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Sample records for causing niemann-pick types

  1. Niemann Pick type A, a case report

    OpenAIRE

    M. Qasemi; F. Mojtahedzadeh

    2006-01-01

    Niemann Pick type A is a very rare hereditary disease with an incidence 1 in 20000-40000 live birth, which is calassified as a shingolipidoses.The disease is marked by the abnormal accumulation of sphingomyelin in most tissues, secondary to sphingomylinase deficiency.The most clinical manifestations are:Splenohepatomegaly–cherry red maculae-neuropathologic findings .This is a case report of an infant with clinical manifestation of Niemann Pick disease type A.

  2. A rare cause of fatal pulmonary alveolar proteinosis: Niemann-Pick disease type C2 and a novel mutation.

    Science.gov (United States)

    Yaman, Ayhan; Eminoğlu, Fatma T; Kendirli, Tanıl; Ödek, Çağlar; Ceylaner, Serdar; Kansu, Aydan; İnce, Elif; Deda, Gülhis

    2015-09-01

    Niemann-Pick disease type C (NPC) is a fatal autosomal recessive lipid storage disease associated with impaired trafficking of unesterified cholesterol and glycolipids in lysosomes and late endosomes. This disease is commonly characterized by hepatosplenomegaly and severe progressive neurological dysfunction. There are two defective genes that cause this illness. One of these genes is NPC1 gene which is the cause of illness in 95% of the patients. The other gene is the rare type NPC2 which is the cause of illness in 5% of the patients. Patients with NPC2 usually present with respiratory distress in early infancy, which is rather unusual with NPC1. This article discusses about a patient who died at an early age from pulmonary involvement and who subsequently was found to have a novel homozygous mutation of NPC2 gene. PMID:26024245

  3. A rare cause of abdominal pain: Massive splenomegaly and hypersplenism due to Niemann-Pick type-B

    OpenAIRE

    ARIKANOĞLU, Zülfü; TAŞKESEN, Fatih; ALİOSMANOĞLU, İbrahim; Gül, Mesut; FIRAT, Uğur; AY, Enver

    2012-01-01

    Niemann-Pick disease is a recessive, autosomal hereditary lysosomal storage disease. Six types of the disease have been identified (NPD types A, B, C, D, E, and F). Clinic of the patient varies depending on the organ in which sphingomyelin accumulates. The diagnosis is generally made during routine diagnostic tests performed in childhood while examining the etiology of hepatosplenomegaly. Supportive treatment is the mostly preferred treatment. However, splenectomy can be performed because of ...

  4. Cholesterol accumulation in Niemann Pick type C (NPC) model cells causes a shift in APP localization to lipid rafts

    International Nuclear Information System (INIS)

    It has been suggested that cholesterol may modulate amyloid-β (Aβ) formation, a causative factor of Alzheimer's disease (AD), by regulating distribution of the three key proteins in the pathogenesis of AD (β-amyloid precursor protein (APP), β-secretase (BACE1) and/or presenilin 1 (PS1)) within lipid rafts. In this work we tested whether cholesterol accumulation upon NPC1 dysfunction, which causes Niemann Pick type C disease (NPC), causes increased partitioning of APP into lipid rafts leading to increased CTF/Aβ formation in these cholesterol-rich membrane microdomains. To test this we used CHO NPC1-/- cells (NPC cells) and parental CHOwt cells. By sucrose density gradient centrifugation we observed a shift in fl-APP/CTF compartmentalization into lipid raft fractions upon cholesterol accumulation in NPC vs. wt cells. Furthermore, γ-secretase inhibitor treatment significantly increased fl-APP/CTF distribution in raft fractions in NPC vs. wt cells, suggesting that upon cholesterol accumulation in NPC1-null cells increased formation of APP-CTF and its increased processing towards Aβ occurs in lipid rafts. Our results support that cholesterol overload, such as in NPC disease, leads to increased partitioning of APP/CTF into lipid rafts resulting in increased amyloidogenic processing of APP in these cholesterol-rich membranes. This work adds to the mechanism of the cholesterol-effect on APP processing and the pathogenesis of Alzheimer's disease and supports the role of lipid rafts in these processes.

  5. Cholesterol accumulation in Niemann Pick type C (NPC) model cells causes a shift in APP localization to lipid rafts

    Energy Technology Data Exchange (ETDEWEB)

    Kosicek, Marko, E-mail: marko.kosicek@irb.hr [Division of Molecular Medicine, Ruder Boskovic Institute, Bijenicka 54, 10000 Zagreb (Croatia); Malnar, Martina, E-mail: martina.malnar@irb.hr [Division of Molecular Medicine, Ruder Boskovic Institute, Bijenicka 54, 10000 Zagreb (Croatia); Goate, Alison, E-mail: goate@icarus.wustl.edu [Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110 (United States); Hecimovic, Silva, E-mail: silva.hecimovic@irb.hr [Division of Molecular Medicine, Ruder Boskovic Institute, Bijenicka 54, 10000 Zagreb (Croatia)

    2010-03-12

    It has been suggested that cholesterol may modulate amyloid-{beta} (A{beta}) formation, a causative factor of Alzheimer's disease (AD), by regulating distribution of the three key proteins in the pathogenesis of AD ({beta}-amyloid precursor protein (APP), {beta}-secretase (BACE1) and/or presenilin 1 (PS1)) within lipid rafts. In this work we tested whether cholesterol accumulation upon NPC1 dysfunction, which causes Niemann Pick type C disease (NPC), causes increased partitioning of APP into lipid rafts leading to increased CTF/A{beta} formation in these cholesterol-rich membrane microdomains. To test this we used CHO NPC1{sup -/-} cells (NPC cells) and parental CHOwt cells. By sucrose density gradient centrifugation we observed a shift in fl-APP/CTF compartmentalization into lipid raft fractions upon cholesterol accumulation in NPC vs. wt cells. Furthermore, {gamma}-secretase inhibitor treatment significantly increased fl-APP/CTF distribution in raft fractions in NPC vs. wt cells, suggesting that upon cholesterol accumulation in NPC1-null cells increased formation of APP-CTF and its increased processing towards A{beta} occurs in lipid rafts. Our results support that cholesterol overload, such as in NPC disease, leads to increased partitioning of APP/CTF into lipid rafts resulting in increased amyloidogenic processing of APP in these cholesterol-rich membranes. This work adds to the mechanism of the cholesterol-effect on APP processing and the pathogenesis of Alzheimer's disease and supports the role of lipid rafts in these processes.

  6. Types A and B Niemann-Pick Disease.

    Science.gov (United States)

    Schuchman, Edward H; Wasserstein, Melissa P

    2016-06-01

    Two distinct metabolic abnormalities are included under the eponym Niemann-Pick disease (NPD). The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM). Patients with ASM deficiency are classified as having types A and B Niemann-Pick disease (NPD). Type A NPD patients exhibit hepatosplenomegaly, frequent pulmonary infections, and profound central nervous system involvement in infancy. They rarely survive beyond two years of age. Type B patients also have hepatosplenomegaly and progressive alterations of their lungs, but there are usually no central nervous system signs. The age of onset and rate of disease progression varies greatly among type B patients, and they frequently live into adulthood. Recently, patients with phenotypes intermediate between types A and B NPD also have been identified. These individuals represent the expected continuum caused by inheriting different mutations in the ASM gene (SMPD1). Patients in the second category are designated as having type C NPD. Impaired intracellular trafficking of cholesterol causes type C NPD, and two distinct gene defects have been found. In this chapter only types A and B NPD will be discussed. PMID:27491215

  7. Niemann-Pick disease type C

    Directory of Open Access Journals (Sweden)

    Vanier Marie T

    2010-06-01

    Full Text Available Abstract Niemann-Pick C disease (NP-C is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood. The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period, gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period, and ataxia not unfrequently following initial psychiatric disturbances (adult form. The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype. Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential

  8. [Niemann-Pick type C disease: pathophysiology, diagnosis and treatment].

    Science.gov (United States)

    Ohno, Kousaku

    2016-03-01

    Niemann-Pick type C (NPC) disease is an autosomal recessive neurodegenerative disorder which is caused in 95% by a mutation in the NPC1 gene on chromosome 18 or by NPC2 mutation, encoding for 2 different lysosomal lipid transport proteins. The impaired protein function leads to systemic intralysosomal accumulation of free cholesterol and shingolipids particularly in the CNS. In Japan, currently 34 living NPC patients are known as of December 2015. Considering the prevalence of the disease in the Western countries, the real number of NPC patients is most likely to be five-folds higher. For NPC, treatment methods are established and an approved disease-specific medications are available. It is important that patients early in their disease are referred to expert centers, in order to ensure timely initiation of treatment and to delay the progression of neurological symptoms as a goal. PMID:27149732

  9. Niemann-Pick disease type B: prenatal diagnosis and enzymatic and chemical studies on fetal brain and liver.

    OpenAIRE

    Wenger, D A; Kudoh, T; Sattler, M; Palmieri, M; Yudkoff, M

    1981-01-01

    Patients with Niemann-Pick disease type A have a severe neurovisceral disease caused by a deficiency of lysosomal sphingomyelinase activity in all tissues examined. The patients with the type B form have signs and symptoms related to storage of sphingomyelin in the spleen, liver, and lungs, while neurologically they remain normal. They also have a severe deficiency of lysosomal sphingomyelinase activity in all tissues previously examined. Here the brain and liver of a fetus with Niemann-Pick ...

  10. Niemann-Pick Disease Type C: Implications for Sedation and Anesthesia for Diagnostic Procedures

    OpenAIRE

    Miao, Ning; Lu, Xiaowei; O’Grady, Naomi P.; Yanjanin, Nicole; Porter, Forbes D.; Quezado, Zenaide M N

    2012-01-01

    Niemann-Pick disease type C, an autosomal recessive lysosomal storage disorder, can present with severe visceral and neurologic involvement and is associated with a significant decrease in life expectancy. As little is known about anesthetic considerations of this disease, we examined the perianesthetic course of patients with Niemann-Pick disease type C. Thirty-two patients with Niemann-Pick disease type C, median age 6.9 years (1.8–33 years), underwent 64 general anesthetics for diagnostic ...

  11. Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches

    OpenAIRE

    Rosenbaum, Anton I.; Maxfield, Frederick R.

    2011-01-01

    Cholesterol is an important lipid of mammalian cells. Its unique physicochemical properties modulate membrane behavior and it serves as the precursor for steroid hormones, oxysterols and vitamin D. Cholesterol is effluxed from the late endosomes/lysosomes via the concerted action of at least two distinct proteins: Niemann-Pick C1 and Niemann-Pick C2. Mutations in these two proteins manifest as Niemann-Pick type C disease – a very rare, usually fatal, autosomal, recessive, neurovisceral, lysos...

  12. Imaging features of type-B Niemann-Pick disease

    Energy Technology Data Exchange (ETDEWEB)

    Muntaner, L. [Dept. of Radiology, Son Dureta University Hospital, Palma de Mallorca (Spain); Galmes, A. [Dept. of Hematology, Son Dureta University Hospital, Palma de Mallorca (Spain); Chabas, A. [Instituto de Bioquimica Clinica Corporacio Sanitaria, Barcelona (Spain); Herrera, M. [Dept. of Radiology, Son Dureta University Hospital, Palma de Mallorca (Spain)

    1997-04-01

    We report two cases of a mild form of type-B Niemann-Pick disease manifesting as an adult-onset chronic non-neuropathic clinical picture. Femoral T1- and T2-weighted low-intensity non-enhancing coarse bone marrow pattern was evident on femoral MR associated with splenic hypodense nodule(s) on abdominal CT. The role of imaging is discussed in relation to current techniques of confirmation of this entity based on demonstration of lipid-laden cells within marrow aspirates (which are often sea-blue histiocytes) and sphingomyelinase assay of cultured skin fibroblasts. (orig.). With 2 figs.

  13. Imaging features of type-B Niemann-Pick disease

    International Nuclear Information System (INIS)

    We report two cases of a mild form of type-B Niemann-Pick disease manifesting as an adult-onset chronic non-neuropathic clinical picture. Femoral T1- and T2-weighted low-intensity non-enhancing coarse bone marrow pattern was evident on femoral MR associated with splenic hypodense nodule(s) on abdominal CT. The role of imaging is discussed in relation to current techniques of confirmation of this entity based on demonstration of lipid-laden cells within marrow aspirates (which are often sea-blue histiocytes) and sphingomyelinase assay of cultured skin fibroblasts. (orig.). With 2 figs

  14. Impaired Autophagy in the Lipid-Storage Disorder Niemann-Pick Type C1 Disease

    OpenAIRE

    2013-01-01

    Autophagy dysfunction has been implicated in misfolded protein accumulation and cellular toxicity in several diseases. Whether alterations in autophagy also contribute to the pathology of lipid-storage disorders is not clear. Here, we show defective autophagy in Niemann-Pick type C1 (NPC1) disease associated with cholesterol accumulation, where the maturation of autophagosomes is impaired because of defective amphisome formation caused by failure in SNARE machinery, whereas the lysosomal prot...

  15. New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat

    OpenAIRE

    Wraith, Ed

    2009-01-01

    James E Wraith, Jackie ImrieWillink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Manchester, UKAbstract: Niemann-Pick disease type C (NP-C) is an autosomal recessive disorder characterized by progressive neurological deterioration leading to premature death. The disease is caused by mutations in one of two genes, NPC1 or NPC2, leading to impaired intracellular lipid transport and build-up of lipids in various tissues, particularly the brain. Miglustat (Z...

  16. Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease

    OpenAIRE

    Elena-Raluca Nicoli; Nada Al Eisa; Celine V M Cluzeau; Wassif, Christopher A.; James Gray; Burkert, Kathryn R.; Smith, David A.; Lauren Morris; Cologna, Stephanie M.; Peer, Cody J.; Sissung, Tristan M.; Constantin-Daniel Uscatu; William D Figg; Pavan, William J.; Vite, Charles H.

    2016-01-01

    Niemann-Pick type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 gene. NPC is characterised by storage of multiple lipids in the late endosomal/lysosomal compartment, resulting in cellular and organ system dysfunction. The underlying molecular mechanisms that lead to the range of clinical presentations in NPC are not fully understood. While evaluating potential small molecule therapies in Npc1 -/- mice, we observed a consistent ...

  17. Epidemiological, clinical and biochemical characterization of the p.(Ala359Asp) SMPD1 variant causing Niemann-Pick disease type B.

    Science.gov (United States)

    Acuña, Mariana; Martínez, Pablo; Moraga, Carol; He, Xingxuan; Moraga, Mauricio; Hunter, Bessie; Nuernberg, Peter; Gutiérrez, Rodrigo A; González, Mauricio; Schuchman, Edward H; Santos, José Luis; Miquel, Juan Francisco; Mabe, Paulina; Zanlungo, Silvana

    2016-02-01

    Niemann-Pick disease type B (NPDB) is a rare, inherited lysosomal storage disorder that occurs due to variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene and the resultant deficiency of acid sphingomyelinase (ASM) activity. While numerous variants causing NPDB have been described, only a small number have been studied in any detail. Herein, we describe the frequency of the p.(Ala359Asp) variant in the healthy Chilean population, and determine the haplotype background of homozygous patients to establish if this variant originated from a common founder. Genomic DNA samples from 1691 healthy individuals were analyzed for the p.(Ala359Asp) variant. The frequency of p.(Ala359Asp) was found to be 1/105.7, predicting a disease incidence of 1/44 960 in Chile, higher than the incidence estimated by the number of confirmed NPDB cases. We also describe the clinical characteristics of 13 patients homozygous for p.(Ala359Asp) and all of them had moderate to severe NPDB disease. In addition, a conserved haplotype and shared 280 Kb region around the SMPD1 gene was observed in the patients analyzed, indicating that the variant originated from a common ancestor. The haplotype frequency and mitochondrial DNA analysis suggest an Amerindian origin for the variant. To assess the effect of the p.(Ala359Asp) variant, we transfected cells with the ASM-p.(Ala359Asp) cDNA and the activity was only 4.2% compared with the wild-type cDNA, definitively demonstrating the causative effect of the variant on ASM function. Information on common variants such as p.(Ala359Asp) is essential to guide the successful implementation for future therapies and benefit to patients. PMID:25920558

  18. Treatment of Niemann-Pick disease type B by allogeneic bone marrow transplantation.

    OpenAIRE

    Vellodi, A.; Hobbs, J. R.; O'Donnell, N M; Coulter, B S; Hugh-Jones, K.

    1987-01-01

    Allogenic bone marrow transplantation was carried out on a 3 year old girl with Niemann-Pick disease type B. Successful engraftment was achieved, and nine months after the procedure there was definite clearing of the sphingomyelin from the liver and pronounced clearing from the bone marrow. Any patient with Niemann-Pick disease type B complicated by early or severe hepatic impairment should be considered for bone marrow transplantation.

  19. Niemann-Pick Disease Type B in a 21 Year Old Male.

    Science.gov (United States)

    Haque, M A; Miah, M Z

    2016-04-01

    Niemann-pick disease is a group of autosomal recessive disorder of lipid storage with progressive accumulation of sphingomyelin and other lipids in the lysosomes of various tissues. We are reporting a 21 year old male who had hepatosplenomegaly, cherry red macula and normal cognitive function. Bone marrow biopsy showed plenty of foam cells and sphingomyelinase level was low, thus conforming our diagnosis. Survival into adulthood and absence of gross neurological involvement suggests Niemann-Pick disease type B. PMID:27277377

  20. Recovery from liver disease in a Niemann-Pick type C mouse model

    OpenAIRE

    Sayre, Naomi L.; Rimkunas, Victoria M.; Graham, Mark J.; Crooke, Rosanne M.; Liscum, Laura

    2010-01-01

    Loss of function of Niemann-Pick C1 (NPC1) leads to lysosomal free cholesterol storage, resulting in the neurodegenerative disease Niemann-Pick disease type C (NPC). Significant numbers of patients with NPC also suffer from liver disease. Currently, no treatments exist that alter patient outcome, and it is unknown if recovery from tissue damage can occur even if a treatment were found. Our laboratory developed a strategy to test whether mice can recover from NPC liver disease. We used antisen...

  1. Niemann-Pick disease

    Science.gov (United States)

    ... there is no effective treatment for type A. Bone marrow transplants have been done on a few patients with ... health care provider if you have a family history of Niemann-Pick disease and you plan to ...

  2. Niemann-Pick disease, type B with TRAP-positive storage cells and secondary sea blue histiocytosis

    Directory of Open Access Journals (Sweden)

    R. Saxena

    2009-09-01

    Full Text Available We present 2 cases of Niemann Pick disease, type B with secondary sea-blue histiocytosis. Strikingly, in both cases the Pick cells were positive for tartrate resistant acid phosphatase, a finding hitherto described only in Gaucher cells. This report highlights the importance of this finding as a potential cytochemical diagnostic pitfall in the diagnosis of Niemann Pick disease.

  3. Niemann-Pick disease, type B with TRAP-positive storage cells and secondary sea blue histiocytosis

    OpenAIRE

    R. Saxena; Pati, H. P.; Dutta, S.; Kar, R.; Sharma, P.

    2009-01-01

    We present 2 cases of Niemann Pick disease, type B with secondary sea-blue histiocytosis. Strikingly, in both cases the Pick cells were positive for tartrate resistant acid phosphatase, a finding hitherto described only in Gaucher cells. This report highlights the importance of this finding as a potential cytochemical diagnostic pitfall in the diagnosis of Niemann Pick disease.

  4. Visualization of cholesterol deposits in lysosomes of Niemann-Pick type C fibroblasts using recombinant perfringolysin O

    OpenAIRE

    Kwiatkowska, Katarzyna; Marszałek–Sadowska, Ewelina; Traczyk, Gabriela; Koprowski, Piotr; Musielak, Małgorzata; Ługowska, Agnieszka; Kulma, Magdalena; Grzelczyk, Anna; Sobota, Andrzej

    2014-01-01

    Background Niemann-Pick disease type C (NPC) is caused by defects in cholesterol efflux from lysosomes due to mutations of genes coding for NPC1 and NPC2 proteins. As a result, massive accumulation of unesterified cholesterol in late endosomes/lysosomes is observed. At the level of the organism these cholesterol metabolism disorders are manifested by progressive neurodegeneration and hepatosplenomegaly. Until now filipin staining of cholesterol deposits in cells has been widely used for NPC d...

  5. Fetal ascites: an unusual presentation of Niemann-Pick disease type C.

    OpenAIRE

    Maconochie, I K; Chong, S; Mieli-Vergani, G; Lake, B D; Mowat, A P

    1989-01-01

    Two infants were seen with severe ascites detected before birth, a previously unreported presentation of Niemann-Pick disease type C. In the second infant no diagnostic storage cells were present in bone marrow. Confirmatory investigations were prompted by experience of the first case.

  6. Recommendations on the diagnosis and management of Niemann-Pick disease type C

    NARCIS (Netherlands)

    J.E. Wraith; M.R. Baumgartner; B. Bembi; A. Covanis; T. Levade; E. Mengel; M. Pineda; F. Sedel; M. Topçu; M.T. Vanier; H. Widner; F.A. Wijburg; M.C. Patterson

    2009-01-01

    Niemann-Pick disease type C (NP-C) is a lysosomal storage disease in which impaired intracellular lipid trafficking leads to excess storage of cholesterol and glycosphingolipids in the brain and other tissues. it is characterized clinically by a variety of progressive, disabling neurological symptom

  7. Niemann-Pick disease.

    Science.gov (United States)

    Elleder, M

    1989-09-01

    Results of the investigation carried out during this decade brought unambigous evidence of biochemical heterogeneity inside the complex of Niemann-Pick disease according to which two entirely different metabolic disorders can be recognized. 1. Niemann-Pick sphingomyelinosis, a clear-cut enzymopathy, the pivotal lesion of which is the deficiency of lysosomal spingomyelinase leading to widespread lysosomal deposition of sphingomyelin liquid crystals. Two main allelic variants are known. The first one, neuronopathic (former type A) known as infantile with rapid course, may also manifest considerably prolonged course or an atypical course with predominantly visceral symptomatology. Patients with the second, visceral, variant (former type B), display mainly slow clinical course and often reach adulthood. With rare exceptions the neuronopathic variant can be biochemically recognized from the visceral one by much lower values of the in vivo sphingomyelin degradation test in the former. 2. The rest of the complex comprising types C-D differs substantially from the sphingomyelinase deficiency group by the remarkable heterogeneity in the lysosomal stored lipid pattern given by differences among the affected cell populations. Sphingomyelin storage could be proved histochemically solely in the histiocytic population together with cholesterol, neutral glycosphingolipids and lysobisphosphatidic acid, whereas the brain neurons displayed only neutral glycosphingolipid storage. There is an increasing evidence of the crucial biochemical lesion in this group being an altered intracellular traffic of exogenously derived cholesterol caused probably by its deficient translocation from lysosomes to other intracellular membrane sites. This leads to decreased cholesterol esterification rate which is the basis of the newly developed diagnostic test. Inconstant depression of sphingomyelinase activity is considered to be a secondary phenomenon. The so-called lactosylceramidosis is a rare

  8. Two Siblings with Adolescent/Adult Onset Niemann-Pick Disease Type C in Korea.

    Science.gov (United States)

    Lee, Su-Yun; Lee, Hyung Jin; Kim, Seong Hwan; Jeong, Young Jin; Jin, Hee Kyung; Bae, Jae-Sung; Cheon, Sang-Myung; Kim, Jae Woo

    2016-07-01

    Niemann-Pick disease, type C (NP-C), is caused by NPC1 or NPC2 gene mutations. Progressive neurological, psychiatric, and visceral symptoms are characteristic. Here, we present cases of a brother (Case 1) and sister (Case 2) in their mid-20s with gait disturbance and psychosis. For the Case 1, neurological examination revealed dystonia, ataxia, vertical supranuclear-gaze palsy (VSGP), and global cognitive impairment. Case 2 showed milder, but similar symptoms, with cortical atrophy. Abdominal computed tomography showed hepatosplenomegaly in both cases. NPC1 gene sequencing revealed compound heterozygote for exon 9 (c.1552C>T [R518W]) and exon 18 (c.2780C>T [A927V]). Filipin-staining tests were also positive. When a young patient with ataxia or dystonia shows VSGP, NP-C should be considered. PMID:27366019

  9. Niemann-Pick disease type C or Gaucher’s disease type 3? A clinical conundrum

    OpenAIRE

    Pandi, Suresh; Chandran, Vijay; Deshpande, Anirudda; Kurien, Annamma

    2014-01-01

    We describe a patient who presented with a neurovisceral syndrome characterised by ataxia, bulbar dysfunction, supranuclear gaze palsy, splenomegaly and foamy histiocytes in the bone marrow. This presentation was suggestive of a lysosomal storage disorder such as Niemann-Pick disease type C or Gaucher's disease type 3. We review the presentation of these disorders, with a focus on the neurological features. In addition, we briefly discuss the disease-modifying therapeutic options which have r...

  10. New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat

    Directory of Open Access Journals (Sweden)

    James E Wraith

    2009-11-01

    Full Text Available James E Wraith, Jackie ImrieWillink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Manchester, UKAbstract: Niemann-Pick disease type C (NP-C is an autosomal recessive disorder characterized by progressive neurological deterioration leading to premature death. The disease is caused by mutations in one of two genes, NPC1 or NPC2, leading to impaired intracellular lipid transport and build-up of lipids in various tissues, particularly the brain. Miglustat (Zavesca®, a reversible inhibitor of glycosphingolipid synthesis, has recently been authorized in the European Union, Brazil and South Korea for the treatment of progressive neurological symptoms in adult and pediatric patients, and represents the first specific treatment for NP-C. Here we review current data on the pharmacology, efficacy, safety and tolerability of miglustat in patients with NP-C, based on findings from a prospective clinical trial, preclinical and retrospective studies, and case reports. Findings demonstrated clinically relevant beneficial effects of miglustat on neurological disease progression in adult, juvenile and pediatric patients with NP-C, particularly those diagnosed in late childhood (6–11 years and in juveniles and adults (12 years and older, compared with those diagnosed in early childhood (younger than 6 years. Miglustat therapy was well-tolerated in all age groups. With the approval of miglustat, treatment of patients with NP-C can now be aimed toward stabilizing neurological disease, which is likely the best attainable therapeutic goal for this disorder.Keywords: Niemann-Pick disease type C, NP-C, miglustat, Zavesca®

  11. Linkage of Niemann-Pick disease type D to the same region of human chromosome 18 as Niemann-Pick disease type C.

    OpenAIRE

    Greer, W. L.; Riddell, D. C.; Byers, D M; Welch, J. P.; Girouard, G S; Sparrow, S M; Gillan, T L; Neumann, P. E.

    1997-01-01

    Niemann-Pick type II disease is a severe disorder characterized by accumulation of tissue cholesterol and sphingomyelin and by progressive degeneration of the nervous system. This disease has two clinically similar subtypes, type C (NPC) and type D (NPD). NPC is clinically variable and has been identified in many ethnic groups. NPD, on the other hand, has been reported only in descendants of an Acadian couple who lived in Nova Scotia in the early 18th century and has a more homogeneous expres...

  12. Successful treatment of cataplexy in patients with early-infantile Niemann-Pick disease type C: use of tricyclic antidepressants.

    Science.gov (United States)

    Cak, Halime Tuna; Haliloğlu, Göknur; Düzgün, Gökçen; Yüce, Aysel; Topçu, Meral

    2014-11-01

    Cataplexy is a brief episode of bilateral loss of muscle tone with intact consciousness, triggered by a variety of strong emotions such as anger, laugh, humor or surprise and it is considered to represent the physiologic atonia of rapid eye movement sleep. On the other hand, Niemann-Pick type C is a neurodegenerative lysosomal storage disease, characterized by the accumulation of cholesterol and glycosphingolipids. Cataplexy is a relatively specific and common neurologic sign seen in almost 50% of all patients with Niemann-Pick type C. The aim of this report is to demonstrate the successful treatment of cataplexy with the use of a tricyclic antidepressant imipiramine, in two patients between the ages 6-9, with mild to moderate mental retardation, molecularly diagnosed as Niemann-Pick type C 1 and currently under miglustat treatment and to discuss the possible mechanisms of drug action in the light of cataplexy and Niemann-Pick type C pathophysiology. PMID:25139345

  13. Effect of dimethylsulfoxide on sphingomyelinase activity and cholesterol metabolism in Niemann-Pick type C fibroblasts

    OpenAIRE

    F.B. Scalco; R. Giugliani; P. Tobo; J. C. COELHO

    1999-01-01

    Niemann-Pick type C (NPC) fibroblasts present a large concentration of cholesterol in their cytoplasm due to a still unidentified deficiency in cholesterol metabolism. The influence of dimethylsulfoxide (DMSO) on the amount of intracellular cholesterol was measured in 8 cultures of normal fibroblasts and in 7 fibroblast cultures from NPC patients. DMSO was added to the fibroblast cultures at three different concentrations (1, 2 and 4%, v/v) and the cultures were incubated for 24 h. Sphingomye...

  14. The aurora sign in a patient with type B Niemann-Pick disease

    International Nuclear Information System (INIS)

    The aurora sign, a sonographic sign found on the sagittal and transverse view, refers to multiple bands of ring-down artifacts posterior to the right hemidiaphragm. Parenchymal lung disease should be suspected when this is present. We report a case of type B Niemann-Pick disease with pulmonary involvement and the aurora sign on abdominal sonography. High-resolution CT of the chest showed corresponding thickened interlobular septa. (orig.)

  15. Unusually prominent horizontal gaze palsy in a case of Niemann-Pick type C disease

    OpenAIRE

    Pritikanta Paul; Banashree Mondal; Arijit Kumar Mukherjee; Madhuparna Paul; Hrishikesh Kumar

    2013-01-01

    Niemann-Pick Type C disease (NPC) is a rare inherited metabolic disorder characterized by lipid accumulation and systemic manifestations due to multiple organ involvement. Only a few cases of NPC have been reported so far from India. Varying presentations and often lack of access to complex diagnostic tests have leaded to initial misdiagnosis on few occasions. We here report a provisionally diagnosed case of NPC with prominent horizontal gaze palsy along with characteristic vertical gaze pals...

  16. Niemann-Pick disease type C: a case series of Brazilian patients

    OpenAIRE

    Paulo José Lorenzoni; Elaine Cardoso; Ana C.S. Crippa; Charles Marques Lourenço; Fernanda Timm Seabra Souza; Roberto Giugliani; Maria Luiza Saraiva-Pereira; Salmo Raskin; Isac Bruck; Cláudia S. K. Kay; Rosana H. Scola; Werneck, Lineu C.; Teive, Hélio A.G.

    2014-01-01

    The aim of the study was to analyze a series of Brazilian patients with Niemann-Pick disease type C (NP-C). Method Correlations between clinical findings, laboratory data, molecular findings and treatment response are presented. Result The sample consisted of 5 patients aged 8 to 26 years. Vertical supranuclear gaze palsy, cerebellar ataxia, dementia, dystonia and dysarthria were present in all cases. Filipin staining showed the “classical” pattern in two patients and a “variant” pattern i...

  17. Lysosomal-specific Cholesterol Reduction by Biocleavable Polyrotaxanes for Ameliorating Niemann-Pick Type C Disease

    OpenAIRE

    Atsushi Tamura; Nobuhiko Yui

    2014-01-01

    Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal trafficking disorder, in which the cholesterols are abnormally accumulated in lysosomes. Recently, the β-cyclodextrin (CD) derivatives are revealed to show therapeutic effect for NPC disease through the removal of accumulated cholesterols in lysosomes. Herein, to enhance the therapeutic effect and reduce the toxicity of β-CD derivatives, biocleavable Pluronic/β-CD-based polyrotaxanes (PRXs) bearing terminal disulfide linkag...

  18. Exosome Secretion Ameliorates Lysosomal Storage of Cholesterol in Niemann-Pick Type C Disease*

    OpenAIRE

    STRAUSS, K; C. GOEBEL; Runz, H.; Mobius, W.; Weiss, S; Feussner, I.; M. Simons; A. Schneider

    2010-01-01

    Niemann-Pick type C1 disease is an autosomal-recessive lysosomal storage disorder. Loss of function of the npc1 gene leads to abnormal accumulation of free cholesterol and sphingolipids within the late endosomal and lysosomal compartments resulting in progressive neurodegeneration and dysmyelination. Here, we show that oligodendroglial cells secrete cholesterol by exosomes when challenged with cholesterol or U18666A, which induces late endosomal cholesterol accumulation. Up-regulation of exos...

  19. Oxidative Stress: A Pathogenic Mechanism for Niemann-Pick Type C Disease

    OpenAIRE

    Mary Carmen Vázquez; Elisa Balboa; Alvarez, Alejandra R.; Silvana Zanlungo

    2012-01-01

    Niemann-Pick type C (NPC) disease is a neurovisceral atypical lipid storage disorder involving the accumulation of cholesterol and other lipids in the late endocytic pathway. The pathogenic mechanism that links the accumulation of intracellular cholesterol with cell death in NPC disease in both the CNS and the liver is currently unknown. Oxidative stress has been observed in the livers and brains of NPC mice and in different NPC cellular models. Moreover, there is evidence of an elevation of ...

  20. The aurora sign in a patient with type B Niemann-Pick disease

    Energy Technology Data Exchange (ETDEWEB)

    Costa e. Silva, Eduardo J. da [Instituto Materno Infantil Professor Fernando Figueira, Departamento de Radiologia, Recife, Pernambuco (Brazil); IMIP, Departamento de Radiologia-Rua dos Coelhos, Recife, PE (Brazil); Cavalcanti de Albuquerque, Silvio; Queiroz Praxedes, Eduardo L. de; Amaral, Fernando J. do [Instituto Materno Infantil Professor Fernando Figueira, Departamento de Radiologia, Recife, Pernambuco (Brazil)

    2007-01-15

    The aurora sign, a sonographic sign found on the sagittal and transverse view, refers to multiple bands of ring-down artifacts posterior to the right hemidiaphragm. Parenchymal lung disease should be suspected when this is present. We report a case of type B Niemann-Pick disease with pulmonary involvement and the aurora sign on abdominal sonography. High-resolution CT of the chest showed corresponding thickened interlobular septa. (orig.)

  1. Rapid Diagnosis of 83 Patients with Niemann Pick Type C Disease and Related Cholesterol Transport Disorders by Cholestantriol Screening

    Directory of Open Access Journals (Sweden)

    Janine Reunert

    2016-02-01

    Full Text Available Niemann Pick type C (NP-C is a rare neurodegenerative disorder caused by an impairment of intracellular lipid transport. Due to the heterogeneous clinical phenotype and the lack of a reliable blood test, diagnosis and therapy are often delayed for years. In the cell, accumulating cholesterol leads to increased formation of oxysterols that can be used as a powerful screening parameter for NP-C. In a large scale study, we evaluated the oxysterol cholestane-3β,5α,6β-triol (c-triol as potential biomarker for a rapid diagnosis of NP-C. Using GC/MS, c-triol has been analyzed in 1902 plasma samples of patients with the suspicion for NP-C. Diagnosis in patients with elevated oxysterols was confirmed by genetic analysis. 71 new NP-C patients (69 NP-C1 and two NP-C2 and 12 Niemann Pick type A/B patients were identified. 24 new mutations in NPC1, one new mutation in NPC2 and three new mutations in the SMPD1 gene were found. Cholestane-3β,5α,6β-triol was elevated in Niemann Pick type C1, type C2, type A/B and in CESD disease. No other study has ever identified so many NP-C patients, proving that c-triol is a rapid and reliable biomarker to detect patients with NP-C disease and related cholesterol transport disorders. It should replace the filipin test as the first-line diagnostic assay.

  2. Rapid Diagnosis of 83 Patients with Niemann Pick Type C Disease and Related Cholesterol Transport Disorders by Cholestantriol Screening.

    Science.gov (United States)

    Reunert, Janine; Fobker, Manfred; Kannenberg, Frank; Du Chesne, Ingrid; Plate, Maria; Wellhausen, Judith; Rust, Stephan; Marquardt, Thorsten

    2016-02-01

    Niemann Pick type C (NP-C) is a rare neurodegenerative disorder caused by an impairment of intracellular lipid transport. Due to the heterogeneous clinical phenotype and the lack of a reliable blood test, diagnosis and therapy are often delayed for years. In the cell, accumulating cholesterol leads to increased formation of oxysterols that can be used as a powerful screening parameter for NP-C. In a large scale study, we evaluated the oxysterol cholestane-3β,5α,6β-triol (c-triol) as potential biomarker for a rapid diagnosis of NP-C. Using GC/MS, c-triol has been analyzed in 1902 plasma samples of patients with the suspicion for NP-C. Diagnosis in patients with elevated oxysterols was confirmed by genetic analysis. 71 new NP-C patients (69 NP-C1 and two NP-C2) and 12 Niemann Pick type A/B patients were identified. 24 new mutations in NPC1, one new mutation in NPC2 and three new mutations in the SMPD1 gene were found. Cholestane-3β,5α,6β-triol was elevated in Niemann Pick type C1, type C2, type A/B and in CESD disease. No other study has ever identified so many NP-C patients, proving that c-triol is a rapid and reliable biomarker to detect patients with NP-C disease and related cholesterol transport disorders. It should replace the filipin test as the first-line diagnostic assay. PMID:26981555

  3. Invariant Natural Killer T cells are not affected by lysosomal storage in patients with Niemann-Pick disease type C

    OpenAIRE

    Speak, Anneliese O; Platt, Nicholas; Salio, Mariolina; te Vruchte, Danielle Taylor; Smith, David A.; Shepherd, Dawn; Veerapen, Natacha; Besra, Gurdyal; Yanjanin, Nicole M.; Simmons, Louise; Imrie, Jackie; Wraith, James E.; Lachmann, Robin; Hartung, Ralf; Runz, Heiko

    2012-01-01

    Invariant Natural Killer T (iNKT) cells are a specialised subset of T cells that are restricted to the MHC class I like molecule, CD1d. The ligands for iNKT cells are lipids, with the canonical superagonist being α-galactosylceramide, a non-mammalian glycosphingolipid. Trafficking of CD1d through the lysosome is required for the development of murine iNKT cells. Niemann-Pick type C (NPC) disease is a lysosomal storage disorder caused by dysfunction in either of two lysosomal proteins, NPC1 or...

  4. Rapid Diagnosis of 83 Patients with Niemann Pick Type C Disease and Related Cholesterol Transport Disorders by Cholestantriol Screening

    OpenAIRE

    Janine Reunert; Manfred Fobker; Frank Kannenberg; Ingrid Du Chesne; Maria Plate; Judith Wellhausen; Stephan Rust; Thorsten Marquardt

    2016-01-01

    Niemann Pick type C (NP-C) is a rare neurodegenerative disorder caused by an impairment of intracellular lipid transport. Due to the heterogeneous clinical phenotype and the lack of a reliable blood test, diagnosis and therapy are often delayed for years. In the cell, accumulating cholesterol leads to increased formation of oxysterols that can be used as a powerful screening parameter for NP-C. In a large scale study, we evaluated the oxysterol cholestane-3β,5α,6β-triol (c-triol) as potential...

  5. Impaired Autophagy in the Lipid-Storage Disorder Niemann-Pick Type C1 Disease

    Directory of Open Access Journals (Sweden)

    Sovan Sarkar

    2013-12-01

    Full Text Available Autophagy dysfunction has been implicated in misfolded protein accumulation and cellular toxicity in several diseases. Whether alterations in autophagy also contribute to the pathology of lipid-storage disorders is not clear. Here, we show defective autophagy in Niemann-Pick type C1 (NPC1 disease associated with cholesterol accumulation, where the maturation of autophagosomes is impaired because of defective amphisome formation caused by failure in SNARE machinery, whereas the lysosomal proteolytic function remains unaffected. Expression of functional NPC1 protein rescues this defect. Inhibition of autophagy also causes cholesterol accumulation. Compromised autophagy was seen in disease-affected organs of Npc1 mutant mice. Of potential therapeutic relevance is that HP-β-cyclodextrin, which is used for cholesterol-depletion treatment, impedes autophagy, whereas stimulating autophagy restores its function independent of amphisome formation. Our data suggest that a low dose of HP-β-cyclodextrin that does not perturb autophagy, coupled with an autophagy inducer, may provide a rational treatment strategy for NPC1 disease.

  6. Diagnostic workup and management of patients with suspected Niemann-Pick type C disease.

    Science.gov (United States)

    Papandreou, Apostolos; Gissen, Paul

    2016-05-01

    Niemann-Pick type C (NP-C) disease is a neurovisceral disorder caused by mutations in the NPC1 and NPC2 genes. It is characterized by lysosomal storage of a broad range of lipids as a result of abnormal intracellular lipid trafficking. Typically patients develop neurodegeneration; however, the speed of disease progression is variable. The exact functions of NPC1 and NPC2 proteins have not been determined and therefore the molecular pathophysiology of NP-C is still not clearly understood. Due to the disease's rarity and clinical heterogeneity, delays from symptom onset to diagnosis and treatment initiation are common. Current therapeutic approaches focus on multidisciplinary symptom control and deceleration (rather than reversal) of disease progression. Thus identification of cases at early stages of disease is particularly important. Recent advances in genetic and biochemical testing have resulted in the generation of relatively non-invasive, quick and cost-effective laboratory assays that are highly sensitive and specific and have the capacity to enhance the clinicians' ability to reach a diagnosis earlier. Miglustat is a compound recently licensed in many countries for the treatment of NP-C that has been shown to decelerate neurological regression, whereas many other promising drugs are currently being trialled in preclinical models or human studies. This review summarizes key clinical, genetic and biochemical features of NP-C, suggests a simple diagnostic investigation strategy and gives an overview of available therapeutic options as well as potential novel treatments currently under development. PMID:27134677

  7. Cell-autonomous death of cerebellar purkinje neurons with autophagy in niemann-pick type C disease.

    Directory of Open Access Journals (Sweden)

    2005-07-01

    Full Text Available Niemann-Pick type C is a neurodegenerative lysosomal storage disorder caused by mutations in either of two genes, npc1 and npc2. Cells lacking Npc1, which is a transmembrane protein related to the Hedgehog receptor Patched, or Npc2, which is a secreted cholesterol-binding protein, have aberrant organelle trafficking and accumulate large quantities of cholesterol and other lipids. Though the Npc proteins are produced by all cells, cerebellar Purkinje neurons are especially sensitive to loss of Npc function. Since Niemann-Pick type C disease involves circulating molecules such as sterols and steroids and a robust inflammatory response within the brain parenchyma, it is crucial to determine whether external factors affect the survival of Purkinje cells (PCs. We investigated the basis of neurodegeneration in chimeric mice that have functional npc1 in only some cells. Death of mutant npc1 cells was not prevented by neighboring wild-type cells, and wild-type PCs were not poisoned by surrounding mutant npc1 cells. PCs undergoing cell-autonomous degeneration have features consistent with autophagic cell death. Chimeric mice exhibited a remarkable delay and reduction of wasting and ataxia despite their substantial amount of mutant tissue and dying cells, revealing a robust mechanism that partially compensates for massive PC death.

  8. Cell-autonomous death of cerebellar purkinje neurons with autophagy in Niemann-Pick type C disease.

    Directory of Open Access Journals (Sweden)

    Dennis C Ko

    2005-07-01

    Full Text Available Niemann-Pick type C is a neurodegenerative lysosomal storage disorder caused by mutations in either of two genes, npc1 and npc2. Cells lacking Npc1, which is a transmembrane protein related to the Hedgehog receptor Patched, or Npc2, which is a secreted cholesterol-binding protein, have aberrant organelle trafficking and accumulate large quantities of cholesterol and other lipids. Though the Npc proteins are produced by all cells, cerebellar Purkinje neurons are especially sensitive to loss of Npc function. Since Niemann-Pick type C disease involves circulating molecules such as sterols and steroids and a robust inflammatory response within the brain parenchyma, it is crucial to determine whether external factors affect the survival of Purkinje cells (PCs. We investigated the basis of neurodegeneration in chimeric mice that have functional npc1 in only some cells. Death of mutant npc1 cells was not prevented by neighboring wild-type cells, and wild-type PCs were not poisoned by surrounding mutant npc1 cells. PCs undergoing cell-autonomous degeneration have features consistent with autophagic cell death. Chimeric mice exhibited a remarkable delay and reduction of wasting and ataxia despite their substantial amount of mutant tissue and dying cells, revealing a robust mechanism that partially compensates for massive PC death.

  9. δ-Tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders.

    Science.gov (United States)

    Xu, Miao; Liu, Ke; Swaroop, Manju; Porter, Forbes D; Sidhu, Rohini; Firnkes, Sally; Finkes, Sally; Ory, Daniel S; Marugan, Juan J; Xiao, Jingbo; Southall, Noel; Pavan, William J; Davidson, Cristin; Walkley, Steven U; Remaley, Alan T; Baxa, Ulrich; Sun, Wei; McKew, John C; Austin, Christopher P; Zheng, Wei

    2012-11-16

    Niemann-Pick disease type C (NPC) and Wolman disease are two members of a family of storage disorders caused by mutations of genes encoding lysosomal proteins. Deficiency in function of either the NPC1 or NPC2 protein in NPC disease or lysosomal acid lipase in Wolman disease results in defective cellular cholesterol trafficking. Lysosomal accumulation of cholesterol and enlarged lysosomes are shared phenotypic characteristics of both NPC and Wolman cells. Utilizing a phenotypic screen of an approved drug collection, we found that δ-tocopherol effectively reduced lysosomal cholesterol accumulation, decreased lysosomal volume, increased cholesterol efflux, and alleviated pathological phenotypes in both NPC1 and Wolman fibroblasts. Reduction of these abnormalities may be mediated by a δ-tocopherol-induced intracellular Ca(2+) response and subsequent enhancement of lysosomal exocytosis. Consistent with a general mechanism for reduction of lysosomal lipid accumulation, we also found that δ-tocopherol reduces pathological phenotypes in patient fibroblasts from other lysosomal storage diseases, including NPC2, Batten (ceroid lipofuscinosis, neuronal 2, CLN2), Fabry, Farber, Niemann-Pick disease type A, Sanfilippo type B (mucopolysaccharidosis type IIIB, MPSIIIB), and Tay-Sachs. Our data suggest that regulated exocytosis may represent a potential therapeutic target for reduction of lysosomal storage in this class of diseases. PMID:23035117

  10. Unusually prominent horizontal gaze palsy in a case of Niemann-Pick type C disease

    Directory of Open Access Journals (Sweden)

    Pritikanta Paul

    2013-01-01

    Full Text Available Niemann-Pick Type C disease (NPC is a rare inherited metabolic disorder characterized by lipid accumulation and systemic manifestations due to multiple organ involvement. Only a few cases of NPC have been reported so far from India. Varying presentations and often lack of access to complex diagnostic tests have leaded to initial misdiagnosis on few occasions. We here report a provisionally diagnosed case of NPC with prominent horizontal gaze palsy along with characteristic vertical gaze palsy and normal findings on microscopic examination of skin biopsy specimen.

  11. Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease

    Science.gov (United States)

    Wassif, Christopher A.; Gray, James; Burkert, Kathryn R.; Smith, David A.; Morris, Lauren; Cologna, Stephanie M.; Peer, Cody J.; Sissung, Tristan M.; Uscatu, Constantin-Daniel; Figg, William D.; Pavan, William J.; Vite, Charles H.; Porter, Forbes D.; Platt, Frances M.

    2016-01-01

    Niemann-Pick type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 gene. NPC is characterised by storage of multiple lipids in the late endosomal/lysosomal compartment, resulting in cellular and organ system dysfunction. The underlying molecular mechanisms that lead to the range of clinical presentations in NPC are not fully understood. While evaluating potential small molecule therapies in Npc1-/- mice, we observed a consistent pattern of toxicity associated with drugs metabolised by the cytochrome P450 system, suggesting a potential drug metabolism defect in NPC1 disease. Investigation of the P450 system in the context of NPC1 dysfunction revealed significant changes in the gene expression of many P450 associated genes across the full lifespan of Npc1-/- mice, decreased activity of cytochrome P450 reductase, and a global decrease of multiple cytochrome P450 catalysed dealkylation reactions. In vivo drug metabolism studies using a prototypic P450 metabolised drug, midazolam, confirmed dysfunction in drug clearance in the Npc1-/- mouse. Expression of the Phase II enzyme uridinediphosphate-glucuronosyltransferase (UGT) was also significantly reduced in Npc1-/- mice. Interestingly, reduced activity within the P450 system was also observed in heterozygous Npc1+/- mice. The reduced activity of P450 enzymes may be the result of bile acid deficiency/imbalance in Npc1-/- mice, as bile acid treatment significantly rescued P450 enzyme activity in Npc1-/- mice and has the potential to be an adjunctive therapy for NPC disease patients. The dysfunction in the cytochrome P450 system were recapitulated in the NPC1 feline model. Additionally, we present the first evidence that there are alterations in the P450 system in NPC1 patients. PMID:27019000

  12. Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease.

    Science.gov (United States)

    Nicoli, Elena-Raluca; Al Eisa, Nada; Cluzeau, Celine V M; Wassif, Christopher A; Gray, James; Burkert, Kathryn R; Smith, David A; Morris, Lauren; Cologna, Stephanie M; Peer, Cody J; Sissung, Tristan M; Uscatu, Constantin-Daniel; Figg, William D; Pavan, William J; Vite, Charles H; Porter, Forbes D; Platt, Frances M

    2016-01-01

    Niemann-Pick type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 gene. NPC is characterised by storage of multiple lipids in the late endosomal/lysosomal compartment, resulting in cellular and organ system dysfunction. The underlying molecular mechanisms that lead to the range of clinical presentations in NPC are not fully understood. While evaluating potential small molecule therapies in Npc1-/- mice, we observed a consistent pattern of toxicity associated with drugs metabolised by the cytochrome P450 system, suggesting a potential drug metabolism defect in NPC1 disease. Investigation of the P450 system in the context of NPC1 dysfunction revealed significant changes in the gene expression of many P450 associated genes across the full lifespan of Npc1-/- mice, decreased activity of cytochrome P450 reductase, and a global decrease of multiple cytochrome P450 catalysed dealkylation reactions. In vivo drug metabolism studies using a prototypic P450 metabolised drug, midazolam, confirmed dysfunction in drug clearance in the Npc1-/- mouse. Expression of the Phase II enzyme uridinediphosphate-glucuronosyltransferase (UGT) was also significantly reduced in Npc1-/- mice. Interestingly, reduced activity within the P450 system was also observed in heterozygous Npc1+/- mice. The reduced activity of P450 enzymes may be the result of bile acid deficiency/imbalance in Npc1-/- mice, as bile acid treatment significantly rescued P450 enzyme activity in Npc1-/- mice and has the potential to be an adjunctive therapy for NPC disease patients. The dysfunction in the cytochrome P450 system were recapitulated in the NPC1 feline model. Additionally, we present the first evidence that there are alterations in the P450 system in NPC1 patients. PMID:27019000

  13. Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease.

    Directory of Open Access Journals (Sweden)

    Elena-Raluca Nicoli

    Full Text Available Niemann-Pick type C (NPC disease is a neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 gene. NPC is characterised by storage of multiple lipids in the late endosomal/lysosomal compartment, resulting in cellular and organ system dysfunction. The underlying molecular mechanisms that lead to the range of clinical presentations in NPC are not fully understood. While evaluating potential small molecule therapies in Npc1-/- mice, we observed a consistent pattern of toxicity associated with drugs metabolised by the cytochrome P450 system, suggesting a potential drug metabolism defect in NPC1 disease. Investigation of the P450 system in the context of NPC1 dysfunction revealed significant changes in the gene expression of many P450 associated genes across the full lifespan of Npc1-/- mice, decreased activity of cytochrome P450 reductase, and a global decrease of multiple cytochrome P450 catalysed dealkylation reactions. In vivo drug metabolism studies using a prototypic P450 metabolised drug, midazolam, confirmed dysfunction in drug clearance in the Npc1-/- mouse. Expression of the Phase II enzyme uridinediphosphate-glucuronosyltransferase (UGT was also significantly reduced in Npc1-/- mice. Interestingly, reduced activity within the P450 system was also observed in heterozygous Npc1+/- mice. The reduced activity of P450 enzymes may be the result of bile acid deficiency/imbalance in Npc1-/- mice, as bile acid treatment significantly rescued P450 enzyme activity in Npc1-/- mice and has the potential to be an adjunctive therapy for NPC disease patients. The dysfunction in the cytochrome P450 system were recapitulated in the NPC1 feline model. Additionally, we present the first evidence that there are alterations in the P450 system in NPC1 patients.

  14. NIEMANN PICK DISEASE – A CASE REPORT

    OpenAIRE

    Vaibhav; Mrs.Joshi

    2012-01-01

    Niemann Pick Disease ( NPD) is a rare autosomal re cessive metabolic disease characterized by lysosomal lipid storage. The diseas e is caused by deficiency of enzyme, acid sphingomyelinase (ASM) which leads to accumulation of sphingomyelin & other lipids in reticuloendothelial cells of various organs like li ver, spleen, bone marrow, lymph node, brain, nerves and kidney. Four types of the disease have be en identified which are A, B, C and D. The type C is divide...

  15. Changes in Caries Risk and Activity of a 9-Year-Old Patient with Niemann-Pick Disease Type C

    OpenAIRE

    Késsia Suênia Fidelis Mesquita-Guimarães; Andiara De Rossi; Aldevina Campos de Freitas; Paulo Nelson-Filho; Raquel Assed da Silva; Alexandra Mussolino Queiroz

    2015-01-01

    Objective. This case report describes the changes in caries risk and activity and dental treatment of a 9-year-old patient who presented with signs and symptoms of Niemann-Pick disease type C (NPC). Treatment. The preventive dental treatment included instructions to caregivers for oral hygiene and diet. A calcium hydroxide pulpotomy and restorative dental treatments were performed in a dental office with desensitization techniques and behavioral management. The patient was attended every 3 mo...

  16. Case Report: Genetic analysis and anesthetic management of a child with Niemann-Pick disease Type A

    OpenAIRE

    Priti G. Dalal; Melissa Coleman; Meagan Horst; Dorothy Rocourt; Ladda, Roger L.; Piotr K. Janicki

    2015-01-01

    A 14-month-old child, recently diagnosed with Niemann-Pick disease type A, presented for a laparoscopic placement of a gastrostomy tube under general anesthesia. The disease was confirmed and further characterized by genetic testing, which revealed evidence of the presence of two known pathogenic mutations in the SMPD1 gene, and enzyme studies showed a corresponding very low level of enzymatic activity of acidic sphingomyelinase. The anesthetic management involved strategies to manage an anti...

  17. Molecular Pathways for Intracellular Cholesterol Accumulation: Common Pathogenic Mechanisms in Niemann-Pick Disease Type C and Cystic Fibrosis

    OpenAIRE

    Cianciola, Nicholas L.; Carlin, Cathleen R.; Kelley, Thomas J.

    2011-01-01

    It has been less than two decades since the underlying genetic defects in Niemann-Pick disease Type C were first identified. These defects impair function of two proteins with a direct role in lipid trafficking, resulting in deposition of free cholesterol within late endosomal compartments and a multitude of effects on cell function and clinical manifestations. The rapid pace of research in this area has vastly improved our overall understanding of intracellular cholesterol homeostasis. Exces...

  18. Stem Cells in Niemann-Pick Disease

    Directory of Open Access Journals (Sweden)

    Sun-Jung Kim

    2008-01-01

    Full Text Available Neural stem cells are multi-potent and able to self renew to maintain its character throughout the life. Loss of self renewal ability of stem cells prevents recovery or replacement of cells damaged by disease with new cells. The Niemann-Pick type C1 (NPC1 disease is one of the neurodegenerative diseases, caused by a mutation of NPC1 gene which affects the function of NPC1 protein. We reported that NPC 1 gene deficiency could lead to lack of the self renewal ability of neural stem cells in Niemann pick type C disease. We also investigated many genes which are involved in stem cells proliferation and differentiation by gene profile in NPC mice.

  19. Olfactory deficits in Niemann-Pick type C1 (NPC1 disease.

    Directory of Open Access Journals (Sweden)

    Marina Hovakimyan

    Full Text Available BACKGROUND: Niemann-Pick type C disease (NPC is a rare autosomal recessive lipid storage disease characterized by progressive neurodegeneration. As only a few studies have been conducted on the impact of NPC on sensory systems, we used a mutant mouse model (NPC1(-/- to examine the effects of this disorder to morphologically distinct regions of the olfactory system, namely the olfactory epithelium (OE and olfactory bulb (OB. METHODOLOGY/PRINCIPAL FINDINGS: For structural and functional analysis immunohistochemistry, electron microscopy, western blotting, and electrophysiology have been applied. For histochemistry and western blotting, we used antibodies against a series of neuronal and glia marker proteins, as well as macrophage markers. NPC1(-/- animals present myelin-like lysosomal deposits in virtually all types of cells of the peripheral and central olfactory system. Especially supporting cells of the OE and central glia cells are affected, resulting in pronounced astrocytosis and microgliosis in the OB and other olfactory cortices. Up-regulation of Galectin-3, Cathepsin D and GFAP in the cortical layers of the OB underlines the critical role and location of the OB as a possible entrance gate for noxious substances. Unmyelinated olfactory afferents of the lamina propria seem less affected than ensheathing cells. Supporting the structural findings, electro-olfactometry of the olfactory mucosa suggests that NPC1(-/- animals exhibit olfactory and trigeminal deficits. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate a pronounced neurodegeneration and glia activation in the olfactory system of NPC1(-/-, which is accompanied by sensory deficits.

  20. Effect of dimethylsulfoxide on sphingomyelinase activity and cholesterol metabolism in Niemann-Pick type C fibroblasts

    Directory of Open Access Journals (Sweden)

    Scalco F.B.

    1999-01-01

    Full Text Available Niemann-Pick type C (NPC fibroblasts present a large concentration of cholesterol in their cytoplasm due to a still unidentified deficiency in cholesterol metabolism. The influence of dimethylsulfoxide (DMSO on the amount of intracellular cholesterol was measured in 8 cultures of normal fibroblasts and in 7 fibroblast cultures from NPC patients. DMSO was added to the fibroblast cultures at three different concentrations (1, 2 and 4%, v/v and the cultures were incubated for 24 h. Sphingomyelinase activity was significantly increased in both groups of cells only when incubated with 2% DMSO (59.4 ± 9.1 and 77.0 ± 9.1 nmol h-1 mg protein-1, controls without and with 2% DMSO, respectively; 47.7 ± 5.2 and 55.8 ± 4.1 nmol h-1 mg protein-1, NPC without and with 2% DMSO, respectively. However, none of the DMSO concentrations used altered the amount of cholesterol in the cytoplasm of NPC cells (0.704 ± 0.049, 0.659 ± 0.041, 0.688 ± 0.063 and 0.733 ± 0.088 mg/mg protein, without DMSO, 1% DMSO, 2% DMSO and 4% DMSO, respectively. This finding suggests that sphingomyelinase deficiency is a secondary defect in NPC and shows that DMSO failed to remove the stored cholesterol. These data do not support the use of DMSO in the treatment of NPC patients.

  1. In vivo quantification of brain injury in adult Niemann-Pick Disease Type C.

    Science.gov (United States)

    Zaaraoui, Wafaa; Crespy, Lydie; Rico, Audrey; Faivre, Anthony; Soulier, Elisabeth; Confort-Gouny, Sylviane; Cozzone, Patrick J; Pelletier, Jean; Ranjeva, Jean-Philippe; Kaphan, Elsa; Audoin, Bertrand

    2011-06-01

    Development of surrogate markers is necessary to assess the potential efficacy of new therapeutics in Niemann-Pick Disease Type C (NP-C). In the present study, magnetization transfer ratio (MTR) imaging, a quantitative MRI imaging technique sensitive to subtle brain microstructural changes, was applied in two patients suffering from adult NP-C. Statistical mapping analysis was performed to compare each patient's MTR maps with those of a group of 34 healthy controls to quantify and localize the extent of brain injury of each patient. Using this method, pathological changes were evidenced in the cerebellum, the thalami and the lenticular nuclei in both patients and also in the fronto-temporal cortices in the patient with the worse functional deficit. In addition, white matter changes were located in the midbrain, the cerebellum and the fronto-temporal lobes in the patient with the higher level of disability and in only one limited periventricular white matter region in the other patient. A 6-month follow-up was performed in the patient with the lower functional deficit and evidenced significant extension of grey matter (GM) and white matter (WM) injuries during the following period (14% of increased injury for GM and 53% for WM). This study demonstrates that significant brain injury related to clinical deficit can be assessed in vivo in adult NP-C using MTR imaging. Although preliminary, these findings suggest that MTR imaging may be a relevant candidate for the development of biomarker in NP-C. PMID:21397539

  2. Reducing GBA2 Activity Ameliorates Neuropathology in Niemann-Pick Type C Mice.

    Directory of Open Access Journals (Sweden)

    André R A Marques

    Full Text Available The enzyme glucocerebrosidase (GBA hydrolyses glucosylceramide (GlcCer in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genetic risk factor for Parkinsonism. Disturbed metabolism of GlcCer may therefore play a role in neuropathology. Besides lysosomal GBA, cells also contain a non-lysosomal glucosylceramidase (GBA2. Given that the two β-glucosidases share substrates, we speculated that over-activity of GBA2 during severe GBA impairment might influence neuropathology. This hypothesis was studied in Niemann-Pick type C (Npc1-/- mice showing secondary deficiency in GBA in various tissues. Here we report that GBA2 activity is indeed increased in the brain of Npc1-/- mice. We found that GBA2 is particularly abundant in Purkinje cells (PCs, one of the most affected neuronal populations in NPC disease. Inhibiting GBA2 in Npc1-/- mice with a brain-permeable low nanomolar inhibitor significantly improved motor coordination and extended lifespan in the absence of correction in cholesterol and ganglioside abnormalities. This trend was recapitulated, although not to full extent, by introducing a genetic loss of GBA2 in Npc1-/- mice. Our findings point to GBA2 activity as therapeutic target in NPC.

  3. Development of a bile acid-based newborn screen for Niemann-Pick disease type C.

    Science.gov (United States)

    Jiang, Xuntian; Sidhu, Rohini; Mydock-McGrane, Laurel; Hsu, Fong-Fu; Covey, Douglas F; Scherrer, David E; Earley, Brian; Gale, Sarah E; Farhat, Nicole Y; Porter, Forbes D; Dietzen, Dennis J; Orsini, Joseph J; Berry-Kravis, Elizabeth; Zhang, Xiaokui; Reunert, Janice; Marquardt, Thorsten; Runz, Heiko; Giugliani, Roberto; Schaffer, Jean E; Ory, Daniel S

    2016-05-01

    Niemann-Pick disease type C (NPC) is a fatal, neurodegenerative, cholesterol storage disorder. With new therapeutics in clinical trials, it is imperative to improve diagnostics and facilitate early intervention. We used metabolomic profiling to identify potential markers and discovered three unknown bile acids that were increased in plasma from NPC but not control subjects. The bile acids most elevated in the NPC subjects were identified as 3β,5α,6β-trihydroxycholanic acid and its glycine conjugate, which were shown to be metabolites of cholestane-3β,5α,6β-triol, an oxysterol elevated in NPC. A high-throughput mass spectrometry-based method was developed and validated to measure the glycine-conjugated bile acid in dried blood spots. Analysis of dried blood spots from 4992 controls, 134 NPC carriers, and 44 NPC subjects provided 100% sensitivity and specificity in the study samples. Quantification of the bile acid in dried blood spots, therefore, provides the basis for a newborn screen for NPC that is ready for piloting in newborn screening programs. PMID:27147587

  4. Niemann-Pick disease type C: a case series of Brazilian patients

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    Paulo José Lorenzoni

    2014-03-01

    Full Text Available The aim of the study was to analyze a series of Brazilian patients with Niemann-Pick disease type C (NP-C. Method Correlations between clinical findings, laboratory data, molecular findings and treatment response are presented. Result The sample consisted of 5 patients aged 8 to 26 years. Vertical supranuclear gaze palsy, cerebellar ataxia, dementia, dystonia and dysarthria were present in all cases. Filipin staining showed the “classical” pattern in two patients and a “variant” pattern in three patients. Molecular analysis found mutations in the NPC1 gene in all alleles. Miglustat treatment was administered to 4 patients. Conclusion Although filipin staining should be used to confirm the diagnosis, bone marrow sea-blue histiocytes often help to diagnosis of NP-C. The p.P1007A mutation seems to be correlated with the “variant” pattern in filipin staining. Miglustat treatment response seems to be correlated with the age at disease onset and disability scale score at diagnosis.

  5. Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target.

    Science.gov (United States)

    Cougnoux, A; Cluzeau, C; Mitra, S; Li, R; Williams, I; Burkert, K; Xu, X; Wassif, C A; Zheng, W; Porter, F D

    2016-01-01

    Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative, lysosomal storage disorder due to mutation of the NPC1 gene. The NPC1 phenotype is characterized by progressive neuronal dysfunction, including cerebellar ataxia and dementia. There is histological evidence of neuroinflammation and progressive neuronal loss, with cerebellar Purkinje cells particularly vulnerable to loss of NPC1 function. Necroptosis was evaluated as a mechanism of neuronal loss. Receptor-interacting protein kinase 1 (RIP1) and RIP3 are key components of the necrosomal complex that regulates necroptotic cell death. We report increased expression of RIP1 and RIP3 in NPC1 fibroblasts, NPC1 iPS cell-derived neuronal precursors, and in cerebellar tissue from both NPC1 mice and patients. Our data suggest a positive correlation between NPC1 neurological disease severity and assembly of the necrosome complex. Furthermore, we demonstrate that pharmacological inhibition of RIP1 decreases cell death both in vitro and in vivo. Treatment of Npc1-mutant mice with necrostatin-1, an allosteric inhibitor of RIP1, significantly delayed cerebellar Purkinje cell loss, progression of neurological symptoms, and death. Collectively, our data identified necroptosis as a key component of the molecular network that contributes to neuronal loss in NPC1 and establish that inhibition of necroptosis is a potential therapeutic intervention. PMID:26986514

  6. Mitochondrial dysfunction in fibroblasts derived from patients with Niemann-Pick type C disease.

    Science.gov (United States)

    Woś, Marcin; Szczepanowska, Joanna; Pikuła, Sławomir; Tylki-Szymańska, Anna; Zabłocki, Krzysztof; Bandorowicz-Pikuła, Joanna

    2016-03-01

    Mutations in the NPC1 or NPC2 genes lead to Niemann-Pick type C (NPC) disease, a rare lysosomal storage disorder characterized by progressive neurodegeneration. These mutations result in cholesterol and glycosphingolipid accumulation in the late endosomal/lysosomal compartment. Complications in the storage of cholesterol in NPC1 mutant cells are associated with other anomalies, such as altered distribution of intracellular organelles and properties of the plasma membrane. The pathomechanism of NPC disease is largely unknown. Interestingly, other storage diseases such as Gaucher and Farber diseases are accompanied by severe mitochondrial dysfunction. This prompted us to investigate the effect of absence or dysfunction of the NPC1 protein on mitochondrial properties to confirm or deny a putative relationship between NPC1 mutations and mitochondrial function. This study was performed on primary skin fibroblasts derived from skin biopsies of two NPC patients, carrying mutations in the NPC1 gene. We observed altered organization of mitochondria in NPC1 mutant cells, significant enrichment in mitochondrial cholesterol content, increased respiration, altered composition of the respiratory chain complex, and substantial reduction in cellular ATP level. Thus, a primary lysosomal defect in NPC1 mutant fibroblasts is accompanied by deregulation of the organization and function of the mitochondrial network. PMID:26869201

  7. A case of variant biochemical phenotype of Niemann-Pick disease type C accompanying savant syndrome.

    Science.gov (United States)

    Hamatani, Mio; Jingami, Naoto; Uemura, Kengo; Nakasone, Naoe; Kinoshita, Hisanori; Yamakado, Hodaka; Ninomiya, Haruaki; Takahashi, Ryosuke

    2016-06-22

    A 40-year-old man was referred to our hospital because of vertical supranuclear gaze palsy, frequent sudden loss of muscle tonus and ataxia for several years. He had a history of prolonged neonatal jaundice. He was given a diagnosis of autism in his childhood, followed by a diagnosis of schizophrenia in his teenage. He also developed a savant skill of calendar calculating. (123)I-IMP-SPECT showed decreased cerebral blood flow in the left frontotemporal lobe as often seen in savant syndrome. Although genetic analysis of NPC1 and NPC2 revealed no pathogenic mutation, filipin staining of cultured fibroblasts from his biopsied skin revealed a certain amount of intracellular cholesterol storage pattern, indicating a variant biochemical phenotype of Niemann-Pick disease type C (NPC). The diagnosis of adulthood onset NPC is difficult and challenging, especially for neurologists, because the symptoms and signs are not as clear as those in the classical childhood onset NPC and this subtype is not yet widely known. However, the diagnosis can be made by a combination of filipin staining of fibroblast and/or gene analysis. As a disease-specific therapy for NPC has been approved in Japan, the diagnosis of NPC is of significance. PMID:27181747

  8. Glucosylceramidase mass and subcellular localization are modulated by cholesterol in Niemann-Pick disease type C.

    Science.gov (United States)

    Salvioli, Rosa; Scarpa, Susanna; Ciaffoni, Fiorella; Tatti, Massimo; Ramoni, Carlo; Vanier, Marie T; Vaccaro, Anna Maria

    2004-04-23

    Niemann-Pick disease type C (NPC) is characterized by the accumulation of cholesterol and sphingolipids in the late endosomal/lysosomal compartment. The mechanism by which the concentration of sphingolipids such as glucosylceramide is increased in this disease is poorly understood. We have found that, in NPC fibroblasts, the cholesterol storage affects the stability of glucosylceramidase (GCase), decreasing its mass and activity; a reduction of cholesterol raises the level of GCase to nearly normal values. GCase is activated and stabilized by saposin C (Sap C) and anionic phospholipids. Here we show by immunofluorescence microscopy that in normal fibroblasts, GCase, Sap C, and lysobisphosphatidic acid (LBPA), the most abundant anionic phospholipid in the endolysosomal system, reside in the same intracellular vesicular structures. In contrast, the colocalization of GCase, Sap C, and LBPA is markedly impaired in NPC fibroblasts but can be re-established by cholesterol depletion. These data show for the first time that the level of cholesterol modulates the interaction of GCase with its protein and lipid activators, namely Sap C and LBPA, regulating the GCase activity and stability. PMID:14757764

  9. Generalized Lichen Nitidus in a boy with Niemann-Pick disease type B*

    OpenAIRE

    Teixeira, Vera Barreto; Coutinho, Inês; CARDOSO, José Carlos; Tellhechea, Óscar

    2013-01-01

    Generalized lichen nitidus is an uncommon chronic inflammatory dermatosis with very characteristic histological findings. Its pathogenesis is still unclear; very rarely it has been associated with genetic disorders. Herein we report the case of a 12-year-old boy with Niemann-Pick disease who developed generalized lichen nitidus.

  10. Characterisation of two deletions involving NPC1 and flanking genes in Niemann-Pick type C disease patients.

    Science.gov (United States)

    Rodríguez-Pascau, Laura; Toma, Claudio; Macías-Vidal, Judit; Cozar, Mónica; Cormand, Bru; Lykopoulou, Lilia; Coll, Maria Josep; Grinberg, Daniel; Vilageliu, Lluïsa

    2012-12-01

    Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal disorder characterised by the accumulation of a complex pattern of lipids in the lysosomal-late endosomal system. More than 300 disease-causing mutations have been identified so far in the NPC1 and NPC2 genes, including indel, missense, nonsense and splicing mutations. Only one genomic deletion, of more than 23 kb, has been previously reported. We describe two larger structural variants, encompassing NPC1 and flanking genes, as a cause of the disease. QMPSF, SNP inheritance and CytoScan® HD Array were used to confirm and further characterise the presence of hemizygous deletions in two patients. One of the patients (NPC-57) bore a previously described missense mutation (p.T1066N) and an inherited deletion that included NPC1, C18orf8 and part of ANKRD29 gene. The second patient (NPC-G1) had a 1-bp deletion (c.852delT; p.F284Lfs*26) and a deletion encompassing the promoter region and exons 1-10 of NPC1 and the adjacent ANKRD29 and LAMA3. This study characterised two novel chromosomal microdeletions at 18q11-q12 that cause NPC disease and provide insight into missing NPC1 mutant alleles. PMID:23142039

  11. Quantitative comparison of the efficacy of various compounds in lowering intracellular cholesterol levels in Niemann-Pick type C fibroblasts.

    Directory of Open Access Journals (Sweden)

    Zachary T Wehrmann

    Full Text Available Niemann-Pick Type C disease (NPC is a lethal, autosomal recessive disorder caused by mutations in the NPC1 and NPC2 cholesterol transport proteins. NPC's hallmark symptoms include an accumulation of unesterified cholesterol and other lipids in the late endosomal and lysosomal cellular compartments, causing progressive neurodegeneration and death. Although the age of onset may vary in those affected, NPC most often manifests in juveniles, and is usually fatal before adolescence. In this study, we investigated the effects of various drugs, many of which modify the epigenetic control of NPC1/NPC2 gene expression, in lowering the otherwise harmful elevated intracellular cholesterol levels in NPC cells. Our studies utilized a previously described image analysis technique, which allowed us to make quantitative comparisons of the efficacy of these drugs in lowering cholesterol levels in a common NPC1 mutant model. Of the drugs analyzed, several that have been previously studied (vorinostat, panobinostat, and β-cyclodextrin significantly lowered the relative amount of unesterified cellular cholesterol, consistent with earlier observations. In addition, a novel potential treatment, rapamycin, likewise alleviated the NPC phenotype. We also studied combinations of effective compounds with β-cyclodextrin; the addition of β-cyclodextrin significantly enhanced the cholesterol-lowering activity of vorinostat and panobinostat, but had mixed effects with rapamycin. Collectively, these results may provide a basis for the eventual development of improved NPC therapies.

  12. Complement is dispensable for neurodegeneration in Niemann-Pick disease type C

    Directory of Open Access Journals (Sweden)

    Lopez Manuel E

    2012-09-01

    Full Text Available Abstract Background The immune system has been implicated in neurodegeneration during development and disease. In various studies, the absence of complement (that is, C1q deficiency impeded the elimination of apoptotic neurons, allowing survival. In the genetic lysosomal storage disease Niemann-Pick C (NPC, caused by loss of NPC1 function, the expression of complement system components, C1q especially, is elevated in degenerating brain regions of Npc1-/- mice. Here we test whether complement is mediating neurodegeneration in NPC disease. Findings In normal mature mice, C1q mRNA was found in neurons, particularly cerebellar Purkinje neurons (PNs. In Npc1-/- mice, C1q mRNA was additionally found in activated microglia, which accumulate during disease progression and PN loss. Interestingly, C1q was not enriched on or near degenerating neurons. Instead, C1q was concentrated in other brain regions, where it partially co-localized with a potential C1q inhibitor, chondroitin sulfate proteoglycan (CSPG. Genetic deletion of C1q, or of the downstream complement pathway component C3, did not significantly alter patterned neuron loss or disease progression. Deletion of other immune response factors, a Toll-like receptor, a matrix metalloprotease, or the apoptosis facilitator BIM, also failed to alter neuron loss. Conclusion We conclude that complement is not involved in the death and clearance of neurons in NPC disease. This study supports a view of neuroinflammation as a secondary response with non-causal relationship to neuron injury in the disease. This disease model may prove useful for understanding the conditions in which complement and immunity do contribute to neurodegeneration in other disorders.

  13. A novel role for Niemann-Pick disease type 2C protein in papillae formation.

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    Masahiro Sugawara

    Full Text Available BACKGROUND: Despite the presence of papillary structures and papillary tumors in humans, the mechanism of papillae formation is unknown. We describe herein a novel role for Niemann-Pick disease type 2C (NPC2 protein, a cholesterol binding protein in the lysosome, in papillae formation. METHODOLOGY/PRINCIPAL FINDING: We examined NPC2 protein expression in surgical samples of papillary tissues by immunohistochemical stain, and all papillary tissues expressed NPC2 protein in the epithelium. To examine our hypothesis of NPC2 protein-mediated papillae formation, we carried out xenograft experiments using wild H460 cells (large cell lung carcinoma cell line that constitutively expressed abundant NPC2 protein and NPC2 protein-depleted H460 cells by NPC2 shRNA. The xenografts of wild H460 cells and empty shRNA vector cells showed distinct papillae formation, whereas NPC2 protein-depleted H460 cells displayed markedly reduced or no papillae. Since all papillary tissues have open spaces we examined whether NPC2 protein might also contribute to the creation of open spaces. The TUNEL assay in the xenografts of wild and empty shRNA vector H460 cells showed massive cell death, and NPC2 protein-depleted cells displayed minimal cell death. Measurement of caspase 3/7 activities in cultured H460 cells supported NPC2 protein-mediated apoptotic cell death. The presence of excess NPC2 protein, however, did not always produce papillae as seen in the xenografts of CHO cells that were stably transfected with NPC2. CONCLUSIONS/SIGNIFICANCE: The NPC2 protein of certain cells forms papillae coupled with apoptosis that creates open space. This protein may have future applications to modulate papillae formation and papillary growth in tumor tissues.

  14. Niemann-Pick type C: focus on the adolescent/adult onset form.

    Science.gov (United States)

    Di Lazzaro, Vincenzo; Marano, Massimo; Florio, Lucia; De Santis, Stefano

    2016-11-01

    Niemann-Pick disease type C (NP-C) is an inherited sphingolipidosis characterized by progressive neurological deterioration and early mortality. The symptomatology and disease progression of NP-C are markedly affected by the age at onset of neurological manifestations, and categorization into early-infantile, late-infantile, juvenile, adolescent/adult neurological onset forms can aid evaluation of disease course and responses to therapy. Here, we review current information on the detection, diagnosis, monitoring and treatment of NP-C, with a focus on the adolescent/adult-onset form. A recent analysis indicated that the combined incidence of NP-C related to NPC1 gene mutations (NPC1) and NP-C related to NPC2 gene mutations (NPC2) is approximately 1 case in every 89 000 live births. In particular, late-onset phenotypes might well provide a greater contribution to the overall incidence than has previously been reported. Some neuropathological features in NP-C are held in common with other advanced age-onset diseases such as Alzheimer's disease. Visceral symptoms such as splenomegaly are frequently asymptomatic in patients with adolescent/adult-onset NP-C, and are only occasionally detected during routine ultrasound assessments. In contrast, most patients with adolescent/adult-onset exhibit some degree of slowly progressive, non-disease-specific movement disorders (e.g. cerebellar ataxia), and/or more pathognomonic neurological signs such as vertical supranuclear gaze palsy. An increasing number of adolescent/adult-onset cases have been reported following initial recognition of cognitive impairment and/or psychiatric signs. The recent development and implementation of new clinical screening tools (e.g. the NP-C suspicion index) and biomarkers (e.g. plasma oxysterols) should help identify patients who warrant further investigation and possible treatment. PMID:26998855

  15. Quantitative proteomic analysis of Niemann-Pick disease, type C1 cerebellum identifies protein biomarkers and provides pathological insight.

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    Stephanie M Cologna

    Full Text Available Niemann-Pick disease, type C1 (NPC1 is a fatal, neurodegenerative disorder for which there is no definitive therapy. In NPC1, a pathological cascade including neuroinflammation, oxidative stress and neuronal apoptosis likely contribute to the clinical phenotype. While the genetic cause of NPC1 is known, we sought to gain a further understanding into the pathophysiology by identifying differentially expressed proteins in Npc1 mutant mouse cerebella. Using two-dimensional gel electrophoresis and mass spectrometry, 77 differentially expressed proteins were identified in Npc1 mutant mice cerebella compared to controls. These include proteins involved in glucose metabolism, detoxification/oxidative stress and Alzheimer disease-related proteins. Furthermore, members of the fatty acid binding protein family, including FABP3, FABP5 and FABP7, were found to have altered expression in the Npc1 mutant cerebellum relative to control. Translating our findings from the murine model to patients, we confirm altered expression of glutathione s-transferase α, superoxide dismutase, and FABP3 in cerebrospinal fluid of NPC1 patients relative to pediatric controls. A subset of NPC1 patients on miglustat, a glycosphingolipid synthesis inhibitor, showed significantly decreased levels of FABP3 compared to patients not on miglustat therapy. This study provides an initial report of dysregulated proteins in NPC1 which will assist with further investigation of NPC1 pathology and facilitate implementation of therapeutic trials.

  16. Altered localization and functionality of TAR DNA Binding Protein 43 (TDP-43) in niemann- pick disease type C.

    Science.gov (United States)

    Dardis, A; Zampieri, S; Canterini, S; Newell, K L; Stuani, C; Murrell, J R; Ghetti, B; Fiorenza, M T; Bembi, B; Buratti, E

    2016-01-01

    Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by the occurrence of visceral and neurological symptoms. At present, the molecular mechanisms causing neurodegeneration in this disease are unknown. Here we report the altered expression and/or mislocalization of the TAR-DNA binding protein 43 (TDP-43) in both NPC mouse and in a human neuronal model of the disease. We also report the neuropathologic study of a NPC patient's brain, showing that while TDP-43 is below immunohistochemical detection in nuclei of cerebellar Purkinje cells, it has a predominant localization in the cytoplasm of these cells. From a functional point of view, the TDP-43 mislocalization, that occurs in a human experimental neuronal model system, is associated with specific alterations in TDP-43 controlled genes. Most interestingly, treatment with N-Acetyl-cysteine (NAC) or beta-cyclodextrin (CD) can partially restore TDP-43 nuclear localization. Taken together, the results of these studies extend the role of TDP-43 beyond the Amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)/Alzheimer disease (AD) spectrum. These findings may open novel research/therapeutic avenues for a better understanding of both NPC disease and the TDP-43 proteinopathy disease mechanism. PMID:27193329

  17. Niemann-Pick type B disease. Identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type A and B patients.

    OpenAIRE

    Levran, O; Desnick, R. J.; Schuchman, E H

    1991-01-01

    Types A and B Niemann-Pick disease both result from the deficient activity of the lysosomal hydrolase, acid sphingomyelinase (E.C. 3.1.4.12). Type A Niemann-Pick disease is a severe neurodegenerative disorder of infancy which leads to death by three years of age, whereas Type B disease has a later age at onset, little or no neurologic involvement, and most patients survive into adulthood. To investigate the molecular basis for the remarkable phenotypic heterogeneity, the nature of the mutatio...

  18. A defect in cholesterol esterification in Niemann-Pick disease (type C) patients.

    OpenAIRE

    Pentchev, P G; Comly, M E; Kruth, H. S.; Vanier, M T; Wenger, D A; Patel, S.; Brady, R O

    1985-01-01

    The demonstration of a defect of cholesterol esterification in a mutant strain of BALB/c mice with an attendant reduction of sphingomyelinase activity [Pentchev, P. G., Boothe, A. D., Kruth, H.S., Weintroub, H., Stivers, J. & Brady, R. O. (1984) J. Biol. Chem. 259, 5784-5791] prompted us to examine the capacity of cultured human Niemann-Pick fibroblasts to esterify exogenously derived cholesterol. Cholesterol was supplied to cell cultures in the form of native or chemically modified, positive...

  19. Case Report: Genetic analysis and anesthetic management of a child with Niemann-Pick disease Type A.

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    Dalal, Priti G; Coleman, Melissa; Horst, Meagan; Rocourt, Dorothy; Ladda, Roger L; Janicki, Piotr K

    2015-01-01

    A 14-month-old child, recently diagnosed with Niemann-Pick disease type A, presented for a laparoscopic placement of a gastrostomy tube under general anesthesia. The disease was confirmed and further characterized by genetic testing, which revealed evidence of the presence of two known pathogenic mutations in the SMPD1 gene, and enzyme studies showed a corresponding very low level of enzymatic activity of acidic sphingomyelinase. The anesthetic management involved strategies to manage an anticipated difficult intubation and avoid post-operative ventilation. PMID:26913189

  20. Clues to Neuro-Degeneration in Niemann-Pick Type C Disease from Global Gene Expression Profiling

    OpenAIRE

    Reddy, Jonathan V.; Ganley, Ian G.; Pfeffer, Suzanne R

    2006-01-01

    Background Niemann-Pick Type C (NPC) disease is a neurodegenerative disease that is characterized by the accumulation of cholesterol and glycosphingolipids in the late endocytic pathway. The majority of NPC cases are due to mutations in the NPC1 gene. The precise function of this gene is not yet known. Methodology/Principal Findings Using cDNA microarrays, we analyzed the genome-wide expression patterns of human fibroblasts homozygous for the I1061T NPC1 mutation that is characterized by a se...

  1. Stem Cells and Niemann Pick Disease

    OpenAIRE

    Andolina, Marino

    2014-01-01

    Background and Objectives: Niemann Pick A disease causes a progressive accumulation of sphyngomyelin in several organs and the survival of the patients is usually limited to three years. We describe the outcome of a patient suffering from Niemann Pick A disease, who first underwent an haploidentical bone marrow transplantation, and then intrathecal and I.V injections of mesenchymal cells. Methods and Results: While the outcome of bone marrow transplantation was a complete failure, one month a...

  2. Pulmonary Involvement in Niemann-Pick Disease: A State-of-the-Art Review.

    Science.gov (United States)

    von Ranke, Felipe Mussi; Pereira Freitas, Heloisa Maria; Mançano, Alexandre Dias; Rodrigues, Rosana Souza; Hochhegger, Bruno; Escuissato, Dante; Araujo Neto, Cesar Augusto; da Silva, Thiago Krieger Bento; Marchiori, Edson

    2016-08-01

    Niemann-Pick disease is a rare autosomal recessive lysosomal storage disease with three subtypes. Types A and B result from a deficiency of acid sphingomyelinase activity, associated with the accumulation of lipid-laden macrophages (so-called Niemann-Pick cells) in various tissues, especially the liver and spleen. Type A is a fatal neurodegenerative disorder of infancy. Type B Niemann-Pick disease is a less severe form with milder neurological involvement, characterized by hepatosplenomegaly, hyperlipidemia, and pulmonary involvement; most patients live into adulthood. Type C Niemann-Pick disease is a complex lipid storage disorder caused by defects in cholesterol trafficking, resulting in a clinical presentation dominated by neurological involvement. Pulmonary involvement occurs in all three types of Niemann-Pick disease, but most frequently in type B. Respiratory manifestations range from a lack of symptoms to respiratory failure. Progression of respiratory disease is slow, but inexorable, due to the accumulation of Niemann-Pick cells in the alveolar septa, bronchial walls, and pleura, potentially leading to a progressively worsening restrictive pattern on pulmonary function testing. Bronchoalveolar lavage has important diagnostic value because it shows the presence of characteristic Niemann-Pick cells. Radiographic findings consist of a reticular or reticulonodular pattern and, eventually, honeycombing, involving mainly the lower lung zones. The most common changes identified by high-resolution computed tomography are ground-glass opacities, mild smooth interlobular septal thickening, and intralobular lines. The aim of this review is to describe the main clinical, imaging, and pathological aspects of Niemann-Pick disease, with a focus on pulmonary involvement. PMID:27164983

  3. Miglustat therapy in the French cohort of paediatric patients with Niemann-Pick disease type C

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    Héron Bénédicte

    2012-06-01

    Full Text Available Abstract Background Niemann-Pick disease type C (NP-C is a rare neurovisceral lysosomal lipid storage disease characterized by progressive neurological deterioration. Published data on the use of miglustat in paediatric patients in clinical practice settings are limited. We report findings from a prospective open-label study in the French paediatric NP-C cohort. Methods Data on all paediatric NP-C patients treated with miglustat in France between October 2006 and December 2010 were compiled. All patients had a confirmed diagnosis of NP-C, and received miglustat therapy according to manufacturer’s recommendations. Pre-treatment and follow-up assessments were conducted according to a standardized protocol. Results Twenty children were enrolled; 19 had NPC1 gene mutations and 1 had NPC2 gene mutations. The median age at diagnosis was 1.5 years, and the median age at miglustat initiation was 6.0 years. Eight NPC1 patients had the early-infantile, eight had the late-infantile, and three had the juvenile-onset forms of NP-C. A history of hepatosplenomegaly and/or other cholestatic symptoms was recorded in all 8 early-infantile onset patients, 3/8 late-infantile patients, and 1/3 juvenile onset patients. Brain imaging indicated white matter abnormalities in most patients. The median (range duration of miglustat therapy was 1.3 (0.6–2.3 years in early-infantile, 1.0 (0.8–5.0 year in late-infantile, and 1.0 (0.6–2.5 year in juvenile onset patients. NP-C disability scale scores indicated either stabilization or improvement of neurological manifestations in 1/8, 6/8, and 1/3 NPC1 patients in these subgroups, respectively. There were no correlations between brain imaging findings and disease course. Mild-to-moderate gastrointestinal disturbances were frequent during the first 3 months of miglustat therapy, but were easily managed with dietary modifications and/or anti-propulsive medication. Conclusions Miglustat can improve or stabilize neurological

  4. Normalisation of brain spectroscopy findings in Niemann-Pick disease type C patients treated with miglustat.

    Science.gov (United States)

    Sedel, Frédéric; Chabrol, Brigitte; Audoin, Bertrand; Kaphan, Elsa; Tranchant, Christine; Burzykowski, Tomasz; Tourbah, Ayman; Vanier, Marie T; Galanaud, Damien

    2016-05-01

    Niemann-Pick disease type C (NP-C) is a fatal progressive neurolipidosis involving neuronal storage of cholesterol and gangliosides. Miglustat, an inhibitor of glycosphingolipid synthesis, has been approved to treat neurological manifestations in adults and children with NP-C. This open-label observational study in adults with confirmed NP-C evaluated the efficacy of miglustat (200 mg t.i.d.) based on composite functional disability (CFD) scores and brain proton magnetic resonance spectroscopy (H-MRS) measurement of choline (Cho)/N-acetyl aspartate (NAA) ratio in the centrum ovale. Overall, 16 patients were included and received miglustat for a mean period of 30.6 months: 12 continued on miglustat throughout follow up, and 4 discontinued miglustat because of adverse effects (n = 2) or perceived lack of efficacy (n = 2). In the 'continued' subgroup, the mean (SD) annual progression of CFD scores decreased from 0.75 (0.94) before treatment to 0.29 (1.29) during the period between miglustat initiation and last follow-up. In the discontinued subgroup, CFD progression increased from 0.48 (0.44) pre-treatment to 1.49 (1.31) at last follow up (off treatment). Mean (SD) Cho/NAA ratio [normal level 0.48 (0.076)] decreased during miglustat treatment in the continued subgroup: 0.64 (0.12) at baseline (miglustat initiation), 0.59 (0.17) at 12-month follow up, and 0.48 (0.09) at 24-month follow up. Cho/NAA ratio remained relatively stable in the discontinued subgroup: 0.57 (0.15), 0.53 (0.04) and 0.55 (0.09), respectively. In conclusion, H-MRS Cho/NAA ratio might serve as an objective, quantitative neurological marker of brain dysfunction in NP-C, allowing longitudinal analysis of the therapeutic effect of miglustat. PMID:26984608

  5. Use of miglustat in a child with late-infantile-onset Niemann-Pick disease type C and frequent seizures: a case report

    OpenAIRE

    Skorpen Johannes; Helland Ingrid B; Tennøe Bjørn

    2012-01-01

    Abstract Introduction Niemann-Pick disease type C is a rare genetic lysosomal storage disease associated with impaired intracellular lipid trafficking and a range of progressive neurological manifestations. The influence of seizure activity on disease course and response to miglustat therapy is not currently clear. Case presentation Niemann-Pick disease type C homozygous for NPC1 mutation p.S940L [c. 2819 C>T] was diagnosed in a four-and-a-half-year-old Norwegian Caucasian girl. The patient, ...

  6. Clues to neuro-degeneration in Niemann-Pick type C disease from global gene expression profiling.

    Directory of Open Access Journals (Sweden)

    Jonathan V Reddy

    Full Text Available BACKGROUND: Niemann-Pick Type C (NPC disease is a neurodegenerative disease that is characterized by the accumulation of cholesterol and glycosphingolipids in the late endocytic pathway. The majority of NPC cases are due to mutations in the NPC1 gene. The precise function of this gene is not yet known. METHODOLOGY/PRINCIPAL FINDINGS: Using cDNA microarrays, we analyzed the genome-wide expression patterns of human fibroblasts homozygous for the I1061T NPC1 mutation that is characterized by a severe defect in the intracellular processing of low density lipoprotein-derived cholesterol. A distinct gene expression profile was identified in NPC fibroblasts from different individuals when compared with fibroblasts isolated from normal subjects. As expected, NPC1 mutant cells displayed an inappropriate homeostatic response to accumulated intracellular cholesterol. In addition, a number of striking parallels were observed between NPC disease and Alzheimer's disease. CONCLUSIONS/SIGNIFICANCE: Many genes involved in the trafficking and processing of amyloid precursor protein and the microtubule binding protein, tau, were more highly expressed. Numerous genes important for membrane traffic and the cellular regulation of calcium, metals and other ions were upregulated. Finally, NPC fibroblasts exhibited a gene expression profile indicative of oxidative stress. These changes are likely contributors to the pathophysiology of Niemann-Pick Type C disease.

  7. Cholinergic Abnormalities, Endosomal Alterations and Up-Regulation of Nerve Growth Factor Signaling in Niemann-Pick Type C Disease

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    Cabeza Carolina

    2012-03-01

    Full Text Available Abstract Background Neurotrophins and their receptors regulate several aspects of the developing and mature nervous system, including neuronal morphology and survival. Neurotrophin receptors are active in signaling endosomes, which are organelles that propagate neurotrophin signaling along neuronal processes. Defects in the Npc1 gene are associated with the accumulation of cholesterol and lipids in late endosomes and lysosomes, leading to neurodegeneration and Niemann-Pick type C (NPC disease. The aim of this work was to assess whether the endosomal and lysosomal alterations observed in NPC disease disrupt neurotrophin signaling. As models, we used i NPC1-deficient mice to evaluate the central cholinergic septo-hippocampal pathway and its response to nerve growth factor (NGF after axotomy and ii PC12 cells treated with U18666A, a pharmacological cellular model of NPC, stimulated with NGF. Results NPC1-deficient cholinergic cells respond to NGF after axotomy and exhibit increased levels of choline acetyl transferase (ChAT, whose gene is under the control of NGF signaling, compared to wild type cholinergic neurons. This finding was correlated with increased ChAT and phosphorylated Akt in basal forebrain homogenates. In addition, we found that cholinergic neurons from NPC1-deficient mice had disrupted neuronal morphology, suggesting early signs of neurodegeneration. Consistently, PC12 cells treated with U18666A presented a clear NPC cellular phenotype with a prominent endocytic dysfunction that includes an increased size of TrkA-containing endosomes and reduced recycling of the receptor. This result correlates with increased sensitivity to NGF, and, in particular, with up-regulation of the Akt and PLC-γ signaling pathways, increased neurite extension, increased phosphorylation of tau protein and cell death when PC12 cells are differentiated and treated with U18666A. Conclusions Our results suggest that the NPC cellular phenotype causes neuronal

  8. Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells

    OpenAIRE

    Dorothea Maetzel; Sovan Sarkar; Haoyi Wang; Lina Abi-Mosleh; Ping Xu; Albert W. Cheng; Qing Gao; Maisam Mitalipova; Rudolf Jaenisch

    2014-01-01

    Summary Niemann-Pick type C (NPC) disease is a fatal inherited lipid storage disorder causing severe neurodegeneration and liver dysfunction with only limited treatment options for patients. Loss of NPC1 function causes defects in cholesterol metabolism and has recently been implicated in deregulation of autophagy. Here, we report the generation of isogenic pairs of NPC patient-specific induced pluripotent stem cells (iPSCs) using transcription activator-like effector nucleases (TALENs). We o...

  9. Intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann-Pick type C fibroblasts

    International Nuclear Information System (INIS)

    Niemann-Pick disease type C (NPC) is characterized by substantial intracellular accumulation of unesterified cholesterol. The accumulation of unesterified cholesterol in NPC fibroblasts cultured with low density lipoprotein (LDL) appears to result from the inability of LDL to stimulate cholesterol esterification in addition to impaired LDL-mediated downregulation of LDL receptor activity and cellular cholesterol synthesis. Although a defect in cholesterol transport in NPC cells has been inferred from previous studies, no experiments have been reported that measure the intracellular movement of LDL-cholesterol specifically. We have used four approaches to assess intracellular cholesterol transport in normal and NPC cells and have determined the following: (a) mevinolin-inhibited NPC cells are defective in using LDL-cholesterol for growth. However, exogenously added mevalonate restores cell growth equally in normal and NPC cells; (b) the transport of LDL-derived [3H]cholesterol to the plasma membrane is slower in NPC cells, while the rate of appearance of [3H]acetate-derived, endogenously synthesized [3H]cholesterol at the plasma membrane is the same for normal and NPC cells; (c) in NPC cells, LDL-derived [3H]cholesterol accumulates in lysosomes to higher levels than normal, resulting in defective movement to other cell membranes; and (d) incubation of cells with LDL causes an increase in cholesterol content of NPC lysosomes that is threefold greater than that observed in normal lysosomes. Our results indicate that a cholesterol transport defect exists in NPC that is specific for LDL-derived cholesterol

  10. Structural Basis of Sterol Binding by NPC2, a Lysosomal Protein Deficient in Niemann-Pick Type C2 Disease

    Energy Technology Data Exchange (ETDEWEB)

    Xu,S.; Benoff, B.; Liou, H.; Lobel, P.; Stock, A.

    2007-01-01

    NPC2 is a small lysosomal glycoprotein that binds cholesterol with submicromolar affinity. Deficiency in NPC2 is the cause of Niemann-Pick type C2 disease, a fatal neurovisceral disorder characterized by accumulation of cholesterol in lysosomes. Here we report the crystal structure of bovine NPC2 bound to cholesterol-3-O-sulfate, an analog that binds with greater apparent affinity than cholesterol. Structures of both apo-bound and sterol-bound NPC2 were observed within the same crystal lattice, with an asymmetric unit containing one molecule of apoNPC2 and two molecules of sterol-bound NPC2. As predicted from a previously determined structure of apoNPC2, the sterol binds in a deep hydrophobic pocket sandwiched between the two {beta}-sheets of NPC2, with only the sulfate substituent of the ligand exposed to solvent. In the two available structures of apoNPC2, the incipient ligand-binding pocket, which ranges from a loosely packed hydrophobic core to a small tunnel, is too small to accommodate cholesterol. In the presence of sterol, the pocket expands, facilitated by a slight separation of the {beta}-strands and substantial reorientation of some side chains, resulting in a perfect molding of the pocket around the hydrocarbon portion of cholesterol. A notable feature is the repositioning of two aromatic residues at the tunnel entrance that are essential for NPC2 function. The NPC2 structures provide evidence of a malleable binding site, consistent with the previously documented broad range of sterol ligand specificity.

  11. Plasma lysosphingomyelin demonstrates great potential as a diagnostic biomarker for Niemann-Pick disease type C in a retrospective study.

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    Richard W D Welford

    Full Text Available Niemann-Pick disease type C (NP-C is a devastating, neurovisceral lysosomal storage disorder which is characterised by variable manifestation of visceral signs, progressive neuropsychiatric deterioration and premature death, caused by mutations in the NPC1 and NPC2 genes. Due to the complexity of diagnosis and the availability of an approved therapy in the EU, improved detection of NP-C may have a huge impact on future disease management. At the cellular level dysfunction or deficiency of either the NPC1 or NPC2 protein leads to a complex intracellular endosomal/lysosomal trafficking defect, and organ specific patterns of sphingolipid accumulation. Lysosphingolipids have been shown to be excellent biomarkers of sphingolipidosis in several enzyme deficient lysosomal storage disorders. Additionally, in a recent study the lysosphingolipids, lysosphingomyelin (SPC and glucosylsphingosine (GlcSph, appeared to be elevated in the plasma of three adult NP-C patients. In order to investigate the clinical utility of SPC and GlcSph as diagnostic markers, an in-depth fit for purpose biomarker assay validation for measurement of these biomarkers in plasma by liquid chromatography-tandem mass spectrometry was performed. Plasma SPC and GlcSph are stable and can be measured accurately, precisely and reproducibly. In a retrospective analysis of 57 NP-C patients and 70 control subjects, median plasma SPC and GlcSph were significantly elevated in NP-C by 2.8-fold and 1.4-fold respectively. For miglustat-naïve NP-C patients, aged 2-50 years, the area under the ROC curve was 0.999 for SPC and 0.776 for GlcSph. Plasma GlcSph did not correlate with SPC levels in NP-C patients. The data indicate excellent potential for the use of lysosphingomyelin in NP-C diagnosis, where it could be used to identify NP-C patients for confirmatory genetic testing.

  12. Dietary cholesterol induces trafficking of intestinal Niemann-Pick Type C1 Like 1 from the brush border to endosomes

    DEFF Research Database (Denmark)

    Skov, Marianne; Tønnesen, Carina K; Hansen, Gert H;

    2011-01-01

    The transmembrane protein Niemann-Pick C1 Like 1 (NPC1L1) belongs to the Niemann-Pick C1 (NPC1) family of cholesterol transporters and is mainly expressed in the liver and the small intestine. NPC1L1 is believed to be the main transporter responsible for the absorption of dietary cholesterol. Like...

  13. Stem Cells in Niemann-Pick Disease

    OpenAIRE

    Sun-Jung Kim; Joon-Suk Park; Kyung-Sun Kang

    2008-01-01

    Neural stem cells are multi-potent and able to self renew to maintain its character throughout the life. Loss of self renewal ability of stem cells prevents recovery or replacement of cells damaged by disease with new cells. The Niemann-Pick type C1 (NPC1) disease is one of the neurodegenerative diseases, caused by a mutation of NPC1 gene which affects the function of NPC1 protein. We reported that NPC 1 gene deficiency could lead to lack of the self renewal ability of neural stem cells in Ni...

  14. Niemann-Pick disease Type C - Sea-blue histiocytosis: Phenotypic and imaging observations and mini review

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    Praveen K

    2007-01-01

    Full Text Available We present a report on an 18-year-old boy with Niemann-Pick disease Type C (NP-C who presented with progressive decline in scholastic performance since 9 years of age. At 12 years, he developed abnormal behavior and after 2 years had insidious onset, progressive gait ataxia and dysarthria followed by dystonia of the right upper extremity, excessive drooling, dysphagia and nasal regurgitation. He had coarse facies, depressed nasal bridge, high arched palate, crowded teeth, splenomegaly and peculiar facial grin. In addition, impaired vertical saccadic and pursuit eye movements, brisk muscle stretch reflexes and limb and gait ataxia were observed. He had a low IQ of 47 on Binet-Kamat test. The ultrasound examination of the abdomen confirmed the presence of moderate splenomegaly. Magnetic resonance imaging brain showed symmetrical leucoencephalopathy and mild cerebellar atrophy. Bone marrow aspiration showed numerous foamy macrophages and sea-blue histiocytes suggesting the diagnosis of NP-C.

  15. Clear Cell Chondrosarcoma in Association With Niemann-Pick Disease

    OpenAIRE

    Sumathi, V. P.; Grimer, R. J.; Davies, A. M.; Kulkarni, A.; Srikanth, K. N.

    2005-01-01

    Purpose: The purpose of this case report is to bring to light this unusual combination of two rare diseases, namely Neimann-Pick disease Type B and clear cell chondrosarcoma occurring in the same patient. This has not previously been reported in the world literature. Subject: Niemann-Pick disease (NPD) is a rare autosomal recessive inborn error of metabolism. Type B NPD is even rarer. It is a lysosomal storage disorder affecting children and adolescents often causing death in early childhood,...

  16. Recent Advances in the Diagnosis and Treatment of Niemann-Pick Disease Type C in Children: A Guide to Early Diagnosis for the General Pediatrician

    OpenAIRE

    Hanna Alobaidy

    2015-01-01

    Niemann-Pick disease (NP-C) is a lysosomal storage disease in which impaired intracellular lipid transport leads to accumulation of cholesterol and glycosphingolipids in various neurovisceral tissues. It is an autosomal recessive disorder, caused by mutations in the NPC1 or NPC2 genes. The clinical spectrum is grouped by the age of onset and onset of neurological manifestation: pre/perinatal; early infantile; late infantile; and juvenile periods. The NP-C Suspicion Index (SI) screening tool w...

  17. Niemann Pick type C cells show cholesterol dependent decrease of APP expression at the cell surface its increased processing through the ?-secretase pathway

    OpenAIRE

    Malnar, Martina; KOŠIČEK, MARKO; Mitterreiter, Stefan; Omerbašić, Damir; Lichtenthaler, Stefan F.; Goate, Alison; Hećimović, Silva

    2010-01-01

    Abstract The link between cholesterol and Alzheimer's disease has recently been revealed in Niemann Pick type C disease. We found that NPC1-/- cells show decreased expression of APP at the cell surface and increased processing of APP through the ?-secretase pathway resulting in increased C99, sAPP? and intracellular A?40 levels. This effect is dependent on increased cholesterol levels, since cholesterol depletion reversed cell surface APP expression and lowered A?/C99 levels in NPC...

  18. Use of miglustat in a child with late-infantile-onset Niemann-Pick disease type C and frequent seizures: a case report

    Directory of Open Access Journals (Sweden)

    Skorpen Johannes

    2012-11-01

    Full Text Available Abstract Introduction Niemann-Pick disease type C is a rare genetic lysosomal storage disease associated with impaired intracellular lipid trafficking and a range of progressive neurological manifestations. The influence of seizure activity on disease course and response to miglustat therapy is not currently clear. Case presentation Niemann-Pick disease type C homozygous for NPC1 mutation p.S940L [c. 2819 C>T] was diagnosed in a four-and-a-half-year-old Norwegian Caucasian girl. The patient, who died at eight years and seven months of age, had a history of prolonged neonatal jaundice and subsequently displayed progressive neurological manifestations that started with delayed speech, ataxia, and gelastic cataplexy. A regimen of 100mg of miglustat three times a day was initiated when she was four years and 11 months old. She showed decreased neurological deterioration during about three and a half years of treatment. However, she displayed periods of distinct worsening that coincided with frequent epileptic seizures. Anti-epileptic therapy reduced seizure frequency and severity and allowed re-stabilization of her neurological function. Prior to her death, which was possibly due to acute cardiac arrest, seizure activity was well controlled. Conclusions Miglustat delayed the expected deterioration of neurological function in this patient with p.S940L-homozygous late-infantile-onset Niemann-Pick disease type C and provided important quality-of-life benefits. This case demonstrates the importance of effective seizure control therapy in achieving and maintaining neurological stabilization in Niemann-Pick disease type C.

  19. Early co-occurrence of a neurologic-psychiatric disease pattern in Niemann-Pick type C disease: a retrospective Swiss cohort study

    OpenAIRE

    Abela, Lucia; Plecko, Barbara; Palla, Antonella; Burda, Patricie; Nuoffer, Jean-Marc; Ballhausen, Diana; Rohrbach, Marianne

    2014-01-01

    Background Niemann-Pick disease type C (NP-C) is a rare autosomal recessive disorder of lysosomal cholesterol transport. The objective of this retrospective cohort study was to critically analyze the onset and time course of symptoms, and the clinical diagnostic work-up in the Swiss NP-C cohort. Methods Clinical, biochemical and genetic data were assessed for 14 patients derived from 9 families diagnosed with NP-C between 1994 and 2013. We retrospectively evaluated diagnostic delays and perio...

  20. Niemann-Pick Disease Type C Presenting as a Developmental Coordination Disorder with Bullying by Peers in a School-Age Child

    OpenAIRE

    Ryo Suzuki; Atsushi Tanaka; Toshiharu Matsui; Tetsuki Gunji; Jun Tohyama; Aya Nairita; Eiji Nanba; Kousaku Ohno

    2015-01-01

    Niemann-Pick disease type C (NPC) is a rare progressive neurodegenerative disorder, often with onset after normal early childhood development. Juvenile onset NPC patients slowly develop cerebellar symptoms and cognitive impairment and often experience difficulties at school. However, these problems may be overlooked due to the unpublicized nature of NPC, given that it is a rare metabolic disorder. In this report, we present an 11-year-old male NPC patient, who suffered from clumsiness and dif...

  1. Dysphagia as a risk factor for mortality in Niemann-Pick disease type C: systematic literature review and evidence from studies with miglustat

    OpenAIRE

    Walterfang Mark; Chien Yin-Hsiu; Imrie Jackie; Rushton Derren; Schubiger Danielle; Patterson Marc C

    2012-01-01

    Abstract Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological deterioration and premature death, and has an estimated birth incidence of 1:120,000. Mutations in the NPC1 gene (in 95% of cases) and the NPC2 gene (in approximately 4% of cases) give rise to impaired intracellular lipid metabolism in a number of tissues, including the brain. Typical neurological manifestations include vertical supranuclear gaze palsy, saccadic eye movement a...

  2. Circadian profiling in two mouse models of lysosomal storage disorders; Niemann Pick type-C and Sandhoff disease.

    Science.gov (United States)

    Richardson, Katie; Livieratos, Achilleas; Dumbill, Richard; Hughes, Steven; Ang, Gauri; Smith, David A; Morris, Lauren; Brown, Laurence A; Peirson, Stuart N; Platt, Frances M; Davies, Kay E; Oliver, Peter L

    2016-01-15

    Sleep and circadian rhythm disruption is frequently associated with neurodegenerative disease, yet it is unclear how the specific pathology in these disorders leads to abnormal rest/activity profiles. To investigate whether the pathological features of lysosomal storage disorders (LSDs) influence the core molecular clock or the circadian behavioural abnormalities reported in some patients, we examined mouse models of Niemann-Pick Type-C (Npc1 mutant, Npc1(nih)) and Sandhoff (Hexb knockout, Hexb(-/-)) disease using wheel-running activity measurement, neuropathology and clock gene expression analysis. Both mutants exhibited regular, entrained rest/activity patterns under light:dark (LD) conditions despite the onset of their respective neurodegenerative phenotypes. A slightly shortened free-running period and changes in Per1 gene expression were observed in Hexb(-/-) mice under constant dark conditions (DD); however, no overt neuropathology was detected in the suprachiasmatic nucleus (SCN). Conversely, despite extensive cholesterol accumulation in the SCN of Npc1(nih) mutants, no circadian disruption was observed under constant conditions. Our results indicate the accumulation of specific metabolites in LSDs may differentially contribute to circadian deregulation at the molecular and behavioural level. PMID:26467605

  3. Clinical and Genetic Characteristics of Mexican Patients with Juvenile Presentation of Niemann-Pick Type C Disease

    Directory of Open Access Journals (Sweden)

    Raul E. Piña-Aguilar

    2014-01-01

    Full Text Available Niemann-Pick type C disease (NPC is a rare lysosomal disease with a protean presentation, ranging from a fatal neonatal course with visceromegaly to an adult presentation with only neurological or psychiatric symptomatology. In this report we describe the genetic and clinical characteristics of 3 Mexican patients from different families with juvenile presentation of NPC. Clinical examination, imaging of central nervous and gastrointestinal system, and EEG were performed. Genetic studies include sequencing and deletion/duplication analysis of NPC1 and NPC2 genes. All patients presented with cognitive impairment, ataxia, and supranuclear vertical gaze palsy; one case had gelastic cataplexy. Also they developed epilepsy and cortical atrophy and two patients had thinning of corpus callosum. The 3 patients were compound heterozygotes for NPC1 sequence variants, including 5 missense and 1 nonsense mutations: p.P1007A and p.F1087L in Case 1; p.Q921P and p.G992R in Case 2; and p.R348* and p.V1165M in case 3. Mexican patients with juvenile NPC presented with a variable clinical phenotype and compound heterozygosity. This suggests a relative high frequency of mutation carriers as it is reported for European population. Consequently, clinicians should consider NPC as a diagnosis possibility in any adolescent or young adult patient with juvenile dementia and/or ataxia, even in absence of gelastic cataplexy and supranuclear vertical gaze palsy.

  4. Cholesterol pathways affected by small molecules that decrease sterol levels in Niemann-Pick type C mutant cells.

    Directory of Open Access Journals (Sweden)

    Madalina Rujoi

    Full Text Available BACKGROUND: Niemann-Pick type C (NPC disease is a genetically inherited multi-lipid storage disorder with impaired efflux of cholesterol from lysosomal storage organelles. METHODOLOGY/PRINCIPAL FINDINGS: The effect of screen-selected cholesterol lowering compounds on the major sterol pathways was studied in CT60 mutant CHO cells lacking NPC1 protein. Each of the selected chemicals decreases cholesterol in the lysosomal storage organelles of NPC1 mutant cells through one or more of the following mechanisms: increased cholesterol efflux from the cell, decreased uptake of low-density lipoproteins, and/or increased levels of cholesteryl esters. Several chemicals promote efflux of cholesterol to extracellular acceptors in both non-NPC and NPC1 mutant cells. The uptake of low-density lipoprotein-derived cholesterol is inhibited by some of the studied compounds. CONCLUSIONS/SIGNIFICANCE: Results herein provide the information for prioritized further studies in identifying molecular targets of the chemicals. This approach proved successful in the identification of seven chemicals as novel inhibitors of lysosomal acid lipase (Rosenbaum et al, Biochim. Biophys. Acta. 2009, 1791:1155-1165.

  5. Saccadic eye movement characteristics in adult Niemann-Pick Type C disease: relationships with disease severity and brain structural measures.

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    Larry A Abel

    Full Text Available Niemann-Pick Type C disease (NPC is a rare genetic disorder of lipid metabolism. A parameter related to horizontal saccadic peak velocity was one of the primary outcome measures in the clinical trial assessing miglustat as a treatment for NPC. Neuropathology is widespread in NPC, however, and could be expected to affect other saccadic parameters. We compared horizontal saccadic velocity, latency, gain, antisaccade error percentage and self-paced saccade generation in 9 adult NPC patients to data from 10 age-matched controls. These saccadic measures were correlated with appropriate MRI-derived brain structural measures (e.g., dorsolateral prefrontal cortex, frontal eye fields, supplemental eye fields, parietal eye fields, pons, midbrain and cerebellar vermis and with measures of disease severity and duration. The best discriminators between groups were reflexive saccade gain and the two volitional saccade measures. Gain was also the strongest correlate with disease severity and duration. Most of the saccadic measures showed strongly significant correlations with neurophysiologically appropriate brain regions. While our patient sample is small, the apparent specificity of these relationships suggests that as new diagnostic methods and treatments become available for NPC, a broader range of saccadic measures may be useful tools for the assessment of disease progression and treatment efficacy.

  6. [Activity of glial cells in the olfactory bulb of Niemann-Pick disease type C1 mice].

    Science.gov (United States)

    Yan, Xin; Qiao, Liang; Yang, En-Hui; Lin, Jun-Tang

    2016-04-25

    To study the pathological mechanisms of Niemann-Pick disease type C1, we observed the changes of activation of glial cells in the olfactory bulb of Npc1 mutant (Npc1(-/-)) mice. The genomic DNA was extracted from mouse tails for genotyping by PCR. Immunofluorescent histochemistry was performed to examine the activation of microglia and astrocytes in the olfactory bulb of Npc1(-/-) mice on postnatal day 30. NeuN, phosphorylated neurofilament (NF), Doublecortin (DCX), CD68 and GFAP were detected by Western blot. The results showed that Npc1 gene mutation strongly increased the activation of astrocytes and microglia in olfactory bulb associated with increased protein levels of CD68 and GFAP. Furthermore, the expression of phosphorylated NF was also significantly increased in the olfactory bulb of Npc1(-/-) mice compared with that in Npc1(+/+) mice. However, DCX expression was significantly reduced. The above results suggest that there are some early changes in the olfactory bulb of Npc1(-/-) mice. PMID:27108900

  7. Infrared spectroscopic imaging of the biochemical modifications induced in the cerebellum of the Niemann-Pick type C mouse

    Science.gov (United States)

    Kidder, Linda H.; Colarusso, Pina; Stewart, Sarah A.; Levin, Ira W.; Appel, Nathan M.; Lester, David S.; Pentchev, Peter G.; Lewis, E. N.

    1999-01-01

    WE have applied Fourier transform infrared (IR) spectroscopic imaging to the investigation of the neuropathologic effects of a genetic lipid storage disease, Niemann-Pick type C (NPC). Tissue sections both from the cerebella of a strain of BALB/c mice that demonstrated morphology and pathology of the human disease and from control animals were used. These samples were analyzed by standard histopathological procedures as well as this new IR imaging approach. The IR absorbance images exhibit contrast based on biochemical variations and allow for the identification of the cellular layers within the tissue samples. Furthermore, these images provide a qualitative description of the localized biochemical differences existing between the diseased and control tissue in the absence of histological staining. Statistical analyses of the IR spectra extracted from individual cell layers of the imaging data sets provide concise quantitative descriptions of these biochemical changes. The results indicate that lipid is depleted specifically in the white matter of the NPC mouse in comparison to the control samples. Minor differences were noted for the granular layers, but no significant differences were observed in the molecular layers of the cerebellar tissue. These changes are consistent with significant demyelination within the cerebellum of the NPC mouse.

  8. PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder.

    Science.gov (United States)

    Brown, Anna; Patel, Siddharth; Ward, Carl; Lorenz, Anna; Ortiz, Mauren; DuRoss, Allison; Wieghardt, Fabian; Esch, Amanda; Otten, Elsje G; Heiser, Laura M; Korolchuk, Viktor I; Sun, Conroy; Sarkar, Sovan; Sahay, Gaurav

    2016-01-01

    2-Hydroxy-propyl-β-cyclodextrin (HPβCD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HPβCD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (ethylene glycol) (PEG)-lipid conjugate enables cholesterol clearance from endo/lysosomes of Npc1 mutant (Npc1(-/-)) cells. Herein, we show that distearyl-phosphatidylethanolamine-PEG (DSPE-PEG), which forms 12-nm micelles above the critical micelle concentration, accumulates heavily inside cholesterol-rich late endosomes in Npc1(-/-) cells. This potentially results in cholesterol solubilization and leakage from lysosomes. High-throughput screening revealed that DSPE-PEG, in combination with HPβCD, acts synergistically to efflux cholesterol without significantly aggravating autophagy defects. These well-known excipients can be used as admixtures to treat NPC1 disorder. Increasing PEG chain lengths from 350 Da-30 kDa in DSPE-PEG micelles, or increasing DSPE-PEG content in an array of liposomes packaged with HPβCD, improved cholesterol egress, while Pluronic block copolymers capable of micelle formation showed slight effects at high concentrations. We postulate that PEG-lipid based nanocarriers can serve as bioactive drug delivery systems for effective treatment of lysosomal storage disorders. PMID:27572704

  9. Role of Diffusion Tensor Imaging in Prognostication and Treatment Monitoring in Niemann-Pick Disease Type C1

    Directory of Open Access Journals (Sweden)

    Meghann W. Lau

    2016-09-01

    Full Text Available Niemann-Pick Disease, type C1 (NPC1 is a rapidly progressive neurodegenerative disorder characterized by cholesterol sequestration within late endosomes and lysosomes, for which no reliable imaging marker exists for prognostication and management. Cerebellar volume deficits are found to correlate with disease severity and diffusion tensor imaging (DTI of the corpus callosum and brainstem, which has shown that microstructural disorganization is associated with NPC1 severity. This study investigates the utility of cerebellar DTI in clinical severity assessment. We hypothesize that cerebellar volume, fractional anisotropy (FA and mean diffusivity (MD negatively correlate with NIH NPC neurological severity score (NNSS and motor severity subscores. Magnetic resonance imaging (MRI was obtained for thirty-nine NPC1 subjects, ages 1–21.9 years (mean = 11.1, SD = 6.1. Using an atlas-based automated approach, the cerebellum of each patient was measured for FA, MD and volume. Additionally, each patient was given an NNSS. Decreased cerebellar FA and volume, and elevated MD correlate with higher NNSS. The cognition subscore and motor subscores for eye movement, ambulation, speech, swallowing, and fine motor skills were also statistically significant. Microstructural disorganization negatively correlated with motor severity in subjects. Additionally, Miglustat therapy correlated with lower severity scores across ranges of FA, MD and volume in all regions except the inferior peduncle, where a paradoxical effect was observed at high FA values. These findings suggest that DTI is a promising prognostication tool.

  10. Circadian profiling in two mouse models of lysosomal storage disorders; Niemann Pick type-C and Sandhoff disease

    Science.gov (United States)

    Richardson, Katie; Livieratos, Achilleas; Dumbill, Richard; Hughes, Steven; Ang, Gauri; Smith, David A.; Morris, Lauren; Brown, Laurence A.; Peirson, Stuart N.; Platt, Frances M.; Davies, Kay E.; Oliver, Peter L.

    2016-01-01

    Sleep and circadian rhythm disruption is frequently associated with neurodegenerative disease, yet it is unclear how the specific pathology in these disorders leads to abnormal rest/activity profiles. To investigate whether the pathological features of lysosomal storage disorders (LSDs) influence the core molecular clock or the circadian behavioural abnormalities reported in some patients, we examined mouse models of Niemann-Pick Type-C (Npc1 mutant, Npc1nih) and Sandhoff (Hexb knockout, Hexb−/−) disease using wheel-running activity measurement, neuropathology and clock gene expression analysis. Both mutants exhibited regular, entrained rest/activity patterns under light:dark (LD) conditions despite the onset of their respective neurodegenerative phenotypes. A slightly shortened free-running period and changes in Per1 gene expression were observed in Hexb−/− mice under constant dark conditions (DD); however, no overt neuropathology was detected in the suprachiasmatic nucleus (SCN). Conversely, despite extensive cholesterol accumulation in the SCN of Npc1nih mutants, no circadian disruption was observed under constant conditions. Our results indicate the accumulation of specific metabolites in LSDs may differentially contribute to circadian deregulation at the molecular and behavioural level. PMID:26467605

  11. Presymptomatic Alterations in Amino Acid Metabolism and DNA Methylation in the Cerebellum of a Murine Model of Niemann-Pick Type C Disease.

    Science.gov (United States)

    Kennedy, Barry E; Hundert, Amos S; Goguen, Donna; Weaver, Ian C G; Karten, Barbara

    2016-06-01

    The fatal neurodegenerative disorder Niemann-Pick type C (NPC) is caused in most cases by mutations in NPC1, which encodes the late endosomal NPC1 protein. Loss of NPC1 disrupts cholesterol trafficking from late endosomes to the endoplasmic reticulum and plasma membrane, causing cholesterol accumulation in late endosomes/lysosomes. Neurons are particularly vulnerable to this cholesterol trafficking defect, but the pathogenic mechanisms through which NPC1 deficiency causes neuronal dysfunction remain largely unknown. Herein, we have investigated amino acid metabolism in cerebella of NPC1-deficient mice at different stages of NPC disease. Imbalances in amino acid metabolism were evident from increased branched chain amino acid and asparagine levels and altered expression of key enzymes of glutamine/glutamate metabolism in presymptomatic and early symptomatic NPC1-deficient cerebellum. Increased levels of several amino acid intermediates of one-carbon metabolism indicated disturbances in folate and methylation pathways. Alterations in DNA methylation were apparent in decreased expression of DNA methyltransferase 3a and methyl-5'-cytosine-phosphodiester-guanine-domain binding proteins, reduced 5-methylcytosine immunoreactivity in the molecular and Purkinje cell layers, demethylation of genome-wide repetitive LINE-1 elements, and hypermethylation in specific promoter regions of single-copy genes in NPC1-deficient cerebellum at early stages of the disease. Alterations in amino acid metabolism and epigenetic changes in the cerebellum at presymptomatic stages of NPC disease represent previously unrecognized mechanisms of NPC pathogenesis. PMID:27083515

  12. Niemann-Pick Type C2 Protein Mediates Hepatic Stellate Cells Activation by Regulating Free Cholesterol Accumulation

    Directory of Open Access Journals (Sweden)

    Yuh-Ching Twu

    2016-07-01

    Full Text Available In chronic liver diseases, regardless of their etiology, the development of fibrosis is the first step toward the progression to cirrhosis, portal hypertension, and hepatocellular carcinoma. Hepatic stellate cells (HSCs are the main profibrogenic cells that promote the pathogenesis of liver fibrosis, and so it is important to identify the molecules that regulate HSCs activation and liver fibrosis. Niemann-Pick type C2 (NPC2 protein plays an important role in the regulation of intracellular cholesterol homeostasis by directly binding with free cholesterol. However, the roles of NPC2 in HSCs activation and liver fibrosis have not been explored in detail. Since a high-cholesterol diet exacerbates liver fibrosis progression in both rodents and humans, we propose that the expression of NPC2 affects free cholesterol metabolism and regulates HSCs activation. In this study, we found that NPC2 is decreased in both thioacetamide- and carbon tetrachloride-induced liver fibrosis tissues. In addition, NPC2 is expressed in quiescent HSCs, but its activation status is down-regulated. Knockdown of NPC2 in HSC-T6 cells resulted in marked increases in transforming growth factor-β1 (TGF-β1-induced collagen type 1 α1 (Col1a1, α-smooth muscle actin (α-SMA expression, and Smad2 phosphorylation. In contrast, NPC2 overexpression decreased TGF-β1-induced HSCs activation. We further demonstrated that NPC2 deficiency significantly increased the accumulation of free cholesterol in HSCs, increasing Col1a1 and α-SMA expression and activating Smad2, and leading to sensitization of HSCs to TGF-β1 activation. In contrast, overexpression of NPC2 decreased U18666A-induced free cholesterol accumulation and inhibited the subsequent HSCs activation. In conclusion, our study has demonstrated that NPC2 plays an important role in HSCs activation by regulating the accumulation of free cholesterol. NPC2 overexpression may thus represent a new treatment strategy for liver fibrosis.

  13. Cerebrospinal Fluid Calbindin D Concentration as a Biomarker of Cerebellar Disease Progression in Niemann-Pick Type C1 Disease

    Science.gov (United States)

    Bagel, Jessica; Sampson, Maureen; Farhat, Nicole; Ding, Wenge; Swain, Gary; Prociuk, Maria; O’Donnell, Patricia; Drobatz, Kenneth; Gurda, Brittney; Wassif, Christopher; Remaley, Alan; Porter, Forbes; Vite, Charles

    2016-01-01

    Niemann-Pick type C (NPC) 1 disease is a rare, inherited, neurodegenerative disease. Clear evidence of the therapeutic efficacy of 2-hydroxypropyl-β-cyclodextrin (HPβCD) in animal models resulted in the initiation of a phase I/IIa clinical trial in 2013 and a phase IIb/III trial in 2015. With clinical trials ongoing, validation of a biomarker to track disease progression and serve as a supporting outcome measure of therapeutic efficacy has become compulsory. In this study, we evaluated calcium-binding protein calbindin D-28K (calbindin) concentrations in the cerebrospinal fluid (CSF) as a biomarker of NPC1 disease. In the naturally occurring feline model, CSF calbindin was significantly elevated at 3 weeks of age, prior to the onset of cerebellar dysfunction, and steadily increased to >10-fold over normal at end-stage disease. Biweekly intrathecal administration of HPβCD initiated prior to the onset of neurologic dysfunction completely normalized CSF calbindin in NPC1 cats at all time points analyzed when followed up to 78 weeks of age. Initiation of HPβCD after the onset of clinical signs (16 weeks of age) resulted in a delayed reduction of calbindin levels in the CSF. Evaluation of CSF from patients with NPC1 revealed that calbindin concentrations were significantly elevated compared with CSF samples collected from unaffected patients. Off-label treatment of patients with NPC1 with miglustat, an inhibitor of glycosphingolipid biosynthesis, significantly decreased CSF calbindin compared with pretreatment concentrations. These data suggest that the CSF calbindin concentration is a sensitive biomarker of NPC1 disease that could be instrumental as an outcome measure of therapeutic efficacy in ongoing clinical trials. PMID:27307499

  14. PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder

    Science.gov (United States)

    Brown, Anna; Patel, Siddharth; Ward, Carl; Lorenz, Anna; Ortiz, Mauren; DuRoss, Allison; Wieghardt, Fabian; Esch, Amanda; Otten, Elsje G.; Heiser, Laura M.; Korolchuk, Viktor I.; Sun, Conroy; Sarkar, Sovan; Sahay, Gaurav

    2016-01-01

    2-Hydroxy-propyl-β-cyclodextrin (HPβCD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HPβCD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (ethylene glycol) (PEG)-lipid conjugate enables cholesterol clearance from endo/lysosomes of Npc1 mutant (Npc1−/−) cells. Herein, we show that distearyl-phosphatidylethanolamine-PEG (DSPE-PEG), which forms 12-nm micelles above the critical micelle concentration, accumulates heavily inside cholesterol-rich late endosomes in Npc1−/− cells. This potentially results in cholesterol solubilization and leakage from lysosomes. High-throughput screening revealed that DSPE-PEG, in combination with HPβCD, acts synergistically to efflux cholesterol without significantly aggravating autophagy defects. These well-known excipients can be used as admixtures to treat NPC1 disorder. Increasing PEG chain lengths from 350 Da-30 kDa in DSPE-PEG micelles, or increasing DSPE-PEG content in an array of liposomes packaged with HPβCD, improved cholesterol egress, while Pluronic block copolymers capable of micelle formation showed slight effects at high concentrations. We postulate that PEG-lipid based nanocarriers can serve as bioactive drug delivery systems for effective treatment of lysosomal storage disorders. PMID:27572704

  15. In vitro evaluation of 2-hydroxyalkylated β-cyclodextrins as potential therapeutic agents for Niemann-Pick Type C disease.

    Science.gov (United States)

    Kondo, Yuki; Tokumaru, Hiroko; Ishitsuka, Yoichi; Matsumoto, Tomoko; Taguchi, Makiko; Motoyama, Keiichi; Higashi, Taishi; Arima, Hidetoshi; Matsuo, Muneaki; Higaki, Katsumi; Ohno, Kousaku; Irie, Tetsumi

    2016-07-01

    This study was conducted to evaluate the attenuating potential of 2-hydroxypropyl-β-cyclodextrin (HPBCD) against Niemann-Pick Type C (NPC) disease, as well as the physical and chemical properties, particularly the cholesterol-solubilizing ability, in an NPC disease model in vitro. As parameters of NPC abnormalities, intracellular free and esterified cholesterol levels and lysosome volume were measured in Npc1 null Chinese hamster ovary cells. HPBCD showed dose-dependent effects against dysfunctional intracellular cholesterol trafficking, such as the accumulation and shortage of free and esterified cholesterols, respectively, in Npc1 null cells. However, the effectiveness was gradually offset by exposure to ≥8mM HPBCD. The same effect was also observed for increasing lysosome volume in Npc1 null cells. The degree of substitution of the hydroxypropyl group had little influence on the attenuating effects of HPBCD against the NPC abnormalities, at least in the range between 2.8 and 7.4. Next, we compared the effects of other hydroxyalkylated β-cyclodextrin derivatives with different cholesterol-solubilizing abilities, such as 2-hydroxyethyl-β-cyclodextrin (HEBCD) and 2-hydroxybutyl-β-cyclodextrin (HBBCD). The cholesterol solubilizing potential, attenuating effects against NPC abnormalities and cytotoxicity induction were HBBCD≫HPBCD>HEBCD, HBBCD=HPBCD>HEBCD and HBBCD≫HPBCD=HEBCD, respectively. HPBCD may be superior in terms of safety and efficacy in Npc1 null cells compared with HEBCD and HBBCD. The results of this study will provide a rationale for the optimization of HPBCD therapy for NPC disease. PMID:27184436

  16. Disruption in connexin-based communication is associated with intracellular Ca²⁺ signal alterations in astrocytes from Niemann-Pick type C mice.

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    Pablo J Sáez

    Full Text Available Reduced astrocytic gap junctional communication and enhanced hemichannel activity were recently shown to increase astroglial and neuronal vulnerability to neuroinflammation. Moreover, increasing evidence suggests that neuroinflammation plays a pivotal role in the development of Niemann-Pick type C (NPC disease, an autosomal lethal neurodegenerative disorder that is mainly caused by mutations in the NPC1 gene. Therefore, we investigated whether the lack of NPC1 expression in murine astrocytes affects the functional state of gap junction channels and hemichannels. Cultured cortical astrocytes of NPC1 knock-out mice (Npc1⁻/⁻ showed reduced intercellular communication via gap junctions and increased hemichannel activity. Similarly, astrocytes of newborn Npc1⁻/⁻ hippocampal slices presented high hemichannel activity, which was completely abrogated by connexin 43 hemichannel blockers and was resistant to inhibitors of pannexin 1 hemichannels. Npc1⁻/⁻ astrocytes also showed more intracellular Ca²⁺ signal oscillations mediated by functional connexin 43 hemichannels and P2Y₁ receptors. Therefore, Npc1⁻/⁻ astrocytes present features of connexin based channels compatible with those of reactive astrocytes and hemichannels might be a novel therapeutic target to reduce neuroinflammation in NPC disease.

  17. Case Report: Genetic analysis and anesthetic management of a child with Niemann-Pick disease Type A [version 1; referees: 2 approved

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    Priti G. Dalal

    2015-12-01

    Full Text Available A 14-month-old child, recently diagnosed with Niemann-Pick disease type A, presented for a laparoscopic placement of a gastrostomy tube under general anesthesia. The disease was confirmed and further characterized by genetic testing, which revealed evidence of the presence of two known pathogenic mutations in the SMPD1 gene, and enzyme studies showed a corresponding very low level of enzymatic activity of acidic sphingomyelinase. The anesthetic management involved strategies to manage an anticipated difficult intubation and avoid post-operative ventilation.

  18. Characterization of Niemann-Pick Type C2 protein expression in multiple cancers using a novel NPC2 monoclonal antibody.

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    Yi-Jen Liao

    Full Text Available Niemann-Pick Type C2 (NPC2 plays an important role in the regulation of intracellular cholesterol homeostasis via direct binding with free cholesterol. However, little is known about the significance of NPC2 in cancer. In this study, we have pinpointed the impact of various different cancers on NPC2 expression. A series of anti-NPC2 monoclonal antibodies (mAbs with the IgG2a isotype were generated and peptide screening demonstrated that the reactive epitope were amino acid residues 31-40 of the human NPC2 protein. The specificity of these mAbs was confirmed by Western blotting using shRNA mediated knock-down of NPC2 in human SK-Hep1 cells. By immunohistochemical staining, NPC2 is expressed in normal kidney, liver, breast, colon, lung, esophageal, uterine cervical, pancreatic and stomach tissue. Strong expression of NPC2 was found in the distal and proximal convoluted tubule of kidney and the hepatocytes of liver. Normal esophageal, uterine cervical, pancreatic, stomach, breast, colon and lung tissue stained moderately to weakly. When compared to their normal tissue equivalents, NPC2 overexpression was observed in cancers of the breast, colon and lung. Regarding to breast cancer, NPC2 up-regulation is associated with estrogen receptor (-, progesterone receptor (- and human epidermal growth factor receptor (+. On the other hand, NPC2 was found to be down-regulated in renal cell carcinoma, liver cirrhosis and hepatoma tissues. By antigen-capture enzyme immunoassay ELISA, the serum NPC2 is increased in patients with cirrhosis and liver cancer. According to western blot data, the change of glycosylated pattern of NPC2 in serum is associated with cirrhosis and liver cancer. To the best of our knowledge, this is the first comprehensive immunohistochemical and serological study investigating the expression of NPC2 in a variety of different human cancers. These novel monoclonal antibodies should help with elucidating the roles of NPC2 in tumor

  19. Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model.

    Science.gov (United States)

    Alam, Md Suhail; Getz, Michelle; Haldar, Kasturi

    2016-02-17

    Histone deacetylase inhibitors (HDACi) are approved for treating rare cancers and are of interest as potential therapies for neurodegenerative disorders. We evaluated a triple combination formulation (TCF) comprising the pan-HDACi vorinostat, the caging agent 2-hydroxypropyl-β-cyclodextrin (HPBCD), and polyethylene glycol (PEG) for treating a mouse model (the Npc1(nmf164) mouse) of Niemann-Pick type C (NPC) disease, a difficult-to-treat cerebellar disorder. Vorinostat alone showed activity in cultured primary cells derived from Npc1(nmf164) mice but did not improve animal survival. However, low-dose, once-weekly intraperitoneal injections of the TCF containing vorinostat increased histone acetylation in the mouse brain, preserved neurites and Purkinje cells, delayed symptoms of neurodegeneration, and extended mouse life span from 4 to almost 9 months. We demonstrate that the TCF boosted the ability of HDACi to cross the blood-brain barrier and was not toxic even when used long term. Further, the TCF enabled dose reduction, which has been a major challenge in HDACi therapy. TCF simultaneously treats neurodegenerative and systemic symptoms of Niemann-Pick type C disease in a mouse model. PMID:26888431

  20. Dysphagia as a risk factor for mortality in Niemann-Pick disease type C: systematic literature review and evidence from studies with miglustat

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    Walterfang Mark

    2012-10-01

    Full Text Available Abstract Niemann-Pick disease type C (NP-C is a rare neurovisceral disease characterised by progressive neurological deterioration and premature death, and has an estimated birth incidence of 1:120,000. Mutations in the NPC1 gene (in 95% of cases and the NPC2 gene (in approximately 4% of cases give rise to impaired intracellular lipid metabolism in a number of tissues, including the brain. Typical neurological manifestations include vertical supranuclear gaze palsy, saccadic eye movement abnormalities, cerebellar ataxia, dystonia, dysmetria, dysphagia and dysarthria. Oropharyngeal dysphagia can be particularly problematic as it can often lead to food or fluid aspiration and subsequent pneumonia. Epidemiological data suggest that bronchopneumonia subsequent to food or fluid aspiration is a major cause of mortality in NP-C and other neurodegenerative disorders. These findings indicate that a therapy capable of improving or stabilising swallowing function might reduce the risk of aspiration pneumonia, and could have a positive impact on patient survival. Miglustat, currently the only approved disease-specific therapy for NP-C in children and adults, has been shown to stabilise key neurological manifestations in NP-C, including dysphagia. In this article we present findings from a systematic literature review of published data on bronchopneumonia/aspiration pneumonia as a cause of death, and on the occurrence of dysphagia in NP-C and other neurodegenerative diseases. We then examine the potential links between dysphagia, aspiration, pneumonia and mortality with a view to assessing the possible effect of miglustat on patient lifespan.

  1. Pre-symptomatic activation of antioxidant responses and alterations in glucose and pyruvate metabolism in Niemann-Pick Type C1-deficient murine brain.

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    Barry E Kennedy

    Full Text Available Niemann-Pick Type C (NPC disease is an autosomal recessive neurodegenerative disorder caused in most cases by mutations in the NPC1 gene. NPC1-deficiency is characterized by late endosomal accumulation of cholesterol, impaired cholesterol homeostasis, and a broad range of other cellular abnormalities. Although neuronal abnormalities and glial activation are observed in nearly all areas of the brain, the most severe consequence of NPC1-deficiency is a near complete loss of Purkinje neurons in the cerebellum. The link between cholesterol trafficking and NPC pathogenesis is not yet clear; however, increased oxidative stress in symptomatic NPC disease, increases in mitochondrial cholesterol, and alterations in autophagy/mitophagy suggest that mitochondria play a role in NPC disease pathology. Alterations in mitochondrial function affect energy and neurotransmitter metabolism, and are particularly harmful to the central nervous system. To investigate early metabolic alterations that could affect NPC disease progression, we performed metabolomics analyses of different brain regions from age-matched wildtype and Npc1 (-/- mice at pre-symptomatic, early symptomatic and late stage disease by (1H-NMR spectroscopy. Metabolic profiling revealed markedly increased lactate and decreased acetate/acetyl-CoA levels in Npc1 (-/- cerebellum and cerebral cortex at all ages. Protein and gene expression analyses indicated a pre-symptomatic deficiency in the oxidative decarboxylation of pyruvate to acetyl-CoA, and an upregulation of glycolytic gene expression at the early symptomatic stage. We also observed a pre-symptomatic increase in several indicators of oxidative stress and antioxidant response systems in Npc1 (-/- cerebellum. Our findings suggest that energy metabolism and oxidative stress may present additional therapeutic targets in NPC disease, especially if intervention can be started at an early stage of the disease.

  2. Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: findings from the ZOOM study.

    Science.gov (United States)

    Bauer, Peter; Balding, David J; Klünemann, Hans H; Linden, David E J; Ory, Daniel S; Pineda, Mercè; Priller, Josef; Sedel, Frederic; Muller, Audrey; Chadha-Boreham, Harbajan; Welford, Richard W D; Strasser, Daniel S; Patterson, Marc C

    2013-11-01

    Niemann-Pick disease type C (NP-C) is a rare, autosomal-recessive, progressive neurological disease caused by mutations in either the NPC1 gene (in 95% of cases) or the NPC2 gene. This observational, multicentre genetic screening study evaluated the frequency and phenotypes of NP-C in consecutive adult patients with neurological and psychiatric symptoms. Diagnostic testing for NP-C involved NPC1 and NPC2 exonic gene sequencing and gene dosage analysis. When available, results of filipin staining, plasma cholestane-3β,5α,6β-triol assays and measurements of relevant sphingolipids were also collected. NPC1 and NPC2 gene sequencing was completed in 250/256 patients from 30 psychiatric and neurological reference centres across the EU and USA [median (range) age 38 (18-90) years]. Three patients had a confirmed diagnosis of NP-C; two based on gene sequencing alone (two known causal disease alleles) and one based on gene sequencing and positive filipin staining. A further 12 patients displayed either single mutant NP-C alleles (8 with NPC1 mutations and 3 with NPC2 mutations) or a known causal disease mutation and an unclassified NPC1 allele variant (1 patient). Notably, high plasma cholestane-3β,5α,6β-triol levels were observed for all NP-C cases (n = 3). Overall, the frequency of NP-C patients in this study [1.2% (95% CI; 0.3%, 3.5%)] suggests that there may be an underdiagnosed pool of NP-C patients among adults who share common neurological and psychiatric symptoms. PMID:23773996

  3. Pulmonary abnormalities in animal models due to Niemann-Pick type C1 (NPC1 or C2 (NPC2 disease.

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    Blair R Roszell

    Full Text Available Niemann-Pick C (NPC disease is due to loss of NPC1 or NPC2 protein function that is required for unesterified cholesterol transport from the endosomal/lysosomal compartment. Though lung involvement is a recognized characteristic of Niemann-Pick type C disease, the pathological features are not well understood. We investigated components of the surfactant system in both NPC1 mutant mice and felines and in NPC2 mutant mice near the end of their expected life span. Histological analysis of the NPC mutant mice demonstrated thickened septae and foamy macrophages/leukocytes. At the level of electron microscopy, NPC1-mutant type II cells had uncharacteristically larger lamellar bodies (LB, mean area 2-fold larger, while NPC2-mutant cells had predominantly smaller lamellar bodies (mean area 50% of normal than wild type. Bronchoalveolar lavage from NPC1 and NPC2 mutant mice had an approx. 4-fold and 2.5-fold enrichment in phospholipid, respectively, and an approx. 9-fold and 35-fold enrichment in cholesterol, consistent with alveolar lipidosis. Phospholipid and cholesterol also were elevated in type II cell LBs and lung tissue while phospholipid degradation was reduced. Enrichment of surfactant protein-A in the lung and surfactant of the mutant mice was found. Immunocytochemical results showed that cholesterol accumulated in the LBs of the type II cells isolated from the affected mice. Alveolar macrophages from the NPC1 and NPC2 mutant mice were enlarged compared to those from wild type mice and were enriched in phospholipid and cholesterol. Pulmonary features of NPC1 mutant felines reflected the disease described in NPC1 mutant mice. Thus, with the exception of lamellar body size, the lung phenotype seen in the NPC1 and NPC2 mutant mice were similar. The lack of NPC1 and NPC2 proteins resulted in a disruption of the type II cell surfactant system contributing to pulmonary abnormalities.

  4. Protein replacement therapy partially corrects the cholesterol-storage phenotype in a mouse model of Niemann-Pick type C2 disease.

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    Gitte Krogh Nielsen

    Full Text Available Niemann-Pick type C2 (NPC2 disease is a fatal autosomal recessive neurovisceral degenerative disorder characterized by late endosomal-lysosomal sequestration of low-density lipoprotein derived cholesterol. The breach in intracellular cholesterol homeostasis is caused by deficiency of functional NPC2, a soluble sterol binding protein targeted to the lysosomes by binding the mannose-6-phosphate receptor. As currently there is no effective treatment for the disorder, we have investigated the efficacy of NPC2 replacement therapy in a murine gene-trap model of NPC2-disease generated on the 129P2/OlaHsd genetic background. NPC2 was purified from bovine milk and its functional competence assured in NPC2-deficient fibroblasts using the specific cholesterol fluorescent probe filipin. For evaluation of phenotype correction in vivo, three-week-old NPC2(-/- mice received two weekly intravenous injections of 5 mg/kg NPC2 until trial termination 66 days later. Whereas the saline treated NPC2(-/- mice exhibited massive visceral cholesterol storage as compared to their wild-type littermates, administration of NPC2 caused a marked reduction in cholesterol build up. The histological findings, indicating an amelioration of the disease pathology in liver, spleen, and lungs, corroborated the biochemical results. Little or no difference in the overall cholesterol levels was observed in the kidneys, blood, cerebral cortex and hippocampus when comparing NPC2(-/- and wild type mice. However, cerebellum cholesterol was increased about two fold in NPC2(-/- mice compared with wild-type littermates. Weight gain performance was slightly improved as a result of the NPC2 treatment but significant motor coordination deficits were still observed. Accordingly, ultrastructural cerebellar abnormalities were detected in both saline treated and NPC2 treated NPC2(-/- animals 87 days post partum. Our data indicate that protein replacement may be a beneficial therapeutic approach in the

  5. Deficiency of a Niemann-Pick, type C1-related protein in toxoplasma is associated with multiple lipidoses and increased pathogenicity.

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    Bao Lige

    2011-12-01

    Full Text Available Several proteins that play key roles in cholesterol synthesis, regulation, trafficking and signaling are united by sharing the phylogenetically conserved 'sterol-sensing domain' (SSD. The intracellular parasite Toxoplasma possesses at least one gene coding for a protein containing the canonical SSD. We investigated the role of this protein to provide information on lipid regulatory mechanisms in the parasite. The protein sequence predicts an uncharacterized Niemann-Pick, type C1-related protein (NPC1 with significant identity to human NPC1, and it contains many residues implicated in human NPC disease. We named this NPC1-related protein, TgNCR1. Mammalian NPC1 localizes to endo-lysosomes and promotes the movement of sterols and sphingolipids across the membranes of these organelles. Miscoding patient mutations in NPC1 cause overloading of these lipids in endo-lysosomes. TgNCR1, however, lacks endosomal targeting signals, and localizes to flattened vesicles beneath the plasma membrane of Toxoplasma. When expressed in mammalian NPC1 mutant cells and properly addressed to endo-lysosomes, TgNCR1 restores cholesterol and GM1 clearance from these organelles. To clarify the role of TgNCR1 in the parasite, we genetically disrupted NCR1; mutant parasites were viable. Quantitative lipidomic analyses on the ΔNCR1 strain reveal normal cholesterol levels but an overaccumulation of several species of cholesteryl esters, sphingomyelins and ceramides. ΔNCR1 parasites are also characterized by abundant storage lipid bodies and long membranous tubules derived from their parasitophorous vacuoles. Interestingly, these mutants can generate multiple daughters per single mother cell at high frequencies, allowing fast replication in vitro, and they are slightly more virulent in mice than the parental strain. These data suggest that the ΔNCR1 strain has lost the ability to control the intracellular levels of several lipids, which subsequently results in the

  6. Alleged Detrimental Mutations in the SMPD1 Gene in Patients with Niemann-Pick Disease

    OpenAIRE

    Cosima Rhein; Christiane Mühle; Johannes Kornhuber; Martin Reichel

    2015-01-01

    Loss-of-function mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene are associated with decreased catalytic activity of acid sphingomyelinase (ASM) and are the cause of the autosomal recessive lysosomal storage disorder Niemann-Pick disease (NPD) types A and B. Currently, >100 missense mutations in SMPD1 are listed in the Human Gene Mutation Database. However, not every sequence variation in SMPD1 is detrimental and gives rise to NPD. We have analysed several alleged SMPD1 mis...

  7. Niemann-Pick Disease

    Science.gov (United States)

    ... Individuals wit Type C who share a common ancestral background in Nova Scotia were previously referred to ... B . The development of enzyme replacement and gene therapies might also be helpful for those with type ...

  8. Niemann-Pick disease

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    ... seen in French Canadian people in Yarmouth County, Nova Scotia. Symptoms Symptoms vary. Other health conditions may ... the eye Feeding difficulties Loss of early motor skills (gets worse over time) Type B symptoms are ...

  9. Rescue of an In Vitro Neuron Phenotype Identified in Niemann-Pick Disease, Type C1 Induced Pluripotent Stem Cell-Derived Neurons by Modulating the WNT Pathway and Calcium Signaling

    OpenAIRE

    Efthymiou, Anastasia G.; Steiner, Joe; Pavan, William J.; Wincovitch, Stephen; Larson, Denise M.; Porter, Forbes D.; Rao, Mahendra S; Malik, Nasir

    2015-01-01

    This study involved the generation of an induced pluripotent stem cell line from a subject homozygous for the most frequent Niemann-Pick disease, type C1 (NPC1) mutation and the subsequent creation of a stable line of neural stem cells as a disease model for NPC1. The clear readout from these cells makes them ideal candidates for high-throughput screening and is a valuable tool to better understand the development of NPC1 and to develop better therapeutic options.

  10. Heat Shock Protein Beta-1 Modifies Anterior to Posterior Purkinje Cell Vulnerability in a Mouse Model of Niemann-Pick Type C Disease

    Science.gov (United States)

    Dell’Orco, James M.; Qin, Zhaohui S.; Kalyana-Sundaram, Shanker; Chinnaiyan, Arul M.; Shakkottai, Vikram G.; Lieberman, Andrew P.

    2016-01-01

    Selective neuronal vulnerability is characteristic of most degenerative disorders of the CNS, yet mechanisms underlying this phenomenon remain poorly characterized. Many forms of cerebellar degeneration exhibit an anterior-to-posterior gradient of Purkinje cell loss including Niemann-Pick type C1 (NPC) disease, a lysosomal storage disorder characterized by progressive neurological deficits that often begin in childhood. Here, we sought to identify candidate genes underlying vulnerability of Purkinje cells in anterior cerebellar lobules using data freely available in the Allen Brain Atlas. This approach led to the identification of 16 candidate neuroprotective or susceptibility genes. We demonstrate that one candidate gene, heat shock protein beta-1 (HSPB1), promoted neuronal survival in cellular models of NPC disease through a mechanism that involved inhibition of apoptosis. Additionally, we show that over-expression of wild type HSPB1 or a phosphomimetic mutant in NPC mice slowed the progression of motor impairment and diminished cerebellar Purkinje cell loss. We confirmed the modulatory effect of Hspb1 on Purkinje cell degeneration in vivo, as knockdown by Hspb1 shRNA significantly enhanced neuron loss. These results suggest that strategies to promote HSPB1 activity may slow the rate of cerebellar degeneration in NPC disease and highlight the use of bioinformatics tools to uncover pathways leading to neuronal protection in neurodegenerative disorders. PMID:27152617

  11. Heat Shock Protein Beta-1 Modifies Anterior to Posterior Purkinje Cell Vulnerability in a Mouse Model of Niemann-Pick Type C Disease.

    Science.gov (United States)

    Chung, Chan; Elrick, Matthew J; Dell'Orco, James M; Qin, Zhaohui S; Kalyana-Sundaram, Shanker; Chinnaiyan, Arul M; Shakkottai, Vikram G; Lieberman, Andrew P

    2016-05-01

    Selective neuronal vulnerability is characteristic of most degenerative disorders of the CNS, yet mechanisms underlying this phenomenon remain poorly characterized. Many forms of cerebellar degeneration exhibit an anterior-to-posterior gradient of Purkinje cell loss including Niemann-Pick type C1 (NPC) disease, a lysosomal storage disorder characterized by progressive neurological deficits that often begin in childhood. Here, we sought to identify candidate genes underlying vulnerability of Purkinje cells in anterior cerebellar lobules using data freely available in the Allen Brain Atlas. This approach led to the identification of 16 candidate neuroprotective or susceptibility genes. We demonstrate that one candidate gene, heat shock protein beta-1 (HSPB1), promoted neuronal survival in cellular models of NPC disease through a mechanism that involved inhibition of apoptosis. Additionally, we show that over-expression of wild type HSPB1 or a phosphomimetic mutant in NPC mice slowed the progression of motor impairment and diminished cerebellar Purkinje cell loss. We confirmed the modulatory effect of Hspb1 on Purkinje cell degeneration in vivo, as knockdown by Hspb1 shRNA significantly enhanced neuron loss. These results suggest that strategies to promote HSPB1 activity may slow the rate of cerebellar degeneration in NPC disease and highlight the use of bioinformatics tools to uncover pathways leading to neuronal protection in neurodegenerative disorders. PMID:27152617

  12. Niemann-Pick Disease Type C Presenting as a Developmental Coordination Disorder with Bullying by Peers in a School-Age Child

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    Ryo Suzuki

    2015-01-01

    Full Text Available Niemann-Pick disease type C (NPC is a rare progressive neurodegenerative disorder, often with onset after normal early childhood development. Juvenile onset NPC patients slowly develop cerebellar symptoms and cognitive impairment and often experience difficulties at school. However, these problems may be overlooked due to the unpublicized nature of NPC, given that it is a rare metabolic disorder. In this report, we present an 11-year-old male NPC patient, who suffered from clumsiness and difficulties in attention and academic and social skills. His symptoms were initially considered to be due to developmental coordination disorder (DCD coexisting with bullying by peers. DCD is a type of neurodevelopmental disorder defined according to DSM-IV and is characterized by clumsiness that interferes with academic achievement and social integration not due to other general medical conditions. However, a detailed investigation of the patient suggested that the problems could be attributed to the onset of NPC. Clinicians should keep neurodegenerative disorders as differential diagnosis of children with multiple school problems.

  13. Heat Shock Protein Beta-1 Modifies Anterior to Posterior Purkinje Cell Vulnerability in a Mouse Model of Niemann-Pick Type C Disease.

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    Chan Chung

    2016-05-01

    Full Text Available Selective neuronal vulnerability is characteristic of most degenerative disorders of the CNS, yet mechanisms underlying this phenomenon remain poorly characterized. Many forms of cerebellar degeneration exhibit an anterior-to-posterior gradient of Purkinje cell loss including Niemann-Pick type C1 (NPC disease, a lysosomal storage disorder characterized by progressive neurological deficits that often begin in childhood. Here, we sought to identify candidate genes underlying vulnerability of Purkinje cells in anterior cerebellar lobules using data freely available in the Allen Brain Atlas. This approach led to the identification of 16 candidate neuroprotective or susceptibility genes. We demonstrate that one candidate gene, heat shock protein beta-1 (HSPB1, promoted neuronal survival in cellular models of NPC disease through a mechanism that involved inhibition of apoptosis. Additionally, we show that over-expression of wild type HSPB1 or a phosphomimetic mutant in NPC mice slowed the progression of motor impairment and diminished cerebellar Purkinje cell loss. We confirmed the modulatory effect of Hspb1 on Purkinje cell degeneration in vivo, as knockdown by Hspb1 shRNA significantly enhanced neuron loss. These results suggest that strategies to promote HSPB1 activity may slow the rate of cerebellar degeneration in NPC disease and highlight the use of bioinformatics tools to uncover pathways leading to neuronal protection in neurodegenerative disorders.

  14. Recent Advances in the Diagnosis and Treatment of Niemann-Pick Disease Type C in Children: A Guide to Early Diagnosis for the General Pediatrician

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    Hanna Alobaidy

    2015-01-01

    Full Text Available Niemann-Pick disease (NP-C is a lysosomal storage disease in which impaired intracellular lipid transport leads to accumulation of cholesterol and glycosphingolipids in various neurovisceral tissues. It is an autosomal recessive disorder, caused by mutations in the NPC1 or NPC2 genes. The clinical spectrum is grouped by the age of onset and onset of neurological manifestation: pre/perinatal; early infantile; late infantile; and juvenile periods. The NP-C Suspicion Index (SI screening tool was developed to identify suspected patients with this disease. It is especially good at recognizing the disease in patients older than four years of age. Biochemical tests involving genetic markers and Filipin staining of skin fibroblast are being employed to assist diagnosis. Therapy is mostly supportive and since 2009, the first specific therapy approved for use was Miglustat (Zavesca aimed at stabilizing the rate of progression of neurological manifestation. The prognosis correlates with age at onset of neurological signs; patients with early onset form progress faster. The NP-C disease has heterogeneous neurovisceral manifestations. A SI is a screening tool that helps in diagnostic process. Filipin staining test is a specific biomarker diagnostic test. Miglustat is the first disease-specific therapy.

  15. Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency.

    Science.gov (United States)

    Pajares, Sonia; Arias, Angela; García-Villoria, Judit; Macías-Vidal, Judit; Ros, Emilio; de las Heras, Javier; Girós, Marisa; Coll, Maria J; Ribes, Antonia

    2015-10-01

    Niemann-Pick type C (NPC) is a progressive neurodegenerative disease characterized by lysosomal/endosomal accumulation of unesterified cholesterol and glycolipids. Recent studies have shown that plasma cholestane-3β,5α,6β-triol (CT) and 7-ketocholesterol (7-KC) could be potential biomarkers for the diagnosis of NPC patients. We aimed to know the sensitivity and specificity of these biomarkers for the diagnosis of NPC compared with other diseases that can potentially lead to oxysterol alterations. We studied 107 controls and 122 patients including 16 with NPC, 3 with lysosomal acid lipase (LAL) deficiency, 8 with other lysosomal diseases, 5 with galactosemia, 11 with cerebrotendinous xanthomatosis (CTX), 3 with Smith-Lemli-Opitz, 14 with peroxisomal biogenesis disorders, 19 with unspecific hepatic diseases, 13 with familial hypercholesterolemia, and 30 with neurological involvement and no evidence of an inherited metabolic disease. CT and 7-KC were analyzed by HPLC-ESI-MS/MS as mono-dimethylglycine derivatives. Levels of 7-KC were high in most of the studied diseases, whereas those of CT were only high in NPC, LAL, and CTX patients. Consequently, although CT is a sensitive biomarker of NPC disease, including those cases with doubtful filipin staining, it is not specific. 7-KC is a very unspecific biomarker. PMID:26239048

  16. Synthesis of 2-hydroxypropyl-β-cyclodextrin/pluronic-based polyrotaxanes via heterogeneous reaction as potential Niemann-Pick type C therapeutics.

    Science.gov (United States)

    Mondjinou, Yawo A; McCauliff, Leslie A; Kulkarni, Aditya; Paul, Lake; Hyun, Seok-Hee; Zhang, Zhaorui; Wu, Zhen; Wirth, Mary; Storch, Judith; Thompson, David H

    2013-12-01

    Five polyrotaxanes were synthesized by threading 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) onto a variety of α,ω-ditriethylenediamino-N-carbamoyl-poly-(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (Pluronic) triblock copolymers using a two-pot strategy under heterogeneous, nonaqueous conditions. The threaded HP-β-CD units were retained on the pseudopolyrotaxane precursors by end-capping the branched diamine termini with sodium 2,4,6-trinitrobenzene sulfonate. Inclusion of the Pluronic copolymers within the HP-β-CD cavities was more favorable in nonpolar solvents, such as diethyl ether and n-hexane, both of which gave better coverage ratios than polar solvents. (1)H NMR and MALDI-TOF were used to estimate the average molecular weights of the purified polyrotaxane products. A globular morphology of aggregated polyrotaxanes was observed by tapping-mode AFM imaging of dried samples. Treatment of Niemann-Pick C (NPC) type 2-deficient fibroblasts with the polyrotaxane derivatives produced substantial reductions in sterol accumulation, as seen by diminished filipin staining in these cells, suggesting that Pluronic-based polyrotaxanes may be promising vehicles for delivery of HP-β-CD to cells with abnormal cholesterol accumulation. PMID:24180231

  17. Niemann ? Pick Hastal??? Olan Bir Olgu

    OpenAIRE

    AT?K, Fatih; KARA, Melek; ZORLU, Pelin

    2006-01-01

    Niemann-Pick Hastal???, otozomal resesif geçen, santral sinir sistemi ba?ta olmak dokularda sfingomyelin ve kolesterolün birikmesiyle karakterize bir lizozomal lipid depo hastal???dır. Burada karın ?i?li?i yakınmasıyla hastanemize ba?vuran ve Niemann-Pick Hastal??? Tip B tanısı alan on aylık kız hasta sunulmuştur.

  18. Defining natural history: assessment of the ability of college students to aid in characterizing clinical progression of Niemann-Pick disease, type C.

    Directory of Open Access Journals (Sweden)

    Jenny Shin

    Full Text Available Niemann-Pick Disease, type C (NPC is a fatal, neurodegenerative, lysosomal storage disorder. It is a rare disease with broad phenotypic spectrum and variable age of onset. These issues make it difficult to develop a universally accepted clinical outcome measure to assess urgently needed therapies. To this end, clinical investigators have defined emerging, disease severity scales. The average time from initial symptom to diagnosis is approximately 4 years. Further, some patients may not travel to specialized clinical centers even after diagnosis. We were therefore interested in investigating whether appropriately trained, community-based assessment of patient records could assist in defining disease progression using clinical severity scores. In this study we evolved a secure, step wise process to show that pre-existing medical records may be correctly assessed by non-clinical practitioners trained to quantify disease progression. Sixty-four undergraduate students at the University of Notre Dame were expertly trained in clinical disease assessment and recognition of major and minor symptoms of NPC. Seven clinical records, randomly selected from a total of thirty seven used to establish a leading clinical severity scale, were correctly assessed to show expected characteristics of linear disease progression. Student assessment of two new records donated by NPC families to our study also revealed linear progression of disease, but both showed accelerated disease progression, relative to the current severity scale, especially at the later stages. Together, these data suggest that college students may be trained in assessment of patient records, and thus provide insight into the natural history of a disease.

  19. OxLDL up-regulates Niemann-Pick type C1 expression through ERK1/2/COX-2/ PPARα-signaling pathway in macrophages

    Institute of Scientific and Technical Information of China (English)

    Xiaohua yu; Chaoke Tang; Xiaoxu Li; Guojun Zhao; Ji Xiao; Zhongcheng Mo; Kai Yin; Zhisheng Jiang; Yuchang Fu; Xiaohui Zha

    2012-01-01

    The Niemann-Pick type C1 (NPC1) is located mainly in the membranes of the late endosome/lysosome and controls the intracellular cholesterol trafficking from the late endosome/lysosome to the plasma membrane.It has been reported that oxidized low-density lipoprotein (oxLDL) can up-regulate NPC1 expression.However,the detailed mechanisms are not fully understood.In this study,we investigated the effect of oxLDL stimulation on NPC1 expression in THP-1 macrophages.Our results showed that oxLDL up-regulated NPC1 expression at both mRNA and protein levels in a dose-dependent and time-dependent manner.In addition,oxLDL also induced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2).Treatment with oxLDL significantly increased cyclooxygenase-2 (COX-2)mRNA and protein expression in the macrophages,and these increases were suppressed by the ERK1/2 inhibitor PD98059 or ERK1/2 small interfering RNA (siRNA) treatment.OxLDL up-regulated the expression of peroxisome proliferator-activated receptor α (PPARα) at the mRNA and protein levels,which could be abolished by COX-2 siRNA or COX-2 inhibitor NS398 treatment in these macrophages.OxLDL dramatically elevated cellular cholesterol efflux,which was abrogated by inhibiting ERK1/2 and/or COX-2.In addition,oxLDL-induced NPC1 expression and cellular cholesterol effiux were reversed by PPARα siRNA or GW6471,an antagonist of PPARα.Taken together,these results provide the evidence that oxLDL can up-regulate the expression of the NPC1 through ERK1/2/COX-2/PPARα-signaling pathway in macrophages.

  20. Three-year follow-up of Niemann-Pick disease with pulmonary involvement: a case report

    International Nuclear Information System (INIS)

    Niemann-Pick disease is a rare inherited metabolic storage disease that causes excessive intracellular storage of sphingomyelin in various organs. We present the pulmonary imaging findings with particular emphasis on the CT findings in a case of Niemann-Pick disease type B with pulmonary involvement. of tchest radiograph showed fine reticulonodular opacities in both basal lung fields, and the high-resolution chest CT showed centrilobular nodular opacities and smooth thickening of the interlobar fissure and interlobular septum with a basal lung predominance. Coronal reformatted CT revealed a prominent interlobular septal thickening around the diaphragm. The follow-up high-resolution chest CT showed no significant interval changes over a 3-years period

  1. Three-year follow-up of Niemann-Pick disease with pulmonary involvement: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Choong Wook; Goo, Hyun Woo [University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2005-07-15

    Niemann-Pick disease is a rare inherited metabolic storage disease that causes excessive intracellular storage of sphingomyelin in various organs. We present the pulmonary imaging findings with particular emphasis on the CT findings in a case of Niemann-Pick disease type B with pulmonary involvement. of tchest radiograph showed fine reticulonodular opacities in both basal lung fields, and the high-resolution chest CT showed centrilobular nodular opacities and smooth thickening of the interlobar fissure and interlobular septum with a basal lung predominance. Coronal reformatted CT revealed a prominent interlobular septal thickening around the diaphragm. The follow-up high-resolution chest CT showed no significant interval changes over a 3-years period.

  2. Synthesis, Characterization, In Vitro Evaluation, and Preclinical Profiling of beta-Cyclodextrin Polyrotaxane Families for Use As Potential Niemann-Pick Type C Therapeutics

    Science.gov (United States)

    Collins, Christopher J.

    Niemann-Pick Disease Type C (NPC) is a rare, autosomal recessive genetic disorder featuring a loss of proteins responsible for unesterified cholesterol (UC) trafficking through the late endosomes/lysosomes (LE/LY) of every cell of the body. Disruption of this pathway leads to abnormal accumulation and storage of UC and other lipids. A broad range of visceral and neurological symptoms result from this accumulation exhibiting a variable age of onset and a disease progression that is ultimately fatal. The disease has an incidence of approximately 1 in 120,000 live births and has no known effective treatment. beta-Cyclodextrin (beta-CD) are natural small molecules macrocycles composed of glucose units with a hydrophobic inner cavity and hydrophilic outer rims. beta-CD derivatives have recently been shown to be effective therapeutics for NPC in cellular and animal models. In the mouse model of the disease, beta-CD therapy increases overall lifetime by as much as 50% and slows the progression of neurodegeneration. The progress has led to the initiation of a National Institutes of Health phase I clinical trial. A main drawback of beta-CD administration is the poor pharmacokinetic profile characterized by rapid renal clearance of the drug through the urine. Libraries of beta-CD derivative carrying high molecular weight polyrotaxane (PR) systems have been designed to prevent glomerular filtration of the injected beta-CD dose. An initial family of unmodified beta-CD PRs was synthesized, characterized, and their therapeutic efficacy was tested in NPC fibroblasts. This was followed by screening of PRs consisting of mixed beta-CD derivative threading featuring charged sulfobutylether beta-CD. Finally, we sought to define PR structure-property effects on in vivo pharmacokinetics, biodistribution, toxicity, immunogenicity, and protein hard corona composition. This was accomplished using a family of gadolinium carrying PRs composed of triblock Pluronic co-polymers of varying

  3. Niemann-Pick disease type C1(NPC1) is involved in resistance against imatinib in the imatinib-resistant Ph+ acute lymphoblastic leukemia cell line SUP-B15/RI.

    Science.gov (United States)

    Naren, Duolan; Wu, Jiahui; Gong, Yuping; Yan, Tianyou; Wang, Ke; Xu, Wenming; Yang, Xi; Shi, Fangfang; Shi, Rui

    2016-03-01

    Niemann-Pick disease type C1 (NPC1) is involved in cholesterol trafficking and may normally function as a transmembrane efflux pump. Previous studies showed that its dysfunction can lead to cholesterol and daunorubicin accumulation in the cytoplasmic endosomal/lysosomal system, lead to Niemann-Pick disease and resistance to anticancer drugs. In the present study, NPC1 was shown by microarray analysis to be more highly expressed in the Ph+ acute lymphoblastic leukemia cell line SUP-B15/RI, an imatinib-resistant variant of SUP-B15/S cells without bcr-abl gene mutation established in our lab. Further investigation revealed a defect in the functional capacity of the NPC1 protein demonstrated by filipin staining accompanied by a lower intracellular imatinib mesylate(IM) concentration by high-performance liquid chromatography in SUP-B15/RI compared with SUP-B15/S cells. Furthermore, U18666A, an inhibitor of NPC1 function, was used to block cholesterol trafficking to imitate the NPC1 defect in SUP-B15/S cells, leading to higher NPC1 expression, stronger filipin fluorescence, lower intracellular IM concentrations and greater resistance against IM. Samples from non-mutated relapsed Ph+ ALL patients also showed higher NPC1 expression compared with IM-sensitive patients. Our experiment may reveal a new mechanism of IM resistance in Ph+ ALL. PMID:26818574

  4. Teaching Children with Niemann-Pick Disease

    Science.gov (United States)

    Gartin, Barbara C.; Murdick, Nikki L.; Cooley, Jennifer; Barnett, Sara

    2013-01-01

    Niemann-Pick Disease (NPD) is a group of rare inherited disorders that are both systemic and degenerative. Knowledge of the disease, its characteristics, and its progression are essential for the teacher and related service personnel to provide an appropriate educational experience for the student. For the teacher who has a student with NPC in…

  5. Anesthesia Management in a Patient with Niemann Pick Disease

    Directory of Open Access Journals (Sweden)

    Zeynep Akoğul

    2013-04-01

    Full Text Available Niemann-Pick disease (NPD is an autosomal recessive, lipid storage disorder caused by the deficiency of the lysosomal enzyme sphingomyelinase or defective cholesterol transport from lysosome to cytosol. The clinical symptoms and signs include dysphagia, loss of motor function, hepatosplenomegaly, recurred respiratory infections, seizure, mental retardation, spasticity, myoclonic jerks and ataxia, but vary depending on the type of this disease. According to the observed pathology, patients require specialized therapy. Due to the high prevalence of the pathology in this group of patients, surgical interventions requiring general anaesthesia are common. Anesthetists have some difficulties with this group of patients. One of them is difficult ventilation because of hepatosplenomegaly and the other is difficult intubation. The metabolism of some of the anesthetic agents may be affected due to chronic use of anticonvulsant agents. Liver enzymes are elevated and platelet counts are reduced. Here we report an anesthesia management, difficulties and post-op follow up in a female child having NPD. Anesthetists have some difficulties in ventilation and intubation with NPD patients. In this situation ventilation should be with low tidal volume and high frequency. Because anesthetic agents might cause liver damage, they should be used cautiously. As a result, with keeping mind all these pathologies, anesthesia management to these patients should be used cautiously. (Journal of Current Pediatrics 2013; 11: 42-4

  6. Niemann - Pick disease associated with hemophagocytic syndrome

    OpenAIRE

    Serap Karaman; Nafiye Urgancı; Günsel Kutluk; Feyzullah Çetinkaya

    2010-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is a disease characterized by phagocytosis of blood cells by macrophages within the lymphoreticular tissue. It can develop secondary to some diseases or be familial as a result of genetic mutations. Niemann-Pick disease (NPD) is a very rare lipid storage disease. A three-month-old girl presented with high fever (39°C), abdominal distension and paleness. The parents were consanguineous. The liver and spleen were palpable 10 cm and 11 cm below the costal...

  7. Niemann-Pick hastalığı tip A ve tip B: İki olgu sunumu

    OpenAIRE

    Zorlu, Pelin; Uçar, Şit; YARALI, Neşe; DEMİRÇEKEN, Fulya

    2014-01-01

    Niemann-Pick disease is an autosomal recessively inherited group of congenital lipidoses in which sphingolipids accumulate in certain tissues, especially reticuloendothelial cells. The clinical phenotype is extremely variable, ranging from an acute neonatal form, to an adult late-onset form. We presented two patients who admitted to our clinic with hepatosplenomegaly and diagnosed as Niemann-Pick disease type A and type B.

  8. Hepatic Primary and Secondary Cholesterol Deposition and Damage in Niemann-Pick Disease.

    Science.gov (United States)

    Bosch, Marta; Fajardo, Alba; Alcalá-Vida, Rafael; Fernández-Vidal, Andrea; Tebar, Francesc; Enrich, Carlos; Cardellach, Francesc; Pérez-Navarro, Esther; Pol, Albert

    2016-03-01

    Niemann-Pick C disease is a neurovisceral disorder caused by mutations in the NPC gene that result in systemic accumulation of intracellular cholesterol. Although neurodegeneration defines the disease's severity, in most patients it is preceded by hepatic complications such as cholestatic jaundice or hepatomegaly. To analyze the contribution of the hepatic disease in Niemann-Pick C disease progression and to evaluate the degree of primary and secondary hepatic damage, we generated a transgenic mouse with liver-selective expression of NPC1 from embryonic stages. Hepatic NPC1 re-expression did not ameliorate the onset and progression of neurodegeneration of the NPC1-null animal. However, the mice showed reduced hepatomegalia and dramatic, although not complete, reduction of hepatic cholesterol and serum bile salts, bilirubin, and transaminase levels. Therefore, hepatic primary and secondary cholesterol deposition and damage occur simultaneously during Niemann-Pick C disease progression. PMID:26784526

  9. Structure of human Niemann-Pick C1 protein.

    Science.gov (United States)

    Li, Xiaochun; Wang, Jiawei; Coutavas, Elias; Shi, Hang; Hao, Qi; Blobel, Günter

    2016-07-19

    Niemann-Pick C1 protein (NPC1) is a late-endosomal membrane protein involved in trafficking of LDL-derived cholesterol, Niemann-Pick disease type C, and Ebola virus infection. NPC1 contains 13 transmembrane segments (TMs), five of which are thought to represent a "sterol-sensing domain" (SSD). Although present also in other key regulatory proteins of cholesterol biosynthesis, uptake, and signaling, the structure and mechanism of action of the SSD are unknown. Here we report a crystal structure of a large fragment of human NPC1 at 3.6 Å resolution, which reveals internal twofold pseudosymmetry along TM 2-13 and two structurally homologous domains that protrude 60 Å into the endosomal lumen. Strikingly, NPC1's SSD forms a cavity that is accessible from both the luminal bilayer leaflet and the endosomal lumen; computational modeling suggests that this cavity is large enough to accommodate one cholesterol molecule. We propose a model for NPC1 function in cholesterol sensing and transport. PMID:27307437

  10. Alleged Detrimental Mutations in the SMPD1 Gene in Patients with Niemann-Pick Disease

    Directory of Open Access Journals (Sweden)

    Cosima Rhein

    2015-06-01

    Full Text Available Loss-of-function mutations in the sphingomyelin phosphodiesterase 1 (SMPD1 gene are associated with decreased catalytic activity of acid sphingomyelinase (ASM and are the cause of the autosomal recessive lysosomal storage disorder Niemann-Pick disease (NPD types A and B. Currently, >100 missense mutations in SMPD1 are listed in the Human Gene Mutation Database. However, not every sequence variation in SMPD1 is detrimental and gives rise to NPD. We have analysed several alleged SMPD1 missense mutations mentioned in a recent publication and found them to be common variants of SMPD1 that give rise to normal in vivo and in vitro ASM activity. (Comment on Manshadi et al. Int. J. Mol. Sci. 2015, 16, 6668–6676.

  11. NIEMANN PICK DISEASE DIAGNOSED ON BONE MARROW ASPIRATION

    OpenAIRE

    Amita; Ankit; Mahendra

    2015-01-01

    Niemann - pick disease is a rare lysosomal storage disorder affecting 1 in 2,50,000 children. We are describing here, a case of Niemann - pick disease in a 19 months old female baby, who presented with distension of abdomen for 9 months and she was not able to sit or stand u n til this age. On examina tion of abdomen there was hepatosplenomegaly. Ultrasound abdomen also revealed hepatosplenomegaly along with multiple mesenteric and periportal lymph no...

  12. Cholesterol-Dependent Energy Transfer between Fluorescent Proteins—Insights into Protein Proximity of APP and BACE1 in Different Membranes in Niemann-Pick Type C Disease Cells

    Directory of Open Access Journals (Sweden)

    Bjoern von Einem

    2012-11-01

    Full Text Available Förster resonance energy transfer (FRET -based techniques have recently been applied to study the interactions between β-site APP-cleaving enzyme-GFP (BACE1-GFP and amyloid precursor protein-mRFP (APP-mRFP in U373 glioblastoma cells. In this context, the role of APP-BACE1 proximity in Alzheimer’s disease (AD pathogenesis has been discussed. FRET was found to depend on intracellular cholesterol levels and associated alterations in membrane stiffness. Here, NPC1 null cells (CHO-NPC1−/−, exhibiting increased cholesterol levels and disturbed cholesterol transport similar to that observed in Niemann-Pick type C disease (NPC, were used to analyze the influence of altered cholesterol levels on APP-BACE1 proximity. Fluorescence lifetime measurements of whole CHO-wild type (WT and CHO-NPC1−/− cells (EPI-illumination microscopy, as well as their plasma membranes (total internal reflection fluorescence microscopy, TIRFM, were performed. Additionally, generalized polarization (GP measurements of CHO-WT and CHO-NPC1−/− cells incubated with the fluorescence marker laurdan were performed to determine membrane stiffness of plasma- and intracellular-membranes. CHO-NPC1−/− cells showed higher membrane stiffness at intracellular- but not plasma-membranes, equivalent to cholesterol accumulation in late endosomes/lysosomes. Along with higher membrane stiffness, the FRET efficiency between BACE1-GFP and APP-mRFP was reduced at intracellular membranes, but not within the plasma membrane of CHO-NPC1−/−. Our data show that FRET combined with TIRF is a powerful technique to determine protein proximity and membrane fluidity in cellular models of neurodegenerative diseases.

  13. Urinary excretion and metabolism of miglustat and valproate in patients with Niemann-Pick type C1 disease: One- and two-dimensional solution-state (1)H NMR studies.

    Science.gov (United States)

    Probert, Fay; Ruiz-Rodado, Victor; Zhang, Xiaoyu; te Vruchte, Danielle; Claridge, Tim D W; Edgar, Mark; Tocchio, Anna Zonato; Lachmann, Robin H; Platt, Frances M; Grootveld, Martin

    2016-01-01

    Niemann-Pick type C1 (NP-C1) disease is a neurodegenerative lysosomal storage disease for which the only approved therapy is miglustat (MGS). In this study we explored the applications and value of both one- and two-dimensional high-resolution NMR analysis strategies to the detection and quantification of MGS and its potential metabolites in urine samples collected from NP-C1 disease patients (n=47), and also applied these techniques to the analysis of the anticonvulsant drug valproate and one of its major metabolites in ca. 30% of these samples (i.e. from those who were also receiving this agent for the control of epileptic seizures). A combination of high-resolution 1D and 2D TOCSY/NOESY techniques confirmed the identity of MGS in the urinary (1)H NMR profiles of NP-C1 patients treated with this agent (n=25), and its quantification was readily achievable via electronic integration of selected 1D resonance intensities. However, this analysis provided little or no evidence for its metabolism in vivo, observations consistent with those acquired in corresponding experiments performed involving an in vitro microsomal system. Contrastingly, the major valproate metabolite 1-O-valproyl-β-glucuronide was readily detectable and quantifiable in 14/47 of the urine samples investigated, despite some resonance overlap problems (identification of this agent was confirmed by experiments involving equilibration of these samples with β-glucuronidase, a process liberating free valproate). In order to facilitate and validate the detection of MGS in urine specimens, full assignments of the (1)H NMR spectra of MGS in both buffered aqueous (pH 7.10) and deuterated methanol solvent systems were also made. The pharmacological and bioanalytical significance of data acquired are discussed, with special reference to the advantages offered by high-resolution NMR analysis. PMID:26397207

  14. Niemann-Pick disease treatment: a systematic review of clinical trials

    OpenAIRE

    Santos-Lozano, Alejandro; Villamandos García, Diana; Sanchís-Gomar, Fabián; Pareja Galeano, Helios; Garatachea, Nuria; Nogales-Gadea, Gisela; Lucía Mulas, Alejandro

    2015-01-01

    The aim of this systematic review was to analyse all the published clinical trials assessing treatments for Niemann-Pick (NP) disease. At present there are only trials investigating the treatment of NP disease type C. Furthermore, there is no uniformity among studies in treatment outcomes or in data analysis and presentation of results. Miglustat is able to delay neurodegeneration, with greater benefits in patients with a late onset of the disease and β-cyclodextrin-hydroxypropyl (HBP-CD) can...

  15. Niemann Pick hastalığı ve hemofagositik sendrom

    OpenAIRE

    Torun, Yasemin Altuner; Canpolat, Mehmet; Özdemir, Mehmet Akif; ASLAN, Duran; Kendirci, Mustafa

    2012-01-01

    Hemophagocytic syndromes represent a severe hyperinflammatory condition with the cardinal symptoms of prolonged fever cytopenias hepatosplenomegaly and hemophagocytosis induced by activated morphologically benign macrophages Hemophagocytic syndrome may be primary or it may be secondary to malignancy metabolic diseases collagen vascular diseases and bacterial viral and fungal infectious diseases Niemann Pick disease is a fatal lysosomal storage disease related to progressive neurodegeneration ...

  16. Four Novel p.N385K, p.V36A, c.1033–1034insT and c.1417–1418delCT Mutations in the Sphingomyelin Phosphodiesterase 1 (SMPD1 Gene in Patients with Types A and B Niemann-Pick Disease (NPD

    Directory of Open Access Journals (Sweden)

    Masoumeh Dehghan Manshadi

    2015-03-01

    Full Text Available Background: Types A and B Niemann-Pick disease (NPD are autosomal-recessive lysosomal storage disorders caused by the deficient activity of acid sphingomyelinase due to mutations in the sphingomyelin phosphodiesterase 1 (SMPD1 gene. Methods: In order to determine the prevalence and distribution of SMPD1 gene mutations, the genomic DNA of 15 unrelated Iranian patients with types A and B NPD was examined using PCR, DNA sequencing and bioinformatics analysis. Results: Of 8 patients with the p.G508R mutation, 5 patients were homozygous, while the other 3 were heterozygous. One patient was heterozygous for both the p.N385K and p.G508R mutations. Another patient was heterozygous for both the p.A487V and p.G508R mutations. Two patients (one homozygous and one heterozygous showed the p.V36A mutation. One patient was homozygous for the c.1033–1034insT mutation. One patient was homozygous for the c.573delT mutation, and 1 patient was homozygous for the c.1417–1418delCT mutation. Additionally, bioinformatics analysis indicated that two new p.V36A and p.N385K mutations decreased the acid sphingomyelinase (ASM protein stability, which might be evidence to suggest the pathogenicity of these mutations. Conclusion: with detection of these new mutations, the genotypic spectrum of types A and B NPD is extended, facilitating the definition of disease-related mutations. However, more research is essential to confirm the pathogenic effect of these mutations.

  17. Parkinsonism Syndrome in Heterozygotes for Niemann Pick C1

    OpenAIRE

    Kluenemann, Hans H.; John G Nutt; Davis, Marie Y.; Bird, Thomas D.

    2013-01-01

    Niemann Pick C (NPC) disease is a rare autosomal recessive lipid storage disorder. We report here the unique occurence of three adult heterozygous carriers of mutations in the NPC1 gene who also have a parkinsonism syndrome. This suggests the possibility that mutations in NPC1 could be a risk factor for Parkinson disease similar to the phenomenon that is now recognized with Gaucher disease and the glucocerebrocidase (GBA) gene. This report should be a stimulus for larger more detailed epidemi...

  18. Intestinal and Hepatic Niemann-Pick C1-Like 1

    OpenAIRE

    Sung-Woo Park

    2013-01-01

    Polytopic transmembrane protein, Niemann-Pick C1-Like 1 (NPC1L1) is localized at the apical membrane of enterocytes and the canalicular membrane of hepatocytes. It mediates intestinal cholesterol absorption and prevents extensive loss of cholesterol by transporting biliary cholesterol into hepatocytes. NPC1L1 is a molecular target of ezetimibe, an agent for hypercholesterolemia. Recently, NPC1L1 inhibition has been shown to prevent metabolic disorders such as fatty liver disease, obesity, dia...

  19. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease

    OpenAIRE

    Porter, Forbes D.; Scherrer, David E.; Lanier, Michael H.; Langmade, S. Joshua; Molugu, Vasumathi; Gale, Sarah E.; Olzeski, Dana; Sidhu, Rohini; Dietzen, Dennis J.; Fu, Rao; Wassif, Christopher A.; Yanjanin, Nicole M.; Marso, Steven P.; House, John; Vite, Charles

    2010-01-01

    Niemann-Pick type C1 (NPC1) disease is a rare progressive neurodegenerative disorder characterized by endolysosomal cholesterol accumulation. Previous studies implicating oxidative stress in NPC1 disease pathogenesis raised the possibility that non-enzymatic formation of cholesterol oxidation products could serve as disease biomarkers. We measured these metabolites in the plasma and tissues of the Npc1−/− mouse model and found several cholesterol oxidation products that were elevated in Npc1−...

  20. Amiodarone impairs trafficking through late endosomes inducing a Niemann-Pick C-like phenotype.

    Science.gov (United States)

    Piccoli, Elena; Nadai, Matteo; Caretta, Carla Mucignat; Bergonzini, Valeria; Del Vecchio, Claudia; Ha, Huy Riem; Bigler, Laurent; Dal Zoppo, Daniele; Faggin, Elisabetta; Pettenazzo, Andrea; Orlando, Rocco; Salata, Cristiano; Calistri, Arianna; Palù, Giorgio; Baritussio, Aldo

    2011-11-01

    Patients treated with amiodarone accumulate lysobisphosphatidic acid (LBPA), also known as bis(monoacylglycero)phosphate, in airway secretions and develop in different tissues vacuoles and inclusion bodies thought to originate from endosomes. To clarify the origin of these changes, we studied in vitro the effects of amiodarone on endosomal activities like transferrin recycling, Shiga toxin processing, ESCRT-dependent lentivirus budding, fluid phase endocytosis, proteolysis and exosome secretion. Furthermore, since the accumulation of LBPA might point to a broader disturbance in lipid homeostasis, we studied the effect of amiodarone on the distribution of LBPA, unesterified cholesterol, sphingomyelin and glycosphyngolipids. Amiodarone analogues were also studied, including the recently developed derivative dronedarone. We found that amiodarone does not affect early endosomal activities, like transferrin recycling, Shiga toxin processing and lentivirus budding. Amiodarone, instead, interferes with late compartments of the endocytic pathway, blocking the progression of fluid phase endocytosis and causing fusion of organelles, collapse of lumenal structures, accumulation of undegraded substrates and amassing of different types of lipids. Not all late endocytic compartments are affected, since exosome secretion is spared. These changes recall the Niemann-Pick type-C phenotype (NPC), but originate by a different mechanism, since, differently from NPC, they are not alleviated by cholesterol removal. Studies with analogues indicate that basic pKa and high water-solubility at acidic pH are crucial requirements for the interference with late endosomes/lysosomes and that, in this respect, dronedarone is at least as potent as amiodarone. These findings may have relevance in fields unrelated to rhythm control. PMID:21878321

  1. Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders.

    Directory of Open Access Journals (Sweden)

    Michael Zech

    Full Text Available Niemann-Pick type C (NPC disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95% or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinson's disease (PD, frontotemporal lobar degeneration (FTLD and progressive supranuclear palsy (PSP, and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n = 563, FTLD (n = 133 and PSP (n = 94, and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1% and seven control subjects (0.8%, but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted.

  2. Genetics Home Reference: Niemann-Pick disease

    Science.gov (United States)

    ... C1 is by far the more common type, accounting for 95 percent of cases. The disease occurs ... lipidosis ClinicalTrials.gov (1 link) ClinicalTrials.gov Scientific articles on PubMed (1 link) PubMed OMIM (4 links) ...

  3. Intestinal and Hepatic Niemann-Pick C1-Like 1

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    Sung-Woo Park

    2013-08-01

    Full Text Available Polytopic transmembrane protein, Niemann-Pick C1-Like 1 (NPC1L1 is localized at the apical membrane of enterocytes and the canalicular membrane of hepatocytes. It mediates intestinal cholesterol absorption and prevents extensive loss of cholesterol by transporting biliary cholesterol into hepatocytes. NPC1L1 is a molecular target of ezetimibe, an agent for hypercholesterolemia. Recently, NPC1L1 inhibition has been shown to prevent metabolic disorders such as fatty liver disease, obesity, diabetes, and atherosclerosis. In this review, the identification and characterization of NPC1L1, NPC1L1-dependent cholesterol transport, the relationship with pathogenesis of metabolic disease and its newly introduced function for virus entry are discussed.

  4. Niemann-Pick disease treatment: a systematic review of clinical trials.

    Science.gov (United States)

    Santos-Lozano, Alejandro; Villamandos García, Diana; Sanchis-Gomar, Fabian; Fiuza-Luces, Carmen; Pareja-Galeano, Helios; Garatachea, Nuria; Nogales Gadea, Gisela; Lucia, Alejandro

    2015-12-01

    The aim of this systematic review was to analyse all the published clinical trials assessing treatments for Niemann-Pick (NP) disease. At present there are only trials investigating the treatment of NP disease type C. Furthermore, there is no uniformity among studies in treatment outcomes or in data analysis and presentation of results. Miglustat is able to delay neurodegeneration, with greater benefits in patients with a late onset of the disease and β-cyclodextrin-hydroxypropyl (HBP-CD) can attenuate clinical symptoms. As for cholesterol-lowering drugs, the combination of lovastatin, cholestyramine and nicotinic acid is the most effective one for lowering cholesterolemia. Further research is much needed, and ongoing trials using enzyme replacement therapy might hopefully show promising results in the foreseeable future. PMID:26807415

  5. Late Niemann-Pick disease with neurovisceral storage: a classification problem.

    OpenAIRE

    J.McFarlane; Murray, L; K. Bradbury; Cowen, P. N.

    1988-01-01

    A 51 year old man presented in 1969 with slowly progressive cerebellar ataxia of unknown origin. He was admitted to hospital aged 68 after a fall, and a ruptured spleen was removed at laparotomy. Histological analysis of the spleen suggested Niemann-Pick disease, which was subsequently confirmed. He deteriorated and died of bronchopneumonia shortly afterwards: subdural haemorrhage with storage material in neurones was found at necropsy. This late onset case of Niemann-Pick disease with neurov...

  6. Antenatal diagnosis of Niemann-Pick disease in a twin pregnancy.

    OpenAIRE

    Donnai, P; Donnai, D.; Harris, R.; STEPHENS, R.; Young, E.; Campbell, S.

    1981-01-01

    An Ashkenazi Jewish woman had a child with Niemann-Pick disease in her first marriage. She subsequently remarried a man who was also heterozygous for the condition and conceived twins. Prenatal diagnostic tests were performed and one twin was shown to be homozygous and the other heterozygous for Niemann-Pick disease. The problems of prenatal diagnosis and counselling in twin pregnancies are discussed.

  7. Coincidence of Niemann-Pick Disease and Beta-Thalassemia; a Case Report

    OpenAIRE

    Fatemeh Farahmand; Vajiheh Modaresi; Mina Izadyar; Fatemeh Mahjob

    2010-01-01

    Background: Niemann-Pick disease and β-thalassemia are distinct conditions with specific clinical and morphological manifestations. β-thalassemia is the most common inherited blood disorder in Iran whereas Niemann-Pick disease, a lysosomal storage disorder, is rarely found in this country.Case Presentation: This 5-month old girl, a known case of β-thalassemia major was hospitalized for failure to thrive and hepathosplenomegaly. Because of unusual splenomegaly and liver enzymes disturbance tha...

  8. Niemann-pick variant disorders: comparison of errors of cellular cholesterol homeostasis in group D and group C fibroblasts.

    OpenAIRE

    Butler, J D; Comly, M E; Kruth, H. S.; Vanier, M; Filling-Katz, M; Fink, J.; Barton, N.; Weintroub, H; Quirk, J M; Tokoro, T

    1987-01-01

    Fluorescence microscopic examination of filipin-stained cultured skin fibroblasts derived from two brothers with group D Niemann-Pick disease revealed abnormal storage of low density lipoprotein (LDL)-derived cholesterol. LDL stimulation of intracellular cholesteryl ester synthesis was severely compromised in the Niemann-Pick D fibroblasts, as it also was in fibroblasts obtained from Niemann-Pick C patients. Cholesteryl ester synthesis was intermediately deficient in cells derived from an obl...

  9. Evaluation of an anti-tumor necrosis factor therapeutic in a mouse model of Niemann-Pick C liver disease.

    Directory of Open Access Journals (Sweden)

    Melanie Vincent

    Full Text Available BACKGROUND: Niemann-Pick type C (NPC disease is a lysosomal storage disease characterized by the accumulation of cholesterol and glycosphingolipids. The majority of NPC patients die in their teen years due to progressive neurodegeneration; however, half of NPC patients also suffer from cholestasis, prolonged jaundice, and hepatosplenomegaly. We previously showed that a key mediator of NPC liver disease is tumor necrosis factor (TNF α, which is involved in both proinflammatory and apoptotic signaling cascades. In this study, we tested the hypothesis that blocking TNF action with an anti-TNF monoclonal antibody (CNTO5048 will slow the progression of NPC liver disease. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of wild-type C57BL/6 mice with NPC1-specific antisense oligonucleotides led to knockdown of NPC1 protein expression in the liver. This caused classical symptoms of NPC liver disease, including hepatic cholesterol accumulation, hepatomegaly, elevated serum liver enzymes, and lipid laden macrophage accumulation. In addition, there was a significant increase in the number of apoptotic cells and a proliferation of stellate cells. Concurrent treatment of NPC1 knockdown mice with anti-TNF had no effect on the primary lipid storage or accumulation of lipid-laden macrophages. However, anti-TNF treatment slightly blunted the increase in hepatic apoptosis and stellate cell activation that was seen with NPC1 knockdown. CONCLUSIONS/SIGNIFICANCE: Current therapeutic options for NPC disease are limited. Our results provide proof of principle that pharmacologically blocking the TNF-α inflammatory cascade can slightly reduce certain markers of NPC disease. Small molecule inhibitors of TNF that penetrate tissues and cross the blood-brain barrier may prove even more beneficial.

  10. Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression.

    Directory of Open Access Journals (Sweden)

    Cristin D Davidson

    Full Text Available Niemann-Pick type C (NPC disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs. While current treatment therapies are limited, a few drugs tested in Npc1(-/- mice have shown partial benefit. During a combination treatment trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ and allopregnanolone, we noted increased lifespan for Npc1(-/- mice receiving only 2-hydroxypropyl-beta-cyclodextrin (CD, the vehicle for allopregnanolone. This finding suggested that administration of CD alone, but with greater frequency, might provide additional benefit.Administration of CD to Npc1(-/- mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS type IIIA, might likewise benefit from CD treatment. Treated Npc2(-/- mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage.Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1(-/- and Npc2(-/- mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis.

  11. Coincidence of Niemann-Pick Disease and Beta-Thalassemia; a Case Report

    Directory of Open Access Journals (Sweden)

    Mina Izadyar

    2010-12-01

    Full Text Available Background: Niemann-Pick disease and β-thalassemia are distinct conditions with specific clinical and morphological manifestations. β-thalassemia is the most common inherited blood disorder in Iran whereas Niemann-Pick disease, a lysosomal storage disorder, is rarely found in this country.Case Presentation: This 5-month old girl, a known case of β-thalassemia major was hospitalized for failure to thrive and hepathosplenomegaly. Because of unusual splenomegaly and liver enzymes disturbance that was not compatible with the first diagnosis, further evaluation revealed cherry red spot and high lipid profile suggestive of lysosomal storage disease. Foamy cells in the bone marrow and low activity of the specific enzyme led to the diagnosis of Niemann-Pick disease.Conclusion: This unique case illustrates the importance of looking for a second pathological condition in a patient whose clinical profile does not support the first diagnosis in its entirety.

  12. Genetic and pharmacological evidence implicates cathepsins in Niemann-Pick C cerebellar degeneration.

    Science.gov (United States)

    Chung, Chan; Puthanveetil, Prasanth; Ory, Daniel S; Lieberman, Andrew P

    2016-04-01

    Niemann-Pick C1 (NPC) disease, an autosomal recessive lipid trafficking disorder caused by loss-of-function mutations in the NPC1 gene, is characterized by progressive neurodegeneration resulting in cognitive impairment, ataxia and early death. Little is known about the cellular pathways leading to neuron loss. Here, we studied the effects of diminishing expression of cystatin B, an endogenous inhibitor of cathepsins B, H and L, on the development of NPC neuropathology. We show that decreased expression of cystatin B in patient fibroblasts enhances cathepsin activity. Deletion of the encoding Cstb gene in Npc1-deficient mice resulted in striking deleterious effects, particularly within the cerebellum where diffuse loss of Purkinje cells was observed in young mice. This severe pathology occurred through cell autonomous mechanisms that triggered Purkinje cell death. Moreover, our analyses demonstrated the mislocalization of lysosomal cathepsins within the cytosol of Npc1-deficient Purkinje cells. We provide evidence that this may be a consequence of damage to lysosomal membranes by reactive oxygen species (ROS), leading to the leakage of lysosomal contents that culminates in apoptotic cell death. Consistent with this notion, toxicity from ROS was attenuated in an NPC cell model by cystatin B over-expression or pharmacological inhibition of cathepsin B. The observation that Npc1 and Cstb deletion genetically interact to potently enhance the degenerative phenotype of the NPC cerebellum provides strong support for the notion that lysosomal membrane permeabilization contributes to cerebellar degeneration in NPC disease. PMID:26908626

  13. Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1.

    Science.gov (United States)

    Wang, Han; Shi, Yi; Song, Jian; Qi, Jianxun; Lu, Guangwen; Yan, Jinghua; Gao, George F

    2016-01-14

    Filoviruses, including Ebola and Marburg, cause fatal hemorrhagic fever in humans and primates. Understanding how these viruses enter host cells could help to develop effective therapeutics. An endosomal protein, Niemann-Pick C1 (NPC1), has been identified as a necessary entry receptor for this process, and priming of the viral glycoprotein (GP) to a fusion-competent state is a prerequisite for NPC1 binding. Here, we have determined the crystal structure of the primed GP (GPcl) of Ebola virus bound to domain C of NPC1 (NPC1-C) at a resolution of 2.3 Å. NPC1-C utilizes two protruding loops to engage a hydrophobic cavity on head of GPcl. Upon enzymatic cleavage and NPC1-C binding, conformational change in the GPcl further affects the state of the internal fusion loop, triggering membrane fusion. Our data therefore provide structural insights into filovirus entry in the late endosome and the molecular basis for design of therapeutic inhibitors of viral entry. PMID:26771495

  14. Clinical evaluation of chitotriosidase enzyme activity in Gaucher and Niemann Pick A/B diseases: A retrospective study from India.

    Science.gov (United States)

    Kadali, Srilatha; Kolusu, Anusha; Sunkara, Satish; Gummadi, Maheshwar Reddy; Undamatla, Jayanthi

    2016-06-01

    Plasma chitotriosidase originates from activated macrophages and is reported to be elevated in many Lysosomal Storage Disorders. Measurement of this enzyme activity has been an available tool for monitoring therapy of Gaucher disease. The degree of elevation of chitotriosidase is useful for differential diagnosis of Gaucher disease and Niemann Pick A/B. However the potential utility of this chitotriosidase assay depends on the frequency of deficient chitotriosidase activity in a particular population. We therefore aim to study the clinical utility of this assay Gaucher and Niemann Pick A/B diseases in the backdrop of chitotriosidase deficiency in our population. The study comprises 173 patients with clinical suspicion of either Gaucher disease (n=108) or Niemann Pick A/B (n=65) and 92 healthy controls. The plasma samples of controls, Gaucher disease, and Niemann Pick A/B showed chitotriosidase deficiency of 12%, 25% and 27% respectively. The degree of elevation of chitotriosidase in Gaucher disease and Niemann Pick A/B patients is 40-326 (11,325.7±6395.4nmol/h/ml) and 7-22 folds (1192.5±463.0nmol/h/ml) respectively. In view of these findings of distinguishable fold elevation of chitotriosidase in Gaucher disease or Niemann Pick A/B, it can be a potential surrogate differential diagnostic marker for these groups of diseases, except in the patients in whom this enzyme is deficient. PMID:26975750

  15. Clear Cell Chondrosarcoma in Association With Niemann-Pick Disease

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    K. N. Srikanth

    2005-01-01

    Full Text Available Purpose: The purpose of this case report is to bring to light this unusual combination of two rare diseases, namely Neimann-Pick disease Type B and clear cell chondrosarcoma occurring in the same patient. This has not previously been reported in the world literature.

  16. Reduction of VLDL secretion decreases cholesterol excretion in niemann-pick C1-like 1 hepatic transgenic mice.

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    Stephanie M Marshall

    Full Text Available An effective way to reduce LDL cholesterol, the primary risk factor of atherosclerotic cardiovascular disease, is to increase cholesterol excretion from the body. Our group and others have recently found that cholesterol excretion can be facilitated by both hepatobiliary and transintestinal pathways. However, the lipoprotein that moves cholesterol through the plasma to the small intestine for transintestinal cholesterol efflux (TICE is unknown. To test the hypothesis that hepatic very low-density lipoproteins (VLDL support TICE, antisense oligonucleotides (ASO were used to knockdown hepatic expression of microsomal triglyceride transfer protein (MTP, which is necessary for VLDL assembly. While maintained on a high cholesterol diet, Niemann-Pick C1-like 1 hepatic transgenic (L1Tg mice, which predominantly excrete cholesterol via TICE, and wild type (WT littermates were treated with control ASO or MTP ASO. In both WT and L1Tg mice, MTP ASO decreased VLDL triglyceride (TG and cholesterol secretion. Regardless of treatment, L1Tg mice had reduced biliary cholesterol compared to WT mice. However, only L1Tg mice treated with MTP ASO had reduced fecal cholesterol excretion. Based upon these findings, we conclude that VLDL or a byproduct such as LDL can move cholesterol from the liver to the small intestine for TICE.

  17. Structural Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol Transfer and Ebola Infection.

    Science.gov (United States)

    Gong, Xin; Qian, Hongwu; Zhou, Xinhui; Wu, Jianping; Wan, Tao; Cao, Pingping; Huang, Weiyun; Zhao, Xin; Wang, Xudong; Wang, Peiyi; Shi, Yi; Gao, George F; Zhou, Qiang; Yan, Nieng

    2016-06-01

    Niemann-Pick disease type C (NPC) is associated with mutations in NPC1 and NPC2, whose gene products are key players in the endosomal/lysosomal egress of low-density lipoprotein-derived cholesterol. NPC1 is also the intracellular receptor for Ebola virus (EBOV). Here, we present a 4.4 Å structure of full-length human NPC1 and a low-resolution reconstruction of NPC1 in complex with the cleaved glycoprotein (GPcl) of EBOV, both determined by single-particle electron cryomicroscopy. NPC1 contains 13 transmembrane segments (TMs) and three distinct lumenal domains A (also designated NTD), C, and I. TMs 2-13 exhibit a typical resistance-nodulation-cell division fold, among which TMs 3-7 constitute the sterol-sensing domain conserved in several proteins involved in cholesterol metabolism and signaling. A trimeric EBOV-GPcl binds to one NPC1 monomer through the domain C. Our structural and biochemical characterizations provide an important framework for mechanistic understanding of NPC1-mediated intracellular cholesterol trafficking and Ebola virus infection. PMID:27238017

  18. Sphingomyelin lipidosis (Niemann-Pick disease) in a juvenile raccoon (Procyon lotor).

    Science.gov (United States)

    Vapniarsky, N; Wenger, D A; Scheenstra, D; Mete, A

    2013-01-01

    A wild caught juvenile male raccoon with neurological disease was humanely destroyed due to poor prognosis. Necropsy examination revealed hepatomegaly, splenomegaly and multicentric lymphadenomegaly with diffuse hepatic pallor and pulmonary consolidation with pinpoint pale subpleural foci. Microscopically, there was marked pale cytoplasmic swelling of the central and peripheral neurons as well as the glial cells in the brain, accompanied by multiorgan infiltration by abundant foamy macrophages. Ultrastructural investigation revealed accumulation of concentrically arranged lamellar material within lysosomes of the affected neurons, macrophages and endothelial cells. Biochemical enzymatic analysis detected sphingomyelinase deficiency and lysosomal storage disease consistent with sphingomyelin lipidosis (Niemann-Pick disease [NPD]) was diagnosed. This is the first report of NPD in a raccoon. PMID:23582974

  19. Extensive macrophage accumulation in young and old Niemann-Pick C1 model mice involves the alternative, M2, activation pathway and inhibition of macrophage apoptosis.

    Science.gov (United States)

    Deutsch, Gail; Muralidhar, Akshay; Le, Ellen; Borbon, Ivan A; Erickson, Robert P

    2016-03-10

    We have studied the pathophysiology of lung disease which occurs in two mouse models of Niemann-Pick C1 disease. We utilized Npc1(-/-) mice transgenic for normal gene expression in glia or neurons and glia at ages several fold the usual and a mouse model of the juvenile form of NPC1, a point mutation, at one age to confirm some findings. Lung weights, as per cent of body weight, increase much more than liver and spleen weights. Although pulmonary function parameters only vary for hysteresis between young and older Npc1(-/-) mice, they are markedly different than those found in normal control mice. Cholesterol accumulation continued in the older mice but sphingosine-1-phosphate was not increased. Bronchoalveolar lavage (BAL) showed a massive increase (26×) in the number of macrophages. Histologic examination from the older, transgenic Npc1(-/-) mice showed small foci of alveolar proteinosis and evidence of hemorrhage, as well as dense macrophage accumulation. A large subset of macrophages was immunopositive for Fizz1 or arginase-1, markers of the alternative activation pathway, while no Fizz1 or arginase-1 positive macrophages were found in wild-type mice. The percentage of marker positive macrophages was relatively stable at 5-10% at various ages and within the 2 transgenic models. Phosphohistone H3 and Ki67 showed low levels of proliferation of these macrophages. Apoptosis was prominent within lung capillary endothelial cells, but limited within macrophages. Thus, activation of the alternative pathway is involved in Niemann-Pick C1 associated pulmonary macrophage accumulation, with low proliferation of these cells balanced by low levels of apoptosis. PMID:26707209

  20. Sterol-modulated glycolipid sorting occurs in niemann-pick C1 late endosomes.

    Science.gov (United States)

    Zhang, M; Dwyer, N K; Neufeld, E B; Love, D C; Cooney, A; Comly, M; Patel, S; Watari, H; Strauss, J F; Pentchev, P G; Hanover, J A; Blanchette-Mackie, E J

    2001-02-01

    The Niemann-Pick C1 (NPC1) protein and endocytosed low density lipoprotein (LDL)-derived cholesterol were shown to enrich separate subsets of vesicles containing lysosomal associated membrane protein 2. Localization of Rab7 in the NPC1-containing vesicles and enrichment of lysosomal hydrolases in the cholesterol-containing vesicles confirmed that these organelles were late endosomes and lysosomes, respectively. Lysobisphosphatidic acid, a lipid marker of the late endosomal pathway, was found in the cholesterol-enriched lysosomes. Recruitment of NPC1 to Rab7 compartments was stimulated by cellular uptake of cholesterol. The NPC1 compartment was shown to be enriched in glycolipids, and internalization of GalNAcbeta1-4[NeuAcalpha2-3]Galbeta1-4Glcbeta1-1'-ceramide (G(M2)) into endocytic vesicles depends on the presence of NPC1 protein. The glycolipid profiles of the NPC1 compartment could be modulated by LDL uptake and accumulation of lysosomal cholesterol. Expression in cells of biologically active NPC1 protein fused to green fluorescent protein revealed rapidly moving and flexible tubular extensions emanating from the NPC1-containing vesicles. We conclude that the NPC1 compartment is a dynamic, sterol-modulated sorting organelle involved in the trafficking of plasma membrane-derived glycolipids as well as plasma membrane and endocytosed LDL cholesterol. PMID:11032830

  1. Loss of Niemann-Pick C1 or C2 protein results in similar biochemical changes suggesting that these proteins function in a common lysosomal pathway.

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    Sayali S Dixit

    Full Text Available Niemann-Pick Type C (NPC disease is a lysosomal storage disorder characterized by accumulation of unesterified cholesterol and other lipids in the endolysosomal system. NPC disease results from a defect in either of two distinct cholesterol-binding proteins: a transmembrane protein, NPC1, and a small soluble protein, NPC2. NPC1 and NPC2 are thought to function closely in the export of lysosomal cholesterol with both proteins binding cholesterol in vitro but they may have unrelated lysosomal roles. To investigate this possibility, we compared biochemical consequences of the loss of either protein. Analyses of lysosome-enriched subcellular fractions from brain and liver revealed similar decreases in buoyant densities of lysosomes from NPC1 or NPC2 deficient mice compared to controls. The subcellular distribution of both proteins was similar and paralleled a lysosomal marker. In liver, absence of either NPC1 or NPC2 resulted in similar alterations in the carbohydrate processing of the lysosomal protease, tripeptidyl peptidase I. These results highlight biochemical alterations in the lysosomal system of the NPC-mutant mice that appear secondary to lipid storage. In addition, the similarity in biochemical phenotypes resulting from either NPC1 or NPC2 deficiency supports models in which the function of these two proteins within lysosomes are linked closely.

  2. Niemann-Pick C1-Like 1 (NPC1L1) Protein in Intestinal and Hepatic Cholesterol Transport

    Science.gov (United States)

    Jia, Lin; Betters, Jenna L.; Yu, Liqing

    2014-01-01

    Increased blood cholesterol is an independent risk factor for atherosclerotic cardiovascular disease. Cholesterol homeostasis in the body is controlled mainly by endogenous synthesis, intestinal absorption, and hepatic excretion. Niemann-Pick C1-Like 1 (NPC1L1) is a polytopic transmembrane protein localized at the apical membrane of enterocytes and the canalicular membrane of hepatocytes. It functions as a sterol transporter to mediate intestinal cholesterol absorption and counterbalances hepatobiliary cholesterol excretion. NPC1L1 is the molecular target of ezetimibe, a potent cholesterol absorption inhibitor that is widely used in treating hypercholesterolemia. Recent findings suggest that NPC1L1 deficiency or ezetimibe treatment also prevents diet-induced hepatic steatosis and obesity in addition to reducing blood cholesterol. Future studies should focus on molecular mechanisms underlying NPC1L1-dependent cholesterol transport and elucidation of how a cholesterol transporter modulates the pathogenesis of metabolic diseases. PMID:20809793

  3. Niemann-Pick C1 like 1 gene expression is down-regulated by LXR activators in the intestine

    International Nuclear Information System (INIS)

    Niemann-Pick C1 like 1 (NPC1L1) is a protein critical for intestinal cholesterol absorption. The nuclear receptors peroxisome proliferator-activated receptor alpha (PPARα) and liver X receptors (LXRα and LXRβ) are major regulators of cholesterol homeostasis and their activation results in a reduced absorption of intestinal cholesterol. The goal of this study was to define the role of PPARα and LXR nuclear receptors in the regulation of NPC1L1 gene expression. We show that LXR activators down-regulate NPC1L1 mRNA levels in the human enterocyte cell line Caco-2/TC7, whereas PPARα ligands have no effect. Furthermore, NPC1L1 mRNA levels are decreased in vivo, in duodenum of mice treated with the LXR agonist T0901317. In conclusion, the present study identifies NPC1L1 as a novel LXR target gene further supporting a crucial role of LXR in intestinal cholesterol homeostasis

  4. Identification of novel bile acids as biomarkers for the early diagnosis of Niemann-Pick C disease.

    Science.gov (United States)

    Mazzacuva, Francesca; Mills, Philippa; Mills, Kevin; Camuzeaux, Stephane; Gissen, Paul; Nicoli, Elena-Raluca; Wassif, Christopher; Te Vruchte, Danielle; Porter, Forbes D; Maekawa, Masamitsu; Mano, Nariyasu; Iida, Takashi; Platt, Frances; Clayton, Peter T

    2016-06-01

    This article describes a rapid UPLC-MS/MS method to quantitate novel bile acids in biological fluids and the evaluation of their diagnostic potential in Niemann-Pick C (NPC). Two new compounds, NPCBA1 (3β-hydroxy,7β-N-acetylglucosaminyl-5-cholenoic acid) and NPCBA2 (probably 3β,5α,6β-trihydroxycholanoyl-glycine), were observed to accumulate preferentially in NPC patients: median plasma concentrations of NPCBA1 and NPCBA2 were 40- and 10-fold higher in patients than in controls. However, NPCBA1 concentrations were normal in some patients because they carried a common mutation inactivating the GlcNAc transferase required for the synthesis of this bile acid. NPCBA2, not containing a GlcNAc moiety, is thus a better NPC biomarker. PMID:27139891

  5. Histochemical and biochemical observations of the spleen in atypical Niemann-Pick disease and in idiopathic thrombocytopenic purpura.

    Science.gov (United States)

    Safanda, J; Fakan, F

    1981-01-01

    In a case of adolescent Niemann-Pick disease (NP) and in a case of idiopathic thrombocytopenic purpura (ITP), the histologic picture of the spleen showed appreciable similarity in localization of sparing cells and in a number of histochemical tests. The sphingomyelin, which was the main organ phospholipid in both conditions, contained substantially elevated content of C24 fatty acids. Detailed analysis of spleen lipids showed great relative increase of lysobisphosphatidic acid and of cholesterol which was in NP mainly in free form but in ITP surprisingly mainly esterified, mostly to oleic and palmitic acid. Possible molecular mechanism of sphingomyelin storage was enzymologically followed in model conditions using separated lipid fractions from NP's spleen. The activity of sphingomyelinase (Cl. perfringens exotoxin) was in comparison to phospholipase C relatively specifically inhibited by lysobisphosphatidic acid. PMID:6168156

  6. Identification of a distinct mutation spectrum in the SMPD1 gene of Chinese patients with acid sphingomyelinase-deficient Niemann-Pick disease

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    Zhang Huiwen

    2013-01-01

    Full Text Available Abstract Background Clinical observations and molecular analysis of the SMPD1 gene in Chinese patients with acid sphingomyelinase deficiency Niemann-Pick disease (NPD are scarce. Methods A cohort of 27 Chinese patients diagnosed with acid sphingomyelinase deficiency, within the past five years, were collected and investigated for genotype, phenotype, and their correlations. Results The majority of our patients (25/27 were under 18 years of age. From the cohort group, eight (30% fulfilled characters of type A. Four other patients experienced neurologic involvement after two years of age, these were classified as intermediate type. The remaining fifteen presented without clear neurologic involvement and were regarded as type B. One patient, from the type B group, presented with the unusual symptom of a secondary amenorrhea. Three patients, one from the type B group and two from the intermediate group, presented with pronounced proteinuria, in the late stages of the disease, indicating possible kidney involvement in NPD. Twenty-four SMPD1 gene mutations had been identified; eighteen of these are novel ones. These included four exonic small deletions/duplications (c.4delC, c.147_150del4, c.842-849dup8, c.1307-1312dup6, one termination mutation (p.Glu248X, and thirteen exonic point mutations (p.Gly336Ser, p.Trp342Cys, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser, p.Trp437Arg, p.Thr451Pro, p.His461Pro, p.Ala484Val, p.Ser486Arg, p.Tyr500His, p.Pro533Leu, p.Val559Leu. Notably, eight mutations had more than one occurrence with c.4delC and p.Glu248X accounting for ~30% of all alleles. Correlation analysis of genotype and phenotype indicated eight mutations, c.842-849dup8, p.Glu248X, p.Arg230Cys, p.Trp437Arg, p.His461Pro, p.Ala484Val p.Ser486Arg, and p.Pro533Leu,to be severe mutations. Five mutations, c.4delC, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser and p.Val559Leu were projected to be mild mutations. Interestingly, three intermediate individuals carried

  7. Mitotic spindle defects and chromosome mis-segregation induced by LDL/cholesterol-implications for Niemann-Pick C1, Alzheimer's disease, and atherosclerosis.

    Directory of Open Access Journals (Sweden)

    Antoneta Granic

    Full Text Available Elevated low-density lipoprotein (LDL-cholesterol is a risk factor for both Alzheimer's disease (AD and Atherosclerosis (CVD, suggesting a common lipid-sensitive step in their pathogenesis. Previous results show that AD and CVD also share a cell cycle defect: chromosome instability and up to 30% aneuploidy-in neurons and other cells in AD and in smooth muscle cells in atherosclerotic plaques in CVD. Indeed, specific degeneration of aneuploid neurons accounts for 90% of neuronal loss in AD brain, indicating that aneuploidy underlies AD neurodegeneration. Cell/mouse models of AD develop similar aneuploidy through amyloid-beta (Aß inhibition of specific microtubule motors and consequent disruption of mitotic spindles. Here we tested the hypothesis that, like upregulated Aß, elevated LDL/cholesterol and altered intracellular cholesterol homeostasis also causes chromosomal instability. Specifically we found that: 1 high dietary cholesterol induces aneuploidy in mice, satisfying the hypothesis' first prediction, 2 Niemann-Pick C1 patients accumulate aneuploid fibroblasts, neurons, and glia, demonstrating a similar aneugenic effect of intracellular cholesterol accumulation in humans 3 oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL, induce chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors, indicating that LDL/cholesterol directly affects the cell cycle, 4 LDL-induced aneuploidy requires the LDL receptor, but not Aß, showing that LDL works differently than Aß, with the same end result, 5 cholesterol treatment disrupts the structure of the mitotic spindle, providing a cell biological mechanism for its aneugenic activity, and 6 ethanol or calcium chelation attenuates lipoprotein-induced chromosome mis-segregation, providing molecular insights into cholesterol's aneugenic mechanism, specifically through its rigidifying effect on the cell membrane, and potentially explaining why ethanol

  8. Reducing GBA2 activity ameliorates neuropathology in niemann-pick type C mice

    NARCIS (Netherlands)

    A.R.A. Marques (André); J. Aten (Jan); R. Ottenhoff (Roelof); C.P.A.A. van Roomen (Cindy); D. Herrera Moro (Daniela); N. Claessen (Nike); M.F. Vinueza Veloz (Maria); K. Zhou (Kuikui); Z. Lin (Zhanmin); M. Mirzaian (Mina); R.G. Boot (Rolf); C.I. de Zeeuw (Chris); H.S. Overkleeft (Herman); Y. Yildiz (Yildiz); J.M.F.G. Aerts (Johannes)

    2015-01-01

    textabstractThe enzyme glucocerebrosidase (GBA) hydrolyses glucosylceramide (GlcCer) in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genet

  9. Reducing GBA2 Activity Ameliorates Neuropathology in Niemann-Pick Type C Mice

    NARCIS (Netherlands)

    Marques, André R A; Aten, Jan; Ottenhoff, Roelof; van Roomen, Cindy P A A; Herrera Moro, Daniela; Claessen, Nike; Vinueza Veloz, María Fernanda; Zhou, Kuikui; Lin, Zhanmin; Mirzaian, Mina; Boot, Rolf G; De Zeeuw, Chris I; Overkleeft, Herman S; Yildiz, Yildiz; Aerts, Johannes M F G

    2015-01-01

    The enzyme glucocerebrosidase (GBA) hydrolyses glucosylceramide (GlcCer) in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genetic risk fact

  10. Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: Disease spectrum and natural course in attenuated patients

    NARCIS (Netherlands)

    Hollak, C.E.M.; Sonnaville, E.S. de; Cassiman, D.; Linthorst, G.E.; Groener, J.E.M.; Morava, E.; Wevers, R.A.; Mannens, M.; Aerts, J.M.F.G.; Meersseman, W.; Akkerman, E.; Niezen-Koning, K.E.; Mulder, M.F.; Visser, G.; Wijburg, F.A.; Lefeber, D.; Poorthuis, B.J.H.M.

    2012-01-01

    Niemann-Pick disease (NPD) is a neurovisceral lysosomal storage disorder caused by acid sphingomyelinase (ASM) deficiency, which can be categorized as either Niemann-Pick disease type A [NPD-A], with progressive neurological disease and death in early childhood, or as Niemann-Pick disease type B [NP

  11. Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium : Disease spectrum and natural course in attenuated patients

    NARCIS (Netherlands)

    Hollak, C. E. M.; de Sonnaville, E. S. V.; Cassiman, D.; Linthorst, G. E.; Groener, J. E.; Morava, E.; Wevers, R. A.; Mannens, M.; Aerts, J. M. F. G.; Meersseman, W.; Akkerman, E.; Niezen-Koning, K. E.; Mulder, M. F.; Visser, G.; Wijburg, F. A.; Lefeber, D.; Poorthuis, B. J. H. M.

    2012-01-01

    Niemann-Pick disease (NPD) is a neurovisceral lysosomal storage disorder caused by acid sphingomyelinase (ASM) deficiency, which can be categorized as either Niemann-Pick disease type A [NPD-A], with progressive neurological disease and death in early childhood, or as Niemann-Pick disease type B [NP

  12. Vitamin E Dietary Supplementation Improves Neurological Symptoms and Decreases c-Abl/p73 Activation in Niemann-Pick C Mice

    Directory of Open Access Journals (Sweden)

    Tamara Marín

    2014-07-01

    Full Text Available Niemann-Pick C (NPC disease is a fatal neurodegenerative disorder characterized by the accumulation of free cholesterol in lysosomes. We have previously reported that oxidative stress is the main upstream stimulus activating the proapoptotic c-Abl/p73 pathway in NPC neurons. We have also observed accumulation of vitamin E in NPC lysosomes, which could lead to a potential decrease of its bioavailability. Our aim was to determine if dietary vitamin E supplementation could improve NPC disease in mice. NPC mice received an alpha-tocopherol (α-TOH supplemented diet and neurological symptoms, survival, Purkinje cell loss, α-TOH and nitrotyrosine levels, astrogliosis, and the c-Abl/p73 pathway functions were evaluated. In addition, the effect of α-TOH on the c-Abl/p73 pathway was evaluated in an in vitro NPC neuron model. The α-TOH rich diet delayed loss of weight, improved coordination and locomotor function and increased the survival of NPC mice. We found increased Purkinje neurons and α-TOH levels and reduced astrogliosis, nitrotyrosine and phosphorylated p73 in cerebellum. A decrease of c-Abl/p73 activation was also observed in the in vitro NPC neurons treated with α-TOH. In conclusion, our results show that vitamin E can delay neurodegeneration in NPC mice and suggest that its supplementation in the diet could be useful for the treatment of NPC patients.

  13. Stimulation of adenosine A2A receptors reduces intracellular cholesterol accumulation and rescues mitochondrial abnormalities in human neural cell models of Niemann-Pick C1.

    Science.gov (United States)

    Ferrante, A; De Nuccio, C; Pepponi, R; Visentin, S; Martire, A; Bernardo, A; Minghetti, L; Popoli, P

    2016-04-01

    Niemann Pick C 1 (NPC1) disease is an incurable, devastating lysosomal-lipid storage disorder characterized by hepatosplenomegaly, progressive neurological impairment and early death. Current treatments are very limited and the research of new therapeutic targets is thus mandatory. We recently showed that the stimulation of adenosine A2A receptors (A2ARs) rescues the abnormal phenotype of fibroblasts from NPC1 patients suggesting that A2AR agonists could represent a therapeutic option for this disease. However, since all NPC1 patients develop severe neurological symptoms which can be ascribed to the complex pathology occurring in both neurons and oligodendrocytes, in the present paper we tested the effects of the A2AR agonist CGS21680 in human neuronal and oligodendroglial NPC1 cell lines (i.e. neuroblastoma SH-SY5Y and oligodendroglial MO3.13 transiently transfected with NPC1 small interfering RNA). The down-regulation of the NPC1 protein effectively resulted in intracellular cholesterol accumulation and altered mitochondrial membrane potential. Both effects were significantly attenuated by CGS21680 (500 nM). The protective effects of CGS were prevented by the selective A2AR antagonist ZM241385 (500 nM). The involvement of calcium modulation was demonstrated by the ability of Bapta-AM (5-7 μM) in reverting the effect of CGS. The A2A-dependent activity was prevented by the PKA-inhibitor KT5720, thus showing the involvement of the cAMP/PKA signaling. These findings provide a clear in vitro proof of concept that A2AR agonists are promising potential drugs for NPC disease. PMID:26631535

  14. Niemann-Pick C1 Is Essential for Ebola Virus Infection and a Target of Small Molecule Inhibitors

    OpenAIRE

    Bruchez, Anna

    2012-01-01

    Ebolavirus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines in response to infection and in many outbreaks, case fatality rate exceeds 75%. The unpredictable onset, ease of transmission, rapid progression of disease, high mortality and lack of effective vaccine or therapy have created a high level of public concern about EboV. Here we report the ...

  15. Comprehensive Evaluation of Plasma 7-Ketocholesterol and Cholestan-3β,5α,6β-Triol in an Italian Cohort of Patients Affected by Niemann-Pick Disease due to NPC1 and SMPD1 Mutations.

    Science.gov (United States)

    Romanello, Milena; Zampieri, Stefania; Bortolotti, Nadia; Deroma, Laura; Sechi, Annalisa; Fiumara, Agata; Parini, Rossella; Borroni, Barbara; Brancati, Francesco; Bruni, Amalia; Russo, Cinzia V; Bordugo, Andrea; Bembi, Bruno; Dardis, Andrea

    2016-04-01

    Niemann-Pick C disease (NPCD) is a rare autosomal recessive neurovisceral disorder with a heterogeneous clinical presentation. Cholestan-3β,5α,6β-triol and 7-ketocholesterol have been proposed as biomarkers for the screening of NPCD. In this work, we assessed oxysterols levels in a cohort of Italian patients affected by NPCD and analyzed the obtained results in the context of the clinical, biochemical and molecular data. In addition, a group of patients affected by Niemann-Pick B disease (NPBD) were also analyzed. NPC patients presented levels of both oxysterols way above the cut off value, except for 5 siblings presenting the variant biochemical phenotype who displayed levels of 3β,5α,6β-triol below or just above the cut-off value; 2 of them presented also normal levels of 7-KC. Both oxysterols were extremely high in a patient presenting the neonatal systemic lethal phenotype. All NPB patients showed increased oxysterols levels. In conclusion, the reported LC-MS/MS assay provides a robust non-invasive screening tool for NPCD. However, false negative results can be obtained in patients expressing the variant biochemical phenotype. These data strengthen the concept that the results should always be interpreted in the context of the patients' clinical picture and filipin staining and/or genetic studies might still be undertaken in patients with normal levels of oxysterols if symptoms are highly suggestive of NPCD. Both oxysterols are significantly elevated in NPB patients; thus a differential diagnosis should always be performed in patients presenting isolated hepatosplenomegaly, a common clinical sign of both NPCD and NPBD. PMID:26790753

  16. Reduction in cholesterol absorption in Caco-2 cells through the down-regulation of Niemann-Pick C1-like 1 by the putative probiotic strains Lactobacillus rhamnosus BFE5264 and Lactobacillus plantarum NR74 from fermented foods.

    Science.gov (United States)

    Yoon, Hong-Sup; Ju, Jae-Hyun; Kim, Han-Nah; Park, Hyun-Joon; Ji, Yosep; Lee, Ji-Eun; Shin, Hyeun-Kil; Do, Myoung-Sool; Holzapfel, Wilhelm

    2013-02-01

    Hypercholesterolaemia is a major risk factor related to atherosclerosis, and it may be influenced by our diet. This study addresses the impact of Lactobacillus rhamnosus BFE5264 (isolated from Maasai fermented milk) and Lactobacillus plantarum NR74 (from Korean kimchi) on the control of cholesterol absorption through down-regulation of Niemann-Pick C1-like 1 (NPC1L1) expression. Caco-2 enterocytes were treated with the live, heat-killed (HK) bacteria, bacterial cell wall extracts and metabolites; mRNA level and protein expression were measured. Caco-2 cells showed lower NPC1L1 expression in the presence of the live test strains than the control, elucidating down-regulation of cholesterol uptake, and were compared well with the positive control, L. rhamnosus GG. This effect was also observed with HK bacteria and cell wall fractions but not with their metabolites. The potential of some Lactobacillus strains associated with traditional fermented foods to suppress cholesterol uptake and promote its efflux in enterocytes has been suggested from these data. PMID:22816655

  17. Disease: H00143 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available idosis type III (ML III) are autosomal recessive lysosomal storage disorders caused by the deficiency of N-a...iency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders

  18. Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV.

    Science.gov (United States)

    Park, Soonhong; Ahuja, Malini; Kim, Min Seuk; Brailoiu, G Cristina; Jha, Archana; Zeng, Mei; Baydyuk, Maryna; Wu, Ling-Gang; Wassif, Christopher A; Porter, Forbes D; Zerfas, Patricia M; Eckhaus, Michael A; Brailoiu, Eugen; Shin, Dong Min; Muallem, Shmuel

    2016-02-01

    Mutations in TRPML1 cause the lysosomal storage disease mucolipidosis type IV (MLIV). The role of TRPML1 in cell function and how the mutations cause the disease are not well understood. Most studies focus on the role of TRPML1 in constitutive membrane trafficking to and from the lysosomes. However, this cannot explain impaired neuromuscular and secretory cells' functions that mediate regulated exocytosis. Here, we analyzed several forms of regulated exocytosis in a mouse model of MLIV and, opposite to expectations, we found enhanced exocytosis in secretory glands due to enlargement of secretory granules in part due to fusion with lysosomes. Preliminary exploration of synaptic vesicle size, spontaneous mEPSCs, and glutamate secretion in neurons provided further evidence for enhanced exocytosis that was rescued by re-expression of TRPML1 in neurons. These features were not observed in Niemann-Pick type C1. These findings suggest that TRPML1 may guard against pathological fusion of lysosomes with secretory organelles and suggest a new approach toward developing treatment for MLIV. PMID:26682800

  19. Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism

    Science.gov (United States)

    2012-11-06

    Hurler's Syndrome; Maroteaux-Lamy Syndrome; Sly Syndrome; Alpha Mannosidosis; Fucosidosis; Aspartylglucosaminuria; Sphingolipidoses; Krabbe Disease; Wolman's Disease; Niemann-Pick Disease Type B; Niemann-Pick Disease, Type C

  20. Sequence Classification: 889801 [

    Lifescience Database Archive (English)

    Full Text Available omolog of human NPC2/He1, which is a cholesterol-binding protein whose deficiency causes Niemann-Pick type C2 disease... involving retention of cholesterol in lysosomes; Npc2p || http://www.ncbi.nlm.nih.gov/protein/6320157 ...

  1. Bloom's Syndrome

    Science.gov (United States)

    ... Niemann-Pick Disease, Type A Spinal Muscular Atrophy Tay-Sachs Disease Usher Syndrome, Type 1F and Type III ... Niemann-Pick Disease, Type A Spinal Muscular Atrophy Tay-Sachs Disease Usher Syndrome, Type 1F and Type III ...

  2. Niemann–Pick disease type C1 presenting with psychosis in an adolescent male

    OpenAIRE

    Sandu, Sabine; Jackowski-Dohrmann, Sabine; Ladner, Axel; Haberhausen, Michael; Bachmann, Christian

    2009-01-01

    Abstract Niemann?Pick disease, a neurovisceral lysosomal lipid storage disorder, is a rare disorder that is unknown to many clinicians. The disease, that often has its onset during childhood or adolescence, shows a polymorphic clinical picture, including psychiatric symptoms. Because of its infrequence, Niemann?Pick disease is diagnosed with an average delay of 6 years. This report presents a case of an adolescent male whose symptoms had led to various hospitalisations and psychiat...

  3. Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases

    OpenAIRE

    Vance, Jean E.

    2012-01-01

    Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), Niemann-Pick type C (NPC) disease and Smith-Lemli Opitz syndrome (SLOS). However, the molecular mechanisms underlying the correlation between altered cholesterol metabolism and the neurological deficits are, for the most part, not clear. NPC disease and SLOS are caused by mutations in...

  4. Causes of type 2 diabetes in China.

    Science.gov (United States)

    Ma, Ronald Ching Wan; Lin, Xu; Jia, Weiping

    2014-12-01

    The prevalence of diabetes in China has increased substantially over recent decades, with more than 100 million people estimated to be affected by the disease presently. During this period there has been an increase in the rates of obesity and a reduction in physical activity. Many of the changes in lifestyle and diet are a result of increased economic development and urbanisation. In addition to an increasingly westernised diet, the traditional Chinese diet also plays a part, with the quantity and quality of rice intake linked to the risk of type 2 diabetes. Familial factors including inherited genetic variants are important, although differences in the genetic architecture suggest a different combination of genetic variants could be most relevant in Chinese when compared with Europeans. Recent advances have also emphasised the role of early life factors in the epidemic of diabetes and non-communicable diseases: maternal undernutrition, maternal obesity, and gestational diabetes are all linked to increased risk of diabetes in offspring. A mismatch between developmentally programmed biology and the modern environment is relevant for countries like China where there has been rapid economic transformation. Multisectoral efforts to address the risks will be needed at different stages throughout the lifecourse to reduce the burden of diabetes. PMID:25218727

  5. Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology

    DEFF Research Database (Denmark)

    Kirkegaard, Thomas; Roth, Anke G; Petersen, Nikolaj H T;

    2010-01-01

    . In acidic environments Hsp70 binds with high affinity and specificity to BMP, thereby facilitating the BMP binding and activity of acid sphingomyelinase (ASM). The inhibition of the Hsp70-BMP interaction by BMP antibodies or a point mutation in Hsp70 (Trp90Phe), as well as the pharmacological and genetic...

  6. Amyloid polyneuropathy caused by wild-type transthyretin

    OpenAIRE

    Lam, L.; Margeta, M; Layzer, R

    2015-01-01

    © 2015 Wiley Periodicals, Inc. Introduction: Amyloidosis derived from transthyretin (TTR) molecules is typically caused by mutations of the TTR gene. Methods: We describe an elderly patient with a severe length-dependent polyneuropathy that unexpectedly proved to be caused by wild-type transthyretin amyloidosis. Results: The diagnosis was made by muscle biopsy, because no amyloid deposits were found in the biopsied nerve segment. Most cases of wild-type transthyretin amyloidosis occur in elde...

  7. Acute myonecrosis in horse caused by Clostridium novyi type A

    Directory of Open Access Journals (Sweden)

    Luana D'avila Farias

    2014-01-01

    Full Text Available The objective of this study was to describe the first report involving a case of equine acute myonecrosis caused by C. novyi type A with an emphasis on clinical signs, the pathological and bacteriological analysis, and molecular identification of the microorganisms as the key of the definitive diagnosis.

  8. Cholesterol Accumulation Sequesters Rab9 and Disrupts Late Endosome Function in NPC1-deficient Cells*

    OpenAIRE

    Ganley, Ian G.; Pfeffer, Suzanne R

    2006-01-01

    Niemann-Pick type C disease is an autosomal recessive disorder that leads to massive accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes. To understand how cholesterol accumulation influences late endosome function, we investigated the effect of elevated cholesterol on Rab9-dependent export of mannose 6-phosphate receptors from this compartment. Endogenous Rab9 levels were elevated 1.8-fold in Niemann-Pick type C cells relative to wild type cells, and its half-l...

  9. Types and causes of medication errors from nurse's viewpoint

    OpenAIRE

    Cheragi, Mohammad Ali; Manoocheri, Human; Mohammadnejad, Esmaeil; Ehsani, Syyedeh R.

    2013-01-01

    Background: The main professional goal of nurses is to provide and improve human health. Medication errors are among the most common health threatening mistakes that affect patient care. Such mistakes are considered as a global problem which increases mortality rates, length of hospital stay, and related costs. This study was conducted to evaluate the types and causes of nursing medication errors. Materials and Methods: This cross-sectional study was conducted in 2009. A total number of 237 n...

  10. Lipidosis with a predominant storage of phosphoglycerides (phospholipidosis type II--Baar, Wiedemann).

    Science.gov (United States)

    Elleder, M; Smíd, F; Kohn, R

    1975-01-01

    A case of a 27 month old girl suffering from a rare form of lipidosis is described. Clinical symtoms consisted of a moderate hepatosplenomegaly and a progressive psychomotor retardation. Bioptical examination of the liver, appendix and skin revealed a pronounced lipid storage in histiocytes, hepatocytes, vascular endothelium and in peripheral nervous system. Histochemically, a generalized storage of phosphoglycerides and cholesterol was found. It was accompanied with a moderate amount of sphingomyelin and a variable amount of glycolipids (predominantly glycosphingolipids), the latter being stored mainly in the peripheral nervous system and in the vascular endothelium. Chromatographically, an increased concentration of lysobisphosphatidic acid and cholesterol could be detected. The ultrastructure of storage cytosomes was rather pleomorphic often with concentrically lamellar appearance. Further details of the investigation are described and the relation of this case to those described by Baar and Hickmans (1956) and Wiedemann et al. (1972) is stressed. Due to a strong evidence that this group of diseases represents a new type of phospholipid storage disease the name "Phospholipidosis Type II" (Baar-Wiedemann) or "Phosphoglyceridosis" is proposed, whereas "Phospholipidosis Type I" or "Sphingomyelinosis" should be reserved for the classical Niemann-Pick complex. PMID:804753

  11. Regulation of Sterol Transport between Membranes and NPC2†

    OpenAIRE

    Xu, Zhi; Farver, William; Kodukula, Sarala; Storch, Judith

    2008-01-01

    Niemann-Pick disease type C (NPC) is caused by defects in either the NPC1 or NPC2 gene and is characterized by accumulation of cholesterol and glycolipids in the late endosome/lysosome compartment. NPC2 is an intralysosomal protein that binds cholesterol in vitro. Previous studies demonstrated rapid rates of cholesterol transfer from NPC2 to model membranes [Cheruku, S. R., et al. (2006) J. Biol. Chem. 281, 31594–31604]. To model the potential role of NPC2 as a lysosomal cholesterol export pr...

  12. Clinical manifestations of CNS infections caused by enterovirus type 71

    OpenAIRE

    Cheol Soon Choi; Yun Jung Choi; Ui Yoon Choi; Ji Whan Han; Dae Chul Jeong; Hyun Hee Kim; Jong Hyun Kim; Jin Han Kang

    2011-01-01

    Purpose: Enterovirus 71, one of the enteroviruses that are responsible for both hand-foot-and-mouth disease and herpangina, can cause neural injury. During periods of endemic spread of hand-foot-andmouth disease caused by enterovirus 71, CNS infections are also frequently diagnosed and may lead to increased complications from neural injury, as well as death. We present the results of our epidemiologic research on the clinical manifestations of children with CNS infections caused by enteroviru...

  13. Are 20 human papillomavirus types causing cervical cancer?

    OpenAIRE

    Arbyn, Marc; Tommasino, Massimo; Depuydt, Christophe; Dillner, Joakim

    2014-01-01

    Abstract: In 2012, the International Agency for Research on Cancer concluded that there was consistent and sufficient epidemiological, experimental and mechanistic evidence of carcinogenicity to humans for 12 HPV types (HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58 and HPV59) for cervical cancer. Therefore, these types were considered as 1A carcinogens. They all belong to the family of the -Papillomaviridae, in particular to the species 5 (HPV51), 6 (HPV56), 7 (H...

  14. Urban revitalization and displacement: types, causes, and public policy

    Energy Technology Data Exchange (ETDEWEB)

    Feagin, J.R.

    1981-05-01

    The policy research report reviews the scholarly and print media literatures on urban revitalization. The extent of revitalization; the incumbent or occupant upgrading; gentrification (displacement of low- and moderate-income households by better-off households); gentrification and displacement from all causes; and the role of powerful actors in revitalization are discussed. Public policy dealing with land use and development in urban areas is discussed. Future research needs are indicated.

  15. Clinical manifestations of CNS infections caused by enterovirus type 71

    Directory of Open Access Journals (Sweden)

    Cheol Soon Choi

    2011-01-01

    Full Text Available Purpose: Enterovirus 71, one of the enteroviruses that are responsible for both hand-foot-and-mouth disease and herpangina, can cause neural injury. During periods of endemic spread of hand-foot-andmouth disease caused by enterovirus 71, CNS infections are also frequently diagnosed and may lead to increased complications from neural injury, as well as death. We present the results of our epidemiologic research on the clinical manifestations of children with CNS infections caused by enterovirus 71. Methods: The study group consisted of 42 patients admitted for CNS infection by enterovirus 71 between April 2009 and October 2009 at the Department of Pediatrics of 5 major hospitals affiliated with the Catholic University of Korea. We retrospectively reviewed initial symptoms and laboratory findings on admission, the specimen from which enterovirus 71 was isolated, fever duration, admission period, treatment and progress, and complications. We compared aseptic meningitis patients with encephalitis patients. Results: Of the 42 patients (23 men, 19 women, hand-foot-and-mouth disease was most prevalent (n=39, followed by herpangina (n=3, upon initial clinical diagnosis. Among the 42 patients, 15 (35.7% were classified as severe, while 27 (64.3% were classified as mild. Factors such as age, fever duration, presence of seizure, and use of intravenous immunoglobulin (IVIG were statistically different between the 2 groups. Conclusion: Our results indicate that patients with severe infection caused by enterovirus 71 tended to be less than 3 years old, presented with at least 3 days of fever as well as seizure activity, and received IVIG treatment.

  16. A Rare Cause of Pheochromocytoma; Neurofibromatosis Type 1-Noonan Syndrome

    Directory of Open Access Journals (Sweden)

    Mazhar Müslüm Tuna

    2014-09-01

    Full Text Available Neurofibromatosis (NF Type 1 (NF-1 is an autosomal dominant disease with a prevalence of about 1/3000. NF-1 is a neurocutaneous syndrome characterized by cafe au lait macules, neurofibroma, optic glioma, lisch nodules, and symptoms involving other systems. Noonan syndrome (NS is a clinically heterogeneous disorder predominantly characterized by dysmorphic facial features, congenital heart disease, proportionate post-natal short stature, neck abnormalities, and chest deformities. NF-NS is a very rare overlapping syndrome sharing many features of both syndromes. Coexistence of pheochromocytoma, which can be life-threatening if not treated properly, is also a very rare complication of this disorder. Here, we report a patient who was admitted with a mass in the right upper quadrant and was diagnosed with pheochromocytoma and NFNS. (The Me­di­cal Bul­le­tin of Ha­se­ki 2014; 52: 227-31

  17. An unusual cause of type 2 respiratory failure

    Directory of Open Access Journals (Sweden)

    Srinivas Rajagopala

    2015-01-01

    Full Text Available We present a female patient who was referred for management of respiratory failure. She was being evaluated and managed as worsening chronic inflammatory demyelinating polyneuropathy with type 2 respiratory failure. Initial examination showed hypertrichosis, clubbing and papilledema along with severe distal and proximal motor-predominant weakness with impending respiratory failure. She was managed with noninvasive ventilation (NIV and plasmapheresis awaiting diagnostic investigations. Immunofixation showed an "M band" and free lambda chain levels were elevated. Radiographs showed the classic osteosclerotic lesions of POEMS (polyradiculoneuropathy, organomegaly, endocrinopathy, M-protein and Skin abnormalities syndrome. Six weeks after commencing radiotherapy to the osteosclerotic lesions, the patient responded favorably and remains off nocturnal NIV support.

  18. Rules for distinguishing toxicants that cause type I and type II narcosis syndromes

    Energy Technology Data Exchange (ETDEWEB)

    Veith, G.D.; Broderius, S.J. (Environmental Protection Agency, Environmental Research Laboratory-Duluth, MN (USA))

    1990-07-01

    Narcosis is a nonspecific reversible state of arrested activity of protoplasmic structures caused by a wide variety of organic chemicals. The vast majority of industrial organic chemicals can be characterized by a baseline structure-toxicity relationship as developed for diverse aquatic organisms, using only the n-octanol/water partition coefficient as a descriptor. There are, however, many apparent narcotic chemicals that are more toxic than baseline narcosis predicts. Some of these chemicals have been distinguished as polar narcotics. Joint toxic theory and isobole diagrams were used to show that chemicals strictly additive with phenol were generally more toxic than predicted by narcosis I models and characterized by a different mode of action called narcosis II syndrome. This type of toxicity is exemplified by certain amides, amines, phenols, and nitrogen heterocycles. Evidence is provided that suggests that narcosis II syndrome may result from the presence of a strong hydrogen bonding group on the molecule, and narcosis I syndrome results from hydrophobic bonding of the chemical to enzymes and/or membranes. This shift in toxic action is apparently indistinguishable for narcotic chemicals with log P greater than about 2.7. General rules for selecting the appropriate models are proposed.

  19. Hot-press hand injury caused by roller type ironing machine

    Directory of Open Access Journals (Sweden)

    Abdul Kerim Yapici

    2016-01-01

    Full Text Available Thermal crush burn injury due to roller type ironing press machine is relatively rare and can cause destructive effects with significant morbidity. These injuries can be avoided by taking some basic precautions. Early debridement after admission and definitive treatment after the extent of injury are delineated and these are the preferred approaches in the management. We present a case of thermal crush injury of the hand caused by laundry roller type ironing press machine.

  20. Osteogenesis imperfecta without features of type V caused by a mutation in the IFITM5 gene

    OpenAIRE

    Grover, Monica; Campeau, Philippe M.; Lietman, Caressa Dee; Lu, James T.; Gibbs, Richard A.; Schlesinger, Alan E.; Lee, Brendan H.

    2013-01-01

    Osteogenesis imperfecta (OI) is typically caused by mutations in type 1 collagen genes, but in recent years new recessive and dominant forms caused by mutations in a plethora of different genes have been characterized. OI type V is a dominant form caused by the recurrent (c.-14C>T) mutation in the 5′UTR of the IFITM5 gene. The mutation adds 5 residues to the N-terminus of the IFITM5 but the pathophysiology of the disease still remains to be elucidated. Typical clinical features present in the...

  1. Hydrological drought types in cold climates: quantitative analysis of causing factors and qualitative survey of impacts

    OpenAIRE

    A. F. Van Loon; S. W. Ploum; Parajka, J.; A. K. Fleig; Garnier, E.; Laaha, G.; H. A. J. van Lanen

    2015-01-01

    For drought management and prediction, knowledge of causing factors and socio-economic impacts of hydrological droughts is crucial. Propagation of meteorological conditions in the hydrological cycle results in different hydrological drought types that require separate analysis. In addition to the existing hydrological drought typology, we here define two new drought types related to snow and ice. A snowmelt drought is a deficiency in the s...

  2. Causes of early-onset type 1 diabetes: toward data-driven environmental approaches

    OpenAIRE

    Bougnères, Pierre; Valleron, Alain-Jacques

    2008-01-01

    A new study reveals distinctive metabolic changes that precede the development of type 1 diabetes (T1D), tossing a stone into the quiet waters of T1D immunology and genetics. The causes of these metabolic changes and their relationship to autoimmunity and β cell destruction are not yet known, but the identification of a metabolic phenotype linked to susceptibility to type I diabetes may help pave the way to a new era of investigation of T1D causality.

  3. Microorganisms causing pyogenic spondylitis: Comparison of community and hospital-acquired types

    OpenAIRE

    Sasaji, Tatsuro; Yamada, Noboru; Iwai, Kazuo

    2012-01-01

    Staphylococcus aureus Pyogenic spondylitis is a common infectious disease caused by various microorganisms. It is difficult to predict the infecting microorganism at the time of initiation of treatment. Pneumonia is generally clarified into community or hospital-acquired types based on where the infection was acquired, and the infecting microorganisms are different for each type. We retrospectively analyzed 20 cases of pyogenic spondylitis treated in our hospital and categorized the cases int...

  4. Unit-based incident reporting and root cause analysis: variation at three hospital unit types

    Science.gov (United States)

    Wagner, Cordula; Merten, Hanneke; Zwaan, Laura; Lubberding, Sanne; Timmermans, Danielle; Smits, Marleen

    2016-01-01

    Objectives To minimise adverse events in healthcare, various large-scale incident reporting and learning systems have been developed worldwide. Nevertheless, learning from patient safety incidents is going slowly. Local, unit-based reporting systems can help to get faster and more detailed insight into unit-specific safety issues. The aim of our study was to gain insight into types and causes of patient safety incidents in hospital units and to explore differences between unit types. Design Prospective observational study. Setting 10 emergency medicine units, 10 internal medicine units and 10 general surgery units in 20 hospitals in the Netherlands participated. Patient safety incidents were reported by healthcare providers. Reports were analysed with root cause analysis. The results were compared between the 3 unit types. Results A total of 2028 incidents were reported in an average reporting period of 8 weeks per unit. More than half had some consequences for patients, such as a prolonged hospital stay or longer waiting time, and a small number resulted in patient harm. Significant differences in incident types and causes were found between unit types. Emergency units reported more incidents related to collaboration, whereas surgical and internal medicine units reported more incidents related to medication use. The distribution of root causes of surgical and emergency medicine units showed more mutual similarities than those of internal medicine units. Conclusions Comparable incidents and causes have been found in all units, but there were also differences between units and unit types. Unit-based incident reporting gives specific information and therefore makes improvements easier. We conclude that unit-based incident reporting has an added value besides hospital-wide or national reporting systems that already exist in various countries. PMID:27329443

  5. Emergence of new types of Theileria orientalis in Australian cattle and possible cause of theileriosis outbreaks

    Directory of Open Access Journals (Sweden)

    Kinyanjui Peter

    2011-02-01

    Full Text Available Abstract Theileria parasites cause a benign infection of cattle in parts of Australia where they are endemic, but have, in recent years, been suspected of being responsible for a number of outbreaks of disease in cattle near the coast of New South Wales. The objective of this study was to identify and characterize the species of Theileria in cattle on six farms in New South Wales where disease outbreaks have occurred, and compare with Theileria from three disease-free farms in Queensland that is endemic for Theileria. Special reference was made to sub-typing of T. orientalis by type-specific PCR and sequencing of the small subunit (SSU rRNA gene, and sequence analysis of the gene encoding a polymorphic merozoite/piroplasm surface protein (MPSP that may be under immune selection. Nucleotide sequencing of SSU rRNA and MPSP genes revealed the presence of four Theileria genotypes: T. orientalis (buffeli, T. orientalis (ikeda, T. orientalis (chitose and T. orientalis type 4 (MPSP or type C (SSU rRNA. The majority of animals showed mixed infections while a few showed single infection. When MPSP nucleotide sequences were translated into amino acids, base transition did not change amino acid composition of the protein product, suggesting possible silent polymorphism. The occurrence of ikeda and type 4 (type C previously not reported to occur and silent mutation is thought to have enhanced parasite evasion of the host immune response causing the outbreak.

  6. We need to talk about error: causes and types of error in veterinary practice.

    Science.gov (United States)

    Oxtoby, C; Ferguson, E; White, K; Mossop, L

    2015-10-31

    Patient safety research in human medicine has identified the causes and common types of medical error and subsequently informed the development of interventions which mitigate harm, such as the WHO's safe surgery checklist. There is no such evidence available to the veterinary profession. This study therefore aims to identify the causes and types of errors in veterinary practice, and presents an evidence based system for their classification. Causes of error were identified from retrospective record review of 678 claims to the profession's leading indemnity insurer and nine focus groups (average N per group=8) with vets, nurses and support staff were performed using critical incident technique. Reason's (2000) Swiss cheese model of error was used to inform the interpretation of the data. Types of error were extracted from 2978 claims records reported between the years 2009 and 2013. The major classes of error causation were identified with mistakes involving surgery the most common type of error. The results were triangulated with findings from the medical literature and highlight the importance of cognitive limitations, deficiencies in non-technical skills and a systems approach to veterinary error. PMID:26489997

  7. Rationally Designed Small Molecules Targeting the RNA That Causes Myotonic Dystrophy Type 1 Are Potently Bioactive

    OpenAIRE

    Childs-Disney, Jessica L.; Hoskins, Jason; Rzuczek, Suzanne G.; Thornton, Charles A.; Disney, Matthew D.

    2012-01-01

    RNA is an important drug target, but it is difficult to design or discover small molecules that modulate RNA function. In the present study, we report that rationally designed, modularly assembled small molecules that bind the RNA that causes myotonic dystrophy type 1 (DM1) are potently bioactive in cell culture models. DM1 is caused when an expansion of r(CUG) repeats, or r(CUG)exp, is present in the 3′ untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) mRNA. r(CUG)e...

  8. Fuel Moisture, Forest Type, and Lightning-Caused Fire in Yellowstone National Park

    OpenAIRE

    Renkin, Roy A; Despain, Don G

    1992-01-01

    The occurrence and behavior of lightning-caused fires in Yellowstone National Park, Wyoming, are evaluated for a 17-yr period (1972-88) during a prescribed natural fire program. Both ignition (occurrence) and spread (stand-replacing fire activity) of fires were strongly influenced by fuel moisture and forest cover type. Fuel moisture estimates of 13% for large (>7.6 cm) dead and downed fuels indicated a threshold below which proportionately more fire starts and increased stand-replacing fire ...

  9. Predictors of all-cause and cardiovascular disease mortality in type 2 diabetes: Diabetes Heart Study

    OpenAIRE

    Raffield, Laura M.; Hsu, Fang-Chi; Cox, Amanda J.; Carr, J. Jeffrey; Freedman, Barry I.; Bowden, Donald W.

    2015-01-01

    Background Many studies evaluated the best predictors for cardiovascular disease (CVD) events in individuals with type 2 diabetes (T2D), but few studies examined the factors most strongly associated with mortality in T2D. The Diabetes Heart Study (DHS), an intensively phenotyped family-based cohort enriched for T2D, provided an opportunity to address this question. Methods Associations with mortality were examined in 1022 European Americans affected by T2D from 476 DHS families. All-cause mor...

  10. Collections and Analyses of Common Cause Failure Data for the Korea Standard and Westinghouse Type NPPs

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Dae Il; Han, S. H

    2007-04-15

    The analyses of the CCF events for domestic NPPs were performed to establish the domestic database for the CCF events and to deliver supply them to the operation office of the international common cause failure data exchange (ICDE) project. We collected and analyzed the CCF events of emergency diesel generators, centrifugal pumps, motor-operated valves, check valves, circuit breakers for the Korean Standard Type nuclear power plants (NPPs), Yonggwang Units 3 and 4 and Ulchin Units 3 and 4, and the Westinghouse type NPPs, Kori Unit 3 and 4 and Yonggwang Units 1 and 2. First, the components to be collected and analyzed were classified into the common cause component groups (CCCGs) according to the ICDE coding guidelines. Next, the CCF events were identified based on reviews of the component database for the PSA and its related documents, and consultations with NPP staff. Fourteen CCF events were identified. The ratio of the number of CCF events to that of individual failure events was identified as approximately 10 percentages. However, an in depth review of the CCF events showed that most failure severities of them were identified as partial CCF events, which can be interpreted as some component failures within the CCCGs. Root causes of the CCF events were identified as 9 internal part failures, 2 human errors, 2 design deficiencies, 1 procedure inadequacy. It could be concluded that the major root causes of the CCF events were internal piece part failures.

  11. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III.

    Science.gov (United States)

    Cichon, Sven; Martin, Ludovic; Hennies, Hans Christian; Müller, Felicitas; Van Driessche, Karen; Karpushova, Anna; Stevens, Wim; Colombo, Roberto; Renné, Thomas; Drouet, Christian; Bork, Konrad; Nöthen, Markus M

    2006-12-01

    Hereditary angioedema (HAE) is characterized clinically by recurrent acute skin swelling, abdominal pain, and potentially life-threatening laryngeal edema. Three forms of HAE have been described. The classic forms, HAE types I and II, occur as a consequence of mutations in the C1-inhibitor gene. In contrast to HAE types I and II, HAE type III has been observed exclusively in women, where it appears to be correlated with conditions of high estrogen levels--for example, pregnancy or the use of oral contraceptives. A recent report proposed two missense mutations (c.1032C-->A and c.1032C-->G) in F12, the gene encoding human coagulation factor XII (FXII, or Hageman factor) as a possible cause of HAE type III. Here, we report the occurrence of the c.1032C-->A (p.Thr328Lys) mutation in an HAE type III-affected family of French origin. Investigation of the F12 gene in a large German family did not reveal a coding mutation. Haplotype analysis with use of microsatellite markers is compatible with locus heterogeneity in HAE type III. To shed more light on the pathogenic relevance of the HAE type III-associated p.Thr328Lys mutation, we compared FXII activity and plasma levels in patients carrying the mutation with that of healthy control individuals. Our data strongly suggest that p.Thr328Lys is a gain-of-function mutation that markedly increases FXII amidolytic activity but that does not alter FXII plasma levels. We conclude that enhanced FXII enzymatic plasma activity in female mutation carriers leads to enhanced kinin production, which results in angioedema. Transcription of F12 is positively regulated by estrogens, which may explain why only women are affected with HAE type III. The results of our study represent an important step toward an understanding of the molecular processes involved in HAE type III and provide diagnostic and possibly new therapeutic opportunities. PMID:17186468

  12. The causes and prognoses of different types of fractures in wild koalas submitted to wildlife hospitals.

    Science.gov (United States)

    Henning, Joerg; Hannon, Christabel; McKinnon, Allan; Larkin, Rebecca; Allavena, Rachel

    2015-12-01

    Fractures are a major problem in wild koalas of great veterinary and conservation importance as their occurrence in different locations of the body might result in varying healing success. The aim of this study was to determine the fracture types (defined by location of the fracture) occurring in wild koalas, temporal patterns, possible causes and risk factors of fracture types, and the prognosis for successfully releasing kolas with healed fracture types into the wild. Data from a total of 2031 wild koalas submitted to wildlife hospitals in South-East Queensland, Australia, over a period of 13 years were analysed. Approximately 56.7% of koalas experienced head fractures, 13.4% had torso fractures, 14.9% had limb fractures and 15% had combination fractures. A total of 84.1% of fractures were caused by vehicle collisions, 9.1% by dog attacks, 3.3% by falls from trees, 1.3% by train collisions, 0.2% by livestock trampling and 1.8% due to unknown causes. Multinominal logistic regression was used to identify risk factors (cause of fracture, age category, sex, year, three-year admission period and season of fracture event) by fracture type. The type of fracture was associated with both the cause of the fracture and the season when it occurred: for example torso fractures (compared to combination fractures) were associated with dog attacks (OR=10.98; 95% CI6.03, 20.01) and falls from trees (OR=4.79; 95% CI2.26, 10.19) relative to vehicle collisions. More submissions of koalas with head fractures due to vehicle collisions occurred in spring compared to autumn and winter, coinciding with the breeding season of koalas and increased animal movement. Prognosis for koalas with fractures was poor, with approximately 63.8% of koalas admitted dead on arrival, 34.2% euthanised, and only 2.0% of koalas able to be released. Given this data, further research into mitigation strategies to decrease the risk of fractures and to increase the observed low recovery rate should be

  13. Discovery of a Genetic Metabolic Cause for Mauriac Syndrome in Type 1 Diabetes.

    Science.gov (United States)

    MacDonald, Michael J; Hasan, Noaman M; Ansari, Israr-Ul H; Longacre, Melissa J; Kendrick, Mindy A; Stoker, Scott W

    2016-07-01

    A mechanistic cause for Mauriac syndrome, a syndrome of growth failure and delayed puberty associated with massive liver enlargement from glycogen deposition in children with poorly controlled type 1 diabetes, is unknown. We discovered a mutation in the catalytic subunit of liver glycogen phosphorylase kinase in a patient with Mauriac syndrome whose liver extended into his pelvis. Glycogen phosphorylase kinase activates glycogen phosphorylase, the enzyme that catalyzes the first step in glycogen breakdown. We show that the mutant subunit acts in a dominant manner to completely inhibit glycogen phosphorylase kinase enzyme activity and that this interferes with glycogenolysis causing increased levels of glycogen in human liver cells. It is known that even normal blood glucose levels physiologically inhibit glycogen phosphorylase to diminish glucose release from the liver when glycogenolysis is not needed. The patient's mother possessed the same mutant glycogen phosphorylase kinase subunit, but did not have diabetes or hepatomegaly. His father had childhood type 1 diabetes in poor glycemic control, but lacked the mutation and had neither hepatomegaly nor growth failure. This case proves that the effect of a mutant enzyme of glycogen metabolism can combine with hyperglycemia to directly hyperinhibit glycogen phosphorylase, in turn blocking glycogenolysis causing the massive liver in Mauriac disease. PMID:27207549

  14. Hydrocephalus and Pressure on Brain Stem Cause Death in Patients with Neurofibromatosis Type 2

    Directory of Open Access Journals (Sweden)

    M. Khazaei

    2014-07-01

    Full Text Available Introduction: Neurofibromatosis type 2 is an inherited autosomal dominant syndrome, charac-terized by multiple neoplasms of the central and peripheral nervous system associated with ocular abnormalities. The most common tumor associated with the disease is the vestibulo-cochlear and in later stages are meningioma and other brain tumors. Case Report: The patient was a 35 year old woman admitted to the Farshchian hospital in Hamadan due to unconciousness and respiratory distress She had sensorineural hearing loss and inability to see due to decrease visulal acuity. In addition, due to lower extremity paresis she has been unable to walk and wheelchair-dependent for many years. Brain CT scan and MRI showed multiple tumors in the posterior fossa causing obstructive hydrocephalus even-tually caused the patient's death . Conclusion: Brain tumors, especially in the posterior fossa can cause death in Neurofibroma-tosis type 2. Early surgery can be life saving. (Sci J Hamadan Univ Med Sci 2014; 21 (2:167-170

  15. Protein complexes and cholesterol in the control of late endosomal dynamicsCholesterol and multi-protein complexes in the control of late endosomal dynamics

    NARCIS (Netherlands)

    Kant, Rik Henricus Nicolaas van der

    2013-01-01

    Late endosomal transport is disrupted in several diseases such as Niemann-Pick type C, ARC syndrome and Alzheimer’s disease. This thesis describes the regulation of late endosomal dynamics by cholesterol and multi-protein complexes. We find that cholesterol acts as a cellular tomtom that steers the

  16. Forehead abscess caused by Klebsiella oxytoca with undiagnosed type 2 diabetes.

    Science.gov (United States)

    Sohn, Won-Il; Seo, Bommie F; Jung, Sung-No

    2012-05-01

    Klebsiella is an opportunistic pathogen that is known to cause septicemia, pneumonia, urinary tract infections, hepatobiliary tract infections, and soft tissue infections in patients who have severe underlying diseases or are under immunosuppression. Most Klebsiella species found are Klebsiella pneumoniae, and Klebsiella oxytoca is rarely cultured in humans. We report a case of a 48-year-old man presenting with a soft fluctuating mass on his forehead. The lesion was an abscess, and percutaneous drainage yielded pus from which K. oxytoca was isolated. Parenteral levofloxacin was administrated leading to resolution of infection signs. Because of the rarity of the pathogen, evaluation for underlying illnesses was done, and the patient was diagnosed with type 2 diabetes mellitus. This is the first report of a patient with previously undiagnosed diabetes who was found with an extraorbital abscess caused by K. oxytoca, which we present with a review of diagnosis, pathogenesis, and treatment. PMID:22627446

  17. Early-Onset Mild Type Leukoencephalopathy Caused by a Homozygous EARS2 Mutation.

    Science.gov (United States)

    Taskin, Birce Dilge; Karalok, Zeynep Selen; Gurkas, Esra; Aydin, Kursad; Aydogmus, Ummu; Ceylaner, Serdar; Karaer, Kadri; Yilmaz, Cahide; Pearl, Phillip Lawrence

    2016-06-01

    Childhood leukoencephalopathies are a broad class of diseases, which are extremely rare. The treatment and classification of these disorders are both challenging. Nearly half of children presenting with a leukoencephalopathy remain without a specific diagnosis. Leukoencephalopathy with thalamus and brain stem involvement and high lactate (LTBL) is a newly described childhood leukoencephalopathy caused by mutations in the gene encoding a mitochondrial aminoacyl-tRNA synthetase specific for glutamate, EARS2 Magnetic resonance images show a characteristic leukoencephalopathy with thalamic and brain stem involvement. Here, we report a different clinical course of LTBL supported by typical MRI features in a Turkish patient who presented with a history of failure to walk. The EARS2 gene mutation analysis identified a c.322C>T transition, predicting a p.R108W change. This is the first reported early-onset mild type LTBL caused by a homozygous EARS2 mutation case in the literature. PMID:26893310

  18. TYPE I CONGENITAL CYSTIC ADENOID MALFORMATION CAUSING RIGHT MEDIASTINAL SHIFT IN A TWO YEARS OLD CHILD

    Directory of Open Access Journals (Sweden)

    Mayuri A

    2014-07-01

    Full Text Available Congenital cystic adenomatoid malformations (CCAM of lung are rare, congenital, cystic, developmental hamartomatous malformation of lung, arising from excessive disorganized proliferation of tubular bronchial structures. Very few cases have been reported in literature. Although it is a disorder of infancy, majority of cases are being diagnosed within first two years of life. We describe CCAM in two years old girl who presented with recurrent lower respiratory tract infections, since infancy and had type I CCAM of upper and middle lobe causing mediastinal shift to right

  19. Type and cause of liver disease in Korea: single-center experience, 2005-2010

    OpenAIRE

    Lee, Sang Soo; Byoun, Young-Sang; Jeong, Sook-Hyang; Kim, Yeo Myung; Gil, Ho; Min, Bo-young; Seong, Mun Hyuk; Jang, Eun Sun; Kim, Jin-Wook

    2012-01-01

    Background/Aims The aim of this study was to describe the types and causes of liver disease in patients from a single community hospital in Korea between April 2005 and May 2010. Methods A cohort of patients who visited the liver clinic of the hospital during the aforementioned time period were consecutively enrolled (n=6,307). Consistent diagnostic criteria for each liver disease were set by a single, experienced hepatologist, and the diagnosis of all of the enrolled patients was confirmed b...

  20. Whiplash-type neck distortion in restrained car drivers: frequency, causes and long-term results.

    Science.gov (United States)

    Richter, M; Otte, D; Pohlemann, T; Krettek, C; Blauth, M

    2000-04-01

    An analysis was made of 1176 whiplash-type neck distortions taken from a total of 3838 restrained car driver incident reports. The percentage of whiplash-type neck distortion among injured drivers increased from less than 10% in 1985 to over 30% in 1997. Most occurred in head-on crashes or crashes with multiple collisions; only 15% occurred in rear-end collisions. More than 1,000 questionnaires were sent to the injured to find out about the duration and type of complaints caused by their cervical spine injury. Although only 138 (12%) returned the questionnaire, which may not be a representative sample, a further analysis was carried out. Of the 138, 121 (88%) indicated that they had suffered or were still suffering from their symptoms. The percentages of the various complaints were as follows: pain (74%), tension (6%) and stiffness (5%) in the head (27%), neck (55%) and shoulder (8%). The duration of the complaints was longest after multiple collisions and when the onset of complaints was longer than 24 h after trauma. Women and elderly persons predominated slightly in the group with longer duration of complaints. A correlation between the severity of the accompanying injuries and duration of complaints was found. Lack of adequate follow-up for patients with less severe injuries posed considerable difficulties for this retrospective study. In order to better evaluate this problem, prospective studies are necessary, with documentation including diagnosis, treatments, complaint duration and type. PMID:10823426

  1. Disease outbreaks caused by steppe-type rabies viruses in China.

    Science.gov (United States)

    Feng, Y; Wang, W; Guo, J; Alatengheli; Li, Y; Yang, G; Su, N; Zhang, L; Xu, W; Sheng, Z; Ma, L; Gui, J; Dejide; Lin, H; Tu, C

    2015-04-01

    While rabies is a significant public health concern in China, the epidemiology of animal rabies in the north and northwest border provinces remains unknown. From February 2013 to March 2014, seven outbreaks of domestic animal rabies caused by wild carnivores in Xinjiang (XJ) and Inner Mongolia (IM) Autonomous Regions, China were reported and diagnosed in brain samples of infected animals by the fluorescent antibody test (FAT) and RT-PCR. Ten field rabies viruses were obtained. Sequence comparison and phylogenetic analysis based on the complete N gene (1353 bp) amplified directly from the original brain tissues showed that these ten strains were steppe-type viruses, closely related to strains reported in Russia and Mongolia. None had been identified previously in China. The viruses from XJ and IM clustered separately into two lineages showing their different geographical distribution. This study emphasizes the importance of wildlife surveillance and of cross-departmental cooperation in the control of transboundary rabies transmission. PMID:25078967

  2. A Drosophila Genome-Wide Screen Identifies Regulators of Steroid Hormone Production and Developmental Timing.

    Science.gov (United States)

    Danielsen, E Thomas; Moeller, Morten E; Yamanaka, Naoki; Ou, Qiuxiang; Laursen, Janne M; Soenderholm, Caecilie; Zhuo, Ran; Phelps, Brian; Tang, Kevin; Zeng, Jie; Kondo, Shu; Nielsen, Christian H; Harvald, Eva B; Faergeman, Nils J; Haley, Macy J; O'Connor, Kyle A; King-Jones, Kirst; O'Connor, Michael B; Rewitz, Kim F

    2016-06-20

    Steroid hormones control important developmental processes and are linked to many diseases. To systematically identify genes and pathways required for steroid production, we performed a Drosophila genome-wide in vivo RNAi screen and identified 1,906 genes with potential roles in steroidogenesis and developmental timing. Here, we use our screen as a resource to identify mechanisms regulating intracellular levels of cholesterol, a substrate for steroidogenesis. We identify a conserved fatty acid elongase that underlies a mechanism that adjusts cholesterol trafficking and steroidogenesis with nutrition and developmental programs. In addition, we demonstrate the existence of an autophagosomal cholesterol mobilization mechanism and show that activation of this system rescues Niemann-Pick type C1 deficiency that causes a disorder characterized by cholesterol accumulation. These cholesterol-trafficking mechanisms are regulated by TOR and feedback signaling that couples steroidogenesis with growth and ensures proper maturation timing. These results reveal genes regulating steroidogenesis during development that likely modulate disease mechanisms. PMID:27326933

  3. Crystallographic and Computational Analyses of AUUCU Repeating RNA That Causes Spinocerebellar Ataxia Type 10 (SCA10).

    Science.gov (United States)

    Park, HaJeung; González, Àlex L; Yildirim, Ilyas; Tran, Tuan; Lohman, Jeremy R; Fang, Pengfei; Guo, Min; Disney, Matthew D

    2015-06-23

    Spinocerebellar ataxia type 10 (SCA10) is caused by a pentanucleotide repeat expansion of r(AUUCU) within intron 9 of the ATXN10 pre-mRNA. The RNA causes disease by a gain-of-function mechanism in which it inactivates proteins involved in RNA biogenesis. Spectroscopic studies showed that r(AUUCU) repeats form a hairpin structure; however, there were no high-resolution structural models prior to this work. Herein, we report the first crystal structure of model r(AUUCU) repeats refined to 2.8 Å and analysis of the structure via molecular dynamics simulations. The r(AUUCU) tracts adopt an overall A-form geometry in which 3 × 3 nucleotide (5')UCU(3')/(3')UCU(5') internal loops are closed by AU pairs. Helical parameters of the refined structure as well as the corresponding electron density map on the crystallographic model reflect dynamic features of the internal loop. The computational analyses captured dynamic motion of the loop closing pairs, which can form single-stranded conformations with relatively low energies. Overall, the results presented here suggest the possibility for r(AUUCU) repeats to form metastable A-from structures, which can rearrange into single-stranded conformations and attract proteins such as heterogeneous nuclear ribonucleoprotein K (hnRNP K). The information presented here may aid in the rational design of therapeutics targeting this RNA. PMID:26039897

  4. Construction Claim Types and Causes for a Large-Scale Hydropower Project in Bhutan

    Directory of Open Access Journals (Sweden)

    Bonaventura H.W. Hadikusumo

    2015-01-01

    Full Text Available Hydropower construction projects are complex and uncertain, have long gestational periods and involve several parties. Furthermore, they require the integration of different components (Civil, Mechanical and Electrical to work together as a single unit. These projects require highly specialised designs, detailed plans and specifications, high-risk construction methods, effective management, skilful supervision and close coordination. Thus, claims are common in such projects. These claims are undesirable because they require significant time and resources to resolve and cause adversarial relationships among the parties involved. Therefore, it is in the common interest of all involved parties to prevent, minimise, or resolve claims as amicably as possible. Identifying common claim types and their causes is essential in devising techniques to minimise and avoid them in future projects. This report details a case study performed on a large-scale hydropower project in Bhutan. The findings of this case study indicate that differing site conditions are the major contributor of impact and change claims and 95% of total claims can be settled by negotiation, whereas 5% of claims can be settled by arbitration.

  5. Causes of two slope-failure types in continental-shelf sediment, northeastern Gulf of Alaska

    Science.gov (United States)

    Schwab, William C.; Lee, Homa J.

    1988-01-01

    Slumps and sediment-gravity flows have been identified in Holocene glaciomarine sediment on declivities less than 1.3 degrees on the Gulf of Alaska continental shelf. Geologic and geotechnical investigation suggest that the processes responsible for these slope failures are earthquake and storm-wave loading, coupled with cyclic degradation of the sediment-shear strength. We propose that the failure type is related to the nature of the failure load. For example, a slump that occurs approximately 30 km seaward of Icy Bay in water depth of 70 to 150 m was most likely caused by earthquake loading, whereas sediment-gravity flows on the Alsek prodelta, which occur in water depths of 35 to 80 m, probably were caused primarily by storm-wave loading. Sediment remolding and redistribution and incorporation of water, which occurs more readily during wave loading from a long storm than during the limited number of loading cycles generated by an earthquake, reduces the shear strength and increases the fluidity of the failed sediment mass. Wave-induced slope failures thereby tend to transform into sediment-gravity flows.

  6. Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

    Institute of Scientific and Technical Information of China (English)

    Gang Ma; Jiang Yu; Yue Xiao; Danny Chan; Bo Gao; Jianxin Hu; Yongxing He

    2011-01-01

    Brachydactyly type A1 (BDA1),the first recorded Mendelian autosomal dominant disorder in humans,is characterized by a shortening or absence of the middle phalanges.Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however,the biochemical consequences of these mutations are unclear.In this paper,we analyzed three BDA1 mutations (E95K,D100E,and E131K)in the N-terminal fragment of Indian Hedgehog (IhhN).Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove,and that the D100E mutation changes the local tertiary structure.Furthermore,we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of lhhN,which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome.Notably,all three mutations affected Hh binding to the receptor Patched1 (PTC1),reducing its capacity to induce cellular differentiation.We propose that these are common features of the mutations that cause BDA1,affecting the Hh tertiary structure,intracellular fate,binding to the receptor/partners,and binding to extracellular components.The combination of these features alters signaling capacity and range,but the impact is likely to be variable and mutation-dependent.The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation,but not the E131K mutation.Taken together,our results suggest that these IHH mutations affect Hh signaling at multiple levels,causing abnormal bone development and abnormal digit formation.

  7. A novel mutation causing mild, atypical fumarylacetoacetase deficiency (Tyrosinemia type I: a case report

    Directory of Open Access Journals (Sweden)

    Kvittingen Eli-Anne

    2009-12-01

    Full Text Available Abstract A male patient, born to unrelated Belgian parents, presented at 4 months with epistaxis, haematemesis and haematochezia. On physical examination he presented petechiae and haematomas, and a slightly enlarged liver. Serum transaminases were elevated to 5-10 times upper limit of normal, alkaline phosphatases were 1685 U/L (180 s ( Fumarylacetoacetase (FAH protein and activity in cultured fibroblasts and liver tissue were decreased but not absent. 4-hydroxyphenylpyruvate dioxygenase activity in liver was normal, which is atypical for tyrosinemia type I. A novel mutation was found in the FAH gene: c.103G>A (Ala35Thr. In vitro expression studies showed this mutation results in a strongly decreased FAH protein expression. Dietary treatment with phenylalanine and tyrosine restriction was initiated at 4 months, leading to complete clinical and biochemical normalisation. The patient, currently aged 12 years, shows a normal physical and psychomotor development. This is the first report of mild tyrosinemia type I disease caused by an Ala35Thr mutation in the FAH gene, presenting atypically without increase of the diagnostically important toxic metabolites succinylacetone and succinylacetoacetate.

  8. Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a

    Energy Technology Data Exchange (ETDEWEB)

    Chou, J.Y.; Lei, K.J.; Shelly, L.L. [National Institutes of Health, Bethesda, MD (United States)

    1994-09-01

    Glycogen storage disease (GSD) type la (von Gierke disease) is caused by the deficiency of glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis. The disease presents with clinical manifestations of severe hypoglycemia, hepatomegaly, growth retardation, lactic acidemia, hyperlipidemia, and hyperuricemia. We have succeeded in isolating a murine G6Pase cDNA from a normal mouse liver cDNA library by differentially screening method. We then isolated the human G6Pase cDNA and gene. To date, we have characterized the G6Pase genes of twelve GSD type la patients and uncovered a total of six different mutations. The mutations are comprised of R83C (an Arg at codon 83 to a Cys), Q347X (a Gly at codon 347 to a stop codon), 459insTA (a two basepair insertion at nucleotide 459 yielding a truncated G6Pase of 129 residues), R295C (an Arg at codon 295 to a Cys), G222R (a Gly at codon 222 to an Arg) and {delta}F327 (a codon deletion for Phe-327 at nucleotides 1058 to 1060). The relative incidences of these mutations are 37.5% (R83C), 33.3% (Q347X), 16.6% (459insTA), 4.2% (G222R), 4.2% (R295C) and 4.2% ({delta}F327). Site-directed mutagenesis and transient expression assays demonstrated that the R83C, Q347X, R295C, and {delta}F327 mutations abolished whereas the G222R mutation greatly reduced G6Pase activity. We further characterized the structure-function requirements of amino acids 83, 222, and 295 in G6Pase catalysis. The identification of mutations in GSD type la patients has unequivocally established the molecular basis of the type la disorder. Knowledge of the mutations may be applied to prenatal diagnosis and opens the way for developing and evaluating new therapeutic approaches.

  9. Rationally designed small molecules targeting the RNA that causes myotonic dystrophy type 1 are potently bioactive.

    Science.gov (United States)

    Childs-Disney, Jessica L; Hoskins, Jason; Rzuczek, Suzanne G; Thornton, Charles A; Disney, Matthew D

    2012-05-18

    RNA is an important drug target, but it is difficult to design or discover small molecules that modulate RNA function. In the present study, we report that rationally designed, modularly assembled small molecules that bind the RNA that causes myotonic dystrophy type 1 (DM1) are potently bioactive in cell culture models. DM1 is caused when an expansion of r(CUG) repeats, or r(CUG)(exp), is present in the 3' untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) mRNA. r(CUG)(exp) folds into a hairpin with regularly repeating 5'CUG/3'GUC motifs and sequesters muscleblind-like 1 protein (MBNL1). A variety of defects are associated with DM1, including (i) formation of nuclear foci, (ii) decreased translation of DMPK mRNA due to its nuclear retention, and (iii) pre-mRNA splicing defects due to inactivation of MBNL1, which controls the alternative splicing of various pre-mRNAs. Previously, modularly assembled ligands targeting r(CUG)(exp) were designed using information in an RNA motif-ligand database. These studies showed that a bis-benzimidazole (H) binds the 5'CUG/3'GUC motif in r(CUG)(exp.) Therefore, we designed multivalent ligands to bind simultaneously multiple copies of this motif in r(CUG)(exp). Herein, we report that the designed compounds improve DM1-associated defects including improvement of translational and pre-mRNA splicing defects and the disruption of nuclear foci. These studies may establish a foundation to exploit other RNA targets in genomic sequence. PMID:22332923

  10. Chronic hypertrophic nonunion of the Type II odontoid fracture causing cervical myelopathy: Case report and review of literature

    Directory of Open Access Journals (Sweden)

    Mohammed F Shamji

    2016-01-01

    Conclusion: Rarely, nonunion of Type II odontoid fractures may be hypertrophic where both instability and compression cause neurological morbidity. Such cases require anterior transoral decompression, posterior cervical decompression, and instrumented fusions.

  11. Surface modifications caused by a swift heavy ion irradiation on crystalline p-type gallium antimonide

    International Nuclear Information System (INIS)

    Surface modifications caused by a swift heavy ion irradiation on crystalline p-type gallium antimonide crystal have been reported. Single crystal, 1 0 0〉 orientations and ∼500 μm thick p-type GaSb samples with carrier concentration of 3.30 × 1017 cm−3 were irradiated at 100 MeV Fe7+ ions. We have used 15UD Pelletron facilities at IUAC with varying fluences of 5 × 1010–1 × 1014 ions cm−2. The effects of irradiation on these samples have been investigated using, spectroscopic ellipsometry, atomic force microscopy and ultraviolet–visible–NIR spectroscopy techniques. Ellipsometry parameters, psi (Ψ) and delta (Δ) for the unirradiated sample and samples irradiated with different fluences were recorded. The data were fit to a three phase model to determine the refractive index and extinction coefficient. The refractive index and extinction coefficient for various fluences in ultraviolet, visible, and infrared, regimes were evaluated. Atomic force microscopy has been used to study these surface modifications. In order to have more statistical information about the surface, we have plotted the height structure histogram for all the samples. For unirradiated sample, we observed the Gaussian fitting. This result indicates the more ordered height structure symmetry. Whereas for the sample irradiated with the fluence of 1 × 1013, 5 × 1013 and 1 × 1014 ions cm−2, we observed the scattered data. The width of the histogram for samples irradiated up to the fluence of 1 × 1013 ion cm−2 was found to be almost same however it decreased at higher fluence. UV reflectance spectra of the sample irradiated with increasing fluences exhibit three peaks at 292, 500 and 617 nm represent the high energy GaSb; E1, E1 + Δ and E2 band gaps in all irradiated samples

  12. Alveolar Type II Cells Escape Stress Failure Caused by Tonic Stretch through Transient Focal Adhesion Disassembly

    Directory of Open Access Journals (Sweden)

    Xiao-Yang Liu, Xiao-Fei Chen, Yan-Hong Ren, Qing-Yuan Zhan, Chen Wang, Chun Yang

    2011-01-01

    Full Text Available Mechanical ventilation-induced excessive stretch of alveoli is reported to induce cellular stress failure and subsequent lung injury, and is therefore an injurious factor to the lung. Avoiding cellular stress failure is crucial to ventilator-induced lung injury (VILI treatment. In the present study, primary rat alveolar type II (ATII cells were isolated to evaluate their viability and the mechanism of their survival under tonic stretch. By the annexin V/ PI staining and flow cytometry assay, we demonstrated that tonic stretch-induced cell death is an immediate injury of mechanical stress. In addition, immunofluorescence and immunoblots assay showed that the cells experienced an expansion-contraction-reexpansion process, accompanied by partial focal adhesion (FA disassembly during contraction. Manipulation of integrin adherent affinity by altering bivalent cation levels in the culture medium and applying an integrin neutralizing antibody showed that facilitated adhesion affinity promoted cell death under tonic stretch, while lower level of adhesion protected the cells from stretch-induced stress failure. Finally, a simplified numerical model was established to reveal that adequate disassembly of FAs reduced the forces transmitting throughout the cell. Taken together, these results indicate that ATII cells escape stress failure caused by tonic stretch via active cell morphological remodeling, during which cells transiently disassemble FAs to unload mechanical forces.

  13. A functional alternative splicing mutation in AIRE gene causes autoimmune polyendocrine syndrome type 1.

    Directory of Open Access Journals (Sweden)

    Junyu Zhang

    Full Text Available Autoimmune polyendocrine syndrome type 1 (APS-1 is a rare autosomal recessive disease defined by the presence of two of the three conditions: mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. Loss-of-function mutations of the autoimmune regulator (AIRE gene have been linked to APS-1. Here we report mutational analysis and functional characterization of an AIRE mutation in a consanguineous Chinese family with APS-1. All exons of the AIRE gene and adjacent exon-intron sequences were amplified by PCR and subsequently sequenced. We identified a homozygous missense AIRE mutation c.463G>A (p.Gly155Ser in two siblings with different clinical features of APS-1. In silico splice-site prediction and minigene analysis were carried out to study the potential pathological consequence. Minigene splicing analysis and subsequent cDNA sequencing revealed that the AIRE mutation potentially compromised the recognition of the splice donor of intron 3, causing alternative pre-mRNA splicing by intron 3 retention. Furthermore, the aberrant AIRE transcript was identified in a heterozygous carrier of the c.463G>A mutation. The aberrant intron 3-retaining transcript generated a truncated protein (p.G155fsX203 containing the first 154 AIRE amino acids and followed by 48 aberrant amino acids. Therefore, our study represents the first functional characterization of the alternatively spliced AIRE mutation that may explain the pathogenetic role in APS-1.

  14. Whole-grain products and whole-grain types are associated with lower all-cause and cause-specific mortality in the Scandinavian HELGA cohort.

    Science.gov (United States)

    Johnsen, Nina F; Frederiksen, Kirsten; Christensen, Jane; Skeie, Guri; Lund, Eiliv; Landberg, Rikard; Johansson, Ingegerd; Nilsson, Lena M; Halkjær, Jytte; Olsen, Anja; Overvad, Kim; Tjønneland, Anne

    2015-08-28

    No study has yet investigated the intake of different types of whole grain (WG) in relation to all-cause and cause-specific mortality in a healthy population. The aim of the present study was to investigate the intake of WG products and WG types in relation to all-cause and cause-specific mortality in a large Scandinavian HELGA cohort that, in 1992-8, included 120 010 cohort members aged 30-64 years from the Norwegian Women and Cancer Study, the Northern Sweden Health and Disease Study, and the Danish Diet Cancer and Health Study. Participants filled in a FFQ from which data on the intake of WG products were extracted. The estimation of daily intake of WG cereal types was based on country-specific products and recipes. Mortality rate ratios (MRR) and 95 % CI were estimated using the Cox proportional hazards model. A total of 3658 women and 4181 men died during the follow-up (end of follow-up was 15 April 2008 in the Danish sub-cohort, 15 December 2009 in the Norwegian sub-cohort and 15 February 2009 in the Swedish sub-cohort). In the analyses of continuous WG variables, we found lower all-cause mortality with higher intake of total WG products (women: MRR 0·89 (95 % CI 0·86, 0·91); men: MRR 0·89 (95 % CI 0·86, 0·91) for a doubling of intake). In particular, intake of breakfast cereals and non-white bread was associated with lower mortality. We also found lower all-cause mortality with total intake of different WG types (women: MRR 0·88 (95 % CI 0·86, 0·92); men: MRR 0·88 (95 % CI 0·86, 0·91) for a doubling of intake). In particular, WG oat, rye and wheat were associated with lower mortality. The associations were found in both women and men and for different causes of deaths. In the analyses of quartiles of WG intake in relation to all-cause mortality, we found lower mortality in the highest quartile compared with the lowest for breakfast cereals, non-white bread, total WG products, oat, rye (only men), wheat and total WG types. The MRR for highest v

  15. 7 CFR 760.611 - Qualifying losses, eligible causes and types of loss.

    Science.gov (United States)

    2010-01-01

    ...) Losses caused by a failure of power supply or brownout as defined in § 760.602; (2) Losses caused by the inability to market nursery stock as a result of quarantine, boycott, or refusal of a buyer to...

  16. Types, Problems and Their Causes, and Solutions to the Offences against the Environmental Laws by Probationers in Maha Sarakham Province

    Science.gov (United States)

    Wanlu, Somchai; Singseewo, Adisak; Suksringarm, Paitool

    2015-01-01

    This study aimed to explore types, problems and their causes, and solutions to the offences against the environmental laws of probationers in Maha Sarakham Province. The study comprised 2 phases: Phase 1 was a study of types of the offences against the environmental laws: and phase 2 was an interview with 25 people directly dealing with the…

  17. Pontine capillary telangiectasia as visualized on MR imaging causing a clinical picture resembling basilar-type migraine: a case report

    OpenAIRE

    Beukers, R.J.; Roos, Y.B.W.E.M.

    2009-01-01

    A case of presumed pontine capillary telangiectasia in an 18-year-old woman with a clinical diagnosis of basilar-type migraine is reported. Since both are very rare diagnoses, this case provides some evidence to suggest that pontine capillary telangiectasia might cause a clinical picture resembling basilar-type migraine.

  18. Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1).

    Science.gov (United States)

    Messiaen, Ludwine; Vogt, Julia; Bengesser, Kathrin; Fu, Chuanhua; Mikhail, Fady; Serra, Eduard; Garcia-Linares, Carles; Cooper, David N; Lazaro, Conxi; Kehrer-Sawatzki, Hildegard

    2011-02-01

    Mosaicism is an important feature of type-1 neurofibromatosis (NF1) on account of its impact upon both clinical manifestations and transmission risk. Using FISH and MLPA to screen 3500 NF1 patients, we identified 146 individuals harboring gross NF1 deletions, 14 of whom (9.6%) displayed somatic mosaicism. The high rate of mosaicism in patients with NF1 deletions supports the postulated idea of a direct relationship between the high new mutation rate in this cancer predisposition syndrome and the frequency of mosaicism. Seven of the 14 mosaic NF1 deletions were type-2, whereas four were putatively type-1, and three were atypical. Two of the four probable type-1 deletions were confirmed as such by breakpoint-spanning PCR or SNP analysis. Both deletions were associated with a generalized manifestation of NF1. Independently, we identified a third patient with a mosaic type-1 NF1 deletion who exhibited segmental NF1. Together, these three cases constitute the first proven mosaic type-1 deletions so far reported. In two of these three mosaic type-1 deletions, the breakpoints were located within PRS1 and PRS2, previously identified as hotspots for nonallelic homologous recombination (NAHR) during meiosis. Hence, NAHR within PRS1 and PRS2 is not confined to meiosis but may also occur during postzygotic mitotic cell cycles. PMID:21280148

  19. Surface modifications caused by a swift heavy ion irradiation on crystalline p-type gallium antimonide

    Energy Technology Data Exchange (ETDEWEB)

    Jadhav, Vidya, E-mail: vj1510@yahoo.com

    2015-09-01

    Surface modifications caused by a swift heavy ion irradiation on crystalline p-type gallium antimonide crystal have been reported. Single crystal, 1 0 0〉 orientations and ∼500 μm thick p-type GaSb samples with carrier concentration of 3.30 × 10{sup 17} cm{sup −3} were irradiated at 100 MeV Fe{sup 7+} ions. We have used 15UD Pelletron facilities at IUAC with varying fluences of 5 × 10{sup 10}–1 × 10{sup 14} ions cm{sup −2}. The effects of irradiation on these samples have been investigated using, spectroscopic ellipsometry, atomic force microscopy and ultraviolet–visible–NIR spectroscopy techniques. Ellipsometry parameters, psi (Ψ) and delta (Δ) for the unirradiated sample and samples irradiated with different fluences were recorded. The data were fit to a three phase model to determine the refractive index and extinction coefficient. The refractive index and extinction coefficient for various fluences in ultraviolet, visible, and infrared, regimes were evaluated. Atomic force microscopy has been used to study these surface modifications. In order to have more statistical information about the surface, we have plotted the height structure histogram for all the samples. For unirradiated sample, we observed the Gaussian fitting. This result indicates the more ordered height structure symmetry. Whereas for the sample irradiated with the fluence of 1 × 10{sup 13}, 5 × 10{sup 13} and 1 × 10{sup 14} ions cm{sup −2}, we observed the scattered data. The width of the histogram for samples irradiated up to the fluence of 1 × 10{sup 13} ion cm{sup −2} was found to be almost same however it decreased at higher fluence. UV reflectance spectra of the sample irradiated with increasing fluences exhibit three peaks at 292, 500 and 617 nm represent the high energy GaSb; E{sub 1}, E{sub 1} + Δ and E{sub 2} band gaps in all irradiated samples.

  20. Waardenburg syndrome type 4: report of two new cases caused by SOX10 mutations in Spain.

    Science.gov (United States)

    Fernández, Raquel M; Núñez-Ramos, Raquel; Enguix-Riego, M Valle; Román-Rodríguez, Francisco José; Galán-Gómez, Enrique; Blesa-Sánchez, Emilio; Antiñolo, Guillermo; Núñez-Núñez, Ramón; Borrego, Salud

    2014-02-01

    Shah-Waardenburg syndrome or Waardenburg syndrome type 4 (WS4) is a neurocristopathy characterized by the association of deafness, depigmentation and Hirschsprung disease. Three disease-causing genes have been identified so far for WS4: EDNRB, EDN3, and SOX10. SOX10 mutations, found in 45-55% of WS4 patients, are inherited in autosomal dominant way. In addition, mutations in SOX10 are also responsible for an extended syndrome involving peripheral and central neurological phenotypes, referred to as PCWH (peripheral demyelinating neuropathy, central dysmyelinating leucodystrophy, Waardenburg syndrome, Hirschsprung disease). Such mutations are mostly private, and a high intra- and inter-familial variability exists. In this report, we present a patient with WS4 and a second with PCWH due to SOX10 mutations supporting again the genetic and phenotypic heterogeneity of these syndromes. Interestingly, the WS4 family carries an insertion of 19 nucleotides in exon 5 of SOX10, which results in distinct phenotypes along three different generations: hypopigmentation in the maternal grandmother, hearing loss in the mother, and WS4 in the proband. Since mosaicism cannot explain the three different related-WS features observed in this family, we propose as the most plausible explanation the existence of additional molecular events, acting in an additive or multiplicative fashion, in genes or regulatory regions unidentified so far. On the other hand, the PCWH case was due to a de novo deletion in exon 5 of the gene. Efforts should be devoted to unravel the mechanisms underlying the intrafamilial phenotypic variability observed in the families affected, and to identify new genes responsible for the still unsolved WS4 cases. PMID:24311220

  1. Large Genomic Deletions in CACNA1A Cause Episodic Ataxia Type 2

    Directory of Open Access Journals (Sweden)

    Jijun eWan

    2011-09-01

    Full Text Available Episodic ataxia (EA syndromes are heritable diseases characterized by dramatic episodes of imbalance and incoordination. Episodic ataxia type 2 (EA2, the most common and the best characterized subtype, is caused by mostly nonsense, splice site, small indel and sometimes missense mutations in CACNA1A. Direct sequencing of CACNA1A fails to identify mutations in some patients with EA2-like features, possibly due to incomplete interrogation of CACNA1A or defects in other EA genes not yet defined. Previous reports described genomic deletions between 4-40kb in EA2. In 47 subjects with EA (26 with EA2-like features who tested negative for mutations in the known EA genes, we used Multiplex Ligation-dependent Probe Amplification (MLPA to analyze CACNA1A for exonic copy number variations. Breakpoints were further defined by long-range PCR. We identified distinct multi-exonic deletions in three probands with classic EA2-like features: episodes of prolonged vertigo and ataxia triggered by stress and fatigue, interictal nystagmus, with onset during infancy or early childhood. The breakpoints in all three probands are located in Alu sequences, indicating errors in homologous recombination of Alu sequences as the underlying mechanism. The smallest deletion spanned exons 39 and 40, while the largest deletion spanned 200kb, missing all but the first three exons. One deletion involving exons 39 through 47 arose spontaneously. The search for mutations in CACNA1A appears most fruitful in EA patients with interictal nystagmus and onset early in life. The finding of large heterozygous deletions suggests haploinsufficiency as a possible pathomechanism of EA2.

  2. Sphingomyelin phosphodiesterase-1 (SMPD1 coding variants do not contribute to low levels of high-density lipoprotein cholesterol

    Directory of Open Access Journals (Sweden)

    Genest Jacques

    2007-12-01

    Full Text Available Abstract Background Niemann-Pick disease type A and B is caused by a deficiency of acid sphingomyelinase due to mutations in the sphingomyelin phosphodiesterase-1 (SMPD1 gene. In Niemann-Pick patients, SMPD1 gene defects are reported to be associated with a severe reduction in plasma high-density lipoprotein (HDL cholesterol. Methods Two common coding polymorphisms in the SMPD1 gene, the G1522A (G508R and a hexanucleotide repeat sequence within the signal peptide region, were investigated in 118 unrelated subjects of French Canadian descent with low plasma levels of HDL-cholesterol (th percentile for age and gender-matched subjects. Control subjects (n = 230 had an HDL-cholesterol level > the 25th percentile. Results For G1522A the frequency of the G and A alleles were 75.2% and 24.8% respectively in controls, compared to 78.6% and 21.4% in subjects with low HDL-cholesterol (p = 0.317. The frequency of 6 and 7 hexanucleotide repeats was 46.2% and 46.6% respectively in controls, compared to 45.6% and 49.1% in subjects with low HDL-cholesterol (p = 0.619. Ten different haplotypes were observed in cases and controls. Overall haplotype frequencies in cases and controls were not significantly different. Conclusion These results suggest that the two common coding variants at the SMPD1 gene locus are not associated with low HDL-cholesterol levels in the French Canadian population.

  3. Effect of Grouping of Evidence Types on Learning about Interactions between Observed and Unobserved Causes

    Science.gov (United States)

    Rottman, Benjamin Margolin; Ahn, Woo-kyoung

    2011-01-01

    When a cause interacts with unobserved factors to produce an effect, the contingency between the observed cause and effect cannot be taken at face value to infer causality. Yet it would be computationally intractable to consider all possible unobserved, interacting factors. Nonetheless, 6 experiments found that people can learn about an unobserved…

  4. Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1)

    OpenAIRE

    Messiaen, Ludwine M; Vogt, Julia; Bengesser, Kathrin; Fu, Chuanhua; Mikhail, Fady; Serra, Eduard; Garcia-Linares, Carles; Cooper, David N.; Lázaro, Conxi; Kehrer-Sawatzki, Hildegard

    2011-01-01

    Abstract Mosaicism is an important feature of type-1 neurofibromatosis (NF1) on account of its impact upon both clinical manifestations and transmission risk. Using FISH and MLPA to screen 3500 NF1 patients, we identified 146 individuals harbouring gross NF1 deletions, 14 of whom (9.6%) displayed somatic mosaicism. The high rate of mosaicism in patients with NF1 deletions supports the postulated idea of a direct relationship between the high new mutation rate in this cancer predisp...

  5. Classical Ehlers-Danlos Syndrome Caused by a Mutation in Type I Collagen

    OpenAIRE

    Nuytinck, Lieve; Freund, Margarida; Lagae, Lieven; Pierard, Gerald E.; Hermanns-Le, Trinh; De Paepe, Anne

    2000-01-01

    Classical Ehlers-Danlos syndrome (EDS) is characterized by skin hyperelasticity, joint hypermobility, increased tendency to bruise, and abnormal scarring. Mutations in type V collagen, a regulator of type I collagen fibrillogenesis, have been shown to underlie this type of EDS. However, to date, mutations have been found in only a limited number of patients, which suggests genetic heterogeneity. In this article, we report two unrelated patients with typical features of classical EDS, includin...

  6. Adult-onset Invasive Haemophilus influenzae Type f Caused by Acute Lower Leg Cellulitis.

    Science.gov (United States)

    Usui, Yuko; Kakuta, Risako; Araki, Makoto; Sato, Taigo; Gu, Yoshiaki; Yano, Hisakazu; Taniuchi, Norihide

    2016-01-01

    In Japan, routine Haemophilus influenzae type b (Hib) vaccination began in 2013. Thus, similar to other countries, a strain shift is expected in the near future. We experienced a case of H. influenzae type f (Hif) bacteremia in a 66-year-old man. The primary focus of the infection was the soft tissue of the left lower leg, which is an extremely rare origin in adults. Subsequently, we conducted multilocus sequence typing and identified the strain as sequence type 124, which is the most common invasive strain of Hif worldwide. This case may mark the beginning of an Hif strain shift in Japan. PMID:27374690

  7. Whole-grain products and whole grain types are associated with lower all-cause and cause-specific mortality in the Scandinavian HELGA cohort

    DEFF Research Database (Denmark)

    Johnsen, Nina Føns; Frederiksen, Kirsten; Christensen, Jane; Skeie, Guri; Lund, Eiliv; Landberg, Rikard; Johansson, Ingegerd; Nilsson, Lena Maria; Halkjær, Jytte; Olsen, Anja; Overvad, Kim; Tjønneland, Anne

    2015-01-01

    %CI 0·86, 0·91) for a doubling of intake). In particular, intake of breakfast cereals and non-white bread was associated with lower mortality. We also found lower all-cause mortality with total intake of different WG types (women: MRR 0·88 (95%CI 0·86, 0·92); men: MRR 0·88 (95%CI 0·86, 0·91) for a...... quartile compared with the lowest for breakfast cereals, non-white bread, total WG products, oat, rye (only men), wheat and total WG types. The MRR for highest v. lowest quartile of intake of total WG products was 0·68 (95% CI 0·62, 0·75, P for trend over quartiles , 0·0001) for women and 0·75 (95%CI 0...

  8. Cause Related Marketing: The Role of Mental Accounting, Price and Product Type

    OpenAIRE

    Baghi, Ilaria; Rubaltelli, Enrico; Tedecshi, Marcello

    2010-01-01

    Cause related marketing is a strategy that aims to communicate a company's striving for corporate social responsibility and to improve brand image. Previous studies showed that psychological factors have a central role in the CRM strategy as they influence the extent of people's emotional reactions toward the productsocial cause link. The aim is to verify if mental accounting should have an impact on people's perception of a CRM programs. The effect of mental accounting should be different wh...

  9. Mutations in PAX3 that cause Waardenburg syndrome type I: Ten new mutations and review of the literature

    Energy Technology Data Exchange (ETDEWEB)

    Baldwin, C.T.; Hoth, C.F.; Milunsky, A. [Boston Univ. School of Medicine, MA (United States)] [and others

    1995-08-28

    Waardenburg syndrome (WS) is an autosomal-dominant disorder characterized by sensorineural hearing loss, dystopia canthorum, and pigmentary disturbances, and it represents the most common form of inherited deafness in infants. WS type I is characterized by the presence of dystopia canthorum, while individuals with WS type II have normally-located canthi. WS type III is similar to WS type I but is also characterized by musculoskeletal abnormalities. Defects in the PAX3 gene, a transcription factor expressed during embryonic development, have been shown to cause WS types I and III in several families. In contrast, mutations in PAX3 do not cause WS type II, and linkage of the disease to other chromosomal regions has been demonstrated. We describe 10 additional mutations in the PAX3 gene in families with WS type I. Eight of these mutations are in the region of PAX3, where only one mutation has been previously described. These mutations, together with those previously reported, cover essentially the entire PAX3 gene and represent a wide spectrum of mutations that can cause WS type I. Thus far, all but one of the mutations are private; only one mutation has been reported in two apparently unrelated families. Our analysis thus far demonstrates little correlation between genotype and phenotype; deletions of the entire PAX3 gene result in phenotypes indistinguishable from those associated with single-base substitutions in the paired domain or homeodomain of PAX3. Moreover, two similar mutations in close proximity can result in significantly different phenotypes, WS type I in one family and WS type III in another. 47 refs., 3 figs., 5 tabs.

  10. Main types of environmental pollution the contributory causes, the effects on environment and the suggested remedial measures

    International Nuclear Information System (INIS)

    In this article the main types of environmental pollution, the contributory causes, the effects on environment and suggested remedial measures have been described. The fundamental types of environmental pollution are land pollution, water pollution and air pollution. Many artificial and natural factors contribute towards land pollution. Several remedial measures have suggested in this article, some of them are provision of clean water by municipal agencies, toxic wastes or nuclear wastes should not disposed off in the sea. (A.B.)

  11. Tricho-rhino-phalangeal syndrome type I as a “cis-ruption disorder” caused by a translocation

    OpenAIRE

    Marques, Bárbara; Ferreira, Cristina; Araújo, Carlos; Vieira, Luís; Martins, Márcia; Pinto, Maximina; Dias, Cristina; David, Dezső

    2011-01-01

    Tricho-rhino-phalangeal syndrome type I (TRPS I; OMIM 190350) and type II (OMIM 150230) are two forms of the rare autosomal-dominant TRP malformation syndrome localised in 8q23.3–24.1. TRPS I is generally caused by point mutations or deletions of the TRPS1 gene, whereas type II is characterised by the presence of multiple cartilage exostoses (EXT) and deletions comprising the TRPS1 and EXT1 genes. In the present study, we have mapped and sequenced the breakpoints of a balanced familial transl...

  12. Novel Type of Streptococcus pneumoniae Causing Multidrug-Resistant Acute Otitis Media in Children

    OpenAIRE

    Xu, Qingfu; Pichichero, Michael E.; Casey, Janet R.; Zeng, Mingtao

    2009-01-01

    After our recent discovery of a Streptococcus pneumoniae 19A “superbug” (Legacy strain) that is resistant to all Food and Drug Administration–approved antimicrobial drugs for treatment of acute otitis media (AOM) in children, other S. pneumoniae isolates from children with AOM were characterized by multilocus sequence typing (MLST). Among 40 isolates studied, 16 (40%) were serotype 19A, and 9 (23%) were resistant to multiple antimicrobial drugs. Two others had unreported sequence types (STs) ...

  13. What causes the activation of contrastive alternatives, the size of focus domain or pitch accent type?

    OpenAIRE

    Braun, Bettina

    2015-01-01

    Theories of information structure argue that focus involves alternative sets; experimental studies have also shown that narrowly focused constituents lead to the activation of alternatives. However, narrow focus can be realized with different accent types, indicating the information status of the referent and it is unclear whether it is focus domain or accent type that conditions the activation of alternatives. In two visual-world eye-tracking experiments in German, we compared narrow focus c...

  14. An ignored cause of chronic kidney disease in children: type 2 cardiorenal syndrome

    OpenAIRE

    Engin Melek; Sercan Aynaci; Bahriye Atmis; Sevcan Erdem; Nazan Ozbarlas; Aysun Karabay Bayazit

    2016-01-01

    Cardiorenal syndrome is a disorder of the heart and kidneys in which acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ. It is well known that the main cause of mortality among patients with end-stage renal disease is due to cardiovascular events and a common complication in patients in acute heart failure is a decrease in renal function. However, when there are no signs and/or symptoms of chronic cardiovascular disease, cardiovascular causes ...

  15. The Impact of Gender, Family Type and Age on Undergraduate Parents' Perception of Causes of Sexual Abuse

    Science.gov (United States)

    Onoyase, Anna

    2016-01-01

    The purpose of this study was to investigate the Impact of Gender, Family type and Age on undergraduate parents' perception of causes of child Sexual Abuse. Three hypotheses were formulated and tested. There was a review of relevant literature. The population for the study were 2014 sandwich contact students of Delta State University, Abraka who…

  16. A progressive familial intrahepatic cholestasis type 2 mutation causes an unstable, temperature-sensitive bile salt export pump

    NARCIS (Netherlands)

    Plass, JRM; Mol, O; Heegsma, J; Geuken, M; Elling, G; Muller, M; Faber, KN; Jansen, PLM

    2004-01-01

    Background Aims: Progressive familial intrahepatic cholestasis type 2 (PFIC-2) patients have a defect in the hepatocanalicular bile salt secretion. The disease is caused by mutations in the bile salt export pump (BSEP). Ten different missense mutations have been described. In this study, we analysed

  17. Pontine capillary telangiectasia as visualized on MR imaging causing a clinical picture resembling basilar-type migraine: a case report

    NARCIS (Netherlands)

    R.J. Beukers; Y.B.W.E.M. Roos

    2009-01-01

    A case of presumed pontine capillary telangiectasia in an 18-year-old woman with a clinical diagnosis of basilar-type migraine is reported. Since both are very rare diagnoses, this case provides some evidence to suggest that pontine capillary telangiectasia might cause a clinical picture resembling

  18. Adenovirus Type F Subtype 41 Causing Disseminated Disease following Bone Marrow Transplantation for Immunodeficiency

    OpenAIRE

    Slatter, Mary A.; Read, Steven; Taylor, Clive E.; Crooks, Bruce N. A.; Abinun, Mario; Flood, Terence J.; Cant, Andrew J; Wright, Christopher; Gennery, Andrew R.

    2005-01-01

    Adenovirus causes disseminated disease following bone marrow transplantation (BMT). We report a child who underwent T-cell-depleted BMT. Adenovirus subgenus F serotype 41 was detected antemortem by PCR in cerebrospinal fluid and postmortem in other tissues. Serotypes 40 and 41, associated with gastrointestinal disease, have not previously been implicated in disseminated disease.

  19. Spinocerebellar Ataxia Type 6 Protein Aggregates Cause Deficits in Motor Learning and Cerebellar Plasticity

    OpenAIRE

    Mark, Melanie D.; Krause, Martin; Boele, Henk-Jan; Kruse, Wolfgang; Pollok, Stefan; Kuner, Thomas; Dalkara, Deniz; Koekkoek, Sebastiaan; De Zeeuw, Chris I.; Herlitze, Stefan

    2015-01-01

    Spinocerebellar ataxia type 6 (SCA6) is linked to poly-glutamine (polyQ) within the C terminus (CT) of the pore-forming subunits of P/Q-type Ca(2+) channels (Cav2.1) and is characterized by CT protein aggregates found in cerebellar Purkinje cells (PCs). One hypothesis regarding SCA6 disease is that a CT fragment of the Cav2.1 channel, which is detected specifically in cytosolic and nuclear fractions in SCA6 patients, is associated with the SCA6 pathogenesis. To test this hypothesis, we expres...

  20. [The differential diagnosis of the types of trauma caused by wheeled tractors].

    Science.gov (United States)

    Zaval'niuk, A Kh

    1993-01-01

    Examinations of 23 corpses and study of 282 expert conclusions concerning the deaths of subjects aged 6 to 78 dead because of wheeled tractor injuries under agricultural conditions helped detect the specific characteristic signs of tractor injury types. Mathematical method of analysis of the characteristic features' quantitative parameters permitted the author to find statistically reliable criteria for differential diagnosis of the types of injuries inflicted by wheeled tractors. The possibility of correct conclusions of an expert using this method is at least 95%. PMID:7940629

  1. Periparturient infection with bovine viral diarrhea virus type 1 causes hemorrhagic proctocolitis in a cow

    OpenAIRE

    Laureyns, Jozef; Pardon, Bart; Letellier, Carine; Deprez, Piet

    2011-01-01

    After 3 cows of a dairy herd had died from severe hemorrhagic diarrhea, a 4th sick cow was transported to the clinic. Blood analyses revealed the complete absence of white blood cells, the presence of a type 1b strain of bovine viral diarrhea virus (BVDV), and seroconversion to BVDV.

  2. Alien plants invade more phylogenetically clustered community types and cause even stronger clustering

    Czech Academy of Sciences Publication Activity Database

    Lososová, Z.; de Bello, Francesco; Chytrý, M.; Kühn, I.; Pyšek, Petr; Sádlo, Jiří; Winter, M.; Zelený, D.

    2015-01-01

    Roč. 24, č. 7 (2015), s. 786-794. ISSN 1466-822X R&D Projects: GA ČR GAP505/12/1296; GA ČR GB14-36079G Institutional support: RVO:67985939 Keywords : biological invasions * phylogenetic diversity * vegetation type Subject RIV: EH - Ecology, Behaviour Impact factor: 6.531, year: 2014

  3. Novel type of Streptococcus pneumoniae causing multidrug-resistant acute otitis media in children.

    Science.gov (United States)

    Xu, Qingfu; Pichichero, Michael E; Casey, Janet R; Zeng, Mingtao

    2009-04-01

    After our recent discovery of a Streptococcus pneumoniae 19A "superbug" (Legacy strain) that is resistant to all Food and Drug Administration-approved antimicrobial drugs for treatment of acute otitis media (AOM) in children, other S. pneumoniae isolates from children with AOM were characterized by multilocus sequence typing (MLST). Among 40 isolates studied, 16 (40%) were serotype 19A, and 9 (23%) were resistant to multiple antimicrobial drugs. Two others had unreported sequence types (STs) that expressed the 19A capsule, and 8 (88%) of the 9 multidrug-resistant strains were serotype 19A, including the Legacy strain with the new ST-2722. In genetic relatedness, ST-2722 belonged to a cluster of reported strains of S. pneumoniae in which all strains had 6 of the same alleles as ST-156. The multidrug-resistant strains related to ST-156 expressed different capsular serotypes: 9V, 14, 11A, 15C, and 19F. PMID:19331730

  4. Analyze of the Possible Causes of Porosity Type Deffects in Aluminium High Pressure Diecast Parts

    Directory of Open Access Journals (Sweden)

    Ferencz Peti

    2011-06-01

    Full Text Available Die casting is a metal casting process that is characterized by forcing molten metal under high pressure into a mold cavity. The mold cavity is created using two hardened tool steel dies which have been machined into shape and work similarly to an injection mold during the process. Most die castings are made from non-ferrous metals, specifically zinc, copper, aluminium, magnesium. Depending on the type of metal being cast, a hot- or cold-chamber machine is used.Die castings are characterized by a very good surface finish (by casting standards and dimensional consistency.The most common deffect that appear in castings is the porosity type of deffect, which can be gas porosity, shrinkage porosity or leaker.

  5. Hemorrhagic Enterotoxemia Caused by Clostridium perfringens Type C in a Foal

    OpenAIRE

    Niilo, L; Chalmers, G A

    1982-01-01

    A four day old Appaloosa foal in Alberta died from hemorrhagic enterotoxemia. Beta-toxin of Clostridium perfringens was demonstrated in the intestinal contents of the foal and a pure culture of C. perfringens type C was grown from the small intestine. Histological examination showed hemorrhage and extensive necrosis of the small intestinal mucosa. Areas of necrotic tissue were surrounded by massive numbers of clostridia-like rods. There was also a moderate degree of thyroid hyperplasia. This ...

  6. In vitro antisense therapeutics for a deep intronic mutation causing Neurofibromatosis type 2

    OpenAIRE

    Castellanos, Elisabeth; Rosas, Imma; Solanes, Ares; Bielsa, Isabel; Lázaro, Conxi; Carrato, Cristina; Hostalot, Cristina; Prades, Pepe; Roca-Ribas, Francesc; Blanco, Ignacio; Serra, Eduard

    2013-01-01

    Neurofibromatosis type 2 (NF2) is an autosomal-dominant disorder affecting about 1:33 000 newborns, mainly characterized by the development of tumors of the nervous system and ocular abnormalities. Around 85% of germline NF2 mutations are point mutations. Among them, ∼25% affect splicing and are associated with a variable disease severity. In the context of our NF2 Multidisciplinary Clinics, we have identified a patient fulfilling clinical criteria for the disease and exhibiting a severe phen...

  7. An autosomal locus causing autoimmune disease: Autoimmune polyglandular disease type I assigned to chromosome 21

    OpenAIRE

    Aaltonen, Johanna; Björses, Petra; Sandkuijl, Lodewijk; Perheentupa, Jaakko; Peltonen, Leena Johanna

    1994-01-01

    textabstractAutoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease characterized by a variable combination of the failure of the endocrine glands. The pathogenesis of this unique autoimmune disease is unknown; unlike many other autoimmune diseases, APECED does not show association to specific HLA haplotypes. Unravelling the APECED locus will identify a novel gene outside the HLA loci influencing the outcome of autoimmune diseases. We have assigned the di...

  8. RANDOM ANALYSIS OF HYDRODYNAMIC CHARACTERISTICS OF TRAJECTORY JET CAUSED BY DIFFERENT TYPES OF PIERS

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    This paper presents some results on different tail patterns of piers with an overflow dam, and discusses in particular the hydrodynamic characteristics, the distance of water jet scour and the range of erosion area fluctuating for different parameters of average flow field when river beds are under the pressure of water jet scour caused by some special broad-tail piers. The present paper also covers some preliminary research on the relationship of movable bed tests, and introduces the method of calculating the erosion depth and area, therefore provides the best pier pattern in the construction of river beds against erosion.

  9. Symptomatic type 1 protein C deficiency caused by a de novo Ser270Leu mutation in the catalytic domain

    DEFF Research Database (Denmark)

    Lind, B; Koefoed, P; Thorsen, S

    2001-01-01

    , which is consistent with a type 1 deficiency. Transient expression of mutant protein C cDNA in human kidney 293 cells and analysis of protein C antigen in culture media and cell lysates showed that the secretion of mutant protein compared with wild-type protein was reduced by at least 97% while the...... the plasma protein C deficiency and are consistent with a disease mechanism that involves synthesis of mutant protein followed by intracellular degradation before its secretion into the extracellular space. The mutation was not present in the parents of the proband, suggesting a de novo mutation. Non...... intracellular content of mutant and wild-type protein was similar. Northern blot analysis of total mRNA from transfected cells showed no reduction of the mutant protein C mRNA compared with wild-type protein C mRNA. Collectively, these results indicate that the Ser270Leu mutation in the affected family caused...

  10. Cause-specific mortality by race in low-income Black and White people with Type 2 diabetes

    Science.gov (United States)

    Conway, B N; May, M E; Fischl, A; Frisbee, J; Han, X; Blot, W J

    2015-01-01

    Aim To investigate, with extended follow-up, cause-specific mortality among low-income Black and White Americans with Type 2 diabetes who have similar socio-economic status. Methods Black and White Americans aged 40–79 years with Type 2 diabetes (n = 12 498) were recruited from community health centres as part of the Southern Community Cohort Study. Multivariable Cox analysis was used to estimate mortality hazard ratios and 95% CIs for subsequent cause-specific mortality, based on both underlying and contributing causes of death. Results During the follow-up (median 5.9 years), 13.3% of the study population died. The leading causes of death in each race were ischaemic heart disease, respiratory disorders, cancer, renal failure and heart failure; however, Blacks were at a lower risk of dying from ischaemic heart disease (hazard ratio 0.70, 95% CI 0.54–0.91) or respiratory disorders (hazard ratio 0.70, 0.53–0.92) than Whites but had higher or similar mortality attributable to renal failure (hazard ratio 1.57, 95% CI 1.02–2.40), heart failure (hazard ratio 1.47, 95% CI 0.98–2.19) and cancer (hazard ratio 0.87, 95% CI 0.62–1.22). Risk factors for each cause of death were generally similar in each race. Conclusions These findings suggest that the leading causes of death and their risk factors are largely similar among Black and White Americans with diabetes. For the two leading causes of death in each race, however, ischaemic heart disease and respiratory disorders, the magnitude of risk is lower among Black Americans and contributes to their higher survival rates. PMID:25112863

  11. Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II

    OpenAIRE

    Shekarabi, Masoud; Girard, Nathalie; Rivière, Jean-Baptiste; Dion, Patrick; Houle, Martin; Toulouse, André; Lafrenière, Ronald G.; Vercauteren, Freya; Hince, Pascale; Laganiere, Janet; Rochefort, Daniel; Faivre, Laurence; Samuels, Mark; Guy A. Rouleau

    2008-01-01

    Hereditary sensory and autonomic neuropathy type II (HSANII) is an early-onset autosomal recessive disorder characterized by loss of perception to pain, touch, and heat due to a loss of peripheral sensory nerves. Mutations in hereditary sensory neuropathy type II (HSN2), a single-exon ORF originally identified in affected families in Quebec and Newfoundland, Canada, were found to cause HSANII. We report here that HSN2 is a nervous system–specific exon of the with-no-lysine(K)–1 (WNK1) gene. W...

  12. Analyze of the Possible Causes of Porosity Type Deffects in Aluminium High Pressure Diecast Parts

    OpenAIRE

    Ferencz Peti; Lucian Grama

    2011-01-01

    Die casting is a metal casting process that is characterized by forcing molten metal under high pressure into a mold cavity. The mold cavity is created using two hardened tool steel dies which have been machined into shape and work similarly to an injection mold during the process. Most die castings are made from non-ferrous metals, specifically zinc, copper, aluminium, magnesium. Depending on the type of metal being cast, a hot- or cold-chamber machine is used.Die castings are characterized ...

  13. Distinction between porcine circovirus type 2 enteritis and porcine proliferative enteropathy caused by Lawsonia intracellularis

    DEFF Research Database (Denmark)

    Jensen, Tim Kåre; Vigre, Håkan; Svensmark, B.;

    2006-01-01

    The presence of porcine circovirus type 2 (PCV2) was studied immunohistochemically in formalin-fixed, paraffin wax-embedded samples of intestinal tissue from 80 pigs with a clinical history suggestive of Lawsonia intracellularis-associated diarrhoea. Histopathologically, enteritis of varying...... in the submucosa, lamina propria and crypt epithelium, as well as in the lymphoid tissue of the ileum and colon. Multinucleated giant cells, however, were seen in both infections. PCV2 was about three times more likely to be detected in L. intracellularis-negative than in L. intracellularis...

  14. Characterization of Two Second-Site Mutations Preventing Wild Type Protein Aggregation Caused by a Dominant Negative PMA1 Mutant

    OpenAIRE

    Pilar Eraso; Francisco Portillo; Mazón, María J.

    2013-01-01

    The correct biogenesis and localization of Pma1 at the plasma membrane is essential for yeast growth. A subset of PMA1 mutations behave as dominant negative because they produce aberrantly folded proteins that form protein aggregates, which in turn provoke the aggregation of the wild type protein. One approach to understand this dominant negative effect is to identify second-site mutations able to suppress the dominant lethal phenotype caused by those mutant alleles. We isolated and character...

  15. Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report

    OpenAIRE

    Jamsheer Aleksander; Sowińska Anna; Kaczmarek Leszek; Latos-Bieleńska Anna

    2012-01-01

    Abstract Background Brachydactyly type E (BDE; MIM#113300) is characterized by shortening of the metacarpal, metatarsal, and often phalangeal bones, and predominantly affects postaxial ray(s) of the limb. BDE may occur as an isolated trait or as part of a syndrome. Isolated BDE is rare and in the majority of cases the molecular pathogenesis has so far not been resolved. Originally, the molecular cause of isolated BDE has been unravelled in 2 families and shown to result from heterozygous miss...

  16. Change in Visual Perception and Balance Caused by Different Types of Hat

    OpenAIRE

    Roh, Hyolyun

    2014-01-01

    [Purpose] This study aimed to determine the effect of the type of hat worn on balance, eye-hand coordination, and visual perception of normal adults. [Subjects and Methods] Eight healthy male (20.87±1.95 years, 171.38±4.03 cm, 60.75±7.94 kg) and seven female (20.14±0.89 years, 160.57±5.25 cm, 57.14±7.92 kg) university students participated in this study. Balance ability, eye-hand coordination, and visual perception were measured when subjects were bare-headed, and when they wore a hat, cap or...

  17. Ultraviolet-B radiation causes shade-type ultrastructural changes in Brassica napus

    International Nuclear Information System (INIS)

    Cell and chloroplast structural changes in palisade cells from mature leaves of Brassica napus L. cv. Paroll were quantified following exposure of plants to enhanced ultraviolet-B (280–320 nm; 13 kJ m−2 day−1 biologically effective UV-B) radiation at two different levels of photosynthetically active radiation (PAR, 400–700 nm; 200 and 700 μmol m−2 s−1). Short-term changes in leaf ultrastructure after 30 min and longer term changes after one day and one week were analyzed using stereological techniques incorporating light and electron microscopy and mathematical reconstruction of a mean cell for each sample. Ultraviolet-B together with either relatively high or low PAR resulted in cell structural changes resembling those typical of plants under shade conditions, with the most marked response occurring after 30 min of UV-B radiation. The ultrastructural changes at the cellular level were generally similar in both the relatively high and low PAR plus UV-B radiation treatments. The surface areas of all three thylakoid types, the appressed, non-appressed and margin thylakoids increased in the palisade tissue under supplemental UV-B irradiation. Although the appressed and non-appressed thylakoids increased in surface area, they did not increase equally, leaving open the possibility that the two thylakoid types have independent regulatory systems or different sensitivity to UV-B radiation. Increased thylakoid packing (mm2 thylakoid membrane per mm2 leaf surface) in UV-B-exposed plants may increase the statistical probability of photon interception. An increased level of UV-absorbing pigments after one week of supplemental UV-B radiation did not prevent or significantly ameliorate UV effects. Our data supported the assumption that UV-B radiation may have a regulatory role besides damaging effects and that an increased UV-B environment will likely increase this regulatory influence of UV-B radiation. (author)

  18. Human papillomavirus (HPV) type 16 E7 protein bodies cause tumour regression in mice

    International Nuclear Information System (INIS)

    Human papillomaviruses (HPV) are the causative agents of cervical cancer in women, which results in over 250 000 deaths per year. Presently there are two prophylactic vaccines on the market, protecting against the two most common high-risk HPV types 16 and 18. These vaccines remain very expensive and are not generally affordable in developing countries where they are needed most. Additionally, there remains a need to treat women that are already infected with HPV, and who have high-grade lesions or cervical cancer. In this paper, we characterize the immunogenicity of a therapeutic vaccine that targets the E7 protein of the most prevalent high-risk HPV - type 16 – the gene which has previously been shown to be effective in DNA vaccine trials in mice. The synthetic shuffled HPV-16 E7 (16E7SH) has lost its transforming properties but retains all naturally-occurring CTL epitopes. This was genetically fused to Zera®, a self-assembly domain of the maize γ-zein able to induce the accumulation of recombinant proteins into protein bodies (PBs), within the endoplasmic reticulum in a number of expression systems. High-level expression of the HPV 16E7SH protein fused to Zera® in plants was achieved, and the protein bodies could be easily and cost-effectively purified. Immune responses comparable to the 16E7SH DNA vaccine were demonstrated in the murine model, with the protein vaccine successfully inducing a specific humoral as well as cell mediated immune response, and mediating tumour regression. The fusion of 16E7SH to the Zera® peptide was found to enhance the immune responses, presumably by means of a more efficient antigen presentation via the protein bodies. Interestingly, simply mixing the free PBs and 16E7SH also enhanced immune responses, indicating an adjuvant activity for the Zera® PBs

  19. Novel mutations in the SCNN1A gene causing Pseudohypoaldosteronism type 1.

    Directory of Open Access Journals (Sweden)

    Jian Wang

    Full Text Available Pseudohypoaldosteronism type 1 (PHA1 is a rare inherited disease characterized by resistance to the actions of aldosterone. Mutations in the subunit genes (SCNN1A, SCNN1B, SCNN1G of the epithelial sodium channel (ENaC and the NR3C2 gene encoding the mineralocorticoid receptor, result in systemic PHA1 and renal PHA1 respectively. Common clinical manifestations of PHA1 include salt wasting, hyperkalaemia, metabolic acidosis and elevated plasma aldosterone levels in the neonatal period. In this study, we describe the clinical and biochemical manifestations in two Chinese patients with systemic PHA1. Sequence analysis of the SCNN1A gene revealed a compound heterozygous mutation (c.1311delG and c.1439+1G>C in one patient and a homozygous mutation (c.814_815insG in another patient, all three variants are novel. Further analysis of the splicing pattern in a minigene construct showed that the c.1439+1G>C mutation can lead to the retainment of intron 9 as the 5'-donor splice site disappears during post-transcriptional processing of mRNA. In conclusion, our study identified three novel SCNN1A gene mutations in two Chinese patients with systemic PHA1.

  20. A special type of scald caused by prolonged exposure to slowly heated water.

    Science.gov (United States)

    Pircher, R; Pollak, S; Vogt, S; Epting, T; Kramer, L; Geisenberger, D

    2016-06-01

    When skin is subjected to water temperatures gradually rising from moderate to critical ranges for a prolonged period of time, the resulting scalds will initially present as reddening, followed by blistering and at last by full-thickness burns. On changing from second- to third-degree burn, the blisters stop to become enlarged and solidify due to heat-induced coagulation necrosis. Such gradually intensifying tissue damage results in multiple firm skin blisters together with third-degree burn of the affected area. The initially serous blister fluid assumes a jelly-like consistency as the proteins undergo denaturation. Scalds of this special type may occur in persons taking a bath and becoming incapable to act so that the warm water tap remains turned on or a hairdryer continues to work after having been dropped into the bath water. On the basis of two relevant fatalities (suicidal electrocutions in bathtubs by means of hairdryers), the macroscopic and histological appearance of blisters which only secondarily turned into a full-thickness scald is compared with blisters in genuine second-degree scalds. The blister fluid of the latter ones was also investigated as to their protein composition and hemoglobin concentration. PMID:27129143

  1. A PROSPECTIVE OBSERVATIONAL STUDY TO ANALYZE THE CAUSES AND TYPES OF PRE SENILE CATARACT IN SOUTH INDIAN PATIENTS

    Directory of Open Access Journals (Sweden)

    Manoj

    2014-10-01

    Full Text Available Cataract is the opacification of the crystalline lens and or its capsule. Senile cataract is the cataract occurring commonly in the elderly who are above 50 years of age. It is one of the major causes of blindness in both the developing and the developed countries. Cataracts which develop prior to age of 50 are defined as pre senile cataract. There may be several reasons for an individual to develop such pre senile cataract. Some of the major identified risk factors are ocular trauma, uncontrolled diabetes, nutritional deficiencies, environmental factors like chronic exposure to sunlight as in tropics, cigarette smoking, refractive errors like high myopia, chronic intake of certain drugs for some systemic illness and certain ocular inflammatory diseases. AIM AND OBJECTIVES: To determine the various types of pre senile cataract and to determine the common causes of pre senile cataract. DESIGN: Prospective Observational study. METHODS & MATERIALS: The patients attending the out-patient clinics of the ophthalmology department who are found to have pre senile cataract and who give consent to participate in the observational study are requested to fill the questionnaire and undergo a complete ocular examination. The type of cataract and any cause of the cataract formation identified from the questionnaire, examination or investigations done are documented and analyzed using frequency distribution. RESULTS: 100 eyes of 54 patients were included in the study. Most common type of cataract was found to be posterior sub capsular cataract. The common causes identified were sunlight exposure, chronic steroid use, diabetes, uveitis and smoking. CONCLUSION: Protection from sunlight, avoidance of chronic steroid usage, screening and adequate control of diabetes, meticulous management of uveitis and avoiding cigarette smoking helps to prevent early development of cataracts.

  2. Inactivation of Fam20C in cells expressing type I collagen causes periodontal disease in mice.

    Directory of Open Access Journals (Sweden)

    Peihong Liu

    Full Text Available FAM20C is a kinase that phosphorylates secretory proteins. Previous studies have shown that FAM20C plays an essential role in the formation and mineralization of bone, dentin and enamel. The present study analyzed the loss-of-function effects of FAM20C on the health of mouse periodontal tissues.By crossbreeding 2.3 kb Col 1a1-Cre mice with Fam20Cfl/fl mice, we created 2.3 kb Col 1a1-Cre;Fam20Cfl/fl (cKO mice, in which Fam20C was inactivated in the cells that express Type I collagen. We analyzed the periodontal tissues in the cKO mice using X-ray radiography, histology, scanning electron microscopy and immunohistochemistry approaches.The cKO mice underwent a remarkable loss of alveolar bone and cementum, along with inflammation of the periodontal ligament and formation of periodontal pockets. The osteocytes and lacuno-canalicular networks in the alveolar bone of the cKO mice showed dramatic abnormalities. The levels of bone sialoprotein, osteopontin, dentin matrix protein 1 and dentin sialoprotein were reduced in the Fam20C-deficient alveolar bone and/or cementum, while periostin and fibrillin-1 were decreased in the periodontal ligament of the cKO mice.Loss of Fam20C function leads to periodontal disease in mice. The reduced levels of bone sialoprotein, osteopontin, dentin matrix protein 1, dentin sialoprotein, periostin and fibrillin-1 may contribute to the periodontal defects in the Fam20C-deficient mice.

  3. Contribution of different soil types to transformation of the downward flow of man-caused radionuclides

    International Nuclear Information System (INIS)

    Full text: The contribution of different soils and soil horizons to transformation of the downward flows of the Chernobyl-born radionuclides was studied in the most contaminated regions in the territory of Russian Federation and Ukraine including the 30-km exclusion zone of the Chernobyl Nuclear Power Plant. On the basis of long-term comprehensive studies carried out in 1986-2005, it was shown that the fate and current status of the aerial fallout in the soils of different ecosystems depend on the intensity of their vertical migration under natural conditions. In coniferous (spruce and pine) forests, the major proportion of radionuclides (over 60%) is retained by the forest litter and topmost (0-1 cm) organic-mineral strata beneath the forest litter. In pine forests, humus sub-horizon of the forest litter contains by 10% more radionuclides than the corresponding sub-horizon in spruce forest, however, the opposite is true for the radionuclide content the in mineral 0-1 cm stratum beneath the forest litter. It can be supposed that forest litter in coniferous ecosystems still serves as an effective biogeochemical barrier preventing radionuclides from intensive vertical migration. In deciduous forests, the forest litter is rather thin and fragmentary, and cannot retain radionuclides as effectively as in coniferous forests. In deciduous forests, the maximum of radionuclides moves to the mineral soil layers where distributes rather uniformly down to the depth of 15-20 cm. The latter is likely to be due to the soil fauna activities (zoogenic factor). Thus, the soils of deciduous forests are devoid of emphasized biogeochemical barriers impeding the downward migration of radionuclide. In these ecosystems, the topmost 0-5 cm soil layer serves as the first barrier for man-caused radionuclides. In deeper soil strata, illuvial horizons may serve as a barrier for these radionuclides. In bog phytocenoses on peat-gley soils, the maximum of radionuclide content is attributed to the

  4. High-throughput bacterial SNP typing identifies distinct clusters of Salmonella Typhi causing typhoid in Nepalese children

    LENUS (Irish Health Repository)

    Holt, Kathryn E

    2010-05-31

    Abstract Background Salmonella Typhi (S. Typhi) causes typhoid fever, which remains an important public health issue in many developing countries. Kathmandu, the capital of Nepal, is an area of high incidence and the pediatric population appears to be at high risk of exposure and infection. Methods We recently defined the population structure of S. Typhi, using new sequencing technologies to identify nearly 2,000 single nucleotide polymorphisms (SNPs) that can be used as unequivocal phylogenetic markers. Here we have used the GoldenGate (Illumina) platform to simultaneously type 1,500 of these SNPs in 62 S. Typhi isolates causing severe typhoid in children admitted to Patan Hospital in Kathmandu. Results Eight distinct S. Typhi haplotypes were identified during the 20-month study period, with 68% of isolates belonging to a subclone of the previously defined H58 S. Typhi. This subclone was closely associated with resistance to nalidixic acid, with all isolates from this group demonstrating a resistant phenotype and harbouring the same resistance-associated SNP in GyrA (Phe83). A secondary clone, comprising 19% of isolates, was observed only during the second half of the study. Conclusions Our data demonstrate the utility of SNP typing for monitoring bacterial populations over a defined period in a single endemic setting. We provide evidence for genotype introduction and define a nalidixic acid resistant subclone of S. Typhi, which appears to be the dominant cause of severe pediatric typhoid in Kathmandu during the study period.

  5. Anelastic relaxation caused by interstitial atoms in β-type sintered Ti-Nb alloys

    International Nuclear Information System (INIS)

    Highlights: → In this study, the internal friction of the sintered β-type Ti-Nb alloys is measured using a dynamic mechanical analysis (DMA) Q800 from TA Instruments in single cantilever mode. The effects of heat treatment and compositions on the internal friction behavior of Ti-Nb alloys were investigated and discussed. The internal friction peak height is determined by the stability and amount of β phase. The peak height presents a maximum in the vicinity of 35 wt.% Nb for the quenched alloys, resulting from the variation of the stability and amount of βM with Nb content. In as-sintered alloys, the height of the peak increases monotonously with increasing Nb content due to the increase of the amount of βS. It has been suggested that the internal friction peak is related to oxygen jumps in lattice and the interactions of oxygen-substitute atoms in βM for the water-quenched alloys and in βS phase for the as-sintered alloys. - Abstract: The internal friction behavior of Ti-Nb alloys is investigated using a dynamic mechanical analysis (DMA) Q800 from TA Instruments in single cantilever mode. Relaxational internal friction peaks are found on the internal friction temperature dependent curves in the sintered alloys. The peak does not appear in the sintered Ti-Nb alloys with low Nb content. The water-quenched Ti-35.4 (wt.%) Nb alloy has much higher the internal friction peak than the as-sintered alloy with identical compositions. Therefore, the peak height depends on heat treatment and Nb content. It is deduced that the peak is linked to the β phase of Ti-Nb alloys and that the peak height is determined by the stability and amount of the β phase. When the stability of the β phase is decreased, the peak height is increased. The increase in the amount of β phase results in the increase of the peak height. The β phase in the quenched Ti-35.4Nb specimen is metastable β phase (βM), which can be transformed into the stable α and βS by aging. The β phase in

  6. Vascular-type Ehlers-Danlos syndrome caused by a hitherto unknown genetic mutation: a case report

    Directory of Open Access Journals (Sweden)

    Kashizaki Fumihiro

    2013-02-01

    Full Text Available Abstract Introduction Vascular-type Ehlers-Danlos syndrome is an autosomal dominant disease that causes arterial spurting, intestinal perforation, uterine rupture and hemopneumothorax due to decreased production of type III collagen. The average age at death is 48 years old, and it is considered to be the most severe form of Ehlers-Danlos syndrome. We report the case of a 64-year-old Japanese woman and her 38-year-old daughter who were diagnosed with this disease. Case presentation A 64-year-old Japanese woman was referred to our hospital because of right anterior chest pain following cough and pharyngeal discomfort. Pleurisy was suspected due to the presence of right pleural effusion, so the next day she was referred to our department, where a detailed examination led to the diagnosis of hemothorax. The bleeding that caused the right hemothorax was difficult to control, so our patient was transferred to the Department of Thoracic Surgery for hemostasis control. Our patient’s personal history of uterine hemorrhage and skin ulcers, as well as the finding of skin fragility during surgery, were indicative of a weak connective tissue disease; therefore, after improvement of the hemothorax, a genetic analysis was performed. This revealed a heterozygous missense mutation in COL3A1, c.2411 G>T p.Gly804Val (exon 36. A detailed investigation conducted at a later date revealed that her daughter also had the same genetic mutation. This led to the diagnosis of vascular-type Ehlers-Danlos syndrome characterized by a new gene mutation. Conclusion We report a new genetic mutation associated with vascular-type Ehlers-Danlos syndrome. We present the clinical and imaging findings, and the disease and treatment course in this patient. We believe this information will be important in treating future cases of vascular-type Ehlers-Danlos syndrome in patients with this mutation.

  7. Formation causes and recovery of the "Black Soil Type" degraded alpine grassland in Qinghai-Tibetan Plateau

    Institute of Scientific and Technical Information of China (English)

    SHANG Zhanhuan; LONG Ruijun

    2007-01-01

    The formation causes and ecological rebuilding of the "Black Soil Type" degraded alpine grassland are summarized.The formation of the "Black Soil Type" degraded grassland was caused mainly by climate warming,decreasing glaciers,overgrazing,and damage by rats.The ecological restoration of the "Black Soil Type" degraded alpine grassland relies not only on grassland building,but also on reasonable management and planning of grassland resources.Guaranty measures for developing the alpine grassland animal husbandry in a healthy way include intensifying the educational investment in pasture regions,practicing long-term contracts for grassland,and strengthening the grassland legislation.The authors believe that the Qinghai-Tibetan Plateau ecosystem has a special characteristic inertia or "inert gases",which weaken the self-renewing capability of the ecosystem and makes its structure frail.The inertia characteristic may be the important reason that makes ecological rebuilding so difficult;in addition,other problems need to be studied deeply to provide scientific bases for the ecological building in the Qinghai-Tibetan Plateau.

  8. A novel mitofusin 2 gene mutation causing Charcot-Marie-Tooth type 2A disease in a Chinese family

    Institute of Scientific and Technical Information of China (English)

    CHEING Chor Kwan; LAU Kwok Kwong; YU Kwok Wai; CHAN Yan Wo Albert; MAK Miu Chloe

    2010-01-01

    @@ Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathies, comprises a genetically heterogeneous group of inherited peripheral neuropathies. Clinically it is characterized by progressive distal weakness, muscle atrophy, distal sensory loss and loss of deep tendon reflexes. Following electrophysiological criteria, CMT is divided into two main forms: the primarily demyelinating neuropathy CMT1 with severely decreased nerve conduction velocity (NCV) (38 m/s) but decreased amplitudes.1 CMT2A, an autosomal dominant disease caused by mitofusin 2 gene (MFN2) mutations, is the most common type of CMT2, accounting for up to 33% of familial CMT2 cases.2 We reported a patient with clinical diagnosis of CMT2 caused by a novel MFN2 mutation. To our knowledge, this is a relatively early report of genetically confirmed CMT2A in Chinese.

  9. Increased orosomucoid in urine is an independent predictor of cardiovascular and all-cause mortality in patients with type 2 diabetes at 10 years of follow-up

    DEFF Research Database (Denmark)

    Svendstrup, Mathilde; Christiansen, Merete Skovdal; Magid, Erik;

    2013-01-01

    To evaluate whether increased urinary orosomucoid excretion rate (UOER) is an independent predictor of cardiovascular and all-cause mortality in type 2 diabetes (T2DM) and type 1 diabetes (T1DM) at 10years of follow-up.......To evaluate whether increased urinary orosomucoid excretion rate (UOER) is an independent predictor of cardiovascular and all-cause mortality in type 2 diabetes (T2DM) and type 1 diabetes (T1DM) at 10years of follow-up....

  10. N-Acetyl-cysteine causes analgesia by reinforcing the endogenous activation of type-2 metabotropic glutamate receptors

    Directory of Open Access Journals (Sweden)

    Bernabucci Matteo

    2012-10-01

    Full Text Available Abstract Background Pharmacological activation of type-2 metabotropic glutamate receptors (mGlu2 receptors causes analgesia in experimental models of inflammatory and neuropathic pain. Presynaptic mGlu2 receptors are activated by the glutamate released from astrocytes by means of the cystine/glutamate antiporter (System xc- or Sxc-. We examined the analgesic activity of the Sxc- activator, N-acetyl-cysteine (NAC, in mice developing inflammatory or neuropathic pain. Results A single injection of NAC (100 mg/kg, i.p. reduced nocifensive behavior in the second phase of the formalin test. NAC-induced analgesia was abrogated by the Sxc- inhibitor, sulphasalazine (8 mg/kg, i.p. or by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.. NAC still caused analgesia in mGlu3−/− mice, but was inactive in mGlu2−/− mice. In wild-type mice, NAC retained the analgesic activity in the formalin test when injected daily for 7 days, indicating the lack of tolerance. Both single and repeated injections of NAC also caused analgesia in the complete Freund’s adjuvant (CFA model of chronic inflammatory pain, and, again, analgesia was abolished by LY341495. Data obtained in mice developing neuropathic pain in response to chronic constriction injury (CCI of the sciatic nerve were divergent. In this model, a single injection of NAC caused analgesia that was reversed by LY341495, whereas repeated injections of NAC were ineffective. Thus, tolerance to NAC-induced analgesia developed in the CCI model, but not in models of inflammatory pain. The CFA and CCI models differed with respect to the expression levels of xCT (the catalytic subunit of Sxc- and activator of G-protein signaling type-3 (AGS3 in the dorsal portion of the lumbar spinal cord. CFA-treated mice showed no change in either protein, whereas CCI mice showed an ipislateral reduction in xCT levels and a bilateral increase in AGS3 levels in the spinal cord. Conclusions These data demonstrate that

  11. Defective Neutrophil Recruitment in Leukocyte Adhesion Deficiency Type I Disease Causes Local IL-17-Driven Inflammatory Bone Loss.

    OpenAIRE

    Moutsopoulos, N. M.; Konkel, J.; Sarmadi, M.; Eskan, M. A.; Wild, T.; N Dutzan; L Abusleme; Zenobia, C; Hosur, K. B.; Abe, T.; Uzel, G.; Chen, W.; Chavakis, T.; Holland, S.M.; Hajishengallis, G

    2014-01-01

    Leukocyte adhesion deficiency Type I (LAD-I), a disease syndrome associated with frequent microbial infections, is caused by mutations on the CD18 subunit of β2 integrins. LAD-I is invariably associated with severe periodontal bone loss, historically attributed to lack of neutrophil surveillance of the periodontal infection. Here, we challenge this dogma by showing that the cytokine IL-17 plays a major role in the oral pathology of LAD-I. Defective neutrophil recruitment in LAD-I patients, or...

  12. Molecular Anatomy and Number of Antigen Specific CD8 T Cells Required to Cause Type 1 Diabetes

    OpenAIRE

    Oldstone, Michael B.A.; Edelmann, Kurt H; McGavern, Dorian B.; Cruite, Justin T.; Welch, Megan J.

    2012-01-01

    We quantified CD8 T cells needed to cause type 1 diabetes and studied the anatomy of the CD8 T cell/beta (β) cell interaction at the immunologic synapse. We used a transgenic model, in situ tetramer staining to distinguish antigen specific CD8 T cells from total T cells infiltrating islets and a variety of viral mutants selected for functional deletion(s) of various CD8 T cell epitopes. Twenty percent of CD8 T cells in the spleen were specific for all immunodominant and subdominant viral glyc...

  13. Disease: H00424 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available A/B and Farber lipogranulomatosis. NPD caused by deficient acid sphingomyelinase...mith EL, Schuchman EH The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of ...uchman EH The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. J Inherit ...PMID:19944693 (NPC) Schuchman EH Acid sphingomyelinase, cell membranes and human disease: Lessons from Niema

  14. Disease: H00137 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available order caused by deficient acid sphingomyelinase (ASM) activity, resulting in accumulation of sphingomyelin a... 607616 PMID:18567738 Smith EL, Schuchman EH The unexpected role of acid sphingomyelinase in cell death and ...2008) PMID:17632693 Schuchman EH The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-P...cta 1484:129-41 (2000) PMID:19944693 Schuchman EH Acid sphingomyelinase, cell membranes and human disease: Lessons from Niemann-Pick disease. FEBS Lett (2009) ...

  15. Crystal structure of mammalian acid sphingomyelinase.

    Science.gov (United States)

    Gorelik, Alexei; Illes, Katalin; Heinz, Leonhard X; Superti-Furga, Giulio; Nagar, Bhushan

    2016-01-01

    Acid sphingomyelinase (ASMase, ASM, SMPD1) converts sphingomyelin into ceramide, modulating membrane properties and signal transduction. Inactivating mutations in ASMase cause Niemann-Pick disease, and its inhibition is also beneficial in models of depression and cancer. To gain a better understanding of this critical therapeutic target, we determined crystal structures of mammalian ASMase in various conformations. The catalytic domain adopts a calcineurin-like fold with two zinc ions and a hydrophobic track leading to the active site. Strikingly, the membrane interacting saposin domain assumes either a closed globular conformation independent from the catalytic domain, or an open conformation, which establishes an interface with the catalytic domain essential for activity. Structural mapping of Niemann-Pick mutations reveals that most of them likely destabilize the protein's fold. This study sheds light on the molecular mechanism of ASMase function, and provides a platform for the rational development of ASMase inhibitors and therapeutic use of recombinant ASMase. PMID:27435900

  16. Identification of the feature that causes the I-band secondary maximum of a type Ia supernova

    CERN Document Server

    Jack, D; Hauschildt, P H

    2015-01-01

    We obtained a time series of spectra covering the secondary maximum in the I-band of the bright Type Ia supernova 2014J in M82 with the TIGRE telescope. Comparing the observations with theoretical models calculated with the time dependent extension of the PHOENIX code, we identify the feature that causes the secondary maximum in the I-band light curve. Fe II 3d6(3D)4s-3d6(5D)4p and similar high excitation transitions produce a blended feature at 7500 {\\AA}, which causes the rise of the light curve towards the secondary maximum. The series of observed spectra of SN 2014J and archival data of SN 2011fe confirm this conclusion. We further studied the plateau phase of the Rband light curve of SN 2014J and searched for features which contribute to the flux. The theoretical models do not clearly indicate a new feature that may cause the Rband plateau phase. However, Co II features in the range of 6500 - 7000 {\\AA} and the Fe II feature of the I-band are clearly seen in the theoretical spectra, but do not appear to ...

  17. Identification of the feature that causes the I-band secondary maximum of a Type Ia supernova

    Science.gov (United States)

    Jack, D.; Baron, E.; Hauschildt, P. H.

    2015-06-01

    We obtained a time series of spectra covering the secondary maximum in the I band of the bright Type Ia supernova 2014J in M82 with the TIGRE telescope. Comparing the observations with theoretical models calculated with the time dependent extension of the PHOENIX code, we identify the feature that causes the secondary maximum in the I-band light curve. Fe II 3d6(3D)4s-3d6(5D)4p and similar high-excitation transitions produce a blended feature at ˜7500 Å, which causes the rise of the light curve towards the secondary maximum. The series of observed spectra of SN 2014J and archival data of SN 2011fe confirm this conclusion. We further studied the plateau phase of the R-band light curve of SN 2014J and searched for features which contribute to the flux. The theoretical models do not clearly indicate a new feature that may cause the R-band plateau phase. However, Co II features in the range of 6500-7000 Å and the Fe II feature of the I band are clearly seen in the theoretical spectra, but do not appear to provide all of the flux necessary for the R-band plateau.

  18. Role of cholesterol and lipid organization in disease

    Science.gov (United States)

    Maxfield, Frederick R.; Tabas, Ira

    2005-12-01

    Membrane lipids are essential for biological functions ranging from membrane trafficking to signal transduction. The composition of lipid membranes influences their organization and properties, so it is not surprising that disorders in lipid metabolism and transport have a role in human disease. Significant recent progress has enhanced our understanding of the molecular and cellular basis of lipid-associated disorders such as Tangier disease, Niemann-Pick disease type C and atherosclerosis. These insights have also led to improved understanding of normal physiology.

  19. Improved sensitivity of an acid sphingomyelinase activity assay using a C6:0 sphingomyelin substrate.

    Science.gov (United States)

    Chuang, Wei-Lien; Pacheco, Joshua; Cooper, Samantha; Kingsbury, Jonathan S; Hinds, John; Wolf, Pavlina; Oliva, Petra; Keutzer, Joan; Cox, Gerald F; Zhang, Kate

    2015-06-01

    Short-chain C6-sphingomyelin is an artificial substrate that was used in an acid sphingomyelinase activity assay for a pilot screening study of patients with Niemann-Pick disease types A and B. Using previously published multiplex and single assay conditions, normal acid sphingomyelinase activity levels (i.e. false negative results) were observed in two sisters with Niemann-Pick B who were compound heterozygotes for two missense mutations, p.C92W and p.P184L, in the SMPD1 gene. Increasing the sodium taurocholate detergent concentration in the assay buffer lowered the activity levels of these two patients into the range observed with other patients with clear separation from normal controls. PMID:26937397

  20. Characterization of two second-site mutations preventing wild type protein aggregation caused by a dominant negative PMA1 mutant.

    Directory of Open Access Journals (Sweden)

    Pilar Eraso

    Full Text Available The correct biogenesis and localization of Pma1 at the plasma membrane is essential for yeast growth. A subset of PMA1 mutations behave as dominant negative because they produce aberrantly folded proteins that form protein aggregates, which in turn provoke the aggregation of the wild type protein. One approach to understand this dominant negative effect is to identify second-site mutations able to suppress the dominant lethal phenotype caused by those mutant alleles. We isolated and characterized two intragenic second-site suppressors of the PMA1-D378T dominant negative mutation. We present here the analysis of these new mutations that are located along the amino-terminal half of the protein and include a missense mutation, L151F, and an in-frame 12bp deletion that eliminates four residues from Cys409 to Ala412. The results show that the suppressor mutations disrupt the interaction between the mutant and wild type enzymes, and this enables the wild type Pma1 to reach the plasma membrane.

  1. Podocyte-specific overexpression of wild type or mutant trpc6 in mice is sufficient to cause glomerular disease.

    Directory of Open Access Journals (Sweden)

    Paola Krall

    Full Text Available Mutations in the TRPC6 calcium channel (Transient receptor potential channel 6 gene have been associated with familiar forms of Focal and Segmental Glomerulosclerosis (FSGS affecting children and adults. In addition, acquired glomerular diseases are associated with increased expression levels of TRPC6. However, the exact role of TRPC6 in the pathogenesis of FSGS remains to be elucidated. In this work we describe the generation and phenotypic characterization of three different transgenic mouse lines with podocyte-specific overexpression of the wild type or any of two mutant forms of Trpc6 (P111Q and E896K previously related to FSGS. Consistent with the human phenotype a non-nephrotic range of albuminuria was detectable in almost all transgenic lines. The histological analysis demonstrated that the transgenic mice developed a kidney disease similar to human FSGS. Differences of 2-3 folds in the presence of glomerular lesions were found between the non transgenic and transgenic mice expressing Trpc6 in its wild type or mutant forms specifically in podocytes. Electron microscopy of glomerulus from transgenic mice showed extensive podocyte foot process effacement. We conclude that overexpression of Trpc6 (wild type or mutated in podocytes is sufficient to cause a kidney disease consistent with FSGS. Our results contribute to reinforce the central role of podocytes in the etiology of FSGS. These mice constitute an important new model in which to study future therapies and outcomes of this complex disease.

  2. AFM studies of a new type of radiation defect on mica surfaces caused by highly charged ion impact

    International Nuclear Information System (INIS)

    Radiation induced defects on mica caused by the impact of slow very highly charged ions (SVHCI) have been investigated with an atomic force microscope (AFM). Freshly cleaved surfaces of different types of muscovite were irradiated with SVHCI extracted from the LLNL electron beam ion trap (EBIT) at velocities of ca. 2 keV/amu. Atomic force microscopy of the surface reveals the formation of blisterlike defects associated with single ion impact. The determined defect volume which appears to increase linearly with the incident charge state and exhibits a threshold incident charge state has been determined using the AFM. These results indicate that target atoms are subjected to mutual electrostatic repulsion due to ionization through potential electron emission upon approach of the ion. If the repulsion leads to permanent atomic displacement, surface defects are formed

  3. A human β-III-spectrin spinocerebellar ataxia type 5 mutation causes high-affinity F-actin binding.

    Science.gov (United States)

    Avery, Adam W; Crain, Jonathan; Thomas, David D; Hays, Thomas S

    2016-01-01

    Spinocerebellar ataxia type 5 (SCA5) is a human neurodegenerative disease that stems from mutations in the SPTBN2 gene encoding the protein β-III-spectrin. Here we investigated the molecular consequence of a SCA5 missense mutation that results in a L253P substitution in the actin-binding domain (ABD) of β-III-spectrin. We report that the L253P substitution in the isolated β-III-spectrin ABD causes strikingly high F-actin binding affinity (Kd = 75.5 nM) compared to the weak F-actin binding affinity of the wild-type ABD (Kd = 75.8 μM). The mutation also causes decreased thermal stability (Tm = 44.6 °C vs 59.5 °C). Structural analyses indicate that leucine 253 is in a loop at the interface of the tandem calponin homology (CH) domains comprising the ABD. Leucine 253 is predicted to form hydrophobic contacts that bridge the CH domains. The decreased stability of the mutant indicates that these bridging interactions are probably disrupted, suggesting that the high F-actin binding affinity of the mutant is due to opening of the CH domain interface. These results support a fundamental role for leucine 253 in regulating opening of the CH domain interface and binding of the ABD to F-actin. This study indicates that high-affinity actin binding of L253P β-III-spectrin is a likely driver of neurodegeneration. PMID:26883385

  4. Mutations in collagen, type XVII, alpha 1 (COL17A1) cause epithelial recurrent erosion dystrophy (ERED).

    Science.gov (United States)

    Jonsson, Frida; Byström, Berit; Davidson, Alice E; Backman, Ludvig J; Kellgren, Therese G; Tuft, Stephen J; Koskela, Timo; Rydén, Patrik; Sandgren, Ola; Danielson, Patrik; Hardcastle, Alison J; Golovleva, Irina

    2015-04-01

    Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology. PMID:25676728

  5. Mutations in MODY Genes Are not Common Cause of Early-Onset Type 2 Diabetes in Mexican Families

    Directory of Open Access Journals (Sweden)

    Bravo-Ríos LE

    2005-05-01

    Full Text Available CONTEXT: Maturity-onset diabetes of the young (MODY is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset and a primary insulin secretion defect. Certain MODY gene sequence variants may be involved in polygenic forms of type 2 diabetes. OBJECTIVE: We assessed the contribution of MODY genes to the etiology of type 2 early-onset diabetes in 23 Mexican families, including five with apparently autosomal dominant inheritance. PATIENTS: Twenty-three unrelated Mexican families with early-onset type 2 diabetes previously screened for the presence of glucokinase mutations, were studied. DESIGN: We screened MODY genes for sequence variants by PCR-SSCP analysis and automated sequencing. We performed a functional analysis of the HNF-1alpha P379H recombinant protein in vitro in both HeLa and RINm5f beta-cell lines. MAIN OUTCOME MEASURES: MODY gene mutation screening and P379H mutant protein transactivation assay. RESULTS: No mutations were detected in the HNF-4alpha, IPF-1, NEUROD1 or HNF-1beta genes in any of the families studied. A new mutation (P379H of the HNF-1alpha gene was identified in one MODY family. RINm5f and HeLa cell transfection assays revealed decreased transactivation activity of the mutant protein on the human insulin promoter. CONCLUSIONS: All known MODY genes were screened for abnormalities in this cohort of early-onset diabetes families which included 5 MODY pedigrees. We identified a new HNF-1alpha MODY mutation (P379H and demonstrated that it reduces the transactivation potential of the mutant protein on the human insulin promoter. No other mutation was identified in this cohort indicating that abnormalities in MODY genes are generally not a common cause of early-onset diabetes and this includes MODY families in Mexico.

  6. Lysosomal storage of heparan sulfate causes mitochondrial defects, altered autophagy, and neuronal death in the mouse model of mucopolysaccharidosis III type C.

    Science.gov (United States)

    Pshezhetsky, Alexey V

    2016-06-01

    The genetic metabolic disease mucopolysaccharidosis III type C (MPS IIIC, Sanfilippo disease type C) causes progressive neurodegeneration in infants and children, leading to dementia and death before adulthood. MPS IIIC stands out among lysosomal diseases because it is the only one caused by a deficiency not of a hydrolase but of HGSNAT (heparan--glucosaminide N-acetyltransferase), which catalyzes acetylation of glycosaminoglycan heparan sulfate (HS) prior to its hydrolysis. PMID:25998837

  7. Heterophile Antibodies to Bovine and Caprine Proteins Causing False-Positive Human Immunodeficiency Virus Type 1 and Other Enzyme-Linked Immunosorbent Assay Results

    OpenAIRE

    Willman, Joseph H.; Martins, Thomas B; Jaskowski, Troy D; Hill, Harry R.; Litwin, Christine M.

    1999-01-01

    Heterophile antibodies are a well-recognized cause of erroneous results in immunoassays. We describe here a 22-month-old child with heterophile antibodies reactive with bovine serum albumin and caprine proteins causing false-positive results to human immunodeficiency virus type 1 and other infectious serology testing.

  8. Acromesomelic dysplasia, type maroteaux caused by novel loss-of-function mutations of the NPR2 gene: Three case reports.

    Science.gov (United States)

    Wang, Wei; Song, Mi Hyun; Miura, Kohji; Fujiwara, Makoto; Nawa, Nobutoshi; Ohata, Yasuhisa; Kitaoka, Taichi; Kubota, Takuo; Namba, Noriyuki; Jin, Dong Kyu; Kim, Ok Hwa; Ozono, Keiichi; Cho, Tae-Joon

    2016-02-01

    The C-type natriuretic peptide (CNP)-natriuretic peptide receptor 2 (NPR2) signaling pathway plays an important role in chondrocyte development. Homozygous loss-of-function mutations of the NPR2 gene cause acromesomelic dysplasia, type Maroteaux (AMDM). The aim of this study was to identify and characterize NPR2 loss-of-function mutations in patients with AMDM. The NPR2 gene was sequenced in three Korean patients with AMDM and functional analysis of the mutated proteins was performed in vitro. Five novel NPR2 mutations were found in the three patients: two compound heterozygous mutations [c.1231T>C (Tyr411His) and c.2761C>T (Arg921X) in Patient 1 and c.1663A>T (Lys555X) and c.1711-1G>C (M571VfsX12) in Patient 3] and a homozygous mutation [c.2762G>A (Arg921Gln) in Patient 2]. Serum NT-proCNP concentration was significantly increased in each patient compared to control subjects. Cells transfected with the expression vector of each mutant except those found in Patient 3 showed a negligible or a markedly low cGMP response after treatment with CNP. HA-tagged wild-type (wt) and HA-mutant NPR2 were expressed at comparable levels: there were two bands of ∼130 and ∼120 kDa in wt and Arg921Gln, a single ∼120 kDa band in Tyr411His, and a single ∼110 kDa in the nonsense mutant. With respect to subcellular localization, Arg921Gln as well as wt-NPR2 reached the cell surface, whereas Tyr411His and Arg921X mutants did not. The Tyr411His and Arg921X NPR2 proteins were co-localized with an endoplasmic reticulum (ER) marker and failed to traffic from the ER to the Golgi apparatus. These results are consistent with deglycosylation experiments. Tyr411His and Arg921X NPR2 are complete loss-of-function mutations, whereas Arg921Gln behaves as a receptor for CNP with limited function. PMID:26567084

  9. p.L18P: a novel IDUA mutation that causes a distinct attenuated phenotype in mucopolysaccharidosis type I patients.

    Science.gov (United States)

    Pasqualim, G; Ribeiro, M G; da Fonseca, G G G; Szlago, M; Schenone, A; Lemes, A; Rojas, M V M; Matte, U; Giugliani, R

    2015-10-01

    Mucopolysaccharidosis type I is a rare autosomal recessive disorder caused by deficiency of α-l-iduronidase (IDUA) which leads to a wide spectrum of clinical severity. Here, we describe the case of four male patients who present the previously undescribed p.L18P mutation. Patient 1 (p.L18P/p.L18P) presents, despite multiple joint contractures, an attenuated phenotype. Patient 2 (p.L18P/p.W402X) was diagnosed at 4 years of age with bone dysplasia, coarse facies, limited mobility, claw hands and underwent bilateral carpal tunnel surgery at 6 years of age. Patients 3 and 4 (both p.L18P/p.L18P) are brothers. Patient 3 was diagnosed at 4 years of age, when presented claw hands, lower limb and shoulder pain, restricted articular movement and bilateral carpal tunnel syndrome. Patient 4 was diagnosed at 17 months of age when presented lower limb pain at night, respiratory allergy and repeated upper airways infections. Bioinformatics analysis indicates that p.L18P mutation reduces the signal peptide to 25 amino acids and alters its secondary structure. In conclusion, we report a new IDUA variant that alters the structure of the signal peptide, which likely impairs transport to lysosomes. Moreover, it leads to a distinct attenuated phenotype with mainly bone and cartilage symptoms, without visceromegalies, heart disease, or cognitive impairment. PMID:25256405

  10. Causes of Diabetes

    Science.gov (United States)

    ... Help for Diabetes Care Diabetes Statistics Causes of Diabetes What is diabetes? Diabetes is a complex group of diseases with ... and type 2 diabetes. What causes type 1 diabetes? Type 1 diabetes is caused by a lack ...

  11. Inherent ER stress in pancreatic islet β cells causes self-recognition by autoreactive T cells in type 1 diabetes.

    Science.gov (United States)

    Marré, Meghan L; Profozich, Jennifer L; Coneybeer, Jorge T; Geng, Xuehui; Bertera, Suzanne; Ford, Michael J; Trucco, Massimo; Piganelli, Jon D

    2016-08-01

    Type 1 diabetes (T1D) is an autoimmune disease characterized by pancreatic β cell destruction induced by islet reactive T cells that have escaped central tolerance. Many physiological and environmental triggers associated with T1D result in β cell endoplasmic reticulum (ER) stress and dysfunction, increasing the potential for abnormal post-translational modification (PTM) of proteins. We hypothesized that β cell ER stress induced by environmental and physiological conditions generates abnormally-modified proteins for the T1D autoimmune response. To test this hypothesis we exposed the murine CD4(+) diabetogenic BDC2.5 T cell clone to murine islets in which ER stress had been induced chemically (Thapsigargin). The BDC2.5 T cell IFNγ response to these cells was significantly increased compared to non-treated islets. This β cell ER stress increased activity of the calcium (Ca(2+))-dependent PTM enzyme tissue transglutaminase 2 (Tgase2), which was necessary for full stress-dependent immunogenicity. Indeed, BDC2.5 T cells responded more strongly to their antigen after its modification by Tgase2. Finally, exposure of non-antigenic murine insulinomas to chemical ER stress in vitro or physiological ER stress in vivo caused increased ER stress and Tgase2 activity, culminating in higher BDC2.5 responses. Thus, β cell ER stress induced by chemical and physiological triggers leads to β cell immunogenicity through Ca(2+)-dependent PTM. These findings elucidate a mechanism of how β cell proteins are modified and become immunogenic, and reveal a novel opportunity for preventing β cell recognition by autoreactive T cells. PMID:27173406

  12. Activities of different types of Thai honey on pathogenic bacteria causing skin diseases, tyrosinase enzyme and generating free radicals

    Directory of Open Access Journals (Sweden)

    Kanyaluck Jantakee

    2015-01-01

    Full Text Available BACKGROUND: Honey is a natural product obtained from the nectar that is collected from flowers by bees. It has several properties, including those of being food and supplementary diet, and it can be used in cosmetic products. Honey imparts pharmaceutical properties since it has antibacterial and antioxidant activities. The antibacterial and antioxidant activities of Thai honey were investigated in this study. RESULTS: The honey from longan flower (source No. 1 gave the highest activity on MRSA when compared to the other types of honey, with a minimum inhibitory concentration of 12.5% (v/v and minimum bactericidal concentration of 25% (v/v. Moreover, it was found that MRSA isolate 49 and S. aureus were completely inhibited by the 50% (v/v longan honey (source No. 1 at 8 and 20 hours of treatment, respectively. Furthermore, it was observed that the honey from coffee pollen (source No. 4 showed the highest phenolic and flavonoid compounds by 734.76 mg gallic/kg of honey and 178.31 mg quercetin/kg of honey, respectively. The antioxidant activity of the honey obtained from coffee pollen was also found to be the highest, when investigated using FRAP and DPPH assay, with 1781.77 mg FeSO4•7H2O/kg of honey and 86.20 mg gallic/kg of honey, respectively. Additionally, inhibition of tyrosinase enzyme was found that honey from coffee flower showed highest inhibition by 63.46%. CONCLUSIONS: Honey demonstrates tremendous potential as a useful source that provides anti-free radicals, anti-tyrosinase and anti-bacterial activity against pathogenic bacteria causing skin diseases.

  13. A Study on Causes and Types of Abnormal Increase in Infants’ Head Circumference in Kashan/Iran

    Directory of Open Access Journals (Sweden)

    Ahmad TALEBIAN

    2013-08-01

    Full Text Available How to Cite This Article: Talebian A, Soltani B, Moravveji AR, Salamati L, Davami M. A Study on Causes and Types of Abnormal Increase in infants’ Head Circumference in Kashan/Iran. Iran J Child Neurol. 2013 Summer; 7(3: 28- 33. ObjectiveHead circumference is a valuable index of brain growth and its disturbances can indicate different disorders of nervous system. Abnormal increased head circumference (macrocephaly is common and observed in about 2% of infants. In this study, the causes and clinical types of abnormal increase in infants’ head circumference were investigated in Kashan, Iran.Materials & MethodsThis cross-sectional study was performed on 90 infants less than 2 years of age with abnormal increase in head circumference in Kashan, during 2009- 2011. The data were collected by history taking, physical examination, growth chart, and imaging.Results65 (72% cases out of 90 infants were male and 25 ( 28% cases were female. Fifty-three (58.8% cases had familial megalencephaly, 30 (33.4% had hydrocephalus, and other causes were observed in 7 (7.8% cases. Eighty-three percent of Infants with familial megalencephaly and 50% with hydrocephalus had normal fontanels. In 90.6% of cases withfamilial megalencephaly, family history for large head was positive. Motor development was normal in 100% of cases with familial megalencephaly and 76.7% of hydrocephalic infants.Conclusion Familial megalencephaly was the most common cause of macrocephaly in the studied infants, and most of them had normal physical examination and development, so, parental head circumferences should be considered in the interpretation of infant’s head circumference and in cases of abnormal physical examination or development, other diagnostic modalities, including brain imaging should be done. References1. Lunde A, Melve KK, Gjessing HK, Skjaerven R, Irgens LM. Genetic and environmental influences on birth weight, Birth length, Head circumference, and gestational age by

  14. Higher plasma soluble Receptor for Advanced Glycation End Products (sRAGE) levels are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes

    DEFF Research Database (Denmark)

    Nin, Johanna W M; Jorsal, Anders; Ferreira, Isabel;

    2010-01-01

    To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunct......To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal...

  15. Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2

    DEFF Research Database (Denmark)

    Vinther-Jensen, Tua; Ek, Jakob; Duno, Morten;

    2013-01-01

    The spinocerebellar ataxias (SCA) are a genetically and clinically heterogeneous group of diseases, characterized by dominant inheritance, progressive cerebellar ataxia and diverse extracerebellar symptoms. A subgroup of the ataxias is caused by unstable CAG-repeat expansions in their respective...

  16. Simultaneous bilateral Mason type IIb radial head fractures in a young female: Was an increased carrying angle the cause?

    LENUS (Irish Health Repository)

    2015-01-01

    Radial head fracture is the most common type of elbow fracture in adults. It results from a fall on an outstretched hand. However, simultaneous bilateral radial head fractures are extremely rare. We report a case of simultaneous bilateral mason type IIb radial head fractures in a young female, which was treated nonoperatively with excellent results

  17. Brd2 gene disruption causes ‘metabolically healthy’ obesity: Epigenetic and chromatin-based mechanisms that uncouple obesity from Type 2 diabetes

    OpenAIRE

    Wang, Fangnian; Deeney, Jude T.; Denis, Gerald V.

    2013-01-01

    Disturbed body energy balance can lead to obesity and obesity-driven diseases such as Type 2 diabetes, which have reached an epidemic level. Evidence indicates that obesity induced inflammation is a major cause of insulin resistance and Type 2 diabetes. Environmental factors, such as nutrients, affect body energy balance through epigenetic or chromatin-based mechanisms. As a bromodomain and external domain family transcription regulator, Brd2 regulates expression of many genes through interpr...

  18. Alteraciones en la homeostasis de calcio y estrés oxidativo en neuronas deficientes en la esfingomielinasa ácida. Implicaciones en la enfermedad de Niemann Pick de tipo A

    OpenAIRE

    Pérez Cañamás, Azucena

    2015-01-01

    Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 15-06-2015 La esfigomielina (SM) es el esfingolópido más abundante que está especialmente enriquecido en las membranas de las neuronas. Su importancia en la fisiología neuronal se pone de manifiesto en las graves alteraciones neurológicas que caracterizan enfermedades donde los niveles de este lípido están alterados. Este es el caso de l...

  19. Epidemiology and transmission characteristics of human adenovirus type 7 caused acute respiratory disease outbreak in military trainees in East China

    OpenAIRE

    Cheng, Jun; Qi, Xiaoping; Chen, Dawei; Xu, Xujian; Wang, Guozheng; Dai, Yuzhu; Cui, Dawei; Chen, Qingyong; Fan, Ping; Ni, Liuda; Liu, Miao; Zhu, Feiyan; Yang, Mei; Wang, Changjun; Li, Yuexi

    2016-01-01

    Background: Human adenovirus type 7 (HAdV7) is globally attracting great concern as its high morbidity and severity in respiratory diseases, especially in Asia. Objective: To investigate the clinical and epidemiologic characteristics of HAdV7 infection outbreak in East China. Methods: The clinical samples were collected from the patients of an ARD outbreak in East Chinafor the detection of causative pathogens by multiplex PCR. The molecular type of human adenovirus isolates were identified by...

  20. Draft Genome Sequence for ICMP 5702, the Type Strain of Pectobacterium carotovorum subsp. carotovorum That Causes Soft Rot Disease on Potato

    OpenAIRE

    Panda, Preetinanda; Lu, Ashley; Armstrong, Karen F.; Pitman, Andrew R.

    2015-01-01

    Pectobacterium species are economically important bacteria that cause soft rotting of potato tubers in the field and in storage. Here, we report the draft genome sequence of the type strain for P. carotovorum subsp. carotovorum, ICMP 5702 (ATCC 15713). The genome sequence of ICMP 5702 will provide an important reference for future phylogenomic and taxonomic studies of the phytopathogenic Enterobacteriaceae.

  1. Draft Genome Sequence for ICMP 5702, the Type Strain of Pectobacterium carotovorum subsp. carotovorum That Causes Soft Rot Disease on Potato.

    Science.gov (United States)

    Panda, Preetinanda; Lu, Ashley; Armstrong, Karen F; Pitman, Andrew R

    2015-01-01

    Pectobacterium species are economically important bacteria that cause soft rotting of potato tubers in the field and in storage. Here, we report the draft genome sequence of the type strain for P. carotovorum subsp. carotovorum, ICMP 5702 (ATCC 15713). The genome sequence of ICMP 5702 will provide an important reference for future phylogenomic and taxonomic studies of the phytopathogenic Enterobacteriaceae. PMID:26251498

  2. What Causes Raynaud's?

    Science.gov (United States)

    ... this page from the NHLBI on Twitter. What Causes Raynaud's? There are two main types of Raynaud’s— ... type of Raynaud's is often called Raynaud's phenomenon. Causes of Secondary Raynaud's Many things can cause secondary ...

  3. What Causes Hemochromatosis?

    Science.gov (United States)

    ... this page from the NHLBI on Twitter. What Causes Hemochromatosis? The two types of hemochromatosis are primary and secondary. Each type has a different cause. Primary Hemochromatosis Primary hemochromatosis is caused by a ...

  4. Common variation in oxidative phosphorylation genes is not a major cause of insulin resistance or type 2 diabetes

    DEFF Research Database (Denmark)

    Snogdal, L S; Wod, M; Grarup, N;

    2012-01-01

    AIMS/HYPOTHESIS: There is substantial evidence that mitochondrial dysfunction is linked to insulin resistance and is present in several tissues relevant to the pathogenesis of type 2 diabetes. Here, we examined whether common variation in genes involved in oxidative phosphorylation (Ox......Phos) contributes to type 2 diabetes susceptibility or influences diabetes-related metabolic traits. METHODS: OxPhos gene variants (n = 10) that had been nominally associated (p < 0.01) with type 2 diabetes in a recent genome-wide meta-analysis (n = 10,108) were selected for follow-up in 3,599 type 2 diabetic and 4......,956 glucose-tolerant Danish individuals. A meta-analysis of these variants was performed in 11,729 type 2 diabetic patients and 43,943 non-diabetic individuals. The impact on OGTT-derived metabolic traits was evaluated in 5,869 treatment-naive individuals from the Danish Inter99 study. RESULTS: The minor...

  5. Contributions of NanI sialidase to Caco-2 cell adherence by Clostridium perfringens type A and C strains causing human intestinal disease.

    Science.gov (United States)

    Li, Jihong; McClane, Bruce A

    2014-11-01

    Previous studies showed that Clostridium perfringens type D animal disease strain CN3718 uses NanI sialidase for adhering to enterocyte-like Caco-2 cells. The current study analyzed whether NanI is similarly important when type A and C human intestinal disease strains attach to Caco-2 cells. A PCR survey determined that the nanI gene was absent from typical type A food poisoning (FP) strains carrying a chromosomal enterotoxin (CPE) gene or the genetically related type C Darmbrand (Db) strains. However, the nanI gene was present in type A strains from healthy humans, type A strains causing CPE-associated antibiotic-associated diarrhea (AAD) or sporadic diarrhea (SD), and type C Pig-Bel strains. Consistent with NanI sialidase being the major C. perfringens sialidase when produced, FP and Db strains had little supernatant sialidase activity compared to other type A or C human intestinal strains. All type A and C human intestinal strains bound to Caco-2 cells, but NanI-producing strains had higher attachment levels. When produced, NanI can contribute to host cell attachment of human intestinal disease strains, since a nanI null mutant constructed in type A SD strain F4969 had lower Caco-2 cell adhesion than wild-type F4969 or a complemented strain. Further supporting a role for NanI in host cell attachment, sialidase inhibitors reduced F4969 adhesion to Caco-2 cells. Collectively, these results suggest that NanI may contribute to the intestinal attachment and colonization needed for the chronic diarrhea of CPE-associated AAD and SD, but this sialidase appears to be dispensable for the acute pathogenesis of type A FP or type C enteritis necroticans. PMID:25135687

  6. Interventional and surgical treatment of a hemothorax caused by a ruptured vertebral artery in a patient with neurofibromatosis type I

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ji Hoon; Kim, Dong Hun; Kim, Dong Hyun; Seo, Hong Joo [Chosun University College of Medicine, Gwangju (Korea, Republic of)

    2014-04-15

    We report a case of a massive hemothorax arising from a ruptured vertebral artery aneurysm in a patient with neurofibromatosis type 1 suffering from sudden onset of dyspnea. The vertebral artery aneurysm was treated with endovascular coil embolization. Then, an open thoracotomy was performed to evacuate the hematoma.

  7. SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants.

    Science.gov (United States)

    Zampieri, Stefania; Filocamo, Mirella; Pianta, Annalisa; Lualdi, Susanna; Gort, Laura; Coll, Maria Jose; Sinnott, Richard; Geberhiwot, Tarekegn; Bembi, Bruno; Dardis, Andrea

    2016-02-01

    Niemann-Pick Types A and B (NPA/B) diseases are autosomal recessive lysosomal storage disorders caused by the deficient activity of acid sphingomyelinase (ASM) because of the mutations in the SMPD1 gene. Here, we provide a comprehensive updated review of already reported and newly identified SMPD1 variants. Among them, 185 have been found in NPA/B patients. Disease-causing variants are equally distributed along the SMPD1 gene; most of them are missense (65.4%) or frameshift (19%) mutations. The most frequently reported mutation worldwide is the p.R610del, clearly associated with an attenuated NP disease type B phenotype. The available information about the impact of 52 SMPD1 variants on ASM mRNA and/or enzymatic activity has been collected and whenever possible, phenotype/genotype correlations were established. In addition, we created a locus-specific database easily accessible at http://www.inpdr.org/genes that catalogs the 417 SMPD1 variants reported to date and provides data on their in silico predicted effects on ASM protein function or mRNA splicing. The information reviewed in this article, providing new insights into the genotype/phenotype correlation, is extremely valuable to facilitate diagnosis and genetic counseling of families affected by NPA/B. PMID:26499107

  8. Taking the next step forward - Diagnosing inherited infantile cholestatic disorders with next generation sequencing.

    Science.gov (United States)

    Herbst, S M; Schirmer, S; Posovszky, C; Jochum, F; Rödl, T; Schroeder, J A; Barth, T F; Hehr, U; Melter, M; Vermehren, J

    2015-10-01

    Identifying rare genetic forms of infantile cholestasis is challenging due to their similar clinical presentation and their diverse etiology. After exclusion of common non-genetic causes a huge list of rare differential diagnosis remains to be solved. More than 90 genes are associated with monogenic forms of infantile cholestasis, thus preventing routine genetic workup by Sanger sequencing. Here we demonstrate a next generation sequencing approach to discover the underlying cause in clinically well characterized patients in whom common causes of infantile cholestasis have been excluded. After validation of the analytical sensitivity massive parallel sequencing was performed for 93 genes in six prospectively studied patients. Six novel mutations (PKHD1: p.Thr777Met, p.Tyr2260Cys; ABCB11: p.Val1112Phe, c.611+1G > A, p.Gly628Trpfs*3 and NPC1: p.Glu391Lys) and two known pathogenic mutations were detected proving our multi gene panel for infantile cholestasis to be a sensitive and specific method overcoming the complexity of the phenotype-based, candidate gene approach. Three exemplary clinical cases of infants with cholestasis are presented and discussed in the context of their genetic and histopathological findings (autosomal recessive polycystic kidney disease, atypical PFIC and Niemann-Pick syndrome type C1). These case reports highlight the critical impact of integrating clinical, histopathological and genetic data during the process of multi gene panel testing to ultimately pinpoint rare genetic diagnoses. PMID:25771912

  9. NOVEL SPLICING MUTATION OF COL1A1 GENE CAUSING OSTEOGENESIS IMPERFECTA TYPE I IN CHINESE PEDIGREE

    Institute of Scientific and Technical Information of China (English)

    WU Xiao-lin; GU Ming-min; CUI Bing; LI Xi-hua; LU Zhen-yu; WANG Zhu-gang; YUAN Wen-tao; SONG Huai-dong

    2007-01-01

    Objective To detect the peculiar mutation in a Chinese family with osteogenesis imperfecta,COL1A1 and COL1A2 being analysed. Methods A genome screen was undertaken covering COL1A1 at 17q21-22 and COL1A2 at 7q22.1. The Linkage ( Version 5.1 ) was used for 2-point analysis. DNA sequencing was used to screen and identify the mutation. Results A linkage to the markers on chromosome 17q21-22 was observed. Sequence analysis of COL1A1 revealed a splicing mutation ( IVS8-2A > G) that converted the 3' end of intron 8 from AG to GG. Conclusion This mutation ( IVS 8-2A > G) is novel, and has not yet been registered in the Human Type Ⅰ and Type Ⅲ Collagen Mutations Database.

  10. Analysis of Escherichia coli Strains Causing Bacteriuria during Pregnancy: Selection for Strains That Do Not Express Type 1 Fimbriae

    OpenAIRE

    Graham, J. C.; Leathart, J. B. S.; Keegan, S. J.; Pearson, J.; Bint, A; Gally, D.L.

    2001-01-01

    Escherichia coli isolates from patients with bacteriuria of pregnancy were compared by PCR with isolates from patients with community-acquired cystitis for the presence of established virulence determinants. The strains from patients with bacteriuria of pregnancy were less likely to carry genes for P-family, S-family, and F1C adhesins, cytotoxic necrotizing factor 1, and aerobactin, but virtually all of the strains carried the genes for type 1 fimbriae. Standard mannose-sensitive agglutinatio...

  11. Hemichorea Hemiballism Syndrome: The First Presentation of Type 2 Diabetes Mellitus as a Rare Cause of Chorea

    Directory of Open Access Journals (Sweden)

    P. Mittal

    2011-06-01

    Full Text Available Hemichorea-hemiballism (HCHB syndrome, which is most commonly related to non-ketotic"nhyperglycemia, is a rare type of chorea. Here, we present an unusual case of HCHB syndrome who"nwas not a known case of diabetes. This case highlights the importance of recognising underlying"nnon-ketotic hyperglycemia, as control of hyperglycemia is helpful in the quick relief of symptoms.

  12. Hemi chorea hemiballism syndrome: the first presentation of type 2 diabetes mellitus as a rare cause of chorea

    International Nuclear Information System (INIS)

    Hemi chorea-hemiballism syndrome, which is most commonly related to non-ketotic hyperglycemia, is a rare type of chorea. Here, we present an unusual case of Hemi chorea-hemiballism syndrome who was not a known case of diabetes. This case highlights the importance of recognising underlying non-ketotic hyperglycemia, as control of hyperglycemia is helpful in the quick relief of symptoms.

  13. Long term low dose rate irradiation causes recovery from type II diabetes and suppression of aging in type II diabetes-prone mice

    International Nuclear Information System (INIS)

    The effects of low dose rate gamma irradiation on model C57BL/KsJ-db/db mice with Type II diabetes mellitus was investigated. These mice develop Type II diabetes by 10 weeks of age, due to obesity, and are characterized by hyperinsulinemia. A group of 12 female 10-week old mice were irradiated at 0.65 mGy/hr in the low dose rate irradiation facility in the Low Dose Radiation Research Center. The urine glucose levels of all of the mice were strongly positive at the beginning of the irradiation. In the irradiated group, a decrease in the glucose level was observed in three mice, one in the 35th week, another in the 52nd week and the third in the 80th week. No recovery from the diabetes was observed in the 12 mice of non-irradiated control group. There was no systematic change of body weight or consumption of food and drinking water between the irradiated group and the non-irradiated group or between the recovered mice and the non-recovered mice. Survival was better in the irradiated group. The surviving fraction at the age of 90 weeks was 75 % in the irradiated group but only 40 % in the non-irradiated. A marked difference was also observed in the appearance of the coat hair, skin and tail. The irradiated group was in much better condition. Mortality was delayed and the healthy appearance was prolonged in the irradiated mice by about 20-30 weeks compared with the control mice. These results suggest that the low dose irradiation modified the condition of the diabetic mice, leading not only to recovery from diabetes, but also to suppression of the aging process

  14. Computation of a Single-phase Shell-Type Transformer Windings Forces Caused by Inrush and Short-circuit Currents

    Directory of Open Access Journals (Sweden)

    M. B.B. Sharifian

    2008-01-01

    Full Text Available This research studies the forces on the windings of transformer due to inrush current. These forces are compared with the corresponding forces due to short-circuit of the windings. Two-dimensional finite element computation of a single-phase shell-type transformer is carried out based on the maximum permissible inrush current value where its amplitude is the same as the rated short-circuit current. To verify the computation results, they are compared with those recently obtained using Artificial Neural Network (ANN.

  15. Microstructural changes caused by yttrium addition to NbTi-modified centrifugally cast HP-type stainless steels

    International Nuclear Information System (INIS)

    Centrifugally cast heat-resistant HP stainless steels are particularly suitable for applications where service conditions comprise high temperatures and aggressive environments; thus, they are extensively used in reformer furnaces, in which hydrogen production takes place. The demand for better performance has motivated developments in these steels. The addition of Nb and Ti as microstructural modifiers has proved successful in providing a more stable microstructure. In this work yttrium was added to centrifugally cast NbTi-modified HP steels. It was observed that its presence increased the level of fragmentation of the chromium carbides, a positive aspect for creep resistance. The main cause of the fragmentation is the formation of yttrium carbides, which serve as heterogeneous nucleation sites for the other carbides. One of the tubes, with a lower titanium content, showed the best creep performance among those tubes studied owing to the presence of a smaller volume fraction of the deleterious G phase

  16. Acid sphingomyelinase (aSMase) deficiency leads to abnormal microglia behavior and disturbed retinal function

    International Nuclear Information System (INIS)

    Mutations in the acid sphingomyelinase (aSMase) coding gene sphingomyelin phosphodiesterase 1 (SMPD1) cause Niemann-Pick disease (NPD) type A and B. Sphingomyelin storage in cells of the mononuclear phagocyte system cause hepatosplenomegaly and severe neurodegeneration in the brain of NPD patients. However, the effects of aSMase deficiency on retinal structure and microglial behavior have not been addressed in detail yet. Here, we demonstrate that retinas of aSMase−/− mice did not display overt neuronal degeneration but showed significantly reduced scotopic and photopic responses in electroretinography. In vivo fundus imaging of aSMase−/− mice showed many hyperreflective spots and staining for the retinal microglia marker Iba1 revealed massive proliferation of retinal microglia that had significantly enlarged somata. Nile red staining detected prominent phospholipid inclusions in microglia and lipid analysis showed significantly increased sphingomyelin levels in retinas of aSMase−/− mice. In conclusion, the aSMase-deficient mouse is the first example in which microglial lipid inclusions are directly related to a loss of retinal function. - Highlights: • aSMase-deficient mice show impaired retinal function and reactive microgliosis. • aSMase-deficient microglia express pro-inflammatory transcripts. • aSMase-deficient microglia proliferate and have increased cell body size. • In vivo imaging shows hyperreflective spots in the fundus of aSMase-deficient mice. • aSMase-deficient microglia accumulate sphingolipid-rich intracellular deposits

  17. Accumulation of cardiolipin and lysocardiolipin in fibroblasts from Tangier disease subjects.

    Science.gov (United States)

    Fobker, M; Voss, R; Reinecke, H; Crone, C; Assmann, G; Walter, M

    2001-07-01

    Tangier disease (TD) is an inherited disorder of lipid metabolism characterized by very low high density lipoprotein (HDL) plasma levels, cellular cholesteryl ester accumulation and reduced cholesterol excretion in response to HDL apolipoproteins. Molecular defects in the ATP binding cassette transporter 1 (ABCA1) have recently been identified as the cause of TD. ABCA1 plays a key role in the translocation of cholesterol across the plasma membrane, and defective ABCA1 causes cholesterol storage in TD cells. Not only cholesterol efflux, but also phospholipid efflux was shown to be impaired in TD cells. By use of thin layer chromatography, high performance liquid chromatography and time-of-flight secondary ion mass spectrometry, we characterized the cellular phospholipid content in fibroblasts from three homozygous TD patients. The cellular content of the major phospholipids was not found to be significantly altered in TD fibroblasts. However, the two phospholipids cardiolipin and lysocardiolipin, which make up minute amounts in normal cells, were at least 3-5-fold enriched in fibroblasts from TD subjects. A structurally closely related phospholipid (lysobisphosphatidic acid) has recently been shown to be enriched in Niemann-Pick type C, another lipid storage disorder. Altogether these data may indicate that the role of these phospholipids is a regulatory one rather than that of a bulk mediator of cholesterol solubilization in sterol trafficking and efflux. PMID:11445077

  18. A PROSPECTIVE STUDY OF PREVALENCE OF VARIOUS CAUSES IN PATIENTS PRESENTING WITH CONDUCTIVE TYPE OF HEARING IMPAIRMENT

    Directory of Open Access Journals (Sweden)

    Naga Manohar

    2014-12-01

    Full Text Available INTRODUCTION: Deafness is the most common presenting complaint in patient presenting to ENT OPD with complaints of ear. Deafness is a potentially morbid condition causing significant problem to the patient in their day-to-day life and livelihood. AIM: This study was undertaken to know the incidence of various diseases presenting as deafness, so that, epidemiological data can be secured and it is helpful to channel the resources and treatment modalities in the right direction. SETTINGS AND DESIGN: The study was carried out in a Teritiary hospital, in Vizianagaram, Andhra Pradesh. It is a prospective study, undertaken to know the prevalence. MATERIALS AND METHODS: Patients presenting to ENT OPD from Sept 2012 to Sept 2014, with a chief complaint of deafness were included in this study. All the Patients were subjected to thorough clinical examination, necessary investigations, viz. pure tone audiometry, Examination under microscopy and wet mopping by way of syringing. RESULTS: Out of the 400 patients included for this study, 272 patients (68% were found to be suffering from Conductive hearing loss; whereas 138 patients (34.5% were found to be suffering from Sensorineural hearing loss. Conductive hearing loss was most common in 20-30 age group in males and 30-40 age group in females; that too middle ear disease were more common than external ear; i.e. 175 patients out of 262 (66.7% had a disease in the middle ear, 87 patients (33.2% had a external ear pathology. External ear disease was earwax or keratosis obturans, (55.1%, the rest contributed by Otomycosis (34.4% and malformed ears (10.3%. Diseases of middle ear were distributed as Acute otitis media (17.7%, Chronic otitis media (28%, Otitis media with effusion (50.2%, Fixation pathology (15.4%, Other causes (5.1%. CONCLUSION: Conductive hearing loss was most common in the middle age groups, between 20-40 yrs of age, females, and more commonly due to a pathology in the middle ear, Otitis media

  19. Characterization of the Zebrafish Homolog of β-Glucosidase 2: A Target of the Drug Miglustat.

    Science.gov (United States)

    Sultana, Saki; Truong, Nhu Y; Vieira, Douglas B; Wigger, Jasper G D; Forrester, A Michael; Veinotte, Chansey J; Berman, Jason N; van der Spoel, Aarnoud C

    2016-06-01

    The small-molecular compound miglustat (N-butyldeoxynojirimycin, Zavesca(®)) has been approved for clinical use in type 1 Gaucher disease and Niemann-Pick type C disease, which are disorders caused by dysfunction of the endosomal-autophagic-lysosomal system. Miglustat inhibits a number of enzymes involved in glycoconjugate and glycan metabolism, including β-glucosidase 2 (GBA2), which is exceptionally sensitive to inhibition by miglustat. GBA2 is a glucosylceramide-degrading enzyme that is located on the plasma membrane/endoplasmic reticulum, and is distinct from the lysosomal enzyme glucocerebrosidase (GBA). Various strands of evidence suggest that inhibition of GBA2 contributes to the therapeutic benefits of miglustat. To further explore the pharmacology and biology of GBA2, we investigated whether the zebrafish homolog of GBA2 has similar enzymatic properties and pharmacological sensitivities to its human counterpart. We established that zebrafish has endogenous β-glucosidase activity toward lipid- and water-soluble GBA2 substrates, which can be inhibited by miglustat, N-butyldeoxygalactonojirimycin, and conduritol B epoxide. β-Glucosidase activities with highly similar characteristics were expressed in cells transfected with the zebrafish gba2 cDNA and in cells transfected with the human GBA2 cDNA. These results provide a foundation for the use of zebrafish in screening GBA2-targeting molecules, and for wider studies investigating GBA2 biology. PMID:26909767

  20. Multidisciplinary Pharmacotherapeutic Options for Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Kei Nakajima

    2012-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD and non-alcoholic steatohepatitis (NASH are multidisciplinary liver diseases that often accompany type 2 diabetes or metabolic syndrome, which are characterized by insulin resistance. Therefore, effective treatment of type 2 diabetes and metabolic syndrome should target not only the cardiometabolic abnormalities, but also the associated liver disorders. In the last decade, it has been shown that metformin, thiazolidinediones, vitamin E, ezetimibe, n-3 polyunsaturated fatty acids, renin-angiotensin system (RAS blockers, and antiobesity drugs may improve hepatic pathophysiological disorders as well as clinical parameters. Accordingly, insulin sensitizers, antioxidative agents, Niemann-Pick C1-like 1 (NPC1L1 inhibitors, RAS blockers, and drugs that target the central nervous system may represent candidate pharmacotherapies for NAFLD and possibly NASH. However, the efficacy, safety, and tolerability of long-term treatment (potentially for many years with these drugs have not been fully established. Furthermore, clinical trials have not comprehensively examined the efficacy of lipid-lowering drugs (i.e., statins, fibrates, and NPC1L1 inhibitors for the treatment of NAFLD. Although clinical evidence for RAS blockers and incretin-based agents (GLP-1 analogs and dipeptidyl peptidase-4 inhibitors is also lacking, these agents are promising in terms of their insulin-sensitizing and anti-inflammatory effects without causing weight gain.

  1. Lysobisphosphatidic acid controls endosomal cholesterol levels.

    Science.gov (United States)

    Chevallier, Julien; Chamoun, Zeina; Jiang, Guowei; Prestwich, Glenn; Sakai, Naomi; Matile, Stefan; Parton, Robert G; Gruenberg, Jean

    2008-10-10

    Most cell types acquire cholesterol by endocytosis of circulating low density lipoprotein, but little is known about the mechanisms of intra-endosomal cholesterol transport and about the primary cause of its aberrant accumulation in the cholesterol storage disorder Niemann-Pick type C (NPC). Here we report that lysobisphosphatidic acid (LBPA), an unconventional phospholipid that is only detected in late endosomes, regulates endosomal cholesterol levels under the control of Alix/AlP1, which is an LBPA-interacting protein involved in sorting into multivesicular endosomes. We find that Alix down-expression decreases both LBPA levels and the lumenal vesicle content of late endosomes. Cellular cholesterol levels are also decreased, presumably because the storage capacity of endosomes is affected and thus cholesterol clearance accelerated. Both lumenal membranes and cholesterol can be restored in Alix knockdown cells by exogenously added LBPA. Conversely, we also find that LBPA becomes limiting upon pathological cholesterol accumulation in NPC cells, because the addition of exogenous LBPA, but not of LBPA isoforms or analogues, partially reverts the NPC phenotype. We conclude that LBPA controls the cholesterol capacity of endosomes. PMID:18644787

  2. Deletion of the basement membrane heparan sulfate proteoglycan type XVIII collagen causes hypertriglyceridemia in mice and humans.

    Directory of Open Access Journals (Sweden)

    Joseph R Bishop

    Full Text Available BACKGROUND: Lipoprotein lipase (Lpl acts on triglyceride-rich lipoproteins in the peripheral circulation, liberating free fatty acids for energy metabolism or storage. This essential enzyme is synthesized in parenchymal cells of adipose tissue, heart, and skeletal muscle and migrates to the luminal side of the vascular endothelium where it acts upon circulating lipoproteins. Prior studies suggested that Lpl is immobilized by way of heparan sulfate proteoglycans on the endothelium, but genetically altering endothelial cell heparan sulfate had no effect on Lpl localization or lipolysis. The objective of this study was to determine if extracellular matrix proteoglycans affect Lpl distribution and triglyceride metabolism. METHODS AND FINDINGS: We examined mutant mice defective in collagen XVIII (Col18, a heparan sulfate proteoglycan present in vascular basement membranes. Loss of Col18 reduces plasma levels of Lpl enzyme and activity, which results in mild fasting hypertriglyceridemia and diet-induced hyperchylomicronemia. Humans with Knobloch Syndrome caused by a null mutation in the vascular form of Col18 also present lower than normal plasma Lpl mass and activity and exhibit fasting hypertriglyceridemia. CONCLUSIONS: This is the first report demonstrating that Lpl presentation on the lumenal side of the endothelium depends on a basement membrane proteoglycan and demonstrates a previously unrecognized phenotype in patients lacking Col18.

  3. Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2.

    Science.gov (United States)

    Zazo Seco, Celia; Serrão de Castro, Luciana; van Nierop, Josephine W; Morín, Matías; Jhangiani, Shalini; Verver, Eva J J; Schraders, Margit; Maiwald, Nadine; Wesdorp, Mieke; Venselaar, Hanka; Spruijt, Liesbeth; Oostrik, Jaap; Schoots, Jeroen; van Reeuwijk, Jeroen; Lelieveld, Stefan H; Huygen, Patrick L M; Insenser, María; Admiraal, Ronald J C; Pennings, Ronald J E; Hoefsloot, Lies H; Arias-Vásquez, Alejandro; de Ligt, Joep; Yntema, Helger G; Jansen, Joop H; Muzny, Donna M; Huls, Gerwin; van Rossum, Michelle M; Lupski, James R; Moreno-Pelayo, Miguel Angel; Kunst, Henricus P M; Kremer, Hannie

    2015-11-01

    Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants. PMID:26522471

  4. Structural and floristic changes caused by gamma radiation in understory vegetation of two forest types in northern Wisconsin

    International Nuclear Information System (INIS)

    Structural and floristic changes of the understory vegetation of gamma-irradiated aspen and maple-aspen-birch (MAB) communities in northern Wisconsin were quantified by comparing the pre- and postirradiation floristic composition and vegetational cover. A size-dependent radiosensitivity was determined among three vegetational strata, the tall shrubs being the most sensitive, low shrubs intermediate, and herbs the most resistant. Corylus cornuta, whose nuclear characteristics indicated that it could be resistant, was very sensitive and was completely eliminated at exposures of 500 r/20-hr day or higher. The cover of Rubus strigosus, minimal before irradiation, increased manifold and accounted for most of the shrub cover 2 years after the conclusion of irradiation. Among herbs, Carex pensylvanica and Luzula acuminata were very resistant, and Trillium grandiflorum, Aralia nudicaulis, Oryzopsis asperifolia, and Clintonia borealis were very sensitive. The herbaceous stratum of the aspen type appeared more resistant than that of the MAB. This difference apparently resulted from differences in floristic composition of the two communities

  5. Triiodothyronine causes rapid reversal of alpha 1/cyclic adenosine monophosphate synergism on brown adipocyte respiration and type II deiodinase activity.

    Science.gov (United States)

    Noronha, M; Raasmaja, A; Moolten, N; Larsen, P R

    1991-12-01

    Previous studies have shown that thyroid status affects the response of brown adipose tissue (BAT) to the sympathetic nervous system. For example, hypothyroidism is associated with the development of a marked synergism between alpha 1- and beta-adrenergic pathways to stimulate type II iodothyronine 5'-deiodinase activity. Hypothyroidism also attenuates the respiratory response (thermogenesis) of isolated brown adipocytes to norepinephrine. To explore the interactions of the sympathetic nervous system and thyroid status in these cells, we compared the thermogenic and 5'-deiodinase responses to adrenergic agonists in isolated brown adipocytes from hypothyroid rats during treatment with 3,5,3'-triiodothyronine (T3). The fivefold synergism of alpha 1- and beta-adrenergic catecholamines to increase the deiodinase activity was progressively reduced, reaching a control euthyroid value of unity after 5 days of T3 treatment. Hypothyroidism reduced both the O2max (twofold to threefold) and increased the concentration of agonist required for 50% stimulation (10-fold) for both norepinephrine and forskolin. In hypothyroid cells, there was a twofold synergism between the alpha 1-agonist cirazoline and forskolin to increase respiration, which was blocked by prazosin and reproduced by the calcium ionophore, A23187. This synergistic effect of the alpha 1-agonist was lost within 2 days of T3 administration. These studies identify a second Ca(2+)-dependent intra-adrenergic synergism, which functions to ameliorate the reduced cyclic adenosine monophosphate (cAMP) responsiveness of the hypothyroid brown adipocyte. PMID:1683679

  6. Meningitis caused by Neisseria Meningitidis, Hemophilus Influenzae Type B and Streptococcus Pneumoniae during 2005–2012 in Turkey

    Science.gov (United States)

    Ceyhan, Mehmet; Gürler, Nezahat; Ozsurekci, Yasemin; Keser, Melike; Aycan, Ahmet Emre; Gurbuz, Venhar; Salman, Nuran; Camcioglu, Yildiz; Dinleyici, Ener Cagri; Ozkan, Sengul; Sensoy, Gulnar; Belet, Nursen; Alhan, Emre; Hacimustafaoglu, Mustafa; Celebi, Solmaz; Uzun, Hakan; Faik Oner, Ahmet; Kurugol, Zafer; Ali Tas, Mehmet; Aygun, Denizmen; Oncel, Eda Karadag; Celik, Melda; Yasa, Olcay; Akin, Fatih; Coşkun, Yavuz

    2014-01-01

    Successful vaccination policies for protection from bacterial meningitis are dependent on determination of the etiology of bacterial meningitis. Cerebrospinal fluid (CSF) samples were obtained prospectively from children from 1 month to ≤ 18 years of age hospitalized with suspected meningitis, in order to determine the etiology of meningitis in Turkey. DNA evidence of Neisseria meningitidis (N. meningitidis), Streptococcus pneumoniae (S. pneumoniae), and Hemophilus influenzae type b (Hib) was detected using multiplex polymerase chain reaction (PCR). In total, 1452 CSF samples were evaluated and bacterial etiology was determined in 645 (44.4%) cases between 2005 and 2012; N. meningitidis was detected in 333 (51.6%), S. pneumoniae in 195 (30.2%), and Hib in 117 (18.1%) of the PCR positive samples. Of the 333 N. meningitidis positive samples 127 (38.1%) were identified as serogroup W-135, 87 (26.1%) serogroup B, 28 (8.4%) serogroup A and 3 (0.9%) serogroup Y; 88 (26.4%) were non-groupable. As vaccines against the most frequent bacterial isolates in this study are available and licensed, these results highlight the need for broad based protection against meningococcal disease in Turkey. PMID:25483487

  7. A Population-Based Cohort Study of All-Cause and Site-Specific Cancer Incidence Among Patients With Type 1 Diabetes Mellitus in Taiwan

    Directory of Open Access Journals (Sweden)

    Pei-Chun Hsu

    2015-09-01

    Full Text Available Background: The relationship between type 1 diabetes mellitus (T1DM and cancer incidence remains unclear. We sought to assess the all-cause and site-specific cancer incidence in patients with T1DM. Methods: A retrospective cohort study design was employed, in which 14 619 patients with T1DM were retrieved from Taiwan’s National Health Insurance medical claims between 2000 and 2007. The study subjects were followed to the end of 2008, and cancer incidence was assessed. We calculated age-, sex-, and calendar year-standardized incidence ratios (SIRs of all-cause cancer incidence and site-specific neoplasm incidence, with reference to the general population. Results: Seven hundred and sixty patients were identified for all-cause cancer over 86 610 person-years, representing an incidence rate of 87.75 cases per 10 000 person-years. The incidence rate was higher in males than in female patients (109.86 vs 69.75 cases per 10 000 person-years. T1DM was associated with a significantly increased SIR of all-cause cancer (1.13; 95% confidence interval [CI], 1.05–1.22. The sex-specific SIR was significantly elevated in female patients (1.19; 95% CI, 1.07–1.33, but the SIR for male patients was insignificantly elevated (1.09; 95% CI, 0.99–1.20. Pancreatic cancer showed the greatest increase in SIR among both male and female patients with T1DM. Male patients experienced significantly increased SIRs for kidney, rectum, liver, and colon neoplasm, and significantly increased SIRs were noted for ovarian, bladder, and colon cancer in female patients. Conclusions: T1DM was associated with a 13% increase in risk of all-cause cancer incidence. Patients with T1DM should be advised to undergo cancer screening for certain types of cancer.

  8. Susceptibility of outer hair cells to cholesterol chelator 2-hydroxypropyl-β-cyclodextrine is prestin-dependent.

    Science.gov (United States)

    Takahashi, Satoe; Homma, Kazuaki; Zhou, Yingjie; Nishimura, Shinichi; Duan, Chongwen; Chen, Jessie; Ahmad, Aisha; Cheatham, Mary Ann; Zheng, Jing

    2016-01-01

    Niemann-Pick type C1 disease (NPC1) is a fatal genetic disorder caused by impaired intracellular cholesterol trafficking. Recent studies reported ototoxicity of 2-hydroxypropyl- β-cyclodextrin (HPβCD), a cholesterol chelator and the only promising treatment for NPC1. Because outer hair cells (OHCs) are the only cochlear cells affected by HPβCD, we investigated whether prestin, an OHC-specific motor protein, might be involved. Single, high-dose administration of HPβCD resulted in OHC death in prestin wildtype (WT) mice whereas OHCs were largely spared in prestin knockout (KO) mice in the basal region, implicating prestin's involvement in ototoxicity of HPβCD. We found that prestin can interact with cholesterol in vitro, suggesting that HPβCD-induced ototoxicity may involve disruption of this interaction. Time-lapse analysis revealed that OHCs isolated from WT animals rapidly deteriorated upon HPβCD treatment while those from prestin-KOs tolerated the same regimen. These results suggest that a prestin-dependent mechanism contributes to HPβCD ototoxicity. PMID:26903308

  9. Host sphingomyelin increases West Nile virus infection in vivo.

    Science.gov (United States)

    Martín-Acebes, Miguel A; Gabandé-Rodríguez, Enrique; García-Cabrero, Ana M; Sánchez, Marina P; Ledesma, María Dolores; Sobrino, Francisco; Saiz, Juan-Carlos

    2016-03-01

    Flaviviruses, such as the dengue virus and the West Nile virus (WNV), are arthropod-borne viruses that represent a global health problem. The flavivirus lifecycle is intimately connected to cellular lipids. Among the lipids co-opted by flaviviruses, we have focused on SM, an important component of cellular membranes particularly enriched in the nervous system. After infection with the neurotropic WNV, mice deficient in acid sphingomyelinase (ASM), which accumulate high levels of SM in their tissues, displayed exacerbated infection. In addition, WNV multiplication was enhanced in cells from human patients with Niemann-Pick type A, a disease caused by a deficiency of ASM activity resulting in SM accumulation. Furthermore, the addition of SM to cultured cells also increased WNV infection, whereas treatment with pharmacological inhibitors of SM synthesis reduced WNV infection. Confocal microscopy analyses confirmed the association of SM with viral replication sites within infected cells. Our results unveil that SM metabolism regulates flavivirus infection in vivo and propose SM as a suitable target for antiviral design against WNV. PMID:26764042

  10. Cholesterol Regulates Syntaxin 6 Trafficking at trans-Golgi Network Endosomal Boundaries

    Directory of Open Access Journals (Sweden)

    Meritxell Reverter

    2014-05-01

    Full Text Available Inhibition of cholesterol export from late endosomes causes cellular cholesterol imbalance, including cholesterol depletion in the trans-Golgi network (TGN. Here, using Chinese hamster ovary (CHO Niemann-Pick type C1 (NPC1 mutant cell lines and human NPC1 mutant fibroblasts, we show that altered cholesterol levels at the TGN/endosome boundaries trigger Syntaxin 6 (Stx6 accumulation into VAMP3, transferrin, and Rab11-positive recycling endosomes (REs. This increases Stx6/VAMP3 interaction and interferes with the recycling of αVβ3 and α5β1 integrins and cell migration, possibly in a Stx6-dependent manner. In NPC1 mutant cells, restoration of cholesterol levels in the TGN, but not inhibition of VAMP3, restores the steady-state localization of Stx6 in the TGN. Furthermore, elevation of RE cholesterol is associated with increased amounts of Stx6 in RE. Hence, the fine-tuning of cholesterol levels at the TGN-RE boundaries together with a subset of cholesterol-sensitive SNARE proteins may play a regulatory role in cell migration and invasion.

  11. The tetraspanin CD63/lamp3 cycles between endocytic and secretory compartments in human endothelial cells.

    Science.gov (United States)

    Kobayashi, T; Vischer, U M; Rosnoblet, C; Lebrand, C; Lindsay, M; Parton, R G; Kruithof, E K; Gruenberg, J

    2000-05-01

    In the present study, we show that in human endothelial cells the tetraspanin CD63/lamp3 distributes predominantly to the internal membranes of multivesicular-multilamellar late endosomes, which contain the unique lipid lysobisphosphatidic acid. Some CD63/lamp3 is also present in Weibel-Palade bodies, the characteristic secretory organelle of these cells. We find that CD63/lamp3 molecules can be transported from late endosomes to Weibel-Palade bodies and thus that CD63/lamp3 cycles between endocytic and biosynthetic compartments; however, movement of CD63/lamp3 is much slower than that of P-selectin, which is known to cycle between plasma membrane and Weibel-Palade bodies. When cells are treated with U18666A, a drug that mimics the Niemann-Pick type C syndrome, both proteins accumulate in late endosomes and fail to reach Weibel-Palade bodies efficiently, suggesting that P-selectin, like CD63/lamp3, cycles via late endosomes. Our data suggest that CD63/lamp3 partitions preferentially within late endosome internal membranes, thus causing its accumulation, and that this mechanism contributes to CD63/lamp3 retention in late endosomes; however, our data also indicate that the protein can eventually escape from these internal membranes and recycle toward Weibel-Palade bodies to be reused. Our observations thus uncover the existence of a selective trafficking route from late endosomes to Weibel-Palade bodies. PMID:10793155

  12. Single nucleotide polymorphisms in the interferon gamma gene are associated with distinct types of retinochoroidal scar lesions presumably caused by Toxoplasma gondii infection

    Directory of Open Access Journals (Sweden)

    Ricardo Guerra Peixe

    2014-02-01

    Full Text Available The association of single nucleotide polymorphisms (SNPs in the interferon (IFN-γ gene ( IFNG with different types of retinal scar lesions presumably caused by toxoplasmosis were investigated in a cross-sectional population-based genetic study. Ten SNPs were investigated and after Bonferroni correction, only the associations between SNPs rs2069718 and rs3181035 with retinal/retinochoroidal scar lesions type A (most severe scar lesions and C (least severe scar lesions, respectively, remained significant. The associations of two different IFNG SNPs with two different types of retinal lesions attributable to toxoplasmosis support the hypothesis that different inflammatory mechanisms underlie the development of these lesions. The in vitro analysis of IFN-γ secretion by peripheral blood mononuclear cells stimulated with Toxoplasma gondii antigens was also investigated. The association between SNP rs2069718 and type A scar lesions revealed that differential IFN-γ levels are correlated with distinct genotypes. However, no correlation was observed with IFN-γ secretion levels and the SNP rs3181035 , which was significantly associated with type C scar lesions. Our findings strongly suggest that immunogenetic studies of individuals with congenital or postnatally acquired infection are needed to better understand the role of IFN-γ and its polymorphisms in the pathogenesis of ocular toxoplasmosis.

  13. Re-emergent Human Adenovirus Genome Type 7d Caused an Acute Respiratory Disease Outbreak in Southern China After a Twenty-one Year Absence

    OpenAIRE

    Zhao, Suhui; Wan, Chengsong; Ke, Changwen; Seto, Jason; Dehghan, Shoaleh; Zou, Lirong; Zhou, Jie; Cheng, Zetao; Jing, Shuping; Zeng, Zhiwei; Zhang, Jing; Wan, Xuan; Wu, Xianbo; Zhao, Wei; Zhu, Li

    2014-01-01

    Human adenoviruses (HAdVs) are highly contagious pathogens causing acute respiratory disease (ARD), among other illnesses. Of the ARD genotypes, HAdV-7 presents with more severe morbidity and higher mortality than the others. We report the isolation and identification of a genome type HAdV-7d (DG01_2011) from a recent outbreak in Southern China. Genome sequencing, phylogenetic analysis, and restriction endonuclease analysis (REA) comparisons with past pathogens indicate HAdV-7d has re-emerged...

  14. Chemical-structural changes during the thermal treatment of hydrogen-rich vitrinites caused by the presence of terpene-type resin

    OpenAIRE

    José Iglesias, María; José Cuesta, María; Laggoun-Défarge, Fatima; Suarez-Ruiz, Isabel

    2006-01-01

    The vitrain from Teruel (North-Eastern Spain) is a good example of a vitrinite whose perhydrous character and anomalous properties are caused by the presence of terpene-type resin. The sample used in this work was isothermally pyrolysed in an open-medium system at temperatures ranging from 250 to 500 °C. A mass balance, a petrographic and geochemical characterisation of the pyrolysates and compositional and structural analyses (GC and NMR) of the generated oils were performed. The results con...

  15. Clinical application of Clostridium botulinum type A neurotoxin purified by a simple procedure for patients with urinary incontinence caused by refractory destrusor overactivity.

    Science.gov (United States)

    Lee, Jae-Chul; Yokoyama, Teruhiko; Hwang, Hyun-Jung; Arimitsu, Hideyuki; Yamamoto, Yumiko; Kawasaki, Makiko; Takigawa, Tomoko; Takeshi, Kouichi; Nishikawa, Atsushi; Kumon, Hiromi; Oguma, Keiji

    2007-10-01

    Type A neurotoxin of Clostridium botulinum was purified by a simple procedure using a lactose gel column. This procedure was previously reported for type B neurotoxin. Hemagglutinin-positive toxins (19S and 16S) were bound to the column under acid conditions, and the neurotoxin alone was dissociated from these hemagglutinin-positive toxins by changing the pH of the column to an alkaline condition. The toxicity of this purified toxin preparation was retained for at least 1 year at -30 degrees C by supplementing it with either 0.1% albumin or 0.05% albumin plus 1% trehalose. This preparation was used to treat 18 patients with urinary incontinence caused by refractory idiopathic and neurogenic detrusor overactivity; 16 of the patients showed excellent improvement. Improvements started within 1 week after injection in most cases and lasted 3-12 months [corrected] PMID:17692094

  16. Serum adiponectin predicts all-cause mortality and end stage renal disease in patients with type I diabetes and diabetic nephropathy

    DEFF Research Database (Denmark)

    Jorsal, A.; Tarnow, L.; Frystyk, J.;

    2008-01-01

    Adiponectin levels are increased in patients with type I diabetes especially in the presence of microangiopathy. Here we determined the predictive value of serum adiponectin levels and 8 adiponectin gene polymorphisms for mortality, cardiovascular events and end-stage renal disease in type I......, age and duration of diabetes. Cox regression analysis of 373 patients showed a covariate-adjusted hazard ratio for all-cause mortality of 1.46 for a change of one standard deviation in log10 of serum adiponectin. There was no association with cardiovascular events; however, serum adiponectin levels...... predicted end stage renal disease in a covariate-adjusted analysis. Two of eight gene polymorphisms, found in the 878 patients, were associated with increased serum adiponectin levels but none of the polymorphisms were associated with a renal or cardiovascular outcome. These studies show that high serum...

  17. Diversity of mating-type chromosome structures in the yeast Zygosaccharomyces rouxii caused by ectopic exchanges between MAT-like loci.

    Directory of Open Access Journals (Sweden)

    Jun Watanabe

    Full Text Available We investigated sex chromosome diversity in Zygosaccharomyces rouxii (Z. rouxii. In the current study, we show that the organization of the mating-type (MAT locus is highly variable in the Z. rouxii population, indicating the MAT, HML, and HMR loci are translocation hotspots. Although NBRC1130 and CBS732 were originally two stocks of the type strain of the species, only NBRC1130 retains the original karyotype. A reciprocal translocation between the MAT and HMR loci appears to have occurred during the early passage culture of CBS732, which was used for genome sequencing. In NBRC1733, NBRC0686, NBRC0740 and NBRC1053, the terminal region of the chromosome containing the HMR locus was replaced with the chromosomal region to the left of the MAT or HML loci. The translocation events found in NBRC1733, NBRC0686, NBRC0740, and NBRC1053 were reconstructed under our experimental conditions using the DA2 background, and the reconstruction suggests that the frequency of this type of translocation is approximately 10(-7. These results suggest that the MAT and MAT-like loci were the susceptible regions in the genome, and the diversity of mating-type chromosome structures in Z. rouxii was caused by ectopic exchanges between MAT-like loci.

  18. What causes type 1 diabetes?

    DEFF Research Database (Denmark)

    Buschard, Karsten

    2011-01-01

    cell driven disease and the beta cells are destroyed in an inflammatory insulitis process. Autoimmunity is breakdown of self-tolerance and the balance between regulator T cells and aggressive effector T cells is disturbed. Inhibition of the T cells (by e.g. anti-CD3 antibody or cyclosporine) will stop...

  19. Assessment of the types of catheter infectivity caused by Candida species and their biofilm formation. First study in an intensive care unit in Algeria.

    Science.gov (United States)

    Seddiki, Sidi Mohammed Lahbib; Boucherit-Otmani, Zahia; Boucherit, Kebir; Badsi-Amir, Souad; Taleb, Mourad; Kunkel, Dennis

    2013-01-01

    Nosocomial candidiasis remains a potential risk in intensive care units (ICUs), wherein Candida albicans is most responsible for its occurrence. Equally, non-C. albicans species, especially C. glabrata, are also involved. These infections are frequently associated with biofilms that contaminate medical devices, such as catheters. These biofilms constitute a significant clinical problem, and cause therapeutic failures, because they can escape the immune response and considerably decrease sensitivity to antifungal therapy. The diagnosis of catheter-related candidiasis is difficult; however, the differentiation between an infection of the catheter (or other medical implant) and a simple contamination is essential to start an antifungal treatment. Among the methods used for this type of study is the Brun-Buisson method, but this method only examines the infectivity of catheters caused by bacteria. For this reason, we wanted to adapt this method to the yeast cells of Candida spp. To assess the various types of infectivity of catheters (contamination, colonization, or infection) and their corresponding rates, as well as the responsible yeast species, we conducted our study, between February 2011 and January 2012, in the ICU at the University Hospital Center of Sidi Bel Abbes, Algeria; during this study, we took photographic images of the tongue of one patient and of that patient's implanted orobronchial catheter. In addition, catheters contaminated by C. albicans biofilms were observed by scanning electron microscopy. PMID:23345986

  20. Re-emergent human adenovirus genome type 7d caused an acute respiratory disease outbreak in Southern China after a twenty-one year absence.

    Science.gov (United States)

    Zhao, Suhui; Wan, Chengsong; Ke, Changwen; Seto, Jason; Dehghan, Shoaleh; Zou, Lirong; Zhou, Jie; Cheng, Zetao; Jing, Shuping; Zeng, Zhiwei; Zhang, Jing; Wan, Xuan; Wu, Xianbo; Zhao, Wei; Zhu, Li; Seto, Donald; Zhang, Qiwei

    2014-01-01

    Human adenoviruses (HAdVs) are highly contagious pathogens causing acute respiratory disease (ARD), among other illnesses. Of the ARD genotypes, HAdV-7 presents with more severe morbidity and higher mortality than the others. We report the isolation and identification of a genome type HAdV-7d (DG01_2011) from a recent outbreak in Southern China. Genome sequencing, phylogenetic analysis, and restriction endonuclease analysis (REA) comparisons with past pathogens indicate HAdV-7d has re-emerged in Southern China after an absence of twenty-one years. Recombination analysis reveals this genome differs from the 1950s-era prototype and vaccine strains by a lateral gene transfer, substituting the coding region for the L1 52/55 kDa DNA packaging protein from HAdV-16. DG01_2011 descends from both a strain circulating in Southwestern China (2010) and a strain from Shaanxi causing a fatality and outbreak (Northwestern China; 2009). Due to the higher morbidity and mortality rates associated with HAdV-7, the surveillance, identification, and characterization of these strains in population-dense China by REA and/or whole genome sequencing are strongly indicated. With these accurate identifications of specific HAdV types and an epidemiological database of regional HAdV pathogens, along with the HAdV genome stability noted across time and space, the development, availability, and deployment of appropriate vaccines are needed. PMID:25482188

  1. Congenital disorders of glycosylation type I: a rare but new cause of hyperechoic kidneys in infants and children due to early microcystic changes

    International Nuclear Information System (INIS)

    There are numerous causes of bilateral hyperechoic kidneys. Congenital disorders of glycosylation (CDGs) are a rapidly growing family of inherited disorders due to defects in the synthesis of the glycans of glycoproteins or other glycoconjugates. To describe renal sonographic abnormalities in CDG type I in infants and children. A retrospective study of renal US in 12 infants and children: 8 CDG-Ia (6 multivisceral forms, 2 neurological forms), 2 CDG-Ib, and 2 CDG-Ix, with detailed functional renal tests in 6. Histology of the kidneys of one 35-week fetus with CDG-Ia was available. Renal US was normal in the two children with the neurological form of CDG-Ia. All patients with the multivisceral form of CDG-Ia or with CDG-Ib showed increased cortical echogenicity, and/or abnormal pyramids (small +/- hyperechoic). The two patients with CDG-Ix showed predominant involvement of the medulla, with inverted corticomedullary differentiation in one. Kidney size was normal in all but two patients. The fetal kidneys exhibited diffuse microcysts arising from the distal tubules. Hyperechoic kidneys are common in CDG-I patients, contrasting with grossly preserved renal function. The US pattern seems to differ slightly according to the type of CDG-I, and is consistent with microcystic changes of the renal parenchyma, which occur prenatally, and may be due to ciliary dysfunction secondary to altered glycosylation of tubular glycoproteins. CDG-I, which remains largely underdiagnosed at present, should be added to the causes of hyperechoic kidneys in children, especially in cases of multivisceral involvement, after ruling out other more frequent causes. (orig.)

  2. [Rash and fever illness caused by herpes simplex virus type 1 needs to be distinguished from hand, foot and mouth disease].

    Science.gov (United States)

    Zhu, Shuang-Li; Liu, Jian-Feng; Sun, Qiang; Li, Jing; Li, Xiao-Lei; Zhang, Yong; Chen, Ying; Wen, Xiao-Yun; Yan, Dong-Mei; Huang, Guo-Hong; Zhang, Bao-Min; Zhang, Bo; An, Hong-Qiu; Li, Hui; Xu, Wen-Bo

    2013-06-01

    An epidemic of rash and fever illnesses suspected of hand, foot and mouth disease (HFMD) occurred in Gansu Province of China in 2008, laboratory tests were performed in order to identify the pathogen that caused this epidemic. Eight clinical specimens collected from the 4 patients (each patient has throat swab and herpes fluid specimens) with rash and febrile illness, were inoculated onto RD and HEp-2 cells for virus isolation, and the viral nucleic acid was then extracted with the positive virus isolates, the dual-channel real-time reverse transcript-polymerase chain reaction (RT-PCR) was performed to detect the nucleic acid of human enterovirus (HEV) in the viral isolates at the same time. For the viral isolates with the negative results of HEV, a sequence independent single primer amplification technique (SISPA) was used for "unknown pathogen" identification. Totally, 6 viral isolates were identified as herpes simplex virus type 1 (HSV-1). Comprehensive analyses results of the clinical manifestations of the patients, epidemiological findings and laboratory test indicated that this epidemic of rash and febrile illness was caused by HSV-1. The differences among the gG region of 6 HSV-1 isolates at nucleotide level and amino acid level were all small, and the identities were up to 98. 8% and 97.9%, respectively, showing that this outbreak was caused by only one viral transmission chain of HSV-1. HSV-1 and other viruses that cause rash and febrile illnesses need differential diagnosis with HFMD. The etiology of rash and febrile illness is sometimes difficult to distinguish from the clinical symptoms and epidemiological data, the laboratory diagnosis is therefore critical. PMID:23895007

  3. The insulin-like growth factor 1 receptor causes acquired resistance to erlotinib in lung cancer cells with the wild-type epidermal growth factor receptor.

    Science.gov (United States)

    Suda, Kenichi; Mizuuchi, Hiroshi; Sato, Katsuaki; Takemoto, Toshiki; Iwasaki, Takuya; Mitsudomi, Tetsuya

    2014-08-15

    Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy often provides a dramatic response in lung cancer patients with EGFR mutations. In addition, moderate clinical efficacy of the EGFR-TKI, erlotinib, has been shown in lung cancer patients with the wild-type EGFR. Numerous molecular mechanisms that cause acquired resistance to EGFR-TKIs have been identified in lung cancers with the EGFR mutations; however, few have been reported in lung cancers with the wild-type EGFR. We used H358 lung adenocarcinoma cells lacking EGFR mutations that showed modest sensitivity to erlotinib. The H358 cells acquired resistance to erlotinib via chronic exposure to the drug. The H358 erlotinib-resistant (ER) cells do not have a secondary EGFR mutation, neither MET gene amplification nor PTEN downregulation; these have been identified in lung cancers with the EGFR mutations. From comprehensive screening of receptor tyrosine kinase phosphorylation, we observed increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) in H358ER cells compared with parental H358 cells. H358ER cells responded to combined therapy with erlotinib and NVP-AEW541, an IGF1R-TKI. Our results indicate that IGF1R activation is a molecular mechanism that confers acquired resistance to erlotinib in lung cancers with the wild-type EGFR. PMID:24458568

  4. Prognostic value of physicians' assessment of compliance regarding all-cause mortality in patients with type 2 diabetes: primary care follow-up study

    Directory of Open Access Journals (Sweden)

    Rüter Gernot

    2006-07-01

    Full Text Available Abstract Background Whether the primary care physician's assessment of patient compliance is a valuable prognostic marker to identify patients who are at increased risk of death, or merely reflects measurement of various treatment parameters such as HbA1C or other laboratory markers is unclear. The objective of this prospective cohort study was to investigate the prognostic value of the physicians' assessment of patient compliance and other factors with respect to all-cause mortality during a one year follow-up period. Methods A prospective cohort study was conducted among 1014 patients with type 2 diabetes aged 40 and over (mean age 69 years, SD 10.4, 45% male who were under medical treatment in 11 participating practices of family physicians and internists working in primary care in a defined region in South Germany between April and June 2000. Baseline data were gathered from patients and physicians by standardized questionnaire. The physician's assessment of patient compliance was assessed by means of a 4-point Likert scale (very good, rather good, rather bad, very bad. In addition, we carried out a survey among physicians by means of a questionnaire to find out which aspects for the assessment of patient compliance were of importance to make this assessment. Active follow-up of patients was conducted after one year to determine mortality. Results During the one year follow-up 48 (4.7% of the 1014 patients died. Among other factors such as patient type (patients presenting at office, nursing home or visited patients, gender, age and a history of macrovascular disease, the physician's assessment of patient compliance was an important predictor of all-cause mortality. Patients whose compliance was assessed by the physician as "very bad" (6% were significantly more likely to die during follow-up (OR = 2.67, 95% CI 1.02–6.97 after multivariable adjustment compared to patients whose compliance was assessed as "rather good" (45% or "very good

  5. Netazepide, a gastrin receptor antagonist, normalises tumour biomarkers and causes regression of type 1 gastric neuroendocrine tumours in a nonrandomised trial of patients with chronic atrophic gastritis.

    Directory of Open Access Journals (Sweden)

    Andrew R Moore

    Full Text Available INTRODUCTION: Autoimmune chronic atrophic gastritis (CAG causes hypochlorhydria and hypergastrinaemia, which can lead to enterochromaffin-like (ECL cell hyperplasia and gastric neuroendocrine tumours (type 1 gastric NETs. Most behave indolently, but some larger tumours metastasise. Antrectomy, which removes the source of the hypergastrinaemia, usually causes tumour regression. Non-clinical and healthy-subject studies have shown that netazepide (YF476 is a potent, highly selective and orally-active gastrin/CCK-2 receptor antagonist. Also, it is effective in animal models of ECL-cell tumours induced by hypergastrinaemia. AIM: To assess the effect of netazepide on tumour biomarkers, number and size in patients with type I gastric NETs. METHODS: We studied 8 patients with multiple tumours and raised circulating gastrin and chromogranin A (CgA concentrations in an open trial of oral netazepide for 12 weeks, with follow-up 12 weeks later. At 0, 6, 12 and 24 weeks, we carried out gastroscopy, counted and measured tumours, and took biopsies to assess abundances of several ECL-cell constituents. At 0, 3, 6, 9, 12 and 24 weeks, we measured circulating gastrin and CgA and assessed safety and tolerability. RESULTS: Netazepide was safe and well tolerated. Abundances of CgA (p<0.05, histidine decarboxylase (p<0.05 and matrix metalloproteinase-7(p<0.10 were reduced at 6 and 12 weeks, but were raised again at follow-up. Likewise, plasma CgA was reduced at 3 weeks (p<0.01, remained so until 12 weeks, but was raised again at follow-up. Tumours were fewer and the size of the largest one was smaller (p<0.05 at 12 weeks, and remained so at follow-up. Serum gastrin was unaffected. CONCLUSION: The reduction in abundances, plasma CgA, and tumour number and size by netazepide show that type 1 NETs are gastrin-dependent tumours. Failure of netazepide to increase serum gastrin further is consistent with achlorhydria. Netazepide is a potential new treatment for type 1 NETs

  6. Nebulin deficiency in adult muscle causes sarcomere defects and muscle-type-dependent changes in trophicity: novel insights in nemaline myopathy.

    Science.gov (United States)

    Li, Frank; Buck, Danielle; De Winter, Josine; Kolb, Justin; Meng, Hui; Birch, Camille; Slater, Rebecca; Escobar, Yael Natelie; Smith, John E; Yang, Lin; Konhilas, John; Lawlor, Michael W; Ottenheijm, Coen; Granzier, Henk L

    2015-09-15

    Nebulin is a giant filamentous protein that is coextensive with the actin filaments of the skeletal muscle sarcomere. Nebulin mutations are the main cause of nemaline myopathy (NEM), with typical adult patients having low expression of nebulin, yet the roles of nebulin in adult muscle remain poorly understood. To establish nebulin's functional roles in adult muscle, we studied a novel conditional nebulin KO (Neb cKO) mouse model in which nebulin deletion was driven by the muscle creatine kinase (MCK) promotor. Neb cKO mice are born with high nebulin levels in their skeletal muscles, but within weeks after birth nebulin expression rapidly falls to barely detectable levels Surprisingly, a large fraction of the mice survive to adulthood with low nebulin levels (NEM (muscle weakness, oxidative fiber-type predominance, variable trophicity effects, nemaline rods) and will be highly useful to test therapeutic approaches to ameliorate muscle weakness. PMID:26123491

  7. Assessment of the types of catheter infectivity caused by Candida species and their biofilm formation. First study in an intensive care unit in Algeria

    Directory of Open Access Journals (Sweden)

    Seddiki SML

    2013-01-01

    Full Text Available Sidi Mohammed Lahbib Seddiki,1 Zahia Boucherit-Otmani,1 Kebir Boucherit,1 Souad Badsi-Amir,2 Mourad Taleb,3 Dennis Kunkel41Laboratory: Antifungal Antibiotic, Physico-Chemical Synthesis and Biological Activity, University of Tlemcen, Algeria; 2Department of Anesthesiology, 3Department of Epidemiology, University Hospital of Sidi Bel Abbes, Algeria; 4Dennis Kunkel Microscopy Inc, Kailua, HI, USAAbstract: Nosocomial candidiasis remains a potential risk in intensive care units (ICUs, wherein Candida albicans is most responsible for its occurrence. Equally, non-C. albicans species, especially C. glabrata, are also involved. These infections are frequently associated with biofilms that contaminate medical devices, such as catheters. These biofilms constitute a significant clinical problem, and cause therapeutic failures, because they can escape the immune response and considerably decrease sensitivity to antifungal therapy. The diagnosis of catheter-related candidiasis is difficult; however, the differentiation between an infection of the catheter (or other medical implant and a simple contamination is essential to start an antifungal treatment. Among the methods used for this type of study is the Brun-Buisson method, but this method only examines the infectivity of catheters caused by bacteria. For this reason, we wanted to adapt this method to the yeast cells of Candida spp. To assess the various types of infectivity of catheters (contamination, colonization, or infection and their corresponding rates, as well as the responsible yeast species, we conducted our study, between February 2011 and January 2012, in the ICU at the University Hospital Center of Sidi Bel Abbes, Algeria; during this study, we took photographic images of the tongue of one patient and of that patient's implanted orobronchial catheter. In addition, catheters contaminated by C. albicans biofilms were observed by scanning electron microscopy.Keywords: ICU, contamination

  8. Analyses of loss-of-function mutations of the MITF gene suggest that haploinsufficiency is a cause of Waardenburg syndrome type 2A

    Energy Technology Data Exchange (ETDEWEB)

    Nobukuni, Yoshitaka; Watanabe, A.; Takeda, Kazushisa; Skarka, Hana; Tachibana, Masayoshi [National Inst. of Health, Bethesda, MD (United States)

    1996-07-01

    Waardenburg syndrome type 2 (WS2) is a dominantly inherited disorder characterized by a pigmentation anomaly and hearing impairment due to lack of melanocyte. Previous work has linked a subset of families with WS2 (WS2A) to the MITF gene that encodes a transcription factor with a basic-helix-loop-helix-leucine zipper (bHLH-Zip) motif and that is involved in melanocyte differentiation. Several splice-site and missense mutations have been reported in individuals affected with WS2A. In this report, we have identified two novel point mutations in the MITF gene in affected individuals from two different families with WS2A. The two mutations (C760{r_arrow}T and C895{r_arrow}T) create stop codons in exons 7 and 8, respectively. Corresponding mutant alleles predict the truncated proteins lacking HLH-Zip or Zip structure. To understand how these mutations cause WS2 in heterozygotes, we generated mutant MITF cDNAs and used them for DNA-binding and luciferase reporter assays. The mutated MITF proteins lose the DNA-binding activity and fail to transactivate the promoter of tyrosinase, a melanocyte-specific enzyme. However, these mutated proteins do not appear to interfere with the activity of wild-type MITF protein in these assays, indicating that they do not show a dominant-negative effect. These findings suggest that the phenotypes of the two families with WS2A in the present study are caused by loss-of-function mutations in one of the two alleles of the MITF gene, resulting in haploinsufficiency of the MITF protein, the protein necessary for normal development of melanocytes. 37 refs., 4 figs.

  9. WtsE, an AvrE-family type III effector protein of Pantoea stewartii subsp. stewartii, causes cell death in non-host plants.

    Science.gov (United States)

    Ham, Jong Hyun; Majerczak, Doris; Ewert, Sophie; Sreerekha, Mysore-Venkatarau; Mackey, David; Coplin, David

    2008-09-01

    Pantoea stewartii subsp. stewartii (Pnss) causes Stewart's bacterial wilt of sweet corn and leaf blight of maize. The pathogenicity of Pnss depends on synthesis of extracellular polysaccharide and an Hrp type III secretion system. WtsE, a type III secreted effector protein, is essential for the virulence of Pnss on corn. It belongs to the AvrE family of effectors, which includes DspA/E from Erwinia amylovora and AvrE1 from Pseudomonas syringae. Previously, WtsE was shown to cause disease-associated cell death in its host plant, sweet corn. Here, we examine the biological activity of WtsE in several non-host plants. WtsE induced cell death in Nicotiana benthamiana, tobacco, beet and Arabidopsis thaliana when it was transiently produced in plant cells following agroinfiltration or translocated into plant cells from Pnss, Escherichia coli or Pseudomonas syringae pv. phaseolicola (Pph). WtsE-induced cell death in N. benthamiana, tobacco and beet resembled a hypersensitive response and in N. benthamiana it was delayed by cycloheximide. Interestingly, WtsE strongly promoted the growth of Pnss in N. benthamiana prior to the onset of cell death. Deletion derivatives of WtsE that failed to induce cell death in N. benthamiana and tobacco also did not complement wtsE mutants of Pnss for virulence in sweet corn, indicating a correlation between the two activities. WtsE also induced cell death in A. thaliana, where it suppressed basal defences induced by Pph. Thus, WtsE has growth-promoting, defence-suppressing and cell death-inducing activities in non-host plants. Expression of WtsE also prevented the growth of yeast, possibly due to an innate toxicity to eukaryotic cells. PMID:19018993

  10. Build-ups in the supply chain of the brain: on the neuroenergetic cause of obesity and type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Achim Peters

    2009-04-01

    Full Text Available Obesity and type 2 diabetes have become the major health problems in many industrialized countries. A few theoretical frameworks have been set up to derive the possible determinative cause of obesity. One concept views that food availability determines food intake, i.e. that obesity is the result of an external energy “push” into the body. Another one views that the energy milieu within the human organism determines food intake, i.e. that obesity is due to an excessive “pull” from inside the organism. Here we present the unconventional concept that a healthy organism is maintained by a „competent brain-pull“ which serves systemic homeostasis, and that the underlying cause of obesity is “incompetent brain-pull”, i.e. that the brain is unable to properly demand glucose from the body. We describe the energy fluxes from the environment, through the body, towards the brain with a mathematical “supply chain” model and test whether its predictions fit medical and experimental data sets from our and other research groups. In this way, we show data-based support of our hypothesis, which states that under conditions of food abundance incompetent brain-pull will lead to build-ups in the supply chain culminating in obesity and type 2 diabetes. In the same way, we demonstrate support of the related hypothesis, which states that under conditions of food deprivation a competent brain-pull mechanism is indispensable for the continuance of the brain´s high energy level. In conclusion, we took the viewpoint of integrative physiology and provided evidence for the necessity of brain-pull mechanisms for the benefit of health. Along these lines, our work supports recent molecular findings from the field of neuroenergetics and continues the work on the “Selfish Brain” theory dealing with the maintenance of the cerebral and peripheral energy homeostasis.

  11. Imaging of macrophage-related lung diseases

    Energy Technology Data Exchange (ETDEWEB)

    Marten, Katharina; Hansell, David M. [Royal Brompton Hospital, Department of Radiology, London (United Kingdom)

    2005-04-01

    Macrophage-related pulmonary diseases are a heterogeneous group of disorders characterized by macrophage accumulation, activation or dysfunction. These conditions include smoking-related interstitial lung diseases, metabolic disorders such as Niemann-Pick or Gaucher disease, and rare primary lung tumors. High-resolution computed tomography abnormalities include pulmonary ground-glass opacification secondary to infiltration by macrophages, centrilobular nodules or interlobular septal thickening reflecting peribronchiolar or septal macrophage accumulation, respectively, emphysema caused by macrophage dysfunction, and honeycombing following macrophage-related lung matrix remodeling. (orig.)

  12. Imaging of macrophage-related lung diseases

    International Nuclear Information System (INIS)

    Macrophage-related pulmonary diseases are a heterogeneous group of disorders characterized by macrophage accumulation, activation or dysfunction. These conditions include smoking-related interstitial lung diseases, metabolic disorders such as Niemann-Pick or Gaucher disease, and rare primary lung tumors. High-resolution computed tomography abnormalities include pulmonary ground-glass opacification secondary to infiltration by macrophages, centrilobular nodules or interlobular septal thickening reflecting peribronchiolar or septal macrophage accumulation, respectively, emphysema caused by macrophage dysfunction, and honeycombing following macrophage-related lung matrix remodeling. (orig.)

  13. Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7 model

    Directory of Open Access Journals (Sweden)

    Ajayi Abiodun

    2012-07-01

    Full Text Available Abstract Background Spinocerebellar ataxia type 7 (SCA7 is one of nine inherited neurodegenerative disorders caused by polyglutamine (polyQ expansions. Common mechanisms of disease pathogenesis suggested for polyQ disorders include aggregation of the polyQ protein and induction of oxidative stress. However, the exact mechanism(s of toxicity is still unclear. Results In this study we show that expression of polyQ expanded ATXN7 in a novel stable inducible cell model first results in a concomitant increase in ROS levels and aggregation of the disease protein and later cellular toxicity. The increase in ROS could be completely prevented by inhibition of NADPH oxidase (NOX complexes suggesting that ATXN7 directly or indirectly causes oxidative stress by increasing superoxide anion production from these complexes. Moreover, we could observe that induction of mutant ATXN7 leads to a decrease in the levels of catalase, a key enzyme in detoxifying hydrogen peroxide produced from dismutation of superoxide anions. This could also contribute to the generation of oxidative stress. Most importantly, we found that treatment with a general anti-oxidant or inhibitors of NOX complexes reduced both the aggregation and toxicity of mutant ATXN7. In contrast, ATXN7 aggregation was aggravated by treatments promoting oxidative stress. Conclusion Our results demonstrates that oxidative stress contributes to ATXN7 aggregation as well as toxicity and show that anti-oxidants or NOX inhibition can ameliorate mutant ATXN7 toxicity.

  14. Two novel splicing mutations in the SLC45A2 gene cause Oculocutaneous Albinism Type IV by unmasking cryptic splice sites.

    Science.gov (United States)

    Straniero, Letizia; Rimoldi, Valeria; Soldà, Giulia; Mauri, Lucia; Manfredini, Emanuela; Andreucci, Elena; Bargiacchi, Sara; Penco, Silvana; Gesu, Giovanni P; Del Longo, Alessandra; Piozzi, Elena; Asselta, Rosanna; Primignani, Paola

    2015-09-01

    Oculocutaneous albinism (OCA) is characterized by hypopigmentation of the skin, hair and eye, and by ophthalmologic abnormalities caused by a deficiency in melanin biosynthesis. OCA type IV (OCA4) is one of the four commonly recognized forms of albinism, and is determined by mutation in the SLC45A2 gene. Here, we investigated the genetic basis of OCA4 in an Italian child. The mutational screening of the SLC45A2 gene identified two novel potentially pathogenic splicing mutations: a synonymous transition (c.888G>A) involving the last nucleotide of exon 3 and a single-nucleotide insertion (c.1156+2dupT) within the consensus sequence of the donor splice site of intron 5. As computer-assisted analysis for mutant splice-site prediction was not conclusive, we investigated the effects on pre-mRNA splicing of these two variants by using an in vitro minigene approach. Production of mutant transcripts in HeLa cells demonstrated that both mutations cause the almost complete abolishment of the physiologic donor splice site, with the concomitant unmasking of cryptic donor splice sites. To our knowledge, this work represents the first in-depth molecular characterization of splicing defects in a OCA4 patient. PMID:26016411

  15. The SARS Coronavirus 3a protein causes endoplasmic reticulum stress and induces ligand-independent downregulation of the type 1 interferon receptor.

    Directory of Open Access Journals (Sweden)

    Rinki Minakshi

    Full Text Available The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV is reported to cause apoptosis of infected cells and several of its proteins including the 3a accessory protein, are pro-apoptotic. Since the 3a protein localizes to the endoplasmic reticulum (ER-Golgi compartment, its role in causing ER stress was investigated in transiently transfected cells. Cells expressing the 3a proteins showed ER stress based on activation of genes for the ER chaperones GRP78 and GRP94. Since ER stress can cause differential modulation of the unfolded protein response (UPR, which includes the inositol-requiring enzyme 1 (IRE-1, activating transcription factor 6 (ATF6 and PKR-like ER kinase (PERK pathways, these were individually tested in 3a-expressing cells. Only the PERK pathway was found to be activated in 3a-expressing cells based on (1 increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF2alpha and inhibitory effects of a dominant-negative form of eIF2alpha on GRP78 promoter activity, (2 increased translation of activating transcription factor 4 (ATF4 mRNA, and (3 ATF4-dependent activation of the C/EBP homologous protein (CHOP gene promoter. Activation of PERK affects innate immunity by suppression of type 1 interferon (IFN signaling. The 3a protein was found to induce serine phosphorylation within the IFN alpha-receptor subunit 1 (IFNAR1 degradation motif and to increase IFNAR1 ubiquitination. Confocal microscopic analysis showed increased translocation of IFNAR1 into the lysosomal compartment and flow cytometry showed reduced levels of IFNAR1 in 3a-expressing cells. These results provide further mechanistic details of the pro-apoptotic effects of the SARS-CoV 3a protein, and suggest a potential role for it in attenuating interferon responses and innate immunity.

  16. The Fruit Fly Drosophila melanogaster as a Model System to Study Cholesterol Metabolism and Homeostasis

    Directory of Open Access Journals (Sweden)

    Ryusuke Niwa

    2011-01-01

    Full Text Available Cholesterol has long been recognized for its versatile roles in influencing the biophysical properties of cell membranes and for serving as a precursor of steroid hormones. While many aspects of cholesterol biosynthesis are well understood, little is currently known about the molecular mechanisms of cholesterol metabolism and homeostasis. Recently, genetic approaches in the fruit fly, Drosophila melanogaster, have been successfully used for the analysis of molecular mechanisms that regulate cholesterol metabolism and homeostasis. This paper summarizes the recent studies on genes that regulate cholesterol metabolism and homeostasis, including neverland, Niemann Pick type C(NPC disease genes, and DHR96.

  17. Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport.

    Science.gov (United States)

    Kobayashi, T; Beuchat, M H; Lindsay, M; Frias, S; Palmiter, R D; Sakuraba, H; Parton, R G; Gruenberg, J

    1999-06-01

    The fate of free cholesterol released after endocytosis of low-density lipoproteins remains obscure. Here we report that late endosomes have a pivotal role in intracellular cholesterol transport. We find that in the genetic disease Niemann-Pick type C (NPC), and in drug-treated cells that mimic NPC, cholesterol accumulates in late endosomes and sorting of the lysosomal enzyme receptor is impaired. Our results show that the characteristic network of lysobisphosphatidic acid-rich membranes contained within multivesicular late endosomes regulates cholesterol transport, presumably by acting as a collection and distribution device. The results also suggest that similar endosomal defects accompany the anti-phospholipid syndrome and NPC. PMID:10559883

  18. Low and moderate concentrations of lysobisphosphatidic acid in brain and liver of patients affected by some storage diseases.

    Science.gov (United States)

    Kahma, K; Brotherus, J; Haltia, M; Renkonen, O

    1976-07-01

    The relative amount of lysobisphosphatidic acid (LBPA), known also as bis(monoacylglycerly)phosphate, among the total phospholipids was analyzed in post mortem samples of brain and liver of patients affected by four storage diseases. In spite of the extensive accumulation of storage lysosomes, none of the samples revealed a highly evelated LBPA content comparable to that found in the liver in Niemann-Pick disease and in the liver in lipidosis induced by 4,4'-diethylaminoethoxyhexestrol. We conclude that, although LBPA is often present in high concentration in lysosomes of many types of cells, it is not always a major component of these organelles. PMID:948249

  19. What Causes Pulmonary Hypertension?

    Science.gov (United States)

    ... from the NHLBI on Twitter. What Causes Pulmonary Hypertension? Pulmonary hypertension (PH) begins with inflammation and changes in the ... different types of PH. Group 1 pulmonary arterial hypertension (PAH) may have no known cause, or the ...

  20. What Causes Hypotension?

    Science.gov (United States)

    ... this page from the NHLBI on Twitter. What Causes Hypotension? Conditions or factors that disrupt the body's ability to control blood pressure cause hypotension. The different types of hypotension have different ...

  1. What Causes Lactose Intolerance?

    Science.gov (United States)

    ... Information Clinical Trials Resources and Publications What causes lactose intolerance? Skip sharing on social media links Share this: ... lactase in the body is the cause of lactose intolerance. The names for the three types of lactose ...

  2. 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.

  3. A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2).

    Science.gov (United States)

    Gorvin, Caroline M; Cranston, Treena; Hannan, Fadil M; Rust, Nigel; Qureshi, Asjid; Nesbit, M Andrew; Thakker, Rajesh V

    2016-06-01

    Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous disorder with three variants, FHH1 to FHH3. FHH1 is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR), a G-protein coupled receptor that predominantly signals via G-protein subunit alpha-11 (Gα11 ) to regulate calcium homeostasis. FHH2 is the result of loss-of-function mutations in Gα11 , encoded by GNA11, and to date only two FHH2-associated Gα11 missense mutations (Leu135Gln and Ile200del) have been reported. FHH3 is the result of loss-of-function mutations of the adaptor protein-2 σ-subunit (AP2σ), which plays a pivotal role in clathrin-mediated endocytosis. We describe a 65-year-old woman who had hypercalcemia with normal circulating parathyroid hormone concentrations and hypocalciuria, features consistent with FHH, but she did not have CaSR and AP2σ mutations. Mutational analysis of the GNA11 gene was therefore undertaken, using leucocyte DNA, and this identified a novel heterozygous GNA11 mutation (c.161C>T; p.Thr54Met). The effect of the Gα11 variant was assessed by homology modeling of the related Gαq protein and by measuring the CaSR-mediated intracellular calcium (Ca(2+) i ) responses of HEK293 cells, stably expressing CaSR, to alterations in extracellular calcium (Ca(2+) o ) using flow cytometry. Three-dimensional modeling revealed the Thr54Met mutation to be located at the interface between the Gα11 helical and GTPase domains, and to likely impair GDP binding and interdomain interactions. Expression of wild-type and the mutant Gα11 in HEK293 cells stably expressing CaSR demonstrate that the Ca(2+) i responses after stimulation with Ca(2+) o of the mutant Met54 Gα11 led to a rightward shift of the concentration-response curve with a significantly (p < 0.01) increased mean half-maximal concentration (EC50 ) value of 3.88 mM (95% confidence interval [CI] 3.76-4.01 mM), when compared with the wild-type EC50 of 2.94 mM (95% CI 2.81-3.07

  4. Does high-dose metformin cause lactic acidosis in type 2 diabetic patients after CABG surgery? A double blind randomized clinical trial

    Directory of Open Access Journals (Sweden)

    Rahman Ghafari

    2011-06-01

    Full Text Available Metformin is a dimethyl biguanide oral anti-hyperglycemic agent. Lactic acidosis due to metformin is a fatal metabolic condition that limits its use in patients in poor clinical condition, consequently reducing the number of patients who benefit from this medication. In a double blind randomized clinical trial, we investigated 200 type 2 diabetic patients after coronary artery bypass surgery in the open heart ICU of the Mazandaran Heart Center, and randomly assigned them to equal intervention and control groups. The intervention group received regular insulin infusion along with 2 metformin 500 mg tablets every twelve hours, while the control group received only intravenous insulin with 2 placebo tablets every twelve hours. Lactate level, pH, base excess, blood glucose and serum creatinine were measured over five 12 h periods, with data averaged for each period. The primary outcome in this study was high lactate levels. Comparison between the 2 groups was made by independent Student’s t-test. To compare changes in multiple measures in each group and analysis of group interaction, a repeated measurement ANOVA test was used. There was no significant difference between the 2 groups regarding pH, base excess, or bicarbonate intake (P>0.05. No patient showed lactic acidosis in either group. Lactate levels were 23.0 vs 23.4 in the insulin-metformin and insulin only groups when the study was started, respectively. At the end of the study, those levels were 18.7 vs 18.9, respectively. In addition, the ANOVA repeated measurement test did not show a significant difference in terms of changes in the amount of lactate level between the 2 groups during the five measurement tests of the study period (P>0.05. High-dose metformin (1,000 mg twice daily with insulin does not cause lactic acidosis in type 2 diabetic patients after coronary artery

  5. Deregulation of the actin cytoskeleton and macropinocytosis in response to phorbol ester by the mutant protein kinase C gamma that causes spinocerebellar ataxia type 14

    Directory of Open Access Journals (Sweden)

    Kazuhiro eYamamoto

    2014-04-01

    Full Text Available Several missense mutations in the protein kinase Cγ (γPKC gene have been found to cause spinocerebellar ataxia type 14 (SCA14, an autosomal dominant neurodegenerative disease. γPKC is a neuron-specific member of the classical PKCs and is activated and translocated to subcellular regions as a result of various stimuli, including diacylglycerol synthesis, increased intracellular Ca2+ and phorbol esters. We investigated whether SCA14 mutations affect the γPKC-related functions by stimulating HeLa cells with TPA (12-O-tetradecanoylpholbol 13-acetate, a type of phorbol ester. Wild-type (WT γPKC-GFP was translocated to the plasma membrane within 10 min of TPA stimulation, followed by its perinuclear translocation and cell shrinkage, in a PKC kinase activity- and microtubule-dependent manner. On the other hand, although SCA14 mutant γPKC-GFP exhibited a similar translocation to the plasma membrane, the subsequent perinuclear translocation and cell shrinkage were significantly impaired in response to TPA. Translocated WT γPKC colocalized with F-actin and formed large vesicular structures in the perinuclear region. The uptake of FITC-dextran, a marker of macropinocytosis, was promoted by TPA stimulation in cells expressing WT γPKC, and FITC-dextran was surrounded by γPKC-positive vesicles. Moreover, TPA induced the phosphorylation of MARCKS, which is a membrane-substrate of PKC, resulting in the translocation of phosphorylated MARCKS to the perinuclear region, suggesting that TPA induces macropinocytosis via γPKC activation. However, TPA failed to activate macropinocytosis and trigger the translocation of phosphorylated MARCKS in cells expressing the SCA14 mutant γPKC. These findings suggest that γPKC is involved in the regulation of the actin cytoskeleton and macropinocytosis in HeLa cells, while SCA14 mutant γPKC fails to regulate these processes due to its reduced kinase activity at the plasma membrane. This property might be involved in

  6. Urinary biomarkers are associated with incident cardiovascular disease, all-cause mortality and deterioration of kidney function in type 2 diabetic patients with microalbuminuria

    DEFF Research Database (Denmark)

    von Scholten, Bernt Johan; Reinhard, Henrik; Hansen, Tine W; Oellgaard, Jens; Parving, Hans-Henrik; Jacobsen, Peter K; Rossing, Peter

    2016-01-01

    AIMS/HYPOTHESIS: We evaluated two urinary biomarkers reflecting different aspects of renal pathophysiology as potential determinants of incident cardiovascular disease (CVD), all-cause mortality and a reduced estimated GFR (eGFR) in patients with type 2 diabetes and microalbuminuria but without......-cholesterol, smoking, HbA1c, plasma creatinine, systolic BP and urinary AER (UAER). The pre-defined endpoint of chronic kidney disease progression was a decline in the eGFR of >30% during follow-up. HRs per 1 SD increment of log-transformed values are presented. RESULTS: Patients had a mean ± SD age of 59 ± 9 years...... with a median (interquartile range) UAER of 103 (39-230) mg/24 h. During a median 6.1 years of follow-up, there were 40 incident CVD events, 26 deaths and 42 patients reached the pre-defined chronic kidney disease progression endpoint after 4.9 years (median). Higher urinary HGF was a determinant of...

  7. Dicty_cDB: Contig-U11697-1 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available pid:none) Vitis vinifera contig VV78X161773.... 155 3e-63 ( P56941 ) RecName: Full=Niemann-Pick C1 protein; Flag...:none) Cryptococcus neoformans var. neo... 150 3e-56 (Q6T3U4) RecName: Full=Niemann-Pick C1-like protein 1; Flag... Penicillium chrysogenum Wiscons... 218 2e-54 (Q6T3U3) RecName: Full=Niemann-Pick C1-like protein 1; Flag...( Q19127 ) RecName: Full=Niemann-Pick C1 protein homolog 1; Flags:... 114 9e-38 A...lcvgmtvvdllavmtlwdiflnaisvvnlimavgisiefcvhiastfirs pkhysrdekvkfaisemganifsgifitkllgcvvlafskseifiiyyfkmyisicllaa vhglvllpvllsi

  8. Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    2005-06-23

    I Cell Disease; Fucosidosis; Globoid Cell Leukodystrophy; Adrenoleukodystrophy; Mannosidosis; Niemann-Pick Disease; Pulmonary Complications; Mucopolysaccharidosis I; Mucopolysaccharidosis VI; Metachromatic Leukodystrophy; Gaucher's Disease; Wolman Disease

  9. Stem Cell Transplant for Inborn Errors of Metabolism

    Science.gov (United States)

    2012-11-06

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

  10. Unrelated Hematopoietic Stem Cell Transplantation(HSCT) for Genetic Diseases of Blood Cells

    Science.gov (United States)

    2016-06-21

    Sickle Cell Disease; Thalassemia; Anemia; Granuloma; Wiskott-Aldrich Syndrome; Chediak Higashi Syndrome; Osteopetrosis; Neutropenia; Thrombocytopenia; Hurler Disease; Niemann-Pick Disease; Fucosidosis

  11. Transient in utero disruption of Cystic Fibrosis Transmembrane Conductance Regulator causes phenotypic changes in Alveolar Type II cells in adult rats

    Directory of Open Access Journals (Sweden)

    Larson Janet E

    2009-03-01

    Full Text Available Abstract Background Mechanicosensory mechanisms regulate cell differentiation during lung organogenesis. We have previously demonstrated that cystic fibrosis transmembrane conductance regulator (CFTR was integral to stretch-induced growth and development and that transient expression of antisense-CFTR (ASCFTR had negative effects on lung structure and function. In this study, we examined adult alveolar type II (ATII cell phenotype after transient knock down of CFTR by adenovirus-directed in utero expression of ASCFTR in the fetal lung. Results In comparison to (reporter gene-treated Controls, ASCFTR-treated adult rat lungs showed elevated phosphatidylcholine (PC levels in the large but not in the small aggregates of alveolar surfactant. The lung mRNA levels for SP-A and SP-B were lower in the ASCFTR rats. The basal PC secretion in ATII cells was similar in the two groups. However, compared to Control ATII cells, the cells in ASCFTR group showed higher PC secretion with ATP or phorbol myristate acetate. The cell PC pool was also larger in the ASCFTR group. Thus, the increased surfactant secretion in ATII cells could cause higher PC levels in large aggregates of surfactant. In freshly isolated ATII cells, the expression of surfactant proteins was unchanged, suggesting that the lungs of ASCFTR rats contained fewer ATII cells. Gene array analysis of RNA of freshly isolated ATII cells from these lungs showed altered expression of several genes including elevated expression of two calcium-related genes, Ca2+-ATPase and calcium-calmodulin kinase kinase1 (CaMkk1, which was confirmed by real-time PCR. Western blot analysis showed increased expression of calmodulin kinase I, which is activated following phosphorylation by CaMkk1. Although increased expression of calcium regulating genes would argue in favor of Ca2+-dependent mechanisms increasing surfactant secretion, we cannot exclude contribution of alternate mechanisms because of other phenotypic

  12. 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

  13. Contributions of NanI Sialidase to Caco-2 Cell Adherence by Clostridium perfringens Type A and C Strains Causing Human Intestinal Disease

    OpenAIRE

    Li, Jihong; McClane, Bruce A.

    2014-01-01

    Previous studies showed that Clostridium perfringens type D animal disease strain CN3718 uses NanI sialidase for adhering to enterocyte-like Caco-2 cells. The current study analyzed whether NanI is similarly important when type A and C human intestinal disease strains attach to Caco-2 cells. A PCR survey determined that the nanI gene was absent from typical type A food poisoning (FP) strains carrying a chromosomal enterotoxin (CPE) gene or the genetically related type C Darmbrand (Db) strains...

  14. Lacritin and other autophagy associated proteins in ocular surface health.

    Science.gov (United States)

    Karnati, Roy; Talla, Venu; Peterson, Katherine; Laurie, Gordon W

    2016-03-01

    Advantage may be taken of macroautophagy ('autophagy') to promote ocular health. Autophagy continually captures aged or damaged cellular material for lysosomal degradation and recyling. When autophagic flux is chronically elevated, or alternatively deficient, health suffers. Chronic elevation of flux and stress are the consequence of inflammatory cytokines or of dry eye tears but not normal tears invitro. Exogenous tear protein lacritin transiently accelerates flux to restore homeostasis invitro and corneal health invivo, and yet the monomeric active form of lacritin appears to be selectively deficient in dry eye. Tissue transglutaminase-dependent cross-linking of monomer decreases monomer quantity and monomer affinity for coreceptor syndecan-1 thereby abrogating activity. Tissue transglutaminase is elevated in dry eye. Mutation of arylsulfatase A, arylsulfatase B, ceroid-lipofuscinosis neuronal 3, mucolipin, or Niemann-Pick disease type C1 respectively underlie several diseases of apparently insufficient autophagic flux that affect the eye, including: metachromatic leukodystrophy, mucopolysaccharidosis type VI, juvenile-onset Batten disease, mucolipidosis IV, and Niemann-Pick type C associated with myelin sheath destruction of corneal sensory and ciliary nerves and of the optic nerve; corneal clouding, ocular hypertension, glaucoma and optic nerve atrophy; accumulation of 'ceroid-lipofuscin' in surface conjunctival cells, and in ganglion and neuronal cells; decreased visual acuity and retinal dystrophy; and neurodegeneration. For some, enzyme or gene replacement, or substrate reduction, therapy is proving to be successful. Here we discuss examples of restoring ocular surface homeostasis through alteration of autophagy, with particular attention to lacritin. PMID:26318608

  15. Work-related musculoskeletal disorders in sonographers: a review of causes and types of injury and best practices for reducing injury risk

    OpenAIRE

    Coffin, Carolyn

    2014-01-01

    Carolyn T Coffin Department of Diagnostic Ultrasound, Seattle University, Seattle, WA, USA Abstract: Work-related musculoskeletal disorders in sonography professionals have a reported incidence of 90%. These disorders are defined as conditions that are either caused by or aggravated by tasks performed in the workplace. These injuries have a financial and emotional impact on the worker and affect workplace productivity and quality patient care. The causes for these injuries are multifactorial...

  16. Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism.

    Science.gov (United States)

    Boenzi, Sara; Deodato, Federica; Taurisano, Roberta; Goffredo, Bianca Maria; Rizzo, Cristiano; Dionisi-Vici, Carlo

    2016-03-01

    Oxysterols are intermediates of cholesterol metabolism and are generated from cholesterol via either enzymatic or nonenzymatic pathways under oxidative stress conditions. Cholestan-3β,5α,6β-triol (C-triol) and 7-ketocholesterol (7-KC) have been proposed as new biomarkers for the diagnosis of Niemann-Pick type C (NP-C) disease, representing an alternative tool to the invasive and time-consuming method of fibroblast filipin test. To test the efficacy of plasma oxysterol determination for the diagnosis of NP-C, we systematically screened oxysterol levels in patients affected by different inherited disorders related with cholesterol metabolism, which included Niemann-Pick type B (NP-B) disease, lysosomal acid lipase (LAL) deficiency, Smith-Lemli-Opitz syndrome (SLOS), congenital familial hypercholesterolemia (FH), and sitosterolemia (SITO). As expected, NP-C patients showed significant increase of both C-triol and 7-KC. Strong increase of both oxysterols was observed in NP-B and less pronounced in LAL deficiency. In SLOS, only 7-KC was markedly increased, whereas in both FH and in SITO, oxysterol concentrations were normal. Interestingly, in NP-C alone, we observed that plasma oxysterols correlate negatively with patient's age and positively with serum total bilirubin, suggesting the potential relationship between oxysterol levels and hepatic disease status. Our results indicate that oxysterols are reliable and sensitive biomarkers of NP-C. PMID:26733147

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1), or Taybi-Linder syndrome is characterized by distinctive skeletal dysplasia, severe intrauterine and postnatal growth retardation, microcephaly, dysmorphic features, and neurological malformations. It is an autosomal recessive...

  18. N-type calcium channel antibody-mediated autoimmune encephalitis: An unlikely cause of a common presentation ☆ ☆☆ ★

    OpenAIRE

    Finkel, Leslie; Koh, Sookyong

    2013-01-01

    We report, to our knowledge, the only known pediatric case with encephalopathy and significantly elevated titers of N-type voltage-gated calcium channel antibody (N-type VGCC). The patient, an 8th grader, was previously healthy and presented with a one-week history of confusion, aphasia, transient fever, headaches, and dizziness. An underlying autoimmune process was suspected because of inflammatory changes in the brain MRI and multiple focal electrographic seizures captured in the EEG in the...

  19. Higher plasma soluble Receptor for Advanced Glycation End Products (sRAGE) levels are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12-year follow-up study

    DEFF Research Database (Denmark)

    Nin, Johanna W M; Jorsal, Anders; Merces Ferreira, Isabel Maria; Schalkwijk, Casper G; Prins, Martin H; Parving, Hans-Henrik; Tarnow, Lise; Rossing, Peter; Stehouwer, Coen D A

    2010-01-01

    To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunct...

  20. Midregional Fragment of Proadrenomedullin, New-Onset Albuminuria, and Cardiovascular and All-Cause Mortality in Patients With Type 2 Diabetes (ZODIAC-30)

    NARCIS (Netherlands)

    Landman, Gijs W. D.; van Dijk, Peter R.; Drion, Iefke; van Hateren, Kornelis J. J.; Struck, Joachim; Groenier, Klaas H.; Gans, Rijk O. B.; Bilo, Henk J. G.; Bakker, Stephan J. L.; Kleefstra, Nanne

    2014-01-01

    OBJECTIVEThe midregional fragment of proadrenomedullin (MR-proADM) is a marker of endothelial dysfunction and has been associated with a variety of diseases. Our aim was to investigate whether MR-proADM is associated with new-onset albuminuria and cardiovascular (CV) and all-cause mortality in patie

  1. Genetic architecture and evolution of the mating type locus in fusaria that cause soybean sudden death syndrome and bean root rot

    Science.gov (United States)

    Fusarium tucumaniae is the only known sexually reproducing species among the seven closely related fusaria that cause soybean sudden death syndrome (SDS) or bean root rot (BRR). Laboratory mating of F. tucumaniae required two mating-compatible strains, indicating that it is heterothallic. To assess ...

  2. Plasma growth differentiation factor-15 independently predicts all-cause and cardiovascular mortality as well as deterioration of kidney function in type 1 diabetic patients with nephropathy

    DEFF Research Database (Denmark)

    Lajer, Maria Stenkil; Jorsal, Anders; Tarnow, Lise;

    2010-01-01

    Growth deferentiation factor-15 (GDF-15) is involved in inflammation and apoptosis. Expression is induced in the heart in response to ischemia and in atherosclerotic plaques. The aim of this study was to investigate GDF-15 levels in relation to all-cause mortality, cardiovascular mortality and mo...

  3. Complete Genome Sequence of Salmonella enterica Serovar Agona Pulsed-Field Type SAGOXB.0066, Cause of a 2008 Pan-European Outbreak

    OpenAIRE

    McCusker, Matthew P.; Hokamp, Karsten; Buckley, James F.; Wall, Patrick G; Martins, Marta; Fanning, Séamus

    2014-01-01

    Salmonella enterica serovar Agona is in the top 10 most common nontyphoidal serovars reported in humans in the European Union. Here we report the complete genome sequence of an S. enterica serovar Agona isolate, designated 24249, that was the cause of a pan-European outbreak in 2008 with 163 confirmed cases reported.

  4. A second mutation in the type II procollagen gene (COL2AI) causing stickler syndrome (arthro-ophthalmopathy) is also a premature termination codon.

    OpenAIRE

    Ahmad, N N; McDonald-McGinn, D M; Zackai, E H; Knowlton, R G; LaRossa, D; DiMascio, J; Prockop, D J

    1993-01-01

    Genetic linkage analyses suggest that mutations in type II collagen may be responsible for Stickler syndrome, or arthro-ophthalmopathy (AO), in many families. In the present study oligonucleotide primers were developed to amplify and directly sequence eight of the first nine exons of the gene for type II procollagen (COL2A1). Analysis of the eight exons in 10 unrelated probands with AO revealed that one had a single-base mutation in one allele that changed the codon of -CGA- for arginine at a...

  5. Comparative considerations on radioactive wastes, and on environmental aesthetical and thermal pollution caused in the normal operation of the main reactor types used in nuclear power plants

    International Nuclear Information System (INIS)

    The paper analyses four types of nuclear reactors, currently used at a world-wide scale from the point of view of the environmental impact due to the radioactive wastes and the thermal and aesthetical pollution. Solid, liquid, gaseous and tritide radioactive products are taken into consideration in case of normal operation conditions of the nuclear power plants. The comparison among the reactor types PWR, BWR, PHWR and HTGR shows a definite lagging for the case of the PHWR reactor, installed at the Cernavoda Nuclear Power Plant. (author). 7 figs., 1 tabs., 12 refs

  6. Causes of Domestic Water Consumption Trends in the City of Alicante: Exploring the Links between the Housing Bubble, the Types of Housing and the Socio-Economic Factors

    Directory of Open Access Journals (Sweden)

    Álvaro-Francisco Morote

    2016-08-01

    Full Text Available The European Mediterranean coastline has experienced major tourism-related urbanization since 1960. This is a dynamic that has led to increased spending on water consumption for urban and tourism-related uses. The objective of this paper is to define and to analyze how domestic water consumption in the city of Alicante evolved between 2000 and 2013. Real billing figures for individual households were analyzed according to the type of housing and the income level of the occupants. The conclusions drawn show that consumption fell over the period studied, and that there are different patterns in water expenditure depending on the type of housing and the inhabitants.

  7. Four patients with Sillence type I osteogenesis imperfecta and mild bone fragility, complicated by left ventricular cardiac valvular disease and cardiac tissue fragility caused by type I collagen mutations

    DEFF Research Database (Denmark)

    Vandersteen, Anthony M; Lund, Allan M; Ferguson, David J P;

    2014-01-01

    Osteogenesis imperfecta (OI) type I is a hereditary disorder of connective tissue (HDCT) characterized by blue or gray sclerae, variable short stature, dentinogenesis imperfecta, hearing loss, and recurrent fractures from infancy. We present four examples of OI type I complicated by valvular hear...

  8. Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis

    OpenAIRE

    Crozat, Karine; Hoebe, Kasper; Ugolini, Sophie; Hong, Nancy A.; Janssen, Edith; Rutschmann, Sophie; Mudd, Suzanne; Sovath, Sosathya; Vivier, Eric; Beutler, Bruce

    2007-01-01

    Mouse cytomegalovirus (MCMV) susceptibility often results from defects of natural killer (NK) cell function. Here we describe Jinx, an N-ethyl-N-nitrosourea–induced MCMV susceptibility mutation that permits unchecked proliferation of the virus, causing death. In Jinx homozygotes, activated NK cells and cytotoxic T lymphocytes (CTLs) fail to degranulate, although they retain the ability to produce cytokines, and cytokine levels are markedly elevated in the blood of infected mutant mice. Jinx w...

  9. The cause of urinary symptoms among Human T Lymphotropic Virus Type I (HLTV-I) infected patients: a cross sectional study

    OpenAIRE

    Salgado Katia; Muniz Andre L; Castro Neviton; Santana Juliana F; Rehem Ana; Rocha Paulo N; Rocha Heonir; Carvalho Edgar M.

    2007-01-01

    Abstract Background HTLV-I infected patients often complain of urinary symptomatology. Epidemiological studies have suggested that these individuals have a higher prevalence and incidence of urinary tract infection (UTI) than seronegative controls. However, the diagnosis of UTI in these studies relied only on patient information and did not require confirmation by urine culture. The purpose of this study was to investigate the role of urinary tract infection (UTI) as the cause of urinary symp...

  10. Prognostic value of physicians' assessment of compliance regarding all-cause mortality in patients with type 2 diabetes: primary care follow-up study

    OpenAIRE

    Rüter Gernot; Rothenbacher Dietrich; Brenner Hermann

    2006-01-01

    Abstract Background Whether the primary care physician's assessment of patient compliance is a valuable prognostic marker to identify patients who are at increased risk of death, or merely reflects measurement of various treatment parameters such as HbA1C or other laboratory markers is unclear. The objective of this prospective cohort study was to investigate the prognostic value of the physicians' assessment of patient compliance and other factors with respect to all-cause mortality during a...

  11. Markers of inflammation and endothelial dysfunction are associated with incident cardiovascular disease, all-cause mortality, and progression of coronary calcification in type 2 diabetic patients with microalbuminuria

    DEFF Research Database (Denmark)

    von Scholten, Bernt Johan; Reinhard, Henrik; Hansen, Tine Willum; Schalkwijk, Casper G; Stehouwer, Coen; Parving, Hans-Henrik; Jacobsen, Peter Karl; Rossing, Peter

    2016-01-01

    artery disease (CAD). METHODS: Prospective study including 200 patients receiving multifactorial treatment. Markers of inflammation (TNF-ɑ, sICAM-1, sICAM-3, hsCRP, SAA, IL-1β, IL-6, IL-8) and endothelial dysfunction (thrombomodulin, sVCAM-1, sICAM-1, sICAM-3, sE-selectin, sP-selectin) were measured at.......1years. In adjusted and fully adjusted Cox models, TNF-ɑ was a determinant of CVD and all-cause mortality (p≤0.007). Further, in adjusted and fully adjusted logistic regression, TNF-ɑ was related to CAC progression (p≤0.042). Of the other biomarkers, sICAM-3 and thrombomodulin were also associated with...... both endpoints (p≤0.046), IL-1β with CVD endpoints (p=0.021), and sVCAM-1 and sICAM-1 with all-cause mortality (p≤0.005). Higher composite z-scores including all markers of inflammation and endothelial dysfunction were associated with CVD and all-cause mortality (p≤0.008). CONCLUSIONS: In patients with...

  12. Copeptin, a surrogate marker for arginine vasopressin, is associated with cardiovascular and all-cause mortality in patients with type 2 diabetes (ZODIAC-31)

    NARCIS (Netherlands)

    Riphagen, Ineke J.; Boertien, Wendy E.; Alkhalaf, Alaa; Kleefstra, Nanno; Gansevoort, Ron T.; Groenier, Klaas H.; van Hateren, Kornelis J. J.; Struck, Joachim; Navis, Gerjan; Bilo, Henk J. G.; Bakker, Stephan J. L.

    2013-01-01

    OBJECTIVE: Copeptin, a surrogate marker for arginine vasopressin, has been associated with cardiovascular (CV) events and mortality in patients with type 2 diabetes complicated by end-stage renal disease or acute myocardial infarction. For stable outpatients, these associations are unknown. Our aim

  13. Risk Profiles and Penetrance Estimations in Multiple Endocrine Neoplasia Type 2A Caused by Germline RET Mutations Located in Exon 10

    NARCIS (Netherlands)

    Frank-Raue, Karin; Rybicki, Lisa A.; Erlic, Zoran; Schweizer, Heiko; Winter, Aurelia; Milos, Ioana; Toledo, Sergio P. A.; Toledo, Rodrigo A.; Tavares, Marcos R.; Alevizaki, Maria; Mian, Caterina; Siggelkow, Heide; Huefner, Michael; Wohllk, Nelson; Opocher, Giuseppe; Dvorakova, Sarka; Bendlova, Bela; Czetwertynska, Malgorzata; Skasko, Elzbieta; Barontini, Marta; Sanso, Gabriela; Vorlaender, Christian; Maia, Ana Luiza; Patocs, Attila; Links, Thera P.; de Groot, Jan Willem; Kerstens, Michiel N.; Valk, Gerlof D.; Miehle, Konstanze; Musholt, Thomas J.; Biarnes, Josefina; Damjanovic, Svetozar; Muresan, Mihaela; Wuester, Christian; Fassnacht, Martin; Peczkowska, Mariola; Fauth, Christine; Golcher, Henriette; Walter, Martin A.; Pichl, Josef; Raue, Friedhelm; Eng, Charis; Neumann, Hartmut P. H.

    2011-01-01

    Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for cl

  14. Acid sphingomyelinase (aSMase) deficiency leads to abnormal microglia behavior and disturbed retinal function

    Energy Technology Data Exchange (ETDEWEB)

    Dannhausen, Katharina; Karlstetter, Marcus; Caramoy, Albert [Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne (Germany); Volz, Cornelia; Jägle, Herbert [Department of Ophthalmology, University Hospital Regensburg, Regensburg (Germany); Liebisch, Gerhard [Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg (Germany); Utermöhlen, Olaf [Institute for Medical Microbiology, Immunology and Hygiene and Center for Molecular Medicine Cologne, University of Cologne, Cologne (Germany); Langmann, Thomas, E-mail: thomas.langmann@uk-koeln.de [Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne (Germany)

    2015-08-21

    Mutations in the acid sphingomyelinase (aSMase) coding gene sphingomyelin phosphodiesterase 1 (SMPD1) cause Niemann-Pick disease (NPD) type A and B. Sphingomyelin storage in cells of the mononuclear phagocyte system cause hepatosplenomegaly and severe neurodegeneration in the brain of NPD patients. However, the effects of aSMase deficiency on retinal structure and microglial behavior have not been addressed in detail yet. Here, we demonstrate that retinas of aSMase{sup −/−} mice did not display overt neuronal degeneration but showed significantly reduced scotopic and photopic responses in electroretinography. In vivo fundus imaging of aSMase{sup −/−} mice showed many hyperreflective spots and staining for the retinal microglia marker Iba1 revealed massive proliferation of retinal microglia that had significantly enlarged somata. Nile red staining detected prominent phospholipid inclusions in microglia and lipid analysis showed significantly increased sphingomyelin levels in retinas of aSMase{sup −/−} mice. In conclusion, the aSMase-deficient mouse is the first example in which microglial lipid inclusions are directly related to a loss of retinal function. - Highlights: • aSMase-deficient mice show impaired retinal function and reactive microgliosis. • aSMase-deficient microglia express pro-inflammatory transcripts. • aSMase-deficient microglia proliferate and have increased cell body size. • In vivo imaging shows hyperreflective spots in the fundus of aSMase-deficient mice. • aSMase-deficient microglia accumulate sphingolipid-rich intracellular deposits.

  15. Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Jean E. Vance

    2012-11-01

    Full Text Available Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer’s disease (AD, Huntington’s disease (HD, Parkinson’s disease (PD, Niemann-Pick type C (NPC disease and Smith-Lemli Opitz syndrome (SLOS. However, the molecular mechanisms underlying the correlation between altered cholesterol metabolism and the neurological deficits are, for the most part, not clear. NPC disease and SLOS are caused by mutations in genes involved in the biosynthesis or intracellular trafficking of cholesterol, respectively. However, the types of neurological impairments, and the areas of the brain that are most affected, differ between these diseases. Some, but not all, studies indicate that high levels of plasma cholesterol correlate with increased risk of developing AD. Moreover, inheritance of the E4 isoform of apolipoprotein E (APOE, a cholesterol-carrying protein, markedly increases the risk of developing AD. Whether or not treatment of AD with statins is beneficial remains controversial, and any benefit of statin treatment might be due to anti-inflammatory properties of the drug. Cholesterol balance is also altered in HD and PD, although no causal link between dysregulated cholesterol homeostasis and neurodegeneration has been established. Some important considerations for treatment of neurodegenerative diseases are the impermeability of the blood-brain barrier to many therapeutic agents and difficulties in reversing brain damage that has already occurred. This article focuses on how cholesterol balance in the brain is altered in several neurodegenerative diseases, and discusses some commonalities and differences among the diseases.

  16. Biallelic Mutations of Methionyl-tRNA Synthetase Cause a Specific Type of Pulmonary Alveolar Proteinosis Prevalent on Réunion Island.

    Science.gov (United States)

    Hadchouel, Alice; Wieland, Thomas; Griese, Matthias; Baruffini, Enrico; Lorenz-Depiereux, Bettina; Enaud, Laurent; Graf, Elisabeth; Dubus, Jean Christophe; Halioui-Louhaichi, Sonia; Coulomb, Aurore; Delacourt, Christophe; Eckstein, Gertrud; Zarbock, Ralf; Schwarzmayr, Thomas; Cartault, François; Meitinger, Thomas; Lodi, Tiziana; de Blic, Jacques; Strom, Tim M

    2015-05-01

    Methionyl-tRNA synthetase (MARS) catalyzes the ligation of methionine to tRNA and is critical for protein biosynthesis. We identified biallelic missense mutations in MARS in a specific form of pediatric pulmonary alveolar proteinosis (PAP), a severe lung disorder that is prevalent on the island of Réunion and the molecular basis of which is unresolved. Mutations were found in 26 individuals from Réunion and nearby islands and in two families from other countries. Functional consequences of the mutated alleles were assessed by growth of wild-type and mutant strains and methionine-incorporation assays in yeast. Enzyme activity was attenuated in a liquid medium without methionine but could be restored by methionine supplementation. In summary, identification of a founder mutation in MARS led to the molecular definition of a specific type of PAP and will enable carrier screening in the affected community and possibly open new treatment opportunities. PMID:25913036

  17. Patients Newly Diagnosed with Clinical Type 2 Diabetes during Oral Glucocorticoid Treatment and Observed for 14 Years: All-Cause Mortality and Clinical Developments

    DEFF Research Database (Denmark)

    Olivarius, Niels de Fine; Siersma, Volkert; Dyring-Andersen, Beatrice; Drivsholm, Thomas Bo; Hansen, Lars J; Henriksen, Jan Erik

    2010-01-01

    sex and to 1.39 (0.92-2.11, p = 0.12, n = 1086) when risk factors, complications and cancer were added to the model. Apart from differences in age and overweight, patients in this relatively small sample of those diagnosed with clinical type 2 diabetes during GC treatment were comparable at diagnosis......  Chronic exposure to glucocorticoids (GCs) has many side effects including glucose intolerance and diabetes and may accelerate the occurrence of cardiovascular disease and increase mortality. We studied the 14-year clinical development of diabetes in patients diagnosed with diabetes during GC...... treatment. A population-based sample of 1369 people newly diagnosed with clinical type 2 diabetes underwent a clinical examination at diagnosis, and surviving patients were followed up 6 and 14 years later. Patients receiving oral GC treatment at diagnosis were compared with the other patients. Of 1369...

  18. Patients newly diagnosed with clinical type 2 diabetes during oral glucocorticoid treatment and observed for 14 years: all-cause mortality and clinical developments

    DEFF Research Database (Denmark)

    Olivarius, Niels de Fine; Siersma, Volkert Dirk; Dyring-Andersen, B.; Drivsholm, Thomas Bo; Hansen, L.J.; Henriksen, J.E.

    2011-01-01

    sex and to 1.39 (0.92-2.11, p = 0.12, n = 1086) when risk factors, complications and cancer were added to the model. Apart from differences in age and overweight, patients in this relatively small sample of those diagnosed with clinical type 2 diabetes during GC treatment were comparable at diagnosis......Chronic exposure to glucocorticoids (GCs) has many side effects including glucose intolerance and diabetes and may accelerate the occurrence of cardiovascular disease and increase mortality. We studied the 14-year clinical development of diabetes in patients diagnosed with diabetes during GC...... treatment. A population-based sample of 1369 people newly diagnosed with clinical type 2 diabetes underwent a clinical examination at diagnosis, and surviving patients were followed up 6 and 14 years later. Patients receiving oral GC treatment at diagnosis were compared with the other patients. Of 1369...

  19. Type I Endoleak-like Phenomenon Causing Rupture of the Replaced Aneurysm Sac 12 Years after Open Repair of Abdominal Aortic Aneurysm

    OpenAIRE

    Matsushita, Masahiro; Ikezawa, Teruo; Banno, Hiroshi

    2008-01-01

    Only a few cases of endoleak following conventional abdominal aortic aneurysm repair have been reported. We treated a patient with a type I endoleak-like phenomenon occuring 12 years after conventional abdominal aortic aneurysm repair. Computed tomography demonstrated dilation of the surgically replaced, once-shrunken aneurysm sac to a diameter of 3.5 cm. Thrombus was identified between the graft and the sac. Four months later the sac ruptured, and emergency repair was performed. Dehiscence o...

  20. Multiple endocrine neoplasia type 2B caused by a single point mutation in RET proto-oncogene in a Chinese patient

    Institute of Scientific and Technical Information of China (English)

    张翼飞; 洪洁; 赵咏桔; 江凌; 戴蒙; 金晓龙; 陈家伦; 宁光

    2004-01-01

    @@ Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary syndrome which can present itself either in a familial form, characterized by a dominant pattern of inheritance, or in a sporadic form. It can be subdivided into multiple endocrine neoplasia type 2A (MEN-2A), multiple endocrine neoplasia type 2B (MEN-2B), and familial medullary thyroid carcinoma (FMTC).1-3 Among these conditions, MEN-2B, which has an extremely low rate of incidence, is the most severe form. Its clinical presentation includes C-cell hyperplasia or medullary thyroid carcinoma, pheochromocytoma, ganglioneuromatosis, accompanied with Marfanoid body habitus.4-8 Using the methods of single-strand conformational polymorphism (SSCP) and direct gene sequencing, Hofstra et al9 and Calson et al10 showed for the first time that MEN-2B is associated with a mutation in the RE arranged during transfection (RET) proto-oncogene, which is a receptor-type tyrosine kinase. The RET gene is located in the centromeric region of chromosome 10q11.2, and consists of 21 exons. Over 95% of MEN-2B patients have a specific point mutation at codon 918 in exon 16 of RET, resulting in the replacement of methionine with threonine [918Met(ATG)→Thr(ACG)].11-16 Although there have been many reports on the gene mutation associated with MEN-2B,17-19 there has been no previous reports on similar genetic studies in Chinese patients. In this study, we identified a MEN-2B Chinese patient and tried to establish the relationship between an RET gene mutation and the onset of MEN-2B, in order to further understand the hereditary characteristics of this disease and a basis for early diagnosis and early intervention.

  1. Bactericidal interactions of a beta-lactam and beta-lactamase inhibitors in experimental Pseudomonas aeruginosa endocarditis caused by a constitutive overproducer of type Id beta-lactamase.

    OpenAIRE

    Bayer, A S; Selecky, M; Babel, K; Hirano, L; Yih, J; Parr, T R

    1987-01-01

    We investigated the in vitro and in vivo effects of a combination of a beta-lactam (ceftazidime) and a beta-lactamase inhibitor (dicloxacillin) to synergistically kill a ceftazidime-resistant variant, Pseudomonas aeruginosa PA-48, which overproduces type Id cephalosporinase constitutively. In vitro, dicloxacillin plus ceftazidime exerted bactericidal synergy at approximately 10(5) CFU/ml of inoculum (but not at approximately 10(7)-CFU inoculum), whereas other beta-lactamase inhibitors (sulbac...

  2. Do gamma rays and alpha particles cause different types of lung cancer? A comparison between atomic bomb survivors and uranium miners

    International Nuclear Information System (INIS)

    Excess lung cancer risk has been associated with exposure to alpha particle radiation from inhaled radon daughter products among uranium miners in Czechoslovakia, Canada, the United States, and elsewhere, and with exposure to gamma rays and neutrons from the atomic bombings of Hiroshima and Nagasaki, Japan. Differences in distribution by histological type, as well as certain epidemiological differences, suggest the possibility of differences in the causation of radiation-induced lung cancer. An epidemiological analysis is summarised of results from a blind pathology panel review of tissue slides from lung cancer cases diagnosed in 108 Japanese A bomb survivors and 92 American uranium miners selected on the basis of radiation exposure, smoking history, sex, age, and source and quality of pathology material. Consensus diagnoses were obtained with respect to principal sub-type, including squamous cell cancer, small cell cancer, adenocarcinoma, and less frequent sub-types. The results were analysed in terms of population, radiation dose, and smoking history. As expected, the proportion of squamous cell cancer was positively related to smoking history in both populations. The relative frequencies of small cell cancer and adenocarcinoma were very different in the two populations, but this difference was adequately accounted for by differences in radiation dose (more specifically, dose-based relative risk estimates based on published risk coefficients). Data for the two populations conformed to a common pattern, in which radiation-induced cancers appeared more likely to be of the small-cell sub-type, and less likely to be adenocarcinomas. No additional explanation in terms of radiation quality (alpha particles or gamma rays), uniform or local irradiation, inhaled as against external radiation source, or other population differences, appeared to be required. (author)

  3. Reliability of Poly B-411, a Polymeric Anthraquinone-Based Dye, in Determining the Rot Type Caused by Wood-Inhabiting Fungi

    OpenAIRE

    Cookson, L. J.

    1995-01-01

    In both Basidiomycotina and Ascomycotina, Poly B-411 decolorization was an excellent indicator of the ability to cause white rot: 109 of the 110 isolates of brown rot fungi tested definitely did not decolorize Poly B-411, and 392 of the 401 mainly active isolates of white rot fungi decolorized Poly B-411. The Bavendamm (tannic acid) reaction was a less reliable test: of 74 white rot isolates examined that could not decay wood, 6 decolorized Poly B-411, but 19 gave positive Bavendamm reactions...

  4. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2

    OpenAIRE

    Lemmers, Richard J. L. F.; Tawil, Rabi; Petek, Lisa M.; Balog, Judit; Block, Gregory J.; Santen, Gijs W. E.; Amell, Amanda M.; van der Vliet, Patrick J.; ALmomani, Rowida; Straasheijm, Kirsten R; Krom, Yvonne D.; Klooster, Rinse; Sun, Yu; den Dunnen, Johan T.; Helmer, Quinta

    2012-01-01

    Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by a contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here we show that mutations in SMCHD1 (structural maintenance of chromosomes flexible hinge domain contai...

  5. Relationship of HbA1c variability, absolute changes in HbA1c, and all-cause mortality in type 2 diabetes

    DEFF Research Database (Denmark)

    Skriver, Mette Vinther; Sandbæk, Annelli; Kristensen, Jette Kolding;

    2015-01-01

    was defined as the mean absolute residual around the line connecting index value with closing value. Cox proportional hazard models with restricted cubic splines were used, with all-cause mortality as the outcome. RESULTS: Variability between 0 and 0.5 HbA1c percentage point was not associated with......OBJECTIVE: We assessed the relationship of mortality with glycated hemoglobin (HbA1c) variability and with absolute change in HbA1c. DESIGN: A population-based prospective observational study with a median follow-up time of 6 years. METHODS: Based on a validated algorithm, 11 205 Danish individuals...

  6. Breast irradiation causes pallor in the nipple-areolar complex in women with Celtic skin type (result from the St. George and Wollongong randomised breast boost trial)

    International Nuclear Information System (INIS)

    The nipple-areolar complex (NAC) has special histological properties with higher melanocyte concentration than breast skin. To date, there are no data describing the late effects on the NAC following breast-conserving therapy (BCT). This study evaluated colour changes in the NAC in patients treated with breast-conserving surgery and adjuvant radiotherapy after 5 years. Digital photographs obtained at 5 years following breast irradiation from the St. George and Wollongong (SGW) trial (NCT00138814) were evaluated by five experts using an iPad® (Apple Inc., Cupertino, CA, USA) application specifically created for this study. The SGW trial randomised 688 patients with Tis-2, N0-1, M0 carcinoma to the control arm of 50Gy in 25 fractions and boost arm of 45Gy in 25 fractions and 16 Gy in 8 fractions electron boost. A total of 141/372 (38%) patients had altered NAC (86% lighter, 10% darker). Patients with Celtic skin type had increased likelihood of having an altered NAC (odds ratio (OR), 1.75 (CI 1.1–2.7, P=0.011)). On subgroup analysis, those with Celtic skin type receiving biologically equivalent dose (BED) Gy3 ≥ 80Gy had OR of 3.03 (95% CI 1.2–7.5, P=0.016) for having altered colour. There was a dose response with more profound changes seen in the NAC compared with irradiated breast skin if BED Gy3 ≥ 80Gy with OR of 2.42 (95% CI 1.1–5.6, P=0.036). In this Caucasian BCT population, over 30% of patients developed lighter NAC and more commonly in women with Celtic skin type. The degree of this effect increased with higher radiation dose.

  7. Mutations Affecting the BHLHA9 DNA-Binding Domain Cause MSSD, Mesoaxial Synostotic Syndactyly with Phalangeal Reduction, Malik-Percin Type

    Science.gov (United States)

    Malik, Sajid; Percin, Ferda E.; Bornholdt, Dorothea; Albrecht, Beate; Percesepe, Antonio; Koch, Manuela C.; Landi, Antonio; Fritz, Barbara; Khan, Rizwan; Mumtaz, Sara; Akarsu, Nurten A.; Grzeschik, Karl-Heinz

    2014-01-01

    Mesoaxial synostotic syndactyly, Malik-Percin type (MSSD) (syndactyly type IX) is a rare autosomal-recessive nonsyndromic digit anomaly with only two affected families reported so far. We previously showed that the trait is genetically distinct from other syndactyly types, and through autozygosity mapping we had identified a locus on chromosome 17p13.3 for this unique limb malformation. Here, we extend the number of independent pedigrees from various geographic regions segregating MSSD to a total of six. We demonstrate that three neighboring missense mutations affecting the highly conserved DNA-binding region of the basic helix-loop-helix A9 transcription factor (BHLHA9) are associated with this phenotype. Recombinant BHLHA9 generated by transient gene expression is shown to be located in the cytoplasm and the cell nucleus. Transcription factors 3, 4, and 12, members of the E protein (class I) family of helix-loop-helix transcription factors, are highlighted in yeast two-hybrid analysis as potential dimerization partners for BHLHA9. In the presence of BHLHA9, the potential of these three proteins to activate expression of an E-box-regulated target gene is reduced considerably. BHLHA9 harboring one of the three substitutions detected in MSSD-affected individuals eliminates entirely the transcription activation by these class I bHLH proteins. We conclude that by dimerizing with other bHLH protein monomers, BHLHA9 could fine tune the expression of regulatory factors governing determination of central limb mesenchyme cells, a function made impossible by altering critical amino acids in the DNA binding domain. These findings identify BHLHA9 as an essential player in the regulatory network governing limb morphogenesis in humans. PMID:25466284

  8. The Explosive Human Immunodeficiency Virus Type 1 Epidemic among Injecting Drug Users of Kathmandu, Nepal, Is Caused by a Subtype C Virus of Restricted Genetic Diversity

    OpenAIRE

    Oelrichs, Robert B.; Shrestha, Iswar L.; Anderson, David A.; Deacon, Nicholas J.

    2000-01-01

    An explosive epidemic of human immunodeficiency virus type 1 (HIV-1) has been documented among the injecting drug user population of Kathmandu, Nepal, whose seropositivity rate has risen from 0 to 40% between 1995 and 1997. By using Catrimox to preserve whole-blood RNA at ambient temperature for transportation, HIV-1 envelope V3–V4 sequences were obtained from 36 patients in this group. Analysis of the sequences indicated a homogenous epidemic of subtype C virus, with at least two independent...

  9. First successful reduction of clinical allergenicity of food by genetic modification: Mal d 1-silenced apples cause fewer allergy symptoms than the wild-type cultivar

    DEFF Research Database (Denmark)

    Dubois, A. E. J.; Pagliarani, G.; Brouwer, R. M.;

    2015-01-01

    BACKGROUND: Genetic modification of allergenic foods such as apple has the potential to reduce their clinical allergenicity, but this has never been studied by oral challenges in allergic individuals. METHODS: We performed oral food challenges in 21 apple-allergic individuals with Elstar apples...... which had undergone gene silencing of the major allergen of apple, Mal d 1, by RNA interference. Downregulation of Mal d 1 gene expression in the apples was verified by qRT-PCR. Clinical responses to the genetically modified apples were compared to those seen with the wild-type Elstar using a visual...... analogue scale (VAS). RESULTS: Gene silencing produced two genetically modified apple lines expressing Mal d 1.02 and other Mal d 1 gene mRNA levels which were extensively downregulated, that is only 0.1-16.4% (e-DR1) and 0.2-9.9% (e-DR2) of those of the wild-type Elstar, respectively. Challenges with...

  10. Lower blood glucose and variability are associated with earlier recovery from renal injury caused by episodic urinary tract infection in advanced type 2 diabetic chronic kidney disease.

    Directory of Open Access Journals (Sweden)

    Ping-Fang Chiu

    Full Text Available In our previous study, type 2 diabetic chronic kidney disease (CKD patients with glomerular filtration rates of 9 days, Group B groups. The differences in the continuous and categorical variables of the two groups were assessed separately. The mean glucose levels and their variability (using the standard deviation and the coefficient of standard deviation were compared at the fasting, midday pre-meal, evening pre-meal, and evening post-meal time points during hospitalization. We have organized the manuscript in a manner compliant with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology statement.Acute kidney injury occurred within the two groups (p = 0.007 and p = 0.001, respectively. The early-morning blood glucose levels (149.7±44.0 mg/dL and average blood glucose levels (185.6±52.0 mg/dL were better in Group A (p = 0.01, p = 0.02. Group A patients also had lower glucose variability than Group B at the different time points (p<0.05. Group A also had earlier renal recovery. More relevant pathogens were identified from blood in Group B (p = 0.038.Early-morning fasting and mean blood glucose levels and their variability can be good indicators of severe infection and predictors of renal outcome in type 2 diabetic patients with CKD and UTI.

  11. Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I).

    OpenAIRE

    Hoth, C F; Milunsky, A; Lipsky, N; Sheffer, R; Clarren, S K; Baldwin, C T

    1993-01-01

    Waardenburg syndrome type I (WS-I) is an autosomal dominant disorder characterized by sensorineural hearing loss, dystopia canthorum, pigmentary disturbances, and other developmental defects. Klein-Waardenburg syndrome (WS-III) is a disorder with many of the same characteristics as WS-I and includes musculoskeletal abnormalities. We have recently reported the identification and characterization of one of the first gene defects, in the human PAX3 gene, which causes WS-I. PAX3 is a DNA-binding ...

  12. Variation in the Vitreous Phenotype of Stickler Syndrome Can Be Caused by Different Amino Acid Substitutions in the X Position of the Type II Collagen Gly-X-Y Triple Helix

    OpenAIRE

    Richards, Allan J; Baguley, David M.; Yates, John R W; Lane, Carol; Nicol, Mary; Harper, Peter S; Scott, John D.; Snead, Martin P

    2000-01-01

    Stickler syndrome is a dominantly inherited disorder characterized by arthropathy, midline clefting, hearing loss, midfacial hypoplasia, myopia, and retinal detachment. These features are highly variable both between and within families. Mutations causing the disorder have been found in the COL2A1 and COL11A1 genes. Premature termination codons in COL2A1 that result in haploinsufficiency of type II collagen are a common finding. These produce a characteristic congenital “membranous” anomaly o...

  13. Recombinant human acid sphingomyelinase as an adjuvant to sorafenib treatment of experimental liver cancer.

    Directory of Open Access Journals (Sweden)

    Radoslav Savić

    Full Text Available BACKGROUND: Hepatocellular carcinoma (HCC is the most common form of liver cancer and the third leading cause of cancer death worldwide. The only approved systemic treatment for unresectable HCC is the oral kinase inhibitor, sorafenib. Recombinant human acid sphingomyelinase (rhASM, which hydrolyzes sphingomyelin to ceramide, is an orphan drug under development for the treatment of Type B Niemann-Pick disease (NPD. Due to the hepatotropic nature of rhASM and its ability to generate pro-apoptotic ceramide, this study evaluated the use of rhASM as an adjuvant treatment with sorafenib in experimental models of HCC. METHODOLOGY/PRINCIPAL FINDINGS: In vitro, rhASM/sorafenib treatment reduced the viability of Huh7 liver cancer cells more than sorafenib. In vivo, using a subcutaneous Huh7 tumor model, mouse survival was increased and proliferation in the tumors decreased to a similar extent in both sorafenib and rhASM/sorafenib treatment groups. However, combined rhASM/sorafenib treatment significantly lowered tumor volume, increased tumor necrosis, and decreased tumor blood vessel density compared to sorafenib. These results were obtained despite poor delivery of rhASM to the tumors. A second (orthotopic model of Huh7 tumors also was established, but modest ASM activity was similarly detected in these tumors compared to healthy mouse livers. Importantly, no chronic liver toxicity or weight loss was observed from rhASM therapy in either model. CONCLUSIONS/SIGNIFICANCE: The rhASM/sorafenib combination exhibited a synergistic effect on reducing the tumor volume and blood vessel density in Huh7 xenografts, despite modest activity of rhASM in these tumors. No significant increases in survival were observed from the rhASM/sorafenib treatment. The poor delivery of rhASM to Huh7 tumors may be due, at least in part, to low expression of mannose receptors. The safety and efficacy of this approach, together with the novel findings regarding enzyme targeting

  14. Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation.

    Directory of Open Access Journals (Sweden)

    Qingyu Qin

    Full Text Available Perturbation of lipid metabolism, especially of cholesterol homeostasis, can be catastrophic to mammalian brain, as it has the highest level of cholesterol in the body. This notion is best illustrated by the severe progressive neurodegeneration in Niemann-Pick Type C (NPC disease, one of the lysosomal storage diseases, caused by mutations in the NPC1 or NPC2 gene. In this study, we found that growth cone collapse induced by genetic or pharmacological disruption of cholesterol egress from late endosomes/lysosomes was directly related to a decrease in axonal and growth cone levels of the phosphorylated form of the tumor suppressor factor p53. Cholesterol perturbation-induced growth cone collapse and decrease in phosphorylated p53 were reduced by inhibition of p38 mitogen-activated protein kinase (MAPK and murine double minute (Mdm2 E3 ligase. Growth cone collapse induced by genetic (npc1-/- or pharmacological modification of cholesterol metabolism was Rho kinase (ROCK-dependent and associated with increased RhoA protein synthesis; both processes were significantly reduced by P38 MAPK or Mdm2 inhibition. Finally, in vivo ROCK inhibition significantly increased phosphorylated p53 levels and neurofilaments in axons, and axonal bundle size in npc1-/- mice. These results indicate that NPC-related and cholesterol perturbation-induced axonal pathology is associated with an abnormal signaling pathway consisting in p38 MAPK activation leading to Mdm2-mediated p53 degradation, followed by ROCK activation. These results also suggest new targets for pharmacological treatment of NPC disease and other diseases associated with disruption of cholesterol metabolism.

  15. Les manifestation oculaires des troubles primitifs du metabolisme des lipides: Étude clinique, génétique et anatomo-pathologique

    Directory of Open Access Journals (Sweden)

    D. Klein

    1955-01-01

    Full Text Available Les lipidoses constituent un groupe d'affections systématisées, caractérisées par une surcharge lipidique des tissus (en premier lieu du système réticulo-endothélial, accessoirement aussi de divers parenchymes. Le processus qui est à la base de ces "thèsaurismoses" consiste en une perturbation primitive du métabolisme des graisses et des substances apparentées, aboutissant à une infiltration lipidique des organes et entraînant des troubles cliniques variés et souvent très graves. La participation prépondérante du système nerveux central et de l'oeil aux désordres cliniques represente un des aspects les plus importants de la pathologie des lipidoses. Toutes ces affections, excepté la maladie de Hand-Schüller-Christian, offrent en outre un intérêt considérable à cause du rôle primordial que joue l'hérédité comme facteur étiologique. On peut distinguer trois principaux types de lipidoses, groupés d'aprés les substances thésaurisées: les lipidoses à phosphatides, qui peuvent être subdivisées en A. les idioties amaurotiques (surcharge en gangliosides et B. la maladie de Niemann-Pick (sphingomyélines; les lipidoses à cérébrosides (cérasine représentées par la maladie de Gaucher; les lipidoses à cholestérol ou xanthomatoses.

  16. The cause of urinary symptoms among Human T Lymphotropic Virus Type I (HLTV-I infected patients: a cross sectional study

    Directory of Open Access Journals (Sweden)

    Salgado Katia

    2007-03-01

    Full Text Available Abstract Background HTLV-I infected patients often complain of urinary symptomatology. Epidemiological studies have suggested that these individuals have a higher prevalence and incidence of urinary tract infection (UTI than seronegative controls. However, the diagnosis of UTI in these studies relied only on patient information and did not require confirmation by urine culture. The purpose of this study was to investigate the role of urinary tract infection (UTI as the cause of urinary symptoms in HTLV-I infected patients. Methods In this cross sectional study we interviewed, and cultured urine from, 157 HTLV-I seropositive individuals followed regularly at a specialized clinic. All patients were evaluated by a neurologist and classified according to the Expanded Disability Status Scale (EDSS. Urodynamic studies were performed at the discretion of the treating physician. Results Sixty-four patients complained of at least one active urinary symptom but UTI was confirmed by a positive urine culture in only 12 of these patients (19%; the majority of symptomatic patients (81% had negative urine cultures. To investigate the mechanism behind the urinary complaints in symptomatic individuals with negative urine cultures, we reviewed the results of urodynamic studies performed in 21 of these patients. Most of them (90.5% had abnormal findings. The predominant abnormalities were detrusor sphincter hyperreflexia and dyssynergia, findings consistent with HTLV-I-induced neurogenic bladder. On a multivariate logistic regression, an abnormal EDSS score was the strongest predictor of urinary symptomatology (OR 9.87, 95% CI 3.465 to 28.116, P Conclusion Urinary symptomatology suggestive of UTI is highly prevalent among HTLV-I seropositive individuals but true UTI is responsible for the minority of cases. We posit that the main cause of urinary symptoms in this population is neurogenic bladder. Our data imply that HLTV-I infected patients with urinary

  17. MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis

    Science.gov (United States)

    2016-08-15

    Mucopolysaccharidosis I; Mucopolysaccharidosis II; Mucopolysaccharidosis VI; Mucopolysaccharidosis VII; Hurler Syndrome; Hunter Syndrome; Maroteaux Lamy Syndrome; Sly Syndrome; Glycoprotein Metabolic Disorders; Alpha Mannosidosis; Fucosidosis; Aspartylglucosaminuria; Adrenoleukodystrophy; Peroxisomal Disorders; Osteopetrosis; Sphingolipidosis; Gangliosidosis; Globoid Cell Leukodystrophy; Metachromatic Leukodystrophy; Niemann Pick B; Niemann Pick C Subtype 2; I-cell Disease

  18. D型动力锅炉过热器管失效原因分析%FAILURE CAUSE ANALYSIS ON SUPERHEATER PIPES OF D TYPE POWER BOILER

    Institute of Scientific and Technical Information of China (English)

    周焕英

    2015-01-01

    Comprehensive performance tests on the superheater pipes of power boiler B in Qilu Olefin Complex including such as macro morphology, components of the surface fouling and over-all properties of the material were made.The results showed that machine direction cracks of the No.1 and No.2 superheater pipes were the material developing creep cracks due to the performance worsen caused by the long time superheat, and surface fouling corrosion which could reduce the pipe wall thickness aggravating the crack speed of the superheater pipes.%通过对烯烃厂动力锅炉B炉过热器管进行宏观形貌、表面垢物成分、材料综合性能检验得知,该锅炉第一、二过热器管发生纵向开裂主要是由于其长期处于过热状态工作造成材料性能恶化所致的蠕变开裂;过热器管表面结垢物腐蚀导致的管壁减薄则加剧了其开裂的速度。

  19. Francisella tularensis type A Strains Cause the Rapid Encystment of Acanthamoeba castellanii and Survive in Amoebal Cysts for Three Weeks post Infection

    Energy Technology Data Exchange (ETDEWEB)

    El-Etr, S H; Margolis, J; Monack, D; Robison, R; Cohen, M; Moore, E; Rasley, A

    2009-07-28

    Francisella tularensis, the causative agent of the zoonotic disease tularemia, has recently gained increased attention due to the emergence of tularemia in geographical areas where the disease has been previously unknown, and the organism's potential as a bioterrorism agent. Although F. tularensis has an extremely broad host range, the bacterial reservoir in nature has not been conclusively identified. In this study, the ability of virulent F. tularensis strains to survive and replicate in the amoeba Acanthamoeba castellanii was explored. We observe that A. castellanii trophozoites rapidly encyst in response to F. tularensis infection and that this rapid encystment phenotype (REP) is caused by factor(s) secreted by amoebae and/or F. tularensis into the co-culture media. Further, our results indicate that in contrast to LVS, virulent strains of F. tularensis can survive in A. castellanii cysts for at least 3 weeks post infection and that induction of rapid amoeba encystment is essential for survival. In addition, our data indicate that pathogenic F. tularensis strains block lysosomal fusion in A. castellanii. Taken together, these data suggest that the interactions between F. tularensis strains and amoeba may play a role in the environmental persistence of F. tularensis.

  20. A novel synonymous mutation in the MPZ gene causing an aberrant splicing pattern and Charcot-Marie-Tooth disease type 1b.

    Science.gov (United States)

    Corrado, L; Magri, S; Bagarotti, A; Carecchio, M; Piscosquito, G; Pareyson, D; Varrasi, C; Vecchio, D; Zonta, A; Cantello, R; Taroni, F; D'Alfonso, S

    2016-08-01

    Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy with a heterogeneous genetic background. Here, we describe two CMT1B families with a mild sensory-motor neuropathy and a novel synonymous variant (c.309G > T, p.G103G) in exon 3 of the MPZ gene. Next generation sequencing analysis on a 94 CMT gene panel showed no mutations in other disease genes. In vitro splicing assay and mRNA expression analysis indicated that the c.309T variant enhances a cryptic donor splice site at position c.304 resulting in the markedly increased expression of the r.304_448del alternative transcript in patients' cells. This transcript is predicted to encode a truncated P0 protein (p.V102Cfs11*) lacking the transmembrane domain, thus suggesting a possible haploinsufficiency mechanism for this mutation. This is the third reported synonymous MPZ variant associated with CMT1 and affecting splicing. These data confirm the functional impact of synonymous variants on MPZ splicing and their possible role as disease-causing mutations rather than silent polymorphisms. PMID:27344971

  1. Approach to Neurometabolic Diseases from a Pediatric Neurological Point of View

    Directory of Open Access Journals (Sweden)

    Parvaneh KARIMZADEH

    2015-01-01

    CW, Cleary MA, Thorburn DR. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology. 2002;59:1406–11.Wolf NI, Smeitink AM. Mitochondrial disorders: A proposal for consensus diagnostic criteria in infants and children. Neurology. 2002;59:1402–5.Majamaa K, Moilanen JS, Uimonen S, et al. Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: Prevalence of the mutation in an adult population. Am J Hum Genet. 1998;63:447–54.Lamont PJ, Surtees R, Woodward CE, Leonard JV, Wood NW, Harding AE. Clinical and laboratory findings in referrals for mitochondrial DNA analysis. Arch Dis Child, Arch Dis Child. 1998 Jul;79(1:22-7.Ferri R. Neurometabolic Disorders.Arch Neurol. 2005;62:1045-1046.PapettiL, ParisiP, LeuzziV, NardecchiaF, NicitaF, UrsittiF, Marra F, Paolino MC, Spalice A. Metabolic epilepsy: an update. Brain & Development. 2013 Oct;35(9:827-41.Salpietro V, Phadke R, Saggar A, Hargreaves IP, Yates R, Fokoloros C, Mankad K, Hertecant J, Ruggieri M, McCormick D, KinaliM. Zellweger syndrome and secondary mitochondrial myopathy. Eur J Pediatr. 2014 Oct 7 (Article in press.Schulz A, Kohlschütter A. NCL Disorders: Frequent Causes of Childhood Dementia. Iran J Child Neurol.2013 Winter; 7(1:1-8.Jalanko A, Braulke T. Neuronal ceroidlipofuscinoses. Biochim Biophys Acta 2009;1793:697-709.Karimzadeh P, Jafari N, NejadBiglari H, Jabbeh Dari S, Ahmad Abadi F, Alaee MR, Nemati H,  SaketS, Tonekaboni SH, Taghdiri MM, Ghofrani M. GM2-Gangliosidosis (Sandhoff and Tay-Sachs disease: Diagnosis and Neuroimaging Findings(An Iranian Pediatric Case Series. Iran J Child Neurol. 2014 Summer;8(3: 55-60.Vanier MT, Duthel S, Rodriguez-Lafrasse C, et al. Genetic heterogeneity in Niemann-Pick C disease: a study using somatic cell hybridization and linkage analysis. Am J Hum Genet. 1996;58(1:118-125.Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010;5:16.Meikle PJ, Hopwood JJ, Clague AE, et al

  2. Puerarin reduces increased c-fos, c-jun, and type Ⅳ collagen expression caused by high glucose in glomerular mesangial cells

    Institute of Scientific and Technical Information of China (English)

    Cai-ping MAO; Zhen-lun GU

    2005-01-01

    Aim: Increased expression of c-fos, c-jun and type Ⅳ collagen (CoⅣ) in glomerular mesangial cells (GMC) are important characteristics of diabetic nephropathy.Both c-fos and c-jun regulate the gene expression of extracellular matrix components, and CoⅣ is the main component of the extracellular matrix. It has been reported that puerarin inhibits aggregation of the extracellular matrix in diabetic rats by an as yet unknown mechanism. The aim of this study is to investigate the effect of puerarin on c-fos, c-jun and CoⅣ expression in GMC cultured in medium containing 5.6 or 27.8 mmol/L glucose. Methods: The expressions ofc-fos and c-jun were measured at the protein level using flow cytometry. CoⅣ content was detected using radioimmunoassay. Protein kinase C (PKC) activity was measured using liquid scintillation counting. Results: Puerarin (10-5 mmol/L) significantly ameliorated the high-glucose effect on c-fos, c-jun and CoⅣ expression.This effect is accompanied by a reduced PKC activity in these cells. Conclusion:Our results suggest that reduced PKC activity and expression of c-fos and c-jun in GMC might participate in the mechanisms underlying the therapeutic effect of puerarin on diabetic nephropathy.

  3. Substitution of Aspartate for glycine 1018 in the Type III procollagen (COL3AI) gene causes type IV Ehlers-Danlos Syndrome: The mutated allele is present in most blood leukocytes of the asymptomatic and mosaic mother

    Energy Technology Data Exchange (ETDEWEB)

    Kontusaari, S.; Tromp, G.; Kuivaniemi, H.; Prockop, D.J. (Thomas Jefferson Univ., Philadelphia, PA (United States)); Stolle, C. (Robert Wood Johnson Medical School, Piscataway, NJ (United States)); Pope, F.M.

    1992-09-01

    A proband with arterial ruptures and skin changes characteristic of the type IV variant of Ehlers-Danlos syndrome was found to have a single-base mutation in the type III procollagen gene, which converted the codon for glycine at amino position 1018 to a codon for aspartate. (Amino acid positions are numbered by the standard convention in which the first glycine of the triple-helical domain of an [alpha] chain is number 1. The numbers of positions in the [alpha]1(III) chains can be converted to positions in the human pro[alpha](III) chain by adding 167.). Nucleotide sequencing of overlapping PCR products in which the two alleles were distinguished demonstrated that the mutation of glycine 1018 was the only mutation that changed the primary structure of type III procollagen. The glycine substitution markedly decreased the amount of type III procollagen secreted into the medium by cultured skin fibroblasts from the proband. It is surprising that the same mutation was found in about 94% of the peripheral blood leukocytes from the proband's asymptomatic 72-year-old mother. Other tissues from the mother contained the mutated allele; it was present in 0%-100% of different samples of hair cells and in about 40% of cells from the oral epithelium. Therefore, the mother was a mosaic for the mutation. Since the mutated allele was present in cells derived from all three germ layers, the results indicated that the mutation arose by the late blastocyst stage of development. The results also indicate that assays of blood leukocytes do not always reveal mosaicism or predict phenotypic involvement of tissues, such as blood vessels, that are derived from the same embryonic cells as are leukocytes. 66 refs., 6 figs., 1 tab.

  4. [VIRAL INFECTIONS: HUMAN PAPILLOMAVIRUS AND GENITAL HERPES TYPE 1 AND TYPE 2 AS A CAUSE OF CHRONIC RECURRENT CYSTITIS WITH SEVERE DYSURIA IN WOMEN WITH URETHRAL HYPERMOBILITY AND HYPOSPADIAS].

    Science.gov (United States)

    Derevjanko, T I; Ryzhkov, V V

    2015-01-01

    Female hypospadias presenting as a misplaced urethral opening is a common cause of chronic recurrent cystitis. Cystitis occurs when urogenital infection and anaerobic bacteria enter the urethra and bladder from the vagina. The authors argue that chronic infections of the lower urinary tract in women with hypospadias should be treated surgically by meatal transposition. They present a study confirming the role of the antiviral drug Panavir in prevention of inflammatory complications in the postoperative period in patients with a history of viral infection (human papillomavirus and herpes). PMID:26665761

  5. Multidrug-Resistant Mycobacterium tuberculosis of the Latin American Mediterranean Lineage, Wrongly Identified as Mycobacterium pinnipedii (Spoligotype International Type 863 [SIT863]), Causing Active Tuberculosis in South Brazil

    KAUST Repository

    Dalla Costa, Elis R.

    2015-09-23

    We recently detected the spoligotype patterns of strains of Mycobacterium pinnipedii, a species of the Mycobacterium tuberculosis complex, in sputum samples from nine cases with pulmonary tuberculosis residing in Porto Alegre, South Brazil. Because this species is rarely encountered in humans, we further characterized these nine isolates by additional genotyping techniques, including 24-locus mycobacterial interspersed repetitive-unit–variable-number tandem-repeat (MIRU-VNTR) typing, verification of the loci TbD1, RD9, pks15/1, RDRio, and fbpC, the insertion of IS6110 at a site specific to the M. tuberculosis Latin American Mediterranean (LAM) lineage, and whole-genome sequencing. The combined analysis of these markers revealed that the isolates are in fact M. tuberculosis and more specifically belong to the LAM genotype. Most of these isolates (n = 8) were shown to be multidrug resistant (MDR), which prompted us to perform partial sequencing of the rpoA, rpoB, rpoC, katG, and inhA genes. Seven isolates (77.8%) carried the S315T mutation in katG, and one of these (11%) also presented the C(−17)T single-nucleotide polymorphism (SNP) in inhA. Interestingly, six of the MDR isolates also presented an undescribed insertion of 12 nucleotides (CCA GAA CAA CCC) in codon 516 of rpoB. No putative compensatory mutation was found in either rpoA or rpoC. This is the first report of an M. tuberculosis LAM family strain with a convergent M. pinnipedii spoligotype. These spoligotypes are observed in genotype databases at a modest frequency, highlighting that care must be taken when identifying isolates in the M. tuberculosis complex on the basis of single genetic markers.

  6. A Novel Mutation Causing 17-β-Hydroxysteroid Dehydrogenase Type 3 Deficiency in an Omani Child: First Case Report and Review of Literature

    Directory of Open Access Journals (Sweden)

    Aisha Al-Sinani

    2015-03-01

    Full Text Available This is the first case report in Oman and the Gulf region of a 17-β-hydroxysteroid dehydrogenase type 3 (17-β-HSD3 deficiency with a novel mutation in the HSD17B3 gene that has not been previously described in the medical literature. An Omani child was diagnosed with 17-β-HSD3 deficiency and was followed up for 11 years at the Pediatric Endocrinology Clinic, Royal Hospital, Oman. He presented at the age of six weeks with ambiguous genitalia, stretched penile and bilateral undescended testes. Ultrasound showed no evidence of any uterine or ovarian structures with oval shaped solid structures in both inguinal regions that were confirmed by histology to be testicular tissues with immature seminiferous tubules only. The diagnosis was made by demonstrating low serum testosterone and high androstenedione, estrone, and androstenedione:testosterone ratio. Karyotyping confirmed 46,XY and the infant was raised as male. Testosterone injections (25mg once monthly were given at two and six months and then three months before his surgeries at five and seven years of age when he underwent multiple operations for orchidopexy and hypospadias correction. At the age of 10 years he developed bilateral gynecomastia (stage 4. Laboratory investigations showed raised follicle-stimulating hormone, luteinizing hormone, androstenedione, and estrone with low-normal testosterone and low androstendiol glucurunide. Testosterone injections (50mg once monthly for six months were given that resulted in significant reduction in his gynecomastia. Molecular analysis revealed a previously unreported homozygous variant in exon eight of the HSD17B3 gene (NM_000197.1:c.576G>A.Trp192*. This variant creates a premature stop codon, which is very likely to result in a truncated protein or loss of protein production. This is the first report in the medical literature of this novel HSD17B3 gene mutation. A literature review was conducted to identify the previous studies related to this

  7. Expression of wild-type PtrIAA14.1, a poplar Aux/IAA gene causes morphological changes in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Shanda eLiu

    2015-06-01

    Full Text Available Aux/IAA proteins are transcriptional repressors that control auxin signaling by interacting with Auxin Response Factors (ARFs. So far all of the identified Aux/IAA mutants with auxin-related phenotypes in Arabidopsis and rice (Oryza sativa are dominant gain-of-function mutants, with mutantions in Domain II that affected stability of the corresponding Aux/IAA proteins. On the other hand, morphological changes were observed in knock-down mutants of Aux/IAA genes in tomato (Solanum lycopersicum, suggesting that functions of Aux/IAA proteins may be specific for certain plant species. We report here the characterization of PtrIAA14.1, a poplar (Populus trichocarpa homologue of IAA7. Bioinformatics analysis showed that PtrIAA14.1 is a classic Aux/IAA protein. It contains four conserved domains with the repressor motif in Domain I, the degron in Domain II, and the conserved amino acid signatures for protein-protein interactions in Domain III and Domain IV. Protoplast transfection assays showed that PtrIAA14.1 is localized in nucleus. It is unable in the presence of auxin, and it represses auxin response reporter gene expression. Expression of wild type PtrIAA14.1 in Arabidopsis resulted in auxin-related phenotypes including down-curling leaves, semi-draft with increased number of branches, and greatly reduced fertility, but expression of the Arabidopsis Aux/IAA genes tested remain largely unchanged in the transgenic plants. Protein-protein interaction assays in yeast and protoplasts showed that PtrIAA14.1 interacted with ARF5, but not other ARFs. Consistent with this observation, vascular patterning was altered in the transgenic plants, and the expression of AtHB8 (Arabidopsis thaliana Homeobox Gene 8 was reduced in transgenic plants.

  8. Abnormal dentin structure in two novel gene mutations [COL1A1, Arg134Cys] and [ADAMTS2, Trp795-to-ter] causing rare type I collagen disorders.

    Science.gov (United States)

    De Coster, P J; Cornelissen, M; De Paepe, A; Martens, L C; Vral, A

    2007-02-01

    Histological and ultrastructural observations of dentin of two patients affected with rare types of type I collagen disorders are presented. In the first case, a homozygous nonsense mutation in ADAMTS2 (substitution of a codon for tryptophan by a stopcodon) causes type VIIC Ehlers-Danlos syndrome (EDS) with multiple tooth agenesis and focal dysplastic dentin defects. In the second case, a missense mutation in COL1A1 (substitution of arginine by cysteine) results in a type I EDS phenotype with clinically normal-appearing dentition. Tooth samples are investigated by using light microscopy (LM), transmission electron microscopy (TEM) and immunostaining for types I and III collagen, and tenascin. These are compared with samples from patients with types III and IV osteogenesis imperfecta (OI) in association with dentinogenesis imperfecta (DI), showing a consistently abnormal appearance of the dentin in all specimens, with variations being primarily those of degree of change. Similarities in histological changes include the alternating presence of normal and severe pathological areas in primary and secondary dentin, the latter being characterized by large canal-like structures in atubular areas. Ultrastructural evidence of pathological dentinogenesis include abnormal distribution, size and organization of collagen fibers, which may also be found in clinically unaffected teeth. The histological and ultrastructural changes seen can be explained on the basis of odontoblast dysfunction which may be secondary to the collagen defect, interfering with different levels of odontoblast cell function and intercellular communication. These observations on (ultra)structural dentin defects associated with the two novel gene mutations are the first ever reported. PMID:17118335

  9. 云浮市无偿献血初筛血型错误原因分析及预防%Cause analysis and prevention of primary screening blood type errors of donating blood in Yunfu City

    Institute of Scientific and Technical Information of China (English)

    高炳谏; 区勇勤; 李惠玲

    2015-01-01

    目的:对无偿献血者ABO血型初筛错误进行原因分析,并采取相应的预防措施,以减少初筛血型的错误率。方法统计2010~2014年本站无偿献血标本94298人次中初筛血型与实验室正反定型检测结果血型进行比较分析。结果94298例无偿献血标本中,发现初筛血型错误368例,错误率0.39%,以B型误判为O型最高,占17.12%,其次为AB型误判为A型,占15.22%;各采血点分布差异明显,新兴、罗定采血点错误率最高,分别占0.58%和0.44%;各年份比较,初筛血型错误率逐年下降。结论初筛血型错误大多是由于人为因素导致,应增强工作人员的质量意识和责任心教育,加强理论知识和操作技能的培训,严格遵守操作规程,改善献血环境和试剂的管理,使献血前ABO血型筛查错误降到最低。%Objective To analyze the causes of primary screening errors of the ABO blood types of voluntary blood donors and take corresponding preventative measures to reduce the error rate of primary screening blood type. Methods The primary screening blood types and the laboratory positive and negative blood grouping test results of 94 298 donat-ing blood specimens of our station between 2010 and 2014 were analyzed comparatively. Results Of the 94 298 donat-ing blood specimens,368 cases of primary screening blood type errors were found,with the error rate of 0.39%,of which type B misjudged as type O was the commonest,accounting for 17.12%,followed by type AB misjudged as type A,ac-counting for 15.22%.The errors distributed significantly differently over each blood collection station and the error rates in Xinxing and Luoding blood collection stations were the highest,accounting for 0.58% and 0.44% respectively.As for the errors of different years,the primary screening blood type error rate decreased year by year. Conclusion As primary screening blood type errors are mainly caused by human factors,enhancement of

  10. Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I)

    Energy Technology Data Exchange (ETDEWEB)

    Hoth, C.F.; Milunsky, A.; Lipsky, N.; Baldwin, C.T. (Boston Univ. School of Medicine, MA (United States)); Sheffer, R. (Hadassah-Hebrew Univ. Medical Center, Jerusalem (Israel)); Clarren, S.K. (Univ. of Washington School of Medicine, Seattle (United States))

    1993-03-01

    Waardenburg syndrome type I (WS-I) is an autosomal dominant disorder characterized by sensorineural hearing loss, dystopia canthorum, pigmentary disturbances, and other developmental defects. Klein-Waardenburg syndrome (WS-III) is a disorder with many of the same characteristics as WS-I and includes musculoskeletal abnormalities. The authors have recently reported the identification and characterization of one of the first gene defects, in the human PAX3 gene, which causes WS-I. PAX3 is a DNA-binding protein that contains a structural motif known as the paired domain and is believed to regulate the expression of other genes. In this report they describe two new mutations, in the human PAX3 gene, that are associated with WS. One mutation was found in a family with WS-I, while the other mutation was found in a family with WS-III. Both mutations were in the highly conserved paired domain of the human PAX3 gene and are similar to other mutations that cause WS. The results indicate that mutations in the PAX3 gene can cause both WS-I and WS-III. 36 refs., 4 figs.

  11. Skeletal overgrowth syndrome caused by overexpression of C-type natriuretic peptide in a girl with balanced chromosomal translocation, t(1;2)(q41;q37.1).

    Science.gov (United States)

    Ko, Jung Min; Bae, Jun-Seok; Choi, Jin Sun; Miura, Kohji; Lee, Hye Ran; Kim, Ok-Hwa; Kim, Nayoung K D; Oh, Sun Kyung; Ozono, Keiichi; Lee, Choon-Ki; Choi, In Ho; Park, Woong-Yang; Cho, Tae-Joon

    2015-05-01

    Chromosomal translocation of 2q37.1 just distal to the NPPC gene coding for C-type natriuretic peptide (CNP) and subsequent overproduction of CNP have been reported to cause a skeletal overgrowth syndrome. Loeys-Dietz syndrome (LDS) is one of marfanoid overgrowth syndromes, of which subtype IV is caused by haploinsufficiency of transforming growth factor beta 2 (TGFB2). We report on a girl with clinical phenotypes of overgrowth syndrome, including long and slim body habitus, macrodactyly of the big toe, scoliosis, ankle valgus deformity, coxa valga, slipped capital femoral epiphysis, and aortic root dilatation. Karyotyping revealed a balanced chromosomal translocation between 1q41 and 2q37.1, and the breakpoints could be mapped by targeted resequencing analysis. On chromosome 2q37.1, the translocation took place 200,365 bp downstream of NPPC, and serum level of the amino terminal of CNP was elevated. The contralateral site of translocation on chromosome 1q41 disrupted TGFB2 gene, presumed to cause its haploinsufficiency. This case supports the concept that NPPC is overexpressed because of the loss of a specific negative regulatory control in the normal chromosomal location, and demonstrates the effectiveness of targeted resequencing in the mapping of breakpoints. PMID:25728306

  12. TAT gene mutation analysis in three Palestinian kindreds with oculocutaneous tyrosinaemia type II; characterization of a silent exonic transversion that causes complete missplicing by exon 11 skipping

    DEFF Research Database (Denmark)

    Maydan, G; Andresen, Brage Storstein; Madsen, Pia Pinholt; Zeigler, M.; Raas-Rothschild, A.; Zlotogorski, A.; Gutman, A.; Korman, S.H.

    2006-01-01

    Deficiency of the hepatic cytosolic enzyme tyrosine aminotransferase (TAT) causes marked hypertyrosinaemia leading to painful palmoplantar hyperkeratoses, pseudodendritic keratitis and variable mental retardation (oculocutaneous tyrosinaemia type II or Richner-Hanhart syndrome). Parents may...... therefore seek prenatal diagnosis, but this is not possible by biochemical assays as tyrosine does not accumulate in amniotic fluid and TAT is not expressed in chorionic villi or amniocytes. Molecular analysis is therefore the only possible approach for prenatal diagnosis and carrier detection. To this end....... Homozygosity for a c.1249C > T (R417X) exon 12 nonsense mutation (previously reported in a French patient) was identified in both patients from the third kindred, enabling successful prenatal diagnosis of an unaffected fetus using chorionic villous tissue....

  13. Association between Highly Active Antiretroviral Therapy and Type of Infectious Respiratory Disease and All-Cause In-Hospital Mortality in Patients with HIV/AIDS: A Case Series.

    Directory of Open Access Journals (Sweden)

    Renata Báez-Saldaña

    Full Text Available Respiratory manifestations of HIV disease differ globally due to differences in current availability of effective highly active antiretroviral therapy (HAART programs and epidemiology of infectious diseases.To describe the association between HAART and discharge diagnosis and all-cause in-hospital mortality among hospitalized patients with infectious respiratory disease and HIV/AIDS.We retrospectively reviewed the records of patients hospitalized at a specialty hospital for respiratory diseases in Mexico City between January 1st, 2010 and December 31st, 2011. We included patients whose discharge diagnosis included HIV or AIDS and at least one infectious respiratory diagnosis. The information source was the clinical chart. We analyzed the association between HAART for 180 days or more and type of respiratory disease using polytomous logistic regression and all-cause hospital mortality by multiple logistic regressions.We studied 308 patients, of whom 206 (66.9% had been diagnosed with HIV infection before admission to the hospital. The CD4+ lymphocyte median count was 68 cells/mm3 [interquartile range (IQR: 30-150]. Seventy-five (24.4% cases had received HAART for more than 180 days. Pneumocystis jirovecii pneumonia (PJP (n = 142, tuberculosis (n = 63, and bacterial community-acquired pneumonia (n = 60 were the most frequent discharge diagnoses. Receiving HAART for more than 180 days was associated with a lower probability of PJP [Adjusted odd ratio (aOR: 0.245, 95% Confidence Interval (CI: 0.08-0.8, p = 0.02], adjusted for sociodemographic and clinical covariates. HAART was independently associated with reduced odds (aOR 0.214, 95% CI 0.06-0.75 of all-cause in-hospital mortality, adjusting for HIV diagnosis previous to hospitalization, age, access to social security, low socioeconomic level, CD4 cell count, viral load, and discharge diagnoses.HAART for 180 days or more was associated with 79% decrease in all-cause in-hospital mortality and lower

  14. CD81-Receptor Associations — Impact for Hepatitis C Virus Entry and Antiviral Therapies

    Directory of Open Access Journals (Sweden)

    Laetitia Zona

    2014-02-01

    Full Text Available Tetraspanins are integral transmembrane proteins organized in microdomains displaying specific and direct interactions with other tetraspanins and molecular partners. Among them, CD81 has been implicated in a variety of physiological and pathological processes. CD81 also plays a crucial role in pathogen entry into host cells, including hepatitis C virus (HCV entry into hepatocytes. HCV is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV entry into hepatocytes is a complex process that requires the coordinated interaction of viral and host factors for the initiation of infection, including CD81, scavenger receptor BI, claudin-1, occludin, membrane-bound host cell kinases, Niemann-Pick C1 Like 1, Harvey rat sarcoma viral oncogene homolog (HRas, CD63 and transferrin receptor 1. Furthermore, recent data in HCV model systems have demonstrated that targeting critical components of tetraspanins and associated cell membrane proteins open new avenues to prevent and treat viral infection.

  15. Cuentan los fragmentos: Clasificación y causas de fractura de artefactos formatizados por talla What fractures have to tell: classification and causes of fracture types in lithic tools

    Directory of Open Access Journals (Sweden)

    Celeste Weitzel

    2012-07-01

    Full Text Available Los artefactos formatizados fracturados pueden brindar información que va más allá del estado de los materiales o del índice de fragmentación. Aquí se presenta una propuesta para clasificar las fracturas en artefactos líticos formatizados por talla. Ésta incluye una descripción detallada de dichas fracturas, orientada a su reconocimiento y a inferir las causas que las originaron. Además, se delinean algunas consideraciones para su análisis. Esta propuesta fue pensada como una herramienta que permita incorporar el estudio de los instrumentos fracturados a distintos temas como el aprovechamiento de las materias primas, las tareas en las que participaron los artefactos y su vinculación con diversas decisiones y prácticas sociales.Broken stone tools provide information beyond the condition of the material or their breakage index. This paper offers a classification of different types of fracture in flaked stone tools. It includes a detailed characterization for each fracture which, in several cases, allows its cause to be identified. Relevant points for the analysis of the fractures are also provided. The analysis was developed as a methodological tool to incorporate the study of broken tools into archaeological topics such as raw material use, inferences about the activities in which stone tools were involved, and the relationship between stone tools and different social choices and practices.

  16. Structure of glycosylated NPC1 luminal domain C reveals insights into NPC2 and Ebola virus interactions.

    Science.gov (United States)

    Zhao, Yuguang; Ren, Jingshan; Harlos, Karl; Stuart, David I

    2016-03-01

    Niemann-pick type C1 (NPC1) is an endo/lysosomal membrane protein involved in intracellular cholesterol trafficking, and its luminal domain C is an essential endosomal receptor for Ebola and Marburg viruses. We have determined the crystal structure of glycosylated NPC1 luminal domain C and find all seven possible sites are glycosylated. Mapping the disease mutations onto the glycosylated structure reveals a potential binding face for NPC2. Knowledge-based docking of NPC1 onto Ebola viral glycoprotein and sequence analysis of filovirus susceptible and refractory species reveals four critical residues, H418, Q421, F502 and F504, some or all of which are likely responsible for the species-specific susceptibility to the virus infection. PMID:26846330

  17. Cyclodextrin induces calcium-dependent lysosomal exocytosis.

    Directory of Open Access Journals (Sweden)

    Fannie W Chen

    Full Text Available Cyclodextrins (CDs have long been used to manipulate cellular cholesterol levels both in vitro and in vivo, but their direct effects at a cellular level are not well characterized. Recently, CDs have garnered much interest because of their ability to clear stored cholesterol from Niemann Pick Type C (NPC cells and markedly prolong the life of NPC1 disease mice. Here, we investigate the hypothesis that treatment with 2-hydroxypropyl- β-cyclodextrin (HPB-CD stimulates lysosomal exocytosis in a calcium-enhanced manner. We propose that this exocytosis is the mechanism by which HPB-CD ameliorates the endolysosomal cholesterol storage phenotype in NPC cells. These findings have significant implications for the use of HPB-CD in biochemical assays and data interpretation as well as for their use for the treatment for NPC and other disorders.

  18. Disseminated langerhans cell histiocytosis presenting as cholestatic jaundice.

    Science.gov (United States)

    Kapoor, Rohit; Loizides, Anthony M; Sachdeva, Soumya; Paul, Premila

    2015-02-01

    Langerhans cell histiocytosis (LCH) is a disorder associated with proliferation of Langerhans cells in various organs. LCH secondary to multisystem involvement can present in a variety of ways. Because of its infiltrative nature, LCH can involve the skin, lymph nodes, the lung or the liver. Jaundice in LCH is a manifestation of liver disease; biliary dilatation secondary to lithiasis or may be due to coexistent Niemann-Pick disease. However, a case of cholestasis has been very rarely described. Cholestasis may result from lymph nodes obstructing the porta hepatis. In this report, we describe a case of type II histiocytosis X with obstructive cholestasis and pulmonary involvement in the form of cysts without significant lymphadenopathy at the porta. PMID:25859497

  19. ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent.

    Science.gov (United States)

    2009-10-01

    Certain autosomal recessive disease conditions are more prevalent in individuals of Eastern European Jewish (Ashkenazi) descent. Previously, the American College of Obstetricians and Gynecologists recommended that individuals of Eastern European Jewish ancestry be offered carrier screening for Tay-Sachs disease, Canavan disease, and cystic fibrosis as part of routine obstetric care. Based on the criteria used to justify offering carrier screening for Tay-Sachs disease, Canavan disease, and cystic fibrosis, the American College of Obstetricians and Gynecologists' Committee on Genetics recommends that couples of Ashkenazi Jewish ancestry also should be offered carrier screening for familial dysautonomia. Individuals of Ashkenazi Jewish descent may inquire about the availability of carrier screening for other disorders. Carrier screening is available for mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia group C, Bloom syndrome, and Gaucher disease. PMID:19888064

  20. Excess sphingomyelin disturbs ATG9A trafficking and autophagosome closure.

    Science.gov (United States)

    Corcelle-Termeau, Elisabeth; Vindeløv, Signe Diness; Hämälistö, Saara; Mograbi, Baharia; Keldsbo, Anne; Bräsen, Jan Hinrich; Favaro, Elena; Adam, Dieter; Szyniarowski, Piotr; Hofman, Paul; Krautwald, Stefan; Farkas, Thomas; Petersen, Nikolaj H T; Rohde, Mikkel; Linkermann, Andreas; Jäättelä, Marja

    2016-05-01

    Sphingomyelin is an essential cellular lipid that traffics between plasma membrane and intracellular organelles until directed to lysosomes for SMPD1 (sphingomyelin phosphodiesterase 1)-mediated degradation. Inactivating mutations in the SMPD1 gene result in Niemann-Pick diseases type A and B characterized by sphingomyelin accumulation and severely disturbed tissue homeostasis. Here, we report that sphingomyelin overload disturbs the maturation and closure of autophagic membranes. Niemann-Pick type A patient fibroblasts and SMPD1-depleted cancer cells accumulate elongated and unclosed autophagic membranes as well as abnormally swollen autophagosomes in the absence of normal autophagosomes and autolysosomes. The immature autophagic membranes are rich in WIPI2, ATG16L1 and MAP1LC3B but display reduced association with ATG9A. Contrary to its normal trafficking between plasma membrane, intracellular organelles and autophagic membranes, ATG9A concentrates in transferrin receptor-positive juxtanuclear recycling endosomes in SMPD1-deficient cells. Supporting a causative role for ATG9A mistrafficking in the autophagy defect observed in SMPD1-deficient cells, ectopic ATG9A effectively reverts this phenotype. Exogenous C12-sphingomyelin induces a similar juxtanuclear accumulation of ATG9A and subsequent defect in the maturation of autophagic membranes in healthy cells while the main sphingomyelin metabolite, ceramide, fails to revert the autophagy defective phenotype in SMPD1-deficient cells. Juxtanuclear accumulation of ATG9A and defective autophagy are also evident in tissues of smpd1-deficient mice with a subsequent inability to cope with kidney ischemia-reperfusion stress. These data reveal sphingomyelin as an important regulator of ATG9A trafficking and maturation of early autophagic membranes. PMID:27070082

  1. What Causes Angina?

    Science.gov (United States)

    ... this page from the NHLBI on Twitter. What Causes Angina? Underlying Causes Angina usually is a symptom of coronary heart ... and cause angina or a heart attack . Immediate Causes Many factors can trigger angina pain, depending on ...

  2. What Causes Lymphocytopenia?

    Science.gov (United States)

    ... low lymphocyte counts with no underlying cause. Acquired Causes Many acquired diseases, conditions, and factors can cause ... anemia . Radiation and chemotherapy (treatments for cancer). Inherited Causes Certain inherited diseases and conditions can lead to ...

  3. What Causes Cardiogenic Shock?

    Science.gov (United States)

    ... this page from the NHLBI on Twitter. What Causes Cardiogenic Shock? Immediate Causes Cardiogenic shock occurs if the heart suddenly can' ... reason why emergency treatment is so important. Underlying Causes The underlying causes of cardiogenic shock are conditions ...

  4. Human Placental-Derived Stem Cell Transplantation

    Science.gov (United States)

    2015-04-29

    Mucopolysaccharidosis I; Mucopolysaccharidosis VI; Adrenoleukodystrophy; Niemann-Pick Disease; Metachromatic Leukodystrophy; Wolman Disease; Krabbe's Disease; Gaucher's Disease; Fucosidosis; Batten Disease; Severe Aplastic Anemia; Diamond-Blackfan Anemia; Amegakaryocytic Thrombocytopenia; Myelodysplastic Syndrome; Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia

  5. An Assessment of Hazards Caused by Electromagnetic Interaction on Humans Present near Short-Wave Physiotherapeutic Devices of Various Types Including Hazards for Users of Electronic Active Implantable Medical Devices (AIMD)

    OpenAIRE

    Jolanta Karpowicz; Krzysztof Gryz

    2013-01-01

    Leakage of electromagnetic fields (EMF) from short-wave radiofrequency physiotherapeutic diathermies (SWDs) may cause health and safety hazards affecting unintentionally exposed workers (W) or general public (GP) members (assisting patient exposed during treatment or presenting there for other reasons). Increasing use of electronic active implantable medical devices (AIMDs), by patients, attendants, and workers, needs attention because dysfunctions of these devices may be caused by electromag...

  6. Facts about Type 2

    Medline Plus

    Full Text Available ... Type 1 Diabetes Get Started Safely Get And Stay Fit Types of Activity Weight Loss Assess Your ... of going into cells, it can cause two problems: Right away, your cells may be starved for ...

  7. 南阳市无偿献血者血型初筛错误原因分析与对策%Analysis and strategies of causes of error of blood type preliminary screening for voluntary blood donors in Nanyang city

    Institute of Scientific and Technical Information of China (English)

    张峰; 王帅

    2015-01-01

    目的:通过对献血者初筛血型错误原因分析,进而提高初筛血型的准确率,确保安全输血。方法对170例初筛检验血型错误结果进行分析。结果初筛血型错误总人数170例。血型错误率为0.053%(排除弱凝集和亚型),各型错误构成比例中,A型误定为AB型的比例最高,占25.3%,其次为AB型误定为A型和AB型误定为B型,各占10.0%,错误率最低为O型误定为AB型,占1.8%。结论造成血型初筛错误的原因是多方面的,主要为人为和环境因素。%Objective To analyze the causes of error of blood type preliminary screening for blood donors, and to fur-ther improve the accuracy of preliminarily screened blood type, so as to ensure the safe blood transfusion. Methods A total of 170 cases with false results of preliminarily screened blood type were analyzed. Results Total number of people with false preliminarily screened blood type was 170. The false rate of blood type was 0.053% (excluding weak aggluti-nation and sub-type). Among the proportion of composition of each false type, the proportion of type A wrongly screened as type AB was the highest, accounting for 25.3%, followed by the proportion of type AB wrongly screened as type A and the proportion of type AB wrongly screened as type B, accounted for 10.0% for each. The lowest proportion was type O wrongly screened as type AB, accounted for 1.8%. Conclusion Causes of false preliminary screening of blood type are multifaceted, and the main causes are human factors and environmental factors.

  8. Imaging manifestations of acute viral encephalitis caused by type Ⅰ herpes simplex vi rus%急性Ⅰ型单纯疱疹病毒感染性脑炎影像学表现

    Institute of Scientific and Technical Information of China (English)

    王成伟; 吴尚锋; 陈松平; 许强宏

    2015-01-01

    目的:探讨急性Ⅰ型单纯疱疹病毒性脑炎(Herpes Simplex Virus Encephalitis ,HSE)不同病理机制多种影像学表现,以提高治愈率。方法回顾性分析2003-2013年16例确诊 HSE有脑出血病灶的患者临床资料,对其进行影像学检查,16例 HSE患者均先行CT检查,根据病情其中有7例患者行MRI检查,对影像学的多种重要表现结合文献进行分析总结。结果 HSE患者发病早期30 min~2 h在CT影像上基底节密度稍增高,基底节突出显示,即“基底节突显征”;发生于基底节、脑灰质及灰白质交界区的细微小灶状、小疱疹样出血,具有一定的典型意义;发生于颞叶脑白质病变多呈水肿、变性样改变,CT上低密度、MRI上呈长 T1长 T2信号,多发生于颞叶而基底节未受累呈现“刀切征”,则是公认的较为典型征像。结论影像诊断多种检查技术联合应用,总结出单纯疱疹病毒(HSV)感染所致 HSE的影像的一些特征性表现,对 HSE患者影像诊断、特别是早期诊断具有重要意义,对降低HSE患者的病死率及致残率有一定价值。%OBJECTIVE To explore the various manifestations of imaging of acute type I herpes simplex encephalitis (HSE) under different pathological mechanisms so as to improve the cure rate .METHODS The retrospective anal‐ysis was conducted on clinical data of 16 patients diagnosed to have lesions of cerebral hemorrhage due to HSE dur‐ing 2003-2013 .The patients received imaging examination .All the 16 HSE patients were first examined by CT , then 7 of them were examined by MRI according to disease condition .The various important manifestations were summarized and analyzed in combination with literature researches .RESULTS In the early period of onset (30 min‐2 h of onset) ,CT imaging showed slightly increased density of basal ganglia and highlighted signs of basal gan‐glia ,i .e .,prominent sign of basal ganglia .Tiny

  9. What Causes Thrombocytopenia?

    Science.gov (United States)

    ... this page from the NHLBI on Twitter. What Causes Thrombocytopenia? Many factors can cause thrombocytopenia (a low ... known for sure. Rare and Serious Conditions That Cause Blood Clots Some rare and serious conditions can ...

  10. What Causes Atherosclerosis?

    Science.gov (United States)

    ... this page from the NHLBI on Twitter. What Causes Atherosclerosis? The exact cause of atherosclerosis isn't known. However, studies show ... blood clots can worsen angina (chest pain) or cause a heart attack or stroke . Researchers continue to ...

  11. What Causes Aplastic Anemia?

    Science.gov (United States)

    ... this page from the NHLBI on Twitter. What Causes Aplastic Anemia? Damage to the bone marrow's stem ... system attacks its own cells by mistake. Acquired Causes Many diseases, conditions, and factors can cause aplastic ...

  12. What Causes Respiratory Failure?

    Science.gov (United States)

    ... page from the NHLBI on Twitter. What Causes Respiratory Failure? Diseases and conditions that impair breathing can cause ... injure your lungs. Normal Lungs and Conditions Causing Respiratory Failure Figure A shows the location of the lungs, ...

  13. About Alzheimer's Disease: Causes

    Science.gov (United States)

    ... Project Act (NAPA) About ADEAR About Alzheimer's Disease: Causes Age-related changes in the brain Genetics Health, ... for the Causes of AD" NIA Information on Causes Alzheimer’s Disease in People with Down Syndrome Understanding ...

  14. Verminous aneurysm caused by filaria.

    Science.gov (United States)

    Toledo, F V; de Araújo, A P; da Cunha, A M; Sidow, J R; Pavão, S G; de Araújo, E D

    1983-06-01

    Aneurysms caused by atherosclerosis are relatively frequent, as a consequence of the high incidence of this degenerative disease of the arteries. Other types of aneurysm, for example, those of infectious etiology, are more uncommon. Bacterias and fungi are able to cause aneurysms in several parts of the arterial tree. Stengel et al (1943), in a review of world literature described 217 cases of mycotic aneurysms. The Stedman's Medical Dictionary refers to a special type of aneurysm observed in horses, caused by intra-vascular migration of a worm, the Strongylus vulgaris. It has been named verminous aneurysm and generally involves the mesenteric arteries. We haven't found in medical literature any similar observations refering to human cases. The purpose of this paper is to describe a case of aneurysm the etiology of which we have imputed to the filaria (Wuchereria bancrofti). This case was observed in Marcilio Dias Naval Hospital, Rio de Janeiro, Brazil. PMID:6346961

  15. Causes of Infertility

    Science.gov (United States)

    Infertility Causes of male infertility Causes of female infertility Infertility is clinically defined as the inability to conceive naturally after one year of frequent, unprotected intercourse. Approximately 7. ...

  16. Corneal alterations during combined therapy with cyclodextrin/allopregnanolone and miglustat in a knock-out mouse model of NPC1 disease.

    Directory of Open Access Journals (Sweden)

    Marine Hovakimyan

    Full Text Available BACKGROUND: Niemann Pick disease type C1 is a neurodegenerative disease caused by mutations in the NPC1 gene, which result in accumulation of unesterified cholesterol and glycosphingolipids in the endosomal-lysosomal system as well as limiting membranes. We have previously shown the corneal involvement in NPC1 pathology in form of intracellular inclusions in epithelial cells and keratocytes. The purpose of the present study was to clarify if these inclusions regress during combined substrate reduction- and by-product therapy (SRT and BPT. METHODOLOGY/PRINCIPAL FINDINGS: Starting at postnatal day 7 (P7 and thereafter, NPC1 knock-out mice (NPC1(-/- and wild type controls (NPC1(+/+ were injected with cyclodextrin/allopregnanolone weekly. Additionally, a daily miglustat injection started at P10 until P23. Starting at P23 the mice were fed powdered chow with daily addition of miglustat. The sham group was injected with 0.9% NaCl at P7, thereafter daily starting at P10 until P23, and fed powdered chow starting at P23. For corneal examination, in vivo confocal laser-scanning microscopy (CLSM was performed one day before experiment was terminated. Excised corneas were harvested for lipid analysis (HPLC/MS and electron microscopy. In vivo CLSM demonstrated a regression of hyperreflective inclusions in all treated NPC1(-/-mice. The findings varied between individual mice, demonstrating a regression, ranging from complete absence to pronounced depositions. The reflectivity of inclusions, however, was significantly lower when compared to untreated and sham-injected NPC1(-/- mice. These confocal findings were confirmed by lipid analysis and electron microscopy. Another important CLSM finding revealed a distinct increase of mature dendritic cell number in corneas of all treated mice (NPC1(-/- and NPC1(+/+, including sham-treated ones. CONCLUSIONS/SIGNIFICANCE: The combined substrate reduction- and by-product therapy revealed beneficial effects on the cornea

  17. Human errors - human caused, environment caused

    International Nuclear Information System (INIS)

    The importance of human error in the safe operation of Nuclear Plants has been well recognised. The human error could be due to a large number of reasons. Eg. coming from factors like sensing, perceiving, predicting, familiarity, skills, rules, individual performance and environmental factors such as ergonomics, work organisation, procedure, time and duration of work, training, physical environment etc. Two incidents highlighting human caused and environmental caused errors are described. Also a distribution of causes of failure and affected systems of Safety Related Unusual Occurrences is presented on the basis of the reports received by the regulatory body. A system to analyse human errors with respect to human caused and environment caused is being developed. The input data for this analysis is obtained from Safety Related Unusual Occurrence reports received by the regulatory body. The regulatory requirement for submission of these reports include first information report (by telex, telephone etc) within 24 hours of the incident and detailed report within 20 days. The detailed report amongst other information also contains information with respect to the cause of the incident. These reports are discussed at various levels and an attempt is made to identify the root cause. (author). 3 figs, 1 tab

  18. Acute Pancreatitis Caused By Mushroom Poisoning

    OpenAIRE

    Karahan, Samet; Erden, Abdulsamet; Cetinkaya, Ali; Avci, Deniz; Ortakoyluoglu, Adile Irfan; Karagoz, Hatice; BULUT, Kadir; Basak, Mustafa

    2016-01-01

    Of the more than 5000 species of mushrooms known, 100 types are toxic and approximately 10% of these toxic types can cause fatal toxicity. A type of mushroom called Amanita phalloides is responsible for 95% of toxic mushroom poisonings. In this article, we report 2 cases of mushroom poisonings caused by Lactarius volemus, known as Tirmit by the local people. The patient and his wife were admitted to the emergency room with abdominal pain, nausea, and vomiting 20 hours after consuming Lactariu...

  19. Pseudo-outbreak of pre-extensively drug-resistant (Pre-XDR) tuberculosis in Kinshasa: collateral damage caused by false detection of fluoroquinolone resistance by GenoType MTBDRsl.

    Science.gov (United States)

    Kaswa, Michel K; Aloni, Muriel; Nkuku, Léontine; Bakoko, Brian; Lebeke, Rossin; Nzita, Albert; Muyembe, Jean Jacques; de Jong, Bouke C; de Rijk, Pim; Verhaegen, Jan; Boelaert, Marleen; Ieven, Margareta; Van Deun, Armand

    2014-08-01

    Fluoroquinolones are the core drugs for the management of multidrug-resistant tuberculosis (MDR-TB). Molecular drug susceptibility testing methods provide considerable advantages for scaling up programmatic management and surveillance of drug-resistant TB. We describe here the misidentification of fluoroquinolone resistance by the GenoType MTBDRsl (MTBDRsl) (Hain Lifescience GmbH, Nehren, Germany) line probe assay (LPA) encountered during a feasibility and validation study for the introduction of this rapid drug susceptibility test in Kinshasa, Democratic Republic of Congo. The double gyrA mutation 80Ala and 90Gly represented 57% of all fluoroquinolone mutations identified from MDR-TB patient sputum samples, as confirmed by DNA sequencing. This double mutation was previously found to be associated with susceptibility to fluoroquinolones, yet it leads to absent hybridization of a wild-type band in the MTBDRsl and is thus falsely scored as resistance. Our findings suggest that MTBDRsl results must be interpreted with caution when the interpretation is based solely on the absence of a wild-type band without confirmation by visualization of a mutant band. Performance of the MTBDRsl LPA might be improved by replacing the gyrA wild-type probes by additional probes specific for well-documented gyrA mutations that confer clinically relevant resistance. PMID:24871222

  20. Relationship between HbA1c levels and risk of cardiovascular adverse outcomes and all-cause mortality in overweight and obese cardiovascular high-risk women and men with type 2 diabetes

    DEFF Research Database (Denmark)

    Andersson, C; van Gaal, L; Caterson, I D;

    2012-01-01

    The optimal HbA(1c) concentration for prevention of macrovascular complications and deaths in obese cardiovascular high-risk patients with type 2 diabetes remains to be established and was therefore studied in this post hoc analysis of the Sibutramine Cardiovascular OUTcomes (SCOUT) trial, which...