutrophils. Investigation of the leucocyte surface ligands CD11b and CD62L shows that the more activated neutrophils and monocytes are sequestered during venous hypertension. Measurement of plasma levels of the soluble parts of the endothelial adhesion molecules VCAM, ICAM, and ELAM show that these are all elevated in patients with chronic venous disease compared to controls. Following 30 minutes of venous hypertension produced by standing, these levels are further increased. These data suggest that venous hypertension causes neutrophil and monocyte activation, which in turn causes injury to the endothelium. Chronic injury to the endothelium leads to a chronic inflammatory condition of the skin that we know clinically as lipodermatosclerosis. This is mediated by perivascular inflammatory cells, principally macrophages, in the skin microcirculation. These stimulate fibroblasts in the skin leading to tissue remodeling and laying down of fibrous tissue. Vascular endothelial growth factor stimulates proliferation of capillaries within the skin. Skin in this state has the potential to ulcerate in response to minor injury.

An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay–Sachs or Sandhoff variants)

Science.gov (United States)

Clarke, Joe T.R.; Mahuran, Don J.; Sathe, Swati; Kolodny, Edwin H.; Rigat, Brigitte A.; Raiman, Julian A.; Tropak, Michael B.

2010-01-01

Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of β-hexosaminidase A (Hex A), resulting from mutations in the HEXA (Tay–Sachs variant) or the HEXB (Sandhoff variant) genes. The enzyme deficiency in many patients with juvenile or adult onset forms of the disease results from the production of an unstable protein, which becomes targeted for premature degradation by the quality control system of the smooth endoplasmic reticulum and is not transported to lysosomes. In vitro studies have shown that many mutations in either the α or β subunit of Hex A can be partially rescued, i.e. enhanced levels of both enzyme protein and activity in lysosomes, following the growth of patient cells in the presence of the drug, pyrimethamine. The objectives of the present clinical trial were to establish the tolerability and efficacy of the treatment of late-onset GM2 gangliosidosis patients with escalating doses of pyrimethamine, to a maximum of 100 mg per day, administered orally in a single daily dose, over a 16-week period. The primary objective, tolerability, was assessed by regular clinical examinations, along with a panel of hematologic and biochemical studies. Although clinical efficacy could not be assessed in this short trial, treatment efficacy was evaluated by repeated measurements of leukocyte Hex A activity, expressed relative to the activity of lysosomal β-glucuronidase. A total of 11 patients were enrolled, 8 males and 3 females, aged 23 to 50 years. One subject failed the initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events which were not drug-related. For the remaining 8 subjects, up to a 4-fold enhancement of Hex A activity at doses of 50 mg per day or less was observed. Additionally marked individual variations in the pharmacokinetics of the drug among the patients were

Principal disease or cause of death in nonsacrifice Segment III beagles receiving gamma radiation during development

International Nuclear Information System (INIS)

Bishop, L.; Kitchen, D.N.; Benjamin, S.A.; Stephens, L.C.; Hargis, A.M.; Lovering, S.L.; Lee, A.C.; Brewster, R.D.; Brooks, R.K.

1981-01-01

Epilepsy, hypothyroidism and neoplasia rank as the three leading causes of death in nonsacrifice Segment III beagles. Chronic renal disease is a fourth major disease entity occurring with increasing frequency in the experimental population. These four major diseases accounted for 57% of the deaths in 1979. Of the four leading causes of death, neoplasia alone can be related to the history of radiation exposure

A rare cause of hematemesis in newborn: fibrocystic breast disease of mother.

Science.gov (United States)

Aksoy, Hatice Tatar; Eras, Zeynep; Erdeve, Omer; Dilmen, Ugur

2013-08-01

Hematemesis in a healthy newborn is most often caused by swallowed maternal blood. Maternal blood due to fibrocystic breast disease in human milk has not previously been reported in the literature. We report here a newborn case with hematemesis in which the mother had fibrocystic breast disease, and we want to emphasize this rare entity. Physicians should be aware of this rare condition, and fibrocystic breast disease of the mother should be included in the differential diagnosis of newborns with hematemesis.

Association of coffee consumption with all-cause and cardiovascular disease mortality.

Science.gov (United States)

Liu, Junxiu; Sui, Xuemei; Lavie, Carl J; Hebert, James R; Earnest, Conrad P; Zhang, Jiajia; Blair, Steven N

2013-10-01

To evaluate the association between coffee consumption and mortality from all causes and from cardiovascular disease. Data from the Aerobics Center Longitudinal Study representing 43,727 participants with 699,632 person-years of follow-up were included. Baseline data were collected by an in-person interview on the basis of standardized questionnaires and a medical examination, including fasting blood chemistry analysis, anthropometry, blood pressure, electrocardiography, and a maximal graded exercise test, between February 3, 1971, and December 30, 2002. Cox regression analysis was used to quantify the association between coffee consumption and all-cause and cause-specific mortality. During the 17-year median follow-up, 2512 deaths occurred (804 [32%] due to cardiovascular disease). In multivariate analyses, coffee intake was positively associated with all-cause mortality in men. Men who drank more than 28 cups of coffee per week had higher all-cause mortality (hazard ratio [HR], 1.21; 95% CI, 1.04-1.40). However, after stratification based on age, younger (coffee consumption (>28 cups per week) and all-cause mortality after adjusting for potential confounders and fitness level (HR, 1.56; 95% CI, 1.30-1.87 for men; and HR, 2.13; 95% CI, 1.26-3.59 for women). In this large cohort, a positive association between coffee consumption and all-cause mortality was observed in men and in men and women younger than 55 years. On the basis of these findings, it seems appropriate to suggest that younger people avoid heavy coffee consumption (ie, averaging >4 cups per day). However, this finding should be assessed in future studies of other populations. Copyright © 2013 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Remnant cholesterol as a cause of ischemic heart disease

DEFF Research Database (Denmark)

Varbo, Anette; Benn, Marianne; Nordestgaard, Børge G

2014-01-01

This review focuses on remnant cholesterol as a causal risk factor for ischemic heart disease (IHD), on its definition, measurement, atherogenicity, and levels in high risk patient groups; in addition, present and future pharmacological approaches to lowering remnant cholesterol levels...... are considered. Observational studies show association between elevated levels of remnant cholesterol and increased risk of cardiovascular disease, even when remnant cholesterol levels are defined, measured, or calculated in different ways. In-vitro and animal studies also support the contention that elevated...... levels of remnant cholesterol may cause atherosclerosis same way as elevated levels of low-density lipoprotein (LDL) cholesterol, by cholesterol accumulation in the arterial wall. Genetic studies of variants associated with elevated remnant cholesterol levels show that an increment of 1mmol/L (39mg...

Milk and dairy consumption and risk of cardiovascular diseases and all-cause mortality

NARCIS (Netherlands)

Guo, Jing; Astrup, Arne; Lovegrove, Julie A.; Gijsbers, Lieke; Givens, David I.; Soedamah-Muthu, Sabita S.

2017-01-01

With a growing number of prospective cohort studies, an updated dose–response meta-analysis of milk and dairy products with all-cause mortality, coronary heart disease (CHD) or cardiovascular disease (CVD) have been conducted. PubMed, Embase and Scopus were searched for articles published up to

Collecting tau neutrinos near the proton dump: an outlook

International Nuclear Information System (INIS)

Asratyan, A.Eh.; Goritchev, P.A.; Kubantsev, M.A.

1984-01-01

The possibilities for the study of tan neutrino interactions in nuclear emulsion placed close to the proton dump are discussed. The processes νsub(tay)N → taysup(-)X with subsequent taysup(-) → lν tildesub(l)νsub(tay) and taysup(-) → νsub(tay) hadrons (l=μ, e) are considered. It is shown that of the approximately 1000 event surviving the kinematic selection criteria, approximately 50 leptonic and approximately 200 hadronic tay decays can be identified in emulsion

Hemolytic disease of the fetus and newborn caused by anti-E

OpenAIRE

Usman, Adiyyatu Sa?idu; Mustaffa, Rapiaah; Ramli, Noraida; Diggi, Sirajo A.

2013-01-01

Objective: Maternal allo-antibody production is stimulated when fetal red blood cells are positive for an antigen absent on the mother′s red cells. The maternal IgG antibodies produced will pass through the placenta and attack fetal red cells carrying the corresponding antigen. Allo-immune hemolytic disease of the fetus and newborn caused by anti-E rarely occurs. Case summary: We report two cases of anti-E hemolytic diseases in neonates. One of the neonates had severe hemolysis presenting wit...

Traiter les causes sociales de la maladie | CRDI - Centre de ...

International Development Research Centre (IDRC) Digital Library (Canada)

28 janv. 2011 ... Cet indice permet de présenter des portraits composites de l'état de bien-être national en combinant les indicateurs purement économiques et différents autres indicateurs fondamentaux, comme l'espérance de vie, le taux d'alphabétisation et l'accès à l'éducation. La santé et l'économie selon Sachs.

Rare Cause of Pleuropnemonia: Tularemia Disease.

Science.gov (United States)

Agca, Meltem; Duman, Dildar; Sulu, Ebru; Ozbaki, Fatma; Barkay, Orcun; Ozturk, Derya; Yarkin, Tulay

2017-09-01

Tularemia is a zoonotic infection which is caused by gram negative coccobacilli, Francisella tularensis. The disease occurs after contact with blood and body fluids of infected animals, bites and ingestion of infected food and water. Although it commonly presents with skin lesions, there may also be serious organ involvements. A55-year woman was consulted for presumptive diagnosis of tuberculosis. Multiple lymphadenopathy in right cervical area was present on physical examination. Pleural effusion on left side was detected with computed tomography. In detailed history, knowledge of a family member with the diagnosis of tularemia was obtained. Both of them had the history of contact with infected animals. Diagnosis of tularemia was confirmed with microagglutination test. With this patient who was initially presumptively diagnosed as tuberculosis, we aim to draw attention to diagnosis of tularemia in the presence of pleuropnemonia and peripheral lymphadenopathy and emphasize importance of detailed patient history.

Biochemical characterization of the GM2 gangliosidosis B1 variant

Directory of Open Access Journals (Sweden)

Tutor J.C.

2004-01-01

Full Text Available The deficiency of the A isoenzyme of ß-hexosaminidase (Hex produced by different mutations of the gene that codes for the alpha subunit (Tay-Sachs disease has two variants with enzymological differences: the B variant consists of the absence of Hex A isoenzyme and the B1 variant produces an inactive Hex A isoenzyme for the hydrolysis of the GM2 ganglioside and synthetic substrates with negative charge. In contrast to the early childhood form of the B variant, the B1 variant appears at a later clinical stage (3 to 7 years of age with neurodegenerative symptoms leading to the death of the patient in the second decade of life. The most frequent mutation responsible for the GM2 gangliosidosis B1 variant is R178H, which has a widespread geographic and ethnic distribution. The highest incidence has been described in Portugal, which has been suggested as the point of origin of this mutation. Biochemical characterization of this lysosomal disease is carried out using negatively charged synthetic alpha subunit-specific sulfated substrates, since Hex A isoenzyme heat-inactivation assays are not applicable. However, the determination of the apparent activation energy of Hex using the neutral substrate 3,3'-dichlorophenolsulfonphthaleinyl N-acetyl-ß-D-glucosaminide, may offer a valid alternative. The presence of an alpha subunit in the alphaß heterodimer Hex A means that its activation energy (41.8 kJ/mol is significantly lower than that of the ßß homodimer Hex B (75.1 kJ/mol; however, as mutation inactivates the alpha subunit, the Hex A of the B1 variant presents an activation energy that is similar to that of the Hex B isoenzyme.

Mutations that Cause Human Disease: A Computational/Experimental Approach

Energy Technology Data Exchange (ETDEWEB)

Beernink, P; Barsky, D; Pesavento, B

2006-01-11

International genome sequencing projects have produced billions of nucleotides (letters) of DNA sequence data, including the complete genome sequences of 74 organisms. These genome sequences have created many new scientific opportunities, including the ability to identify sequence variations among individuals within a species. These genetic differences, which are known as single nucleotide polymorphisms (SNPs), are particularly important in understanding the genetic basis for disease susceptibility. Since the report of the complete human genome sequence, over two million human SNPs have been identified, including a large-scale comparison of an entire chromosome from twenty individuals. Of the protein coding SNPs (cSNPs), approximately half leads to a single amino acid change in the encoded protein (non-synonymous coding SNPs). Most of these changes are functionally silent, while the remainder negatively impact the protein and sometimes cause human disease. To date, over 550 SNPs have been found to cause single locus (monogenic) diseases and many others have been associated with polygenic diseases. SNPs have been linked to specific human diseases, including late-onset Parkinson disease, autism, rheumatoid arthritis and cancer. The ability to predict accurately the effects of these SNPs on protein function would represent a major advance toward understanding these diseases. To date several attempts have been made toward predicting the effects of such mutations. The most successful of these is a computational approach called ''Sorting Intolerant From Tolerant'' (SIFT). This method uses sequence conservation among many similar proteins to predict which residues in a protein are functionally important. However, this method suffers from several limitations. First, a query sequence must have a sufficient number of relatives to infer sequence conservation. Second, this method does not make use of or provide any information on protein structure, which

Opinions in Denmark on the causes of peptic ulcer disease. A survey among Danish physicians and patients

DEFF Research Database (Denmark)

Christensen, A H; Gjørup, T; Andersen, I B

1994-01-01

of medicine, and working conditions played a causal role. Around 95% of the physicians indicated that medical drugs and smoking were contributory causes of peptic ulcer disease, and around 80% that alcohol and psychologic factors were so. Only 30-40% of the physicians believed that coffee/tea, food habits...... stated more causes than did their male colleagues (p smoking, side effects......, infection, and working conditions could play a causal role in ulcer disease. It is concluded that the opinion on causal agents in peptic ulcer disease differ considerably among both patients and physicians. Opinions on causes of diseases may influence the way we treat and advise our patients, and attempts...

Cholesteryl ester storage disease: a rare and possibly treatable cause of premature vascular disease and cirrhosis.

Science.gov (United States)

Reynolds, Tim

2013-11-01

Cholesteryl ester storage disease (CESD) is an autosomal recessive lysosomal storage disorder caused by a variety of mutations of the LIPA gene. These cause reduced activity of lysosomal acid lipase, which results in accumulation of cholesteryl esters in lysosomes. If enzyme activity is very low/absent, presentation is in infancy with failure to thrive, malabsorption, hepatosplenomegaly and rapid early death (Wolman disease). With higher but still low enzyme activity, presentation is later in life with hepatic fibrosis, dyslipidaemia and early atherosclerosis.Identification of this rare disorder is difficult as it is essential to assay leucocyte acid phosphatase activity. An assay using specific inhibitors has now been developed that facilitates measurement in dried blood spots. Treatment of CESD has until now been limited to management of the dyslipidaemia, but this does not influence the liver effects. A new enzyme replacement therapy (Sebelipase) has now been developed that could change treatment options for the future.

Prevalence of chronic liver disease and cirrhosis by underlying cause in understudied ethnic groups: The multiethnic cohort.

Science.gov (United States)

Setiawan, Veronica Wendy; Stram, Daniel O; Porcel, Jacqueline; Lu, Shelly C; Le Marchand, Loïc; Noureddin, Mazen

2016-12-01

Chronic liver disease (CLD) and cirrhosis are major sources of morbidity and mortality in the United States. Little is known about the epidemiology of these two diseases in ethnic minority populations in the United States. We examined the prevalence of CLD and cirrhosis by underlying etiologies among African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites in the Multiethnic Cohort. CLD and cirrhosis cases were identified using Medicare claims between 1999 and 2012 among the fee-for-service participants (n = 106,458). We used International Classification of Diseases Ninth Revision codes, body mass index, history of diabetes mellitus, and alcohol consumption from questionnaires to identify underlying etiologies. A total of 5,783 CLD (3,575 CLD without cirrhosis and 2,208 cirrhosis) cases were identified. The prevalence of CLD ranged from 3.9% in African Americans and Native Hawaiians to 4.1% in whites, 6.7% in Latinos, and 6.9% in Japanese. Nonalcoholic fatty liver disease (NAFLD) was the most common cause of CLD in all ethnic groups combined (52%), followed by alcoholic liver disease (21%). NAFLD was the most common cause of cirrhosis in the entire cohort. By ethnicity, NAFLD was the most common cause of cirrhosis in Japanese Americans, Native Hawaiians, and Latinos, accounting for 32% of cases. Alcoholic liver disease was the most common cause of cirrhosis in whites (38.2%), while hepatitis C virus was the most common cause in African Americans (29.8%). We showed racial/ethnic variations in the prevalence of CLD and cirrhosis by underlying etiology; NAFLD was the most common cause of CLD and cirrhosis in the entire cohort, and the high prevalence of NAFLD among Japanese Americans and Native Hawaiians is a novel finding, warranting further studies to elucidate the causes. (Hepatology 2016;64:1969-1977). © 2016 by the American Association for the Study of Liver Diseases.

Chewing betel quid and the risk of metabolic disease, cardiovascular disease, and all-cause mortality: a meta-analysis.

Science.gov (United States)

Yamada, Tomohide; Hara, Kazuo; Kadowaki, Takashi

2013-01-01

Betel nut (Areca nut) is the fruit of the Areca catechu tree. Approximately 700 million individuals regularly chew betel nut (or betel quid) worldwide and it is a known risk factor for oral cancer and esophageal cancer. We performed a meta-analysis to assess the influence of chewing betel quid on metabolic diseases, cardiovascular disease, and all-cause mortality. We searched Medline, Cochrane Library, Web of Science, and Science Direct for pertinent articles (including the references) published between 1951 and 2013. The adjusted relative risk (RR) and 95% confidence interval were calculated using the random effect model. Sex was used as an independent category for comparison. Of 580 potentially relevant studies, 17 studies from Asia (5 cohort studies and 12 case-control studies) covering 388,134 subjects (range: 94 to 97,244) were selected. Seven studies (N = 121,585) showed significant dose-response relationships between betel quid consumption and the risk of events. According to pooled analysis, the adjusted RR of betel quid chewers vs. non-chewers was 1.47 (PBetel quid chewing is associated with an increased risk of metabolic disease, cardiovascular disease, and all-cause mortality. Thus, in addition to preventing oral cancer, stopping betel quid use could be a valuable public health measure for metabolic diseases that are showing a rapid increase in South-East Asia and the Western Pacific.

Echinococcal disease of the bone: An unusual cause of a pathological fracture

Directory of Open Access Journals (Sweden)

Matthew Goodier

2010-12-01

Full Text Available Echinococcosis is caused by the larva of the tapeworm, Echinococcus granulosus or Echinococcus multiloccularis and is endemic in many rural areas of Southern Africa. Echinococcosis of the bone is an unusual manifestation of echinococcal disease and a rare cause of a lytic lesion of bone. This report describes a 30-yr old female who presented with an Echinococcal cyst of the right radius complicated by a pathological fracture.

[Moyamoya disease as a rare cause of ischaemic stroke--case report].

Science.gov (United States)

Kułakowska, Alina; Kapica-Topczewska, Katarzyna; Borowik, Helena; Drozdowski, Wiesław

2009-10-01

Moyamoya disease is a rare, progressive disease of the vessels diagnosed according to characteristic abnormalities of brain arteries in the angiography. The incidence of moyamoya disease in Europe is lower than in Asia and its clinical course in European population is probably different from Asiatic (older age of onset and rare incidence of hemorrhagic strokes). Two young patients were diagnosed as moyamoya disease on the basis of clinical symptoms (ischaemic stroke) and results of brain vessels' angiography, which documented an occlusion of both internal carotid arteries above branching-off the ocular arteries in the first patient and stenosis of distal internal carotid arteries and proximal medial and anterior cerebral arteries in the second one. Both patients are under control of the Neurological Outpatient Department and their neurological state is stable. Despite that moyamoya disease is a rare cause of ischaemic stroke, it should be always considered as one of etiologic factors, especially in young patients.

Annual all-cause mortality rate for patients with diabetic kidney disease in Singapore

Directory of Open Access Journals (Sweden)

Yee Gary Ang

2016-06-01

Conclusion: Our study estimated the annual all-cause mortality rate for Singaporean patients with diabetic kidney disease by CKD stages and identified predictors of all-cause mortality. This study has affirmed the poor prognosis of these patients and an urgency to intervene early so as to retard the progression to later stages of CKD.

Adult Scheuermann’s disease as cause of mechanic dorsalgia

Directory of Open Access Journals (Sweden)

F.P. Cantatore

2011-09-01

Full Text Available Scheuermann’s disease (SD or vertebral osteochondrosis is the most frequent cause of non postural kyphosis and one of more frequent cause of adolescent’s dorsalgia. The criteria for the diagnosis are: more than 5° of wedging of at least three adjacent vertebrae at the apex of the kyphosis; a toracic kyphosis of more than 45° of Cobb’s degree; Schmorl’s nodes and endplates irregularities. In addition to classic SD, there are radiological alterations that remain asintomatic for a long time to reveal in adult age: in that case it speaks of adult Scheuermann’s disease (ASD. We considered the diagnosis of patients came from April 2006 to April 2007 on Day Hospital in our Clinic. ASD was diagnosed, besides, in 10 of these patients. 7 patients had previous diagnosis such as: dorsal Spondiloarthrosis (4 subjects; Osteoporosis with vertebral fractures (3 subjects. All these diagnosis was not confirmed by us. In case of chronic dorsalgia of adult, ASD is rarely considered as differential diagnosis. Besides, the vertebral dorsalgia, even in absence of red flags as fever, astenia, ipersedimetry, functional loss and aching spinal processes to tapping, could hide a serious scene that lead us to be careful in the differential diagnosis, because of similar radiological pictures of the MSA to other pathology as spondylodiscitis, primitive or metastasic spinal tumors, and brittleness vertebral fractures

Disease patterns and causes of death of hospitalized HIV-positive adults in West Africa

DEFF Research Database (Denmark)

Lewden, Charlotte; Drabo, Youssoufou J; Zannou, Djimon M

2014-01-01

%) and cerebral toxoplasmosis (10%). Overall, 315 (38%) patients died during hospitalization and the underlying cause of death was AIDS (63%), non-AIDS-defining infections (26%), other diseases (7%) and non-specific illness or unknown cause (4%). Among them, the most frequent fatal diseases were: tuberculosis (36......%), cerebral toxoplasmosis (10%), cryptococcosis (9%) and sepsis (7%). Older age, clinical WHO stage 3 and 4, low CD4 count, and AIDS-defining infectious diagnoses were associated with hospital fatality. CONCLUSIONS: AIDS-defining conditions, primarily tuberculosis, and bacterial infections were the most...

Non-melanoma skin cancer and risk of Alzheimer's disease and all-cause dementia.

Directory of Open Access Journals (Sweden)

Sigrun A J Schmidt

Full Text Available Cancer patients may be at decreased risk of Alzheimer's disease. This hypothesis is best developed for non-melanoma skin cancer (NMSC, but supportive epidemiological data are sparse. We therefore conducted a nationwide cohort study of the association between NMSC and Alzheimer's disease (main outcome and all-cause dementia. Using Danish medical databases, we identified adults diagnosed with NMSC between 1 January 1980 and 30 November 2013 (n = 216,221 and a comparison cohort of five individuals matched to each NMSC patient by sex and birth year (n = 1,081,097. We followed individuals from the time of diagnosis, or corresponding date for matched comparators, until a dementia diagnosis, death, emigration, or 30 November 2013, whichever came first. We used stratified Cox regression adjusted for comorbidities to compute hazard ratios (HRs associating NMSC with dementia. We computed cumulative risks of dementia, treating death as a competing risk. NMSC was associated with a HR of 0.95 (95% confidence interval [CI]: 0.92-0.98 for Alzheimer's disease and 0.92 (95% CI: 0.90-0.94 for all-cause dementia. HRs were similar for basal cell and squamous cell carcinoma, the two most common forms of NMSC. Estimates of risk reduction were more pronounced in the beginning of follow-up, reaching null after 5-10 years. At the end of follow-up (34 years, cumulative risk of Alzheimer's disease was 4.6% (95% CI: 4.4%-4.8% among patients with NMSC vs. 4.7% (95% CI: 4.6%-4.9% in the comparison cohort. In conclusion, NMSC was associated with 2%-10% reductions in relative risks of Alzheimer's disease and all-cause dementia. However, these small inverse associations may have been caused by ascertainment bias due to decreased awareness of NMSC tumors in persons with undiagnosed early cognitive impairment or by confounding from a more neuroprotective lifestyle among persons with NMSC.

Pheromones cause disease: the exocrinology of anorexia nervosa.

Science.gov (United States)

Nicholson, B

2000-03-01

The aetiology of anorexia nervosa is exocrinological. This notion is supported by physical evidence in animal models with directly comparable symptomatology. Anorexia nervosa (AN) syndrome would be a puberty delay caused by reception and autoreception of conspecific pheromone emissions: a pheromone-induced puberty delay (PIPD). As such, it would be amenable to medical treatment drawing from forty years of research in animals. This hypothesis is testable. For instance, since food ad libitum is a prerequisite for PIPD, occasional supervised fasting in healthy peripuberal subjects should prevent AN. Besides, tolerating an untestable thought disease (1,2) with symptoms of a curable well-understood animal condition would be anti-scientific and perpetuates medical disaster. Even their endocrinologies are identical. Pheromone feedback tunes animal appetites and immunity to available resources and prospects. In addition to timing puberty, pheromones regulate fertility. Pheromones will probably be implicated in the aetiology of the psychiatric and autoimmune diseases. This is the second in a series of twelve papers to explore this contention systematically. (c) 2000 Harcourt Publishers Ltd Copyright 2000 Harcourt Publishers Ltd.

On the intrinsic relation between technology and morality : and what this means for machine learning.

NARCIS (Netherlands)

Gabriels, K.

2017-01-01

When Microsoft released its AI chatbot Tay on Twitter in March 2016, Tay was supposed to learn to chat as an average American teenage girl. However, she quickly became sexist, racist, and anti-Semitic. Microsoft turned out to be overly naïve about the intentions of users who had to ‘train’ Tay. In

Successful therapy for protein-losing enteropathy caused by chronic neuronopathic Gaucher disease

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A.A. Mhanni

2016-03-01

Full Text Available Gaucher disease (OMIM #230800 is caused by β-glucosidase deficiency and primarily involves the mononuclear phagocyte system (also called Reticuloendothelial System or Macrophage System. The disease is classified into three main phenotypes based on the presence or absence of neurological manifestations: non-neuronopathic (type 1, acute neuronopathic (type 2 and chronic neuronopathic (type 3. Typical manifestations include hepatosplenomegaly, skeletal deformities, hematological abnormalities, interstitial lung fibrosis and neurodegeneration in neuronopathic cases. Mesenteric lymphadenopathy with resultant protein losing enteropathy (PLE has only been rarely described. Mesenteric lymphadenopathy may lead to intestinal lymphatic obstruction and secondary lymphangiectasia resulting in chronic diarrhea, abdominal pain and weight loss. Fecal protein loss with secondary hypoalbuminemia can be significant. We report a male with Chronic Neuronopathic Gaucher disease (GD (homozygous for c.1448T>C (NM_000157.3 GBA mutation who at 16 years of age developed intractable abdominal pain, diarrhea and weight loss. This was caused by PLE secondary to intestinal lymphangiectasia caused by calcified mesenteric lymphadenopathy despite prior long term enzyme replacement therapy (ERT and/or substrate reduction therapy (SRT. His older similarly affected sister who had been receiving treatment with ERT and/or SRT remains stable on these treatments with no evidence of mesenteric lymphadenopathy. Medical management with total parenteral nutrition, daily medium chain triglyceride-oil (MCT supplementation, low dose oral budesonide, continued oral SRT and an increased dose of parenteral ERT has stabilized his condition with resolution of the gastrointestinal symptoms and appropriate weight gain.

Causes and timing of end-stage renal disease after living kidney donation.

Science.gov (United States)

Matas, Arthur J; Berglund, Danielle M; Vock, David M; Ibrahim, Hassan N

2018-05-01

End-stage renal disease (ESRD) is a risk after kidney donation. We sought, in a large cohort of kidney donors, to determine the causes of donor ESRD, the interval from donation to ESRD, the role of the donor/recipient relationship, and the trajectory of the estimated GFR (eGFR) from donation to ESRD. From 1/1/1963 thru 12/31/2015, 4030 individuals underwent living donor nephrectomy at our center, as well as ascertainment of ESRD status. Of these, 39 developed ESRD (mean age ± standard deviation [SD] at ESRD, 62.4 ± 14.1 years; mean interval between donation and ESRD, 27.1 ± 9.8 years). Donors developing ESRD were more likely to be male, as well as smokers, and younger at donation, and to have donated to a first-degree relative. Of donors with a known cause of ESRD (n = 25), 48% was due to diabetes and/or hypertension; only 2 from a disease that would have affected 1 kidney (cancer). Of those 25 with an ascertainable ESRD cause, 4 shared a similar etiology of ESRD with their recipient. Almost universally, thechange of eGFR over time was stable, until new-onset disease (kidney or systemic). Knowledge of factors contributing to ESRD after living kidney donation can improve donor selection and counseling, as well as long-term postdonation care. © 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.

Dental erosion caused by gastroesophageal reflux disease: a case report.

Science.gov (United States)

Cengiz, Seda; Cengiz, M Inanç; Saraç, Y Sinasi

2009-07-22

Chronic regurgitation of gastric acids in patients with gastroesophageal reflux disease may cause dental erosion, which can lead in combination with attrition or bruxism to extensive loss of coronal tooth tissue. This clinical report describes treatment of severe tooth wear of a gastroesophageal reflux disease patient who is 54-year-old Turkish male patient. After his medical treatment, severe tooth wear, bruxism and decreased vertical dimensions were determined. The vertical dimension was re-established and maxillary and mandibular anterior and posterior teeth were prepared for metal-ceramic restorations. Metal-ceramic fixed partial dentures were fabricated as full mouth restorations for both maxillary and mandibular arches because of splinting all teeth. And then maxillary stabilization splint was fabricated for his bruxism history. Significant loss of coronal tooth structure must taken into consideration. Gastroesophageal reflux disease by itself or in combination with attrition, abrasion or bruxism may be responsible for the loss. An extensive diagnostic evaluation is essential for the medical and dental effects of the problem.

Vitamin D status and incident cardiovascular disease and all-cause mortality

DEFF Research Database (Denmark)

Skaaby, Tea; Husemoen, Lise Lotte Nystrup; Pisinger, Charlotta

2013-01-01

Low vitamin D status has been associated with cardiovascular disease (CVD) and mortality primarily in selected groups, smaller studies, or with self-reported vitamin D intake. We investigated the association of serum vitamin D status with the incidence of a registry-based diagnosis of ischemic...... heart disease (IHD), stroke, and all-cause mortality in a large sample of the general population. A total of 9,146 individuals from the two population-based studies, Monica10 and Inter99, were included. Measurements of serum 25-hydroxyvitamin D at baseline were carried out using the IDS ISYS immunoassay...

First report of laurel wilt disease caused by Raffaelea lauricola on pondspice in Florida

Science.gov (United States)

M. Hughes; J.A. Smith; A.E. Mayfield III; M.C. Minno; K. Shin

2011-01-01

Laurel wilt is a fungal vascular disease of redbay (Persea borbonia (L.) Spreng) and other plants in the family Lauraceae in the southeastern United States (1). The disease is caused by Raffaelea lauricola T. C. Harr., Fraedrich & Aghayeva, which is vectored by the exotic redbay ambrosia beetle (Xyleborus glabratus...

Does radioiodine cause the ophthalmopathy of Graves' disease; Editorial

Energy Technology Data Exchange (ETDEWEB)

McDougall, I.R. (Stanford Univ., CA (United States). Medical Center)

1993-02-01

This editorial briefly reviews studies which might answer the question as to whether radioiodine treatment causes the ophthalmopathy of Graves' disease. However, the data do not allow any conclusion one way or the other. Other possible causal factors are discussed. Further studies are required to define whether treatment of hyperthyroidism aggravates the ophthalmopathy and whether one thereby is worse than the others and by how much. (UK).

Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

Science.gov (United States)

2015-01-10

Up-to-date evidence on levels and trends for age-sex-specific all-cause and cause-specific mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries between 1990, and 2013. We used the results to assess whether there is epidemiological convergence across countries. We estimated age-sex-specific all-cause mortality using the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data. We generally estimated cause of death as in the GBD 2010. Key improvements included the addition of more recent vital registration data for 72 countries, an updated verbal autopsy literature review, two new and detailed data systems for China, and more detail for Mexico, UK, Turkey, and Russia. We improved statistical models for garbage code redistribution. We used six different modelling strategies across the 240 causes; cause of death ensemble modelling (CODEm) was the dominant strategy for causes with sufficient information. Trends for Alzheimer's disease and other dementias were informed by meta-regression of prevalence studies. For pathogen-specific causes of diarrhoea and lower respiratory infections we used a counterfactual approach. We computed two measures of convergence (inequality) across countries: the average relative difference across all pairs of countries (Gini coefficient) and the average absolute difference across countries. To summarise broad findings, we used multiple decrement life-tables to decompose probabilities of death from birth to exact age 15 years, from exact age 15 years to exact age 50 years, and from exact age 50 years to exact age 75 years, and life expectancy at birth into major causes. For all quantities reported, we computed 95% uncertainty intervals (UIs). We constrained cause-specific fractions within each age-sex-country-year group to sum

The suggestion of common cause of disease, characteristics of human body, and medical treatment

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Byung-Jun Cho

2011-06-01

Full Text Available Objectives & Methods: This suggestion was attempted to be elevated the recognition of common characteristics in disease. So, we performed to analyze the correlation of common cause of disease, characteristics of human body, and medical treatment. And the results are as follows. Results: 1. The cause of disease is consist of genetic factor, aging, habit, food of not good in health, weather, environment, deficit of the physical activity, stress and so on. 2. Generally, human has common and individual weakness. Individual weakness is appeared similar to the occurrence of volcano and lapse. 3. The correlation of disease and medical treatments is possible to explain using the quotation of the law of motion made by Isaac Newton, the great physicist. 4. When the process of the medical treatment was not progressed, the prognosis is determined by the correlation of the homeostasis(H' in human body and the homeostasis(H of disease. 5. The prognosis of disease is determined by the relationship between the energy of disease(F and medical treatment(F'. 6. The exact diagnosis is possible to predict the treatment sequence, and the facts that homeostasis in human body and disease, relationship between the energy of disease(F and medical treatment(F', action and reaction are important to determine the prognosis. 7. The careful observation of improving response and worsening action of disease becomes available for exact prognosis. Conclusion: The above described contents may be useful in clinical studies, and the concrete clinical reports about this will be made afterward.

Quantifying cause-related mortality by weighting multiple causes of death

Science.gov (United States)

Moreno-Betancur, Margarita; Lamarche-Vadel, Agathe; Rey, Grégoire

2016-01-01

Abstract Objective To investigate a new approach to calculating cause-related standardized mortality rates that involves assigning weights to each cause of death reported on death certificates. Methods We derived cause-related standardized mortality rates from death certificate data for France in 2010 using: (i) the classic method, which considered only the underlying cause of death; and (ii) three novel multiple-cause-of-death weighting methods, which assigned weights to multiple causes of death mentioned on death certificates: the first two multiple-cause-of-death methods assigned non-zero weights to all causes mentioned and the third assigned non-zero weights to only the underlying cause and other contributing causes that were not part of the main morbid process. As the sum of the weights for each death certificate was 1, each death had an equal influence on mortality estimates and the total number of deaths was unchanged. Mortality rates derived using the different methods were compared. Findings On average, 3.4 causes per death were listed on each certificate. The standardized mortality rate calculated using the third multiple-cause-of-death weighting method was more than 20% higher than that calculated using the classic method for five disease categories: skin diseases, mental disorders, endocrine and nutritional diseases, blood diseases and genitourinary diseases. Moreover, this method highlighted the mortality burden associated with certain diseases in specific age groups. Conclusion A multiple-cause-of-death weighting approach to calculating cause-related standardized mortality rates from death certificate data identified conditions that contributed more to mortality than indicated by the classic method. This new approach holds promise for identifying underrecognized contributors to mortality. PMID:27994280

Socioeconomic inequalities in cause-specific mortality after disability retirement due to different diseases.

Science.gov (United States)

Polvinen, A; Laaksonen, M; Gould, R; Lahelma, E; Leinonen, T; Martikainen, P

2015-03-01

Socioeconomic inequalities in both disability retirement and mortality are large. The aim of this study was to examine socioeconomic differences in cause-specific mortality after disability retirement due to different diseases. We used administrative register data from various sources linked together by Statistics Finland and included an 11% sample of the Finnish population between the years 1987 and 2007. The data also include an 80% oversample of the deceased during the follow-up. The study included men and women aged 30-64 years at baseline and those who turned 30 during the follow-up. We used Cox regression analysis to examine socioeconomic differences in mortality after disability retirement. Socioeconomic differences in mortality after disability retirement were smaller than in the population in general. However, manual workers had a higher risk of mortality than upper non-manual employees after disability retirement due to mental disorders and cardiovascular diseases, and among men also diseases of the nervous system. After all-cause disability retirement, manual workers ran a higher risk of cardiovascular and alcohol-related death. However, among men who retired due to mental disorders or cardiovascular diseases, differences in social class were found for all causes of death examined. For women, an opposite socioeconomic gradient in mortality after disability retirement from neoplasms was found. Conclusions: The disability retirement process leads to smaller socioeconomic differences in mortality compared with those generally found in the population. This suggests that the disability retirement system is likely to accurately identify chronic health problems with regard to socioeconomic status. © 2014 the Nordic Societies of Public Health.

Fitness, work, and leisure-time physical activity and ischaemic heart disease and all-cause mortality among men with pre-existing cardiovascular disease

DEFF Research Database (Denmark)

Holtermann, Andreas; Mortensen, Ole Steen; Burr, Hermann

2010-01-01

Our aim was to study the relative impact of physical fitness, physical demands at work, and physical activity during leisure time on ischaemic heart disease (IHD) and all-cause mortality among employed men with pre-existing cardiovascular disease (CVD)....

Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013 : a systematic analysis for the Global Burden of Disease Study 2013

NARCIS (Netherlands)

Naghavi, Mohsen; Wang, Haidong; Lozano, Rafael; Davis, Adrian; Liang, Xiaofeng; Zhou, Maigeng; Vollset, Stein Emil; Ozgoren, Ayse Abbasoglu; Abdalla, Safa; Abd-Allah, Foad; Aziz, Muna I. Abdel; Abera, Semaw Ferede; Aboyans, Victor; Abraham, Biju; Abraham, Jerry P.; Abuabara, Katrina E.; Abubakar, Ibrahim; Abu-Raddad, Laith J.; Abu-Rmeileh, Niveen M. E.; Achoki, Tom; Adelekan, Ademola; Ademi, Zanfi Na; Adofo, Koranteng; Adou, Arsene Kouablan; Adsuar, Jose C.; Aernlov, Johan; Agardh, Emilie Elisabet; Akena, Dickens; Al Khabouri, Mazin J.; Alasfoor, Deena; Albittar, Mohammed; Alegretti, Miguel Angel; Aleman, Alicia V.; Alemu, Zewdie Aderaw; Alfonso-Cristancho, Rafael; Alhabib, Samia; Ali, Mohammed K.; Ali, Raghib; Alla, Francois; Al Lami, Faris; Allebeck, Peter; AlMazroa, Mohammad A.; Salman, Rustam Al-Shahi; Alsharif, Ubai; Alvarez, Elena; Alviz-Guzman, Nelson; Amankwaa, Adansi A.; Amare, Azmeraw T.; Ameli, Omid; Hoek, Hans W.

2015-01-01

Background Up-to-date evidence on levels and trends for age-sex-specifi c all-cause and cause-specifi c mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries

Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015

NARCIS (Netherlands)

Wang, Haidong; Naghavi, Mohsen; Allen, Christine; Barber, R.M.; Bhutta, Zulfiqar; Carter, Austin; Casey, Daniel C.; Charlson, Fiona J.; Chen, Alan Z.; Coates, M.; Geleijnse, J.M.

2016-01-01

Background
Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249

SERCA2 Haploinsufficiency in a Mouse Model of Darier Disease Causes a Selective Predisposition to Heart Failure

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Vikram Prasad

2015-01-01

Full Text Available Null mutations in one copy of ATP2A2, the gene encoding sarco/endoplasmic reticulum Ca2+-ATPase isoform 2 (SERCA2, cause Darier disease in humans, a skin condition involving keratinocytes. Cardiac function appears to be unimpaired in Darier disease patients, with no evidence that SERCA2 haploinsufficiency itself causes heart disease. However, SERCA2 deficiency is widely considered a contributing factor in heart failure. We therefore analyzed Atp2a2 heterozygous mice to determine whether SERCA2 haploinsufficiency can exacerbate specific heart disease conditions. Despite reduced SERCA2a levels in heart, Atp2a2 heterozygous mice resembled humans in exhibiting normal cardiac physiology. When subjected to hypothyroidism or crossed with a transgenic model of reduced myofibrillar Ca2+-sensitivity, SERCA2 deficiency caused no enhancement of the disease state. However, when combined with a transgenic model of increased myofibrillar Ca2+-sensitivity, SERCA2 haploinsufficiency caused rapid onset of hypertrophy, decompensation, and death. These effects were associated with reduced expression of the antiapoptotic Hax1, increased levels of the proapoptotic genes Chop and Casp12, and evidence of perturbations in energy metabolism. These data reveal myofibrillar Ca2+-sensitivity to be an important determinant of the cardiac effects of SERCA2 haploinsufficiency and raise the possibility that Darier disease patients are more susceptible to heart failure under certain conditions.

Documentation of Occupational Accidents and Diseases caused by Ionising Radiation

International Nuclear Information System (INIS)

Fehringer, F.; Seitz, G.

2004-01-01

. One of the major goals of the institutions for statutory accident insurance is the prevention of occupational diseases. To perform a successful prevention work it is necessary not only to count the number of accidents or diseases in the various working fields but to look for details of the conditions of work and the human response to those conditions. The institutions for statutory accident insurance have engaged the institution for statutory accident insurance in the precision engineering and electrical industry to carry out documentation, in form of a data bank, for all cases of occupational diseases which could be caused by ionising radiation. Those are not only the cases which are accepted as occupational disease but also the cases where a suspicion of an occupational disease is announced but finally rejected. At the moment about 1700 cases are included in the data bank. For preserving the anonymity information to name and residence are deleted. Various data to one single case are linked by a case-specific key-number. Information to occupation and field of working, to details of a possible exposure to ionising radiation like kind of radiation, time and duration of radiation, exposure of the whole body or of parts of the body and whole body or organ doses are collected. Additional information refers to medical aspects like diagnosis and date of diagnosis. (Author)

Xanthomonas euvesicatoria Causes Bacterial Spot Disease on Pepper Plant in Korea

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Min-Seong Kyeon

2016-10-01

Full Text Available In 2004, bacterial spot-causing xanthomonads (BSX were reclassified into 4 species—Xanthomonas euvesicatoria, X. vesicatoria, X. perforans, and X. gardneri. Bacterial spot disease on pepper plant in Korea is known to be caused by both X. axonopodis pv. vesicatoria and X. vesicatoria. Here, we reidentified the pathogen causing bacterial spots on pepper plant based on the new classification. Accordingly, 72 pathogenic isolates were obtained from the lesions on pepper plants at 42 different locations. All isolates were negative for pectolytic activity. Five isolates were positive for amylolytic activity. All of the Korean pepper isolates had a 32 kDa-protein unique to X. euvesicatoria and had the same band pattern of the rpoB gene as that of X. euvesicatoria and X. perforans as indicated by PCR-restriction fragment length polymorphism analysis. A phylogenetic tree of 16S rDNA sequences showed that all of the Korean pepper plant isolates fit into the same group as did all the reference strains of X. euvesicatoria and X. perforans. A phylogenetic tree of the nucleotide sequences of 3 housekeeping genes—gapA, gyrB, and lepA showed that all of the Korean pepper plant isolates fit into the same group as did all of the references strains of X. euvesicatoria. Based on the phenotypic and genotypic characteristics, we identified the pathogen as X. euvesicatoria. Neither X. vesicatoria, the known pathogen of pepper bacterial spot, nor X. perforans, the known pathogen of tomato plant, was isolated. Thus, we suggest that the pathogen causing bacterial spot disease of pepper plants in Korea is X. euvesicatoria.

Spot Anthracnose Disease Caused by Colletotrichum gloeosporioides on Tulip Tree in Korea.

Science.gov (United States)

Choi, Okryun; Choi, Okhee; Kwak, Youn-Sig; Kim, Jinwoo; Kwon, Jin-Hyeuk

2012-03-01

The tulip tree (Liriodendron chinense) has been widely cultivated in Korea as a street or garden tree for its large flowers, which have a superficial resemblance to tulips. Occurrence of anthracnose disease on the leaves of tulip trees growing on the campus of Gyeongsang National University, Jinju, Korea, has been observed. Based on mycological characteristics, pathogenicity, and internal transcribed spacer sequence, the causal fungus was identified as Colletotrichum gloeosporioides. This is the first report on anthracnose disease caused by C. gloeosporioides on tulip trees in Korea.

S-phase-dependent cell cycle disturbances caused by Aleutian mink disease parvovirus

DEFF Research Database (Denmark)

Oleksiewicz, M.B.; Alexandersen, Søren

1997-01-01

We examined replication of the autonomous parovirus Aleutian mink disease parovirus (ADV) in relation to cell cycle progression of permissive Crandell feline kidney (CRFK) cells. Flow cytometric analysis showed that ADV caused a composite, binary pattern of cell cycle arrest. ADV-induced cell cyc...

Cerebrovascular and hypertensive diseases as multiple causes of death in Brazil from 2004 to 2013.

Science.gov (United States)

Villela, P B; Klein, C H; Oliveira, G M M

2018-06-02

The proportion of deaths attributed to hypertensive diseases (HYPDs) was only 50% of that registered for cerebrovascular diseases (CBVDs) in 2013 in Brazil. This article aims to evaluate mortality related to HYPDs and CBVDs as multiple causes of death, in Brazil from 2004 to 2013. Analysis of historical series of secondary data obtained from Brazilian official registries. Data about the deaths were obtained from the Mortality Information System of the Brazilian Ministry of Health, available on the DATASUS website. CBVDs and HYPDs were evaluated according to their mentions as the underlying cause of death or entry in any line of the death certificates (DCs), according to their International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes. When CBVDs were the underlying causes of death, HYPDs were mentioned in 40.9% of the DCs. When HYPDs were the underlying causes of death, CBVDs were mentioned in only 5.0%. When CBVDs were mentioned without HYPDs, they were selected as the underlying cause of death 74.4% of the time. When HYPDs were mentioned in DCs without CBVDs, HYPDs were selected 30.0% of the time. In 2004, the frequency of any mention of HYPDs relative to the frequency of HYPDs cited as underlying causes increased fourfold and was followed by a plateau until 2013. In contrast, the frequency of any mention of CBVDs relative to the frequency of CBVDs as underlying causes decreased in the same period. Because this study was based on DC records, it was limited by the way these documents were completed, which may have included lack of record of the causes related to the sequence that culminated in death. When deaths related to HYPDs were evaluated as multiple causes of death, they were mentioned up to four times more often than when they were selected as underlying causes of death. This reinforces the need for better control of hypertension to prevent deaths. Copyright © 2018 The Royal Society for Public Health. Published by

Thiopurines, a previously unrecognised cause for fatigue in patients with inflammatory bowel disease.

Science.gov (United States)

Lee, Thomas W T; Iser, John H; Sparrow, Miles P; Newnham, Evan D; Headon, Belinda J; Gibson, Peter R

2009-09-01

Active inflammatory bowel disease, anaemia, iron deficiency and depression, alone or in combination, are known contributing factors of fatigue in inflammatory bowel disease. However, in some patients, fatigue cannot be attributed to known causes. Thiopurines are not a recognized cause. To describe the clinical scenario of a series of patients where thiopurines were the likely cause of fatigue. The clinical scenario of 5 patients was examined with specific reference to the temporal association of thiopurine therapy with fatigue, the effect of its withdrawal and rechallenge, and drug specificity. The onset of severe fatigue was related to the introduction of azathioprine or 6-mercaptopurine, rapid relief was experienced on its withdrawal in all patients, and fatigue rapidly occurred on rechallenge. The speed of onset was rapid in two patients and in the context of gradual withdrawal of moderate steroid dose, but recurred rapidly on rechallenge when not on steroids. Marked fatigue is a previously unrecognized adverse effect of thiopurines. It does not appear to be drug-specific. Its onset might be masked by concurrent steroid therapy.

Loss of stability and hydrophobicity of presenilin 1 mutations causing Alzheimer's Disease

DEFF Research Database (Denmark)

Somavarapu, Arun Kumar; Kepp, Kasper Planeta

2016-01-01

Nearly 200 mutations in the gene coding for presenilin 1 (PSEN1) cause early-onset Alzheimer's Disease, yet the molecular mechanism remains obscure. As a meta-analysis, we compiled available clinical and biochemical data for PSEN1 variants and correlated these to chemical properties of the mutant...

The Nature and Causes of Chronic Obstructive Pulmonary Disease: A Historical Perspective

Directory of Open Access Journals (Sweden)

C Peter W Warren

2009-01-01

Full Text Available Chronic obstructive pulmonary disease (COPD is the currently favoured name for the diseases formerly known as emphysema and bronchitis. COPD has been recognized for more than 200 years. Its cardinal symptoms are cough, phlegm and dyspnea, and its pathology is characterized by enlarged airspaces and obstructed airways. In the 19th century, the diagnosis of COPD depended on its symptoms and signs of a hyperinflated chest, and reduced expiratory breath sounds. The airflow obstruction evident on spirometry was identified in that century, but did not enter into clinical practice. Bronchitis, and the mechanical forces required to overcome its obstruction, was believed to be responsible for emphysema, although the inflammation present was recognized. The causes of bronchitis, and hence emphysema, included atmospheric and domestic air pollution, as well as dusty occupations. Cigarette smoking only became recognized as the dominant cause in the 20th century. The lessons learned of the risks for COPD in 19th-century Britain are very pertinent to the world today.

Differences in relative amounts of two novel mutant HEXA transcripts in a juvenile TSD Druze patient

Energy Technology Data Exchange (ETDEWEB)

Drucker, L.; Navon, R. [Tel Aviv Univ. (Israel)]|[Sapir Medical Center, Kfar Sava (Israel)

1994-09-01

An Israeli-Druze patient with juvenile Tay-Sachs disease, born to first cousins, was found to be a compound heterozygote for two novel mutant HEXA alleles. SSCP analysis of the parents` genomic DNA revealed alterations in both exons 5 and 8. Direct sequencing showed a novel missense mutation T{sup 835}{r_arrow}C (Ser{sup 279}{r_arrow}Pro) in exon 8, of maternal origin. The mutant allele of paternal origin carried a novel double mutation in exon 5, (i) a C{sup 496} deletion, resulting in a frameshift and eventually a stop codon, (ii) a C{sup 496}{r_arrow}G transition which is a silent mutation. Both these latter mutations occur in the same codon. New restriction sites for ScrFI were introduced into the two mutant alleles, enabling rapid screening for their presence. In order to detect differences of the relative levels of the transcripts originating from the two mutant alleles, we applied allele-specific transcripts polymerase chain reaction (AST-PCR) to the RNA extractions prepared from the heterozygous parents (each carry a normal and mutant allele). In order to distinguish between the transcripts originating from the normal allele and those originating from each of the mutant alleles, the transcripts were digested by ScrFI. A severe depletion of the mRNA coded by the allele carrying the mutation in exon 5 was found. The phenomena corresponds with citations in the literature in cases of stop mutations. The allele carrying the transversion in exon 8, contrary to our expectations, also had a distinctly lower level of transcripts. The AST-PCR approach offers a molecular tool to study allele-specific gene expression in heterozygous individuals.

Citrus leprosis virus N: A New Dichorhavirus Causing Citrus Leprosis Disease.

Science.gov (United States)

Ramos-González, Pedro Luis; Chabi-Jesus, Camila; Guerra-Peraza, Orlene; Tassi, Aline Daniele; Kitajima, Elliot Watanabe; Harakava, Ricardo; Salaroli, Renato Barbosa; Freitas-Astúa, Juliana

2017-08-01

Citrus leprosis (CL) is a viral disease endemic to the Western Hemisphere that produces local necrotic and chlorotic lesions on leaves, branches, and fruit and causes serious yield reduction in citrus orchards. Samples of sweet orange (Citrus × sinensis) trees showing CL symptoms were collected during a survey in noncommercial citrus areas in the southeast region of Brazil in 2013 to 2016. Transmission electron microscopy analyses of foliar lesions confirmed the presence of rod-like viral particles commonly associated with CL in the nucleus and cytoplasm of infected cells. However, every attempt to identify these particles by reverse-transcription polymerase chain reaction tests failed, even though all described primers for the detection of known CL-causing cileviruses and dichorhaviruses were used. Next-generation sequencing of total RNA extracts from three symptomatic samples revealed the genome of distinct, although highly related (>92% nucleotide sequence identity), viruses whose genetic organization is similar to that of dichorhaviruses. The genome sequence of these viruses showed trees and those used for the transmission of one of the characterized isolates to Arabidopsis plants were anatomically recognized as Brevipalpus phoenicis sensu stricto. Molecular and biological features indicate that the identified viruses belong to a new species of CL-associated dichorhavirus, which we propose to call Citrus leprosis N dichorhavirus. Our results, while emphasizing the increasing diversity of viruses causing CL disease, lead to a reevaluation of the nomenclature of those viruses assigned to the genus Dichorhavirus. In this regard, a comprehensive discussion is presented.

17 CFR 240.17Ad-18 - Year 2000 Reports to be made by certain transfer agents.

Science.gov (United States)

2010-04-01

... non-bank transfer agent must file Part I of Form TA-Y2K (§ 249.619 of this chapter) with the Commission describing the transfer agent's preparation for Year 2000 Problems. Part I of Form TA-Y2K shall be filed no later than August 31, 1998, and April 30, 1999. Part I of Form TA-Y2K shall reflect the...

[Occupational diseases caused by ionizing radiation in Poland, 1971-2006].

Science.gov (United States)

Wilczyńska, Urszula; Szeszenia-Dabrowska, Neonila

2008-01-01

The whole spectrum of disorders of the hematopoietic tissue, eye and skin induced by ionizing radiation covers complex pathologies termed as a postirradiation syndrome, as well as various malignancies. The aim of this work is to present the data on incidence of occupational diseases with ionizing radiation as a causative agent. The work is based on the data compiled from "Occupational Diseases Reporting Forms" for the years 1971-2006 collected in the Central Register of Occupational Diseases. The incidence of certified occupational diseases with ionizing radiation as a causative agent is expressed in absolute numbers and the rate per 100 000 employees. The data comprise information on disease entities, gender, age, exposure duration and the branch of national economy. In total, 599 diseases (0.2% of all occupational diseases) were diagnosed as those induced by ionizong radiation. Annual incidence rates per 100,000 employees fell within the range of 0.0-0.7. Miners formed the major (51.9%) occupational group affected by ionizing radiation. They were followed by health care (34.3%) and construction (6.4%) workers. Cancers made over 50% of pathologies located at 28 sites. These included cancers of lung (59.2%), skin (10.0%) and hematopoietic tissue (8.7%). Almost all (99.35) diseases recorded in the mining industry were cancers. Non-cancer diseases were more frequent in health care workers, among them postradiation cataract occupied the first place. A great deal of reported cancer sites give rise to controversy in terms of the cause-effect association with ionizing radiation exposure and also due to incomplete data on exposure level. Postradiation cancers among health care workers have not been registered over recent years, which means that occupational exposure surveillance carried out for many years proves to be effective. Distant effects of exposure to ionizing radiation, revealed in workers of no longer existing uranium mine, appeared to be a particular problem

Occupational Diseases Caused by Ionizing Radiation in Poland, 1971-2006

International Nuclear Information System (INIS)

Wilczynska, U.; Szeszenia-Dabrowska, N.

2008-01-01

The whole spectrum of disorders of the hematopoietic tissue, eye and skin induced by ionizing radiation covers complex pathologies termed as a postirradiation syndrome, as well as various malignancies. The aim of this work is to present the data on incidence of occupational diseases with ionizing radiation as a causative agent. The work is based on the data compiled from 'Occupational Diseases Reporting Forms' for the years 1971-2006 collected in the Central Register of Occupational Diseases. The incidence of certified occupational diseases with ionizing radiation as a causative agent is expressed in absolute numbers and the rate per 100 000 employees. The data comprise information on disease entities, gender, age, exposure duration and the branch of national economy. In total, 599 diseases (0.2% of all occupational diseases) were diagnosed as those induced by ionizing radiation. Annual incidence rates per 100 000 employees fell within the range of 0.0-0.7. Miners formed the major (51.9%) occupational group affected by ionizing radiation. They were followed by health care (34.3%) and construction (6.4%) workers. Cancers made over 50% of pathologies located at 28 sites. These included cancers of lung (59.2%), skin (10.0%) and hematopoietic tissue (8.7%). Almost all (99.35) diseases recorded in the mining industry were cancers. Non-cancer diseases were more frequent in health care workers, among them postradiation cataract occupied the first place. A great deal of reported cancer sites give rise to controversy in terms of the cause-effect association with ionizing radiation exposure and also due to incomplete data on exposure duration. Postradiation cancers among health care workers have not been registered over recent years, which means that occupational exposure surveillance carried out for many years proves to be effective. Distant effects of exposure to ionizing radiation, revealed in workers of no longer existing uranium mine, appeared to be a particular problem

Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015

DEFF Research Database (Denmark)

Roth, Gregory A; Johnson, Catherine; Abajobir, Amanuel

2017-01-01

BACKGROUND: The burden of cardiovascular diseases (CVDs) remains unclear in many regions of the world. OBJECTIVES: The GBD (Global Burden of Disease) 2015 study integrated data on disease incidence, prevalence, and mortality to produce consistent, up-to-date estimates for cardiovascular burden......-income countries. Ischemic heart disease was the leading cause of CVD health lost globally, as well as in each world region, followed by stroke. As SDI increased beyond 0.25, the highest CVD mortality shifted from women to men. CVD mortality decreased sharply for both sexes in countries with an SDI >0...... be used to guide policymakers who are focused on reducing the overall burden of noncommunicable disease and achieving specific global health targets for CVD....

pia

African Journals Online (AJOL)

Dessie et al., 2003). Rearing of scavenging chickens is constrained especially by disease and predation problems (Takele Taye and Oli Wakeyo, 2011). In recent years in connection with the growing poultry sector, coccidiosis is receiving due attention. And because of this it is becoming among the researchable areas.

Parasitic diseases as the cause of death of prisoners of war during the Korean War (1950-1953).

Science.gov (United States)

Huh, Sun

2014-06-01

To determine the cause of death of prisoners of war during the Korean War (1950-1953), death certificates or medical records were analyzed. Out of 7,614 deaths, 5,013 (65.8%) were due to infectious diseases. Although dysentery and tuberculosis were the most common infectious diseases, parasitic diseases had caused 14 deaths: paragonimiasis in 5, malaria in 3, amoebiasis in 2, intestinal parasitosis in 2, ascariasis in 1, and schistosomiasis in 1. These results showed that paragonimiasis, malaria, and amoebiasis were the most fatal parasitic diseases during the early 1950s in the Korean Peninsula. Since schistosomiasis is not endemic to Korea, it is likely that the infected private soldier moved from China or Japan to Korea.

Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.

Science.gov (United States)

Herrera, Raúl; Orantes, Carlos M; Almaguer, Miguel; Alfonso, Pedro; Bayarre, Héctor D; Leiva, Irma M; Smith, Magaly J; Cubias, Ricardo A; Torres, Carlos G; Almendárez, Walter O; Cubias, Francisco R; Morales, Fabrizio E; Magaña, Salvador; Amaya, Juan C; Perdomo, Edgard; Ventura, Mercedes C; Villatoro, Juan F; Vela, Xavier F; Zelaya, Susana M; Granados, Delmy V; Vela, Eduardo; Orellana, Patricia; Hevia, Reynaldo; Fuentes, E Jackeline; Mañalich, Reinaldo; Bacallao, Raymed; Ugarte, Mario; Arias, María I; Chávez, Jackelin; Flores, Nelson E; Aparicio, Claudia E

2014-04-01

Chronic kidney disease is a serious health problem in El Salvador. Since the 1990s, there has been an increase in cases unassociated with traditional risk factors. It is the second leading cause of death in men aged >18 years. In 2009, it was the first cause of in-hospital death for men and the fifth for women. The disease has not been thoroughly studied. Characterize clinical manifestations (including extrarenal) and pathophysiology of chronic kidney disease of nontraditional causes in Salvadoran farming communities. A descriptive clinical study was carried out in 46 participants (36 men, 10 women), identified through chronic kidney disease population screening of 5018 persons. Inclusion criteria were age 18-59 years; chronic kidney disease at stages 2, 3a and 3b, or at 3a and 3b with diabetes or hypertension and without proteinuria; normal fundoscopic exam; no structural abnormalities on renal ultrasound; and HIV-negative. Examinations included social determinants; psychological assessment; clinical exam of organs and systems; hematological and biochemical parameters in blood and urine; urine sediment analysis; markers of renal damage; glomerular and tubular function; and liver, pancreas and lung functions. Renal, prostate and gynecological ultrasound; and Doppler echocardiography and peripheral vascular and renal Doppler ultrasound were performed. Patient distribution by chronic kidney disease stages: 2 (32.6%), 3a (23.9%), 3b (43.5%). Poverty was the leading social determinant observed. Risk factor prevalence: agrochemical exposure (95.7%), agricultural work (78.3%), male sex (78.3%), profuse sweating during work (76.3%), malaria (43.5%), NSAID use (41.3%), hypertension (36.9%), diabetes (4.3%). General symptoms: arthralgia (54.3%), asthenia (52.2%), cramps (45.7%), fainting (30.4). Renal symptoms: nycturia (65.2%), dysuria (39.1%), foamy urine (63%). Markers of renal damage: macroalbuminuria (80.4%), ß2 microglobulin (78.2%), NGAL (26.1%). Renal function

How the factoid of wind turbines causing 'vibroacoustic disease' came to be 'irrefutably demonstrated'.

Science.gov (United States)

Chapman, Simon; St George, Alexis

2013-06-01

In recent years, claims have proliferated in cyberspace that wind turbines cause a large variety of symptoms and diseases. One of these, "vibroacoustic disease" (VAD) is frequently mentioned. The aim of this study is to examine the quality of the evidence on how VAD came to be associated with wind turbine exposure by wind farm opponents. Searches of the web (Google advanced) and major research databases for papers on VAD and wind turbines. Self-citation analysis of research papers on VAD. Google returned 24,700 hits for VAD and wind turbines. Thirty-five research papers on VAD were found, none reporting any association between VAD and wind turbines. Of the 35 papers, 34 had a first author from a single Portuguese research group. Seventy-four per cent of citations to these papers were self-citations by the group. Median self-citation rates in science are around 7%. Two unpublished case reports presented at conferences were found asserting that VAD was "irrefutably demonstrated" to be caused by wind turbines. The quality of these reports was abject. VAD has received virtually no scientific recognition beyond the group who coined and promoted the concept. There is no evidence of even rudimentary quality that vibroacoustic disease is associated with or caused by wind turbines. The claim that wind turbines cause VAD is a factoid that has gone 'viral' in cyberspace and may be contributing to nocebo effects among those living near turbines. © 2013 The Authors. ANZJPH © 2013 Public Health Association of Australia.

Traffic air pollution and mortality from cardiovascular disease and all causes: a Danish cohort study.

Science.gov (United States)

Raaschou-Nielsen, Ole; Andersen, Zorana Jovanovic; Jensen, Steen Solvang; Ketzel, Matthias; Sørensen, Mette; Hansen, Johnni; Loft, Steffen; Tjønneland, Anne; Overvad, Kim

2012-09-05

Traffic air pollution has been linked to cardiovascular mortality, which might be due to co-exposure to road traffic noise. Further, personal and lifestyle characteristics might modify any association. We followed up 52 061 participants in a Danish cohort for mortality in the nationwide Register of Causes of Death, from enrollment in 1993-1997 through 2009, and traced their residential addresses from 1971 onwards in the Central Population Registry. We used dispersion-modelled concentration of nitrogen dioxide (NO₂) since 1971 as indicator of traffic air pollution and used Cox regression models to estimate mortality rate ratios (MRRs) with adjustment for potential confounders. Mean levels of NO₂ at the residence since 1971 were significantly associated with mortality from cardiovascular disease (MRR, 1.26; 95% confidence interval [CI], 1.06-1.51, per doubling of NO₂ concentration) and all causes (MRR, 1.13; 95% CI, 1.04-1.23, per doubling of NO₂ concentration) after adjustment for potential confounders. For participants who ate fruit and vegetables per day, the MRR was 1.45 (95% CI, 1.13-1.87) for mortality from cardiovascular disease and 1.25 (95% CI, 1.11-1.42) for mortality from all causes. Traffic air pollution is associated with mortality from cardiovascular diseases and all causes, after adjustment for traffic noise. The association was strongest for people with a low fruit and vegetable intake.

Identification and Chacterization of new strains of Enterobacter spp. causing Mulberry (Morus alba) wilt disease in China

Science.gov (United States)

A new mulberry wilt disease (MWD) was recently identified in Hangzhou, Zhejiang province, China. Typical symptoms of the disease are dark brown discolorations in vascular tissues, leaf wilt, defoliation, and tree decline. Unlike the bacterial wilt disease caused by Ralstonia solanacearum, the leaf w...

Evaluation of sugarcane introgression lines for resistance to brown rust disease caused by Puccinia melanocephala

OpenAIRE

Wang, Xiao-Yan; Wen-Feng, Li; Ying-Kun, Huang; Xin, Lu; Zhi-Ming, Luo; Jiong, Yin; Hong-Li, Shan; Rong-Yue, Zhang

2013-01-01

Sugarcane brown rust disease caused by Puccinia melanocephala is one of the important fungal diseases affecting sugarcane yield around the world. Cultivar resistance is the most appropriate control method for this disease. In this study, 62 introgression lines chosen from the crossing Saccharum officinarum L. cv. Ludashi x Erianthus rockii Yunnan 95-19 were evaluated for brown rust resistance using artificial inoculation. More than 30% of the introgression lines were identified as resistant. ...

Dehydration as a Cause of Chronic Kidney Disease: Role of Fructokinase

Science.gov (United States)

2016-10-01

hyperfiltration and albuminuria in humans and laboratory animals (2- 4). In this study we sought to examine the role of vasopressin in our heat stress...and Use of Laboratory Animals . The animal protocol was approved by the Animal Care and Use Committee of the University of Colorado. Biochemical...SUPPLEMENTARY NOTES 14. ABSTRACT Our studies evaluate how recurrent dehydration can cause chronic kidney disease, an important question for the

Assessing the burden of medical impoverishment by cause: a systematic breakdown by disease in Ethiopia.

Science.gov (United States)

Verguet, Stéphane; Memirie, Solomon Tessema; Norheim, Ole Frithjof

2016-10-21

Out-of-pocket (OOP) medical expenses often lead to catastrophic expenditure and impoverishment in low- and middle-income countries. Yet, there has been no systematic examination of which specific diseases and conditions (e.g., tuberculosis, cardiovascular disease) drive medical impoverishment, defined as OOP direct medical costs pushing households into poverty. We used a cost and epidemiological model to propose an assessment of the burden of medical impoverishment in Ethiopia, i.e., the number of households crossing a poverty line due to excessive OOP direct medical expenses. We utilized disease-specific mortality estimates from the Global Burden of Disease study, epidemiological and cost inputs from surveys, and secondary data from the literature to produce a count of poverty cases due to OOP direct medical costs per specific condition. In Ethiopia, in 2013, and among 20 leading causes of mortality, we estimated the burden of impoverishment due to OOP direct medical costs to be of about 350,000 poverty cases. The top three causes of medical impoverishment were diarrhea, lower respiratory infections, and road injury, accounting for 75 % of all poverty cases. We present a preliminary attempt for the estimation of the burden of medical impoverishment by cause for high mortality conditions. In Ethiopia, medical impoverishment was notably associated with illness occurrence and health services utilization. Although currently used estimates are sensitive to health services utilization, a systematic breakdown of impoverishment due to OOP direct medical costs by cause can provide important information for the promotion of financial risk protection and equity, and subsequent design of health policies toward universal health coverage, reduction of direct OOP payments, and poverty alleviation.

Hyposplenism as a cause of pneumococcal meningoencephalitis in an adult patient with coeliac disease

Directory of Open Access Journals (Sweden)

Paolo Caraceni

2013-03-01

Full Text Available Introduction: Coeliac disease can be associated with hyposplenism and splenic atrophy, which may increase the patient’s risk for fatal infections caused by Streptococcus pneumoniae or Pneumococcus. It is general opinion that many more patients with coeliac disease have died from hyposplenism-related infections than those reported in literature. Case report: A 62-year-old woman with recently diagnosed coeliac disease was hospitalized with high fever, disorientation, and nuchal rigidity. Cerebral computed tomography was negative. Laboratory tests showed an elevated leukocyte count and very high levels of C reactive protein. The cerebrospinal fluid (CSF contained an increased number of mononuclear cells associated with a low glucose level and high protein concentrations. The CSF culture was positive for Streptococcus pneumoniae. Neurological conditions rapidly deteriorated with the onset of coma, and magnetic resonance imaging of the brain revealed initial signs of encephalitis extending above and below the tentorium. Abdominal ultrasonography disclosed splenic hypotrophy that raised the suspicion of hyposplenism. The diagnosis of hyposplenism was confirmed by demonstration of Howell-Jolly bodies in a peripheral blood smear. Discussion: This is the first reported case of pneumococcal meningoencephalitis caused by splenic hypofunction in a patient with coeliac disease. When coeliac disease is diagnosed with a marked delay in an elderly patient, spleen function should always be assessed. If impaired, the patient should undergo vaccination with pneumococcal conjugate vaccine to prevent pneumococcal infections.

Changes in causes of death and risk of cancer in Danish patients with autosomal dominant polycystic kidney disease and end-stage renal disease.

Science.gov (United States)

Orskov, Bjarne; Sørensen, Vibeke Rømming; Feldt-Rasmussen, Bo; Strandgaard, Svend

2012-04-01

With the improved prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD), causes of death and the risk of cancer might have changed. This was investigated in a Danish population with ADPKD and end-stage renal disease (ESRD) between 1 January 1993 and 31 December 2008. Data were retrieved from three Danish national registries and a total of 823 patients were identified of which 431 had died during the study period. The 16 years were divided into two 8-year periods and the causes of death were divided into six categories: cancer, cardiovascular, cerebrovascular, infection, other and unknown. Cardiovascular disease was the major cause of death. A multivariate competing risk model comparing the two 8-year periods, adjusted for age at ESRD, gender and treatment modality, showed that deaths from cardiovascular disease decreased by 35% [hazard ratios (HR) 0.65, P=0.008] and deaths from cerebrovascular disease decreased by 69% (HR 0.31, P=0.0003) from the first to the second time period. There were no significant changes between the time periods in death from cancer, infection, other or unknown. From the first to the second 8-year interval, the prevalence of cancer increased by 35% (P=0.0002) while the cancer incidence was stable. In Danish patients with ADPKD and ESRD, there was a significant reduction in cardiovascular and cerebrovascular deaths from 1993 to 2008. The prevalence of cancer increased without significant change in cancer incidence or deaths from cancer.

Obstructive sleep apnea syndrome as a novel cause for Ménière's disease.

Science.gov (United States)

Nakayama, Meiho; Kabaya, Kayoko

2013-10-01

Several recent reports have described the relation between sleep disorders and inner ear function. There are also many reports that insomnia is observed in Ménière's patients. However, the possibility that obstructive sleep apnea syndrome (OSAS) might affect Ménière's disease or other neurotological consequences was not noticed, until studies using polysomnography for these patients. OSAS may cause not only vestibular but also auditory dysfunction. Several reports suggest that insufficient supply of blood via the vertebral basilar artery, which supplies the inner ear, may cause hydropic distension of the endolymphatic system and lead to Ménière's disease. However, few people noticed that in OSAS this insufficient supply might be exacerbated in the night while patients are sleeping. Even more, we should note that Ménière's patients may not only suffer from insomnia, but also that the impaired sleep might be caused by OSAS. Physicians routinely prescribe benzodiazepines or other drugs that have hypnotic, muscle relaxing, antianxiety, and anticonvulsant properties for insomnia, but these properties may have the effect of aggravating OSAS symptoms. Continuous positive airway pressure (CPAP) is an effective therapy used worldwide for the treatment of OSAS. CPAP or surgeries for OSAS may also be useful as one aspect of treatment for Ménière's disease patients with OSAS.

The glucocerobrosidase E326K variant predisposes to Parkinson's disease, but does not cause Gaucher's disease.

Science.gov (United States)

Duran, Raquel; Mencacci, Niccolo E; Angeli, Aikaterini V; Shoai, Maryam; Deas, Emma; Houlden, Henry; Mehta, Atul; Hughes, Derralynn; Cox, Timothy M; Deegan, Patrick; Schapira, Anthony H; Lees, Andrew J; Limousin, Patricia; Jarman, Paul R; Bhatia, Kailash P; Wood, Nicholas W; Hardy, John; Foltynie, Tom

2013-02-01

Heterozygous loss-of-function mutations in the acid beta-glucocerebrosidase (GBA1) gene, responsible for the recessive lysosomal storage disorder, Gaucher's disease (GD), are the strongest known risk factor for Parkinson's disease (PD). Our aim was to assess the contribution of GBA1 mutations in a series of early-onset PD. One hundred and eighty-five PD patients (with an onset age of ≤50) and 283 age-matched controls were screened for GBA1 mutations by Sanger sequencing. We show that the frequency of GBA1 mutations is much higher in this patient series than in typical late-onset patient cohorts. Furthermore, our results reveal that the most prevalent PD-associated GBA1 mutation is E326K, a variant that does not, when homozygous, cause GD. Our results confirm recent reports that the mutation, E326K, predisposes to PD and suggest that, in addition to reduced GBA1 activity, other molecular mechanisms may contribute to the development of the disease. Copyright © 2012 Movement Disorders Society.

Causes and risk factors of falls in patients with Parkinson's disease.

Science.gov (United States)

Rudzińska, Monika; Bukowczan, Sylwia; Banaszkiewicz, Krzysztof; Stozek, Joanna; Zajdel, Katarzyna; Szczudlik, Andrzej

2008-01-01

Falls are a common and serious problem among Parkinson's disease (PD) patients. However, knowledge about the causes and risk factors of falls is limited. There have been a few attempts to classify the causes of falls. The classification suggested by Olanow seems to be the most comprehensive one. The aim of this study was to analyze retrospectively the causes of falls and risk factors of falls in PD patients. One hundred and four patients with moderately advanced PD were included in the study. The patients were asked to describe the circumstances and consequences of falls which occurred during 12 months preceding the examination. The falls were classified according to the Olanow classification of causes of falls. Fifty-two patients (50%) reported at least one fall during the previous year with a mean number of 1.5 falls per year. The most common causes of falls were environmental factors, sudden falls and postural instability. There were no falls caused by severe dyskinesia, drugs or cardiovascular disorders. The only independent risk factors of the recurrent falls identified in this study were UPDRS part II score (OR 1.17, 95% CI: 1.02-1.37) and Mini Mental State Examination score (OR 0.85, 95% CI: 0.72-0.99). Considering these results we may be able to prevent most falls by means of the education of patients about environmental factors and using adequate rehabilitation techniques concentrating on postural stability and gait.

Pinpointing Synaptic Loss Caused by Alzheimer?s Disease with fMRI

OpenAIRE

Brickman, Adam M.; Small, Scott A.; Fleisher, Adam

2009-01-01

During its earliest stage, before cell loss and independent of amyloid plaques and neurofibrillary tangles, Alzheimer's disease (AD) causes synaptic loss affecting the basal functional properties of neurons. In principle, synaptic loss can be detected by measuring AD-induced changes in basal function, or by measuring stimulus-evoked responses on top of basal changes. Functional magnetic resonance imaging (fMRI) is sensitive to both basal changes and evoked-responses, and there are therefore t...

Causes of Death Data in the Global Burden of Disease Estimates for Ischemic and Hemorrhagic Stroke.

Science.gov (United States)

Truelsen, Thomas; Krarup, Lars-Henrik; Iversen, Helle K; Mensah, George A; Feigin, Valery L; Sposato, Luciano A; Naghavi, Mohsen

2015-01-01

Stroke mortality estimates in the Global Burden of Disease (GBD) study are based on routine mortality statistics and redistribution of ill-defined codes that cannot be a cause of death, the so-called 'garbage codes' (GCs). This study describes the contribution of these codes to stroke mortality estimates. All available mortality data were compiled and non-specific cause codes were redistributed based on literature review and statistical methods. Ill-defined codes were redistributed to their specific cause of disease by age, sex, country and year. The reassignment was done based on the International Classification of Diseases and the pathology behind each code by checking multiple causes of death and literature review. Unspecified stroke and primary and secondary hypertension are leading contributing 'GCs' to stroke mortality estimates for hemorrhagic stroke (HS) and ischemic stroke (IS). There were marked differences in the fraction of death assigned to IS and HS for unspecified stroke and hypertension between GBD regions and between age groups. A large proportion of stroke fatalities are derived from the redistribution of 'unspecified stroke' and 'hypertension' with marked regional differences. Future advancements in stroke certification, data collections and statistical analyses may improve the estimation of the global stroke burden. © 2015 S. Karger AG, Basel.

A mouse model for studying viscerotropic disease caused by yellow fever virus infection.

Directory of Open Access Journals (Sweden)

Kathryn C Meier

2009-10-01

Full Text Available Mosquito-borne yellow fever virus (YFV causes highly lethal, viscerotropic disease in humans and non-human primates. Despite the availability of efficacious live-attenuated vaccine strains, 17D-204 and 17DD, derived by serial passage of pathogenic YFV strain Asibi, YFV continues to pose a significant threat to human health. Neither the disease caused by wild-type YFV, nor the molecular determinants of vaccine attenuation and immunogenicity, have been well characterized, in large part due to the lack of a small animal model for viscerotropic YFV infection. Here, we describe a small animal model for wild-type YFV that manifests clinical disease representative of that seen in primates without adaptation of the virus to the host, which was required for the current hamster YF model. Investigation of the role of type I interferon (IFN-alpha/beta in protection of mice from viscerotropic YFV infection revealed that mice deficient in the IFN-alpha/beta receptor (A129 or the STAT1 signaling molecule (STAT129 were highly susceptible to infection and disease, succumbing within 6-7 days. Importantly, these animals developed viscerotropic disease reminiscent of human YF, instead of the encephalitic signs typically observed in mice. Rapid viremic dissemination and extensive replication in visceral organs, spleen and liver, was associated with severe pathologies in these tissues and dramatically elevated MCP-1 and IL-6 levels, suggestive of a cytokine storm. In striking contrast, infection of A129 and STAT129 mice with the 17D-204 vaccine virus was subclinical, similar to immunization in humans. Although, like wild-type YFV, 17D-204 virus amplified within regional lymph nodes and seeded a serum viremia in A129 mice, infection of visceral organs was rarely established and rapidly cleared, possibly by type II IFN-dependent mechanisms. The ability to establish systemic infection and cause viscerotropic disease in A129 mice correlated with infectivity for A129

A mouse model for studying viscerotropic disease caused by yellow fever virus infection.

Science.gov (United States)

Meier, Kathryn C; Gardner, Christina L; Khoretonenko, Mikhail V; Klimstra, William B; Ryman, Kate D

2009-10-01

Mosquito-borne yellow fever virus (YFV) causes highly lethal, viscerotropic disease in humans and non-human primates. Despite the availability of efficacious live-attenuated vaccine strains, 17D-204 and 17DD, derived by serial passage of pathogenic YFV strain Asibi, YFV continues to pose a significant threat to human health. Neither the disease caused by wild-type YFV, nor the molecular determinants of vaccine attenuation and immunogenicity, have been well characterized, in large part due to the lack of a small animal model for viscerotropic YFV infection. Here, we describe a small animal model for wild-type YFV that manifests clinical disease representative of that seen in primates without adaptation of the virus to the host, which was required for the current hamster YF model. Investigation of the role of type I interferon (IFN-alpha/beta) in protection of mice from viscerotropic YFV infection revealed that mice deficient in the IFN-alpha/beta receptor (A129) or the STAT1 signaling molecule (STAT129) were highly susceptible to infection and disease, succumbing within 6-7 days. Importantly, these animals developed viscerotropic disease reminiscent of human YF, instead of the encephalitic signs typically observed in mice. Rapid viremic dissemination and extensive replication in visceral organs, spleen and liver, was associated with severe pathologies in these tissues and dramatically elevated MCP-1 and IL-6 levels, suggestive of a cytokine storm. In striking contrast, infection of A129 and STAT129 mice with the 17D-204 vaccine virus was subclinical, similar to immunization in humans. Although, like wild-type YFV, 17D-204 virus amplified within regional lymph nodes and seeded a serum viremia in A129 mice, infection of visceral organs was rarely established and rapidly cleared, possibly by type II IFN-dependent mechanisms. The ability to establish systemic infection and cause viscerotropic disease in A129 mice correlated with infectivity for A129-derived, but not WT

Cause-specific mortality for 249 causes in Brazil and states during 1990–2015: a systematic analysis for the global burden of disease study 2015

Directory of Open Access Journals (Sweden)

Elisabeth B. França

2017-11-01

Full Text Available Abstract Background Reliable data on cause of death (COD are fundamental for planning and resource allocation priorities. We used GBD 2015 estimates to examine levels and trends for the leading causes of death in Brazil from 1990 to 2015. Methods We describe the main analytical approaches focused on both overall and specific causes of death for Brazil and Brazilian states. Results There was an overall improvement in life expectancy at birth from 1990 to 2015, but with important heterogeneity among states. Reduced mortality due to diarrhea, lower respiratory infections, and other infectious diseases contributed the most for increasing life expectancy in most states from the North and Northeast regions. Reduced mortality due to cardiovascular diseases was the highest contributor in the South, Southeast, and Center West regions. However, among men, intentional injuries reduced life expectancy in 17 out of 27 states. Although age-standardized rates due to ischemic heart disease (IHD and cerebrovascular disease declined over time, these remained the leading CODs in the country and states. In contrast, leading causes of premature mortality changed substantially - e.g., diarrheal diseases moved from 1st to 13th and then the 36th position in 1990, 2005, and 2015, respectively, while violence moved from 7th to 1st and to 2nd. Overall, the total age-standardized years of life lost (YLL rate was reduced from 1990 to 2015, bringing the burden of premature deaths closer to expected rates given the country’s Socio-demographic Index (SDI. In 1990, IHD, stroke, diarrhea, neonatal preterm birth complications, road injury, and violence had ratios higher than the expected, while in 2015 only violence was higher, overall and in all states, according to the SDI. Conclusions A widespread reduction of mortality levels occurred in Brazil from 1990 to 2015, particularly among children under 5 years old. Major shifts in mortality rates took place among communicable

Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015.

Science.gov (United States)

2016-10-08

Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation

Mining tissue specificity, gene connectivity and disease association to reveal a set of genes that modify the action of disease causing genes

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Reverter Antonio

2008-09-01

Full Text Available Abstract Background The tissue specificity of gene expression has been linked to a number of significant outcomes including level of expression, and differential rates of polymorphism, evolution and disease association. Recent studies have also shown the importance of exploring differential gene connectivity and sequence conservation in the identification of disease-associated genes. However, no study relates gene interactions with tissue specificity and disease association. Methods We adopted an a priori approach making as few assumptions as possible to analyse the interplay among gene-gene interactions with tissue specificity and its subsequent likelihood of association with disease. We mined three large datasets comprising expression data drawn from massively parallel signature sequencing across 32 tissues, describing a set of 55,606 true positive interactions for 7,197 genes, and microarray expression results generated during the profiling of systemic inflammation, from which 126,543 interactions among 7,090 genes were reported. Results Amongst the myriad of complex relationships identified between expression, disease, connectivity and tissue specificity, some interesting patterns emerged. These include elevated rates of expression and network connectivity in housekeeping and disease-associated tissue-specific genes. We found that disease-associated genes are more likely to show tissue specific expression and most frequently interact with other disease genes. Using the thresholds defined in these observations, we develop a guilt-by-association algorithm and discover a group of 112 non-disease annotated genes that predominantly interact with disease-associated genes, impacting on disease outcomes. Conclusion We conclude that parameters such as tissue specificity and network connectivity can be used in combination to identify a group of genes, not previously confirmed as disease causing, that are involved in interactions with disease causing

A Novel Virus Causes Scale Drop Disease in Lates calcarifer.

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Ad de Groof

2015-08-01

Full Text Available From 1992 onwards, outbreaks of a previously unknown illness have been reported in Asian seabass (Lates calcarifer kept in maricultures in Southeast Asia. The most striking symptom of this emerging disease is the loss of scales. It was referred to as scale drop syndrome, but the etiology remained enigmatic. By using a next-generation virus discovery technique, VIDISCA-454, sequences of an unknown virus were detected in serum of diseased fish. The near complete genome sequence of the virus was determined, which shows a unique genome organization, and low levels of identity to known members of the Iridoviridae. Based on homology of a series of putatively encoded proteins, the virus is a novel member of the Megalocytivirus genus of the Iridoviridae family. The virus was isolated and propagated in cell culture, where it caused a cytopathogenic effect in infected Asian seabass kidney and brain cells. Electron microscopy revealed icosahedral virions of about 140 nm, characteristic for the Iridoviridae. In vitro cultured virus induced scale drop syndrome in Asian seabass in vivo and the virus could be reisolated from these infected fish. These findings show that the virus is the causative agent for the scale drop syndrome, as each of Koch's postulates is fulfilled. We have named the virus Scale Drop Disease Virus. Vaccines prepared from BEI- and formalin inactivated virus, as well as from E. coli produced major capsid protein provide efficacious protection against scale drop disease.

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.

Effectiveness of siwak Salvadora Persica extract to Aggregatibacter Actinomycetemcomitans as one of pathogenic bacteria causing periodontal disease

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Arni Irawaty Djais

2017-04-01

Full Text Available Objective : Periodontal disease is one of oral and dental diseases which most commonly found in humans caused by several factors, one of them due to the accumulation of bacterial plaque. Aggregatibacter actinomycetemcomitans is a bacterial pathogen that frequently causes periodontal disease. Material and Methods : To inhibit the growth of these bacteria can be done by using natural ingredients that contain anti-bacterial agent. One of the natural ingredients that contain antibacterial substances is Siwak. To determine the effect of siwak extract against bacteria Aggregatibacter actinobaciluscomnitans as one of the pathogenic bacteria causing periodontal diseases. The study was laboratory experimental with posttest only control group design. Results : This study used sample of Aggregatibacter actinomycetemcomitans colonies in MHA medium. Twenty four samples were divided into six treatment groups, they were 5 groups given the extract siwak with concentration of 3.125%, 6:25%, 12.5%, 25%, 50% and 1 group treated with control DMSO 5%. Inhibition zone was measured after 48 hours incubation at 37°C and measured using caliper. Data analysis was performed using Kruskal Wallis test. The mean diameter of inhibition zone at concentrations of 3.125%, 6:25%, 12.5%, 25%, and 50% were 6.4 mm, 7.0 mm, 7.2 mm, 7.9 mm and 8.6 mm. Conclusion : Siwak extract can inhibit the growth of Aggregatibacter actinomycetemcomitans as one of the pathogenic bacteria causing periodontal diseases with the largest concentration is a concentration of 50% and the smallest concentration that is 3.125%.

Taxonomy of Fungi Causing Mucormycosis and Entomophthoramycosis (Zygomycosis) and Nomenclature of the Disease: Molecular Mycologic Perspectives

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2012-01-01

Molecular phylogenetic analysis confirmed the phylum Zygomycota to be polyphyletic, and the taxa conventionally classified in Zygomycota are now distributed among the new phylum Glomeromycota and 4 subphyla incertae sedis (uncertain placement). Because the nomenclature of the disease zygomycosis was based on the phylum Zygomycota (Zygomycetes) in which the etiologic agents had been classified, the new classification profoundly affects the name of the disease. Zygomycosis was originally described as a convenient and inclusive name for 2 clinicopathologically different diseases, mucormycosis caused by members of Mucorales and entomophthoramycosis caused by species in the order Entomophthorales of Zygomycota. Without revision of original definition, the name “zygomycosis,” however, has more often been used as a synonym only for mucormycosis. This article reviews the progress and changes in taxonomy and nomenclature of Zygomycota and the disease zygomycosis. The article also reiterates the reasons why the classic names “mucormycosis” and “entomophthoramycosis” are more appropriate than “zygomycosis.” PMID:22247451

Pulmonary Hypertension Due to Left Ventricular Cardiomyopathy: Is it the Result or Cause of Disease Progression?

Science.gov (United States)

Adusumalli, Srinath; Mazurek, Jeremy A

2017-12-01

The purpose of this review is to define pulmonary hypertension in the setting of left heart disease (PH-LHD), discuss its epidemiology and pathophysiology, and highlight the cause and effect relationship it has with disease progression in the setting of cardiomyopathy. Both pulmonary hypertension (PH) and heart failure are becoming increasingly common. As such, PH-LHD is now the most common form of PH. The pathophysiology of the condition relates to backward transmission of elevated left ventricular filling pressures into the pulmonary circulation and, ultimately, right ventricular (RV) strain/dysfunction. It is evident that these pathophysiologic processes are both the effect and cause of left heart disease progression. In this review, we describe the complex relationship between disease progression in left ventricular cardiomyopathy and PH-LHD. Clinicians and researchers should take note of the importance of PH-LHD and RV dysfunction to appropriately risk stratify patients and develop therapies for the condition.

Assessment of the efficiency of essential oils in the preservation of postharvest papaya in an antimicrobial packaging system Avaliação da eficiência de óleos essenciais na preservação pós-colheita de mamão mediante um sistema de embalagem antimicrobiana

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Paula Judith Perez Espitia

2012-12-01

Full Text Available Rot and damage caused by post-harvest phytopathogenic fungi affect fruit quality. Essential oils (EO are considered as an alternative to fungicides. Postharvest diseases of fruits may also be controlled by the bagging approach and the use of antimicrobial packaging. Based on the beneficial properties of EO and the concepts of bagging and antimicrobial packaging, this study aimed to develop sachets containing EO to be used as part of an antimicrobial packaging system. The activities of oregano, cinnamon and lemon grass EO were evaluated testing the sachets in vitro against the phytopathogenic fungi Alternaria alternata, Fusarium semitectum, Lasiodiplodia theobromae and Rhizopus stolonifer. The effects of the sachets on the microbiological and physicochemical parameters of post-harvest papaya were also evaluated. Both pure and sachet-incorporated EO showed antifungal activity in vitro against all tested fungi. For papaya, sachets containing cinnamon, oregano and lemon grass showed a significant reduction in the growth of mesophilic aerobic bacteria, yeasts and mould, with the cinnamon sachet causing the greatest reduction in microorganisms at the end of the storage time. Physicochemical parameters of papaya, such as weight loss, colour, firmness, total soluble solids/titratable acidity ratio and pH were not significantly altered by the presence of EO sachets, thus not affecting the natural ripening process of the papaya.Podridão e danos pós-colheita causados por fungos fitopatogênicos afetam a qualidade das frutas. Óleos essenciais (OE têm sido considerados como uma alternativa ao uso de fungicidas. Uma alternativa para o controle de doenças pós-colheita dos frutos é a técnica de ensacamento. Portanto, baseado nas propriedades benéficas dos OE e no conceito de ensacamento, este trabalho teve como objetivo desenvolver sachês incorporados com OE para serem usados como parte de um sistema de embalagem antimicrobiana. A atividade dos OE de

Evaluation of bakanae disease progression caused by Fusarium fujikuroi in Oryza sativa L.

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Hwang, In Sun; Kang, Woo-Ri; Hwang, Duk-Ju; Bae, Shin-Chul; Yun, Sung-Hwan; Ahn, Il-Pyung

2013-12-01

Bakanae disease caused by Fusarium fujikuroi is an important fungal disease in rice. Among the seven strains isolated from symptomatic rice grains in this study, one strain, FfB14, triggered severe root growth inhibition and decay in the crown and root of rice seedlings. The remaining six strains caused typical Bakanae symptoms such as etiolation and abnormal succulent rice growth. To reveal the relationship between mycelial growth in the infected tissues and Bakanae disease progression, we have established a reliable quantification method using real time PCR that employs a primer pair and dual-labeled probe specific to a unigene encoding F. fujikuroi PNG1 (FfPNG1), which is located upstream of the fumonisin biosynthesis gene cluster. Plotting the crossing point (CP) values from the infected tissue DNAs on a standard curve revealed the active fungal growth of FfB14 in the root and crown of rice seedlings, while the growth rate of FfB20 in rice was more than 4 times lower than FfB14. Massive infective mycelial growth of FfB14 was evident in rice stems and crown; however, FfB20 did not exhibit vigorous growth. Our quantitative evaluation system is applicable for the identification of fungal virulence factors other than gibberellin.

Pneumococcal serotypes and serogroups causing invasive disease in Pakistan, 2005-2013.

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Sadia Shakoor

Full Text Available While pneumococcal conjugate vaccines have been implemented in most countries worldwide, use in Asia has lagged in part because of a lack of data on the amount of disease that is vaccine preventable in the region. We describe pneumococcal serotypes elicited from 111 episodes of invasive pneumococcal disease (IPD from 2005 to 2013 among children and adults in Pakistan. Seventy-three percent (n = 81 of 111 IPD episodes were cases of meningitis (n = 76 in children 0-15 years and n = 5 among adults. Serotypes were determined by target amplification of DNA extracted from pneumococcal isolates (n = 52 or CSF specimens (n = 59. Serogroup 18 was the most common serogroup causing meningitis in children <5 years, accounting for 21% of cases (n = 13. The 10-valent pneumococcal conjugate vaccine (PCV 10 or PCV10- related serotypes were found in 61% (n = 47 of childhood (age 0-15 years meningitis episodes. PCV-13 increased this coverage to 63% (one additional serotype 19A; n = 48. Our data indicate that use of PCVs would prevent a large proportion of serious pneumococcal disease.

The new French 2010 Rabbit Hemorrhagic Disease Virus causes an RHD-like disease in the Sardinian Cape hare (Lepus capensis mediterraneus).

Science.gov (United States)

Puggioni, Giantonella; Cavadini, Patrizia; Maestrale, Caterina; Scivoli, Rosario; Botti, Giuliana; Ligios, Ciriaco; Le Gall-Reculé, Ghislaine; Lavazza, Antonio; Capucci, Lorenzo

2013-10-07

Lagovirus is an emerging genus of Caliciviridae, which includes the Rabbit Hemorrhagic Disease Virus (RHDV) of rabbits and the European brown hare syndrome virus (EBHSV) of hares that cause lethal hepatitis. In 2010, a new RHDV related virus (RHDV2) with a unique genetic and antigenic profile and lower virulence was identified in France in rabbits. Here we report the identification of RHDV2 as the cause in Sardinia of several outbreaks of acute hepatitis in rabbits and Cape hare (Lepus capensis mediterraneus). This is the first account of a lagovirus that causes fatal hepatitis in both rabbits and hares.

Features of 5'-splice-site efficiency derived from disease-causing mutations and comparative genomics

DEFF Research Database (Denmark)

Roca, Xavier; Olson, Andrew J; Rao, Atmakuri R

2008-01-01

Many human diseases, including Fanconi anemia, hemophilia B, neurofibromatosis, and phenylketonuria, can be caused by 5'-splice-site (5'ss) mutations that are not predicted to disrupt splicing, according to position weight matrices. By using comparative genomics, we identify pairwise dependencies...

Coffee intake, cardiovascular disease and all-cause mortality: observational and Mendelian randomization analyses in 95 000-223 000 individuals.

Science.gov (United States)

Nordestgaard, Ask Tybjærg; Nordestgaard, Børge Grønne

2016-12-01

Coffee has been associated with modestly lower risk of cardiovascular disease and all-cause mortality in meta-analyses; however, it is unclear whether these are causal associations. We tested first whether coffee intake is associated with cardiovascular disease and all-cause mortality observationally; second, whether genetic variations previously associated with caffeine intake are associated with coffee intake; and third, whether the genetic variations are associated with cardiovascular disease and all-cause mortality. First, we used multivariable adjusted Cox proportional hazard regression models evaluated with restricted cubic splines to examine observational associations in 95 366 White Danes. Second, we estimated mean coffee intake according to five genetic variations near the AHR (rs4410790; rs6968865) and CYP1A1/2 genes (rs2470893; rs2472297; rs2472299). Third, we used sex- and age adjusted Cox proportional hazard regression models to examine genetic associations with cardiovascular disease and all-cause mortality in 112 509 Danes. Finally, we used sex and age-adjusted logistic regression models to examine genetic associations with ischaemic heart disease including the Cardiogram and C4D consortia in a total of up to 223 414 individuals. We applied similar analyses to ApoE genotypes associated with plasma cholesterol levels, as a positive control. In observational analyses, we observed U-shaped associations between coffee intake and cardiovascular disease and all-cause mortality; lowest risks were observed in individuals with medium coffee intake. Caffeine intake allele score (rs4410790 + rs2470893) was associated with a 42% higher coffee intake. Hazard ratios per caffeine intake allele were 1.02 (95% confidence interval: 1.00-1.03) for ischaemic heart disease, 1.02 (0.99-1.02) for ischaemic stroke, 1.02 (1.00-1.03) for ischaemic vascular disease, 1.02 (0.99-1.06) for cardiovascular mortality and 1.01 (0.99-1.03) for all-cause mortality. Including

An emergent disease causes directional changes in forest species composition in coastal California

Science.gov (United States)

Margaret Metz; Kerri Frangioso; Allison Wickland; Ross Meentemeyer; David Rizzo

2012-01-01

Non-native forest pathogens can cause dramatic and long-lasting changes to the composition of forests, and these changes may have cascading impacts on community interactions and ecosystem functioning. Phytophthora ramorum, the causal agent of the emergent forest disease sudden oak death (SOD), has a wide host range, but mortality is concentrated in...

An overall estimation of losses caused by diseases in the Brazilian fish farms.

Science.gov (United States)

Tavares-Dias, Marcos; Martins, Maurício Laterça

2017-12-01

Parasitic and infectious diseases are common in finfish, but are difficult to accurately estimate the economic impacts on the production in a country with large dimensions like Brazil. The aim of this study was to estimate the costs caused by economic losses of finfish due to mortality by diseases in Brazil. A model for estimating the costs related to parasitic and bacterial diseases in farmed fish and an estimative of these economic impacts are presented. We used official data of production and mortality of finfish for rough estimation of economic losses. The losses herein presented are related to direct and indirect economic costs for freshwater farmed fish, which were estimated in US$ 84 million per year. Finally, it was possible to establish by the first time an estimative of overall losses in finfish production in Brazil using data available from production. Therefore, this current estimative must help researchers and policy makers to approximate the economic costs of diseases for fish farming industry, as well as for developing of public policies on the control measures of diseases and priority research lines.

Daytime Napping and the Risk of Cardiovascular Disease and All-Cause Mortality: A Prospective Study and Dose-Response Meta-Analysis.

Science.gov (United States)

Yamada, Tomohide; Hara, Kazuo; Shojima, Nobuhiro; Yamauchi, Toshimasa; Kadowaki, Takashi

2015-12-01

To summarize evidence about the association between daytime napping and the risk of cardiovascular disease and all-cause mortality, and to quantify the potential dose-response relation. Meta-analysis of prospective cohort studies. Electronic databases were searched for articles published up to December 2014 using the terms nap, cardiovascular disease, and all-cause mortality. We selected well-adjusted prospective cohort studies reporting risk estimates for cardiovascular disease and all-cause mortality related to napping. Eleven prospective cohort studies were identified with 151,588 participants (1,625,012 person-years) and a mean follow-up period of 11 years (60% women, 5,276 cardiovascular events, and 18,966 all-cause deaths). Pooled analysis showed that a long daytime nap (≥ 60 min/day) was associated with a higher risk of cardiovascular disease (rate ratio [RR]: 1.82 [1.22-2.71], P = 0.003, I(2) = 37%) compared with not napping. All-cause mortality was associated with napping for ≥ 60 min/day (RR: 1.27 [1.11-1.45], P napping. In contrast, napping for nap time and cardiovascular disease (P for nonlinearity = 0.01). The RR initially decreased from 0 to 30 min/day. Then it increased slightly until about 45 min/day, followed by a sharp increase at longer nap times. There was also a positive linear relation between nap time and all-cause mortality (P for non-linearity = 0.97). Nap time and cardiovascular disease may be associated via a J-curve relation. Further studies are needed to confirm the efficacy of a short nap. © 2015 Associated Professional Sleep Societies, LLC.

Prenatal famine exposure and adult mortality from cancer, cardiovascular disease, and other causes through age 63 years.

Science.gov (United States)

Ekamper, Peter; van Poppel, Frans; Stein, Aryeh D; Bijwaard, Govert E; Lumey, L H

2015-02-15

Nutritional conditions in early life may affect adult health, but prior studies of mortality have been limited to small samples. We evaluated the relationship between pre-/perinatal famine exposure during the Dutch Hunger Winter of 1944-1945 and mortality through age 63 years among 41,096 men born in 1944-1947 and examined at age 18 years for universal military service in the Netherlands. Of these men, 22,952 had been born around the time of the Dutch famine in 6 affected cities; the remainder served as unexposed controls. Cox proportional hazards models were used to estimate hazard ratios for death from cancer, heart disease, other natural causes, and external causes. After 1,853,023 person-years of follow-up, we recorded 1,938 deaths from cancer, 1,040 from heart disease, 1,418 from other natural causes, and 523 from external causes. We found no increase in mortality from cancer or cardiovascular disease after prenatal famine exposure. However, there were increases in mortality from other natural causes (hazard ratio = 1.24, 95% confidence interval: 1.03, 1.49) and external causes (hazard ratio = 1.46, 95% confidence interval: 1.09, 1.97) after famine exposure in the first trimester of gestation. Further follow-up of the cohort is needed to provide more accurate risk estimates of mortality from specific causes of death after nutritional disturbances during gestation and very early life. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.