Mutation analysis of 28 gaucher disease patients: The Australasian experience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lewis, B.D.; Nelson, P.V.; Robertson, E.F.

1994-01-15

Gaucher disease is the most common lysomal storage disease. It is an autosomal recessive disorder that results from a deficiency of {beta}-glucocerrebrosidase. Three clinical phenotypes have been described: non-neuronopathic, acute neuronopathic, and subacuteneuronopathic. Genomic DNA from 28 Australasian patients of diverse ethnic origin with Gaucher disease was screened for 3 common mutations (1226G, 1448C and 84GG) using the amplification refractory mutation system (ARMS), and one uncommon mutation (1504T) by restriction enzyme digestion. Thirty-eight of the 56 independent alleles in these patients were characterized, with 1448C present in 42% and 1226G in 28% of the alleles. The 1226G mutation was associatedmore » only with the nonneuronopathic phenotype and 7 of the 15 patients who carried the 1448C mutation developed neuronopathic disease. Three infants who died in the neonatal period following a rapidly progressive neurodegenerative course carried no identifiable mutations. The 84GG mutation was carried by 2 Jewish patients and 1504T was present in one patient. It is now possible to rapidly identify the common Gaucher mutations using ARMS and restriction enzyme digestion, and our findings confirm the heterogeneity of mutations in Gaucher disease. It is also possible to predict in part the phenotypic outcome when screening patients for these mutations. The authors consider mutation analysis to be of most use in prenatal diagnosis and for carrier detection within affected families. 27 refs., 2 figs., 2 tabs.« less

Gaucher's disease in a black child in South Africa. A case report.

PubMed

Patel, R; MacDougall, L G

1984-09-01

A 7-year-old Black boy presented with massive splenomegaly and a tendency to haemorrhage due to type 1 Gaucher's disease. After splenectomy he became asymptomatic and the haematological parameters returned to normal. Although type 1 Gaucher's disease has been described in adult Blacks, it has not been reported previously in a Black child in southern Africa.

Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice.

PubMed

Xu, You-hai; Xu, Kui; Sun, Ying; Liou, Benjamin; Quinn, Brian; Li, Rong-hua; Xue, Ling; Zhang, Wujuan; Setchell, Kenneth D R; Witte, David; Grabowski, Gregory A

2014-08-01

Gaucher disease, a prevalent lysosomal storage disease (LSD), is caused by insufficient activity of acid β-glucosidase (GCase) and the resultant glucosylceramide (GC)/glucosylsphingosine (GS) accumulation in visceral organs (Type 1) and the central nervous system (Types 2 and 3). Recent clinical and genetic studies implicate a pathogenic link between Gaucher and neurodegenerative diseases. The aggregation and inclusion bodies of α-synuclein with ubiquitin are present in the brains of Gaucher disease patients and mouse models. Indirect evidence of β-amyloid pathology promoting α-synuclein fibrillation supports these pathogenic proteins as a common feature in neurodegenerative diseases. Here, multiple proteins are implicated in the pathogenesis of chronic neuronopathic Gaucher disease (nGD). Immunohistochemical and biochemical analyses showed significant amounts of β-amyloid and amyloid precursor protein (APP) aggregates in the cortex, hippocampus, stratum and substantia nigra of the nGD mice. APP aggregates were in neuronal cells and colocalized with α-synuclein signals. A majority of APP co-localized with the mitochondrial markers TOM40 and Cox IV; a small portion co-localized with the autophagy proteins, P62/LC3, and the lysosomal marker, LAMP1. In cultured wild-type brain cortical neural cells, the GCase-irreversible inhibitor, conduritol B epoxide (CBE), reproduced the APP/α-synuclein aggregation and the accumulation of GC/GS. Ultrastructural studies showed numerous larger-sized and electron-dense mitochondria in nGD cerebral cortical neural cells. Significant reductions of mitochondrial adenosine triphosphate production and oxygen consumption (28-40%) were detected in nGD brains and in CBE-treated neural cells. These studies implicate defective GCase function and GC/GS accumulation as risk factors for mitochondrial dysfunction and the multi-proteinopathies (α-synuclein-, APP- and Aβ-aggregates) in nGD. © The Author 2014. Published by Oxford University

Phenotype/genotype correlations in Gaucher disease type 1: Clinical and therapeutic implications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sibille, A.; Eng, C.M.; Kim, S.J.

1993-06-01

Gaucher disease is the most frequent lysosomal storage disease and the most prevalent genetic disease among Ashkenazi Jews. Gaucher disease type 1 is characterized by marked variability of the phenotype and by the absence of neuronopathic involvement. To test the hypothesis that this phenotypic variability was due to genetic compounds of several different mutant alleles, 161 symptomatic patients with Gaucher disease type 1 (> 90% Ashkenazi Jewish) were analyzed for clinical involvement, and their genotypes were determined. Qualitative and quantitative measures of disease involvement included age at onset of the disease manifestations, hepatic and splenic volumes, age at splenectomy, andmore » severity of bony disease. High statistically significant differences (P < .005) were found in each clinical parameter in patients with the N370S/N370S genotype compared with those patients with the N370S/84GG, N370S/L444P, and N370/ genotypes. The symptomatic N370S homozygotes had onset of their disease two to three decades later than patients with the other genotypes. In addition, patients with the latter genotypes have much more severely involved livers, spleens, and bones and had a higher incidence of splenectomy at an earlier age. These predictive genotype analyses provide the basis for genetic care delivery and therapeutic recommendations in patients affected with Gaucher disease type 1. 38 refs., 1 fig., 4 tabs.« less

Enzyme replacement and substrate reduction therapy for Gaucher disease.

PubMed

Shemesh, Elad; Deroma, Laura; Bembi, Bruno; Deegan, Patrick; Hollak, Carla; Weinreb, Neal J; Cox, Timothy M

2015-03-27

Gaucher disease, a rare disorder, is caused by inherited deficiency of the enzyme glucocerebrosidase. It is unique among the ultra-orphan disorders in that four treatments are currently approved by various regulatory authorities for use in routine clinical practice. Hitherto, because of the relatively few people affected worldwide, many of whom started therapy during a prolonged period when there were essentially no alternatives to imiglucerase, these treatments have not been systematically evaluated in studies such as randomized controlled trials now considered necessary to generate the highest level of clinical evidence. To summarize all available randomized controlled study data on the efficacy and safety of enzyme replacement therapies and substrate reduction therapy for treating Gaucher disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register. Additional searches were conducted on ClinicalTrials.gov for any ongoing studies with potential interim results, and through PubMed. We also searched the reference lists of relevant articles and reviews.Date of last search: 07 August 2014. All randomized and quasi-randomized controlled studies (including open-label studies and cross-over studies) assessing enzyme replacement therapy or substrate reduction therapy, or both, in all types of Gaucher disease were included. Two authors independently assessed the risk of bias in the included studies, and extracted relevant data. Of the 488 studies retrieved by the electronic searches, eight met the inclusion criteria and were analysed (300 participants). Response parameters were restricted to haemoglobin concentration, platelet count, spleen and liver volume and serum biomarkers (chitotriosidase and CCL18). Only one publication reported a 'low risk of bias' score in all parameters assessed, and all studies included were randomized.Four studies reported the responses to enzyme replacement therapy of previously

Evaluation of neopterin as a biomarker for the monitoring of Gaucher disease patients.

PubMed

Drugan, Cristina; Drugan, Tudor C; Miron, Nicolae; Grigorescu-Sido, Paula; Naşcu, Ioana; Cătană, Cristina

2016-07-01

Biomarker research is an important area of investigation in Gaucher disease, caused by an inherited deficiency of a lysosomal enzyme, glucocerebrosidase. We evaluated the usefulness of neopterin, as a novel biomarker reflecting chronic inflammation and immune system activation in Gaucher disease and analysed its evolution in response to enzyme replacement therapy (ERT). Circulating plasma neopterin levels in 31 patients with non-neuronopathic Gaucher disease were measured before and after the onset of ERT and were compared with those of 18 healthy controls. Plasma chitotriosidase activity was also monitored, as a reference biomarker, against which we evaluated the evolution of neopterin. Neopterin levels were significantly increased in treatment-naïve patients (mean 11.90 ± 5.82 nM) compared with controls (6.63 ± 5.59 nM, Mann-Whitney U test P = 0.001), but returned to normal levels (6.92 ± 4.66 nM) following ERT. Investigating the diagnostic value of neopterin by receiver operating characteristic analysis, we found a cut-off value of 7.613 nM that corresponds to an area under the curve of 0.780 and indicates a good discrimination capacity, with a sensitivity of 0.774 and a specificity of 0.778. Our results suggest that measurement of circulating neopterin may be considered as a novel test for the confirmation of diagnosis and monitoring of the efficacy of therapeutic intervention in Gaucher disease. Plasma neopterin levels reflect the global accumulation and activation of Gaucher cells and the extent of chronic immune activation in this disorder. Neopterin may be an alternative storage cell biomarker in Gaucher disease, especially in chitotriosidase-deficient patients.

Novel insertion mutation in a non-Jewish Caucasian type 1 Gaucher disease patient

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choy, F.Y.M.; Humphries, M.L.; Ferreira, P.

1997-01-20

Gaucher disease is the most prevalent lysosomal storage disorder. It is autosomal recessive, resulting in lysosomal glucocerebrosidase deficiency. Three clinical forms of Gaucher disease have been described: type 1 (nonneuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic). We performed PCR-thermal cycle sequence analysis of glucocerebrosidase genomic DNA and identified a novel mutation in a non-Jewish type 1 Gaucher disease patient. It is a C insertion in exon 3 at cDNA nucleotide position 122 and genomic nucleotide position 1626. This mutation causes a frameshift and, subsequently, four of the five codons immediately downstream of the insertion were changed whilemore » the sixth was converted to a stop codon, resulting in premature termination of protein translation. The 122CC insertion abolishes a Cac81 restriction endonuclease cleavage site, allowing a convenient and reliable method for detection using RFLP analysis of PCR-amplified glucocerebrosidase genomic DNA. The mutation in the other Gaucher allele was found to be an A{r_arrow}G substitution at glucocerebrosidase cDNA nucleotide position 1226 that so far has only been reported among type 1 Gaucher disease patients. Since mutation 122CC causes a frameshift and early termination of protein translation, it most likely results in a meaningless transcript and subsequently no residual glucocerebrosidase enzyme activity. We speculate that mutation 122CC may result in a worse prognosis than mutations associated with partial activity. When present in the homozygous form, it could be a lethal allele similar to what has been postulated for the other known insertion mutation, 84GG. Our patient, who is a compound heterozygote 122CC/1226G, has moderately severe type 1 Gaucher disease. Her clinical response to Ceredase{reg_sign} therapy that began 31 months ago has been favorable, though incomplete. 30 refs., 3 figs., 2 tabs.« less

Lentiviral Gene Therapy Using Cellular Promoters Cures Type 1 Gaucher Disease in Mice

PubMed Central

Dahl, Maria; Doyle, Alexander; Olsson, Karin; Månsson, Jan-Eric; Marques, André R A; Mirzaian, Mina; Aerts, Johannes M; Ehinger, Mats; Rothe, Michael; Modlich, Ute; Schambach, Axel; Karlsson, Stefan

2015-01-01

Gaucher disease is caused by an inherited deficiency of the enzyme glucosylceramidase. Due to the lack of a fully functional enzyme, there is progressive build-up of the lipid component glucosylceramide. Insufficient glucosylceramidase activity results in hepatosplenomegaly, cytopenias, and bone disease in patients. Gene therapy represents a future therapeutic option for patients unresponsive to enzyme replacement therapy and lacking a suitable bone marrow donor. By proof-of-principle experiments, we have previously demonstrated a reversal of symptoms in a murine disease model of type 1 Gaucher disease, using gammaretroviral vectors harboring strong viral promoters to drive glucosidase β-acid (GBA) gene expression. To investigate whether safer vectors can correct the enzyme deficiency, we utilized self-inactivating lentiviral vectors (SIN LVs) with the GBA gene under the control of human phosphoglycerate kinase (PGK) and CD68 promoter, respectively. Here, we report prevention of, as well as reversal of, manifest disease symptoms after lentiviral gene transfer. Glucosylceramidase activity above levels required for clearance of glucosylceramide from tissues resulted in reversal of splenomegaly, reduced Gaucher cell infiltration and a restoration of hematological parameters. These findings support the use of SIN-LVs with cellular promoters in future clinical gene therapy protocols for type 1 Gaucher disease. PMID:25655314

Diagnosis and Management of Gaucher Disease in India - Consensus Guidelines of the Gaucher Disease Task Force of the Society for Indian Academy of Medical Genetics and the Indian Academy of Pediatrics.

PubMed

Puri, Ratna Dua; Kapoor, Seema; Kishnani, Priya S; Dalal, Ashwin; Gupta, Neerja; Muranjan, Mamta; Phadke, Shubha R; Sachdeva, Anupam; Verma, Ishwar C; Mistry, Pramod K

2018-02-15

Gaucher disease (GD) is amongst the most frequently occurring lysosomal storage disorder in all ethnicities. The clinical manifestations and natural history of GD is highly heterogeneous with extreme geographic and ethnic variations. The literature on GD has paucity of information and optimal management guidelines for Indian patients. Gaucher Disease Task Force was formed under the auspices of the Society for Indian Academy of Medical Genetics. Invited experts from various specialties formulated guidelines for the management of patients with GD. A writing committee was formed and the draft guidelines were circulated by email to all members for comments and inputs. The guidelines were finalized in December 2016 at the annual meeting of the Indian Academy of Medical Genetics. These guidelines are intended to serve as a standard framework for treating physicians and the health care systems for optimal management of Gaucher disease in India and to define unique needs of this patient population. Manifestations of GD are protean and a high index of suspicion is essential for timely diagnosis. Patients frequently experience diagnostic delays during which severe irreversible complications occur. Leucocyte acid b-glucosidase activity is mandatory for establishing the diagnosis of Gaucher disease; molecular testing can help identify patients at risk of neuronopathic disease. Enzyme replacement therapy for type 1 and type 3 Gaucher disease is the standard of care. Best outcomes are achieved by early initiation of therapy before onset of irreversible complications. However, in setting of progressive neurological symptoms such as seizures and or/ neuroregression, ERT is not recommended, as it cannot cross the blood brain barrier. The recommendations herein are for diagnosis, for initiation of therapy, therapeutic goals, monitoring and follow up of patients. We highlight that prevention of recurrence of the disease through genetic counseling and prenatal diagnosis is essential

A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

PubMed Central

Stirnemann, Jérôme; Belmatoug, Nadia; Camou, Fabrice; Serratrice, Christine; Froissart, Roseline; Caillaud, Catherine; Levade, Thierry; Astudillo, Leonardo; Serratrice, Jacques; Brassier, Anaïs; Rose, Christian; Billette de Villemeur, Thierry; Berger, Marc G.

2017-01-01

Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to 1/60,000 births, rising to 1/800 in Ashkenazi Jews. The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. Type-1 Gaucher disease, which affects the majority of patients (90% in Europe and USA, but less in other regions), is characterized by effects on the viscera, whereas types 2 and 3 are also associated with neurological impairment, either severe in type 2 or variable in type 3. A diagnosis of GD can be confirmed by demonstrating the deficiency of acid glucocerebrosidase activity in leukocytes. Mutations in the GBA1 gene should be identified as they may be of prognostic value in some cases. Patients with type-1 GD—but also carriers of GBA1 mutation—have been found to be predisposed to developing Parkinson’s disease, and the risk of neoplasia associated with the disease is still subject to discussion. Disease-specific treatment consists of intravenous enzyme replacement therapy (ERT) using one of the currently available molecules (imiglucerase, velaglucerase, or taliglucerase). Orally administered inhibitors of glucosylceramide biosynthesis can also be used (miglustat or eliglustat). PMID:28218669

Gaucher disease in the Afrikaner population of South Africa.

PubMed

Goldblatt, J; Beighton, P

1979-02-10

The chronic non-neuropathic form of Gaucher disease has been encountered in 10 individuals in the Afrikaner population of South Africa. The minimum prevalence in this community is 1 in 200 000 with a gene frequency of 0,0022, a heterozygote rate of 0,0044 and at least 9 000 clinically asymptomatic carriers of the abnormal gene. This gene must be present in about 1 in every 220 Afrikaners. The majority of previously reported patients have been Ashkenazi Jews, in whom the condition is relatively benign. By contrast, the disorder in the Afrikaners is precocious in onset, with serious complications and rapid progression. The occurrence of Gaucher disease in a relatively high frequency in the Afrikaner population is important in terms of differential diagnosis, genetic counselling and prevention.

Connecting Gaucher and Parkinson Disease: Considerations for Clinical and Research Genetic Counseling Settings.

PubMed

Cook, Lola; Schulze, Jeanine

2017-12-01

There are multiple autosomal recessive disorders in which carriers may be at risk for other diseases. This observation calls into question the previous understanding that carriers of autosomal recessive disorders escape clinical consequences. We also know that childhood genetic conditions may have adult disease counterparts (Zimran et al., The Israel Medical Association Journal: IMAJ, 16(11), 723-724, 2014). Individuals who have Gaucher disease and carriers of the disorder are at increased risk for a seemingly unrelated and complex neurological condition, Parkinson disease. Parkinson disease is, in part, caused by the same mutations in the GBA gene that lead to Gaucher disease, and the two conditions are thought to have shared pathophysiology. Briefly reviewed are how these two diseases historically became linked, where their paths cross, potential problems and considerations in disclosure of the link, and current guidelines and research in this area. Genetic counseling experience with a large Parkinson disease cohort is used as a starting point to question the state of clinical and nonclinical practice in disclosing this unusual connection We conclude that more research and discussion are needed to inform practice regarding the crossroads of Gaucher and Parkinson disease.

Gaucher disease: Gene frequencies in the Ashkenazi Jewish population

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beutler, E.; West, C.; Gelbart, T.

1993-01-01

DNA from over 2,000 Ashkenazi Jewish subjects has been examined for the four most common Jewish Gaucher disease mutations, which collectively account for about 96% of the disease-producing alleles in Jewish patients. This population survey has made possible the estimation of gene frequencies for these alleles. Eighty-seven of 1,528 individuals were heterozygous for the 1226G (N370S) mutation, and four presumably well persons were homozygous for this mutation. The gene frequency for the 1226G allele was calculated to be .0311, and when these data were pooled with those obtained previously from another 593 Jewish subjects, a gene frequency of .032 withmore » a standard error of .004 was found. Among 2,305 normal subjects, 10 were found to be heterozygous for the 84GG allele, giving a gene frequency of .00217 with a standard error of .00096. No examples of the IVS2(+1) mutation were found among 1,256 samples screened, and no 1448C (L444P) mutations were found among 1,528 samples examined. Examination of the distribution of Gaucher disease gene frequencies in the general population shows that the ratio of 1226G mutations to 84GG mutations is higher than that in the patient population. This is presumed to be due to the fact that homozygotes for the 1226G mutation often have late-onset disease or no significant clinical manifestations at all. To bring the gene frequency in the patient population into conformity with the gene frequency in the general population, nearly two-thirds of persons with a Gaucher disease genotype would be missing from the patient population, presumably because their clinical manifestations were very mild. 10 refs., 3 tabs.« less

Involvement of hepcidin in iron metabolism dysregulation in Gaucher disease.

PubMed

Lefebvre, Thibaud; Reihani, Niloofar; Daher, Raed; de Villemeur, Thierry Billette; Belmatoug, Nadia; Rose, Christian; Colin-Aronovicz, Yves; Puy, Hervé; Le Van Kim, Caroline; Franco, Mélanie; Karim, Zoubida

2018-04-01

Gaucher disease (GD) is an inherited deficiency of glucocerebrosidase leading to accumulation of glucosylceramide in tissues such as the spleen, liver, and bone marrow. The resulting lipid-laden macrophages lead to the appearance of "Gaucher cells". Anemia associated with an unexplained hyperferritinemia is a frequent finding in GD, but whether this pathogenesis is related to an iron metabolism disorder has remained unclear. To investigate this issue, we explored the iron status of a large cohort of 90 type I GD patients, including 66 patients treated with enzyme replacement therapy. Ten of the patients treated with enzyme replacement were followed up before and during treatment. Serum levels of hepcidin, the iron regulatory peptide, remained within the physiological range, while the transferrin saturation was slightly decreased in children. Inflammation-independent hyperferritinemia was found in 65% of the patients, and Perl's staining of the spleen and marrow smear revealed iron accumulation in Gaucher cells. Treated patients exhibited reduced hyperferritinemia, increased transferrin saturation and transiently increased systemic hepcidin. In addition, the hepcidin and ferritin correlation was markedly improved, and, in most patients, the hemoglobin level was normalized. To further explore eventual iron sequestration in macrophages, we produce a Gaucher cells model by treating the J774 macrophage cell line with a glucocerebrosidase inhibitor and showed induced local hepcidin and membrane retrieval of the iron exporter, ferroportin. These data reveal the involvement of Gaucher cells in abnormal iron sequestration, which may explain the mechanism of hyperferritinemia in GD patients. Local hepcidin-ferroportin interaction was involved in this pathogenesis. Copyright© 2018 Ferrata Storti Foundation.

Mutation analysis of Australasian Gaucher disease patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nelson, P.V.; Carey, W.F.; Morris, C.P.

1995-09-25

We have previously reported phenotype and genotype analyses in 28 Australasian Gaucher patients who were screened for several of the common Gaucher mutations: N370S, L444P, 84GG, and R463C. Horowitz and Zimran have reported that the complex alleles recNciI and recTL, which contain several point mutations including L444P, are relatively common, especially in non-Jewish Gaucher patients. Zimran and Horowitz have also stated that these recombinant alleles could easily be missed by laboratories testing only for the common Gaucher point mutations. Failure to correctly identify these mutations would influence any attempt to correlate genotype with phenotype. We have therefore retested our Gauchermore » patients for recNciI (L444P, A456P, and V46OV) and recTL (D409H, L444P, A456P, and V46OV) by PCR amplification, followed by hybridization with allele-specific oligonucleotides. 4 refs.« less

DNA analysis of an uncommon missense mutation in a Gaucher disease patient of Jewish-Polish-Russian descent

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choy, F.Y.M.; Wei, C.; Applegarth, D.A.

1994-06-01

Gaucher disease is the most frequent lysosomal lipid storage disease. It results from deficient glucocerebrosidase activity and is transmitted as an autosomal recessive trait. Three clinical forms of Gaucher disease have been described: type 1, non-neuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic. We have sequenced the full length cDNA of the glucocerebrosidase gene and identified an uncommon mutation in nucleotide position 1604 (genoma DNA nucleotide position 6683) from a Gaucher disease patient of Jewish-Polish-Russian descent with type 1 Gaucher disease. It is a G{yields}A transition in exon 11 that results in {sup 496}Arg{yields}{sup 496}His of glucocerebrosidase. Thismore » missense mutation is present in the heterozygous form and creates a new cleavage site for the endonuclease HphI. We have developed a simple method to detect the presence of this mutation by using HphI restriction fragment length polymorphism analysis of glucocerebrosidase genomic DNA or cDNA. The mutation in the other Gaucher allele of this patient is an A{yields}G transition at cDNA nucleotide position 1226 which creates an XhoI cleavage site after PCR mismatch amplification. The presence of this mutation was also confirmed by sequence analysis. Based on previous reports that mutation 1226 is present only in type 1 Gaucher disease and the observation that there is no neurological involvement in this patient, we conclude that our patient with the 1226/1604 genotype is diagnosed as having type 1 Gaucher disease. Since it was also postulated that mutation 1226 in the homozygous form will usually result in a good prognosis, we speculate that the orthopedic complications and the unusual presence of glomerulosclerosis in this patient may be attributable to the mutation at nucleotide 1604. This speculation will require a description of more patients with this mutation for confirmation. 32 refs., 5 figs.« less

Use of various diagnostic methods in a patient with Gaucher disease type I.

PubMed

Farahati, J; Trenn, G; John-Mikolajewski, V; Zander, C; Pastores, G M; Sciuk, J; Reiners, C

1996-08-01

A series of plain radiographs, bone scans, bone marrow scans, and MRIs is reported in a patient with Gaucher disease type I, in whom two episodes of acute bone crisis developed during a 6-year period of follow-up. Acute bone crisis and global indolent bone marrow displacement could both be assessed by bone marrow scintigraphy, whereas MRI could better clarify the corti-comedullary alteration after bone infarction. Thus, MRI and bone marrow scintigraphy could be used as complementary imaging methods in the management of patients with Gaucher disease.

Differentiation of the glucocerebrosidase gene from pseudogene by long-template PCR: Implications for Gaucher disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tayebi, N.; Cushner, S.; Sidransky, E.

1996-09-01

We describe the use of long-template PCR to differentiate the glucocerebrosidase gene from its pseudogene, which will simplify molecular diagnostic testing and the detection of known and new mutations in patients with Gaucher disease. Gaucher disease results from the inherited deficiency of the lysosomal enzyme, glucocerebrosidase. Sixteen kilobases downstream of the glucocerebrosidase gene is a pseudogene, which is {approximately}2 kb shorter and has >96% identity to the coding regions of the functional gene. Many mutations encountered in Gaucher patients are identical to sequences ordinarily found only in the pseudogene, and some result from recombination between the gene and pseudogene. Thus,more » for diagnostic purposes it is essential to differentiate between sequences from the gene and pseudogene. 9 refs., 1 fig.« less

Exploring the patient journey to diagnosis of Gaucher disease from the perspective of 212 patients with Gaucher disease and 16 Gaucher expert physicians.

PubMed

Mehta, Atul; Belmatoug, Nadia; Bembi, Bruno; Deegan, Patrick; Elstein, Deborah; Göker-Alpan, Özlem; Lukina, Elena; Mengel, Eugen; Nakamura, Kimitoshi; Pastores, Gregory M; Pérez-López, Jordi; Schwartz, Ida; Serratrice, Christine; Szer, Jeffrey; Zimran, Ari; Di Rocco, Maja; Panahloo, Zoya; Kuter, David J; Hughes, Derralynn

2017-11-01

Gaucher disease (GD) is a rare hereditary disorder caused by a deficiency of the lysosomal enzyme β-glucocerebrosidase. Diagnosis is challenging owing to a wide variability in clinical manifestations and severity of symptoms. Many patients may experience marked delays in obtaining a definitive diagnosis. The two surveys reported herein aimed to explore the patient journey to diagnosis of GD from the perspectives of Gaucher expert physicians and patients. Findings from the surveys revealed that many patients experienced diagnostic delays and misdiagnoses, with nearly 1 in 6 patients stating that they were not diagnosed with GD for 7years or more after first consulting a doctor. Physicians and patients both reported multiple referrals to different specialties before a diagnosis of GD was obtained, with primary care, haematology/haematology-oncology and paediatrics the main specialties to which patients first presented. Splenomegaly, thrombocytopenia, anaemia and bone pain were reported as the most common medical problems at first presentation in both surveys. These findings support a clear need for straightforward and easy-to-follow guidance designed to assist non-specialists to identify earlier patients who are at risk of GD. Copyright © 2017 The Authors and Shire HGT Inc. Published by Elsevier Inc. All rights reserved.

Gaucher cell, photomicrograph (image)

MedlinePlus

Gaucher disease is called a "lipid storage disease" where abnormal amounts of lipids called "glycosphingolipids" are stored in special cells called reticuloendothelial cells. Classically, the nucleus is ...

Osteocyte Alterations Induce Osteoclastogenesis in an In Vitro Model of Gaucher Disease.

PubMed

Bondar, Constanza; Ormazabal, Maximiliano; Crivaro, Andrea; Ferreyra-Compagnucci, Malena; Delpino, María Victoria; Rozenfeld, Paula Adriana; Mucci, Juan Marcos

2017-01-13

Gaucher disease (GD) is caused by mutations in the glucosylceramidase β ( GBA 1 ) gene that confer a deficient level of activity of glucocerebrosidase (GCase). This deficiency leads to the accumulation of the glycolipid glucocerebroside in the lysosomes of cells, mainly in the monocyte/macrophage lineage. Its mildest form is Type I GD, characterized by non-neuronopathic involvement. Bone compromise is the most disabling aspect of the Gaucher disease. However, the pathophysiological aspects of skeletal alterations are not yet fully understood. The bone tissue homeostasis is maintained by a balance between resorption of old bone by osteoclasts and new bone formation by osteoblasts. A central player in this balance is the osteocyte as it controls both processes. We studied the involvement of osteocytes in an in vitro chemical model of Gaucher disease. The osteocyte cell line MLO-Y4 was exposed to conduritol-β-epoxide (CBE), an inhibitor of GCase, for a period of 7, 14 and 21 days. Conditioned media from CBE-treated osteocytes was found to induce osteoclast differentiation. GCase inhibition caused alterations in Cx43 expression and distribution pattern and an increase in osteocyte apoptosis. Osteoclast differentiation involved osteocyte apoptotic bodies, receptor activator of nuclear factor κ-B ligand (RANKL) and soluble factors. Thus, our results indicate that osteocytes may have a role to play in the bone pathophysiology of GD.

Genetic heterogeneity in type 1 Gaucher disease: Multiple genotypes in Ashkenazic and non-Ashkenazic individuals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsuji, Shoji; Martin, B.M.; Stubblefield, B.K.

1988-04-01

Nucleotide sequence analysis of a genomic clone from an Ashkenazic Jewish patient with type 1 Gaucher disease revealed a single-base mutation (adenosine to guanosine transition) in exon 9 of the glucocerebrosidase gene. This change results in the amino acid substitution of serine for asparagine. Transient expression studies following oligonucleotide-directed mutagenesis of the normal cDNA confirmed that the mutation results in loss of glucocerebrosidase activity. Allele-specific hybridization with oligonucleotide probes demonstrated that this mutation was found exclusively in type 1 phenotype. None of the 6 type 2 patients, 11 type 3 patients, or 12 normal controls had this allele. In contrast,more » 15 of 24 type 1 patients had one allele with this mutation, and 3 others were homozygous for the mutation. Furthermore, some of the Ashkenazic Jewish type 1 patients had only one allele with this mutation, suggesting that even in this population there is allelic heterozygosity. These findings indicate that there are multiple allelic mutations responsible for type 1 Gaucher disease in both the Jewish and non-Jewish populations. Allelic-specific hybridization demonstrating this mutation in exon 9, used in conjunction with the Nci I restriction fragment length polymorphism described as a marker for neuronopathic Gaucher disease, provides a tool for diagnosis and genetic counseling that is {approx}80% informative in all Gaucher patients studied.« less

Transformation in pretreatment manifestations of Gaucher disease type 1 during two decades of alglucerase/imiglucerase enzyme replacement therapy in the International Collaborative Gaucher Group (ICGG) Gaucher Registry

PubMed Central

Batista, Julie L.; Andersson, Hans C.; Balwani, Manisha; Burrow, Thomas Andrew; Charrow, Joel; Kaplan, Paige; Khan, Aneal; Kishnani, Priya S.; Kolodny, Edwin H.; Rosenbloom, Barry; Scott, C. Ronald; Weinreb, Neal

2017-01-01

Abstract This study tests the hypothesis that the prevalence of severe clinical manifestations in Gaucher disease type 1 (GD1) patients at the time of treatment initiation has changed since alglucerase/imiglucerase enzyme replacement therapy (ERT) was approved in the United States (US) in 1991. US alglucerase/imiglucerase‐treated GD1 patients from the International Collaborative Gaucher Group Gaucher Registry clinicaltrials.gov NCT00358943 were stratified by age at ERT initiation (<18, 18 to <50, ≥50 years), era of ERT initiation (1991‐1995, 1996‐2000, 2001‐2005, 2006‐2009), and splenectomy status pre‐ERT. Prevalence of splenectomy decreased dramatically across the eras among all age groups. Bone manifestations were more prevalent in splenectomized patients than non‐splenectomized patients in all age groups. Prevalence of bone manifestations differed across eras in certain age groups: non‐splenectomized patients had a lower prevalence of ischemic bone events (pediatric patients) and bone crisis (pediatric patients and adults 18 to <50 years) in later eras; splenectomized adult (18 to <50 years) patients had a lower prevalence of ischemic bone events and bone crisis in later eras. Over two decades after the introduction of ERT, the prevalence of splenectomy and associated skeletal complications has declined dramatically. Concomitantly, the interval between diagnosis and initiation of ERT has decreased, most strikingly in pediatric patients who have the most severe disease. Together, these findings suggest that since the introduction of alglucerase/imiglucerase ERT, optimal standard of care has become established in the US to prevent destructive complications of GD1. PMID:28569047

A new glucocerebrosidase-deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease

PubMed Central

Westbroek, Wendy; Nguyen, Matthew; Siebert, Marina; Lindstrom, Taylor; Burnett, Robert A.; Aflaki, Elma; Jung, Olive; Tamargo, Rafael; Rodriguez-Gil, Jorge L.; Acosta, Walter; Hendrix, An; Behre, Bahafta; Tayebi, Nahid; Fujiwara, Hideji; Sidhu, Rohini; Renvoise, Benoit; Ginns, Edward I.; Dutra, Amalia; Pak, Evgenia; Cramer, Carole; Ory, Daniel S.; Pavan, William J.

2016-01-01

ABSTRACT Glucocerebrosidase is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease, a recessive lysosomal storage disorder, is caused by mutations in the gene GBA1. Dysfunctional glucocerebrosidase leads to accumulation of glucosylceramide and glycosylsphingosine in various cell types and organs. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease and related synucleinopathies. In recent years, research on the pathophysiology of Gaucher disease, the molecular link between Gaucher and Parkinson disease, and novel therapeutics, have accelerated the need for relevant cell models with GBA1 mutations. Although induced pluripotent stem cells, primary rodent neurons, and transfected neuroblastoma cell lines have been used to study the effect of glucocerebrosidase deficiency on neuronal function, these models have limitations because of challenges in culturing and propagating the cells, low yield, and the introduction of exogenous mutant GBA1. To address some of these difficulties, we established a high yield, easy-to-culture mouse neuronal cell model with nearly complete glucocerebrosidase deficiency representative of Gaucher disease. We successfully immortalized cortical neurons from embryonic null allele gba−/− mice and the control littermate (gba+/+) by infecting differentiated primary cortical neurons in culture with an EF1α-SV40T lentivirus. Immortalized gba−/− neurons lack glucocerebrosidase protein and enzyme activity, and exhibit a dramatic increase in glucosylceramide and glucosylsphingosine accumulation, enlarged lysosomes, and an impaired ATP-dependent calcium-influx response; these phenotypical characteristics were absent in gba+/+ neurons. This null allele gba−/− mouse neuronal model provides a much-needed tool to study the pathophysiology of Gaucher disease and to evaluate new therapies. PMID:27482815

Treatment patterns from 647 patients with Gaucher disease: An analysis from the Gaucher Outcome Survey.

PubMed

Deegan, P; Fernandez-Sasso, D; Giraldo, P; Lau, H; Panahloo, Z; Zimran, A

2018-02-01

The Gaucher Outcome Survey (GOS) is an international disease-specific registry established in 2010 for patients with a confirmed diagnosis of Gaucher disease (GD), regardless of GD type or treatment status. For insight into how GD management varies among countries, we analyzed treatment patterns in GOS. As of October 30, 2015, data on GD-specific treatment (enzyme replacement therapy, substrate reduction therapy, or chemical chaperone therapy) received at any time were available for 647 patients. At analysis, velaglucerase alfa (316/573, 55.1%) and imiglucerase (184/573, 32.1%) were the treatments most widely used. Of the 647 treated patients, 446 (68.9%) had been treated for >5years and 368 (56.9%) had received only one GD-specific drug therapy. There were 377 patients who received velaglucerase alfa. Velaglucerase alfa was most widely used at 60U/kg every other week (134/492 dose entries, 27.2%), but there were differences in dosing between the three highest-enrolling countries (defined as >100 GOS patients enrolled in each), with most patients in Israel receiving <20U/kg, most patients in the United Kingdom receiving 20 to <40U/kg, and most in the United States receiving 60U/kg. This analysis provides a foundation upon which to examine real-life outcomes data from different treatment regimens globally. Copyright © 2016 Shire Human Genetic Therapies, Inc. Published by Elsevier Inc. All rights reserved.

Gaucher cell, photomicrograph #2 (image)

MedlinePlus

Gaucher disease is called a "lipid storage disease" where abnormal amounts of lipids called "glycosphingolipids" are stored in special cells called reticuloendothelial cells. Classically, the nucleus is ...

Baseline characteristics and outcome in Romanian patients with Gaucher disease type 1.

PubMed

Grigorescu-Sido, Paula; Drugan, Cristina; Alkhzouz, Camelia; Zimmermann, Anca; Coldea, Cristina; Denes, Carmen; Grigorescu, Mircea Dan; Cret, Victoria; Bucerzan, Simona

2010-04-01

To present clinical and genetic characteristics of all Romanian patients with Gaucher disease type 1, in whom specific diagnosis has been confirmed by enzymatic and molecular methods and to analyze their outcome with and without enzymatic replacement therapy (ERT). There are fifty patients (F/M - 1.63/1) with Gaucher disease type 1. Clinical status, haemoglobin, thrombocytes, hepatic/splenic volume, bone mineral density and severity score were assessed at baseline and every six months thereafter. Thirty-nine patients (78%) received imiglucerase (44.4+/-13.6 U/kg/2 weeks) for 3.1+/-1.4 years. Based on general prevalence data, our group represents 22.7% of the expected total number of patients with Gaucher disease type 1 in Romania. Mean age was 15.5 years at clinical onset and 28.9 years at confirmation of diagnosis. The genotype N370S/L444P was frequent in our group (35.9% of alleles). Anaemia, thrombocytopenia, splenomegaly and bone disease were present at 38%, 70%, 100% and 84%, respectively. Mean values for haemoglobin, thrombocytes, hepatic volume and chitotriosidase normalized after 0.5, 1.5, 2.5 and 3 years of ERT, respectively. Splenomegaly regressed from 14.4 x N (normal) to 3.06 x N over four years of treatment. Bone disease was ameliorated under ERT, yet bone mineral density worsened in patients treated with 30 U/kg/2 weeks. The genotype N370S/L444P is frequent in our patients, in line with the severe phenotypes. ERT improved haematological parameters and visceromegaly, without a clear benefit for bone mineral density. To attain therapeutic goals, an early treatment start with optimal dosage is mandatory. Copyright 2009 Elsevier B.V. All rights reserved.

Identification of the second common Jewish Gaucher disease mutation makes possible population-based screening for the heterozygous state

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beutler, E.; Gelbart, T.; Kuhl, W.

1991-12-01

Gaucher disease is an autosomal recessive glycolipid storage disease characterized by a deficiency of glucocerebrosidase. The disease is most common in persons of Ashkenazi Jewish ancestry and the most common mutation, accounting for about 75% of the mutant alleles in this population, is known to be an A {yields} G substitution at cDNA nucleotide (nt) 1,226. Screening for this disease has not been possible because nearly 25% of the mutant alleles had not been identified, but linkage analysis led to the suggestion that most of these could be accounted for by a single mutation. The authors now report the discoverymore » of this mutation. The insertion of a single nucleotide, a second guanine at cDNA nt 84 (the 84GG mutation), has been detected in the 5{prime} coding region of the glucocerebrosidase gene. The amount mRNA produced is shown to be normal but since the frameshift produces early termination, no translation product is seen. This finding is consistent with the virtual absence of antigen found in patients carrying this mutation. The 84GG mutation accounts for most of the previously unidentified Gaucher disease mutations in Jewish patients. The common Jewish mutation at nt 1,448 accounted for 95% of all of the Gaucher disease-producing alleles in 71 Jewish patients. This now makes it possible to screen for heterozygotes on a DNA level with a relatively low risk of missing couples at risk for producing infants with Gaucher disease.« less

Unexpected cure from cutaneous leukocytoclastic vasculitis in a patient treated with N-butyldeoxynojirimycin (miglustat) for Gaucher disease.

PubMed

Machaczka, M; Klimkowska, M; Hägglund, H

2012-06-01

Cutaneous leukocytoclastic vasculitis (CLV) is a necrotizing inflammation of the small vessels in the dermis. We report the case of a Swedish man with an untreated N370S/L444P Gaucher disease who developed CLV at the age of 79 years. The patient has been treated for CLV with topical and oral corticosteroids, moisturizing agents, and periodically with antibiotics for 3 years without improvement. Administration of miglustat (N-butyldeoxynojirimycin; Zavesca®) because of progress of Gaucher disease resulted in a prompt and durable cure of the CLV.

Type II Gaucher disease: compound heterozygote with RecNciI and L444P mutations.

PubMed

Lee, Y S; Poh, L K; Ida, H; Loke, K Y

2001-04-01

We report the phenotype and genotype of an Indonesian Chinese boy with type II Gaucher disease. He had a unique presentation of recurrent cyanosis from laryngospasm. He was compound heterozygous for L444P/L444P + A456P + V460V. There have been few reports of this heterozygosity and its phenoptype. This genotype-phenotype correlation will be important for physicians in genetic counselling. Type II Gaucher disease in Southeast Asia may not be as rare as was perceived, but may be a condition that is under-reported. The success of our technique together with the results have made it possible for us to perform prenatal diagnosis and carrier detection for the family.

Characteristics of 26 patients with type 3 Gaucher disease: A descriptive analysis from the Gaucher Outcome Survey.

PubMed

Schwartz, Ida Vanessa D; Göker-Alpan, Özlem; Kishnani, Priya S; Zimran, Ari; Renault, Lydie; Panahloo, Zoya; Deegan, Patrick

2018-03-01

The Gaucher Outcome Survey (GOS) is an international disease-specific registry established in 2010 for patients with a confirmed diagnosis of Gaucher disease (GD), regardless of GD type or treatment status. Historically, there has been a limited understanding of type 3 GD (GD3) and its natural history in patients irrespective of their treatment status. Here, we describe the disease characteristics of patients with GD3 enrolled in GOS. As of October 2015, 1002 patients had been enrolled, 26 of whom were reported as GD3. The majority of patients with GD3 were from the US (13; 50.0%), seven (26.9%) were from the UK, three (11.5%) from Israel, and three (11.5%) from Brazil. No patients were of Ashkenazi Jewish origin. Median age of symptom onset was 1.4 (interquartile range: 0.5-2.0) years. The most common GBA1 mutation genotype was L444P/L444P, occurring in 16 (69.6%) of 23 patients who had genotyping information available. Nine patients reported a family history of GD (any type). Of 21 patients with treatment status information, 20 (95.2%) had received GD-specific treatment at any time, primarily imiglucerase (14 patients) and/or velaglucerase alfa (13 patients). Hemoglobin concentrations and platelet counts at GOS entry were within normal ranges for most patients, and there were no reports of severe hepatomegaly or of splenomegaly in non-splenectomized patients, most likely indicative of the effects of treatment received prior to GOS entry. This analysis provides information on the characteristics of patients with GD3 that could be used as the baseline for longitudinal follow-up of these patients.

Iron storage in liver, bone marrow and splenic Gaucheroma reflects residual disease in type 1 Gaucher disease patients on treatment.

PubMed

Regenboog, Martine; Bohte, Anneloes E; Akkerman, Erik M; Stoker, Jaap; Hollak, Carla E M

2017-11-01

Gaucher disease (GD) is a lysosomal storage disorder characterized by the storage of glycosphingolipids in macrophages. Despite effective therapy, residual disease is present in varying degrees and may be associated with late complications, such as persistent bone or liver disease and increased cancer risk. Gaucher macrophages are capable of storing iron and locations of residual disease may thus be detectable with iron imaging. Forty type 1 GD (GD1) patients and 40 matched healthy controls were examined using a whole-body magnetic resonance imaging protocol consisting of standard sequences, allowing analysis of iron content per organ, expressed as R2* (Hz). Median R2* values were significantly elevated in GD1 patients as compared to healthy controls in liver [41 Hz (range 29-165) vs. 38 Hz (range 28-53), P < 0·01], femoral bone marrow [54 Hz (range 37-129) vs. 49 Hz (range 39-69), P = 0·036] and vertebral bone marrow (118 Hz (range 82-210) vs. 105 Hz (range 76-149), P < 0·01). In the spleen, primarily focal Gaucher lesions known as Gaucheroma were found to have increased R2* values. R2* values of liver, spleen and vertebral bone marrow strongly correlated with serum ferritin levels. GD1 patients with persistent hyperferritinaemia demonstrate increased iron levels in liver and bone marrow, which may carry a risk for liver fibrosis and cancer. © 2017 John Wiley & Sons Ltd.

Abnormal pupillary light reflex with chromatic pupillometry in Gaucher disease.

PubMed

Narita, Aya; Shirai, Kentarou; Kubota, Norika; Takayama, Rumiko; Takahashi, Yukitoshi; Onuki, Takanori; Numakura, Chikahiko; Kato, Mitsuhiro; Hamada, Yusuke; Sakai, Norio; Ohno, Atsuko; Asami, Maya; Matsushita, Shoko; Hayashi, Anri; Kumada, Tomohiro; Fujii, Tatsuya; Horino, Asako; Inoue, Takeshi; Kuki, Ichiro; Asakawa, Ken; Ishikawa, Hitoshi; Ohno, Koyo; Nishimura, Yoko; Tamasaki, Akiko; Maegaki, Yoshihiro; Ohno, Kousaku

2014-02-01

The hallmark of neuronopathic Gaucher disease (GD) is oculomotor abnormalities, but ophthalmological assessment is difficult in uncooperative patients. Chromatic pupillometry is a quantitative method to assess the pupillary light reflex (PLR) with minimal patient cooperation. Thus, we investigated whether chromatic pupillometry could be useful for neurological evaluations in GD. In our neuronopathic GD patients, red light-induced PLR was markedly impaired, whereas blue light-induced PLR was relatively spared. In addition, patients with non-neuronopathic GD showed no abnormalities. These novel findings show that chromatic pupillometry is a convenient method to detect neurological signs and monitor the course of disease in neuronopathic GD.

Demographics and patient characteristics of 1209 patients with Gaucher disease: Descriptive analysis from the Gaucher Outcome Survey (GOS)

PubMed Central

Belmatoug, Nadia; Bembi, Bruno; Deegan, Patrick; Elstein, Deborah; Fernandez‐Sasso, Diego; Giraldo, Pilar; Goker‐Alpan, Ozlem; Lau, Heather; Lukina, Elena; Panahloo, Zoya; Schwartz, Ida Vanessa D.

2017-01-01

Abstract The Gaucher Outcome Survey (GOS) is an international Gaucher disease (GD) registry established in 2010 for patients with a confirmed GD diagnosis, regardless of GD type or treatment status, designed to evaluate the safety and long‐term effectiveness of velaglucerase alfa and other GD‐related treatments. As of February 25, 2017, 1209 patients had enrolled, the majority from Israel (44.3%) and the US (31.4%). Median age at GOS entry was 40.4 years, 44.1% were male, and 13.3% had undergone a total splenectomy. Most patients had type 1 GD (91.5%) and were of Ashkenazi Jewish ethnicity (55.8%). N370S/N370S was the most prevalent genotype, accounting for 44.2% of genotype‐confirmed individuals (n = 847); however, there was considerable variation between countries. A total of 887 (73.4%) patients had received ≥1 GD‐specific treatment at any time, most commonly imiglucerase (n = 587), velaglucerase alfa (n = 507), and alglucerase (n = 102). Hematological and visceral findings at the time of GOS entry were close to normal for most patients, probably a result of previous treatment; however, spleen volume of patients in Israel was almost double that of patients elsewhere (7.2 multiples of normal [MN] vs. 2.7, 2.9 and 4.9 MN in the US, UK and rest of world), which may be explained by a greater disease severity in this cohort. This analysis aimed to provide an overview of GOS and present baseline demographic and disease characteristics of participating patients to help improve the understanding of the natural history of GD and inform the overall management of patients with the disease. PMID:29090476

Demographics and patient characteristics of 1209 patients with Gaucher disease: Descriptive analysis from the Gaucher Outcome Survey (GOS).

PubMed

Zimran, Ari; Belmatoug, Nadia; Bembi, Bruno; Deegan, Patrick; Elstein, Deborah; Fernandez-Sasso, Diego; Giraldo, Pilar; Goker-Alpan, Ozlem; Lau, Heather; Lukina, Elena; Panahloo, Zoya; Schwartz, Ida Vanessa D

2018-02-01

The Gaucher Outcome Survey (GOS) is an international Gaucher disease (GD) registry established in 2010 for patients with a confirmed GD diagnosis, regardless of GD type or treatment status, designed to evaluate the safety and long-term effectiveness of velaglucerase alfa and other GD-related treatments. As of February 25, 2017, 1209 patients had enrolled, the majority from Israel (44.3%) and the US (31.4%). Median age at GOS entry was 40.4 years, 44.1% were male, and 13.3% had undergone a total splenectomy. Most patients had type 1 GD (91.5%) and were of Ashkenazi Jewish ethnicity (55.8%). N370S/N370S was the most prevalent genotype, accounting for 44.2% of genotype-confirmed individuals (n = 847); however, there was considerable variation between countries. A total of 887 (73.4%) patients had received ≥1 GD-specific treatment at any time, most commonly imiglucerase (n = 587), velaglucerase alfa (n = 507), and alglucerase (n = 102). Hematological and visceral findings at the time of GOS entry were close to normal for most patients, probably a result of previous treatment; however, spleen volume of patients in Israel was almost double that of patients elsewhere (7.2 multiples of normal [MN] vs. 2.7, 2.9 and 4.9 MN in the US, UK and rest of world), which may be explained by a greater disease severity in this cohort. This analysis aimed to provide an overview of GOS and present baseline demographic and disease characteristics of participating patients to help improve the understanding of the natural history of GD and inform the overall management of patients with the disease. © 2017 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.

Mutant glucocerebrosidase in Gaucher disease recruits Hsp27 to the Hsp90 chaperone complex for proteasomal degradation

PubMed Central

Yang, Chunzhang; Wang, Herui; Zhu, Dongwang; Hong, Christopher S.; Dmitriev, Pauline; Zhang, Chao; Li, Yan; Ikejiri, Barbara; Brady, Roscoe O.; Zhuang, Zhengping

2015-01-01

Gaucher disease is caused by mutations of the GBA1 gene, which encodes the lysosomal anchored gluococerebrosidase (GCase). GBA1 mutations commonly result in protein misfolding, abnormal chaperone recognition, and premature degradation, but are less likely to affect catalytic activity. In the present study, we demonstrate that the Hsp90/HOP/Cdc37 complex recruits Hsp27 after recognition of GCase mutants with subsequent targeting of GCase mutant peptides to degradation mechanisms such as VCP and the 26S proteasome. Inhibition of Hsp27 not only increased the quantity of enzyme but also enhanced GCase activity in fibroblasts derived from patients with Gaucher disease. These findings provide insight into a possible therapeutic strategy for protein misfolding diseases by correcting chaperone binding and altering subsequent downstream patterns of protein degradation. PMID:25583479

Mutant glucocerebrosidase in Gaucher disease recruits Hsp27 to the Hsp90 chaperone complex for proteasomal degradation.

PubMed

Yang, Chunzhang; Wang, Herui; Zhu, Dongwang; Hong, Christopher S; Dmitriev, Pauline; Zhang, Chao; Li, Yan; Ikejiri, Barbara; Brady, Roscoe O; Zhuang, Zhengping

2015-01-27

Gaucher disease is caused by mutations of the GBA1 gene, which encodes the lysosomal anchored gluococerebrosidase (GCase). GBA1 mutations commonly result in protein misfolding, abnormal chaperone recognition, and premature degradation, but are less likely to affect catalytic activity. In the present study, we demonstrate that the Hsp90/HOP/Cdc37 complex recruits Hsp27 after recognition of GCase mutants with subsequent targeting of GCase mutant peptides to degradation mechanisms such as VCP and the 26S proteasome. Inhibition of Hsp27 not only increased the quantity of enzyme but also enhanced GCase activity in fibroblasts derived from patients with Gaucher disease. These findings provide insight into a possible therapeutic strategy for protein misfolding diseases by correcting chaperone binding and altering subsequent downstream patterns of protein degradation.

Association Between Progranulin and Gaucher Disease.

PubMed

Jian, Jinlong; Zhao, Shuai; Tian, Qing-Yun; Liu, Helen; Zhao, Yunpeng; Chen, Wen-Chi; Grunig, Gabriele; Torres, Paola A; Wang, Betty C; Zeng, Bai; Pastores, Gregory; Tang, Wei; Sun, Ying; Grabowski, Gregory A; Kong, Max Xiangtian; Wang, Guilin; Chen, Ying; Liang, Fengxia; Overkleeft, Herman S; Saunders-Pullman, Rachel; Chan, Gerald L; Liu, Chuan-Ju

2016-09-01

Gaucher disease (GD) is a genetic disease caused by mutations in the GBA1 gene which result in reduced enzymatic activity of β-glucocerebrosidase (GCase). This study identified the progranulin (PGRN) gene (GRN) as another gene associated with GD. Serum levels of PGRN were measured from 115 GD patients and 99 healthy controls, whole GRN gene from 40 GD patients was sequenced, and the genotyping of 4 SNPs identified in GD patients was performed in 161 GD and 142 healthy control samples. Development of GD in PGRN-deficient mice was characterized, and the therapeutic effect of rPGRN on GD analyzed. Serum PGRN levels were significantly lower in GD patients (96.65±53.45ng/ml) than those in healthy controls of the general population (164.99±43.16ng/ml, p<0.0001) and of Ashkenazi Jews (150.64±33.99ng/ml, p<0.0001). Four GRN gene SNPs, including rs4792937, rs78403836, rs850713, and rs5848, and three point mutations, were identified in a full-length GRN gene sequencing in 40 GD patients. Large scale SNP genotyping in 161 GD and 142 healthy controls was conducted and the four SNP sites have significantly higher frequency in GD patients. In addition, "aged" and challenged adult PGRN null mice develop GD-like phenotypes, including typical Gaucher-like cells in lung, spleen, and bone marrow. Moreover, lysosomes in PGRN KO mice exhibit a tubular-like appearance. PGRN is required for the lysosomal appearance of GCase and its deficiency leads to GCase accumulation in the cytoplasm. More importantly, recombinant PGRN is therapeutic in various animal models of GD and human fibroblasts from GD patients. Our data demonstrates an unknown association between PGRN and GD and identifies PGRN as an essential factor for GCase's lysosomal localization. These findings not only provide new insight into the pathogenesis of GD, but may also have implications for diagnosis and alternative targeted therapies for GD. Copyright © 2016 Forschungsgesellschaft für Arbeitsphysiologie und

Abnormal pupillary light reflex with chromatic pupillometry in Gaucher disease

PubMed Central

Narita, Aya; Shirai, Kentarou; Kubota, Norika; Takayama, Rumiko; Takahashi, Yukitoshi; Onuki, Takanori; Numakura, Chikahiko; Kato, Mitsuhiro; Hamada, Yusuke; Sakai, Norio; Ohno, Atsuko; Asami, Maya; Matsushita, Shoko; Hayashi, Anri; Kumada, Tomohiro; Fujii, Tatsuya; Horino, Asako; Inoue, Takeshi; Kuki, Ichiro; Asakawa, Ken; Ishikawa, Hitoshi; Ohno, Koyo; Nishimura, Yoko; Tamasaki, Akiko; Maegaki, Yoshihiro; Ohno, Kousaku

2014-01-01

The hallmark of neuronopathic Gaucher disease (GD) is oculomotor abnormalities, but ophthalmological assessment is difficult in uncooperative patients. Chromatic pupillometry is a quantitative method to assess the pupillary light reflex (PLR) with minimal patient cooperation. Thus, we investigated whether chromatic pupillometry could be useful for neurological evaluations in GD. In our neuronopathic GD patients, red light-induced PLR was markedly impaired, whereas blue light-induced PLR was relatively spared. In addition, patients with non-neuronopathic GD showed no abnormalities. These novel findings show that chromatic pupillometry is a convenient method to detect neurological signs and monitor the course of disease in neuronopathic GD. PMID:25356393

Gaucher disease: the role of the specialist on metabolic bone diseases.

PubMed

Masi, Laura; Brandi, Maria Luisa

2015-01-01

According to European legislation, a disease can be considered rare or "orphan" when it affects less than 1 subject of 2000 (1). Often these diseases affecting the pediatric age, are complex diseases and chronically debilitating and for this motive need the intervention of multidisciplinary skills specific. Among the rare disease as affecting the skeleton more than 400 are characterized by dysplastic changes of the skeleton (2). Alongside the disorders affecting the skeleton primitively, many systemic diseases can have a bone involvement. Among these, the Gaucher disease (GD), an heterogeneous lysosomal storage determined by hereditary enzyme deficiency of β-glucosidase. Patients with this disease have skeletal disorders of varying severity (Erlenmeyer flask deformity, lytic lesions and osteonecrosis, pathological fractures) that affects both the bone marrow, both mineralized bone with progressive damage of the tissue. The bone disease is the most debilitating of GD and can have a significant impact on the quality of life of patients. Thorough evaluations by monitoring biochemical markers of bone turnover and instrumental, with a quantitative and qualitative evaluation of the bone, are of fundamental importance to intervene early so they can prevent complications irreversible.

Gaucher disease: the role of the specialist on metabolic bone diseases

PubMed Central

Masi, Laura; Brandi, Maria Luisa

2015-01-01

Summary According to European legislation, a disease can be considered rare or “orphan” when it affects less than 1 subject of 2000 (1). Often these diseases affecting the pediatric age, are complex diseases and chronically debilitating and for this motive need the intervention of multidisciplinary skills specific. Among the rare disease as affecting the skeleton more than 400 are characterized by dysplastic changes of the skeleton (2). Alongside the disorders affecting the skeleton primitively, many systemic diseases can have a bone involvement. Among these, the Gaucher disease (GD), an heterogeneous lysosomal storage determined by hereditary enzyme deficiency of β-glucosidase. Patients with this disease have skeletal disorders of varying severity (Erlenmeyer flask deformity, lytic lesions and osteonecrosis, pathological fractures) that affects both the bone marrow, both mineralized bone with progressive damage of the tissue. The bone disease is the most debilitating of GD and can have a significant impact on the quality of life of patients. Thorough evaluations by monitoring biochemical markers of bone turnover and instrumental, with a quantitative and qualitative evaluation of the bone, are of fundamental importance to intervene early so they can prevent complications irreversible. PMID:26604943

Imiglucerase in the treatment of Gaucher disease: a history and perspective

PubMed Central

Deegan, Patrick B; Cox, Timothy M

2012-01-01

The scientific and therapeutic development of imiglucerase (Cerezyme®) by the Genzyme Corporation is a paradigm case for a critical examination of current trends in biotechnology. In this article the authors argue that contemporary interest in treatments for rare diseases by major pharmaceutical companies stems in large part from an exception among rarities: the astonishing commercial success of Cerezyme. The fortunes of the Genzyme Corporation, latterly acquired by global giant Sanofi SA, were founded on the evolution of a blockbuster therapy for a single but, as it turns out, propitious ultra-orphan disorder: Gaucher disease. PMID:22563238

Reported outcomes of 453 pregnancies in patients with Gaucher disease: An analysis from the Gaucher outcome survey.

PubMed

Lau, Heather; Belmatoug, Nadia; Deegan, Patrick; Goker-Alpan, Ozlem; Schwartz, Ida Vanessa D; Shankar, Suma P; Panahloo, Zoya; Zimran, Ari

2018-02-01

Gaucher disease (GD) may worsen during pregnancy, leading to the discussion of continuing treatment during pregnancy. We examined fetal outcomes of pregnancies reported in the Gaucher Outcome Survey, an international GD-specific registry established in 2010. A total of 453 pregnancies were reported. Most pregnancies (336/453, 74.2%) were in women who did not receive GD-specific treatment during pregnancy, while enzyme replacement therapy (ERT) was received during 117/453 (25.8%) pregnancies. No pregnancies exposed to substrate reduction therapy were reported. The percentage of normal outcomes (live birth delivered at term with no congenital abnormalities) was similar in untreated and treated pregnancies (92.9% vs. 91.4%). The percentage of spontaneous abortions in untreated pregnancies was 3.6% (95% CI, 1.9%- 6.2%) compared with 6.9% (95% CI, 3.0%-13.1%) in treated pregnancies (p=0.1866). In women who received velaglucerase alfa <1month prior to conception and/or during pregnancy, 34/36 (94.4%) pregnancies had normal outcomes and 2 (5.6%) ended in spontaneous abortion. Normal outcomes were observed in the 20 pregnancies with velaglucerase alfa exposure starting <1month prior to conception and continuing through all trimesters. These observations, in addition to information in the literature, suggest that continuation of ERT during pregnancy may be appropriate for GD patients. Copyright © 2016 Shire Human Genetic Therapies, Inc. Published by Elsevier Inc. All rights reserved.

Identification of six new Gaucher disease mutations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beutler, E.; Gelbart, T.; West, C.

1993-01-01

The four most common mutations account for 97% of the Gaucher disease-producing alleles in Jewish patients and 75% of the alleles in non-Jewish patients. Although at least 15 other mutations and some examples of gene conversion and/or fusion genes have been described, a number of mutations remain unidentified. We have now identified six new mutations, a deletion of a C at the 72 position of the cDNA, a 481C[yields]T mutation (122p[sup Gly[yields]Ser]), a 751T [yields] C (212 [sup Tyr[yields]His]), a 1549G [yields] A (478[sup Gly[yields]Ser]), a 1604G [yields] A (496 [sup Arg[yields]His]), and a 55-bp deletion. All but one ofmore » these were found in single families. The 1604A mutation, however, was observed in four unrelated individuals. 7 refs., 2 tabs.« less

Effects of switching from a reduced dose imiglucerase to velaglucerase in type 1 Gaucher disease: clinical and biochemical outcomes

PubMed Central

van Dussen, Laura; Cox, Timothy M.; Hendriks, Erik J.; Morris, Elizabeth; Akkerman, Erik M.; Maas, Mario; Groener, Johanna E. M.; Aerts, Johannes M.F.G.; Deegan, Patrick B.; Hollak, Carla E. M.

2012-01-01

This paper describes the effects of a switch to velaglucerase alfa in a group of adult patients with type 1 Gaucher disease, all of whom had previously had their dose reduced as a consequence of the worldwide imiglucerase shortage. Thirty-two patients from two large European Gaucher centers switched to treatment with velaglucerase alfa after 1-8.5 months of dose reduction. The course of important Gaucher disease parameters was studied at four time points: one year before the shortage, just before the shortage, before a switch to velaglucerase and after up to one year of treatment with velaglucerase. These parameters included hemoglobin concentration, platelet count, plasma chitotriosidase activity in all patients, and spleen and liver volumes (as well as bone marrow fat fraction images) in 10 patients. Decreases in platelet counts as a result of reduced treatment with imiglucerase were quickly restored on treatment with velaglucerase alfa. Chitotriosidase activity declined overall after switching. Five out of 10 patients had an increase in liver volume of at least 10% after six months of velaglucerase treatment, which was reversible in 3. Most patients received infusions at home and no important side effects were observed. Velaglucerase alfa appears to be a safe and effective alternative for imiglucerase. PMID:22773601

Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease.

PubMed

Biegstraaten, M; Cox, T M; Belmatoug, N; Berger, M G; Collin-Histed, T; Vom Dahl, S; Di Rocco, M; Fraga, C; Giona, F; Giraldo, P; Hasanhodzic, M; Hughes, D A; Iversen, P O; Kiewiet, A I; Lukina, E; Machaczka, M; Marinakis, T; Mengel, E; Pastores, G M; Plöckinger, U; Rosenbaum, H; Serratrice, C; Symeonidis, A; Szer, J; Timmerman, J; Tylki-Szymańska, A; Weisz Hubshman, M; Zafeiriou, D I; Zimran, A; Hollak, C E M

2018-02-01

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Correction of glucocerebrosidase deficiency after retroviral-mediated gene transfer into hematopoietic progenitor cells from patients with Gaucher disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fink, J.K.; Correll, P.H.; Perry, L.K.

1990-03-01

Retroviral gene transfer has been used successfully to correct the glucocerebrosidase (GCase) deficiency in primary hematopoietic cells from patients with Gaucher disease. For this model of somatic gene therapy, the authors developed a high-titer, amphotropic retroviral vector designated NTG in which the human GCase gene was driven by the mutant polyoma virus enhancer/herpesvirus thymidine kinase gene (tk) promoter (Py{sup +}/Htk). NTG normalized GCase activity in transduced Gaucher fibroblasts and efficiently infected human monocytic and erythroleukemic cell lines. RNA blot-hybridization (Northern blot) analysis of these hemaptopoietic cell lines showed unexpectedly high-level expression from the Moloney murine leukemia virus long terminal repeatmore » (Mo-MLV LTR) and levels of Py{sup +}/Htk enhancer/promoter-initiated human GCase RNA that approximated endogenous GCase RNA levels. Furthermore, NTG efficiently infected human hematopoietic progenitor cells. Detection of the provirus in approximately one-third of NTG-infected progenitor colonies that had not been selected in G418-containing medium indicates that relative resistance to G418 underestimated the actual gene transfer efficiency. Northern blot analysis of NTG-infected, progenitor-derived cells showed expression from both the Mo-MLV LTR and the Py{sup +}/Htk enhancer/promoter. NTG-transduced hematopoietic progenitor cells from patients with Gaucher disease generated progeny in which GCase activity has been normalized.« less

Prevalence of nine mutations among Jewish and non-Jewish Gaucher disease patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Horowitz, M.; Tzuri, G.; Eyal, N.

1993-10-01

The frequency of nine different mutated alleles known to occur in the glucocerebrosidase gene was determined in 247 Gaucher patients, of whom 176 were of Jewish extraction, 2 were Jewish with one converted parent, and 69 were of non-Jewish origin. DNA was prepared from peripheral blood, active glucocerebrosidase sequences were amplified by using the PCR technique, and the mutations were identified by using the allele-specific oligonucleotide hybridization method. The N37OS mutation appeared in 69.77% of the mutated alleles in Jewis patients and in 22.86% of the mutated alleles in non-Jews. The 84GG mutation, which has not been found so farmore » among non-Jewish patients, existed in 10.17% of the disease alleles among Jewish patients. The IVS2+1 mutation constituted 2.26% of the disease alleles among Jewish Patients and 1.43% among the non-Jewish patients. RecTL, a complex allele containing four single-base-pair changes, occurred in 2.26% of the alleles in Jewish patients and was found in two (1.43%) of the patients of non-Jewish extraction. Another complex allele, designated [open quotes]RecNcil[close quotes] and containing three single-point mutations, appeared in 7.8% of alleles of non-Jewish patients and in only two (0.56%) of the Jewish families. The prevalence of the L444P mutation among non-Jewish Gaucher patients was 31.43%, while its prevalence among Jewish patients was only 4.24%. The prevalence of two other point mutations-D409H and R463C- was 5.00% and 3.57%, respectively, among non-Jewish patients and was not found among the Jewish Gaucher patient population. The prevalence of the R496H mutation, found so far only among Jewish patients, is 1.13%. The results presented demonstrate that seven mutations identify 90.40% of the mutations among Jewish patients and that these seven mutations allow diagnosis of only 73.52% of the non-Jewish patients. Identification of additional mutant alleles will enhance the accuracy of carrier detection. 33 refs, 3 figs

Selective chaperone effect of aminocyclitol derivatives on G202R and other mutant glucocerebrosidases causing Gaucher disease.

PubMed

Serra-Vinardell, Jenny; Díaz, Lucía; Gutiérrez-de Terán, Hugo; Sánchez-Ollé, Gessamí; Bujons, Jordi; Michelakakis, Helen; Mavridou, Irene; Aerts, Johannes M F G; Delgado, Antonio; Grinberg, Daniel; Vilageliu, Lluïsa; Casas, Josefina

2014-09-01

Gaucher disease is an autosomal recessive lysosomal disorder characterized by the accumulation of glucosylceramide as a result of a deficiency of the enzyme glucocerebrosidase. Several competitive glucocerebrosidase inhibitors are able to act as pharmacological chaperones for an efficient rescue of the mutated, misfolded forms of the enzyme. Along this line, we report in this work on the ability of several aminocyclitols to increase the residual glucocerebrosidase activity in patient fibroblasts with different genotypes. Some of the compounds were slightly active on fibroblasts bearing some mutations, including the highly prevalent N370S mutation. All compounds were highly active as enzyme activity enhancers on fibroblasts from Gaucher disease patients containing the G202R mutation. Moreover, using the novel tagged sphingolipid ω-azidosphingosine, a reduction in the tagged glucosylceramide accumulation was also observed for selected aminocyclitols. Attempts to explain the activity impairment observed in glucocerebrosidase bearing the G202R mutation by comparative molecular dynamic studies on wild type and the G202R mutated proteins (free and isofagomine-bound, in both cases) were unsuccessful. Under the simulation conditions used, no clear effect of the G202R mutation neither over the global structure of the protein nor on the loops that constitute the glucocerebrosidase active site was observed. Since the G202R residue is located on the protein surface, altered protein-membrane or protein-protein interactions could account for the observed differences. In conclusion, we have tested novel compounds that have shown some chaperone effect on particular glucocerebrosidase mutant enzymes, supporting the enhancement therapy as an alternative approach for Gaucher disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

The prognostic value of the serum ferritin in a southern Brazilian cohort of patients with Gaucher disease.

PubMed

Koppe, Tiago; Doneda, Divair; Siebert, Marina; Paskulin, Livia; Camargo, Matheus; Tirelli, Kristiane Michelin; Vairo, Filippo; Daudt, Liane; Schwartz, Ida Vanessa D

2016-03-01

The clinical utility of serum ferritin as a biomarker of disease severity and prognosis in Gaucher disease (GD) is still debated. Here, we aimed to evaluate ferritin and its relation to clinicolaboratory parameters of GD patients seen at the Reference Center for Gaucher Disease of Rio Grande do Sul, Brazil, so as to gather evidence on the utility of ferritin as a biomarker of this condition. A retrospective chart review was performed collecting pre-and posttreatment data from GD patients. Eighteen patients with ferritin levels available before and after treatment were included in the study. Nine of these participants were males, and seventeen had type I GD. All patients were given either enzyme replacement (n = 16) or substrate reduction therapy (n = 2), and ferritin was found to decrease from 756 [318-1441] ng/mL at baseline to 521 [227-626] ng/mL (p=0.025) after 28.8 month soft treatment. Serum ferritin levels did not correlate with measures of disease severity, but showed an association with age at onset of treatment (ρ= 0.880; n = 18; p < 0.001). In conclusion, although serum ferritin did not correlate with disease severity, after a median 28.8 months of treatment, clinical outcomes had clearly improved, and ferritin levels had decreased.

Gaucher disease: Pseudoreversion of a disease mutation`s effects--implications for structure/function and genotype/phenotype correlations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ponce, E.; Mear, J; Grabowski, G.A.

1994-09-01

Numerous mutations ({approximately}45) of the acid {beta}-glucosidase gene have been identified in patients with Gaucher disease. Many of these have been characterized by partial sequencing of cDNAs derived by RT-PCR or PCR of genomic DNA. In addition, genotype/phenotype correlations have been based on screening for known mutations. Thus, only a part of the gene is characterized in any population of affected patients. Several Gaucher disease alleles contain multiple, authentic point mutations that raises concern about conclusions based on only partial genetic characterization. Several wild-type cDNAs for acid {beta}-glucosidase have been sequenced. One contained a cloning artifact encoding R495H. We expressedmore » this cDNA and showed that the R495H enzyme had normal kinetic and stability properties. A disease-associated allele encoding R496H has been found by several groups. The close association and similarities of these two substitutions led us to question the disease casuality of the R496H allele. To evaluate this, we created and/or expressed cDNAs encoding R495, R496 (wild-type), (R495H, R496), (R495, R496H) and (R495H, R496H). The (wild-type) and (R495H, R496) enzymes had indistinguishable properties whereas the (R495, R496H) enzyme was essentially inactive. The introduction of both mutations (R495H, R496H) produced an enzyme whose activity was 25 to 50% of the wild-type. These results indicate that a pseudoreversion to a functional enzyme can occur by introducing a functionally neutral mutation together with a severe mutation. These results have major implications to structure/function and genotype/phenotype correlations in this disease.« less

Crystallization and preliminary X-ray analysis of recombinant human acid beta-glucocerebrosidase, a treatment for Gaucher's disease

NASA Technical Reports Server (NTRS)

Roeber, Dana; Achari, Aniruddha; Manavalan, Partha; Edmunds, Tim; Scott, David L.

2003-01-01

Acid beta-glucocerebrosidase (N-acylsphingosyl-1-O-beta-D-glucoside:glucohydrolase) is a lysosomal glycoprotein that catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide. Inadequate levels of this enzyme underly the pathophysiology of Gaucher's disease. Cerezyme (Genzyme Corporation, Cambridge, MA, USA) is a partially deglycosylated form of recombinant human acid beta-glucocerebrosidase that is used in the treatment of Gaucher patients. Although acid beta-glucocerebrosidase belongs to a large family of glycosidases, relatively little is known regarding its structural biology. Here, the crystallization and the initial diffraction analysis of Cerezyme are reported. The crystals are C-centered orthorhombic, with unit-cell parameters a = 285.0, b = 110.2, c = 91.7 A. A 99.9% complete data set has been collected to 2.75 A with an R(sym) of 8.8%.

Crystallization and Preliminary X-ray analysis of Human Recombinant Acid beta-glucocerebrosidase, a treatment for Gaucher's Disease

NASA Technical Reports Server (NTRS)

Roeber, Dana F.; Achari, Aniruddha; Manavalan, Partha; Edmunds, Tim; Scott, David L.; Curreri, Peter A. (Technical Monitor)

2002-01-01

Acid beta-glucocerebrosidase (N-acylsphingosyl - O - beta-D - glucoside:glucohydrolase) is a lysosomal glycoprotein that catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide. Inadequate levels of this enzyme underly the pathophysiology of Gaucher's disease. Cerezyme(R) (Genzyme Corporation, Cambridge, MA) is a partially deglycosylated form of recombinant human acid beta-glucocerebrosidase that is commercially available for the treatment of Gaucher patients. Although acid beta-glucocerebrosidase belongs to a large family of glycosidases, relatively little is known regarding its structural biology. We report the crystallization and the initial diffraction analysis of Cerezyme(R). The crystals are C-centered orthorhombic, with unit-cell parameters of a = 285.0 A, b = 110.2 A, and c = 91.7 A. A 99.9 A complete data set has been collected to 2.75 A with an R(sub sym) of 8.8 %.

Color Discrimination in Patients with Gaucher Disease and Parkinson Disease.

PubMed

Simon-Tov, Shlomi; Dinur, Tama; Giladi, Nir; Bar-Shira, Anat; Zelis, Mayaan; Zimran, Ari; Elstein, Deborah

2015-01-01

Poor color discrimination among patients with Parkinson disease (PD) has long been recognized. It has been shown that carrying one or two mutations in the β-glucocerebrosidase gene (GBA) for the autosomal disease Gaucher disease (GD), as based initially on clinical evidence, is a genetic risk factor for early-onset PD. The purpose of this study was to assess color discrimination in patients with one or two GBA mutations relative to healthy controls to ascertain whether this function is affected when persons with GD or even one GBA mutation develop PD. The Farnsworth-Munsell 100 hue test (FMHT) was evaluated among patients with GD+PD compared to patients with GD only, obligate GBA carriers with and without PD, patients with PD only, and healthy controls. FMHT outcome include computer-generated TES (Total Error Score) and values recommended by Vingrys & King-Smith. Six groups of 10 persons were tested. Significant differences were seen for male GD+PD and for age in PD. The highest mean TES was in the PD only group, the lowest in the GD only group. There was a significant difference because of PD in groups with GD and GBA carriers. GD+PD means were between GD only and PD only mean scores. These findings confirm that PD impacts color discrimination, more in males with GD+PD but nonetheless, GD+PD patients (but not GBA carriers) had better scores than PD only patients.

Cost-effectiveness of enzyme replacement therapy for type 1 Gaucher disease

PubMed Central

2014-01-01

Objective To evaluate the cost-effectiveness of enzyme replacement therapy (ERT) compared to standard medical care without ERT in the Dutch cohort of patients with type 1 Gaucher disease (GD I). Design Cost-effectiveness analysis was performed using a life-time state-transition model of the disease’s natural course. Transition probabilities, effectiveness data and costs were derived from retrospective data and prospective follow-up of the Dutch study cohort. Setting The tertiary referral center for Gaucher disease in the Netherlands. Participants The Dutch cohort of patients with GD I. Intervention ERT versus standard medical care without ERT in symptomatic patients. Main outcome measures Years free of end organ damage (YFEOD) (splenectomy, bone complication, malignancy, multiple complications), quality adjusted life years (QALY), and costs. Results Over an 85 year lifetime, an untreated GD I patient will generate 48.9 YFEOD and 55.86 QALYs. Starting ERT in a symptomatic patient increases the YFEOD by 12.8 years, while the number of QALYs gained increases by 6.27. The average yearly ERT medication costs range between €124,000 and €258,000 per patient. The lifetime costs of ERT starting in the symptomatic stage are €5,716,473 against €171,780 without ERT, a difference of €5,544,693. Consequently, the extra costs per additional YFEOD or per additional QALY are €434,416 and €884,994 respectively. After discounting effects by 1.5% and costs by 4% and under a reasonable scenario of ERT unit cost reduction by 25%, these incremental cost-effectiveness ratios could decrease to €149,857 and €324,812 respectively. Discussion ERT is a highly potential drug for GD I with substantial health gains. The conservatively estimated incremental cost-effectiveness ratios are substantially lower than for Pompe and Fabry disease. We suggest that the high effectiveness has contributed importantly to acceptance of reimbursement of ERT for GD I. The present study may

Characterization of a novel gene at the Gaucher disease locus spanning the region between the glucocerebrosidase (GC) pseudogene and thrombospondin (TSP)3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ginns, E.I.; Winfield, S.; Sidransky, E.

1994-09-01

The human GC locus on chromosome 1q21 encompasses a 7 kb functional gene encoding the enzyme deficient in Gaucher disease, and a highly homologous sequence 16 Kb downstream that has the properties of a pseudogene. A novel gene, gene X, spanning the 6 kb region between the pseudogene and TSP3 has been identified and characterized in the mouse, and appears to be critical for normal embryonic development. As in the mouse, the human gene X is located 5{prime} to the TSP3 gene and two genes are transcribed divergently from a bidirectional promoter; the direction of transcription of gene X andmore » GC is convergent. However, in the human, gene X and GC are separated by gene X and GC pseudogenes that are the consequence of a gene duplication. The gene X pseudogene lacks the first exon and part of the second exon of the functional gene and may not be transcribed. Northern blot analyses indicate that gene X is transcribed in both normal individuals and in patients with Gaucher disease, but the function of this gene is still unknown. The possibility that mutations in gene X could account for some of the diversity of symptoms encountered in individuals with the more atypical presentations of Gaucher disease is under investigation.« less

Skeletal involvement in Gaucher disease: An observational multicenter study of prognostic factors in the Argentine Gaucher disease patients.

PubMed

Drelichman, Guillermo; Fernández Escobar, Nicolás; Basack, Nora; Aversa, Luis; Larroude, María Silvia; Aguilar, Gabriela; Szlago, Marina; Schenone, Andrea; Fynn, Alcyra; Cuello, María Fernanda; Aznar, Marcela; Fernández, Ramiro; Ruiz, Alba; Reichel, Paola; Guelbert, Norberto; Robledo, Hugo; Watman, Nora; Bolesina, Moira; Elena, Graciela; Veber, S Ernesto; Pujal, Graciela; Galván, Graciela; Chain, Juan José; Arizo, Adriana; Bietti, Julieta; Bar, Daniel; Dragosky, Marta; Marquez, Marisa; Feldman, Leonardo; Muller, Katja; Zirone, Sandra; Buchovsky, Greogorio; Lanza, Victoria; Sanabria, Alba; Fernández, Ignacio; Jaureguiberry, Rossana; Contte, Marcelo; Barbieri María, Angie; Maro, Alejandra; Zárate, Graciela; Fernández, Gabriel; Rapetti, María Cristina; Donato, Hugo; Degano, Adriana; Kantor, Gustavo; Albina, Roberto; Á Lvarez Bollea, María; Brun, María; Bacciedoni, Viviana; Del Río, Francis; Soberón, Bárbara; Boido, Nazario; Schweri, Maya; Borchichi, Sandra; Welsh, Victoria; Corrales, Marcela; Cedola, Alejandra; Carvani, Analía; Diez, Blanca; Richard, Lucía; Baduel, Ccecilia; Nuñez, Gabriela; Colimodio, Rubén; Barazzutti, Lucía; Medici, Hugo; Meschengieser, Susana; Damiani, Germán; Nucifora, María; Girardi, Beatriz; Gómez, Sergio; Papucci, Maura; Verón, David; Quiroga, Luis; Carro, Gustavo; De Ambrosio, Patricia; Ferro, José; Pujol, Marcelo; Castella, Cristina Cabral; Franco, Liliana; Nisnovich, Gisela; Veloso, María; Pacheco, Isabel; Savarino, Mario; Marino, Andrés; Saavedra, José Luis

2016-10-01

Patients with Gaucher type 1 (GD1) throughout Argentina were enrolled in the Argentine bone project to evaluate bone disease and its determinants. We focused on presence and predictors of bone lesions (BL) and their relationship to therapeutic goals (TG) with timing and dose of enzyme replacement therapy (ERT). A total of 124 patients on ERT were enrolled in a multi-center study. All six TG were achieved by 82% of patients: 70.1% for bone pain and 91.1% for bone crisis. However, despite the fact that bone TGs were achieved, residual bone disease was present in 108 patients on ERT (87%) at time 0. 16% of patients showed new irreversible BL (bone infarcts and avascular osteonecrosis) despite ERT, suggesting that they appeared during ERT or were not detected at the moment of diagnosis. We observed 5 prognostic factors that predicted a higher probability of being free of bone disease: optimal ERT compliance; early diagnosis; timely initiation of therapy; ERT initiation dose ≥45 UI/kg/EOW; and the absence of history of splenectomy. Skeletal involvement was classified into 4 major phenotypic groups according to BL: group 1 (12.9%) without BL; group 2 (28.2%) with reversible BL; group 3 (41.9%) with reversible BL and irreversible chronic BL; and group 4 (16.9%) with acute irreversible BL. Our study identifies prognostic factors for achieving best therapeutic outcomes, introduces new risk stratification for patients and suggests the need for a redefinition of bone TG. Am. J. Hematol. 91:E448-E453, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The Pharmacological Chaperone Isofagomine Increases Activity of the Gaucher Disease L444P Mutant Form of β-Glucosidase

PubMed Central

Khanna, Richie; Benjamin, Elfrida R.; Pellegrino, Lee; Schilling, Adriane; Rigat, Brigitte A.; Soska, Rebecca; Nafar, Hadis; Ranes, Brian E.; Feng, Jessie; Lun, Yi; Powe, Allan C.; Palling, David J.; Wustman, Brandon A.; Schiffmann, Raphael; Mahuran, Don J.; Lockhart, David J.; Valenzano, Kenneth J.

2010-01-01

SUMMARY Gaucher disease is caused by mutations in the gene that encodes the lysosomal enzyme acid β-glucosidase (GCase). We have shown previously that the small molecule pharmacological chaperone isofagomine (IFG) binds and stabilizes N370S GCase, resulting in increased lysosomal trafficking and cellular activity. In this study, we investigated the effect of IFG on L444P GCase. Incubation of Gaucher patient-derived lymphoblastoid cell lines (LCLs) or fibroblasts with IFG led to approximately 3.5- and 1.3-fold increases in L444P GCase activity, respectively, as measured in cell lysates. The effect in fibroblasts was increased approximately 2-fold using glycoprotein-enrichment, GCase-immunocapture, or by incubating cells overnight in IFG-free media prior to assay, methods designed to maximize GCase activity by reducing IFG carryover and inhibition in the enzymatic assay. IFG incubation also increased the lysosomal trafficking and in situ activity of L444P GCase in intact cells, as measured by reduction in endogenous glucosylceramide levels. Importantly, this reduction was seen only following three-day incubation in IFG-free media, underscoring the importance of IFG removal to restore lysosomal GCase activity. In mice expressing murine L444P GCase, oral administration of IFG resulted in significant increases (2- to 5-fold) in GCase activity in disease-relevant tissues, including brain. Additionally, eight-week IFG administration significantly lowered plasma chitin III and IgG levels, and 24-week administration significantly reduced spleen and liver weights. Taken together, these data suggest that IFG can increase the lysosomal activity of L444P GCase in cells and tissues. Moreover, IFG is orally available and distributes into multiple tissues, including brain, and may thus merit therapeutic evaluation for patients with neuronopathic and non-neuronopathic Gaucher disease. PMID:20148966

Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis

PubMed Central

Mistry, Pramod K; Deegan, Patrick; Vellodi, Ashok; Cole, J Alexander; Yeh, Michael; Weinreb, Neal J

2009-01-01

Data from the International Collaborative Gaucher Group Gaucher Registry were analysed to assess the relationship between enzyme replacement therapy with imiglucerase (ERT) and incidence of avascular necrosis (AVN) in type 1 Gaucher disease (GD1), and to determine whether the time interval between diagnosis and initiation of ERT influences the incidence rate of AVN. All patients with GD1 enrolled in the Gaucher Registry who received ERT and did not report AVN prior to starting therapy (n = 2700) were included. The incidence rate of AVN following initiation of ERT was determined. An incidence rate of AVN of 13·8 per 1000 person-years was observed in patients receiving ERT. Patients who initiated ERT within 2 years of diagnosis had an incidence rate of 8·1 per 1000 person-years; patients who started ERT ≥2 years after diagnosis had an incidence rate of 16·6 per 1000 person-years. The adjusted incidence rate ratio was 0·59 [95% confidence interval (CI) 0·36–0·96, P = 0·0343]. Splenectomy was an independent risk factor for AVN (adjusted incidence rate ratio 2·23, 95% CI 1·61–3·08, P < 0·0001). In conclusion, the risk of AVN was reduced among patients who initiated ERT within 2 years of diagnosis, compared to initiating treatment ≥2 years after diagnosis. A higher risk of AVN was observed among patients who had previously undergone splenectomy. PMID:19732054

Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease

PubMed Central

Zheng, Wei; Padia, Janak; Urban, Daniel J.; Jadhav, Ajit; Goker-Alpan, Ozlem; Simeonov, Anton; Goldin, Ehud; Auld, Douglas; LaMarca, Mary E.; Inglese, James; Austin, Christopher P.; Sidransky, Ellen

2007-01-01

Gaucher disease is an autosomal recessive lysosomal storage disorder caused by mutations in the glucocerebrosidase gene. Missense mutations result in reduced enzyme activity that may be due to misfolding, raising the possibility of small-molecule chaperone correction of the defect. Screening large compound libraries by quantitative high-throughput screening (qHTS) provides comprehensive information on the potency, efficacy, and structure–activity relationships (SAR) of active compounds directly from the primary screen, facilitating identification of leads for medicinal chemistry optimization. We used qHTS to rapidly identify three structural series of potent, selective, nonsugar glucocerebrosidase inhibitors. The three structural classes had excellent potencies and efficacies and, importantly, high selectivity against closely related hydrolases. Preliminary SAR data were used to select compounds with high activity in both enzyme and cell-based assays. Compounds from two of these structural series increased N370S mutant glucocerebrosidase activity by 40–90% in patient cell lines and enhanced lysosomal colocalization, indicating chaperone activity. These small molecules have potential as leads for chaperone therapy for Gaucher disease, and this paradigm promises to accelerate the development of leads for other rare genetic disorders. PMID:17670938

The outcome of clinical parameters in adults with severe Type I Gaucher disease using very low dose enzyme replacement therapy.

PubMed

Wilson, Callum; Spearing, Ruth; Teague, Lochie; Robertson, Patsy; Blacklock, Hilary

2007-01-01

Enzyme replacement therapy is now well established as the treatment of choice in Type I Gaucher disease. Historically higher dosage regimens have been used in preference to lower doses despite the little clinical evidence in the way of large controlled clinical trials to support this. Moreover, the extraordinary cost of therapy means that not all eligible patients are able to be treated at the higher dose. Twelve type I adult patients with relatively severe disease were commenced on a very low dose of 7.5U of alglucerase/imiglucerase per kg every two weeks (initially given thrice weekly and later weekly). Follow-up 5 year data reveal a good visceral and haematological response with outcomes consistent with recently published treatment guidelines. Satisfactory clinical and radiological skeletal improvement was also demonstrated in most patients. Three patients had an inadequate overall skeletal response to therapy. Biomarkers also steadily improved although perhaps not quite at the same rate as that seen in higher doses. Very low dose enzyme replacement therapy may be appropriate for adult type I Gaucher patients with mild-moderate skeletal disease.

The motor and cognitive features of Parkinson's disease in patients with concurrent Gaucher disease over 2 years: a case series.

PubMed

Collins, Lucy M; Williams-Gray, Caroline H; Morris, Elizabeth; Deegan, Patrick; Cox, Timothy M; Barker, Roger A

2018-05-29

We report the cognitive features and progression of Parkinson's disease (PD) in five patients with concurrent Gaucher disease. The patients presented at an earlier age than patients with sporadic PD, as previously noted by others; but in contrast to many previous reports, our patients followed a variable clinical course. While two patients developed early cognitive deficits and dementia, three others remained cognitively intact over the follow-up period. Thus, in this small case series, PD in the context of GD more closely resembles idiopathic PD in terms of its clinical heterogeneity in contrast to PD associated with GBA heterozygote mutations.

Multiplex newborn screening for Pompe, Fabry, Hunter, Gaucher, and Hurler diseases using a digital microfluidic platform.

PubMed

Sista, Ramakrishna S; Wang, Tong; Wu, Ning; Graham, Carrie; Eckhardt, Allen; Winger, Theodore; Srinivasan, Vijay; Bali, Deeksha; Millington, David S; Pamula, Vamsee K

2013-09-23

New therapies for lysosomal storage diseases (LSDs) have generated interest in screening newborns for these conditions. We present performance validation data on a digital microfluidic platform that performs multiplex enzymatic assays for Pompe, Fabry, Hunter, Gaucher, and Hurler diseases. We developed an investigational disposable digital microfluidic cartridge that uses a single dried blood spot (DBS) punch for performing a 5-plex fluorometric enzymatic assay on up to 44 DBS samples. Precision and linearity of the assays were determined by analyzing quality control DBS samples; clinical performance was determined by analyzing 600 presumed normal and known affected samples (12 for Pompe, 7 for Fabry and 10 each for Hunter, Gaucher and Hurler). Overall coefficient of variation (CV) values between cartridges, days, instruments, and operators ranged from 2 to 21%; linearity correlation coefficients were ≥0.98 for all assays. The multiplex enzymatic assay performed from a single DBS punch was able to discriminate presumed normal from known affected samples for 5 LSDs. Digital microfluidic technology shows potential for rapid, high-throughput screening for 5 LSDs in a newborn screening laboratory environment. Sample preparation to enzymatic activity on each cartridge is less than 3h. Copyright © 2013 Elsevier B.V. All rights reserved.

How Do I Talk to My Family about Gaucher?

MedlinePlus

... or in fact have Gaucher. This includes siblings, parents, and children as well as more distant relatives such as ... chances of having Gaucher or the chance of children inheriting Gaucher from their parents. Websites and brochures that have been useful for ...

Gauchers disease--a reappraisal of hematopoietic stem cell transplantation.

PubMed

Ito, Sawa; Barrett, A John

2013-03-01

Hematopoietic stem cell transplantation (HSCT), first performed in 1984, was the first treatment approach for Gaucher's disease (GD) which had curative intent. The early successes in HSCT were soon eclipsed by the introduction of a highly effective enzyme replacement therapy (ERT), which has remained the single most widely used treatment. Experience with HSCT is limited to about 50 reported cases, mainly performed in the last century, with an overall survival around 85%. HSCT typically achieves complete correction of visceral and bony changes and can fully stabilize neurological features in otherwise progressive type II and III GD. ERT, in contrast, is completely safe and effective, but is limited by cost, incomplete resolution of visceral, hematological, and bony features in some patients, and lack of neurological correction in type II and III disease. In this review, we summarize and compare HSCT and ERT. With 20 years of experience of ERT, its limitations as well as its advantages are now well delineated. Meanwhile progress in HSCT over the last decade suggests that transplantation would today represent a very safe curative approach for GD offering one time complete correction of the disease, contrasting with the lifelong need for ERT with its associated expense and dependence on sophisticated drug manufacture. Additionally, unlike ERT, HSCT can be beneficial for neurological forms of GD. We conclude that the time has come to re-evaluate HSCT in selected patients with GD where ERT is less likely to fully eradicate symptoms of the disease.

Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment.

PubMed

Weinreb, Neal J; Goldblatt, Jack; Villalobos, Jacobo; Charrow, Joel; Cole, J Alexander; Kerstenetzky, Marcelo; vom Dahl, Stephan; Hollak, Carla

2013-05-01

We studied the effect of long-term alglucerase/imiglucerase (Ceredase®/Cerezyme®, Genzyme, a Sanofi company, Cambridge, MA, USA) treatment on hematological, visceral, and bone manifestations of Gaucher disease type 1 (GD1). The International Collaborative Gaucher Group (ICGG) Gaucher Registry identified GD1 patients treated with alglucerase/imiglucerase who had dose and clinical data at first infusion and after 10 years of follow-up. Data for hemoglobin, platelet count, organ volumes, bone pain, and bone crisis were analyzed. Tests of the null hypothesis (no change from first infusion to 10 years) were performed using t tests for within-patient absolute change in continuous measurements and McNemar/chi-square tests for change in distributions using categorical values. An alpha level of 0.05 designated statistical significance. As of October 2011, 557 nonsplenectomized and 200 splenectomized patients met the inclusion criteria. The majority of GD1 patients had at least one N370S allele. Compared with nonsplenectomized patients at first infusion, splenectomized patients had lower percentages of anemia (26.0 % vs. 42.8 %) and thrombocytopenia (14.2 % vs. 76.3 %), similar percentages of moderate or severe hepatomegaly (81.2 % vs. 80.0 %), and higher percentages of bone pain (88.9 % vs. 52.4 %) and bone crises (38.3 % vs. 16.0 %). After 10 years, both groups showed significant (p < 0.05) improvements in mean hemoglobin levels, platelet count, liver, and spleen (nonsplenectomized) volumes, and bone crises. Initial dosing in both groups ranged from <15 U/kg to ≤90 U/kg every 2 weeks. After 10 years, the majority was receiving 15 to ≤45 U/kg every 2 weeks. Ten years of imiglucerase treatment results in sustainable improvements in all GD1 parameters.

Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies.

PubMed

Mazzulli, Joseph R; Xu, You-Hai; Sun, Ying; Knight, Adam L; McLean, Pamela J; Caldwell, Guy A; Sidransky, Ellen; Grabowski, Gregory A; Krainc, Dimitri

2011-07-08

Parkinson's disease (PD), an adult neurodegenerative disorder, has been clinically linked to the lysosomal storage disorder Gaucher disease (GD), but the mechanistic connection is not known. Here, we show that functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of α-synuclein (α-syn), and results in neurotoxicity through aggregation-dependent mechanisms. Glucosylceramide (GlcCer), the GCase substrate, directly influenced amyloid formation of purified α-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that α-syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of α-syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies. Copyright © 2011 Elsevier Inc. All rights reserved.

Outcomes after 18 months of eliglustat therapy in treatment‐naïve adults with Gaucher disease type 1: The phase 3 ENGAGE trial

PubMed Central

Lukina, Elena; Ben Turkia, Hadhami; Shankar, Suma P.; Baris, Hagit; Ghosn, Marwan; Mehta, Atul; Packman, Seymour; Pastores, Gregory; Petakov, Milan; Assouline, Sarit; Balwani, Manisha; Danda, Sumita; Hadjiev, Evgueniy; Ortega, Andres; Gaemers, Sebastiaan J. M.; Tayag, Regina; Peterschmitt, M. Judith

2017-01-01

Abstract Eliglustat, an oral substrate reduction therapy, is a first‐line treatment for adults with Gaucher disease type 1 (GD1) who are poor, intermediate, or extensive CYP2D6 metabolizers (>90% of patients). In the primary analysis of the Phase 3 ENGAGE trial (NCT00891202), eliglustat treatment for 9 months resulted in significant reductions in spleen and liver volumes and increases in hemoglobin concentration and platelet count compared with placebo. We report 18‐month outcomes of patients who entered the trial extension period, in which all patients received eliglustat. Of 40 trial patients, 39 entered the extension period, and 38 completed 18 months. Absolute values and percent change over time were determined for spleen and liver volume, hemoglobin concentration, platelet count, bone mineral density, bone marrow burden, and Gaucher disease biomarkers. For patients randomized to eliglustat in the double‐blind period, continuing treatment with eliglustat for 9 more months resulted in incremental improvement of all disease parameters. For patients randomized to placebo in the double‐blind period, eliglustat treatment during the 9‐month, open‐label period resulted in significant decrease of spleen and liver volumes and significant increase of hemoglobin and platelets, with a similar rate of change to patients who had received eliglustat in the double‐blind period. Eliglustat treatment was also associated with improvement in bone marrow burden score, bone mineral density, and established biomarkers of Gaucher disease, including reduction of the bioactive lipid, glucosylsphingosine. These findings underscore the efficacy of eliglustat in treatment‐naïve patients. Eliglustat was well‐tolerated, and there were no new safety concerns with longer‐term exposure. PMID:28762527

Protective effect of catechin in type I Gaucher disease cells by reducing endoplasmic reticulum stress

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Yea-Jin; Kim, Sung-Jo, E-mail: sungjo@hoseo.edu; Heo, Tae-Hwe, E-mail: thhur92@catholic.ac.kr

Highlights: {yields} Catechin reduces the expression level of ER stress marker protein in type I Gaucher disease cells. {yields} Catechin induces the proliferation rate of GD cells similar levels to normal cells. {yields} Catechin improves wound healing activity. {yields} Catechin-mediated reductions in ER stress may be associated with enhanced cell survival. {yields} We identified catechin as a protective agent against ER stress in GD cells. -- Abstract: Gaucher disease (GD) is the most common lysosomal storage disorder (LSD) and is divided into three phenotypes, I, II, and III. Type I is the most prevalent form and has its onset inmore » adulthood. The degree of endoplasmic reticulum (ER) stress is one of the factors that determine GD severity. It has recently been reported that antioxidants reduce ER stress and apoptosis by scavenging the oxidants that cause oxidative stress. For this report, we investigated the possibility that catechin can act on type I GD patient cells to alleviate the pathogenic conditions of GD. We treated GD cells with catechin and examined the expression level of GRP78/BiP (an ER stress marker) by western blots and fluorescence microscopy, the proliferation rate of GD cells, and scratch-induced wound healing activity. Our results show that catechin reduces the expression level of GRP78/BiP, leads to cell proliferation rates of GD cells similar levels to normal cells, and improves wound healing activity. We conclude that catechin protects against ER stress in GD cells and catechin-mediated reductions in ER stress may be associated with enhanced cell survival.« less

Spotlight on taliglucerase alfa in the treatment of pediatric patients with type 1 Gaucher disease.

PubMed

Gupta, Punita; Pastores, Gregory M

2017-01-01

Gaucher disease (GD) is a heritable storage disorder caused by functional defects of the lysosomal acid β-glucosidase and the accumulation of glucosylceramide within macrophages, resulting in multiple organ dysfunction. There are three commercially available enzyme replacement therapy (ERT) products for the treatment of GD type 1 (GD1): imiglucerase, velaglucerase alfa, and taliglucerase alfa. Imiglucerase and velaglucerase alfa are produced in different mammalian cell systems; imiglucerase requires postproduction deglycosylation to expose terminal α-mannose residues, which are required for mannose receptor-mediated uptake by target macrophages. These steps are critical to the success of ERT for the treatment of visceral and hematologic manifestations of GD. Taliglucerase alfa is the first US Food and Drug Administration-approved plant-cell-expressed recombinant human protein, using carrot root cell cultures. Furthermore, it does not require postproduction glycosidic modifications. It is indicated for treatment of adults with GD1 in the US, Israel, Australia, Canada, Chile, Brazil, and other countries, and it is additionally approved for the treatment of pediatric patients in the US, Australia, and Canada and for the treatment of hematologic manifestations in pediatric patients with Type 3 GD in Canada and other countries. Our review focuses on the role of taliglucerase alfa in the pediatric population. A literature search through PubMed (from 1995 up till November 2016) of English language articles was performed with the following terms: Gaucher disease, lysosomal storage disease, taliglucerase. Secondary and tertiary references were obtained by reviewing related articles as well as the website www.Clinicaltrials.gov. It has been demonstrated that taliglucerase alfa is efficacious, with a well-established safety profile in pediatric, ERT-naïve patients with symptomatic GD1, as well as for those patients previously treated with imiglucerase.

Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study.

PubMed

Narita, Aya; Shirai, Kentarou; Itamura, Shinji; Matsuda, Atsue; Ishihara, Akiko; Matsushita, Kumi; Fukuda, Chisako; Kubota, Norika; Takayama, Rumiko; Shigematsu, Hideo; Hayashi, Anri; Kumada, Tomohiro; Yuge, Kotaro; Watanabe, Yoriko; Kosugi, Saori; Nishida, Hiroshi; Kimura, Yukiko; Endo, Yusuke; Higaki, Katsumi; Nanba, Eiji; Nishimura, Yoko; Tamasaki, Akiko; Togawa, Masami; Saito, Yoshiaki; Maegaki, Yoshihiro; Ohno, Kousaku; Suzuki, Yoshiyuki

2016-03-01

Gaucher disease (GD) is a lysosomal storage disease characterized by a deficiency of glucocerebrosidase. Although enzyme-replacement and substrate-reduction therapies are available, their efficacies in treating the neurological manifestations of GD are negligible. Pharmacological chaperone therapy is hypothesized to offer a new strategy for treating the neurological manifestations of this disease. Specifically, ambroxol, a commonly used expectorant, has been proposed as a candidate pharmacological chaperone. The purpose of this study was to evaluate the safety, tolerability, and neurological efficacy of ambroxol in patients with neuronopathic GD. This open-label pilot study included five patients who received high-dose oral ambroxol in combination with enzyme replacement therapy. Safety was assessed by adverse event query, physical examination, electrocardiography, laboratory studies, and drug concentration. Biochemical efficacy was assessed through evidence of glucocerebrosidase activity in the lymphocytes and glucosylsphingosine levels in the cerebrospinal fluid. Neurological efficacy was evaluated using the Unified Myoclonus Rating Scale, Gross Motor Function Measure, Functional Independence Measure, seizure frequency, pupillary light reflex, horizontal saccadic latency, and electrophysiologic studies. High-dose oral ambroxol had good safety and tolerability, significantly increased lymphocyte glucocerebrosidase activity, permeated the blood-brain barrier, and decreased glucosylsphingosine levels in the cerebrospinal fluid. Myoclonus, seizures, and pupillary light reflex dysfunction markedly improved in all patients. Relief from myoclonus led to impressive recovery of gross motor function in two patients, allowing them to walk again. Pharmacological chaperone therapy with high-dose oral ambroxol shows promise in treating neuronopathic GD, necessitating further clinical trials.

Treatment-naïve Gaucher disease patients achieve therapeutic goals and normalization with velaglucerase alfa by 4years in phase 3 trials.

PubMed

Zimran, Ari; Elstein, Deborah; Gonzalez, Derlis E; Lukina, Elena A; Qin, Yulin; Dinh, Quinn; Turkia, Hadhami Ben

2018-02-01

Gaucher disease is an inherited metabolic disease characterized by β-glucocerebrosidase deficiency and commonly treated with enzyme replacement therapy (ERT). The efficacy of ERT with velaglucerase alfa was assessed based on the achievement of published therapeutic goals and the normalization of disease parameters in 39 treatment-naïve patients with type 1 Gaucher disease, 6 to 62years of age, enrolled in phase 3 clinical trials. After 4years of ERT, therapeutic goals for thrombocytopenia and splenomegaly had been achieved in 100% of patients; goals for anemia and hepatomegaly had been achieved in 95% and 94% of patients, respectively. Consistent with the goal for bone mineral density, lumbar spine bone density improved in 87% of patients ≥18years of age. At year 4, compared with clinical ranges for healthy individuals, 86% of patients with a low baseline hemoglobin concentration had normalized, 60% with a low baseline platelet count had normalized, 67% with baseline splenomegaly had normalized, 58% with hepatomegaly had normalized, and lumbar spine bone density had normalized in 53% of adults. The decade-old therapeutic goals do not reflect the potential for normalization of clinical parameters in ERT-treated patients. Goals consistent with normalization or near-normalization should be considered. ClinicalTrials.gov identifiers: NCT00430625, NCT00553631, NCT00635427. Copyright © 2016 Shire Human Genetic Therapies, Inc. Published by Elsevier Inc. All rights reserved.

Design of a framework for the deployment of collaborative independent rare disease-centric registries: Gaucher disease registry model.

PubMed

Bellgard, Matthew I; Napier, Kathryn R; Bittles, Alan H; Szer, Jeffrey; Fletcher, Sue; Zeps, Nikolajs; Hunter, Adam A; Goldblatt, Jack

2018-02-01

Orphan drug clinical trials often are adversely affected by a lack of high quality treatment efficacy data that can be reliably compared across large patient cohorts derived from multiple governmental and country jurisdictions. It is critical that these patient data be captured with limited corporate involvement. For some time, there have been calls to develop collaborative, non-proprietary, patient-centric registries for post-market surveillance of aspects related to orphan drug efficacy. There is an urgent need for the development and sustainable deployment of these 'independent' registries that can capture comprehensive clinical, genetic and therapeutic information on patients with rare diseases. We therefore extended an open-source registry platform, the Rare Disease Registry Framework (RDRF) to establish an Independent Rare Disease Registry (IRDR). We engaged with an established rare disease community for Gaucher disease to determine system requirements, methods of data capture, consent, and reporting. A non-proprietary IRDR model is presented that can serve as autonomous data repository, but more importantly ensures that the relevant data can be made available to appropriate stakeholders in a secure, timely and efficient manner to improve clinical decision-making and the lives of those with a rare disease. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Mutational analysis in a patient with a variant form of Gaucher disease caused by SAP-2 deficiency

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rafi, M.A.; Gala, G. de; Xunling Zhang

1993-01-01

It is now clear that the lysosomal hydrolysis of sphingolipids requires both lysosomal enzymes and so-called sphingolipid activator proteins (SAPs). One gene, called prosaposin, codes for a precursor protein that is proteolytically cut into four putative SAPs. These four SAPs, of about 80 amino acids, share some structural features but differ somewhat in their specificity. Domain 3 of prosaposin mRNA contains the coding region for SAP-2, an activator of glucocerebrosidase. While most patients with Gaucher disease store glucosylceramide due to defects in glucocerebrosidase, a few patients store this lipid in the presence of normal enzyme levels. In this paper themore » authors describe the identification of a point mutation in domain 3 of a patient who died with this variant form of Gaucher disease. Polymerase chain reaction amplification was performed in the small amount of genomic DNA available using primers generated from the intronic sequence surrounding domain 3. The patient was found to have a T-to-G substitution at position 1144 (counting from the A of ATG initiation codon) in half of the M13 recombinant clones. This changes the codon for cysteine[sub 382] to glycine. His father and unaffected brother also had this mutation, but his mother did not. She was found to have half of the normal amount of mRNA for prosaposin in her cultured skin fibroblasts. Therefore, this child inherited a point mutation in domain 3 from his father and a deficiency of all four SAPs coded for by prosaposin from his mother. 29 refs., 3 figs., 1 tab.« less

Intraobserver and interobserver variability of the bone marrow burden (BMB) score for the assessment of disease severity in Gaucher disease. Possible impact of reporting experience.

PubMed

Lai, Jeffrey K C; Robertson, Patricia L; Goh, Christine; Szer, Jeff

2018-02-01

To evaluate the intraobserver and interobserver agreement for bone marrow burden (BMB) scores for individual examinations and for the change in BMB score over time in the same patient. A total of 119 sets of MR images of the lumbar spine and femora from 60 patients with Gaucher disease were included. Each set of MR images was scored using the BMB score independently by two experienced MSK radiologists. One radiologist performed a second read four weeks later. Intraobserver and interobserver agreement was assessed using Bland-Altman analysis and weighted kappa scores. BMB scores (n=119) demonstrated fair intraobserver agreement (weighted kappa=0.53) with a mean difference of -0.20 and 95% limits of agreement (LOA) of (-3.41, 3.01). Inter observer agreement was poor with weighted kappa 0.28 with mean difference of -0.16 and 95% LOA of (-4.45, 4.11). Change in BMB scores over time (n=59) demonstrated poor/fair intraobserver agreement (weighted kappa 0.41, mean difference-0.20 and 95% LOA (-4.35, 3.94)). Interobserver agreement was poor (weighted kappa 0.25, mean difference -0.12 with wide 95% LOA (-6.23, 5.99)). Significant interobserver, and to a lesser extent intraobserver, variation occurs with blinded BMB scoring of Gaucher disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Application of a comprehensive protocol for the identification of Gaucher disease in Brazil.

PubMed

Michelin, Kristiane; Wajner, Alessandro; de Souza, Fernanda T S; de Mello, Alexandre S; Burin, Maira G; Pereira, Maria Luiza S; Pires, Ricardo F; Giugliani, Roberto; Coelho, Janice C

2005-07-01

Gaucher disease (GD) is a sphingolipidosis caused by a genetic defect that leads to glucocerebrosidase (beta-glucosidase) deficiency. Between January 1982 and October 2003, 1,081 blood samples from patients suspected of having GD were referred for biochemical analysis. The activities of the enzymes beta-glucosidase (beta-glu) and chitotriosidase (CT) were measured in these samples. Among the 412 diagnosed cases of GD (38.1%), the great majority were GD type 1. The Brazilian regions with the greatest concentration of these patients were the Southeast, South, and Northeast. The mean age of patients at diagnosis was 19 years. The activity of beta-glu in patients with GD was, on average, 10.7% of that of normal individuals. CT was, on average, 269 times more elevated in this group of patients. Among the 669 cases with no confirmation of GD, there were patients with Niemann-Pick disease types A, B, or C (44 cases), possible heterozygotes for GD (59 cases), patients with other lysosomal storage diseases (LSDs) (19 cases) or with other inborn errors of metabolism (3 cases). In 508 cases, no metabolic disorder was found. This study shows that the biochemical protocol employed was effective for the detection of GD, a disease that is reasonably frequent in Brazil. Copyright (c) 2005 Wiley-Liss, Inc.

In silico identification of genetic variants in glucocerebrosidase (GBA) gene involved in Gaucher's disease using multiple software tools.

PubMed

Manickam, Madhumathi; Ravanan, Palaniyandi; Singh, Pratibha; Talwar, Priti

2014-01-01

Gaucher's disease (GD) is an autosomal recessive disorder caused by the deficiency of glucocerebrosidase, a lysosomal enzyme that catalyses the hydrolysis of the glycolipid glucocerebroside to ceramide and glucose. Polymorphisms in GBA gene have been associated with the development of Gaucher disease. We hypothesize that prediction of SNPs using multiple state of the art software tools will help in increasing the confidence in identification of SNPs involved in GD. Enzyme replacement therapy is the only option for GD. Our goal is to use several state of art SNP algorithms to predict/address harmful SNPs using comparative studies. In this study seven different algorithms (SIFT, MutPred, nsSNP Analyzer, PANTHER, PMUT, PROVEAN, and SNPs&GO) were used to predict the harmful polymorphisms. Among the seven programs, SIFT found 47 nsSNPs as deleterious, MutPred found 46 nsSNPs as harmful. nsSNP Analyzer program found 43 out of 47 nsSNPs are disease causing SNPs whereas PANTHER found 32 out of 47 as highly deleterious, 22 out of 47 are classified as pathological mutations by PMUT, 44 out of 47 were predicted to be deleterious by PROVEAN server, all 47 shows the disease related mutations by SNPs&GO. Twenty two nsSNPs were commonly predicted by all the seven different algorithms. The common 22 targeted mutations are F251L, C342G, W312C, P415R, R463C, D127V, A309V, G46E, G202E, P391L, Y363C, Y205C, W378C, I402T, S366R, F397S, Y418C, P401L, G195E, W184R, R48W, and T43R.

Previously unrecognized behavioral phenotype in Gaucher disease type 3

PubMed Central

Potegal, Michael; Shapiro, Elsa G.; Nestrasil, Igor

2017-01-01

Objective: To provide a comprehensive description of abnormal behaviors in patients with Gaucher disease type 3 (GD3) and relate these behaviors to demographic, neurodevelopmental, and neurologic characteristics. Methods: Thirty-four Egyptian patients with GD3 (mean age of 7.9 years) were enrolled in the study. They were selected based on parent report and/or physician observation of one or more abnormal behaviors documented in 2 settings and by 2 different individuals and/or by video recording. Behaviors were grouped into 4 categories: Crying/Withdrawal, Impatience/Overactivity, Anger/Aggression, and Repetitive Acts. Baseline and follow-up 6–12 monthly neurologic evaluations included IQ assessment and an EEG. All patients were receiving enzyme replacement therapy (30–60 IU/kg every 2 weeks) and were followed for periods of 3–10 years. Results: Supranuclear palsy of horizontal gaze, and of both horizontal and vertical gaze, bulbar symptoms, seizures, convergent strabismus, abnormal gait, and neck retroflexion were present in 97.1%, 50%, 55.9%, 29.4%, 29.4%, 20.6%, and 4.4% of patients, respectively. The most abnormal behavioral features were excessive anger (88.2%) and aggression (64.7%), and both were significantly higher in males. Anger/Aggression scores were highly correlated with IQ but not with either EEG/Seizure status or neurologic signs. Conclusions: We describe behavioral problems with a unique pattern of excessive anger and aggression in patients with GD3. Defining these components using quantitative behavioral scoring methods holds promise to provide a marker of neurologic disease progression and severity. PMID:28634598

[Cliniko-laboratory indicators of efficiency fermento-substitution therapy of Gaucher disease in Ukraine].

PubMed

Ol'khovych, N V; Gryshchenko, O M; Pichkur, N O; Nedoboĭ, A M; Trofimova, N S; Ivanova, T P; Gorovenko, N G

2011-01-01

The analysis of efficiency of treatment of 17 patients with Gaucher disease (GD) in Ukraine who had received fermento-substitution therapy for 2 years and more was conducted on the basis of clinical and laboratory monitoring data. Regular infusions of recombinant glucocerebroside reduced signs of hepatosplenomegaly and pancytopenia, reduced a bone pain and a bone crisis at the majority of patients with GD I type that led to considerable improvement of health state and improvement of patients life quality. Efficiency of treatment depended on regularity of drug administration, dosage and severity level of the disease at the start of the therapy. Adult patients were not seen to have corrections of bones and neurologic disorders after the treatment that confirmed necessity of an early initiation of the treatment, before formation of irreversible changes in these organs and systems. Chitiotriodase activity in blood plasma is the most complex laboratory indicator which displays activity of pathological process in patients with GD, therefore it is necessary to use it for an estimation of treatment efficiency to correct a recombinant glucocerebroside dosage.

Gaucher disease: molecular heterogeneity and phenotype-genotype correlations.

PubMed

Theophilus, B; Latham, T; Grabowski, G A; Smith, F I

1989-08-01

Gaucher disease (GD) is the most prevalent lysosomal storage disease. This autosomal recessive trait results from the defective activity of acid beta-glucosidase (beta-Glc). Four different exonic point mutations have been identified as causal alleles for GD. To facilitate screening for these alleles, assays were developed using allele-specific oligonucleotide hybridization to amplified genomic DNA sequences. Specifically, intron bases flanking exons 5, 9, and 10 were determined, and conditions for PCR amplification of these exons were obtained. Two different procedures were developed to distinguish signals obtained from the structural beta-Glc gene exons and those from the pseudogene. These procedures were used to determine the distribution of all known GD alleles in a population of 44 affected patients of varying phenotypes and ethnicity. The high frequency of one of the exon 9 mutations in Ashkenazi Jewish GD type 1 patients was confirmed, and, in addition, this mutation was present in ethnically diverse non-Jewish type 1 GD patients. Homozygotes (N = 5) for this allele were midly affected older individuals, and this mutant allele was not found in any patient with neuronopathic disease. The exon 10 mutation was confirmed as the predominant allele in types 2 and 3 GD. However, several type 1 GD patients, including one of Ashkenazi-Jewish heritage, also were heterozygous for this allele. The presence of this allele in type 1 patients did not correlate with the severity of clinical symptoms. The second exon 9 mutation and the exon 5 mutation were rare, since they occurred only heterozygously either in one type 2 GD patient or in two related Ashkenazi-Jewish GD patients, respectively. Although most GD patients (38 of 44) had at least one of the known mutant alleles, 57% were heterozygotes for only one of these mutations. Fourteen percent of patients were negative for all mutations. A total of 73% of GD patients had at least one unknown allele. The varying clinical

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... has used its fundraising efforts to help further research programs at Mount Sinai. Spotlight: Gaucher Gaucher Disease is the most common of the lipid storage diseases. Learn about its symptoms, how it ...

Lung Transplantation in Gaucher Disease: A Learning Lesson in Trying to Avoid Both Scylla and Charybdis.

PubMed

de Boer, Geertje M; van Dussen, Laura; van den Toorn, Leon M; den Bakker, Michael A; Hoek, Rogier A S; Hesselink, Dennis A; Hollak, Carla E M; van Hal, Peter Th W

2016-01-01

Gaucher disease (GD), a lysosomal storage disorder, may result in end-stage lung disease. We report successful bilateral lung transplantation in a 49-year-old woman with GD complicated by severe pulmonary hypertension and fibrotic changes in the lungs. Before receiving the lung transplant, the patient was undergoing both enzyme replacement therapy (imiglucerase) and triple pulmonary hypertension treatment (epoprostenol, bosentan, and sildenafil). She had a history of splenectomy, severe bone disease, and renal involvement, all of which were related to GD and considered as relative contraindications for a lung transplantation. In the literature, lung transplantation has been suggested for severe pulmonary involvement in GD but has been reported only once in a child. To our knowledge, until now, no successful procedure has been reported in adults, and no reports deal with the severe potential posttransplantation complications specifically related to GD. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Gaucher disease types 1, 2, and 3: differential mutations of the acid beta-glucosidase active site identified with conduritol B epoxide derivatives and sphingosine.

PubMed Central

Grabowski, G A; Dinur, T; Osiecki, K M; Kruse, J R; Legler, G; Gatt, S

1985-01-01

To elucidate the genetic heterogeneity in Gaucher disease, the residual beta-glucosidase in cultured fibroblasts from affected patients with each of the major phenotypes was investigated in vitro and/or in viable cells by inhibitor studies using the covalent catalytic site inhibitors, conduritol B epoxide or its bromo derivative, and the reversible cationic inhibitor, sphingosine. These studies delineated three distinct groups (designated A, B, and C) of residual activities with characteristic responses to these inhibitors. Group A residual enzymes had normal I50 values (i.e., the concentration of inhibitor that results in 50% inhibition) for the inhibitors and normal or nearly normal t1/2 values for conduritol B epoxide. All neuronopathic (types 2 and 3) and most non-Jewish nonneuronopathic (type 1) patients had group A residual activities and, thus, could not be distinguished by these inhibitor studies. Group B residual enzymes had about four- to fivefold increased I50 values for the inhibitors and similarly increased t1/2 values for conduritol B epoxide. All Ashkenazi Jewish type 1 and only two non-Jewish type 1 patients had group B residual activities. The differences in I50 values between groups A and B also were confirmed by determining the uninhibited enzyme activity after culturing the cells in the presence of bromo-conduritol B epoxide. Group C residual activity had intermediate I50 values for the inhibitors and represented a single Afrikaner type 1 patient: this patient was a genetic compound for the group A (type 2) and group B (type 1) mutations. These inhibition studies indicated that: Gaucher disease type 1 is biochemically heterogeneous, neuronopathic and non-Jewish nonneuronopathic phenotypes cannot be reliably distinguished by these inhibitor studies, and the Ashkenazi Jewish form of Gaucher disease type 1 results from a unique mutation in a specific active site domain of acid beta-glucosidase that leads to a defective enzyme with a decreased Vmax

Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48-month longitudinal cohort study

PubMed Central

Sims, KB; Pastores, GM; Weinreb, NJ; Barranger, J; Rosenbloom, BE; Packman, S; Kaplan, P; Mankin, H; Xavier, R; Angell, J; Fitzpatrick, MA; Rosenthal, D

2008-01-01

Sims KB, Pastores GM, Weinreb NJ, Barranger J, Rosenbloom BE, Packman S, Kaplan P, Mankin H, Xavier R, Angell J, Fitzpatrick MA, Rosenthal D. Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48-month longitudinal cohort study. Clin Genet 2008: 73: 430–440. © Blackwell Munksgaard, 2008 Progressive skeletal disease accounts for some of the most debilitating complications of type 1 Gaucher disease. In this 48-month, prospective, non-randomized, open-label study of the effect of enzyme replacement therapy on bone response, 33 imiglucerase-naïve patients (median age 43 years with one or more skeletal manifestations such as osteopenia, history of bone crisis, or other documented bone pathology) received imiglucerase 60 U/kg/2 weeks. Substantial improvements were observed in bone pain (BP), bone crises (BC), and bone mineral density (BMD). Improvements in BP were observed at 3 months (p < 0.001 vs baseline) and continued progressively throughout the study, with 39% of patients reporting pain at 48 months vs 73% at baseline. Eleven of the 13 patients with a pre-treatment history of BC had no recurrences. Biochemical markers for bone formation increased; markers for bone resorption decreased. Steady improvement of spine and femoral neck BMD, measured using dual-energy X-ray absorptiometry was noted. Mean Z score for spine increased from −0.72 ± 1.302 at baseline to near-normal levels (−0.09 ± 1.503) by month 48 (p = 0.042) and for femoral neck from −0.59 ± 1.352 to −0.17 ± 1.206 (p = 0.035) at month 36. This increase was sustained at 48 months. With imiglucerase treatment, patients should anticipate resolution of BC, rapid improvement in BP, increases in BMD, and decreased skeletal complications. PMID:18312448

Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent.

PubMed

Ilan, Yaron; Elstein, Deborah; Zimran, Ari

2009-10-01

Gaucher disease (GD) is caused by the reduced activity of a lysosomal enzyme, glucocerebrosidase, leading to the accumulation of glucocerebroside (GC). The relatively high prevalence of this disease within an ethnic group is believed to reflect a selective advantage. Treatment with enzyme replacement therapy (ERT) is safe and effective in ameliorating the primary symptoms of the disease, yet there have been reports that some patients on ERT have developed type 2 diabetes or metabolic syndrome, malignancies and central nervous system disorders. A series of animal studies suggest that these complications may be related to the reduction of GC levels by the enzyme administered. GC has been shown to have an immunomodulatory effect through the promotion of dendritic cells, natural killer T cells, and regulatory T cells. The break down of GC to ceramide can underline part of these findings. Clinical trials suggested a beneficial effect of GC in type 2 diabetes or nonalcoholic steatohepatitis. This review of the data from animal models and humans proposes that the increased level of GC may provide an evolutionary advantage for patients with GD. Indirectly, these data support treating symptomatic patients with mild/moderate GD with low-dose ERT and re-evaluating the use of ERT in asymptomatic patients.

Fluorinated Chaperone-β-Cyclodextrin Formulations for β-Glucocerebrosidase Activity Enhancement in Neuronopathic Gaucher Disease.

PubMed

García-Moreno, M Isabel; de la Mata, Mario; Sánchez-Fernández, Elena M; Benito, Juan M; Díaz-Quintana, Antonio; Fustero, Santos; Nanba, Eiji; Higaki, Katsumi; Sánchez-Alcázar, José A; García Fernández, José M; Ortiz Mellet, Carmen

2017-03-09

Amphiphilic glycomimetics encompassing a rigid, undistortable nortropane skeleton based on 1,6-anhydro-l-idonojirimycin and a polyfluorinated antenna, when formulated as the corresponding inclusion complexes with β-cyclodextrin (βCD), have been shown to behave as pharmacological chaperones (PCs) that efficiently rescue lysosomal β-glucocerebrosidase mutants associated with the neuronopathic variants of Gaucher disease (GD), including the highly refractory L444P/L444P and L444P/P415R single nucleotide polymorphs, in patient fibroblasts. The body of work here presented includes the design criteria for the PC prototype, the synthesis of a series of candidates, the characterization of the PC:βCD complexes, the determination of the selectivity profiles toward a panel of commercial and human lysosomal glycosidases, the evaluation of the chaperoning activity in type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (adult neuronopathic) GD fibroblasts, the confirmation of the rescuing mechanism by immunolabeling, and the analysis of the PC:GCase binding mode by docking experiments.

Computerized cognitive testing in patients with type I Gaucher disease: effects of enzyme replacement and substrate reduction.

PubMed

Elstein, Deborah; Guedalia, Judith; Doniger, Glen M; Simon, Ely S; Antebi, Vered; Arnon, Yael; Zimran, Ari

2005-02-01

Because of concern for drug-induced cognitive dysfunction during clinical trials using substrate reduction therapy (miglustat) in type 1 Gaucher disease and because it has been suggested that some patients with type 1 Gaucher disease may develop neurocognitive impairment as part of the natural history, two different batteries of neuropsychological tests were devised to examine these issues. Using these tests, cognitive function was assessed in patients treated with miglustat, in patients receiving enzyme replacement (standard care for symptomatic patients), and in untreated (milder) patients. For this study, 55/60 patients exposed to miglustat in Israel participated in psychologist-administered testing; 36/55 participated in computerized testing. Of these, 31 enzyme-treated patients and 22 untreated patients participated in the psychologist-administered testing, and 15 enzyme-treated patients and 18 untreated patients participated in computerized testing. The psychologist-administered battery consisted of 18 standard neuropsychological subtests specific to executive and visuospatial functioning. The computerized battery (Mindstreams, NeuroTrax Corp., New York, NY) consisted of 10 subtests tapping multiple cognitive domains. Between-group analyses for each modality compared cognitive performance. In the psychologist-administered testing, patients exposed to miglustat performed significantly less well than the other groups in 5/18 subtests. On the computerized tests, all patients performed comparably to normal controls. Scores in patients exposed to miglustat were higher than in untreated patients, particularly in visuospatial function, whereas enzyme-treated patients performed less well. However, with the exception of visuospatial function, these results were not statistically significant. It is unclear why different testing methods yielded discordant results. Any dysfunction suggested by the current study is apparently subtle and of doubtful clinical relevance

The 1448C mutation in Chinese with type 1 and 2 Gaucher disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsai, F.J.; Tsai, C.H.

1994-09-01

Gaucher disease (GD) is the most common glycolipid storage disorder. Just 5 mutations account for over 97% of all the alleles that produce enzyme deficiency in the Ashkenazic Jewish population. However, GD occurs in all populations but with a much lower frequency, as is the case with other mutations that are common in a single ethnic group. To characterize the molecular basis of Chinese with GD, two cases of GD was analyzed (type 1 and type 2) by selective amplification and restriction endonuclease analysis. Homozygosity of this mutation seems to result in neuronopathic GD (type 2 or 3), but somemore » exceptional cases have been reported. Our results show that the existence of the 1448C mutation in Chinese patients is similar to that of other ethnic groups. In our case 2, who had a homozygotic 1448C mutation but without any CNS manifestation, type 1 GD was diagnosed. In view of the young age of the patient (11 year old), he may develop neurological disease later in life. We suggest that such a case should be followed to observe if any neurological sign becomes present. Patients with GD sharing identical genotypes can exhibit different phenotypic pictures. Thus one cannot rely solely on DNA mutation analysis to predict prognosis in GD. The Chinese mutation data of GD presented here can support this hypothesis.« less

Gaucher disease epidemiology and natural history: a comprehensive review of the literature.

PubMed

Nalysnyk, Luba; Rotella, Philip; Simeone, Jason C; Hamed, Alaa; Weinreb, Neal

2017-03-01

The objectives of this research were: (1) to heighten awareness of Gaucher disease (GD), a rare lysosomal storage disorder with highly heterogeneous patterns of organ involvement and disease severity, to clinicians most likely to encounter these patients, and; (2) to summarize the published evidence on GD epidemiology which is essential to accurately depict the total societal burden of this rare worldwide disorder. A comprehensive literature review was undertaken to summarize the published evidence on the epidemiology of GD. MEDLINE, EMBASE, CENTRAL, and 'grey' literature sources published in English between January 1990 and March 2015 were searched to identify relevant publications. In total, 188 full-text articles were reviewed and findings from 49 studies are summarized herein. The standardized birth incidence of GD in the general population varied from 0.39 to 5.80 per 100 000, and prevalence ranged from 0.70 to 1.75 per 100 000, respectively. Time from onset of GD symptoms to clinical diagnosis was highly variable, with median delays of up to 7 years reported. The incidence and prevalence of GD is substantially higher among the Ashkenazi Jewish population than the general population. Limited epidemiologic information was available from Latin America, Africa, Asia, and developed nations such as the United States, Germany, and the United Kingdom. Signs and symptoms of GD frequently mimic more common hematologic conditions resulting in missed or delayed diagnosis. Early diagnosis and prompt initiation of treatment when indicated is crucial to prevent or minimize life-altering or life-threatening liver and skeletal complications.

Re-evaluation of bone pain in patients with type 1 Gaucher disease suggests that bone crises occur in small bones as well as long bones.

PubMed

Baris, Hagit N; Weisz Hubshman, Monika; Bar-Sever, Zvi; Kornreich, Liora; Shkalim Zemer, Vered; Cohen, Ian J

2016-09-01

Bone crises in type 1 Gaucher disease are reported in long bones and occasionally in weight bearing bones and other bones, but rarely in small bones of the hands and feet. We retrospectively examined the incidence of bone pain in patients followed at the Rabin Medical Center, Israel, before and following the initiation of enzyme replacement therapy (ERT) and evaluated them for bone crises. Of 100 type I Gaucher disease patients, 30 (30%) experienced one or more bone crises. Small bone crises represented 31.5% of all bone crises and were always preceded by crises in other bones. While the incidence of long bone crises reduced after the initiation of ERT, small bone crises increased. Almost 60% of patients with bone crises were of the N370S/84GG genotype suggesting a greater susceptibility of N370S/84GG patients to severe bone complications. These patients also underwent the greatest number of splenectomies (70.6% of splenectomised patients). Splenectomised patients showed a trend towards increased long and small bone crises after surgery. Active investigation of acute pain in the hands and feet in patients in our cohort has revealed a high incidence of small bone crises. Physicians should consider imaging studies to investigate unexplained pain in these areas. Copyright © 2015 Elsevier Inc. All rights reserved.

[Gaucher's disease and imiglucerase in 2009/2010: what leads to a suddenly enforced prioritisation?].

PubMed

Hofstetter, K; Raspe, H; Stumpf, S; Framke, S

2015-02-01

Gaucher's disease is, when left untreated, a progressive and in some subsets even life-threatening lysosomal storage disease. It is caused by a genetically linked deficit of acid beta-glucocerebrosidase. The enzyme can be replaced by Cerezyme(®)/imiglucerase produced by Genzyme Corp. The therapy has the potential to induce remis-sion and normalise the patient's life. In June 2009 Genzyme had to announce a viral contamination of its bioreactors which led to a sudden stop of the entire production of imiglucerase. Subsequently only 50-20% of the former supply could be provided worldwide. The situation was not normalised until the beginning of the year 2011. Due to this unexpected shortage the relevant actors had to clarify quickly and unprepared which patient groups to prioritise and whom to supply with what quantities of imiglucerase. The shortly enforced prioritisation and rationing provide an opportunity to describe and analyse the spontaneously choosen prioritisation criteria and reveal value preferences shared by clinicians, patients, patient representatives, and company representatives. To reconstruct the chain of events and reactions and the revealed criteria and value preferences partly standardised interviews with representatives of the relevant stakeholder groups were conducted. Very clearly, the actors spontaneously chose to follow a medical need and a social solidarity principle. © Georg Thieme Verlag KG Stuttgart · New York.

Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells.

PubMed

McNeill, Alisdair; Magalhaes, Joana; Shen, Chengguo; Chau, Kai-Yin; Hughes, Derralyn; Mehta, Atul; Foltynie, Tom; Cooper, J Mark; Abramov, Andrey Y; Gegg, Matthew; Schapira, Anthony H V

2014-05-01

Gaucher disease is caused by mutations in the glucocerebrosidase gene, which encodes the lysosomal hydrolase glucosylceramidase. Patients with Gaucher disease and heterozygous glucocerebrosidase mutation carriers are at increased risk of developing Parkinson's disease. Indeed, glucocerebrosidase mutations are the most frequent risk factor for Parkinson's disease in the general population. Therefore there is an urgent need to understand the mechanisms by which glucocerebrosidase mutations predispose to neurodegeneration to facilitate development of novel treatments. To study this we generated fibroblast lines from skin biopsies of five patients with Gaucher disease and six heterozygous glucocerebrosidase mutation carriers with and without Parkinson's disease. Glucosylceramidase protein and enzyme activity levels were assayed. Oxidative stress was assayed by single cell imaging of dihydroethidium. Glucosylceramidase enzyme activity was significantly reduced in fibroblasts from patients with Gaucher disease (median 5% of controls, P = 0.0001) and heterozygous mutation carriers with (median 59% of controls, P = 0.001) and without (56% of controls, P = 0.001) Parkinson's disease compared with controls. Glucosylceramidase protein levels, assessed by western blot, were significantly reduced in fibroblasts from Gaucher disease (median glucosylceramidase levels 42% of control, P < 0.001) and heterozygous mutation carriers with (median 59% of control, P < 0.001) and without (median 68% of control, P < 0.001) Parkinson's disease. Single cell imaging of dihydroethidium demonstrated increased production of cytosolic reactive oxygen species in fibroblasts from patients with Gaucher disease (dihydroethidium oxidation rate increased by a median of 62% compared to controls, P < 0.001) and heterozygous mutation carriers with (dihydroethidium oxidation rate increased by a median of 68% compared with controls, P < 0.001) and without (dihydroethidium oxidation rate increased by a

Binding of 3,4,5,6-Tetrahydroxyazepanes to the Acid-[beta]-glucosidase Active Site: Implications for Pharmacological Chaperone Design for Gaucher Disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Orwig, Susan D.; Tan, Yun Lei; Grimster, Neil P.

2013-03-07

Pharmacologic chaperoning is a therapeutic strategy being developed to improve the cellular folding and trafficking defects associated with Gaucher disease, a lysosomal storage disorder caused by point mutations in the gene encoding acid-{beta}-glucosidase (GCase). In this approach, small molecules bind to and stabilize mutant folded or nearly folded GCase in the endoplasmic reticulum (ER), increasing the concentration of folded, functional GCase trafficked to the lysosome where the mutant enzyme can hydrolyze the accumulated substrate. To date, the pharmacologic chaperone (PC) candidates that have been investigated largely have been active site-directed inhibitors of GCase, usually containing five- or six-membered rings, suchmore » as modified azasugars. Here we show that a seven-membered, nitrogen-containing heterocycle (3,4,5,6-tetrahydroxyazepane) scaffold is also promising for generating PCs for GCase. Crystal structures reveal that the core azepane stabilizes GCase in a variation of its proposed active conformation, whereas binding of an analogue with an N-linked hydroxyethyl tail stabilizes GCase in a conformation in which the active site is covered, also utilizing a loop conformation not seen previously. Although both compounds preferentially stabilize GCase to thermal denaturation at pH 7.4, reflective of the pH in the ER, only the core azepane, which is a mid-micromolar competitive inhibitor, elicits a modest increase in enzyme activity for the neuronopathic G202R and the non-neuronopathic N370S mutant GCase in an intact cell assay. Our results emphasize the importance of the conformational variability of the GCase active site in the design of competitive inhibitors as PCs for Gaucher disease.« less

Accumulation and distribution of α-synuclein and ubiquitin in the CNS of Gaucher disease mouse models

PubMed Central

Xu, YH; Sun, Y; Ran, H; Quinn, B; Witte, D; Grabowski, GA

2011-01-01

Gaucher disease, a prevalent lysosomal storage disease, is caused by insufficient activity of acid β-glucosidase (GCase) and resultant glucosylceramide accumulation. Recently in Parkinson disease (PD) patients, heterozygous mutations in GCase have been associated with earlier onset and more progressive PD. To understand the pathogenic relationships between GCase variants and Parkinsonism, α-synuclein and ubiquitin distributions and levels in the brains of several mouse models containing GCase variants were evaluated by immunohistochemistry. Progressive α-synuclein and ubiquitin aggregate accumulations were observed in the cortex, hippocampus, basal ganglia, brainstem, and some cerebellar regions between 4-24 wks in mice that were homozygous for GCase [D409H (9H) or V394L (4L)] variants and also had a prosaposin hypomorphic (PS-NA) transgene. In 4L/PS-NA and 9H/PS-NA mice, this was coincident with progressive neurological manifestations and brain glucosylceramide accumulation. Ultrastructural studies showed electron dense inclusion bodies in neurons and axons of 9H/PS-NA brains. α-Synuclein aggregates were also observed in ventricular, brainstem, and cerebellar regions of older mice (>42-wk) with the GCase variant (D409H/D409H) without overt neurological disease. In a chemically induced GCase deficiency, α-synuclein aggregates and glucosylceramide accumulation also occurred. These studies demonstrate a relationship between glucosylceramide accumulation and α-synuclein aggregates, and implicate glucosylceramide accumulation as risk factor for the α-synucleinopathies. PMID:21257328

Gaucher disease: A G[sup +1][yields]A[sup +1] IVS2 splice donor site mutation causing exon 2 skipping in the acid [beta]-glucosidase mRNA

DOE Office of Scientific and Technical Information (OSTI.GOV)

He, Guo-Shun; Grabowski, G.A.

1992-10-01

Gaucher disease is the most frequent lysosomal storage disease and the most prevalent Jewish genetic disease. About 30 identified missense mutations are causal to the defective activity of acid [beta]-glucosidase in this disease. cDNAs were characterized from a moderately affected 9-year-old Ashkenazi Jewish Gaucher disease type 1 patient whose 80-years-old, enzyme-deficient, 1226G (Asn[sup 370][yields]Ser [N370S]) homozygous grandfather was nearly asymptomatic. Sequence analyses revealed four populations of cDNAs with either the 1226G mutation, an exact exon 2 ([Delta] EX2) deletion, a deletion of exon 2 and the first 115 bp of exon 3 ([Delta] EX2-3), or a completely normal sequence. Aboutmore » 50% of the cDNAs were the [Delta] EX2, the [Delta] EX2-3, and the normal cDNAs, in a ratio of 6:3:1. Specific amplification and characterization of exon 2 and 5[prime] and 3[prime] intronic flanking sequences from the structural gene demonstrated clones with either the normal sequence or with a G[sup +1][yields]A[sup +1] transition at the exon 2/intron 2 boundary. This mutation destroyed the splice donor consensus site (U1 binding site) for mRNA processing. This transition also was present at the corresponding exon/intron boundary of the highly homologous pseudogene. This new mutation, termed [open quotes]IVS2 G[sup +1],[close quotes] is the first in the Ashkenazi Jewish population. The occurrence of this [open quotes]pseudogene[close quotes]-type mutation in the structural gene indicates the role of acid [beta]-glucosidase pseudogene and structural gene rearrangements in the pathogenesis of this disease. 33 refs., 8 figs., 1 tab.« less

The management of Gaucher disease in developing countries: a successful experience in Southern Brazil.

PubMed

Krug, B C; Schwartz, I V; Lopes de Oliveira, F; Alegra, T; Campos Martins, N L; Todeschini, L A; Picon, P D

2010-01-01

Gaucher disease (GD) is a genetic disease caused by glucocerebrosidase deficiency. GD is treated by enzyme replacement therapy (ERT) with imiglucerase, a high-cost drug provided by the Brazilian Ministry of Health (BMH). This study reports the implementation of the BMH guidelines for GD in the southernmost state of the country. We review the clinical and laboratorial data for patients seen at the reference center for GD from Rio Grande do Sul, Brazil (July 2003 to June 2006). Twenty-five patients were included in this study. At baseline, 19/20 were on ERT (mean dosage of imiglucerase = 51.8 U/kg/infusion), 3/17 presented anemia, and 5/16 thrombocytopenia. The amount of imiglucerase prescribed to these patients was adjusted according to the guidelines in July 2003; out of them, 18 were receiving ERT in the reference center at month 36 (mean dosage of imiglucerase = 27.5 U/kg/infusion), 2/18 presented anemia, and 4/18 presented thrombocytopenia. The analysis of the liver, spleen, and bone data presented some limitations, but the available information suggests that patients did not deteriorate. GD patients who initiated ERT after July 2003 (n = 5) received lower dosage of imiglucerase since the beginning of the treatment; most of them demonstrated clinical and laboratorial response. From baseline to month 36, the consumption of imiglucerase by the reference center showed a significant reduction, which represented savings of USD 3 million to the public health system. The model of care of GD patients suggested by the BMH guidelines appears to be cost-effective and could be an example for management of rare diseases in underdeveloped countries. Copyright © 2009 S. Karger AG, Basel.

Selection of transduced CD34+ progenitors and enzymatic correction of cells from Gaucher patients, with bicistronic vectors.

PubMed Central

Migita, M; Medin, J A; Pawliuk, R; Jacobson, S; Nagle, J W; Anderson, S; Amiri, M; Humphries, R K; Karlsson, S

1995-01-01

The gene transfer efficiency of human hematopoietic stem cells is still inadequate for efficient gene therapy of most disorders. To overcome this problem, a selectable retroviral vector system for gene therapy has been developed for gene therapy of Gaucher disease. We constructed a bicistronic retroviral vector containing the human glucocerebrosidase (GC) cDNA and the human small cell surface antigen CD24 (243 bp). Expression of both cDNAs was controlled by the long terminal repeat enhancer/promoter of the Molony murine leukemia virus. The CD24 selectable marker was placed downstream of the GC cDNA and its translation was enhanced by inclusion of the long 5' untranslated region of encephalomyocarditis virus internal ribosomal entry site. Virus-producing GP+envAM12 cells were created by multiple supernatant transductions to create vector producer cells. The vector LGEC has a high titer and can drive expression of GC and the cell surface antigen CD24 simultaneously in transduced NIH 3T3 cells and Gaucher skin fibroblasts. These transduced cells have been successfully separated from untransduced cells by fluorescence-activated cell sorting, based on cell surface expression of CD24. Transduced and sorted NIH 3T3 cells showed higher GC enzyme activity than the unsorted population, demonstrating coordinated expression of both genes. Fibroblasts from Gaucher patients were transduced and sorted for CD24 expression, and GC enzyme activity was measured. The transduced sorted Gaucher fibroblasts had a marked increase in enzyme activity (149%) compared with virgin Gaucher fibroblasts (17% of normal GC enzyme activity). Efficient transduction of CD34+ hematopoietic progenitors (20-40%) was accomplished and fluorescence-activated cell sorted CD24(+)-expressing progenitors generated colonies, all of which (100%) were vector positive. The sorted, CD24-expressing progenitors generated erythroid burst-forming units, colony-forming units (CFU)-granulocyte, CFU-macrophage, CFU

[Neurological manifestations in patients with Gaucher disease and in their relatives].

PubMed

Giraldo, Pilar; Capablo, José Luis; Alfonso, Pilar; Latre, Paz; García, Beatriz; Pocoví, Miguel

2008-07-05

Gaucher disease (GD) is characterized by a wide spectrum of manifestations. Previous reports indicate that GD relatives could develop neurological abnormalities more frequently than the general population. We aimed to know the presence of neurological symptoms (NS) in GD patients and their relatives. From January to December 2006 we performed a postal survey contacting 42 physicians and 92 families to evaluate NS and correlate them with genetic characteristics. Statistical analysis using descriptive parameters, ANOVA, t-test and a correlation study including Pearson coefficient were performed. Information from 72 families (78.3% responses) including 99 patients and 266 relatives was obtained. Thirty type 1 GD (32.6%) reported NS: tremor 8 (8.7%), uncoordinated movements 9 (9.8%), concentration defects 11 (11.9%), strabism 7 (7.6%), deafness 8 (8.7%), Parkinson disease (PD) 7 (7.6%) and peripheral neuropathy 10 (10.9%). Thirty-six (13.5%) first or second degrees relatives presented the following NS: PD 14 (4.9%), epilepsy 8 (3.0%), tremor 7 (2.6%), deafness 2 (0.7%) and others 5 (1.9%). 17.3% of carriers had NS versus 5.7% in non-carriers (p = 0.0096). Patients with PD had mutations in S364R, D409H, L444P, [IVS4-2a ==> g; c.(-203)A ==> G], c.500insT and L336P. In relatives with PD a wide spectrum of mutations was observed: L444P, N370S, V398I, G202R, c.1439-1445del7, [E326K; N188S] and c.953delT. In other NS, predominant mutations were D409H, G195W, R120W, R147X, L336P and G377S. A higher incidence than expected of PD and other NS in GD type 1 patients and relatives was observed. These manifestations appear frequently in L444P or rare mutations carriers. It is important to perform a systematic neurological exam in type 1 GD patients and carriers with risk mutations.

A multicentre observational study for early diagnosis of Gaucher disease in patients with Splenomegaly and/or Thrombocytopenia.

PubMed

Motta, Irene; Filocamo, Mirella; Poggiali, Erika; Stroppiano, Marina; Dragani, Alfredo; Consonni, Dario; Barcellini, Wilma; Gaidano, Gianluca; Facchini, Luca; Specchia, Giorgina; Cappellini, Maria Domenica

2016-04-01

Gaucher disease (GD) is the most common lysosomal disorder resulting from deficient activity of the β-glucosidase enzyme that causes accumulation of glucosylceramide in the macrophage-monocyte system. Notably, because of non-specific symptoms and a lack of awareness, patients with GD experience long diagnostic delays. The aim of this study was to apply a diagnostic algorithm to identify GD type 1 among adults subjects referred to Italian haematology outpatient units because of splenomegaly and/or thrombocytopenia and, eventually, to estimate the prevalence of GD in this selected population. One hundred and ninety-six subjects (61 females, 135 males; mean age 47.8 ± 18.2 years) have been enrolled in the study and tested for β-glucosidase enzyme activity on dried blood spot (DBS). Seven of 196 patients have been diagnosed with GD, (5 females and 2 males) with mean age 31.8 ± 8.2 years, with a prevalence of 3.6% (with a prevalence of 3.6% (I95% CI 1.4-7.2; 1/28 patients) in this population. These results show that the use of an appropriate diagnostic algorithm and a simple diagnostic method, such as DBS, are important tools to facilitate the diagnosis of a rare disease even for not disease-expert physicians. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Machine learning based analytics of micro-MRI trabecular bone microarchitecture and texture in type 1 Gaucher disease.

PubMed

Sharma, Gulshan B; Robertson, Douglas D; Laney, Dawn A; Gambello, Michael J; Terk, Michael

2016-06-14

Type 1 Gaucher disease (GD) is an autosomal recessive lysosomal storage disease, affecting bone metabolism, structure and strength. Current bone assessment methods are not ideal. Semi-quantitative MRI scoring is unreliable, not standardized, and only evaluates bone marrow. DXA BMD is also used but is a limited predictor of bone fragility/fracture risk. Our purpose was to measure trabecular bone microarchitecture, as a biomarker of bone disease severity, in type 1 GD individuals with different GD genotypes and to apply machine learning based analytics to discriminate between GD patients and healthy individuals. Micro-MR imaging of the distal radius was performed on 20 type 1 GD patients and 10 healthy controls (HC). Fifteen stereological and textural measures (STM) were calculated from the MR images. General linear models demonstrated significant differences between GD and HC, and GD genotypes. Stereological measures, main contributors to the first two principal components (PCs), explained ~50% of data variation and were significantly different between males and females. Subsequent PCs textural measures were significantly different between GD patients and HC individuals. Textural measures also significantly differed between GD genotypes, and distinguished between GD patients with normal and pathologic DXA scores. PCA and SVM predictive analyses discriminated between GD and HC with maximum accuracy of 73% and area under ROC curve of 0.79. Trabecular STM differences can be quantified between GD patients and HC, and GD sub-types using micro-MRI and machine learning based analytics. Work is underway to expand this approach to evaluate GD disease burden and treatment efficacy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lysosomal storage diseases

PubMed Central

Ferreira, Carlos R.; Gahl, William A.

2016-01-01

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

Gaucher disease: Physical, kinetic and immunologic investigations of human and canine acid. beta. -glucosidase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fabbro, D.E.

1988-01-01

Kinetic and immunologic techniques were developed to investigate the nature of the acid {beta}-glucosidase ({beta}-Glc) defects which results in human and canine Gaucher disease (GD). Two new affinity columns, using the potent inhibitors of {beta}-Glc (N-alkyl-deoxynojirimycins) as affinity ligands, were synthesized and methods were developed to obtain homogeneous {beta}-Glc from normal human placenta. Polyclonal and monoclonal (representing 14 different epitopes from 18 clones) antibodies were produced to the pure normal {beta}-Glc. Monospecific polyclonal IgG and tritiated-bromo-conduritol B epoxide (({sup 3}H)Br-CBE), a specific covalent active site directed inhibitor of {beta}-Glc, were used to quantitate the functional catalytic sites in normal andmore » Type 1 Ashkenazi Jewish GD (AJGD) enzyme preparations: The k{sub cat} values for several new substrates with the mutant enzymes from spleen were about 1.5-fold less than the respective normal enzyme, indicating a nearly normal catalytic capacity of the mutant enzymes. Immunoblotting studies with polyclonal or several monoclonal antibodies indicated three molecular forms of {beta}-Glc (M{sub r} = 67,000, 62,000 to 65,000 and 58,000) in fibroblast extracts from normals and Type 1 AJGD patients. In comparison, only one form of cross-reacting immunologic material (CRIM) was detected in fibroblast extracts from Types 2 and 3 or several non-Jewish Type 1 GD patients.« less

Development of anti-velaglucerase alfa antibodies in clinical trial-treated patients with Gaucher disease.

PubMed

Pastores, Gregory M; Turkia, Hadhami Ben; Gonzalez, Derlis E; Ida, Hiroyuki; Tantawy, Azza A G; Qin, Yulin; Qiu, Yongchang; Dinh, Quinn; Zimran, Ari

2016-07-01

Anti-drug antibodies may develop with biological therapies, possibly leading to a reduction of treatment efficacy and to allergic and other adverse reactions. Patients with Gaucher disease were tested for anti-drug antibodies every 6 or 12weeks in clinical studies of velaglucerase alfa enzyme replacement therapy, as part of a range of safety endpoints. In 10 studies between April 2004 and March 2015, 289 patients aged 2-84years (median 43years) were assessed for the development of anti-velaglucerase alfa antibodies. Sixty-four patients were treatment-naïve at baseline and 225 patients were switched to velaglucerase alfa from imiglucerase treatment. They received velaglucerase alfa treatment for a median of 36.4weeks (interquartile range 26.4-155.4weeks). Four patients (1.4%) became positive for anti-velaglucerase alfa IgG antibodies, two of whom had antibodies that were neutralizing in vitro, but there were no apparent changes in patients' platelet counts, hemoglobin levels or levels of CCL18 and chitotriosidase, suggestive of clinical deterioration after anti-velaglucerase alfa antibodies were detected, and no infusion-related adverse events were reported. Less than 2% of patients exposed to velaglucerase alfa tested positive for antibodies and there was no apparent correlation between anti-velaglucerase alfa antibodies and adverse events or pharmacodynamic or clinical responses. Copyright © 2016. Published by Elsevier Inc.

Glucosylceramide accumulation is not confined to the lysosome in fibroblasts from patients with Gaucher disease.

PubMed

Fuller, Maria; Rozaklis, Tina; Lovejoy, Melanie; Zarrinkalam, Krystyna; Hopwood, John J; Meikle, Peter J

2008-04-01

Gaucher disease (GD) is an inborn error of glycosphingolipid metabolism resulting from a deficiency of the lysosomal enzyme beta-glucosidase leading to the accumulation of glucosylceramide (GC) in lysosomes of affected cells. In order to determine the effect of GC accumulation on intracellular lipid content in fibroblasts from patients with GD, we measured individual species of ceramide, di- and trihexosylceramide, sphingomyelin, phosphatidylcholine, phosphatidylinositol and phosphatidylglycerol using electrospray ionisation-tandem mass spectrometry. The different subspecies of each lipid class correlated with each other and were summed to give total lipid concentrations. In addition to GC, we also noted secondary elevations in other lipids, especially in type 2 GD. Sub-cellular fractionation showed that GC was not confined to the lysosome but increased throughout the cell. The sequelae of extra-lysosomal accumulation may have implications in the pathogenic mechanisms of GD by interaction with biochemical and metabolic pathways located outside the lysosome. The elevation of ceramide in confluent type 2 GD fibroblasts redistributed from its primary site of accumulation in the lysosome to the endosomal region at four-weeks post-confluence. The accumulation of lipids in the endosome and lysosome suggests both impaired trafficking of lipids and reduced capacity of the lysosome to degrade lipids.

Serum lipid alterations in GBA-associated Parkinson's disease.

PubMed

Guedes, Leonor Correia; Chan, Robin Barry; Gomes, Marcos António; Conceição, Vasco A; Machado, Raquel Bouça; Soares, Tiago; Xu, Yimeng; Gaspar, Paulo; Carriço, Joao André; Alcalay, Roy N; Ferreira, Joaquim J; Outeiro, Tiago Fleming; Miltenberger-Miltenyi, Gabriel

2017-11-01

Mutations in the GBA gene, encoding for the lysosomal enzyme glucocerebrosidase, are associated with Gaucher disease. Alterations in plasma sphingolipids have been reported in Gaucher, and similarly in brain extracts in Lewy body disease. As GBA mutations are prevalent risk factors for Parkinson's disease and overlap of molecular pathways are presumable, here we assessed the lipid profiles in Parkinson's patients with and without GBA mutations. We sequenced all GBA exons in 415 Parkinson's patients, previously genotyped for LRRK2. 64 patients (29 GBA positive vs. 35 non-GBA-carriers including 18 LRRK2 positive and 17 non-mutated) were analyzed for chitotriosidase activity and for the concentration of 40 lipid classes using HPLC-MS. 29/415 patients (6.9%) carried 8 different GBA mutations associated with Gaucher or Parkinson's, including one novel mutation. Chitotriosidase activity was similar across the genetic groups, while the levels of key lipids were altered in GBA mutation carriers: Monohexosylceramide, Ceramide and Sphingomyelin were elevated; while Phosphatidic acid (PA), Phosphatidylethanolamine (PE), Plasmalogen phosphatidylethanolamine (PEp) and Acyl Phosphatidylglycerol (AcylPG) were decreased. The results suggest an important role for these lipids in GBA mediated Parkinson's disease and assist in the identification of common pathways between Gaucher and Parkinson's. Ultimately, our findings may lead to the identification of novel biomarkers for individuals at increased risk of developing Parkinson's disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

Plant-based oral delivery of β-glucocerebrosidase as an enzyme replacement therapy for Gaucher's disease.

PubMed

Shaaltiel, Yoseph; Gingis-Velitski, Svetlana; Tzaban, Salit; Fiks, Nadia; Tekoah, Yoram; Aviezer, David

2015-10-01

Gaucher's disease (GD), a lysosomal storage disorder caused by mutations in the gene encoding glucocerebrosidase (GCD), is currently treated by enzyme replacement therapy (ERT) using recombinant GCD that is administered intravenously every 2 weeks. However, intravenous administration includes discomfort or pain and might cause local and systemic infections that may lead to low patient compliance. An orally administered drug has the potential to alleviate these problems. In this study, we describe the potential use of plant cells as a vehicle for the oral delivery of recombinant human GCD (prGCD) expressed in carrot cells. The in vitro results demonstrate that the plant cells protect the recombinant protein in the gastric fluids and may enable absorption into the blood. Feeding experiments, with rat and pig as model animals, using carrot cells containing prGCD, show that active recombinant prGCD was found in the digestive tract and blood system and reached both, liver and spleen, the target organs in GD. These results demonstrate that the oral administration of proteins encapsulated in plant cells is feasible. Specifically, carrot cells containing recombinant human prGCD can be used as an oral delivery system and are a feasible alternative to intravenous administration of ERT for GD. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

Biochemical properties of beta-glucosidase in leukocytes from patients and obligated heterozygotes for Gaucher disease carriers.

PubMed

Michelin, Kristiane; Wajner, Alessandro; Bock, Hugo; Fachel, Angela; Rosenberg, Roberto; Pires, Ricardo Flores; Pereira, Maria Luiza Saraiva; Giugliani, Roberto; Coelho, Janice Carneiro

2005-12-01

Gaucher's disease (GD) is a disorder caused by the deficiency of lysosomal beta-glucosidase, an enzyme that participates in the degradation of glycosphingolipids. Deficiency of this enzyme results in the storage of glucocerebrosides in lysosomes of macrophage. No studies are available in the literature comparing biochemical and kinetic behavior of this enzyme in leukocytes and fibroblasts from normal individuals, obligate heterozygotes and patients with GD. The behavior of beta-glu in terms of optimum pH, heat stability, Km and Vmax in leukocytes from patients with GD and obligated heterozygotes with different genotypes and normal individuals were characterized. Optimum pH was similar in all groups analyzed. In terms of Km and Vmax, several differences among heterozygotes and homozygotes groups and among these groups and normal enzyme were observed. Enzyme from all groups were inactivated when preincubated at 60 degrees C, but some enzymes were more stable than other. Results showed a different behavior of the enzyme in the 3 groups under analysis. Such behavior varied according to individual mutation. The catalytic gradient presented by beta-glu allowed the correlation of N370S mutation-which presented more stable biochemical properties-with the non-neurological clinical condition of the disease and the catalytically less stable mutation (D409H), with the neurological clinical condition of GD. This study contributes to a better understanding of the repercussion of the different mutations on the protein function, thus allowing to predict the severity of such complex metabolic disorder and to anticipate the most appropriate intervention for each case specifically.

Ultramicro-fluorometric assay for the diagnosis of Gaucher disease in dried blood spots on filter paper.

PubMed

Herrera, D; Monaga, M; Campos, D; Pampín, Y; González, E C; Lavaut, K

2013-01-01

Gaucher disease (GD) is a lysosomal storage disorder characterized by a deficiency of the lysosomal acid β-D-glucosidase (GBA). The aim of this study was to develop an ultramicro-fluorometric assay based on the method of Chamoles et al. for determining GBA activity in dried blood spots on filter paper (DBS). The assay used 3-mm diameter blood spot and 8 mmol/l of 4-methylumbelliferyl-β-D-glucoside as enzymatic substrate. The reaction occurred in plates incubated at 37°C for 20 hours and the enzyme activity was expressed in μmol hydrolysed substrate/l blood/h. The fluorescence of the enzyme product was automatically measured in a fluorometer-photometer reader (SUMA Technology). The intra and inter-assay coefficients of variation were lower than 9 and 12%, respectively, and the recovery range was 97-109%.Three patients with GD were correctly diagnosed using the ultramicroassay. Healthy newborn DBS samples (n = 3003) from the National Neonatal Screening Program were analyzed, and the mean GBA activity was 5.7 μmol/l blood/h. Our assay showed high Pearson (n = 26; r = 0.99) and concordance correlations (ρc = 0.99) with the traditional method described by Chamoles et al. The analytical performance characteristics of our ultramicro-fluorometric assay suggest that it can be used in the diagnosis of GD in newborns and adults.

Pharmacological Chaperones and Coenzyme Q10 Treatment Improves Mutant β-Glucocerebrosidase Activity and Mitochondrial Function in Neuronopathic Forms of Gaucher Disease

PubMed Central

de la Mata, Mario; Cotán, David; Oropesa-Ávila, Manuel; Garrido-Maraver, Juan; Cordero, Mario D.; Villanueva Paz, Marina; Delgado Pavón, Ana; Alcocer-Gómez, Elizabet; de Lavera, Isabel; Ybot-González, Patricia; Paula Zaderenko, Ana; Ortiz Mellet, Carmen; Fernández, José M. García; Sánchez-Alcázar, José A.

2015-01-01

Gaucher disease (GD) is caused by mutations in the GBA1 gene, which encodes lysosomal β-glucocerebrosidase. Homozygosity for the L444P mutation in GBA1 is associated with high risk of neurological manifestations which are not improved by enzyme replacement therapy. Alternatively, pharmacological chaperones (PCs) capable of restoring the correct folding and trafficking of the mutant enzyme represent promising alternative therapies.Here, we report on how the L444P mutation affects mitochondrial function in primary fibroblast derived from GD patients. Mitochondrial dysfunction was associated with reduced mitochondrial membrane potential, increased reactive oxygen species (ROS), mitophagy activation and impaired autophagic flux.Both abnormalities, mitochondrial dysfunction and deficient β-glucocerebrosidase activity, were partially restored by supplementation with coenzyme Q10 (CoQ) or a L-idonojirimycin derivative, N-[N’-(4-adamantan-1-ylcarboxamidobutyl)thiocarbamoyl]-1,6-anhydro-L-idonojirimycin (NAdBT-AIJ), and more markedly by the combination of both treatments. These data suggest that targeting both mitochondria function by CoQ and protein misfolding by PCs can be promising therapies in neurological forms of GD. PMID:26045184

Reducing selection bias in case-control studies from rare disease registries.

PubMed

Cole, J Alexander; Taylor, John S; Hangartner, Thomas N; Weinreb, Neal J; Mistry, Pramod K; Khan, Aneal

2011-09-12

In clinical research of rare diseases, where small patient numbers and disease heterogeneity limit study design options, registries are a valuable resource for demographic and outcome information. However, in contrast to prospective, randomized clinical trials, the observational design of registries is prone to introduce selection bias and negatively impact the validity of data analyses. The objective of the study was to demonstrate the utility of case-control matching and the risk-set method in order to control bias in data from a rare disease registry. Data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry were used as an example. A case-control matching analysis using the risk-set method was conducted to identify two groups of patients with type 1 Gaucher disease in the ICGG Gaucher Registry: patients with avascular osteonecrosis (AVN) and those without AVN. The frequency distributions of gender, decade of birth, treatment status, and splenectomy status were presented for cases and controls before and after matching. Odds ratios (and 95% confidence intervals) were calculated for each variable before and after matching. The application of case-control matching methodology results in cohorts of cases (i.e., patients with AVN) and controls (i.e., patients without AVN) who have comparable distributions for four common parameters used in subject selection: gender, year of birth (age), treatment status, and splenectomy status. Matching resulted in odds ratios of approximately 1.00, indicating no bias. We demonstrated bias in case-control selection in subjects from a prototype rare disease registry and used case-control matching to minimize this bias. Therefore, this approach appears useful to study cohorts of heterogeneous patients in rare disease registries.

Long-term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment-naïve patients with Gaucher disease.

PubMed

Zimran, Ari; Durán, Gloria; Mehta, Atul; Giraldo, Pilar; Rosenbaum, Hanna; Giona, Fiorina; Amato, Dominick J; Petakov, Milan; Muñoz, Eduardo Terreros; Solorio-Meza, Sergio Eduardo; Cooper, Peter A; Varughese, Sheeba; Chertkoff, Raul; Brill-Almon, Einat

2016-07-01

Taliglucerase alfa is an intravenous enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell-expressed recombinant therapeutic protein. Herein, we report long-term safety and efficacy results of taliglucerase alfa in treatment-naïve adult patients with GD. Patients were randomized to receive taliglucerase alfa 30 or 60 U/kg every other week, and 23 patients completed 36 months of treatment. Taliglucerase alfa (30 U/kg; 60 U/kg, respectively) resulted in mean decreases in spleen volume (50.1%; 64.6%) and liver volume (25.6%; 24.4%) with mean increases in hemoglobin concentration (16.0%; 35.8%) and platelet count (45.7%; 114.0%), and mean decreases in chitotriosidase activity (71.5%; 82.2%). All treatment-related adverse events were mild to moderate in intensity and transient. The most common adverse events were nasopharyngitis, arthralgia, upper respiratory tract infection, headache, pain in extremity, and hypertension. These 36-month results of taliglucerase alfa in treatment-naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns. These findings extend the taliglucerase alfa clinical safety and efficacy dataset. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:656-660, 2016. © 2016 Wiley Periodicals, Inc. © 2016 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.

Characterization of the c.(-203)A>G variant in the glucocerebrosidase gene and its association with phenotype in Gaucher disease.

PubMed

Alfonso, Pilar; Pampín, Sandra; García-Rodríguez, Beatriz; Tejedor, Teresa; Domínguez, Carmen; Rodríguez-Rey, Jose C; Giraldo, Pilar; Pocoví, Miguel

2011-01-30

Gaucher disease (GD) is a rare autosomal recessive disorder caused mainly by mutations in the glucocerebrosidase (GBA) gene. Great phenotypic variability has been observed among patients with the same genotype, suggesting other factors, such as polymorphic variants, might influence GD phenotypes. We previously reported the c.(-203)A>G (g.1256A>G) variant in exon 1 of the GBA gene in Spanish GD patients. We analyzed the frequency and transcriptional activity of the promoter carrying the G-allele using restriction isotyping, electrophoretic mobility shift assay, cell culture, transfection, and luciferase assays. We found the variant is present at a similar frequency to the control group. In our patients, the G-allele was always found in combination with another mutation in the same allele, and patients carrying the c.(-203)A>G variant showed a more severe GD phenotype. The promoter containing the G-allele showed a 35% reduction in promoter activity when transfected into HepG2 cells. The c.(-203)A>G variant seems to be a polymorphism resulting in a decrease in activity of the GBA promoter. The change, per se, is not enough to elicit a GD phenotype, but it may produce a more severe phenotype in GD patients when combined with an already defective GBA protein. Copyright © 2010 Elsevier B.V. All rights reserved.

Long-term safety and efficacy of taliglucerase alfa in pediatric Gaucher disease patients who were treatment-naïve or previously treated with imiglucerase.

PubMed

Zimran, Ari; Gonzalez-Rodriguez, Derlis Emilio; Abrahamov, Aya; Cooper, Peter A; Varughese, Sheeba; Giraldo, Pilar; Petakov, Milan; Tan, Ee Shien; Chertkoff, Raul

2018-02-01

Taliglucerase alfa is an enzyme replacement therapy approved for treatment of Gaucher disease (GD) in children and adults in several countries. This multicenter extension study assessed the efficacy and safety of taliglucerase alfa in pediatric patients with GD who were treatment-naïve (n=10) or switched from imiglucerase (n=5). Patients received taliglucerase alfa 30 or 60U/kg (treatment-naïve) or the same dose as previously treated with imiglucerase every other week. In treatment-naïve patients, taliglucerase alfa 30 and 60U/kg, respectively, reduced mean spleen volume (-18.6 multiples of normal [MN] and -26.0MN), liver volume (-0.8MN and -0.9MN), and chitotriosidase activity (-72.7% and -84.4%), and increased mean Hb concentration (+2.0g/dL and +2.3g/dL) and mean platelet count (+38,200/mm 3 and +138,250/mm 3 ) from baseline through 36 total months of treatment. In patients previously treated with imiglucerase, these disease parameters remained stable through 33 total months of treatment with taliglucerase alfa. Most adverse events were mild/moderate; treatment was well tolerated. These findings extend the taliglucerase alfa safety and efficacy profile and demonstrate long-term clinical improvement in treatment-naïve children receiving taliglucerase alfa and maintenance of disease stability in children switched to taliglucerase alfa. Treatment was well-tolerated, with no new safety signals. This study is registered at www.clinicaltrials.gov as NCT01411228. Copyright © 2016 Shire Human Genetic Therapies, Inc. Published by Elsevier Inc. All rights reserved.

Age estimate of the N370S mutation causing Gaucher disease in Ashkenazi Jews and European populations: A reappraisal of haplotype data.

PubMed

Colombo, R

2000-02-01

The N370S mutation at the GBA locus on human chromosome 1q21, which causes Gaucher disease (GD), has a high frequency in the Ashkenazim and is the second-most-widespread GD mutation in the European non-Jewish population. A common ancient origin for the N370S mutation in the Ashkenazi Jewish and Spanish populations has been proposed on the basis of both a similar haplotype for associated markers and an age estimate that suggests that this mutation appeared several thousand years ago. However, a reappraisal of haplotype data, using the Risch formula properly along with a Luria-Delbrück setting of the genetic clock, allows identification of the likely origin of the N370S mutation in Ashkenazi Jews between the 11th and 13th centuries. This result is consistent with the estimated ages of other mutations that are frequent among Ashkenazim, with the exception of type II (Glu117Stop) factor XI deficiency, which is deemed to be >3000 years old, predating the separation of the Ashkenazi and Iraqi Jews. The present finding supports the hypothesis of a more recent origin for the N370S mutation and is consistent with both a founder chromosome transfer from Ashkenazim who assimilated in some European populations and a non-Jewish origin of the European N370S-bearing chromosomes.

Age Estimate of the N370S Mutation Causing Gaucher Disease in Ashkenazi Jews and European Populations: A Reappraisal of Haplotype Data

PubMed Central

Colombo, Roberto

2000-01-01

Summary The N370S mutation at the GBA locus on human chromosome 1q21, which causes Gaucher disease (GD), has a high frequency in the Ashkenazim and is the second-most-widespread GD mutation in the European non-Jewish population. A common ancient origin for the N370S mutation in the Ashkenazi Jewish and Spanish populations has been proposed on the basis of both a similar haplotype for associated markers and an age estimate that suggests that this mutation appeared several thousand years ago. However, a reappraisal of haplotype data, using the Risch formula properly along with a Luria-Delbrück setting of the genetic clock, allows identification of the likely origin of the N370S mutation in Ashkenazi Jews between the 11th and 13th centuries. This result is consistent with the estimated ages of other mutations that are frequent among Ashkenazim, with the exception of type II (Glu117Stop) factor XI deficiency, which is deemed to be >3000 years old, predating the separation of the Ashkenazi and Iraqi Jews. The present finding supports the hypothesis of a more recent origin for the N370S mutation and is consistent with both a founder chromosome transfer from Ashkenazim who assimilated in some European populations and a non-Jewish origin of the European N370S-bearing chromosomes. PMID:10677327

Progression of Behavioral and CNS Deficits in a Viable Murine Model of Chronic Neuronopathic Gaucher Disease.

PubMed

Dai, Mei; Liou, Benjamin; Swope, Brittany; Wang, Xiaohong; Zhang, Wujuan; Inskeep, Venette; Grabowski, Gregory A; Sun, Ying; Pan, Dao

2016-01-01

To study the neuronal deficits in neuronopathic Gaucher Disease (nGD), the chronological behavioral profiles and the age of onset of brain abnormalities were characterized in a chronic nGD mouse model (9V/null). Progressive accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) in the brain of 9V/null mice were observed at as early as 6 and 3 months of age for GC and GS, respectively. Abnormal accumulation of α-synuclein was present in the 9V/null brain as detected by immunofluorescence and Western blot analysis. In a repeated open-field test, the 9V/null mice (9 months and older) displayed significantly less environmental habituation and spent more time exploring the open-field than age-matched WT group, indicating the onset of short-term spatial memory deficits. In the marble burying test, the 9V/null group had a shorter latency to initiate burying activity at 3 months of age, whereas the latency increased significantly at ≥12 months of age; 9V/null females buried significantly more marbles to completion than the WT group, suggesting an abnormal response to the instinctive behavior and an abnormal activity in non-associative anxiety-like behavior. In the conditional fear test, only the 9V/null males exhibited a significant decrease in response to contextual fear, but both genders showed less response to auditory-cued fear compared to age- and gender-matched WT at 12 months of age. These results indicate hippocampus-related emotional memory defects. Abnormal gait emerged in 9V/null mice with wider front-paw and hind-paw widths, as well as longer stride in a gender-dependent manner with different ages of onset. Significantly higher liver- and spleen-to-body weight ratios were detected in 9V/null mice with different ages of onsets. These data provide temporal evaluation of neurobehavioral dysfunctions and brain pathology in 9V/null mice that can be used for experimental designs to evaluate novel therapies for nGD.

Progression of Behavioral and CNS Deficits in a Viable Murine Model of Chronic Neuronopathic Gaucher Disease

PubMed Central

Dai, Mei; Liou, Benjamin; Swope, Brittany; Wang, Xiaohong; Zhang, Wujuan; Inskeep, Venette; Grabowski, Gregory A.; Sun, Ying; Pan, Dao

2016-01-01

To study the neuronal deficits in neuronopathic Gaucher Disease (nGD), the chronological behavioral profiles and the age of onset of brain abnormalities were characterized in a chronic nGD mouse model (9V/null). Progressive accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) in the brain of 9V/null mice were observed at as early as 6 and 3 months of age for GC and GS, respectively. Abnormal accumulation of α-synuclein was present in the 9V/null brain as detected by immunofluorescence and Western blot analysis. In a repeated open-field test, the 9V/null mice (9 months and older) displayed significantly less environmental habituation and spent more time exploring the open-field than age-matched WT group, indicating the onset of short-term spatial memory deficits. In the marble burying test, the 9V/null group had a shorter latency to initiate burying activity at 3 months of age, whereas the latency increased significantly at ≥12 months of age; 9V/null females buried significantly more marbles to completion than the WT group, suggesting an abnormal response to the instinctive behavior and an abnormal activity in non-associative anxiety-like behavior. In the conditional fear test, only the 9V/null males exhibited a significant decrease in response to contextual fear, but both genders showed less response to auditory-cued fear compared to age- and gender-matched WT at 12 months of age. These results indicate hippocampus-related emotional memory defects. Abnormal gait emerged in 9V/null mice with wider front-paw and hind-paw widths, as well as longer stride in a gender-dependent manner with different ages of onset. Significantly higher liver- and spleen-to-body weight ratios were detected in 9V/null mice with different ages of onsets. These data provide temporal evaluation of neurobehavioral dysfunctions and brain pathology in 9V/null mice that can be used for experimental designs to evaluate novel therapies for nGD. PMID:27598339

Taliglucerase alfa: safety and efficacy across 6 clinical studies in adults and children with Gaucher disease.

PubMed

Zimran, Ari; Wajnrajch, Michael; Hernandez, Betina; Pastores, Gregory M

2018-02-23

Taliglucerase alfa is an enzyme replacement therapy (ERT) approved for treatment of adult and paediatric patients with Type 1 Gaucher disease (GD) in several countries and the first plant cell-expressed recombinant therapeutic protein approved by the US Food and Drug Administration for humans. Here, we review the findings across six key taliglucerase alfa clinical studies. A total of 33 treatment-naïve adult patients were randomized to taliglucerase alfa 30 U/kg or 60 U/kg in a 9-month, multicentre, randomized, double-blind, parallel-group, dose-comparison pivotal study, after which eligible patients continued into two consecutive extension studies; 17 treatment-naïve adult patients completed 5 total years of treatment with taliglucerase alfa. In the only ERT study focused on exclusively paediatric patients with GD, 11 treatment-naïve children were randomized to taliglucerase alfa 30 U/kg or 60 U/kg in a 12-month, multicentre, double-blind study; nine completed 3 total years of treatment in a dedicated paediatric extension study. The effect of switching patients from imiglucerase to taliglucerase alfa was also investigated in a separate 9-month study that included 26 adults and five children; 10 adults completed a total of 3 years and two children completed a total of 2.75 years of taliglucerase alfa treatment in the extension studies. All studies evaluated safety and spleen volume, liver volume, platelet count, haemoglobin concentration, and biomarkers as measures of efficacy. Detailed results from baseline through the end of these studies are presented. Taliglucerase alfa was well tolerated, and adverse events were generally mild/moderate in severity and transient. Treatment with taliglucerase alfa resulted in improvements (treatment-naïve patients) or stability (patients switched from imiglucerase) in visceral, haematologic, and biomarker parameters. Together, this comprehensive data set supports the treatment of adult and paediatric patients with GD

Long-term efficacy and safety results of taliglucerase alfa through 5years in adult treatment-naïve patients with Gaucher disease.

PubMed

Zimran, Ari; Durán, Gloria; Giraldo, Pilar; Rosenbaum, Hanna; Giona, Fiorina; Petakov, Milan; Terreros Muñoz, Eduardo; Solorio-Meza, Sergio Eduardo; Cooper, Peter A; Varughese, Sheeba; Alon, Sari; Chertkoff, Raul

2016-07-18

Taliglucerase alfa, the first available plant cell-expressed recombinant therapeutic protein, is an enzyme replacement therapy approved for Gaucher disease (GD). PB-06-001, a pivotal phase 3, multicenter, randomized, double-blind, parallel-dose study investigated taliglucerase alfa 30 or 60U/kg every other week through 9months in treatment-naïve adults with GD; 30-month extension study PB-06-003 followed. Patients completing PB-06-001 and PB-06-003 could continue treatment in PB-06-007. Nineteen patients enrolled in PB-06-007 (30U/kg, n=8; 60U/kg, n=9; dose adjusted, n=2); 17 completed 5 total years of treatment. In these 3 groups, respectively, taliglucerase alfa resulted in mean decreases in spleen volume (-8.7, -6.9, -12.4 multiples of normal), liver volume (-0.6, -0.4, -0.5 multiples of normal), chitotriosidase activity (-83.1%, -93.4%, -87.9%), and chemokine (CC motif) ligand 18 concentration (-66.7%, -83.3%, -78.9%), as well as mean increases in hemoglobin concentration (+2.1, +2.1, +1.8mg/dL) and platelet count (+31,871, +106,800, +34,000/mm 3 ). The most common adverse events were nasopharyngitis and arthralgia. Most adverse events were mild/moderate; no serious adverse events were considered treatment-related. These results demonstrate continued improvement of disease parameters during 5years of taliglucerase alfa therapy in 17 treatment-naive patients with no new safety concerns, extending the taliglucerase alfa clinical efficacy and safety dataset. This study was registered at www.clinicaltrials.gov as NCT01422187. Copyright © 2016 Elsevier Inc. All rights reserved.

Long-term velaglucerase alfa treatment in children with Gaucher disease type 1 naïve to enzyme replacement therapy or previously treated with imiglucerase.

PubMed

Smith, Laurie; Rhead, William; Charrow, Joel; Shankar, Suma P; Bavdekar, Ashish; Longo, Nicola; Mardach, Rebecca; Harmatz, Paul; Hangartner, Thomas; Lee, Hak-Myung; Crombez, Eric; Pastores, Gregory M

2016-02-01

Gaucher Disease type 1 (GD1) often manifests in childhood. Early treatment with enzyme replacement therapy (ERT) may prevent disease complications. We report the assessment of velaglucerase alfa ERT in pediatric GD1 patients who participated in a long-term extension study (HGT-GCB-044, ClinicalTrials.gov Identifier NCT00635427). Safety and efficacy were evaluated in pediatric patients receiving velaglucerase alfa 30-60U/kg by intravenous infusion every other week. In addition to key hematological and visceral efficacy assessments, exploratory assessments conducted specifically in pediatric patients included evaluation of height, bone age, bone marrow burden, and Tanner stage of puberty. The study included 24 pediatric patients. Fifteen patients were naïve to ERT on entry into the preceding trials TKT032 (12-month trial) or HGT-GCB-039 (9-month trial): in the preceding trials, ten of these 15 patients received velaglucerase alfa and five patients received imiglucerase ERT. Nine patients in the study were previously treated with imiglucerase for >30months and were switched to velaglucerase alfa in the preceding trial TKT034 (12-month trial). Cumulative ERT exposure in the clinical studies ranged from 2.0 to 5.8years. Three serious adverse events, including a fatal convulsion, were reported; none were deemed related to velaglucerase alfa. One patient tested positive for anti-velaglucerase alfa antibodies. An efficacy assessment at 24months showed that velaglucerase alfa had positive effects on primary hematological and visceral parameters in treatment-naïve patients, which were maintained with longer-term treatment. Disease parameters were stable in patients switched from long-term imiglucerase ERT. Exploratory results may suggest benefits of early treatment to enable normal growth in pediatric patients. The safety profile and clinical response seen in pediatric patients are consistent with results reported in adults. Copyright © 2016 Shire Development LLC

Tissue Localization of Glycosphingolipid Accumulation in a Gaucher Disease Mouse Brain by LC-ESI-MS/MS and High-Resolution MALDI Imaging Mass Spectrometry.

PubMed

Jones, E Ellen; Zhang, Wujuan; Zhao, Xueheng; Quiason, Cristine; Dale, Stephanie; Shahidi-Latham, Sheerin; Grabowski, Gregory A; Setchell, Kenneth D R; Drake, Richard R; Sun, Ying

2017-12-01

To better understand regional brain glycosphingolipid (GSL) accumulation in Gaucher disease (GD) and its relationship to neuropathology, a feasibility study using mass spectrometry and immunohistochemistry was conducted using brains derived from a GD mouse model (4L/PS/NA) homozygous for a mutant GCase (V394L [4L]) and expressing a prosaposin hypomorphic (PS-NA) transgene. Whole brains from GD and control animals were collected using one hemisphere for MALDI FTICR IMS analysis and the other for quantitation by LC-ESI-MS/MS. MALDI IMS detected several HexCers across the brains. Comparison with the brain hematoxylin and eosin (H&E) revealed differential signal distributions in the midbrain, brain stem, and CB of the GD brain versus the control. Quantitation of serial brain sections with LC-ESI-MS/MS supported the imaging results, finding the overall HexCer levels in the 4L/PS-NA brains to be four times higher than the control. LC-ESI-MS/MS also confirmed that the elevated hexosyl isomers were glucosylceramides rather than galactosylceramides. MALDI imaging also detected differential analyte distributions of lactosylceramide species and gangliosides in the 4L/PS-NA brain, which was validated by LC-ESI-MS/MS. Immunohistochemistry revealed regional inflammation, altered autophagy, and defective protein degradation correlating with regions of GSL accumulation, suggesting that specific GSLs may have distinct neuropathological effects.

A multicenter, open-label extension study of velaglucerase alfa in Japanese patients with Gaucher disease: Results after a cumulative treatment period of 24months.

PubMed

Ida, Hiroyuki; Tanaka, Akemi; Matsubayashi, Tomoko; Murayama, Kei; Hongo, Teruaki; Lee, Hak-Myung; Mellgard, Björn

2016-07-01

Enzyme replacement therapy (ERT) with exogenous glucocerebrosidase is indicated to treat symptomatic Gaucher disease (GD), a rare, inherited metabolic disorder. ERT with velaglucerase alfa, which is produced in a human cell line using gene activation technology, was studied in a 12-month phase III trial in Japanese patients with type 1 or 3 GD who were switched from imiglucerase ERT (n=6); the current, open-label, 12-month extension study was designed to assess longer-term safety and efficacy. Two adult and three pediatric patients (aged <18years) were enrolled into the extension study. Every-other-week intravenous infusions were administered for 63-78weeks at average doses between 51.5 and 60.7units/kg. Three non-serious adverse events were considered related to velaglucerase alfa treatment, but no patient discontinued from the study. Six serious but non-drug-related adverse events were reported. No patient tested positive for anti-velaglucerase alfa antibodies. Hemoglobin concentrations, platelet counts, and liver and spleen volumes (normalized to body weight) in these patients were generally stable over a cumulative 24-month period from the baseline of the parent trial. The data suggest that velaglucerase alfa was well tolerated and maintained clinical stability in Japanese GD patients over 2years after switching from imiglucerase. ClinicalTrials.gov identifier NCT01842841. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

A molecular analysis of the GBA gene in Caucasian South Africans with Parkinson's disease.

PubMed

Barkhuizen, Melinda; Anderson, David G; van der Westhuizen, Francois H; Grobler, Anne F

2017-03-01

The molecular basis of Parkinson's disease in South African population groups remains elusive. To date, substitutions in the GBA gene are the most common large-effect genetic risk factor for Parkinson's disease. The primary objective of this study was to determine the prevalence of GBA substitutions in South Africans with idiopathic Parkinson's disease. Participants were recruited from tertiary hospitals in the Gauteng Province in South Africa. All participants were screened for substitutions in GBA exon 8-11 and the full coding region was analysed in 20 participants. Peripheral β -glucocerebrosidase enzymatic activity of GBA -carriers was measured in mixed leukocytes. Of 105 Caucasian Parkinson's disease participants (82.7% Afrikaner) with an average age of disease onset of 61.9 ± 12.2 years and 40 controls (age 73.4 ± 12.4 years) were included. Heterozygous GBA substitutions were identified in 12.38% of affected participants (p.G35A, p.E326K, p.I368T, p.T369M, p.N370S, p.P387L and p.K441N) and 5.00% of controls (p.E326K and p.T369M). The substitutions ranged from predicted benign to moderately damaging; with p.E326K and p.T369M most prevalent, followed by the Afrikaner Gaucher disease substitution p.P387L. Severe Gaucher disease mutations, like p.L444P, were absent in this cohort. Enzyme activity analysis revealed a nonsignificant reduction in the GBA -Parkinson's disease individuals (14.49 ± 2.30 nmol/h/mg protein vs. 15.98 ± 3.06 nmol/h/mg in control samples). GBA substitutions occur in both young-onset and late-onset Parkinson's cases in the cohort. Mild GBA substitutions that may not cause Gaucher disease were a common risk factor for Parkinson's disease in the participant group.

Mendelian diseases among Roman Jews: implications for the origins of disease alleles.

PubMed

Oddoux, C; Guillen-Navarro, E; Ditivoli, C; Dicave, E; Cilio, M R; Clayton, C M; Nelson, H; Sarafoglou, K; McCain, N; Peretz, H; Seligsohn, U; Luzzatto, L; Nafa, K; Nardi, M; Karpatkin, M; Aksentijevich, I; Kastner, D; Axelrod, F; Ostrer, H

1999-12-01

The Roman Jewish community has been historically continuous in Rome since pre-Christian times and may have been progenitor to the Ashkenazi Jewish community. Despite a history of endogamy over the past 2000 yr, the historical record suggests that there was admixture with Ashkenazi and Sephardic Jews during the Middle Ages. To determine whether Roman and Ashkenazi Jews shared common signature mutations, we tested a group of 107 Roman Jews, representing 176 haploid sets of chromosomes. No mutations were found for Bloom syndrome, BRCA1, BRCA2, Canavan disease, Fanconi anemia complementation group C, or Tay-Sachs disease. Two unrelated individuals were positive for the 3849 + 10C->T cystic fibrosis mutation; one carried the N370S Gaucher disease mutation, and one carried the connexin 26 167delT mutation. Each of these was shown to be associated with the same haplotype of tightly linked microsatellite markers as that found among Ashkenazi Jews. In addition, 14 individuals had mutations in the familial Mediterranean fever gene and three unrelated individuals carried the factor XI type III mutation previously observed exclusively among Ashkenazi Jews. These findings suggest that the Gaucher, connexin 26, and familial Mediterranean fever mutations are over 2000 yr old, that the cystic fibrosis 3849 + 10kb C->T and factor XI type III mutations had a common origin in Ashkenazi and Roman Jews, and that other mutations prevalent among Ashkenazi Jews are of more recent origin.

Use of complementary and alternative medicine by patients with lysosomal storage diseases.

PubMed

Balwani, Manisha; Fuerstman, Laura; Desnick, Robert J; Buckley, Brian; McGovern, Margaret M

2009-10-01

To evaluate the extent of complementary and alternative medicine use and perceived effectiveness in patients with lysosomal storage diseases. A 26-item survey was distributed to 495 patients with type 1 Gaucher, Fabry, and type B Niemann-Pick diseases who were seen at the Lysosomal Storage Disease Program at the Mount Sinai School of Medicine. Survey responses were entered into an access database and analyzed using descriptive statistics. Surveys were completed by 167 respondents with an overall response rate of 34%. Complementary and alternative medicines were used by 45% of patients with type 1 Gaucher disease, 41% of patients with Fabry disease, and 47% of patients with type B Niemann-Pick for symptoms related to their disease. Complementary and alternative medicines were used most frequently by adult females (55%), in patients who reported having one or more invasive procedures due to their disease, patients who use one or more conventional medical therapies, or those with depression and/or anxiety. Overall perceived effectiveness of complementary and alternative medicine supplements was low; however, complementary and alternative medicine therapies were perceived as effective. Complementary and alternative medicines are commonly used among patients with lysosomal storage diseases. Assessment of the effectiveness of these approaches in the lysosomal storage diseases is needed, and physicians should be aware of complementary and alternative medicine therapies used by patients to evaluate safety and possible drug interactions.

Minos-insertion mutant of the Drosophila GBA gene homologue showed abnormal phenotypes of climbing ability, sleep and life span with accumulation of hydroxy-glucocerebroside.

PubMed

Kawasaki, Haruhisa; Suzuki, Takahiro; Ito, Kumpei; Takahara, Tsubasa; Goto-Inoue, Naoko; Setou, Mitsutoshi; Sakata, Kazuki; Ishida, Norio

2017-05-30

Gaucher's disease in humans is considered a deficiency of glucocerebrosidase (GlcCerase) that result in the accumulation of its substrate, glucocerebroside (GlcCer). Although mouse models of Gaucher's disease have been reported from several laboratories, these models are limited due to the perinatal lethality of GlcCerase gene. Here, we examined phenotypes of Drosophila melanogaster homologues genes of the human Gaucher's disease gene by using Minos insertion. One of two Minos insertion mutants to unknown function gene (CG31414) accumulates the hydroxy-GlcCer in whole body of Drosophila melanogaster. This mutant showed abnormal phenotypes of climbing ability and sleep, and short lifespan. These abnormal phenotypes are very similar to that of Gaucher's disease in human. In contrast, another Minos insertion mutant (CG31148) and its RNAi line did not show such severe phenotype as observed in CG31414 gene mutation. The data suggests that Drosophila CG31414 gene mutation might be useful for unraveling the molecular mechanism of Gaucher's disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Gaucher Disease

MedlinePlus

... the most common form, causes liver and spleen enlargement, bone pain and broken bones, and, sometimes, lung ... type 3, there may be liver and spleen enlargement. The brain is gradually affected. It usually starts ...

Evidence for a link between sphingolipid metabolism and expression of CD1d and MHC-class II: monocytes from Gaucher disease patients as a model.

PubMed

Balreira, Andrea; Lacerda, Lúcia; Miranda, Clara Sá; Arosa, Fernando A

2005-06-01

Gaucher disease (GD) is an autosomal recessive inherited defect of the lysosomal enzyme glucocerebrosidase (GluCerase) that leads to glucosylceramide (GluCer) accumulation. We previously demonstrated the existence of imbalances in certain lymphocyte populations in GD patients. We now show that GluCerase-deficient monocytes from GD patients or monocytes from healthy subjects treated with conduritol-B-epoxide (CBE), an irreversible inhibitor of GluCerase activity, display high levels of surface expression of the lipid-binding molecule CD1d. GluCerase-deficient monocytes from GD patients also showed increased surface expression of major histocompatibility complex (MHC)-class II, but not of other lysosomal trafficking molecules, such as CD63 and MHC-class I. However, CD1d and MHC-class II mRNA levels were not increased. GluCerase-deficient monocytes from GD patients undergoing enzyme replacement therapy also exhibited increased levels of CD1d and MHC-class II and imbalances in the percentage of CD4+, CD8+, and Valpha24+ T cells. Interestingly, follow-up studies revealed that enzyme replacement therapy induced a decrease in MHC-class II expression and partial correction of the CD4+ T cell imbalances. These results reveal a new link between sphingolipid accumulation in monocytes and the expression of certain MHC molecules that may result in imbalances of regulatory T cell subsets. These immunological anomalies may contribute to the clinical heterogeneity in GD patients.

[New therapies for children affected by bone diseases].

PubMed

Ballhausen, Diana; Dépraz, Nuria Garcia; Kern, Ilse; Unger, Sheila; Bonafé, Luisa

2012-02-22

Considerable progress has been achieved in recent years in treating children affected by bone diseases. Advances in the understanding of the molecular pathophysiology of genetic bone diseases have led to the development of enzyme replacement therapies for various lysosomal storage diseases, following the breakthrough initiated in treating Gaucher disease. Clinical studies are underway with tailored molecules correcting bone fragility and alleviating chronic bone pain and other manifestations of hypophosphatasia, or promoting growth of long bones in achondroplasia patients. We further report our very encouraging experience with intravenous bisphosphonate treatment in children suffering from secondary osteopenia and the high prevalence of calcium and vitamin D deficits in these severely disabled children.

Lysosomal storage diseases: natural history and ethical and economic aspects.

PubMed

Beutler, Ernest

2006-07-01

Potential treatment for lysosomal diseases now includes enzyme replacement therapy, substrate reduction therapy, and chaperone therapy. The first two of these have been implemented commercially, and the spectrum of diseases that are now treatable has expanded from Gaucher disease to include several other disorders. Treatment of these diseases is extremely costly. We explore some of the reasons for the high cost and discuss how, by proper selection of patients and appropriate dosing, the economic burden on society of treating these disease may be ameliorated, at least in part. However, the cost of treating rare diseases is a growing problem that society needs to address.

A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase.

PubMed

Pastores, Gregory M; Petakov, Milan; Giraldo, Pilar; Rosenbaum, Hanna; Szer, Jeffrey; Deegan, Patrick B; Amato, Dominick J; Mengel, Eugen; Tan, Ee Shien; Chertkoff, Raul; Brill-Almon, Einat; Zimran, Ari

2014-12-01

Taliglucerase alfa is a β-glucosidase enzyme replacement therapy (ERT) approved in the US and other countries for the treatment of Gaucher disease (GD) in adults and is approved in pediatric and adult patients in Australia and Canada. It is the first approved plant cell-expressed recombinant human protein. A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2years. Patients with stable disease were offered taliglucerase alfa treatment using the same dose (9-60U/kg body weight) and regimen of administration (every 2weeks) as imiglucerase. This report summarizes results from 26 adult and 5 pediatric patients who participated in the trial. Disease parameters (spleen and liver volumes, hemoglobin concentration, platelet count, and biomarker levels) remained stable through 9months of treatment in adults and children following the switch from imiglucerase. All treatment-related adverse events were mild or moderate in severity and transient in nature. Exploratory parameters of linear growth and development showed positive outcomes in pediatric patients. These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. This trial was registered at www.clinicaltrials.gov as # NCT00712348. Copyright © 2014 Elsevier Inc. All rights reserved.

Application of Fourier transform infrared spectroscopy to biomolecular profiling of cultured fibroblast cells from Gaucher disease patients: A preliminary investigation.

PubMed

Igci, Nasit; Sharafi, Parisa; Demiralp, Duygu Ozel; Demiralp, Cemil Ozerk; Yuce, Aysel; Emre, Serap Dokmeci

2017-10-01

Gaucher disease (GD) is defined as an autosomal recessive disorder resulting from the deficiency of glucocerebrosidase (E.C. 3.2.1.45). Glucocerebrosidase is responsible for the degradation of glucosylceramide into ceramide and glucose. The deficiency of this enzyme results in the accumulation of undegraded glucosylceramide, almost exclusively in macrophages. With Fourier transform infrared (FTIR) spectroscopy, the complete molecular diversity of the samples can be studied comparatively and the amount of the particular materials can be determined. Also, the secondary structure ratios of proteins can be determined by analysing the amide peaks. The primary aim of this study is to introduce FTIR-ATR spectroscopy technique to GD research for the first time in the literature and to assess its potential as a new molecular method. Primary fibroblast cell cultures obtained from biopsy samples were used, since this material is widely used for the diagnosis of GD. Intact cells were placed onto a FTIR-ATR crystal and dried by purging nitrogen gas. Spectra were recorded in the mid-infrared region between 4500-850 cm-1 wavenumbers. Each peak in the spectra was assigned to as organic biomolecules according to their chemical bond information. A quantitative analysis was performed using peak areas and we also used a hierarchical cluster analysis as a multivariate spectral analysis. We obtained FTIR spectra of fibroblast samples and assigned the biomolecule origins of the peaks. We observed individual heterogeneity in FTIR spectra of GD fibroblast samples, confirming the well-known phenotypic heterogeneity in GD at the molecular level. Significant alterations in protein, lipid and carbohydrate levels related to the enzyme replacement therapy were also observed, which is also supported by cluster analysis. Our results showed that the application of FTIR spectroscopy to GD research deserves more attention and detailed studies with an increased sample size in order to evaluate its

Inherited disorders in the Afrikaner population of southern Africa. Part I. Historical and demographic background, cardiovascular, neurological, metabolic and intestinal conditions.

PubMed

Botha, M C; Beighton, P

1983-10-08

Certain genetic disorders occur with unusually high frequency in the Afrikaner population of southern Africa. Conditions of this type (reviewed in Part I of this article) include familial hypercholesterolaemia, progressive familial heart block, Huntington's chorea, porphyria variegata, Gaucher's disease, cystic fibrosis and familial colonic polyposis. This genetic situation is explicable to some extent on the basis of the demographic development of the Afrikaner population during the 14 generations since the arrival of the first immigrants from Holland more than 330 years ago.

Significant and continuous improvement in bone mineral density among type 1 Gaucher disease patients treated with velaglucerase alfa: 69-month experience, including dose reduction.

PubMed

Elstein, Deborah; Foldes, A Joseph; Zahrieh, David; Cohn, Gabriel M; Djordjevic, Maja; Brutaru, Costin; Zimran, Ari

2011-06-15

Since bone pathology is a major concern in type 1 Gaucher disease (GD1), we evaluated bone mineral density (BMD) in adults receiving velaglucerase alfa in the seminal Phase I/II and extension trial. Ten treatment-naïve symptomatic patients with GD1 (four men, six women; median age 35years, range 18-62years) were included; of these, four patients were receiving bisphosphonates at enrollment. Using WHO criteria to classify the lumbar spine (LS) and femoral neck (FN) BMD T-scores, respectively, one (10%) and four (40%) patients had osteoporosis; eight (80%) and five (50%) had osteopenia; and one each (10%) was in the normal range, at baseline. By Month 69, two LS and one FN osteopenic patients normalized and one FN osteoporotic patient became osteopenic; change was seen only in patients not receiving bisphosphonates. Significant improvements in BMD Z-scores were seen at the LS by Month 24 and at the FN by Month 33 and were continuous thereafter. In linear mixed models, Z-scores were significantly lower than the reference population at baseline and improved significantly with treatment (LS and FN both P<0.01); analysis of the subgroup of patients not receiving bisphosphonates showed similar results. In conclusion, in this small cohort, velaglucerase alfa was associated with clinically meaningful and statistically significant LS and FN BMD improvements as early as Month 24 (LS) and 33 (FN), despite dose reduction and significant baseline skeletal pathology. These results suggest that velaglucerase alfa may hold promise in the management of skeletal pathology associated with GD1. Copyright © 2011 Elsevier Inc. All rights reserved.

Association of Radon Background and Total Background Ionizing Radiation with Alzheimer's Disease Deaths in U.S. States.

PubMed

Lehrer, Steven; Rheinstein, Peter H; Rosenzweig, Kenneth E

2017-01-01

Exposure of the brain to ionizing radiation might promote the development of Alzheimer's disease (AD). Analysis of AD death rates versus radon background radiation and total background radiation in U.S. states. Total background, radon background, cosmic and terrestrial background radiation measurements are from Assessment of Variations in Radiation Exposure in the United States and Report No. 160 - Ionizing Radiation Exposure of the Population of the United States. 2013 AD death rates by U.S. state are from the Alzheimer's Association. Radon background ionizing radiation was significantly correlated with AD death rate in 50 states and the District of Columbia (r = 0.467, p = 0.001). Total background ionizing radiation was also significantly correlated with AD death rate in 50 states and the District of Columbia (r = 0.452, p = 0.001). Multivariate linear regression weighted by state population demonstrated that AD death rate was significantly correlated with radon background (β= 0.169, p < 0.001), age (β= 0.231, p < 0.001), hypertension (β= 0.155, p < 0.001), and diabetes (β= 0.353, p < 0.001). Our findings, like other studies, suggest that ionizing radiation is a risk factor for AD. Intranasal inhalation of radon gas could subject the rhinencephalon and hippocampus to damaging radiation that initiates AD. The damage would accumulate over time, causing age to be a powerful risk factor.

Sphingolipid metabolism diseases.

PubMed

Kolter, Thomas; Sandhoff, Konrad

2006-12-01

Human diseases caused by alterations in the metabolism of sphingolipids or glycosphingolipids are mainly disorders of the degradation of these compounds. The sphingolipidoses are a group of monogenic inherited diseases caused by defects in the system of lysosomal sphingolipid degradation, with subsequent accumulation of non-degradable storage material in one or more organs. Most sphingolipidoses are associated with high mortality. Both, the ratio of substrate influx into the lysosomes and the reduced degradative capacity can be addressed by therapeutic approaches. In addition to symptomatic treatments, the current strategies for restoration of the reduced substrate degradation within the lysosome are enzyme replacement therapy (ERT), cell-mediated therapy (CMT) including bone marrow transplantation (BMT) and cell-mediated "cross correction", gene therapy, and enzyme-enhancement therapy with chemical chaperones. The reduction of substrate influx into the lysosomes can be achieved by substrate reduction therapy. Patients suffering from the attenuated form (type 1) of Gaucher disease and from Fabry disease have been successfully treated with ERT.

The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow.

PubMed

Goker-Alpan, Ozlem; Masdeu, Joseph C; Kohn, Philip D; Ianni, Angela; Lopez, Grisel; Groden, Catherine; Chapman, Molly C; Cropp, Brett; Eisenberg, Daniel P; Maniwang, Emerson D; Davis, Joie; Wiggs, Edythe; Sidransky, Ellen; Berman, Karen F

2012-08-01

Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls. Patients with GBA mutations generally have an earlier onset of Parkinson disease and more cognitive impairment than those without GBA mutations. We investigated whether GBA mutations alter the neurobiology of Parkinson disease, studying brain dopamine synthesis and resting regional cerebral blood flow in 107 subjects (38 women, 69 men). We measured dopamine synthesis with (18)F-fluorodopa positron emission tomography, and resting regional cerebral blood flow with H(2)(15)O positron emission tomography in the wakeful, resting state in four study groups: (i) patients with Parkinson disease and Gaucher disease (n = 7, average age = 56.6 ± 9.2 years); (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 ± 7.1 years); (iii) patients with Gaucher disease without parkinsonism, but with a family history of Parkinson disease (n = 14, 52.6 ± 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson disease (n = 7, 50.1 ± 18 years). We compared each study group with a matched control group. Data were analysed with region of interest and voxel-based methods. Disease duration and Parkinson disease functional and staging scores were similar in the two groups with parkinsonism, as was striatal dopamine synthesis: both had greatest loss in the caudal striatum (putamen Ki loss: 44 and 42%, respectively), with less reduction in the caudate (20 and 18% loss). However, the group with both Parkinson and Gaucher diseases showed decreased resting regional cerebral blood flow in the lateral parieto-occipital association cortex and precuneus bilaterally. Furthermore, two subjects with Gaucher disease without parkinsonian manifestations showed diminished striatal dopamine. In conclusion

The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow

PubMed Central

Goker-Alpan, Ozlem; Masdeu, Joseph C.; Kohn, Philip D.; Ianni, Angela; Lopez, Grisel; Groden, Catherine; Chapman, Molly C.; Cropp, Brett; Eisenberg, Daniel P.; Maniwang, Emerson D.; Davis, Joie; Wiggs, Edythe; Berman, Karen F.

2012-01-01

Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls. Patients with GBA mutations generally have an earlier onset of Parkinson disease and more cognitive impairment than those without GBA mutations. We investigated whether GBA mutations alter the neurobiology of Parkinson disease, studying brain dopamine synthesis and resting regional cerebral blood flow in 107 subjects (38 women, 69 men). We measured dopamine synthesis with 18F-fluorodopa positron emission tomography, and resting regional cerebral blood flow with H215O positron emission tomography in the wakeful, resting state in four study groups: (i) patients with Parkinson disease and Gaucher disease (n = 7, average age = 56.6 ± 9.2 years); (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 ± 7.1 years); (iii) patients with Gaucher disease without parkinsonism, but with a family history of Parkinson disease (n = 14, 52.6 ± 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson disease (n = 7, 50.1 ± 18 years). We compared each study group with a matched control group. Data were analysed with region of interest and voxel-based methods. Disease duration and Parkinson disease functional and staging scores were similar in the two groups with parkinsonism, as was striatal dopamine synthesis: both had greatest loss in the caudal striatum (putamen Ki loss: 44 and 42%, respectively), with less reduction in the caudate (20 and 18% loss). However, the group with both Parkinson and Gaucher diseases showed decreased resting regional cerebral blood flow in the lateral parieto-occipital association cortex and precuneus bilaterally. Furthermore, two subjects with Gaucher disease without parkinsonian manifestations showed diminished striatal dopamine. In conclusion, the

Miglustat (NB-DNJ) works as a chaperone for mutated acid beta-glucosidase in cells transfected with several Gaucher disease mutations.

PubMed

Alfonso, Pilar; Pampín, Sandra; Estrada, Jorge; Rodríguez-Rey, José Carlos; Giraldo, Pilar; Sancho, Javier; Pocoví, Miguel

2005-01-01

Gaucher disease (GD) is a disorder of glycosphinglipid metabolism caused by deficiency of lysosomal acid beta-glucosidase (GC), resulting in progressive deposition of glucosylceramide in macrophages. The glucose analogue, N-butyl-deoxynojirimycin (NB-DNJ, Miglustat), is an inhibitor of the ceramide-specific glucosyltransferase (CSG) which catalyzes the first step of glycosphingolipids biosynthesis and is currently approved for the oral treatment of type 1 GD. Using site-directed mutagenesis, we constructed plasmids containing wild-type and several mutations in glucocerebrosidase (GBA) gene. The plasmids were transfected into COS-7 cells and stable transfected cell lines were obtained by geneticin (G418) selection. Cells were cultured during 6 days with medium with or without 10 microM NB-DNJ. The addition of NB-DNJ to COS-7 cell medium leads to 1.3-, 2.1-, 2.3-, 3.6-, and 9.9-fold increase in the activity of S364R, wild-type, N370S, V15M, and M123T GC, respectively. However, no significant changes were observed in the activity of the L444P, L336P, and S465del mutated proteins, but a small decrease in the rare P266L variant was observed. These results suggest that NB-DNJ, in addition to the inhibitory effect on CSG, also works as a "chemical chaperone", increasing the activity of acid beta-glucosidase of wild-type and several GC mutated proteins, including the most frequent N370S mutation. The specific location of the Miglustat binding site in GC is unknown. Potential binding sites in the enzyme have been searched for using computational molecular docking. The searching strategy identified three potential GC binding sites for Miglustat, one being the substrate-binding site of the enzyme, which was the best-ranked site by AutoDock program. Therefore, it is possible that Miglustat exerts its chaperoning activity on acid beta-glucosidase by acting as an inhibitor bound at the active site. This increase on the activity of the acid beta-glucosidase would imply that

Quantification of Bone Marrow Involvement in Treated Gaucher Disease With Proton MR Spectroscopy: Correlation With Bone Marrow MRI Scores and Clinical Status.

PubMed

Jaramillo, Diego; Bedoya, Maria A; Wang, Dah-Jyuu; Pena, Andres H; Delgado, Jorge; Jaimes, Camilo; Ho-Fung, Victor; Kaplan, Paige

2015-06-01

The objective of our study was to use proton MR spectroscopy (MRS) to quantitatively evaluate bone marrow infiltration by measuring the fat fraction (FF) and to compare the FF with semiquantitative bone marrow MRI scores and clinical status in children treated for type 1 Gaucher disease (GD). Over a 2-year period, we prospectively evaluated 10 treated GD patients (six males, four females; median age, 15.1 years) and 10 healthy age-matched control subjects (five males, five females; median age, 15.3 years) using 3-T proton MRS of L5 and the femoral neck. Water and lipid AUCs were measured to calculate the FF. Two blinded pediatric musculoskeletal radiologists performed a semiquantitative analysis of the conventional MR images using the bone marrow burden score and modified Spanish MRI score. We evaluated symptoms, spleen and liver volumes, platelet levels, hemoglobin levels, and bone complications. In the femur, the FF was higher in the control subjects (median, 0.71) than the GD patients (0.54) (p = 0.02). In L5, the difference in FF--higher FF in control subjects (0.37) than in GD patients (0.26)--was not significant (p = 0.16). In both groups and both regions, the FF increased with patient age (p < 0.02). Semiquantitative scores showed no differences between control subjects and treated GD patients (p > 0.11). Eight of 10 GD patients were asymptomatic and two had chronic bone pain. The median age of patients at symptom onset was 4.0 years, the median age of patients at the initiation of enzyme replacement therapy was 4.3 years, and the median treatment duration was 10.2 years. Hemoglobin level, platelet count, and liver volume at MRI were normal. Mean pretreatment spleen volume (15.4-fold above normal) decreased to 2.8-fold above normal at the time of MRI (p = 0.01). Proton MRS detected FF differences that were undetectable using conventional MRI; for that reason, proton MRS can be used to optimize treatment of GD patients.

Enzyme replacement therapy with taliglucerase alfa: 36-month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase.

PubMed

Pastores, Gregory M; Shankar, Suma P; Petakov, Milan; Giraldo, Pilar; Rosenbaum, Hanna; Amato, Dominick J; Szer, Jeffrey; Chertkoff, Raul; Brill-Almon, Einat; Zimran, Ari

2016-07-01

Taliglucerase alfa is the first available plant cell-expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB-06-002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB-06-002 who continued receiving taliglucerase alfa in extension Study PB-06-003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB-06-003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30-33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, -1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), -19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, -51.5% (±8.1%; n = 10); and CCL18 concentration, -36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment-related adverse events were mild or moderate and transient. The 36-month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661-665, 2016. © 2016 Wiley Periodicals, Inc. © 2016 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.

Prevalence of glucocerebrosidase mutations in the Israeli Ashkenazi Jewish population.

PubMed

Horowitz, M; Pasmanik-Chor, M; Borochowitz, Z; Falik-Zaccai, T; Heldmann, K; Carmi, R; Parvari, R; Beit-Or, H; Goldman, B; Peleg, L; Levy-Lahad, E; Renbaum, P; Legum, S; Shomrat, R; Yeger, H; Benbenisti, D; Navon, R; Dror, V; Shohat, M; Magal, N; Navot, N; Eyal, N

1998-01-01

Gaucher disease is the most prevalent inherited disease among Ashkenazi Jews. It is very heterogeneous due to a large number of mutations within the glucocerebrosidase gene, whose impaired activity is the cause for this disease. Aiming at determining Gaucher carrier frequency among the Ashkenazi Jewish population in Israel, 1,208 individuals were molecularly diagnosed for six mutations known to occur among Ashkenazi Jewish Gaucher patients, using the newly developed Pronto Gaucher kit. The following mutations were tested: N370S, 84GG, IVS2+1, D409H, L444P, and V394L. Molecular testing of these mutations also allows identification of the recTL allele. The results indicated that Gaucher carrier frequency is 1:17 within the tested population. The prevalence of N370S carriers is 1:17.5. This implies that approximately 1:1225 Ashkenazi Jews will be homozygous for the N370S mutation. Actually, in our study of 1,208 individuals one was found to be homozygous for the N370S mutation. The actual number of known Ashkenazi Jewish Gaucher patients with this genotype is much lower than that expected according to the frequency of the N370S mutation, suggesting a low penetrance of this mutation. Results of loading experiments in cells homozygous for the N370S mutation, as well as cells homozygous for the L444P and the D409H mutations, exemplified this phenomenon.

Niemann-Pick disease, Type C: evidence for the deficiency of an activating factor stimulating sphingomyelin and glucocerebroside degradation.

PubMed

Christomanou, H

1980-10-01

1) Qualitative lipid analyses by thin-layer chromatography of 4 Niemann-Pick type C spleens confirmed sphingomyelin accumulation together with increase in the amount of glucocerebroside. 2) In the presence of crude sodium taurocholate as detergent, sphingomyelin degradation rates of normal and Niemann-Pick type C-cultured fibroblasts were fairly close under standard conditions at pH 5.0. In the absence of sodium taurocholate, sphingomyelinase activity was optimal at pH 4.0. Sphingomyelinase activities of fibroblasts from two patients with Niemann-Pick disease type C measured without detergent, were about 30% of that of controls. 3) Extracts from Gaucher spleen heated to 90 degrees C and devoid of sphingomyelinase activity stimulated at the optimal pH of 4.0 sphingomyelin degradation by cultured normal fibroblasts (2--4-fold, Niemann-Pick type C fibroblasts (5--9-fold), whereas similarly treated extracts from Niemann-Pick type C spleen showed no stimulation of sphingomyelin catabolism. Heated extracts from normal human spleen exhibited a smaller stimulation than that shown by Gaucher spleen. This stimulating effect could not be observed in fibroblasts from patients suffering from Niemann-Pick type B (sphingomyelinase defect). 4) Heat-treated extracts of Gaucher spleen were fractionated by ion exchange chromatography, isoelectric focusing and gel filtration. The active fractions obtained by these procedures stimulated sphingomyelin as well as glucocerebroside degradation and were absent from the corresponding Niemann-Pick type C preparations. Enriched activator preparations of Gaucher spleen stimulated sphingomyelinase activity of Niemann-Pick type C fibroblasts 25--38-fold and that of normal cells 3-fold. 5) The activating factor had an isoelectric point of 4.0 and an apparent molecular weight, as estimated by gel filtration, of 25000. Treatment with pronase E abolished its activity.

The background puzzle: how identical mutations in the same gene lead to different disease symptoms.

PubMed

Kammenga, Jan E

2017-10-01

Identical disease-causing mutations can lead to different symptoms in different people. The reason for this has been a puzzling problem for geneticists. Differential penetrance and expressivity of mutations has been observed within individuals with different and similar genetic backgrounds. Attempts have been made to uncover the underlying mechanisms that determine differential phenotypic effects of identical mutations through studies of model organisms. From these studies evidence is accumulating that to understand disease mechanism or predict disease prevalence, an understanding of the influence of genetic background is as important as the putative disease-causing mutations of relatively large effect. This review highlights current insights into phenotypic variation due to gene interactions, epigenetics and stochasticity in model organisms, and discusses their importance for understanding the mutational effect on disease symptoms. © 2017 Federation of European Biochemical Societies.

Background sequence characteristics influence the occurrence and severity of disease-causing mtDNA mutations

PubMed Central

Wei, Wei; Hudson, Gavin

2017-01-01

Inherited mitochondrial DNA (mtDNA) mutations have emerged as a common cause of human disease, with mutations occurring multiple times in the world population. The clinical presentation of three pathogenic mtDNA mutations is strongly associated with a background mtDNA haplogroup, but it is not clear whether this is limited to a handful of examples or is a more general phenomenon. To address this, we determined the characteristics of 30,506 mtDNA sequences sampled globally. After performing several quality control steps, we ascribed an established pathogenicity score to the major alleles for each sequence. The mean pathogenicity score for known disease-causing mutations was significantly different between mtDNA macro-haplogroups. Several mutations were observed across all haplogroup backgrounds, whereas others were only observed on specific clades. In some instances this reflected a founder effect, but in others, the mutation recurred but only within the same phylogenetic cluster. Sequence diversity estimates showed that disease-causing mutations were more frequent on young sequences, and genomes with two or more disease-causing mutations were more common than expected by chance. These findings implicate the mtDNA background more generally in recurrent mutation events that have been purified through natural selection in older populations. This provides an explanation for the low frequency of mtDNA disease reported in specific ethnic groups. PMID:29253894

Multi-center analysis of glucocerebrosidase mutations in Parkinson disease

PubMed Central

Sidransky, Ellen; Nalls, Michael A.; Aasly, Jan O.; Aharon-Peretz, Judith; Annesi, Grazia; Barbosa, Egberto Reis; Bar-Shira, Anat; Berg, Daniela; Bras, Jose; Brice, Alexis; Chen, Chiung-Mei; Clark, Lorraine N.; Condroyer, Christel; De Marco, Elvira Valeria; Dürr, Alexandra; Eblan, Michael J.; Fahn, Stanley; Farrer, Matthew; Fung, Hon-Chung; Gan-Or, Ziv; Gasser, Thomas; Gershoni-Baruch, Ruth; Giladi, Nir; Griffith, Alida; Gurevich, Tanya; Januario, Cristina; Kropp, Peter; Lang, Anthony E.; Lee-Chen, Guey-Jen; Lesage, Suzanne; Marder, Karen; Mata, Ignacio F.; Mirelman, Anat; Mitsui, Jun; Mizuta, Ikuko; Nicoletti, Giuseppe; Oliveira, Catarina; Ottman, Ruth; Orr-Urtreger, Avi; Pereira, Lygia V.; Quattrone, Aldo; Rogaeva, Ekaterina; Rolfs, Arndt; Rosenbaum, Hanna; Rozenberg, Roberto; Samii, Ali; Samaddar, Ted; Schulte, Claudia; Sharma, Manu; Singleton, Andrew; Spitz, Mariana; Tan, Eng-King; Tayebi, Nahid; Toda, Tatsushi; Troiano, André; Tsuji, Shoji; Wittstock, Matthias; Wolfsberg, Tyra G.; Wu, Yih-Ru; Zabetian, Cyrus P.; Zhao, Yi; Ziegler, Shira G.

2010-01-01

Background Recent studies indicate an increased frequency of mutations in the gene for Gaucher disease, glucocerebrosidase (GBA), among patients with Parkinson disease. An international collaborative study was conducted to ascertain the frequency of GBA mutations in ethnically diverse patients with Parkinson disease. Methods Sixteen centers participated, including five from the Americas, six from Europe, two from Israel and three from Asia. Each received a standard DNA panel to compare genotyping results. Genotypes and phenotypic data from patients and controls were analyzed using multivariate logistic regression models and the Mantel Haenszel procedure to estimate odds ratios (ORs) across studies. The sample included 5691 patients (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews). Results All 16 centers could detect GBA mutations, L444P and N370S, and the two were found in 15.3% of Ashkenazi patients with Parkinson disease (ORs = 4.95 for L444P and 5.62 for N370S), and in 3.2% of non-Ashkenazi patients (ORs = 9.68 for L444P and 3.30 for N370S). GBA was sequenced in 1642 non-Ashkenazi subjects, yielding a frequency of 6.9% for all mutations, demonstrate that limited mutation screens miss half the mutant alleles. The presence of any GBA mutation was associated with an OR of 5.43 across studies. Clinically, although phenotypes varied, subjects with a GBA mutation presented earlier, and were more likely to have affected relatives and atypical manifestations. Conclusion Data collected from sixteen centers demonstrate that there is a strong association between GBA mutations and Parkinson disease. PMID:19846850

Stem Cell Transplant for Inborn Errors of Metabolism

ClinicalTrials.gov

2017-12-03

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

Analysis of the multiple forms of Gaucher spleen sphingolipid activator protein 2.

PubMed Central

Paton, B C; Poulos, A

1988-01-01

Gaucher spleen sphingolipid activator protein 2 was fractionated into concanavalin A binding- and non-binding fractions. These fractions each contained several bands on non-denaturing polyacrylamide gel electrophoresis (PAGE). The two fractions were further fractionated by electroblotting the proteins from preparative gels onto nitrocellulose, staining with Ponceau S to locate the bands of protein and then eluting the protein components from the nitrocellulose. A total of ten fractions, each containing only one or two major components, was collected. All of these subfractions activated beta-glucocerebrosidase and sphingomyelinase and most subfractions also activated beta-galactocerebrosidase. The structural relationship of the bands was investigated using endoglycosidase digestions. The results indicated that the two bands with the fastest mobility on non-denaturing PAGE did not contain any carbohydrate. The remaining bands showed only limited or partial digestion with endoglycosidase H and endoglycosidase D, but were readily hydrolysed with endoglycosidase F. The products of these digestions included bands with similar mobilities to the non-carbohydrate containing bands. Images Fig. 1. Fig. 2. Fig. 3. PMID:3178760

Parkinsonism Associated with Glucocerebrosidase Mutation

PubMed Central

Sunwoo, Mun-Kyung; Kim, Seung-Min; Lee, Sarah

2011-01-01

Background Gaucher's disease is an autosomal recessive, lysosomal storage disease caused by mutations of the β-glucocerebrosidase gene (GBA). There is increasing evidence that GBA mutations are a genetic risk factor for the development of Parkinson's disease (PD). We report herein a family of Koreans exhibiting parkinsonism-associated GBA mutations. Case Report A 44-year-old woman suffering from slowness and paresthesia of the left arm for the previous 1.5years, visited our hospital to manage known invasive ductal carcinoma. During a preoperative evaluation, she was diagnosed with Gaucher's disease and double mutations of S271G and R359X in GBA. Parkinsonian features including low amplitude postural tremors, rigidity, bradykinesia and shuffling gait were observed. Genetic analysis also revealed that her older sister, who had also been diagnosed with PD and had been taking dopaminergic drugs for 8-years, also possessed a heterozygote R359X mutation in GBA. 18F-fluoropropylcarbomethoxyiodophenylnortropane positron-emission tomography in these patients revealed decreased uptake of dopamine transporter in the posterior portion of the bilateral putamen. Conclusions This case study demonstrates Korean familial cases of PD with heterozygote mutation of GBA, further supporting the association between PD and GBA mutation. PMID:21779299

Specific Genetic Disorders

MedlinePlus

... Gaucher Disease Hemochromatosis Hemophilia Holoprosencephaly Huntington's disease Klinefelter syndrome Marfan syndrome Myotonic Dystrophy Neurofibromatosis Noonan Syndrome Osteogenesis Imperfecta ...

Learning about Gaucher Disease

MedlinePlus

... Links for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for Teachers ... at the Medical Genetics Branch of the National Human Genome Research Institute by Dr. Ellen Sidransky. Dr. Sidransky ...

Plasma chitotriosidase activity versus CCL18 level for assessing type I Gaucher disease severity: protocol for a systematic review with meta-analysis of individual participant data.

PubMed

Raskovalova, Tatiana; Deegan, Patrick B; Yang, Ruby; Pavlova, Elena; Stirnemann, Jérome; Labarère, José; Zimran, Ari; Mistry, Pramod K; Berger, Marc

2017-04-20

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by deficiency in acid beta-glucosidase. GD exhibits a wide clinical spectrum of disease severity with an unpredictable natural course. Plasma chitotriosidase activity and CC chemokine ligand 18 (CCL18) have been exchangeably used for monitoring GD activity and response to enzyme replacement therapy in conjunction with clinical assessment. Yet, a large-scale head-to-head comparison of these two biomarkers is currently lacking. We propose a collaborative systematic review with meta-analysis of individual participant data (IPD) to compare the accuracy of plasma chitotriosidase activity and CCL18 in assessing type I (i.e., non-neuropathic) GD severity. Eligible studies include cross-sectional, cohort, and randomized controlled studies recording both plasma chitotriosidase activity and CCL18 level at baseline and/or at follow-up in consecutive children or adult patients with type I GD. Pre-specified surrogate outcomes reflecting GD activity include liver and spleen volume, hemoglobin concentration, platelet count, and symptomatic bone events with imaging confirmation. Primary studies will be identified by searching Medline (1995 onwards), EMBASE (1995 onwards), and Cochrane Central Register of Controlled Trials (CENTRAL). Electronic search will be complemented by contacting research groups in order to identify unpublished relevant studies. Where possible, IPD will be extracted from published articles. Corresponding authors will be invited to collaborate by supplying IPD. The methodological quality of retrieved studies will be appraised for each study outcome, using a checklist adapted from the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The primary outcome will be a composite of liver volume >1.25 multiple of normal (MN), spleen volume >5 MN, hemoglobin concentration <11 g/dL, or platelet count <100 × 10 9 /L. Effect size estimates for biomarker comparative accuracy in

Genetic background in nonalcoholic fatty liver disease: A comprehensive review

PubMed Central

Macaluso, Fabio Salvatore; Maida, Marcello; Petta, Salvatore

2015-01-01

In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease. PMID:26494964

77 FR 43605 - Prospective Grant of Exclusive License: Use of Glucocerebrosidase Activators for the Treatment of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-25

... Nervous System Proteinopathies, Including Parkinson's Disease AGENCY: National Institutes of Health... limited to ``Treatment of Gaucher disease and human central nervous system proteinopathies, including...

Advances in human genetics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harris, H.; Hirschhorn, K.

1993-01-01

This book has five chapters covering peroxisomal diseases, X-linked immunodeficiencies, genetic mutations affecting human lipoproteins and their receptors and enzymes, genetic aspects of cancer, and Gaucher disease. The chapter on peroxisomes covers their discovery, structure, functions, disorders, etc. The chapter on X-linked immunodeficiencies discusses such diseases as agammaglobulinemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, animal models, linkage analysis, etc. Apolipoprotein formation, synthesis, gene regulation, proteins, etc. are the main focus of chapter 3. The chapter on cancer covers such topics as oncogene mapping and the molecular characterization of some recessive oncogenes. Gaucher disease is covered from its diagnosis, classification, and prevention,more » to its organ system involvement and molecular biology.« less

Developmental analysis and influence of genetic background on the Lhx3 W227ter mouse model of combined pituitary hormone deficiency disease.

PubMed

Prince, Kelly L; Colvin, Stephanie C; Park, Soyoung; Lai, Xianyin; Witzmann, Frank A; Rhodes, Simon J

2013-02-01

Combined pituitary hormone deficiency (CPHD) diseases result in severe outcomes for patients including short stature, developmental delays, and reproductive deficiencies. Little is known about their etiology, especially the developmental profiles and the influences of genetic background on disease progression. Animal models for CPHD provide valuable tools to investigate disease mechanisms and inform diagnostic and treatment protocols. Here we examined hormone production during pituitary development and the influence of genetic background on phenotypic severity in the Lhx3(W227ter/W227ter) mouse model. Lhx3(W227ter/W227ter) embryos have deficiencies of ACTH, α-glycoprotein subunit, GH, PRL, TSHβ, and LHβ during prenatal development. Furthermore, mutant mice have significant reduction in the critical pituitary transcriptional activator-1 (PIT1). Through breeding, the Lhx3(W227ter/W227ter) genotype was placed onto the 129/Sv and C57BL/6 backgrounds. Intriguingly, the genetic background significantly affected viability: whereas Lhx3(W227ter/W227ter) animals were found in the expected frequencies in C57BL/6, homozygous animals were not viable in the 129/Sv genetic environment. The hormone marker and PIT1 reductions observed in Lhx3(W227ter/W227ter) mice on a mixed background were also seen in the separate strains but in some cases were more severe in 129/Sv. To further characterize the molecular changes in diseased mice, we conducted a quantitative proteomic analysis of pituitary proteins. This showed significantly lower levels of PRL, pro-opiomelanocortin (ACTH), and α-glycoprotein subunit proteins in Lhx3(W227ter/W227ter) mice. Together, these data show that hormone deficiency disease is apparent in early prenatal stages in this CPHD model system. Furthermore, as is noted in human disease, genetic background significantly impacts the phenotypic outcome of these monogenic endocrine diseases.

Developmental Analysis and Influence of Genetic Background on the Lhx3 W227ter Mouse Model of Combined Pituitary Hormone Deficiency Disease

PubMed Central

Prince, Kelly L.; Colvin, Stephanie C.; Park, Soyoung; Lai, Xianyin; Witzmann, Frank A.

2013-01-01

Combined pituitary hormone deficiency (CPHD) diseases result in severe outcomes for patients including short stature, developmental delays, and reproductive deficiencies. Little is known about their etiology, especially the developmental profiles and the influences of genetic background on disease progression. Animal models for CPHD provide valuable tools to investigate disease mechanisms and inform diagnostic and treatment protocols. Here we examined hormone production during pituitary development and the influence of genetic background on phenotypic severity in the Lhx3W227ter/W227ter mouse model. Lhx3W227ter/W227ter embryos have deficiencies of ACTH, α-glycoprotein subunit, GH, PRL, TSHβ, and LHβ during prenatal development. Furthermore, mutant mice have significant reduction in the critical pituitary transcriptional activator-1 (PIT1). Through breeding, the Lhx3W227ter/W227ter genotype was placed onto the 129/Sv and C57BL/6 backgrounds. Intriguingly, the genetic background significantly affected viability: whereas Lhx3W227ter/W227ter animals were found in the expected frequencies in C57BL/6, homozygous animals were not viable in the 129/Sv genetic environment. The hormone marker and PIT1 reductions observed in Lhx3W227ter/W227ter mice on a mixed background were also seen in the separate strains but in some cases were more severe in 129/Sv. To further characterize the molecular changes in diseased mice, we conducted a quantitative proteomic analysis of pituitary proteins. This showed significantly lower levels of PRL, pro-opiomelanocortin (ACTH), and α-glycoprotein subunit proteins in Lhx3W227ter/W227ter mice. Together, these data show that hormone deficiency disease is apparent in early prenatal stages in this CPHD model system. Furthermore, as is noted in human disease, genetic background significantly impacts the phenotypic outcome of these monogenic endocrine diseases. PMID:23288907

Selective Action of the Iminosugar Isofagomine, a Pharmacological Chaperone For Mutant Forms of Acid-β-Glucosidase

PubMed Central

Steet, Richard; Chung, Stephen; Lee, Wang-Sik; Pine, Corey W.; Do, Hung; Kornfeld, Stuart

2007-01-01

Gaucher disease is a lysosomal glycolipid storage disorder characterized by defects in acid-β-glucosidase (GlcCerase), the enzyme responsible for the catabolism of glucosylceramide. We recently demonstrated that isofagomine (IFG), an iminosugar that binds to the active site of GlcCerase, enhances the folding, transport and activity of the N370S mutant form of GlcCerase. In this study we compared the effects of IFG on a number of other glucosidases and glucosyltransferases. We report that IFG has little or no inhibitory activity towards intestinal disaccharidase enzymes, ER α-glucosidase II or glucosylceramide synthase at concentrations previously shown to enhance N370S GlcCerase folding and trafficking in Gaucher fibroblasts. Furthermore, treatment of wild type fibroblasts with high doses of IFG did not alter the processing of newly synthesized N-linked oligosaccharides. These findings support further evaluation of IFG as a potential therapeutic agent in the treatment of some forms of Gaucher disease. PMID:17217920

Genetics Home Reference: Gaucher disease

MedlinePlus

... Campbell PE, Charrow J, Cohen IJ, Harris CM, Kaplan P, Mengel E, Pocovi M, Vellodi A. Pediatric ... Updated Pages Reviewed : September 2014 Published : June 19, 2018 The resources on this site should not be ...

Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals.

PubMed

Wang, Raymond Y; Bodamer, Olaf A; Watson, Michael S; Wilcox, William R

2011-05-01

To develop educational guidelines for the diagnostic confirmation and management of individuals identified by newborn screening, family-based testing after proband identification, or carrier testing in at-risk populations, and subsequent prenatal or postnatal testing of those who are presymptomatic for a lysosomal storage disease. Review of English language literature and discussions in a consensus development panel comprised an international group of experts in the clinical and laboratory diagnosis, treatment and management, newborn screening, and genetic aspects of lysosomal storage diseases. Although clinical trial and longitudinal data were used when available, the evidence in the literature is limited and consequently the recommendations must be considered as expert opinion. Guidelines were developed for Fabry, Gaucher, and Niemann-Pick A/B diseases, glycogen storage type II (Pompe disease), globoid cell leukodystrophy (Krabbe disease), metachromatic leukodystrophy, and mucopolysaccharidoses types I, II, and VI. These guidelines serve as an educational resource for confirmatory testing and subsequent clinical management of presymptomatic individuals suspected to have a lysosomal storage disease; they also help to define a research agenda for longitudinal studies such as the American College of Medical Genetics/National Institutes of Health Newborn Screening Translational Research Network.

Molecular facets of sphingolipids: mediators of diseases.

PubMed

Ozbayraktar, Fatma Betul Kavun; Ulgen, Kutlu O

2009-07-01

Sphingolipids constitute a biologically active lipid class that is significantly important from both structural and regulatory aspects. The manipulation of sphingolipid metabolism is currently being studied as a novel strategy for cancer therapy. The basics of this therapeutic approach lie in the regulation property of sphingolipids on cellular processes, which are important in a cell's fate, such as cell proliferation, apoptosis, cell cycle arrest, senescence, and inflammation. Furthermore, the mutations in the enzymes catalyzing some specific reactions in the sphingolipid metabolism cause mortal lysosomal storage diseases like Fabry, Gaucher, Niemann-Pick, Farber, Krabbe, and Metachromatic Leukodystrophy. Therefore, the alteration of the sphingolipid metabolic pathway determines the choice between life and death. Understanding the sphingolipid metabolism and regulation is significant for the development of new therapeutic approaches for all sphingolipid-related diseases, as well as for cancer. An important feature of the sphingolipid metabolic pathway is the compartmentalization into endoplasmic reticulum, the Golgi apparatus, lysosome and plasma membrane, and this compartmentalization makes the transport of sphingolipids critical for proper functioning. This paper focuses on the structures, metabolic pathways, localization, transport mechanisms, and diseases of sphingolipids in Saccharomyces cerevisiae and humans, and provides the latest comprehensive information on sphingolipid research.

[The German program for disease management guidelines. Background, methods, and development process].

PubMed

Ollenschläger, Günter; Kopp, Ina; Lelgemann, Monika; Sänger, Sylvia; Heymans, Lothar; Thole, Henning; Trapp, Henrike; Lorenz, Wilfried; Selbmann, Hans-Konrad; Encke, Albrecht

2006-10-15

The Program for National Disease Management Guidelines (German DM-CPG Program) was established in 2002 by the German Medical Association (umbrella organization of the German Chambers of Physicians) and joined by the Association of the Scientific Medical Societies (AWMF; umbrella organization of more than 150 professional societies) and by the National Association of Statutory Health Insurance Physicians (NASHIP) in 2003. The program provides a conceptual basis for disease management, focusing on high-priority health-care topics and aiming at the implementation of best practice recommendations for prevention, acute care, rehabilitation and chronic care. It is organized by the German Agency for Quality in Medicine, a founding member of the Guidelines International Network (G-I-N). The main objective of the German DM-CPG Program is to establish consensus of the medical professions on evidence-based key recommendations covering all sectors of health-care provision and facilitating the coordination of care for the individual patient through time and across interfaces. Within the last year, DM-CPGs have been published for asthma, chronic obstructive pulmonary disease, type 2 diabetes, and coronary heart disease. In addition, experts from national patient self-help groups have been developing patient guidance based upon the recommendations for health-care providers. The article describes background, methods, and tools of the DM-CPG Program, and is the first of a publication series dealing with innovative recommendations and aspects of the program.

The Genetic Background of Neonatal Disease.

PubMed

Göpel, Wolfgang; Westermann, Eva; Pagel, Friederike

2018-01-01

More than 27,000 human genes have been sequenced and described. Only a few of these genes are relevant for common human diseases with regard to diagnostic or therapeutic purposes. This review describes the genetics of common traits and diseases with a particular focus on perspectives for drug discovery and drug therapy in neonates. © 2018 S. Karger AG, Basel.

Newborn screening for lysosomal storage disorders by tandem mass spectrometry in North East Italy.

PubMed

Burlina, Alberto B; Polo, Giulia; Salviati, Leonardo; Duro, Giovanni; Zizzo, Carmela; Dardis, Andrea; Bembi, Bruno; Cazzorla, Chiara; Rubert, Laura; Zordan, Roberta; Desnick, Robert J; Burlina, Alessandro P

2018-03-01

Lysosomal storage diseases (LSDs) are inborn errors of metabolism resulting from 50 different inherited disorders. The increasing availability of treatments and the importance of early intervention have stimulated newborn screening (NBS) to diagnose LSDs and permit early intervention to prevent irreversible impairment or severe disability. We present our experience screening newborns in North East Italy to identify neonates with Mucopolysaccharidosis type I (MPS I) and Pompe, Fabry, and Gaucher diseases. Activities of acid β-glucocerebrosidase (ABG; Gaucher), acid α-glucosidase (GAA; Pompe), acid α-galactosidase (GLA; Fabry), and acid α-L-iduronidase (IDUA; MPS-I) in dried blood spots (DBS) from all newborns during a 17-month period were determined by multiplexed tandem mass spectrometry (MS/MS) using the NeoLSD ® assay system. Enzymatic activity cutoff values were determined from 3500 anonymous newborn DBS. In the screening study, samples were retested if the value was below cutoff and a second spot was requested, with referral for confirmatory testing and medical evaluation if a low value was obtained. From September 2015 to January 2017, 44,411 newborns were screened for the four LSDs. We recalled 40 neonates (0.09%) for collection of a second DBS. Low activity was confirmed in 20, who had confirmatory testing. Ten of 20 had pathogenic mutations: two Pompe, two Gaucher, five Fabry, and one MPS-I. The incidences of Pompe and Gaucher diseases were similar (1/22,205), with Fabry disease the most frequent (1/8882) and MPS-I the rarest (1/44411). The combined incidence of the four disorders was 1/4411 births. Simultaneously determining multiple enzyme activities by MS/MS, with a focus on specific biochemical markers, successfully detected newborns with LSDs. The high incidence of these disorders supports this screening program.

Language background in early life may be related to neuropsychiatry symptoms in patients with Alzheimer disease.

PubMed

Liu, Yi-Chien; Hsu, Jung-Lung; Wang, Shuu-Jin; Yip, Ping-Keung; Meguro, Kenichi; Fuh, Jong-Ling

2017-02-10

The relationship between early life experience and the occurrence of neuropsychiatry symptoms (NPSs) in patients with Alzheimer disease (AD) is unclear. From 2012 to 2014, we prospectively recruited 250 patients with probable AD from the memory clinic of Taipei Veterans General Hospital. All patients underwent standard assessments, including brain magnetic resonance imaging or computed tomography, neuropsychological tests, neuropsychiatry inventory (NPI-Q) and related blood tests. A linear regression analysis was performed to investigate the relationship between NPSs and age, gender, disease severity, depression, language background (with or without Japanese education). Among the 250 participants, 113 (45.2%) were women. Their average age was 82.6 years. Of all the participants, 93 (37.2%) had received formal Japanese education, whereas 157 (62.8%) did not receive Japanese education. The participants with Japanese education were slightly younger (83.1 ± 3.6 vs. 81.4 ± 3.4, P = 0.006), with a higher proportion of them were women (30.5% vs. 69.8%, P < 0.001) and fewer years of total education (10.8 ± 4.5 vs. 7.7 ± 3.2, P < 0.001), compared to the participants without Japanese education. NPI-Q scores significantly differed between the two groups (15.8 vs. 24.1, P = 0.024). Both disease severity and language background predicted NPI-Q scores. Language background in early life may be related to NPSs in patients with AD, and this effect is more significant in patients with a lower education level than in those with a higher education level. More NPSs may be the result of negative effects on dominant language or early life experiences.

Longitudinal Study of Neurodegenerative Disorders

ClinicalTrials.gov

2018-01-31

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

4th Rare Disease South Eastern Europe (See) Meeting Skopje, Macedonia (November 14th, 2015).

PubMed

Gucev, Zoran; Tasic, Velibor; Polenakovic, Momir

2015-01-01

diagnosis and treatment. New methods are expanding our capabilities for a fast and precise diagnosis. Novel knowledge offers better distinction on whom to treat with which medications (e.g. steroid dependent nephrotic syndrome). Novel diseases or variants are published (segmental overgrowth). The authors of the report are particularly keen on stating that one of the main goals of the meeting, namely to help the treatment of patients with rare disease has begun to bear fruits. Namely, the Health Fund of Macedonia for the first time treats the patients with Gaucher's disease. We are hopeful that the number of patients treated for Gaucher's disease and the number of treated patients with other treatable RDs diseases will continue to grow.

Genomic background-related activation of microglia and reduced β-amyloidosis in a mouse model of Alzheimer's disease.

PubMed

Fröhlich, Christina; Paarmann, Kristin; Steffen, Johannes; Stenzel, Jan; Krohn, Markus; Heinze, Hans-Jochen; Pahnke, Jens

2013-03-01

Alzheimer's disease (AD) is by far the most common neurodegenerative disease. AD is histologically characterized not only by extracellular senile plaques and vascular deposits consisting of β-amyloid (Aβ) but also by accompanying neuroinflammatory processes involving the brain's microglia. The importance of the microglia is still in controversial discussion, which currently favors a protective function in disease progression. Recent findings by different research groups highlighted the importance of strain-specific and mitochondria-specific genomic variations in mouse models of cerebral β-amyloidosis. Here, we want to summarize our previously presented data and add new results that draw attention towards the consideration of strain-specific genomic alterations in the setting of APP transgenes. We present data from APP-transgenic mice in commonly used C57Bl/6J and FVB/N genomic backgrounds and show a direct influence on the kinetics of Aβ deposition and the activity of resident microglia. Plaque size, plaque deposition rate and the total amount of Aβ are highest in C57Bl/6J mice as compared to the FVB/N genomic background, which can be explained at least partially by a reduced microglia activity towards amyloid deposits in the C57BL/6J strain.

A sensitive and reproducible fluorescent-based HPLC assay to measure the activity of acid as well as neutral beta-glucocerebrosidases.

PubMed

Hayashi, Yasuhiro; Zama, Kouta; Abe, Eriko; Okino, Nozomu; Inoue, Takehiko; Ohno, Kousaku; Ito, Makoto

2008-12-01

The activity of lysosomal acid beta-glucocerebrosidase (AGC, EC 3.2.1.45), which hydrolyzes the O-glycosidic linkage between D-glucose and ceramide of glucosylceramide (GlcCer), is a marker for the diagnosis of Gaucher disease because the disease is caused by dysfunction of AGC due to mutations in the gene. The activity of AGC is potently inhibited by conduritol B epoxide (CBE), whereas CBE-insensitive nonlysosomal neutral beta-glucocerebrosidase (NGC) activities have been found in various vertebrates, including humans. We report here a new reliable method to determine AGC as well as NGC activities using normal-phase high-performance liquid chromatography (HPLC) and NBD (4-nitrobenzo-2-oxa-1,3-diazole)- or BODIPY (4,4-difluoro-4-boro-3a,4a-diaza-s-indacene)-labeled GlcCer as a substrate. The reaction products of the enzymes, C6-NBD-ceramide and C12-BODIPY-ceramide, were clearly separated from the corresponding substrates on a normal-phase column within 5 min using a different solvent system. Reaction products could be detected quantitatively at concentrations ranging from 50 fmol to 50 pmol for C6-NBD-ceramide and from 10 fmol to 5 pmol for C12-BODIPY-ceramide. V(max)/K(m) values of human fibroblast AGC for fluorescent GlcCer were much higher than those for 4-methylumbelliferyl-beta-d-glucoside (4MU-Glc), which is used prevalently for Gaucher disease diagnosis. As a result, AGC activity was detected quantitatively using fluorescent GlcCer, but not 4MU-Glc, using 5 microl of human serum or 1 x 10(4) cultured human fibroblasts. The current method clearly showed the decrease of AGC activities in fibroblasts and serum from the patient with Gaucher disease compared with normal individuals, suggesting that the method is applicable for the diagnosis of Gaucher disease. Furthermore, this method was found to be useful for measuring the activities of nonlysosomal NGC of various cells and tissues in the presence of CBE.

Experience with Carrier Screening and Prenatal Diagnosis for Sixteen Ashkenazi Jewish Genetic Diseases

PubMed Central

Scott, Stuart A.; Edelmann, Lisa; Liu, Liu; Luo, Minjie; Desnick, Robert J.; Kornreich, Ruth

2010-01-01

The success of prenatal carrier screening as a disease prevention strategy in the Ashkenazi Jewish (AJ) population has driven the expansion of screening panels as disease-causing founder mutations have been identified. However, the carrier frequencies of many of these mutations have not been reported in large AJ cohorts. We determined the carrier frequencies of over 100 mutations for 16 recessive disorders in the New York metropolitan area AJ population. Among the 100% AJ-descended individuals, screening for 16 disorders resulted in ~1 in 3.3 being a carrier for one disease and ~1 in 24 for two diseases. The carrier frequencies ranged from 0.066 (1 in 15.2; Gaucher disease) to 0.006 (1 in 168; nemaline myopathy), which averaged ~15% higher than those for all screenees. Importantly, over 95% of screenees chose to be screened for all possible AJ diseases, including disorders with lower carrier frequencies and/or detectability. Carrier screening also identified rare individuals homozygous for disease-causing mutations who had previously unrecognized clinical manifestations. Additionally, prenatal testing results and experience for all 16 disorders (n = 574) are reported. Together, these data indicate the general acceptance, carrier frequencies, and prenatal testing results for an expanded panel of 16 diseases in the AJ population. PMID:20672374

Wolman disease associated with hemophagocytic lymphohistiocytosis: attempts for an explanation.

PubMed

Taurisano, Roberta; Maiorana, Arianna; De Benedetti, Fabrizio; Dionisi-Vici, Carlo; Boldrini, Renata; Deodato, Federica

2014-10-01

The lysosomal acid lipase (LAL) is the enzyme responsible of the hydrolysis of cholesteryl esters and triglycerides within endo-lysosomes. Loss of enzyme activity leads to accumulation of cholesteryl esters and triglycerides in the lysosome of most tissues. The complete deficiency of LAL is responsible of Wolman disease (WD), a severe systemic disease manifesting in the first days of life with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, jaundice, anemia, and thrombocytopenia. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition which may be genetically determined or secondary to infections, malignancies, immune deficiencies, and rheumatologic disorders. So far, some inborn errors of metabolism have been associated with HLH (e.g., lysinuric protein intolerance, Gaucher's disease), and it has been anecdotally described in three WD patients, without any specific pathogenetic hypothesis. Here, we report on a WD patient, showing clear clinical, biochemical, and histological features indicative of HLH. We discuss the pathophysiological role of cholesteryl ester-induced inflammasome activation in macrophages, leading to a secondary HLH. This case indicates that WD can cause secondary HLH and suggests that a careful metabolic workup should be performed when facing to a pediatric patient with HLH.

Bisphosphonate Treatment and Pregnancy

MedlinePlus

... paternal- exposures- pregnancy/ pdf/ . Selected References: Cox TM et al. 2008. Management of non-neuronopathic Gaucher disease ... Inherit Metab Dis. 31: 319-336. Djokanovic N et al. 2008. Does treatment with Bisphosphonates endanger the ...

Evaluation of estimation methods and power of tests of discrete covariates in repeated time-to-event parametric models: application to Gaucher patients treated by imiglucerase.

PubMed

Vigan, Marie; Stirnemann, Jérôme; Mentré, France

2014-05-01

Analysis of repeated time-to-event data is increasingly performed in pharmacometrics using parametric frailty models. The aims of this simulation study were (1) to assess estimation performance of Stochastic Approximation Expectation Maximization (SAEM) algorithm in MONOLIX, Adaptive Gaussian Quadrature (AGQ), and Laplace algorithm in PROC NLMIXED of SAS and (2) to evaluate properties of test of a dichotomous covariate on occurrence of events. The simulation setting is inspired from an analysis of occurrence of bone events after the initiation of treatment by imiglucerase in patients with Gaucher Disease (GD). We simulated repeated events with an exponential model and various dropout rates: no, low, or high. Several values of baseline hazard model, variability, number of subject, and effect of covariate were studied. For each scenario, 100 datasets were simulated for estimation performance and 500 for test performance. We evaluated estimation performance through relative bias and relative root mean square error (RRMSE). We studied properties of Wald and likelihood ratio test (LRT). We used these methods to analyze occurrence of bone events in patients with GD after starting an enzyme replacement therapy. SAEM with three chains and AGQ algorithms provided good estimates of parameters much better than SAEM with one chain and Laplace which often provided poor estimates. Despite a small number of repeated events, SAEM with three chains and AGQ gave small biases and RRMSE. Type I errors were closed to 5%, and power varied as expected for SAEM with three chains and AGQ. Probability of having at least one event under treatment was 19.1%.

Optimization of ultra-high pressure liquid chromatography - tandem mass spectrometry determination in plasma and red blood cells of four sphingolipids and their evaluation as biomarker candidates of Gaucher's disease.

PubMed

Chipeaux, Caroline; de Person, Marine; Burguet, Nathalie; Billette de Villemeur, Thierry; Rose, Christian; Belmatoug, Nadia; Héron, Sylvie; Le Van Kim, Caroline; Franco, Mélanie; Moussa, Fathi

2017-11-24

While important advances have been recently achieved in the optimization of lipid classes' separation, information on the specific determination of medium polarity lipids such as sphingolipids (SLs) in highly complex matrices remains fragmentary. In human, disorders of SL metabolism known as sphingolipidoses are a heterogeneous group of inherited disorders affecting primarily the central nervous. Early diagnosis of these conditions is of importance notably when a corrective therapy is available. The diagnosis is generally based on the determination of specific SLs in plasma and red blood cells (RBCs). For instance, glucosylceramide (GL1), glucosylsphingosine (Lyso-GL1), sphingosine (Sph), and sphingosine-1-phosphate (S1P) are proposed as relevant biomarkers for Gaucher disease (GD). Our main objective was to evaluate these biomarker candidates in a cohort of GD patients. However, most of current methods of GL1, Lyso-GL1, Sph, and S1P determination in plasma of GD patients require at least two liquid chromatographic runs. On the other hand, except for GL1 nothing is known concerning the RBC sphingolipid content. Yet, several reversed phase LC-MS methods of SLs separation and/or determination in various media with different sample preparation approaches have been proposed since 2010. Here we focused on stationary phase selection and mobile phase composition as well as on the sample preparation step to optimize and validate an UHPLC-MS/MS method for the simultaneous quantification of the four sphingolipids in both plasma and RBCs. A comparison between seven stationary phases including two RP18, two polar embedded RP18, and three HILIC phases shows that under our conditions polar embedded RP18 phases are the most appropriate for the separation of the four SLs, in terms of efficiency, peak symmetry, and separation time. In the same way, a comparison between a single step extraction with methanol and a liquid-liquid extraction with a mixture of methanol/methyl tert

Pilot study of newborn screening for six lysosomal storage diseases using Tandem Mass Spectrometry☆

PubMed Central

Elliott, Susan; Buroker, Norman; Cournoyer, Jason J.; Potier, Anna M.; Trometer, Joseph D.; Elbin, Carole; Schermer, Mack J.; Kantola, Jaana; Boyce, Aaron; Turecek, Frantisek; Gelb, Michael H.; Scott, C. Ronald

2017-01-01

Background There is current expansion of newborn screening (NBS) programs to include lysosomal storage disorders because of the availability of treatments that produce an optimal clinical outcome when started early in life. Objective To evaluate the performance of a multiplex-tandem mass spectrometry (MS/MS) enzymatic activity assay of 6 lysosomal enzymes in a NBS laboratory for the identification of newborns at risk for developing Pompe, Mucopolysaccharidosis-I (MPS-I), Fabry, Gaucher, Niemann Pick-A/B, and Krabbe diseases. Methods and Results Enzyme activities (acid α-glucosidase (GAA), galactocerebrosidase (GALC), glucocerebrosidase (GBA), α-galactosidase A (GLA), α-iduronidase (IDUA) and sphingomyeline phosphodiesterase-1 (SMPD-1)) were measured on ~43,000 de-identified dried blood spot (DBS) punches, and screen positive samples were submitted for DNA sequencing to obtain genotype confirmation of disease risk. The 6-plex assay was efficiently performed in the Washington state NBS laboratory by a single laboratory technician at the bench using a single MS/MS instrument. The number of screen positive samples per 100,000 newborns were as follows: GAA (4.5), IDUA (13.6), GLA (18.2), SMPD1 (11.4), GBA (6.8), and GALC (25.0). Discussion A 6-plex MS/MS assay for 6 lysosomal enzymes can be successfully performed in a NBS laboratory. The analytical ranges (enzyme-dependent assay response for the quality control HIGH sample divided by that for all enzyme-independent processes) for the 6-enzymes with the MS/MS is 5- to 15-fold higher than comparable fluorimetric assays using 4-methylumbelliferyl substrates. The rate of screen positive detection is consistently lower for the MS/MS assay compared to the fluorimetric assay using a digital microfluidics platform. PMID:27238910

A novel approach for quantitation of glucosylceramide in human dried blood spot using LC-MS/MS.

PubMed

Ji, Allena Ji; Wang, Haixing; Ziso-Qejvanaj, Enida; Zheng, Kefei; Chung, Lee Lee; Foley, Timothy; Chuang, Wei-Lien; Richards, Susan; Sung, Crystal

2015-01-01

Glucosylceramide, an efficacy biomarker for Gaucher Type 1 disease, exhibits poor solubility in polar solvents and whole blood which makes it difficult to prepare a homogenous blood standard. We developed a novel method using standard addition approach by spiking a small volume of analyte solution on the surface of prespotted dried blood spot. The whole spots were punched out for subsequent extraction and LC-MS/MS analysis. The assay performance met all validation acceptance criteria. Glucosylceramide concentrations in 50 paired plasma and dry blood spot samples obtained from Gaucher Type 1 patients were tested and the results demonstrated the feasibility of using the DBS method for clinical biomarker monitoring. The new approach greatly improves assay precision and accuracy.

The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background

PubMed Central

Marsh, Sharon; Hu, Junbo; Feng, Wenke

2016-01-01

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and it comprises a spectrum of hepatic abnormalities from simple hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, and liver cancer. While the pathogenesis of NAFLD remains incompletely understood, a multihit model has been proposed that accommodates causal factors from a variety of sources, including intestinal and adipose proinflammatory stimuli acting on the liver simultaneously. Prior cellular and molecular studies of patient and animal models have characterized several common pathogenic mechanisms of NAFLD, including proinflammation cytokines, lipotoxicity, oxidative stress, and endoplasmic reticulum stress. In recent years, gut microbiota has gained much attention, and dysbiosis is recognized as a crucial factor in NAFLD. Moreover, several genetic variants have been identified through genome-wide association studies, particularly rs738409 (Ile748Met) in PNPLA3 and rs58542926 (Glu167Lys) in TM6SF2, which are critical risk alleles of the disease. Although a high-fat diet and inactive lifestyles are typical risk factors for NAFLD, the interplay between diet, gut microbiota, and genetic background is believed to be more important in the development and progression of NAFLD. This review summarizes the common pathogenic mechanisms, the gut microbiota relevant mechanisms, and the major genetic variants leading to NAFLD and its progression. PMID:27247565

High resolution time-course mapping of early transcriptomic, molecular and cellular phenotypes in Huntington's disease CAG knock-in mice across multiple genetic backgrounds.

PubMed

Ament, Seth A; Pearl, Jocelynn R; Grindeland, Andrea; St Claire, Jason; Earls, John C; Kovalenko, Marina; Gillis, Tammy; Mysore, Jayalakshmi; Gusella, James F; Lee, Jong-Min; Kwak, Seung; Howland, David; Lee, Min Young; Baxter, David; Scherler, Kelsey; Wang, Kai; Geman, Donald; Carroll, Jeffrey B; MacDonald, Marcy E; Carlson, George; Wheeler, Vanessa C; Price, Nathan D; Hood, Leroy E

2017-03-01

Huntington's disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, molecular and cellular phenotypes in the striatum of six distinct knock-in mouse models of the HD mutation. We studied the effects of the HttQ111 allele on the C57BL/6J, CD-1, FVB/NCr1, and 129S2/SvPasCrl genetic backgrounds, and of two additional alleles, HttQ92 and HttQ50, on the C57BL/6J background. We describe the emergence of a transcriptomic signature in HttQ111/+  mice involving hundreds of differentially expressed genes and changes in diverse molecular pathways. We also show that this time course spanned the onset of mutant huntingtin nuclear localization phenotypes and somatic CAG-length instability in the striatum. Genetic background strongly influenced the magnitude and age at onset of these effects. This work provides a foundation for understanding the earliest transcriptional and molecular changes contributing to HD pathogenesis. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[Consumer involvement in the Disease Management Guideline for Asthma--a background report].

PubMed

Senger, Sylvia; Lelgemann, Monika; Kopp, Ina

2006-01-01

In the past clinical guidelines were mainly developed by experts and in everyday clinical practice almost exclusively used by clinical experts, while issues that were relevant from the patients' (consumers') point of view tended to be neglected. But then, the majority of patient information has not been perceptibly connected to clinical guidelines. Connecting the development of clinical guidelines with the development of patient information publications would make good sense for both products, though. On the one hand, evidence-based treatment guidelines could be made available to the actual target group of the clinical care process--i.e. the patients or consumers--and on the other hand, patient experiences and competencies (social evidence) might inform the production of guidelines. Such a procedure demands the cooperation of clinical experts and patients. So far there are no generally accepted methods in Germany for the practical implementation of consumer involvement on both the organizational and content level with the aim of involving patients in the development process of guidelines as well as the production of the respective patient information versions. Such a methodology shall be established as part of the National Program for Disease Management Guidelines. For the first time in this program, patient involvement is being exercised within the scope of the National Disease Management Guideline for Asthma (NDM Asthma). Here, patients are involved in the NDM development process by providing the opportunity to comment on the consented guideline draft and to participate in the translation of the NDM Asthma into a patient version. The present paper is a background report describing the current state of work and indicating consequences for some future developments.

Single-Tube Multiplexed Molecular Detection of Endemic Porcine Viruses in Combination with Background Screening for Transboundary Diseases

PubMed Central

Wernike, Kerstin; Hoffmann, Bernd

2013-01-01

Detection of several pathogens with multiplexed real-time quantitative PCR (qPCR) assays in a one-step setup allows the simultaneous detection of two endemic porcine and four different selected transboundary viruses. Reverse transcription (RT)-qPCR systems for the detection of porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2), two of the most economically important pathogens of swine worldwide, were combined with a screening system for diseases notifiable to the World Organization of Animal Health, namely, classical and African swine fever, foot-and-mouth disease, and Aujeszky's disease. Background screening was implemented using the identical fluorophore for all four different RT-qPCR assays. The novel multiplex RT-qPCR system was validated with a large panel of different body fluids and tissues from pigs and other animal species. Both reference samples and clinical specimens were used for a complete evaluation. It could be demonstrated that a highly sensitive and specific parallel detection of the different viruses was possible. The assays for the notifiable diseases were even not affected by the simultaneous amplification of very high loads of PRRSV- and PCV2-specific sequences. The novel broad-spectrum multiplex assay allows in a unique form the routine investigation for endemic porcine pathogens with exclusion diagnostics of the most important transboundary diseases in samples from pigs with unspecific clinical signs, such as fever or hemorrhages. The new system could significantly improve early detection of the most important notifiable diseases of swine and could lead to a new approach in syndromic surveillance. PMID:23303496

Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease.

PubMed

Robak, Laurie A; Jansen, Iris E; van Rooij, Jeroen; Uitterlinden, André G; Kraaij, Robert; Jankovic, Joseph; Heutink, Peter; Shulman, Joshua M

2017-12-01

Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Perceptions of disease aetiology and the effect of own behaviour on health among poly-pharmacy patients with non-Western backgrounds in Denmark.

PubMed

Molin, Katrine Rutkær; Mygind, Anna; Nørgaard, Lotte Stig

2013-12-01

To examine the perceptions of disease aetiology and the effect of own behaviour on health among poly-pharmacy patients with non-Western backgrounds in Denmark. The study was based on 26 extended medication reviews with patients of non-Western backgrounds aged 50+ who use at least four prescription drugs regularly. The reviews were conducted by 12 pharmacists with the same mother-tongue background as the participants. The reviews included patient interviews on which the data in this article are based. In total, four open-ended questions from the patient interviews were analysed by the means of Giorgi's phenomenological method. The analysis shows that stress was most commonly perceived as the cause of the participants' diseases for reasons that included (1) having left their country of origin and family, (2) worry over the political situation in their country of origin and (3) the problems involved in living as an immigrant in Denmark. Most of the participants perceived their own efforts as having little impact on their own health status, although some participants considered them as having considerable influence. To a great extent, the explanations of the participants about possible disease aetiology are focused on stress, immigration and psychological well-being. Although many participants perceived that their own efforts did not have much impact on their health status, our study revealed a large diversity in the responses of non-Western immigrants, particularly regarding the importance of their own efforts on their health status. © 2013 The Authors. IJPP © 2013 Royal Pharmaceutical Society.

Proof-of-principle rapid noninvasive prenatal diagnosis of autosomal recessive founder mutations

PubMed Central

Zeevi, David A.; Altarescu, Gheona; Weinberg-Shukron, Ariella; Zahdeh, Fouad; Dinur, Tama; Chicco, Gaya; Herskovitz, Yair; Renbaum, Paul; Elstein, Deborah; Levy-Lahad, Ephrat; Rolfs, Arndt; Zimran, Ari

2015-01-01

BACKGROUND. Noninvasive prenatal testing can be used to accurately detect chromosomal aneuploidies in circulating fetal DNA; however, the necessity of parental haplotype construction is a primary drawback to noninvasive prenatal diagnosis (NIPD) of monogenic disease. Family-specific haplotype assembly is essential for accurate diagnosis of minuscule amounts of circulating cell-free fetal DNA; however, current haplotyping techniques are too time-consuming and laborious to be carried out within the limited time constraints of prenatal testing, hampering practical application of NIPD in the clinic. Here, we have addressed this pitfall and devised a universal strategy for rapid NIPD of a prevalent mutation in the Ashkenazi Jewish (AJ) population. METHODS. Pregnant AJ couples, carrying mutation(s) in GBA, which encodes acid β-glucosidase, were recruited at the SZMC Gaucher Clinic. Targeted next-generation sequencing of GBA-flanking SNPs was performed on peripheral blood samples from each couple, relevant mutation carrier family members, and unrelated individuals who are homozygotes for an AJ founder mutation. Allele-specific haplotypes were constructed based on linkage, and a consensus Gaucher disease–associated founder mutation–flanking haplotype was fine mapped. Together, these haplotypes were used for NIPD. All test results were validated by conventional prenatal or postnatal diagnostic methods. RESULTS. Ten parental alleles in eight unrelated fetuses were diagnosed successfully based on the noninvasive method developed in this study. The consensus mutation–flanking haplotype aided diagnosis for 6 of 9 founder mutation alleles. CONCLUSIONS. The founder NIPD method developed and described here is rapid, economical, and readily adaptable for prenatal testing of prevalent autosomal recessive disease-causing mutations in an assortment of worldwide populations. FUNDING. SZMC, Protalix Biotherapeutics Inc., and Centogene AG. PMID:26426075

Newborn screening for six lysosomal storage disorders in a cohort of Mexican patients: Three-year findings from a screening program in a closed Mexican health system.

PubMed

Navarrete-Martínez, Juana Inés; Limón-Rojas, Ana Elena; Gaytán-García, Maria de Jesús; Reyna-Figueroa, Jesús; Wakida-Kusunoki, Guillermo; Delgado-Calvillo, Ma Del Rocío; Cantú-Reyna, Consuelo; Cruz-Camino, Héctor; Cervantes-Barragán, David Eduardo

2017-05-01

To evaluate the results of a lysosomal newborn screening (NBS) program in a cohort of 20,018 Mexican patients over the course of 3years in a closed Mexican Health System (Petróleos Mexicanos [PEMEX] Health Services). Using dried blood spots (DBS), we performed a multiplex tandem mass spectrometry enzymatic assay for six lysosomal storage disorders (LSDs) including Pompe disease, Fabry disease, Gaucher disease, mucopolysaccharidosis type I (MPS-I), Niemann-Pick type A/B, and Krabbe disease. Screen-positive cases were confirmed using leukocyte enzymatic activity and DNA molecular analysis. From July 2012 to April 2016, 20,018 patients were screened; 20 patients were confirmed to have an LSD phenotype (99.9 in 100,000 newborns). Final distributions include 11 Pompe disease, five Fabry disease, two MPS-I, and two Niemann-Pick type A/B patients. We did not find any Gaucher or Krabbe patients. A final frequency of 1 in 1001 LSD newborn phenotypes was established. NBS is a major public health achievement that has decreased the morbidity and mortality of inborn errors of metabolism. The introduction of NBS for LSD presents new challenges. This is the first multiplex Latin-American study of six LSDs detected through NBS. Copyright © 2017 Elsevier Inc. All rights reserved.

Selenoureido-iminosugars: A new family of multitarget drugs.

PubMed

Olsen, Jacob Ingemar; Plata, Gabriela B; Padrón, José M; López, Óscar; Bols, Mikael; Fernández-Bolaños, José G

2016-11-10

Herein we report the synthesis of N-alkylated deoxynojirimycin derivatives decorated with a selenoureido motif at the hydrocarbon tether as an example of unprecedented multitarget agents. Title compounds were designed as dual drugs for tackling simultaneously the Gaucher disease (by selective inhibition of β-glucosidase, Ki = 1.6-5.5 μM, with improved potency and selectivity compared to deoxynojirimycin) and its neurological complications (by inhibiting AChE, Ki up to 5.8 μM). Moreover, an excellent mimicry of the selenoenzyme glutathione peroxidase was also found for the catalytic scavenging of H2O2 (Kcat/Kuncat up to 640) using PhSH as a cofactor, with improved activity compared to known positive controls, like (PhSe)2 and ebselen; therefore, such compounds are also excellent scavengers of peroxides, an example of reactive oxygen species present at high concentrations in patients of Gaucher disease and neurological disorders. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Targeted disruption of a novel gene contiguous to both glucocerebrodisidase (GC) and thrombospondin 3 (TSP3), results in an embryonic lethal phenotype in the mouse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bornstein, P.; Shingu, T.; LaMarca, M.E.

1994-09-01

We have identified a new murine gene, termed gene X, that spans the 6 kb interval separating GC from TSP3. Mutations in GC result in Gaucher disease, the most common lysosomal storage disorder. Gene X and GC are transcribed convergently; their major polyadenylation sites are separated by only 431 bp. On the other hand, gene X and TSP3 are transcribed divergently and share a bidirectional promoter. The cDNA for gene X encodes a 317 amino acid protein, without either a signal sequence or N-linked glycosylation. Gene X is expressed ubiquitously in tissues of the young adult mouse, but no closemore » homologues have been found in the DNA or protein data bases. A targeted point mutation was introduced into the GC gene (Asn to Ser in exon 9) by homologous recombination in embryonic stem cells to establish a mouse model for a mild form of Gaucher disease. In the process, a PGK-neomycin gene cassette was inserted in the 3{prime} flanking region of GC as a selectable marker, in a sequence that was subsequently identified as exon 8 of gene X. Mice homozygous for the combined mutation die early in gestation. Since the amino acid mutation in humans is associated with milder type 1 Gaucher disease, we conclude that gene X is essential for embryonic development in mice. The locations of human and murine GC, gene X and TSP3 are similar, but the human genome includes a duplication that has produced GC and gene X pseudogenes. We are currently studying the possible functional interactions of GC, gene X and TSP3 in both mice and humans.« less

Glyco-engineering strategies for the development of therapeutic enzymes with improved efficacy for the treatment of lysosomal storage diseases

PubMed Central

Oh, Doo-Byoung

2015-01-01

Lysosomal storage diseases (LSDs) are a group of inherent diseases characterized by massive accumulation of undigested compounds in lysosomes, which is caused by genetic defects resulting in the deficiency of a lysosomal hydrolase. Currently, enzyme replacement therapy has been successfully used for treatment of 7 LSDs with 10 approved therapeutic enzymes whereas new approaches such as pharmacological chaperones and gene therapy still await evaluation in clinical trials. While therapeutic enzymes for Gaucher disease have N-glycans with terminal mannose residues for targeting to macrophages, the others require N-glycans containing mannose-6-phosphates that are recognized by mannose-6-phosphate receptors on the plasma membrane for cellular uptake and targeting to lysosomes. Due to the fact that efficient lysosomal delivery of therapeutic enzymes is essential for the clearance of accumulated compounds, the suitable glycan structure and its high content are key factors for efficient therapeutic efficacy. Therefore, glycan remodeling strategies to improve lysosomal targeting and tissue distribution have been highlighted. This review describes the glycan structures that are important for lysosomal targeting and provides information on recent glyco-engineering technologies for the development of therapeutic enzymes with improved efficacy. [BMB Reports 2015; 48(8): 438-444] PMID:25999178

Glyco-engineering strategies for the development of therapeutic enzymes with improved efficacy for the treatment of lysosomal storage diseases.

PubMed

Oh, Doo-Byoung

2015-08-01

Lysosomal storage diseases (LSDs) are a group of inherent diseases characterized by massive accumulation of undigested compounds in lysosomes, which is caused by genetic defects resulting in the deficiency of a lysosomal hydrolase. Currently, enzyme replacement therapy has been successfully used for treatment of 7 LSDs with 10 approved therapeutic enzymes whereas new approaches such as pharmacological chaperones and gene therapy still await evaluation in clinical trials. While therapeutic enzymes for Gaucher disease have N-glycans with terminal mannose residues for targeting to macrophages, the others require N-glycans containing mannose-6-phosphates that are recognized by mannose-6-phosphate receptors on the plasma membrane for cellular uptake and targeting to lysosomes. Due to the fact that efficient lysosomal delivery of therapeutic enzymes is essential for the clearance of accumulated compounds, the suitable glycan structure and its high content are key factors for efficient therapeutic efficacy. Therefore, glycan remodeling strategies to improve lysosomal targeting and tissue distribution have been highlighted. This review describes the glycan structures that are important for lysosomal targeting and provides information on recent glyco-engineering technologies for the development of therapeutic enzymes with improved efficacy.

Necroptosis in health and diseases.

PubMed

Zhou, Wen; Yuan, Junying

2014-11-01

Necroptosis is a form of regulated necrosis that can be activated by ligands of death receptors and stimuli that induce the expression of death receptor ligands under apoptotic deficient conditions. Activation of necroptosis by ligands of death receptors requires the kinase activity of RIP1, which mediates the activation of RIP3 and MLKL, two critical downstream mediators of necroptosis. Blocking the kinase activity of RIP1, a key druggable target in the necroptosis pathway, by necrostatins inhibits the activation of necroptosis and allows cell survival and proliferation in the presence of death receptor ligands. The activation of necroptosis is modulated by different forms of ubiquitination, including K63, linear and K48 ubiquitination, as well as phosphorylation of RIP1, RIP3 and MLKL. Necroptosis is suppressed by caspase-8/FADD-mediated apoptosis. Deficiency in caspase-8 and FADD leads to embryonic lethality, tissue degeneration and inflammation which can be suppressed by inhibition of RIP1 kinase and RIP3. On the other hand, the lack of RIP3 kinase activity leads to early embryonic lethality which can be suppressed by the loss of caspase-8, suggesting that although the kinase activity of RIP3 is involved in mediating necroptosis, the basal activity of RIP3 kinase may be required for suppressing caspase-8 mediated apoptosis. Necroptosis as well as RIP1- and RIP3-mediated inflammatory response have been implicated in mediating multiple human diseases including TNF-mediated hypothermia and systemic inflammation, ischemic reperfusion injury, neurodegeneration, Gaucher's disease, progressive atherosclerotic lesions, etc. Targeting RIP1 kinase may provide therapeutic benefits for the treatment of human diseases characterized by necrosis and inflammation. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Genetic background of osteoporosis.

PubMed

Obermayer-Pietsch, B; Chararas, C; Kotschan, S; Walter, D; Leb, G

2000-01-01

Osteoporosis is a systemic disorder of decreased skeletal mass as measured by bone mineral density (BMD), and disturbed skeletal architecture and function which results in an increased risk for bone fractures with consecutively increased morbidity and mortality. Twin and family studies have shown an important genetic component of BMD of about 40-60%. This exceeds other well known factors influencing BMD such as environmental factors like dietary calcium, physical activity or several drugs and diseases. Therefore, interest increased in the genetic background of bone mineral density. Polymorphisms of the Vitamin D receptor gene were the first to be published in this area. Studies on other loci or candidate genes such as the estrogen receptor gene or the collagen type I alpha1 gene also showed associations with bone mineral density that could explain at least a part of the genetic background of osteoporosis. Recently published data suggest that these genetic markers of bone metabolism are important in interaction with each other or in certain bone-affecting diseases. In the future, genetic studies on osteoporosis will have to screen further relevant genes and markers for bone metabolism as well as to evaluate the complex interactions of genetic influences, so that it would be possible to calculate a patient's individual risk for osteoporosis in the context of environmental influences.

Differences in genetic background influence the induction of innate and acquired immune responses in chickens depending on the virulence of the infecting infectious bursal disease virus (IBDV) strain.

PubMed

Aricibasi, Merve; Jung, Arne; Heller, E Dan; Rautenschlein, Silke

2010-05-15

Previous studies and field observations have suggested that genetic background influences infectious bursal disease virus (IBDV) pathogenesis. However, the influence of the virulence of the infecting IBDV strain and the mechanisms underlying the differences in susceptibility are not known. In the present study IBDV pathogenesis was compared between specific-pathogen-free layer-type (LT) chickens, which are the most susceptible chicken for IBDV and have been used as the model for pathogenesis studies, and broiler-type (BT) chickens, which are known to be less susceptible to clinical infectious bursal disease (IBD). The innate and acquired immune responses were investigated after inoculation of an intermediate (i), virulent (v) or very virulent (vv) strain of IBDV. IBDV pathogenesis was comparable among genetic backgrounds after infection with iIBDV. After infection with vIBDV and vvIBDV, LT birds showed severe clinical disease and mortality, higher bursal lesion scores and IBDV-antigen load relative to BT birds. Circulating cytokine induction varied significantly in both timing and quantity between LT and BT birds and among virus strains (P<0.05). Evaluation of different immune cell populations by flow-cytometric analysis in the bursa of Fabricius provided circumstantial evidence of a stronger local T cell response in BT birds vs. LT birds after infection with the virulent strain. On the other hand, LT birds showed a more significant increase in circulating macrophage-derived immune mediators such as total interferon (IFN) and serum nitrite than BT birds on days 2 and 3 post-vIBDV infection (P<0.05). Stronger stimulation of innate immune reactions especially after vIBDV infection in the early phase may lead to faster and more severe lesion development accompanied by clinical disease and death in LT chickens relative to BT chickens. Interestingly, no significant differences were seen between genetic backgrounds in induction of the IBDV-specific humoral response

Impact of glucocerebrosidase mutations on motor and nonmotor complications in Parkinson's disease.

PubMed

Oeda, Tomoko; Umemura, Atsushi; Mori, Yuko; Tomita, Satoshi; Kohsaka, Masayuki; Park, Kwiyoung; Inoue, Kimiko; Fujimura, Harutoshi; Hasegawa, Hiroshi; Sugiyama, Hiroshi; Sawada, Hideyuki

2015-12-01

Homozygous mutations of the glucocerebrosidase gene (GBA) cause Gaucher disease (GD), and heterozygous mutations of GBA are a major risk factor for Parkinson's disease (PD). This study examined the impact of GBA mutations on the longitudinal clinical course of PD patients by retrospective cohort design. GBA-coding regions were fully sequenced in 215 PD patients and GD-associated GBA mutations were identified in 19 (8.8%) PD patients. In a retrospective cohort study, time to develop dementia, psychosis, wearing-off, and dyskinesia were examined. Survival time analysis followed a maximum 12-year observation (median 6.0 years), revealing that PD patients with GD-associated mutations developed dementia and psychosis significantly earlier than those without mutations (p < 0.001 and p = 0.017, respectively). Adjusted hazard ratios of GBA mutations were 8.3 for dementia (p < 0.001) and 3.1 for psychosis (p = 0.002). No statistically significant differences were observed for wearing-off and dyskinesia between the groups. N-isopropyl-p[(123)I] iodoamphetamine single-photon emission tomography pixel-by-pixel analysis revealed that regional cerebral blood flow was reduced in the bilateral parietal cortex, including the precuneus of GD-associated mutant PD patients, compared with matched PD controls without mutations. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Vestibular function in patients with Niemann-Pick type C disease.

PubMed

Bremova, Tatiana; Krafczyk, Siegbert; Bardins, Stanislavs; Reinke, Jörg; Strupp, Michael

2016-11-01

We investigated whether vestibular dysfunction may cause or contribute to postural imbalance and falls in patients with Niemann-Pick type C disease (NP-C). Eight patients with NP-C disease and 20 healthy controls were examined using the video-based head impulse test (vHIT) and caloric irrigation to investigate horizontal canal function as well as ocular- and cervical vestibular evoked myogenic potentials (o- and cVEMP), and binocular subjective visual vertical estimation (SVV) for otolith function, and static posturography. There were no significant differences in vestibulo-ocular gain, caloric excitability, o-/cVEMP measures or SVV between the two groups. Posturographic total sway path (tSP) and root mean square (RMS) were significantly higher in NP-C than in controls in 3 out of 4 conditions. The Romberg quotient (RQ) to assess the amount of visual stabilization was significantly lower in the NP-C than in the HC group. In contrast to other inherited metabolic disorders, such as Morbus Gaucher type 3, we did not find any evidence for an impairment of canal or otolith function in patients with NP-C as their cause of postural imbalance. Since RQ was low in NP-C patients, indicating proper sensory input, the observed increased postural sway is most likely due to a cerebellar dysfunction in NP-C, which may therefore, explain postural imbalance.

Newborn Screening for Lysosomal Storage Disorders: Views of Genetic Healthcare Providers.

PubMed

Lisi, Emily C; McCandless, Shawn E

2016-04-01

Lysosomal storage diseases (LSDs), lysosomal enzyme deficiencies causing multi-system organ damage, have come to the forefront in newborn screening (NBS) initiatives due to new screening technologies and emerging treatments. We developed a qualitative discussion tool to explore opinions of genetic healthcare providers (HCPs) regarding population-based NBS for MPS types 1 and 2, Pompe, Gaucher, Fabry, and Krabbe diseases. Thirty-eight telephone interviews conducted by a single researcher were analyzed and coded for thematic trends. Six major themes emerged: 1) treatment availability and efficacy is crucial; 2) early age of disease onset is important; 3) ambiguity regarding prognosis is undesirable; 4) parents' ability to make reproductive decisions is seen by some as a benefit of NBS; 5) paucity of resources for follow-up exists; and 6) the decision-making process for adding conditions to mandated NBS is concerning to HCPs. Among the LSDs discussed, Pompe was considered most appropriate, and Krabbe least appropriate, for NBS. MPS1 and MPS2 were overall considered favorably for screening, but MPS1 ranked higher, due to a perception of better efficacy of therapeutic options. Fabry and Gaucher diseases were viewed less favorably due to later age of onset. The themes identified in this study must be addressed by decision-makers in expanding NBS for LSDs and may be applied to many diseases being considered for NBS in the future.

Prevalence of major cardiovascular risk factors and cardiovascular diseases among Hispanic/Latino individuals of diverse backgrounds in the United States.

PubMed

Daviglus, Martha L; Talavera, Gregory A; Avilés-Santa, M Larissa; Allison, Matthew; Cai, Jianwen; Criqui, Michael H; Gellman, Marc; Giachello, Aida L; Gouskova, Natalia; Kaplan, Robert C; LaVange, Lisa; Penedo, Frank; Perreira, Krista; Pirzada, Amber; Schneiderman, Neil; Wassertheil-Smoller, Sylvia; Sorlie, Paul D; Stamler, Jeremiah

2012-11-07

Major cardiovascular diseases (CVDs) are leading causes of mortality among US Hispanic and Latino individuals. Comprehensive data are limited regarding the prevalence of CVD risk factors in this population and relations of these traits to socioeconomic status (SES) and acculturation. To describe prevalence of major CVD risk factors and CVD (coronary heart disease [CHD] and stroke) among US Hispanic/Latino individuals of different backgrounds, examine relationships of SES and acculturation with CVD risk profiles and CVD, and assess cross-sectional associations of CVD risk factors with CVD. Multicenter, prospective, population-based Hispanic Community Health Study/Study of Latinos including individuals of Cuban (n = 2201), Dominican (n = 1400), Mexican (n = 6232), Puerto Rican (n = 2590), Central American (n = 1634), and South American backgrounds (n = 1022) aged 18 to 74 years. Analyses involved 15,079 participants with complete data enrolled between March 2008 and June 2011. Adverse CVD risk factors defined using national guidelines for hypercholesterolemia, hypertension, obesity, diabetes, and smoking. Prevalence of CHD and stroke were ascertained from self-reported data. Age-standardized prevalence of CVD risk factors varied by Hispanic/Latino background; obesity and current smoking rates were highest among Puerto Rican participants (for men, 40.9% and 34.7%; for women, 51.4% and 31.7%, respectively); hypercholesterolemia prevalence was highest among Central American men (54.9%) and Puerto Rican women (41.0%). Large proportions of participants (80% of men, 71% of women) had at least 1 risk factor. Age- and sex-adjusted prevalence of 3 or more risk factors was highest in Puerto Rican participants (25.0%) and significantly higher (P < .001) among participants with less education (16.1%), those who were US-born (18.5%), those who had lived in the United States 10 years or longer (15.7%), and those who preferred English (17.9%). Overall, self-reported CHD and stroke

Glucocerebrosidase Mutations in Parkinson Disease.

PubMed

O'Regan, Grace; deSouza, Ruth-Mary; Balestrino, Roberta; Schapira, Anthony H

2017-01-01

Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD. The clinical similarity with idiopathic PD and the chance to identify PD at a pre-clinical stage provides a unique opportunity to research therapeutic options for early PD, before major irreversible neurodegeneration occurs. However, to date, the molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are not fully elucidated. Experimental models to define the molecular mechanisms and test therapeutic options include cell culture, transgenic mice and other in vivo models amenable to genetic manipulation, such as drosophilia. Some key pathological pathways of interest in the context of GBA mutations include alpha synuclein aggregation, lysosomal-autophagy axis changes and endoplasmic reticulum stress. Therapeutic agents that exploit these pathways are being developed and include the small molecule chaperone Ambroxol. This review aims to summarise the main features of GBA-PD and provide insights into the pathological relevance of GBA mutations on molecular pathways and the therapeutic implications for PD resulting from investigation of the role of GBA in PD.

PATIENT-REPORTED OUTCOMES IN RARE LYSOSOMAL STORAGE DISEASES: KEY INFORMANT INTERVIEWS AND A SYSTEMATIC REVIEW PROTOCOL.

PubMed

Miller, Patricia A; Mulla, Sohail M; Adams-Webber, Thomasin; Sivji, Yasmin; Guyatt, Gordon H; Johnston, Bradley C

2016-01-01

To investigate the use, challenges and opportunities associated with using patient-reported outcomes (PROs) in studies with patients with rare lysosomal storage diseases (LSDs), we conducted interviews with researchers and health technology assessment (HTA) experts, and developed the methods for a systematic review of the literature. The purpose of the review is to identify the psychometrically sound generic and disease-specific PROs used in studies with patients with five LSDs of interest: Fabry, Gaucher (Type I), Niemann-Pick (Type B) and Pompe diseases, and mucopolysaccharidosis (Types I and II). Researchers and HTA experts who responded to an email invitation participated in a telephone interview. We used qualitative content analysis to analyze the anonymized transcripts. We conducted a comprehensive literature search for studies that used PROs to investigate burden of disease or to assess the impact of interventions across the five LSDs of interest. Interviews with seven researchers and six HTA experts representing eight countries revealed five themes. These were: (i) the importance of using psychometrically sound PROs in studies with rare diseases, (ii) the paucity of disease-specific PROs, (iii) the importance of having PRO data for economic analyses, (iv) practical and psychometric limitations of existing PROs, and (v) suggestions for new PROs. The systematic review has been completed. The interviews highlight current challenges and opportunities experienced by researchers and HTA experts involved in work with rare LSDs. The ongoing systematic review will highlight the experience, opportunities, and limitations of PROs in LSDs and provide suggestions for future research.

Endoplasmic reticulum and lysosomal Ca²⁺ stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts.

PubMed

Kilpatrick, Bethan S; Magalhaes, Joana; Beavan, Michelle S; McNeill, Alisdair; Gegg, Matthew E; Cleeter, Michael W J; Bloor-Young, Duncan; Churchill, Grant C; Duchen, Michael R; Schapira, Anthony H; Patel, Sandip

2016-01-01

Mutations in β-glucocerebrosidase (encoded by GBA1) cause Gaucher disease (GD), a lysosomal storage disorder, and increase the risk of developing Parkinson disease (PD). The pathogenetic relationship between the two disorders is unclear. Here, we characterised Ca(2+) release in fibroblasts from type I GD and PD patients together with age-matched, asymptomatic carriers, all with the common N370S mutation in β-glucocerebrosidase. We show that endoplasmic reticulum (ER) Ca(2+) release was potentiated in GD and PD patient fibroblasts but not in cells from asymptomatic carriers. ER Ca(2+) signalling was also potentiated in fibroblasts from aged healthy subjects relative to younger individuals but not further increased in aged PD patient cells. Chemical or molecular inhibition of β-glucocerebrosidase in fibroblasts and a neuronal cell line did not affect ER Ca(2+) signalling suggesting defects are independent of enzymatic activity loss. Conversely, lysosomal Ca(2+) store content was reduced in PD fibroblasts and associated with age-dependent alterations in lysosomal morphology. Accelerated remodelling of Ca(2+) stores by pathogenic GBA1 mutations may therefore feature in PD. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Strain Background Modifies Phenotypes in the ATP8B1-Deficient Mouse

PubMed Central

Vargas, Julie C.; Xu, Hongmei; Groen, Annamiek; Paulusma, Coen C.; Grenert, James P.; Pawlikowska, Ludmila; Sen, Saunak; Elferink, Ronald P. J. Oude; Bull, Laura N.

2010-01-01

Background Mutations in ATP8B1 (FIC1) underlie cases of cholestatic disease, ranging from chronic and progressive (progressive familial intrahepatic cholestasis) to intermittent (benign recurrent intrahepatic cholestasis). The ATP8B1-deficient mouse serves as an animal model of human ATP8B1 deficiency. Methodology/Principal Findings We investigated the effect of genetic background on phenotypes of ATP8B1-deficient and wild-type mice, using C57Bl/6 (B6), 129, and (B6-129) F1 strain backgrounds. B6 background resulted in greater abnormalities in ATP8B1-deficient mice than did 129 and/or F1 background. ATP8B1-deficient pups of B6 background gained less weight. In adult ATP8B1-deficient mice at baseline, those of B6 background had lower serum cholesterol levels, higher serum alkaline phosphatase levels, and larger livers. After challenge with cholate-supplemented diet, these mice exhibited higher serum alkaline phosphatase and bilirubin levels, greater weight loss and larger livers. ATP8B1-deficient phenotypes in mice of F1 and 129 backgrounds are usually similar, suggesting that susceptibility to manifestations of ATP8B1 deficiency may be recessive. We also detected differences in hepatobiliary phenotypes between wild-type mice of differing strains. Conclusions/Significance Our results indicate that the ATP8B1-deficient mouse in a B6 background may be a better model of human ATP8B1 deficiency and highlight the importance of informed background strain selection for mouse models of liver disease. PMID:20126555

Chronically Ill Children in America: Background and Recommendations.

ERIC Educational Resources Information Center

Hobbs, Nicholas; And Others

The report examines chronic illness in children and considers issues and recommendations for change in public policies and programs affecting chronically ill children and their families. The background chapter notes the significance of the problem, reviews 11 diseases that are representative of the severe chronic illnesses of childhood: juvenile…

Rapid screening for lipid storage disorders using biochemical markers. Expert center data and review of the literature.

PubMed

Voorink-Moret, M; Goorden, S M I; van Kuilenburg, A B P; Wijburg, F A; Ghauharali-van der Vlugt, J M M; Beers-Stet, F S; Zoetekouw, A; Kulik, W; Hollak, C E M; Vaz, F M

2018-02-01

In patients suspected of a lipid storage disorder (sphingolipidoses, lipidoses), confirmation of the diagnosis relies predominantly on the measurement of specific enzymatic activities and genetic studies. New UPLC-MS/MS methods have been developed to measure lysosphingolipids and oxysterols, which, combined with chitotriosidase activity may represent a rapid first tier screening for lipid storage disorders. A lysosphingolipid panel consisting of lysoglobotriaosylceramide (LysoGb3), lysohexosylceramide (LysoHexCer: both lysoglucosylceramide and lysogalactosylceramide), lysosphingomyelin (LysoSM) and its carboxylated analogue lysosphingomyelin-509 (LysoSM-509) was measured in control subjects and plasma samples of predominantly untreated patients affected with lipid storage disorders (n=74). In addition, the oxysterols cholestane-3β,5α,6β-triol and 7-ketocholesterol were measured in a subset of these patients (n=36) as well as chitotriosidase activity (n=43). A systematic review of the literature was performed to assess the usefulness of these biochemical markers. Specific elevations of metabolites, i.e. without overlap between controls and other lipid storage disorders, were found for several lysosomal storage diseases: increased LysoSM levels in acid sphingomyelinase deficiency (Niemann-Pick disease type A/B), LysoGb3 levels in males with classical phenotype Fabry disease and LysoHexCer (i.e. lysoglucosylceramide/lysogalactosylceramide) in Gaucher and Krabbe diseases. While elevated levels of LysoSM-509 and cholestane-3β,5α,6β-triol did not discriminate between Niemann Pick disease type C and acid sphingomyelinase deficiency, LysoSM-509/LysoSM ratio was specifically elevated in Niemann-Pick disease type C. In Gaucher disease type I, mild increases in several lysosphingolipids were found including LysoGb3 with levels in the range of non-classical Fabry males and females. Chitotriosidase showed specific elevations in symptomatic Gaucher disease, and was mildly

Background and design of the symptom burden in end-stage liver disease patient-caregiver dyad study.

PubMed

Hansen, Lissi; Lyons, Karen S; Dieckmann, Nathan F; Chang, Michael F; Hiatt, Shirin; Solanki, Emma; Lee, Christopher S

2017-10-01

Over half a million Americans are affected by cirrhosis, the cause of end-stage liver disease (ESLD). Little is known about how symptom burden changes over time in adults with ESLD and their informal caregivers, which limits our ability to develop palliative care interventions that can optimize symptom management and quality of life in different patient-caregiver dyads. The purpose of this article is to describe the background and design of a prospective, longitudinal descriptive study, "Symptom Burden in End-Stage Liver Disease Patient-Caregiver Dyads," which is currently in progress. The study is designed to (i) identify trajectories of change in physical and psychological symptom burden in adults with ESLD; (ii) identify trajectories of change in physical and psychological symptom burden in caregivers of adults with ESLD; and (iii) determine predictors of types of patient-caregiver dyads that would benefit from tailored palliative care interventions. We aim for a final sample of 200 patients and 200 caregivers who will be followed over 12 months. Integrated multilevel and latent growth mixture modeling will be used to identify trajectories of change in symptom burden, linking those changes to clinical events, and quality of life outcomes and characterizing types of patient-caregiver dyads based on patient-, caregiver-, and dyad-level factors. Challenges we have encountered include unexpected attrition of study participants, participants not returning their baseline questionnaires, and hiring and training of research staff. The study will lay the foundation for future research and innovation in ESLD, end-of-life and palliative care, and caregiving. © 2017 Wiley Periodicals, Inc.

The Australasian Society for Infectious Diseases and Refugee Health Network of Australia recommendations for health assessment for people from refugee-like backgrounds: an abridged outline.

PubMed

Chaves, Nadia J; Paxton, Georgia A; Biggs, Beverley-Ann; Thambiran, Aesen; Gardiner, Joanne; Williams, Jan; Smith, Mitchell M; Davis, Joshua S

2017-04-17

In 2009, the Australasian Society of Infectious Diseases published guidelines on the post-arrival health assessment of recently arrived refugees. Since then, the number of refugees and asylum seekers reaching Australia has increased substantially (17 555 refugees in 2015-16) and the countries of origin have changed. These groups are likely to have had poor access to health care pre-arrival and, consequently, are at risk of a range of chronic and infectious diseases. We established an advisory group that included infectious diseases physicians, general practitioners, public health specialists, paediatricians and refugee health nurses to update the 2009 guidelines.Main recommendations: All people from refugee-like backgrounds, including children, should be offered a tailored comprehensive health assessment and management plan, ideally within 1 month of arrival in Australia. This can be offered at any time if initial contact with a GP or clinic is delayed. Recommended screening depends on history, examination and previous investigations, and is tailored based on age, gender, countries of origin and transit and risk profile. The full version of the guidelines is available at http://www.asid.net.au/documents/item/1225.Changes in management as a result of this guideline: These guidelines apply to all people from refugee-like backgrounds, including asylum seekers. They provide more information about non-communicable diseases and consider Asia and the Middle East as regions of origin as well as Africa. Key changes include an emphasis on person-centred care; risk-based rather than universal screening for hepatitis C virus, malaria, schistosomiasis and sexually transmissible infections; updated immunisation guidelines; and new recommendations for other problems, such as nutritional deficiencies, women's health and mental health.

Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines

PubMed Central

Black, Steven; Eskola, Juhani; Siegrist, Claire-Anne; Halsey, Neal; MacDonald, Noni; Law, Barbara; Miller, Elizabeth; Andrews, Nick; Stowe, Julia; Salmon, Daniel; Vannice, Kirsten; Izurieta, Hector S; Akhtar, Aysha; Gold, Mike; Oselka, Gabriel; Zuber, Patrick; Pfeifer, Dina; Vellozzi, Claudia

2010-01-01

Because of the advent of a new influenza A H1N1 strain, many countries have begun mass immunisation programmes. Awareness of the background rates of possible adverse events will be a crucial part of assessment of possible vaccine safety concerns and will help to separate legitimate safety concerns from events that are temporally associated with but not caused by vaccination. We identified background rates of selected medical events for several countries. Rates of disease events varied by age, sex, method of ascertainment, and geography. Highly visible health conditions, such as Guillain-Barré syndrome, spontaneous abortion, or even death, will occur in coincident temporal association with novel influenza vaccination. On the basis of the reviewed data, if a cohort of 10 million individuals was vaccinated in the UK, 21·5 cases of Guillain-Barré syndrome and 5·75 cases of sudden death would be expected to occur within 6 weeks of vaccination as coincident background cases. In female vaccinees in the USA, 86·3 cases of optic neuritis per 10 million population would be expected within 6 weeks of vaccination. 397 per 1 million vaccinated pregnant women would be predicted to have a spontaneous abortion within 1 day of vaccination. PMID:19880172

Splenomegaly - Diagnostic validity, work-up, and underlying causes.

PubMed

Curovic Rotbain, Emelie; Lund Hansen, Dennis; Schaffalitzky de Muckadell, Ove; Wibrand, Flemming; Meldgaard Lund, Allan; Frederiksen, Henrik

2017-01-01

Our aim was to assess the validity of the ICD-10 code for splenomegaly in the Danish National Registry of Patients (DNRP), as well as to investigate which underlying diseases explained the observed splenomegaly. Splenomegaly is a common finding in patients referred to an internal medical department and can be caused by a large spectrum of diseases, including haematological diseases and liver cirrhosis. However, some patients remain without a causal diagnosis, despite extensive medical work-up. We identified 129 patients through the DNRP, that had been given the ICD-10 splenomegaly diagnosis code in 1994-2013 at Odense University Hospital, Denmark, excluding patients with prior splenomegaly, malignant haematological neoplasia or liver cirrhosis. Medical records were reviewed for validity of the splenomegaly diagnosis, diagnostic work-up, and the underlying disease was determined. The positive predictive value (PPV) with 95% confidence interval (CI) was calculated for the splenomegaly diagnosis code. Patients with idiopathic splenomegaly in on-going follow-up were also invited to be investigated for Gaucher disease. The overall PPV was 92% (95% CI: 85, 96). Haematological diseases were the underlying causal diagnosis in 39%; hepatic diseases in 18%, infectious disease in 10% and other diseases in 8%. 25% of patients with splenomegaly remained without a causal diagnosis. Lymphoma was the most common haematological causal diagnosis and liver cirrhosis the most common hepatic causal diagnosis. None of the investigated patients with idiopathic splenomegaly had Gaucher disease. Our findings show that the splenomegaly diagnosis in the DNRP is valid and can be used in registry-based studies. However, because of suspected significant under-coding, it should be considered if supplementary data sources should be used in addition, in order to attain a more representative population. Haematological diseases were the most common cause, however in a large fraction of patients no

Treatment of cataplexy in Niemann-Pick disease type C with the use of miglustat.

PubMed

Zarowski, Marcin; Steinborn, Barbara; Gurda, Barbara; Dvorakova, Lenka; Vlaskova, Hana; Kothare, Sanjeev V

2011-01-01

Cataplexy is the sudden muscle weakness brought on by strong emotions, particularly joking, laughter, or anger. Cataplexy may involve only certain group of muscles or the entire voluntary musculature. In rare cases, symptoms of cataplexy can be seen during the course of some inherited diseases (Niemann-Pick type C (NPC), Prader-Willi syndrome, myotonic dystrophy, Norrie disease). We report the successful use of miglustat, a reversible inhibitor of the enzyme glucosylceramide synthase, approved for use in Gaucher's disease, and which catalyses the first step in the biosynthesis of most glycosphingolipid, in a boy with NPC with cataplexy. A 9-year-old boy was admitted for assessments of frequent "drop attacks" while laughing. The filipin fluorescence tests of cultured skin fibroblasts revealed massive accumulation of unesterified cholesterol, confirming the diagnosis of NPC disease. Molecular studies confirmed the diagnosis of NPC too. After approval from the bioethics committee, miglustat was initiated on the child at 100mg three times a day. Cataplectic attacks disappeared completely after 6 months on treatment, and patient continues to be in remission from the cataplectic attacks at 16 months follow-up. There was no further progression of neurological signs or symptoms or splenomegaly, with some improvement in cognitive function as well as social, affective and attention problems, up-gaze, and gait. Miglustat was well tolerated with no side effects observed. In summary, this is the first report of miglustat treatment of cataplexy in NPC. Long-term follow-up for continuing efficacy and tolerability in a larger cohort with NPC is needed to substantiate our observation. © 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload.

PubMed

Fetterman, Jessica L; Zelickson, Blake R; Johnson, Larry W; Moellering, Douglas R; Westbrook, David G; Pompilius, Melissa; Sammy, Melissa J; Johnson, Michelle; Dunham-Snary, Kimberly J; Cao, Xuemei; Bradley, Wayne E; Zhang, Jinju; Wei, Chih-Chang; Chacko, Balu; Schurr, Theodore G; Kesterson, Robert A; Dell'italia, Louis J; Darley-Usmar, Victor M; Welch, Danny R; Ballinger, Scott W

2013-10-15

Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mtDNA sequence variation contributes to disease susceptibility. In the present study we show a novel animal model of mtDNA polymorphisms, the MNX (mitochondrial-nuclear exchange) mouse, in which the mtDNA from the C3H/HeN mouse has been inserted on to the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harbouring the C57/BL6J mtDNA generate more ROS (reactive oxygen species) and have a higher mitochondrial membrane potential relative to those with C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the 'mitochondrial paradigm' for the development of disease susceptibility, and show that the mtDNA modulates cellular bioenergetics, mitochondrial ROS generation and susceptibility to cardiac stress.

Parkinson's disease: acid-glucocerebrosidase activity and alpha-synuclein clearance.

PubMed

Blanz, Judith; Saftig, Paul

2016-10-01

The role of mutations in the gene GBA1 encoding the lysosomal hydrolase β-glucocerebrosidase for the development of synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, was only very recently uncovered. The knowledge obtained from the study of carriers or patients suffering from Gaucher disease (a common lysosomal storage disorder because of GBA1 mutations) is of particular importance for understanding the role of the enzyme and its catabolic pathway in the development of synucleinopathies. Decreased activity of β-glucocerebrosidase leads to lysosomal dysfunction and the accumulation of its substrate glucosylceramide and related lipid derivatives. Glucosylceramide is suggested to stabilize toxic oligomeric forms of α-synuclein that negatively influence the activity of β-glucocerebrosidase and to partially block export of newly synthesized β-glucocerebrosidase from the endoplasmic reticulum to late endocytic compartments, amplifying the pathological effects of α-synuclein and ultimately resulting in neuronal cell death. This pathogenic molecular feedback loop and most likely other factors (such as impaired endoplasmic reticulum-associated degradation, activation of the unfolded protein response and dysregulation of calcium homeostasis induced by misfolded GC mutants) are involved in shifting the cellular homeostasis from monomeric α-synuclein towards oligomeric neurotoxic and aggregated forms, which contribute to Parkinson's disease progression. From a therapeutic point of view, strategies aiming to increase either the expression, stability or delivery of the β-glucocerebrosidase to lysosomes are likely to decrease the α-synuclein burden and may be useful for an in depth evaluation at the organismal level. Lysosomes are critical for protein and lipid homeostasis. Recent research revealed that dysfunction of this organelle contributes to the development of neurodegenerative diseases such as Parkinson's disease (PD). Mutations in the

Background stratified Poisson regression analysis of cohort data.

PubMed

Richardson, David B; Langholz, Bryan

2012-03-01

Background stratified Poisson regression is an approach that has been used in the analysis of data derived from a variety of epidemiologically important studies of radiation-exposed populations, including uranium miners, nuclear industry workers, and atomic bomb survivors. We describe a novel approach to fit Poisson regression models that adjust for a set of covariates through background stratification while directly estimating the radiation-disease association of primary interest. The approach makes use of an expression for the Poisson likelihood that treats the coefficients for stratum-specific indicator variables as 'nuisance' variables and avoids the need to explicitly estimate the coefficients for these stratum-specific parameters. Log-linear models, as well as other general relative rate models, are accommodated. This approach is illustrated using data from the Life Span Study of Japanese atomic bomb survivors and data from a study of underground uranium miners. The point estimate and confidence interval obtained from this 'conditional' regression approach are identical to the values obtained using unconditional Poisson regression with model terms for each background stratum. Moreover, it is shown that the proposed approach allows estimation of background stratified Poisson regression models of non-standard form, such as models that parameterize latency effects, as well as regression models in which the number of strata is large, thereby overcoming the limitations of previously available statistical software for fitting background stratified Poisson regression models.

Cardiovascular disease and diabetes in patients with African or Asian background.

PubMed

Aambø, Arild; Klemsdal, Tor Ole

2017-11-28

Population groups of different ancestry appear to have varying prevalence of diabetes, different risks of developing cardiovascular disease and different responses to certain drugs that are used for these conditions. We wished to review the literature in this field. We have performed searches in several databases for systematic review articles published from the year 2000 onwards, and supplemented these with articles from reference lists, our own literature archives and a pyramid search in the Norwegian Electronic Health Library database. Altogether 37 articles were included. With regard to diagnosed diabetes, the prevalence of coronary heart disease and stroke varies among groups of South Asian, East Asian, African and European ancestry. In patients of South Asian ancestry, the risk of coronary heart disease appears to be twice that of Europeans, and the disease occurs 5–10 years earlier. The prevalence of stroke is especially high in persons of African ancestry. Risk factors such as dyslipidemia and hypertension are distributed differently among these groups. The therapeutic response to drugs such as beta blockers, ACE inhibitors and various statins differs; for example, statin doses in Asians may often be halved in relation to those used for Caucasians, and ACE inhibitors are not recommended as monotherapy for hypertension in persons of African ancestry. These differences are partly attributable to variations in genetic disposition. The findings are clinically significant – better insight in this field enables optimal tailoring of treatment for each patient, with more rapid achievement of goals and reduced risk of adverse effects. The recommendations given in this article are consistent with and complement the Directorate of Health’s revised guidelines for the treatment of diabetes.

Effect of genetic background on the dystrophic phenotype in mdx mice

PubMed Central

Coley, William D.; Bogdanik, Laurent; Vila, Maria Candida; Yu, Qing; Van Der Meulen, Jack H.; Rayavarapu, Sree; Novak, James S.; Nearing, Marie; Quinn, James L.; Saunders, Allison; Dolan, Connor; Andrews, Whitney; Lammert, Catherine; Austin, Andrew; Partridge, Terence A.; Cox, Gregory A.; Lutz, Cathleen; Nagaraju, Kanneboyina

2016-01-01

Genetic background significantly affects phenotype in multiple mouse models of human diseases, including muscular dystrophy. This phenotypic variability is partly attributed to genetic modifiers that regulate the disease process. Studies have demonstrated that introduction of the γ-sarcoglycan-null allele onto the DBA/2J background confers a more severe muscular dystrophy phenotype than the original strain, demonstrating the presence of genetic modifier loci in the DBA/2J background. To characterize the phenotype of dystrophin deficiency on the DBA/2J background, we created and phenotyped DBA/2J-congenic Dmdmdx mice (D2-mdx) and compared them with the original, C57BL/10ScSn-Dmdmdx (B10-mdx) model. These strains were compared with their respective control strains at multiple time points between 6 and 52 weeks of age. Skeletal and cardiac muscle function, inflammation, regeneration, histology and biochemistry were characterized. We found that D2-mdx mice showed significantly reduced skeletal muscle function as early as 7 weeks and reduced cardiac function by 28 weeks, suggesting that the disease phenotype is more severe than in B10-mdx mice. In addition, D2-mdx mice showed fewer central myonuclei and increased calcifications in the skeletal muscle, heart and diaphragm at 7 weeks, suggesting that their pathology is different from the B10-mdx mice. The new D2-mdx model with an earlier onset and more pronounced dystrophy phenotype may be useful for evaluating therapies that target cardiac and skeletal muscle function in dystrophin-deficient mice. Our data align the D2-mdx with Duchenne muscular dystrophy patients with the LTBP4 genetic modifier, making it one of the few instances of cross-species genetic modifiers of monogenic traits. PMID:26566673

Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons

PubMed Central

Rotger, Margalida; Glass, Tracy R.; Junier, Thomas; Lundgren, Jens; Neaton, James D.; Poloni, Estella S.; van 't Wout, Angélique B.; Lubomirov, Rubin; Colombo, Sara; Martinez, Raquel; Rauch, Andri; Günthard, Huldrych F.; Neuhaus, Jacqueline; Wentworth, Deborah; van Manen, Danielle; Gras, Luuk A.; Schuitemaker, Hanneke; Albini, Laura; Torti, Carlo; Jacobson, Lisa P.; Li, Xiuhong; Kingsley, Lawrence A.; Carli, Federica; Guaraldi, Giovanni; Ford, Emily S.; Sereti, Irini; Hadigan, Colleen; Martinez, Esteban; Arnedo, Mireia; Egaña-Gorroño, Lander; Gatell, Jose M.; Law, Matthew; Bendall, Courtney; Petoumenos, Kathy; Rockstroh, Jürgen; Wasmuth, Jan-Christian; Kabamba, Kabeya; Delforge, Marc; De Wit, Stephane; Berger, Florian; Mauss, Stefan; de Paz Sierra, Mariana; Losso, Marcelo; Belloso, Waldo H.; Leyes, Maria; Campins, Antoni; Mondi, Annalisa; De Luca, Andrea; Bernardino, Ignacio; Barriuso-Iglesias, Mónica; Torrecilla-Rodriguez, Ana; Gonzalez-Garcia, Juan; Arribas, José R.; Fanti, Iuri; Gel, Silvia; Puig, Jordi; Negredo, Eugenia; Gutierrez, Mar; Domingo, Pere; Fischer, Julia; Fätkenheuer, Gerd; Alonso-Villaverde, Carlos; Macken, Alan; Woo, James; McGinty, Tara; Mallon, Patrick; Mangili, Alexandra; Skinner, Sally; Wanke, Christine A.; Reiss, Peter; Weber, Rainer; Bucher, Heiner C.; Fellay, Jacques; Telenti, Amalio; Tarr, Philip E.

2013-01-01

Background Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. Methods In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. Results A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9×10−4). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05–2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06–1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16–1.96), diabetes (OR = 1.66; 95% CI, 1.10–2.49), ≥1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06–1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17–2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. Conclusions In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD. PMID:23532479

Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons.

PubMed

Rotger, Margalida; Glass, Tracy R; Junier, Thomas; Lundgren, Jens; Neaton, James D; Poloni, Estella S; van 't Wout, Angélique B; Lubomirov, Rubin; Colombo, Sara; Martinez, Raquel; Rauch, Andri; Günthard, Huldrych F; Neuhaus, Jacqueline; Wentworth, Deborah; van Manen, Danielle; Gras, Luuk A; Schuitemaker, Hanneke; Albini, Laura; Torti, Carlo; Jacobson, Lisa P; Li, Xiuhong; Kingsley, Lawrence A; Carli, Federica; Guaraldi, Giovanni; Ford, Emily S; Sereti, Irini; Hadigan, Colleen; Martinez, Esteban; Arnedo, Mireia; Egaña-Gorroño, Lander; Gatell, Jose M; Law, Matthew; Bendall, Courtney; Petoumenos, Kathy; Rockstroh, Jürgen; Wasmuth, Jan-Christian; Kabamba, Kabeya; Delforge, Marc; De Wit, Stephane; Berger, Florian; Mauss, Stefan; de Paz Sierra, Mariana; Losso, Marcelo; Belloso, Waldo H; Leyes, Maria; Campins, Antoni; Mondi, Annalisa; De Luca, Andrea; Bernardino, Ignacio; Barriuso-Iglesias, Mónica; Torrecilla-Rodriguez, Ana; Gonzalez-Garcia, Juan; Arribas, José R; Fanti, Iuri; Gel, Silvia; Puig, Jordi; Negredo, Eugenia; Gutierrez, Mar; Domingo, Pere; Fischer, Julia; Fätkenheuer, Gerd; Alonso-Villaverde, Carlos; Macken, Alan; Woo, James; McGinty, Tara; Mallon, Patrick; Mangili, Alexandra; Skinner, Sally; Wanke, Christine A; Reiss, Peter; Weber, Rainer; Bucher, Heiner C; Fellay, Jacques; Telenti, Amalio; Tarr, Philip E

2013-07-01

Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9 × 10(-4)). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05-2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16-1.96), diabetes (OR = 1.66; 95% CI, 1.10-2.49), ≥ 1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06-1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

A lysosomal lair for a pathogenic protein pair.

PubMed

Dawson, Ted M; Dawson, Valina L

2011-07-13

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects movement. Although many of the causes of PD remain unclear, a consistent finding is the abnormal accumulation of the protein α-synuclein. In a recent issue of Cell, Mazzuli et al. provide a molecular explanation for the unexpected link between PD and Gaucher's disease, a glycolipid lysosomal storage disorder caused by loss of the enzyme glucocerebrosidase (GBA). They report a reciprocal connection between loss of GBA activity and the accumulation of α-synuclein in lysosomes that establishes a bidirectional positive feedback loop with pathogenic consequences. Understanding how lysosomes are implicated in PD may reveal new therapeutic targets for treating this disease.

Case Study of the Minimum Provable Risk Considering the Variation in Background Risk: Effect of Residual Risk on Epidemiological Studies and a Comparative Assessment of Fatal Disease Risk Due to Radiation Exposure.

PubMed

Sasaki, Michiya; Ogino, Haruyuki; Hattori, Takatoshi

2018-06-08

In order to prove a small increment in a risk of concern in an epidemiological study, a large sample of a population is generally required. Since the background risk of an end point of interest, such as cancer mortality, is affected by various factors, such as lifestyle (diet, smoking, etc.), adjustment for such factors is necessary. However, it is impossible to inclusively and completely adjust for such factors; therefore, uncertainty in the background risk remains for control and exposed populations, indicating that there is a minimum limit to the lower bound for the provable risk regardless of the sample size. In this case study, we developed and discussed the minimum provable risk considering the uncertainty in background risk for hypothetical populations by referring to recent Japanese statistical information to grasp the extent of the minimum provable risk. Risk of fatal diseases due to radiation exposure, which has recently been the focus of radiological protection, was also examined by comparative assessment of the minimum provable risk for cancer and circulatory diseases. It was estimated that the minimum provable risk for circulatory disease mortality was much greater than that for cancer mortality, approximately five to seven times larger; circulatory disease mortality is more difficult to prove as a radiation risk than cancer mortality under the conditions used in this case study.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

TALEN-mediated generation and genetic correction of disease-specific human induced pluripotent stem cells.

PubMed

Ramalingam, Sivaprakash; Annaluru, Narayana; Kandavelou, Karthikeyan; Chandrasegaran, Srinivasan

2014-01-01

Generation and precise genetic correction of patient-derived hiPSCs have great potential in regenerative medicine. Such targeted genetic manipulations can now be achieved using gene-editing nucleases. Here, we report generation of cystic fibrosis (CF) and Gaucher's disease (GD) hiPSCs respectively from CF (homozygous for CFTRΔF508 mutation) and Type II GD [homozygous for β-glucocerebrosidase (GBA) 1448T>C mutation] patient fibroblasts, using CCR5- specific TALENs. Site-specific addition of loxP-flanked Oct4/Sox2/Klf4/Lin28/Nanog/eGFP gene cassette at the endogenous CCR5 site of patient-derived disease-specific primary fibroblasts induced reprogramming, giving rise to both monoallele (heterozygous) and biallele CCR5-modified hiPSCs. Subsequent excision of the donor cassette was done by treating CCR5-modified CF and GD hiPSCs with Cre. We also demonstrate site-specific correction of sickle cell disease (SCD) mutations at the endogenous HBB locus of patient-specific hiPSCs [TNC1 line that is homozygous for mutated β- globin alleles (βS/βS)], using HBB-specific TALENs. SCD-corrected hiPSC lines showed gene conversion of the mutated βS to the wild-type βA in one of the HBB alleles, while the other allele remained a mutant phenotype. After excision of the loxP-flanked DNA cassette from the SCD-corrected hiPSC lines using Cre, we obtained secondary heterozygous βS/βA hiPSCs, which express the wild-type (βA) transcript to 30-40% level as compared to uncorrected (βS/βS) SCD hiPSCs when differentiated into erythroid cells. Furthermore, we also show that TALEN-mediated generation and genetic correction of disease-specific hiPSCs did not induce any off-target mutations at closely related sites.

Background characterization of an ultra-low background liquid scintillation counter

DOE PAGES

Erchinger, J. L.; Orrell, John L.; Aalseth, C. E.; ...

2017-01-26

The Ultra-Low Background Liquid Scintillation Counter developed by Pacific Northwest National Laboratory will expand the application of liquid scintillation counting by enabling lower detection limits and smaller sample volumes. By reducing the overall count rate of the background environment approximately 2 orders of magnitude below that of commercially available systems, backgrounds on the order of tens of counts per day over an energy range of ~3–3600 keV can be realized. Finally, initial test results of the ULB LSC show promising results for ultra-low background detection with liquid scintillation counting.

Health care to empower self-care in adolescents with type 1 diabetes mellitus and an immigrant minority background

PubMed Central

Boman, Åse; Bohlin, Margareta; Eklöf, Mats; Forsander, Gun; Munthe, Christian; Törner, Marianne

2017-01-01

Background: The pediatric diabetes team aims to support health, quality of life, and normal growth and development among adolescents with type 1 diabetes mellitus. Adolescents with an immigrant background have been found less successful in self-care. Previous research indicated that adolescents who had integrated the disease as a part of their self-image reasoned differently about their self-care to those who had not. Objective: The aim of this study was to identify elements in the patient–pediatrician consultations that might influence such integration of the disease among adolescents with type 1 diabetes mellitus. Methods: A total of 12 pediatrician–adolescent consultations were video-recorded and analyzed. The adolescents all had an immigrant background. Results: Integration of the disease appeared enabled when responsibility was shared; when hope, autonomy, and emotions were confirmed; and when the pediatrician asked probing questions. Letting objective data dominate the adolescent’s experiences, using risk as a motivator, neutralizing emotions in relation to having diabetes, and confirming forgetfulness, may instead inhibit disease integration. Conclusion: An extended person-centered approach with focus on the adolescent’s experiences of everyday life with a chronic disease and less attention on physical parameters in the pediatrician–adolescent consultations may increase integration of the disease. PMID:28491304

Mitochondrial Genetic Background Modulates Bioenergetics and Susceptibility to Acute Cardiac Volume – Overload

PubMed Central

Fetterman, Jessica L.; Zelickson, Blake R.; Johnson, Larry W.; Moellering, Douglas R.; Westbrook, David G.; Pompilius, Melissa; Sammy, Melissa J.; Johnson, Michelle; Dunham-Snary, Kimberly J.; Cao, Xuemei; Bradley, Wayne E.; Zhang, Jinju; Wei, Chih-Chang; Chacko, Balu; Schurr, Theodore G.; Kesterson, Robert A.; Dell’Italia, Louis J.; Darley-Usmar, Victor M.; Welch, Danny R.; Ballinger, Scott W.

2013-01-01

Synopsis Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mitochondrial DNA (mtDNA) sequence variation contributes to disease susceptibility. In this study we present a novel animal model of mtDNA polymorphisms, the mitochondrial nuclear exchange mouse (MNX), in which the mtDNA from C3H/HeN mouse has been inserted onto the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harboring the C57/BL6J mtDNA generate more reactive oxygen species (ROS) and have a higher mitochondrial membrane potential relative to those having the C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the “mitochondrial paradigm” for the development of disease susceptibility, and show that the mtDNA modulates, cellular bioenergetics, mitochondrial reactive oxygen species generation and susceptibility to cardiac stress. PMID:23924350

Display conditions and lesion detectability: effect of background light

NASA Astrophysics Data System (ADS)

Razavi, Mahmood; Hall, Theodore R.; Aberle, Denise R.; Hayrapetian, Alek S.; Loloyan, Mansur; Eldredge, Sandra L.

1990-08-01

We assessed the effect of high background light on observer performance for the detection of a variety of chest radiographic abnormalities. Five observers reviewed 66 digital hard copy chest images formatted to 1 1 x 14 inch size under two display conditions: 1) on a specially prepared 1 1 x 14 inch illuminated panel with no peripheral light and 2) on a standard viewing panel designed for 14 x 17 inch radiographs. The images contained one - or more of the following conditions: pneumothorax, interstitial disease, nodules, alveolar process, or no abnormality. The results of receiver operator characteristic analysis show that extraneous light does reduce observer performance and the detectability of nodules, interstitial disease.

Agalsidase beta treatment is associated with improved quality of life in patients with Fabry disease: findings from the Fabry Registry.

PubMed

Watt, Torquil; Burlina, Alessandro P; Cazzorla, Chiara; Schönfeld, Dorothee; Banikazemi, Maryam; Hopkin, Robert J; Martins, Ana Maria; Sims, Katherine; Beitner-Johnson, Dana; O'Brien, Fanny; Feldt-Rasmussen, Ulla

2010-11-01

To evaluate the effect of agalsidase beta on longitudinal health-related quality of life in patients with Fabry disease. The SF-36® Health Survey was used to measure health-related quality of life in Fabry Registry patients. Seventy-one men and 59 women who were treated with agalsidase beta (median dose: 1.0 mg/kg/² weeks) and who had baseline and at least 2 yearly posttreatment health-related quality of life measurements were included in these analyses. A repeated measures model was used to analyze change in score from baseline. Men improved in the physical component summary and in all eight scales of the SF-36 after 1 and 2 years and in the mental component summary after 1 year of agalsidase beta treatment (P < 0.05). Women improved in the mental component summary and in six of the eight scales after 1 and/or 2 years of treatment. Patients whose baseline SF-36 scores were below the median showed the greatest improvements. These responses were comparable with or greater than the published effects of various treatments for multiple sclerosis, rheumatoid arthritis, central neuropathic pain, and Gaucher disease. Long-term treatment with agalsidase beta resulted in substantial improvements in health-related quality of life in both men and women; the effect was more pronounced in men.

Genetic Background and Climatic Droplet Keratopathy Incidence in a Mapuche Population from Argentina

PubMed Central

Schurr, Theodore G.; Dulik, Matthew C.; Cafaro, Thamara A.; Suarez, María F.

2013-01-01

Purpose To determine whether the incidence of and susceptibility to climatic droplet keratopathy (CDK), an acquired, often bilateral degenerative corneal disease, is influenced by the genetic background of the individuals who exhibit the disorder. Methods To determine whether the disease expression was influenced by the genetic ancestry of CDK cases in native Mapuche of the northwest area of Patagonia in Argentina, we examined mitochondrial DNA and Y-chromosome variation in 53 unrelated individuals. Twenty-nine of them were part of the CDK (patient) population, while 24 were part of the control group. The analysis revealed the maternal and paternal lineages that were present in the two study groups. Results This analysis demonstrated that nearly all persons had a Native American mtDNA background, whereas 50% of the CDK group and 37% of the control group had Native American paternal ancestry, respectively. There was no significant difference in the frequencies of mtDNA haplogroups between the CDK patient and control groups. Although the Y-chromosome data revealed differences in specific haplogroup frequencies between these two groups, there was no statistically significant relationship between individual paternal genetic backgrounds and the incidence or stage of disease. Conclusions These results indicate a lack of correlation between genetic ancestry as represented by haploid genetic systems and the incidence of CDK in Mapuche populations. In addition, the mtDNA appears to play less of a role in CDK expression than for other complex diseases linked to bioenergetic processes. However, further analysis of the mtDNA genome sequence and other genes involved in corneal function may reveal the more precise role that mitochondria play in the expression of CDK. PMID:24040292

Genetic background and climatic droplet keratopathy incidence in a Mapuche population from Argentina.

PubMed

Schurr, Theodore G; Dulik, Matthew C; Cafaro, Thamara A; Suarez, María F; Urrets-Zavalia, Julio A; Serra, Horacio M

2013-01-01

To determine whether the incidence of and susceptibility to climatic droplet keratopathy (CDK), an acquired, often bilateral degenerative corneal disease, is influenced by the genetic background of the individuals who exhibit the disorder. To determine whether the disease expression was influenced by the genetic ancestry of CDK cases in native Mapuche of the northwest area of Patagonia in Argentina, we examined mitochondrial DNA and Y-chromosome variation in 53 unrelated individuals. Twenty-nine of them were part of the CDK (patient) population, while 24 were part of the control group. The analysis revealed the maternal and paternal lineages that were present in the two study groups. This analysis demonstrated that nearly all persons had a Native American mtDNA background, whereas 50% of the CDK group and 37% of the control group had Native American paternal ancestry, respectively. There was no significant difference in the frequencies of mtDNA haplogroups between the CDK patient and control groups. Although the Y-chromosome data revealed differences in specific haplogroup frequencies between these two groups, there was no statistically significant relationship between individual paternal genetic backgrounds and the incidence or stage of disease. These results indicate a lack of correlation between genetic ancestry as represented by haploid genetic systems and the incidence of CDK in Mapuche populations. In addition, the mtDNA appears to play less of a role in CDK expression than for other complex diseases linked to bioenergetic processes. However, further analysis of the mtDNA genome sequence and other genes involved in corneal function may reveal the more precise role that mitochondria play in the expression of CDK.

Lower Prevalence of Atopic Dermatitis and Allergic Sensitization among Children and Adolescents with a Two-Sided Migrant Background.

PubMed

Ernst, Sinja Alexandra; Schmitz, Roma; Thamm, Michael; Ellert, Ute

2016-02-26

In industrialized countries atopic diseases have been reported to be less likely in children and adolescents with a migrant background compared to non-migrants. This paper aimed at both examining and comparing prevalence of asthma, allergic rhinoconjunctivitis and atopic dermatitis and allergic sensitization to specific IgE antibodies in children and adolescents with and without a migrant background. Using data of the population-based German Health Interview and Examination Survey for children and adolescents (KiGGS;n = 17,450; 0-17 years), lifetime and 12-month prevalence of atopic diseases and point prevalence of 20 common allergic sensitizations were investigated among migrants compared to non-migrants. Multiple regression models were used to estimate the association of atopic disease and allergic sensitization with migrant background. In multivariate analyses with substantial adjustment we found atopic dermatitis about one-third less often (OR 0.73, 0.57-0.93) in participants with a two-sided migrant background. Statistically significant associations between allergic sensitizations and a two-sided migrant background remained for birch (OR 0.73, 0.58-0.90), soybean (OR 0.72, 0.54-0.96), peanut (OR 0.69, 0.53-0.90), rice (OR 0.64, 0.48-0.87), potato (OR 0.64, 0.48-0.85), and horse dander (OR 0.58, 0.40-0.85). Environmental factors and living conditions might be responsible for the observed differences.

Illness Perception and Clinical Treatment Experiences in Patients with M. Maroteaux-Lamy (Mucopolysaccharidosis Type VI) and a Turkish Migration Background in Germany

PubMed Central

Dilger, Hansjörg; Leissner, Linn; Bosanska, Lenka; Lampe, Christina; Plöckinger, Ursula

2013-01-01

Introduction Mucopolysaccharidosis VI (MPS VI) is an inherited lysosomal storage disease caused by a mutation of the gene for arylsulfatase B (ASB). Of the thirty-one patients registered in Germany, almost fifty percent have a Turkish migration background. MPS VI is treated by enzyme replacement therapy (ERT), which is time-consuming and expensive. Methods This interdisciplinary study explored the illness perceptions and clinical treatment experiences among ten MPS VI patients with a Turkish migration background in two centers for metabolic diseases (Berlin and Mainz, Germany). The clinical treatment situation was observed and semi-structured interviews were conducted with patients and health care personnel, in addition to participatory observation in four patients' everyday environments in Berlin. The data from the interviews, patient records, and personal field notes were encoded, cross-related, and analyzed. Results Patients' acknowledgement of the disease and coping strategies are influenced predominantly by the perception of their individual health status and the handling of the disease within their family. Patients' willingness to cooperate with treatment strategies is further modified by their knowledge of the disease and the relationships with their health care providers. In this analysis, cultural factors turned out to be marginally relevant. Conclusion As with other chronic and debilitating diseases, effective treatment strategies have to reach beyond delivering medication. Health care providers need to strengthen the support for patients with a migration background. In this regard, they should respect the patients' cultural and social background and their personal perception of the disease and the therapy. Yet structural and social aspects (clinical setting, family and educational background) may be more crucial here than “cultural barriers.” PMID:23826140

Optimal background matching camouflage.

PubMed

Michalis, Constantine; Scott-Samuel, Nicholas E; Gibson, David P; Cuthill, Innes C

2017-07-12

Background matching is the most familiar and widespread camouflage strategy: avoiding detection by having a similar colour and pattern to the background. Optimizing background matching is straightforward in a homogeneous environment, or when the habitat has very distinct sub-types and there is divergent selection leading to polymorphism. However, most backgrounds have continuous variation in colour and texture, so what is the best solution? Not all samples of the background are likely to be equally inconspicuous, and laboratory experiments on birds and humans support this view. Theory suggests that the most probable background sample (in the statistical sense), at the size of the prey, would, on average, be the most cryptic. We present an analysis, based on realistic assumptions about low-level vision, that estimates the distribution of background colours and visual textures, and predicts the best camouflage. We present data from a field experiment that tests and supports our predictions, using artificial moth-like targets under bird predation. Additionally, we present analogous data for humans, under tightly controlled viewing conditions, searching for targets on a computer screen. These data show that, in the absence of predator learning, the best single camouflage pattern for heterogeneous backgrounds is the most probable sample. © 2017 The Authors.

Background sources at PEP

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lynch, H.; Schwitters, R.F.; Toner, W.T.

Important sources of background for PEP experiments are studied. Background particles originate from high-energy electrons and positrons which have been lost from stable orbits, ..gamma..-rays emitted by the primary beams through bremsstrahlung in the residual gas, and synchrotron radiation x-rays. The effect of these processes on the beam lifetime are calculated and estimates of background rates at the interaction region are given. Recommendations for the PEP design, aimed at minimizing background are presented. 7 figs., 4 tabs.

75 FR 65431 - Change in Disease Status of Japan Because of Foot-and-Mouth Disease

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-25

.... APHIS-2010-0077] Change in Disease Status of Japan Because of Foot-and-Mouth Disease AGENCY: Animal and... removing Japan from the list of regions considered to be free of foot-and-mouth disease (FMD) and also from.... SUPPLEMENTARY INFORMATION: Background Foot-and-mouth disease (FMD) is a severe and highly contagious viral...

Aseptic necrosis of the femoral head after pregnancy: a case report.

PubMed

Nassar, Kawtar; Rachidi, Wafae; Janani, Saadia; Mkinsi, Ouafa

2016-01-01

A documented case of beginning aseptic necrosis of the femoral head associated with pregnancy together with a review of the literature about this rare complication of pregnancy is presented. The known risk factors of osteonecrosis are; steroid use, alcoholism, organ transplantation, especially after kidney transplant or bone marrow transplantation bone, systemic lupus erythematosus, dyslipidemia especially hypertriglyceridemia, dysbaric decompression sickness, drepanocytosis and Gaucher's disease. Among the less established factors, we mention procoagulations abnormalities, HIV infection, chemotherapy. We report a case of osteonecrosis of femoral head after pregnancy.

Features of GBA-associated Parkinson's disease at presentation in the UK Tracking Parkinson's study.

PubMed

Malek, Naveed; Weil, Rimona S; Bresner, Catherine; Lawton, Michael A; Grosset, Katherine A; Tan, Manuela; Bajaj, Nin; Barker, Roger A; Burn, David J; Foltynie, Thomas; Hardy, John; Wood, Nicholas W; Ben-Shlomo, Yoav; Williams, Nigel W; Grosset, Donald G; Morris, Huw R

2018-01-29

To examine the influence of the glucocerebrosidase ( GBA ) mutation carrier state on age at onset of Parkinson's disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function. We prospectively recruited patients with PD in the Tracking Parkinson's study. We fully sequenced the GBA gene in all recently diagnosed patients (≤3.5 years). We examined cognitive (Montreal Cognitive Assessment) and motor (Movement Disorder Society Unified Parkinson's Disease Rating Scale part 3) function at a baseline assessment, at an average of 1.3 years after diagnosis. We used logistic regression to determine predictors of PD with mild cognitive impairment and PD with dementia. We studied 1893 patients with PD: 48 (2.5%) were heterozygous carriers for known Gaucher's disease (GD) causing pathogenic mutations; 117 (6.2%) had non-synonymous variants, previously associated with PD, and 28 (1.5%) patients carried variants of unknown significance in the GBA gene. L444P was the most common pathogenic GBA mutation. Patients with pathogenic GBA mutations were on average 5 years younger at disease onset compared with non-carriers (P=0.02). PD patients with GD-causing mutations did not have an increased family risk of PD. Patients with GBA mutations were more likely to present with the postural instability gait difficulty phenotype compared with non-carriers (P=0.02). Patients carrying pathogenic mutations in GBA had more advanced Hoehn and Yahr stage after adjustment for age and disease duration compared with non-carriers (P=0.005). There were no differences in cognitive function between GBA mutation carriers and non-carriers at this early disease stage. Our study confirms the influence of GBA mutations on the age of onset, disease severity and motor phenotype in patients with PD. Cognition did not differ between GBA

Complex interplay between neutral and adaptive evolution shaped differential genomic background and disease susceptibility along the Italian peninsula.

PubMed

Sazzini, Marco; Gnecchi Ruscone, Guido Alberto; Giuliani, Cristina; Sarno, Stefania; Quagliariello, Andrea; De Fanti, Sara; Boattini, Alessio; Gentilini, Davide; Fiorito, Giovanni; Catanoso, Mariagrazia; Boiardi, Luigi; Croci, Stefania; Macchioni, Pierluigi; Mantovani, Vilma; Di Blasio, Anna Maria; Matullo, Giuseppe; Salvarani, Carlo; Franceschi, Claudio; Pettener, Davide; Garagnani, Paolo; Luiselli, Donata

2016-09-01

The Italian peninsula has long represented a natural hub for human migrations across the Mediterranean area, being involved in several prehistoric and historical population movements. Coupled with a patchy environmental landscape entailing different ecological/cultural selective pressures, this might have produced peculiar patterns of population structure and local adaptations responsible for heterogeneous genomic background of present-day Italians. To disentangle this complex scenario, genome-wide data from 780 Italian individuals were generated and set into the context of European/Mediterranean genomic diversity by comparison with genotypes from 50 populations. To maximize possibility of pinpointing functional genomic regions that have played adaptive roles during Italian natural history, our survey included also ~250,000 exomic markers and ~20,000 coding/regulatory variants with well-established clinical relevance. This enabled fine-grained dissection of Italian population structure through the identification of clusters of genetically homogeneous provinces and of genomic regions underlying their local adaptations. Description of such patterns disclosed crucial implications for understanding differential susceptibility to some inflammatory/autoimmune disorders, coronary artery disease and type 2 diabetes of diverse Italian subpopulations, suggesting the evolutionary causes that made some of them particularly exposed to the metabolic and immune challenges imposed by dietary and lifestyle shifts that involved western societies in the last centuries.

Insights into the background of autonomic medicine.

PubMed

Laranjo, Sérgio; Geraldes, Vera; Oliveira, Mário; Rocha, Isabel

2017-10-01

Knowledge of the physiology underlying the autonomic nervous system is pivotal for understanding autonomic dysfunction in clinical practice. Autonomic dysfunction may result from primary modifications of the autonomic nervous system or be secondary to a wide range of diseases that cause severe morbidity and mortality. Together with a detailed history and physical examination, laboratory assessment of autonomic function is essential for the analysis of various clinical conditions and the establishment of effective, personalized and precise therapeutic schemes. This review summarizes the main aspects of autonomic medicine that constitute the background of cardiovascular autonomic dysfunction. Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Idiopathic avascular necrosis of the femoral heads in five members of a Moroccan family.

PubMed

Sekkat, Jihane; Rachidi, Ouafaa; Janani, Saadia; Mkinsi, Ouafaa

2012-10-01

Avascular necrosis (AVN) is idiopathic in about 40% of cases. The pathophysiology of avascular necrosis remains incompletely elucidated. Here, we report a case that underlines the role for inherited factors in AVN of the femoral heads. Idiopathic AVN of the femoral heads occurred in five members of the same family (a woman, her two paternal aunts, her male paternal cousin and her female paternal cousin) at a mean age of 42.4 years (range, 33-58 years). Standard pelvic radiographs showed Arlet and Ficat stage 4 AVN in three patients and stage 3 in two patients. None of the patients had a history of glucocorticoid therapy, alcohol abuse, or trauma. All five patients underwent investigations for a cause, including blood cell counts, a lipid profile, coagulation tests, testing for antinuclear antibodies, hemoglobin electrophoresis, ultrasonography of the abdomen, and standard radiographs of the long limb bones. The results were normal or negative, ruling out known hereditary causes of AVN such as sickle cell anemia and Gaucher disease. Many cases of familial AVN of the femoral head have been described in patients with sickle cell anemia or Gaucher disease. However, only five families with idiopathic familial AVN of the femoral heads have been reported (three in the US and two in Taiwan). All the patients in these families had isolated bilateral AVN of the femoral heads without AVN at other sites. Copyright © 2012. Published by Elsevier SAS.

Health care to empower self-care in adolescents with type 1 diabetes mellitus and an immigrant minority background.

PubMed

Boman, Åse; Bohlin, Margareta; Eklöf, Mats; Forsander, Gun; Munthe, Christian; Törner, Marianne

2017-01-01

The pediatric diabetes team aims to support health, quality of life, and normal growth and development among adolescents with type 1 diabetes mellitus. Adolescents with an immigrant background have been found less successful in self-care. Previous research indicated that adolescents who had integrated the disease as a part of their self-image reasoned differently about their self-care to those who had not. The aim of this study was to identify elements in the patient-pediatrician consultations that might influence such integration of the disease among adolescents with type 1 diabetes mellitus. A total of 12 pediatrician-adolescent consultations were video-recorded and analyzed. The adolescents all had an immigrant background. Integration of the disease appeared enabled when responsibility was shared; when hope, autonomy, and emotions were confirmed; and when the pediatrician asked probing questions. Letting objective data dominate the adolescent's experiences, using risk as a motivator, neutralizing emotions in relation to having diabetes, and confirming forgetfulness, may instead inhibit disease integration. An extended person-centered approach with focus on the adolescent's experiences of everyday life with a chronic disease and less attention on physical parameters in the pediatrician-adolescent consultations may increase integration of the disease.

Backgrounds in Language.

ERIC Educational Resources Information Center

Maxwell, John C.; Long, Barbara K.

"Backgrounds in Language," a field-tested inservice course designed for use by groups of 15 or 25 language arts teachers, provides the subject matter background teachers need to make informed decisions about what curriculum materials to use in what way, at what time, and with which students. The course is comprised of eight 2-hour sessions,…

Limited responsiveness related to the minimal important difference of patient-reported outcomes in rare diseases.

PubMed

Johnston, Bradley C; Miller, Patricia A; Agarwal, Arnav; Mulla, Sohail; Khokhar, Rabia; De Oliveira, Kyle; Hitchcock, Christine L; Sadeghirad, Behnam; Mohiuddin, Mukarram; Sekercioglu, Nigar; Seweryn, Michal; Koperny, Magdalena; Bala, Malgorzata M; Adams-Webber, Thomasin; Granados, Alicia; Hamed, Alaa; Crawford, Mark W; van der Ploeg, Ans T; Guyatt, Gordon H

2016-11-01

To explore the responsiveness of patient-reported outcomes (PROs) in interventional studies involving patients with rare lysosomal storage diseases (LSDs). We searched eight databases for experimental and nonexperimental studies. Pairs of trained reviewers independently screened articles and subsequently extracted data from the eligible studies. Among studies with 10 or more patients using a valid PRO, we assessed the responsiveness of PROs based on a reanalysis of the data using minimal important difference estimates. Our analyses focused on statistically significant within-group differences in PROs for observational studies or the statistically significant between-group differences in PRO scores for controlled studies. Of 2,679 unique records, 62 interventional studies addressing patients with Fabry (55%), Gaucher (19%), Pompe (16%), and mucopolysaccharidoses (11%) proved eligible. The most frequently used PROs were the Short-Form-36 (25 studies), Brief Pain Inventory (20 studies), EuroQoL-5D (9 studies), and the Fatigue Severity Scale (6 studies). Observational studies suggest that PROs sometimes detect significant within-group changes when present. Randomized trials raise questions regarding the responsiveness of PROs to small differences between groups. Most studies have relied on generic PROs to evaluate quality of life and symptoms in patients with rare LSDs. PROs appear more responsive in observational studies than randomized trials. Copyright © 2016 Elsevier Inc. All rights reserved.

Visual signal detection in structured backgrounds. II. Effects of contrast gain control, background variations, and white noise

NASA Technical Reports Server (NTRS)

Eckstein, M. P.; Ahumada, A. J. Jr; Watson, A. B.

1997-01-01

Studies of visual detection of a signal superimposed on one of two identical backgrounds show performance degradation when the background has high contrast and is similar in spatial frequency and/or orientation to the signal. To account for this finding, models include a contrast gain control mechanism that pools activity across spatial frequency, orientation and space to inhibit (divisively) the response of the receptor sensitive to the signal. In tasks in which the observer has to detect a known signal added to one of M different backgrounds grounds due to added visual noise, the main sources of degradation are the stochastic noise in the image and the suboptimal visual processing. We investigate how these two sources of degradation (contrast gain control and variations in the background) interact in a task in which the signal is embedded in one of M locations in a complex spatially varying background (structured background). We use backgrounds extracted from patient digital medical images. To isolate effects of the fixed deterministic background (the contrast gain control) from the effects of the background variations, we conduct detection experiments with three different background conditions: (1) uniform background, (2) a repeated sample of structured background, and (3) different samples of structured background. Results show that human visual detection degrades from the uniform background condition to the repeated background condition and degrades even further in the different backgrounds condition. These results suggest that both the contrast gain control mechanism and the background random variations degrade human performance in detection of a signal in a complex, spatially varying background. A filter model and added white noise are used to generate estimates of sampling efficiencies, an equivalent internal noise, an equivalent contrast-gain-control-induced noise, and an equivalent noise due to the variations in the structured background.

[CLINICAL BACKGROUND ANALYSIS ABOUT TRANSURETHRAL ELECTROCOAGULATION].

PubMed

Katsui, Masahiro; Kikuchi, Eiji; Yazawa, Satoshi; Hagiwara, Masayuki; Morita, Shinya; Shinoda, Kazunobu; Kosaka, Takeo; Mizuno, Ryuichi; Shinojima, Toshiaki; Asanuma, Hiroshi; Miyajima, Akira; Oya, Mototsugu

2015-10-01

Transurethral electrocoagulation (TUC) is a rare event but occurs in a constant manner with various causes or disorders and reduces patient quality of life. So far there have been no reports focusing on the details of TUC. We focused on the clinical background and related causes in cases of TUC in our institution. We identified 76 cases (65 patients) who underwent TUC at Keio University Hospital between April 2001 and March 2011. We focused on patient background, especially with respect to the primary disease, treatment modality, use of antiplatelet or anticoagulant agent, timing of TUC, type of electrosurgical device, and the incidence of transfusion. The primary disease for TUC included bladder tumor (BT) in 31 cases, benign prostate hyperplasia (BPH) in 13, prostate cancer (PCa) in 13, idiopathic bladder bleeding in 4, periarteritis nodosa in 3, uterine cervical cancer in 3, and others in 9. TUC after transurethral resection (TUR) was found in 38 cases, including transurethral resection of bladder tumor (TURBT) in 26 of 31 BT cases and transurethral resection of prostate (TURP) in 12 of 13 BPH cases. After TURBT, TUC was performed before removal of a urethral catheter in 7 cases, and after removal of a urethral catheter in 19 cases. With regard to TUC associated with TURP, the average estimated prostate volume in TUC cases before removal of the urethral catheter was 66.2 ml, which was significantly larger than that in TUC cases after removal of the urethral catheter (46.1 ml, p = 0.045). TUC after the radiation therapy was observed in 21 cases, and the average time from the radiation therapy to TUC was 3.4 years (7 months-10 years). TUC was caused by multiple causes or disorders, and 75% of our TUC was associated with BT, BPH or PCa. TUC associated with TURBT frequently occurred within 1 week after TURBT but was still observed after 1 month following the operation. All TUC associated with TURP occurred within 3 weeks after operation. The average period from

Illuminating the Background: Topics in Cosmic Microwave Background Polarization Research

NASA Astrophysics Data System (ADS)

Miller, Nathan J.

The cosmic microwave background provides a wealth of information about the origin and history of the universe. The statistics of the anisotropy and the polarization of the cosmic microwave background, among other things, can tell us about the distribution of matter, the redshift of reionization, and the nature of the primordial uctuations. From the lensing of cosmic microwave background due to intervening matter, we can extract information about neutrinos and the equation of state of dark energy. A measurement of the large angular scale B-mode polarization has been called the "smoking gun" of in ation, a theory that describes a possible early rapid expansion of the universe. The focus of current experiments is to measure this B-mode polarization, while several experiments, such as POLARBEAR, are also looking to measure the lensing of the cosmic microwave background. This dissertation will discuss several different topics in cosmic microwave background polarization research. I will make predictions for future experiments and I will also show analysis for two current experiments, POLARBEAR and BICEP. I will show how beam systematics affect the measurement of cosmological parameters and how well we must limit these systematics in order to get unbiased constraints on cosmological parameters for future experiments. I will discuss a novel way of using the temperature-polarization cross correlation to constrain the amount of inflationary gravitational waves. Through Markov Chain Monte Carlo methods, I will determine how well future experiments will be able to constrain the neutrino masses and their degeneracy parameters. I will show results from current data analysis and calibration being done on the Cedar Flat deployment for the POLARBEAR experiment which is currently being constructed in the Atacama desert in Chile. Finally, I will analyze the claim of detection of cosmological birefringence in the BICEP data and show that there is reason to believe it is due to

Thyroid nodularity and chromosome aberrations among women in areas of high background radiation in China

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Z.Y.; Boice, J.D. Jr.; Wei, L.X.

1990-03-21

Thyroid nodularity following continuous low-dose radiation exposure in China was determined in 1,001 women aged 50-65 years who resided in areas of high background radiation (330 mR/yr) their entire lives, and in 1,005 comparison subjects exposed to normal levels of radiation (114 mR/yr). Cumulative doses to the thyroid were estimated to be of the order of 14 cGy and 5 cGy, respectively. Personal interviews and physical examinations were conducted, and measurements were made of serum thyroid hormone levels, urinary iodine concentrations, and chromosome aberrations in circulating lymphocytes. For all nodular disease, the prevalences in the high background and control areasmore » were 9.5% and 9.3%, respectively. For single nodules, the prevalences were 7.4% in the high background area and 6.6% in the control area (prevalence ratio = 1.13; 95% confidence interval = 0.82-1.55). There were no differences found in serum levels of thyroid hormones. Women in the high background region, however, had significantly lower concentrations of urinary iodine and significantly higher frequencies of stable and unstable chromosome aberrations. Increased intake of allium vegetables such as garlic and onions was associated with a decreased risk of nodular disease, which seems consistent with experimental studies suggesting that allium compounds can inhibit tumor growth and proliferation. The prevalence of mild diffuse goiter was higher in the high background radiation region, perhaps related to a low dietary intake of iodine. These data suggest that continuous exposure to low-level radiation throughout life is unlikely to appreciably increase the risk of thyroid cancer. However, such exposure may cause chromosomal damage.« less

Effect of genetic background on the contribution of New Zealand Black loci to autoimmune lupus nephritis

PubMed Central

Rozzo, Stephen J.; Vyse, Timothy J.; Drake, Charles G.; Kotzin, Brian L.

1996-01-01

Autoimmune diseases such as systemic lupus erythematosus are complex genetic traits with contributions from major histocompatibility complex (MHC) genes and multiple unknown non-MHC genes. Studies of animal models of lupus have provided important insight into the immunopathogenesis of disease, and genetic analyses of these models overcome certain obstacles encountered when studying human patients. Genome-wide scans of different genetic crosses have been used to map several disease-linked loci in New Zealand hybrid mice. Although some consensus exists among studies mapping the New Zealand Black (NZB) and New Zealand White (NZW) loci that contribute to lupus-like disease, considerable variability is also apparent. A variable in these studies is the genetic background of the non-autoimmune strain, which could influence genetic contributions from the affected strain. A direct examination of this question was undertaken in the present study by mapping NZB nephritis-linked loci in backcrosses involving different non-autoimmune backgrounds. In a backcross with MHC-congenic C57BL/6J mice, H2z appeared to be the strongest genetic determinant of severe lupus nephritis, whereas in a backcross with congenic BALB/cJ mice, H2z showed no influence on disease expression. NZB loci on chromosomes 1, 4, 11, and 14 appeared to segregate with disease in the BALB/cJ cross, but only the influence of the chromosome 1 locus spanned both crosses and showed linkage with disease when all mice were considered. Thus, the results indicate that contributions from disease-susceptibility loci, including MHC, may vary markedly depending on the non-autoimmune strain used in a backcross analysis. These studies provide insight into variables that affect genetic heterogeneity and add an important dimension of complexity for linkage analyses of human autoimmune disease. PMID:8986781

Background Underground at WIPP

NASA Astrophysics Data System (ADS)

Esch, Ernst-Ingo; Hime, A.; Bowles, T. J.

2001-04-01

Recent interest to establish a dedicated underground laboratory in the United States prompted an experimental program at to quantify the enviromental backgrounds underground at the Waste Isolation Pilot Plant (WIPP) in Carlsbad, New Mexico. An outline of this program is provided along with recent experimental data on the cosmic ray muon flux at the 650 meter level of WIPP. The implications of the cosmic ray muon and fast neutron background at WIPP will be discussed in the context of new generation, low background experiments envisioned in the future.

Generation of a Chinese Hamster Ovary Cell Line Producing Recombinant Human Glucocerebrosidase

PubMed Central

Novo, Juliana Branco; Morganti, Ligia; Moro, Ana Maria; Paes Leme, Adriana Franco; Serrano, Solange Maria de Toledo; Raw, Isaias; Ho, Paulo Lee

2012-01-01

Impaired activity of the lysosomal enzyme glucocerebrosidase (GCR) results in the inherited metabolic disorder known as Gaucher disease. Current treatment consists of enzyme replacement therapy by administration of exogenous GCR. Although effective, it is exceptionally expensive, and patients worldwide have a limited access to this medicine. In Brazil, the public healthcare system provides the drug free of charge for all Gaucher's patients, which reaches the order of $ 84 million per year. However, the production of GCR by public institutions in Brazil would reduce significantly the therapy costs. Here, we describe a robust protocol for the generation of a cell line producing recombinant human GCR. The protein was expressed in CHO-DXB11 (dhfr−) cells after stable transfection and gene amplification with methotrexate. As expected, glycosylated GCR was detected by immunoblotting assay both as cell-associated (~64 and 59 kDa) and secreted (63–69 kDa) form. Analysis of subclones allowed the selection of stable CHO cells producing a secreted functional enzyme, with a calculated productivity of 5.14 pg/cell/day for the highest producer. Although being laborious, traditional methods of screening high-producing recombinant cells may represent a valuable alternative to generate expensive biopharmaceuticals in countries with limited resources. PMID:23091360

Dilatonic parallelizable NS-NS backgrounds

NASA Astrophysics Data System (ADS)

Kawano, Teruhiko; Yamaguchi, Satoshi

2003-08-01

We complete the classification of parallelizable NS-NS backgrounds in type II supergravity by adding the dilatonic case to the result of Figueroa-O'Farrill on the non-dilatonic case. We also study the supersymmetry of these parallelizable backgrounds. It is shown that all the dilatonic parallelizable backgrounds have sixteen supersymmetries.

Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population

PubMed Central

Rivas, Manuel A.; Avila, Brandon E.; Koskela, Jukka; Stevens, Christine; Pirinen, Matti; Neale, Benjamin M.; Ganna, Andrea; Graham, Daniel; Glaser, Benjamin; Peter, Inga; Atzmon, Gil; Barzilai, Nir; Levine, Adam P.; Schiff, Elena; Weisburd, Ben; Lek, Monkol; Bloom, Jonathan; Minikel, Eric V.; Petersen, Britt-Sabina; Beaugerie, Laurent; Seksik, Philippe; Cosnes, Jacques; Schreiber, Stefan; Bokemeyer, Bernd; Bethge, Johannes; Ahmad, Tariq; Plagnol, Vincent; Segal, Anthony W.; Targan, Stephan; Turner, Dan; Saavalainen, Paivi; Farkkila, Martti; Kontula, Kimmo; Palotie, Aarno; Brant, Steven R.; Duerr, Richard H.; Silverberg, Mark S.; Weersma, Rinse K.; Franke, Andre; Jostins, Luke; Barrett, Jeffrey C.; MacArthur, Daniel G.; Jalas, Chaim; Sokol, Harry; Xavier, Ramnik J.; Pulver, Ann; Cho, Judy H.; McGovern, Dermot P. B.; Daly, Mark J.

2018-01-01

As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv), including those that account for 10–100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn's disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn's disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel

Organization for rare diseases India (ORDI) - addressing the challenges and opportunities for the Indian rare diseases' community.

PubMed

Rajasimha, Harsha Karur; Shirol, Prasannakumar Basayya; Ramamoorthy, Preveen; Hegde, Madhuri; Barde, Sangeeta; Chandru, Vijay; Ravinandan, M E; Ramchandran, Ramani; Haldar, Kasturi; Lin, Jimmy C; Babar, Imran A; Girisha, Katta M; Srinivasan, Sudha; Navaneetham, Duraiswamy; Battu, Rajani; Devarakonda, Rajashree; Kini, Usha; Vijayachandra, Kinnimulki; Verma, Ishwar C

2014-08-13

In order to address the unmet needs and create opportunities that benefit patients with rare disease in India, a group of volunteers created a not-for-profit organization named Organization for Rare Diseases India (ORDI; www.ordindia.org). ORDI plans to represent the collective voice and advocate the needs of patients with rare diseases and other stakeholders in India. The ORDI team members come from diverse backgrounds such as genetics, molecular diagnostics, drug development, bioinformatics, communications, information technology, patient advocacy and public service. ORDI builds on the lessons learned from numerous similar organizations in the USA, European Union and disease-specific rare disease foundations in India. In this review, we provide a background on the landscape of rare diseases and the organizations that are active in this area globally and in India. We discuss the unique challenges in tackling rare diseases in India, and highlight the unmet needs of the key stakeholders of rare diseases. Finally, we define the vision, mission, goals and objectives of ORDI, identify the key developments in the health care context in India and welcome community feedback and comments on our approach.

Background Paper for the update of meningococcal vaccination recommendations in Germany: use of the serogroup B vaccine in persons at increased risk for meningococcal disease.

PubMed

Hellenbrand, Wiebke; Koch, Judith; Harder, Thomas; Bogdan, Christian; Heininger, Ulrich; Tenenbaum, Tobias; Terhardt, Martin; Vogel, Ulrich; Wichmann, Ole; von Kries, Rüdiger

2015-11-01

In December 2013 Bexsero® became available in Germany for vaccination against serogroup B meningococci (MenB). In August 2015 the German Standing Committee on Vaccination (STIKO) endorsed a recommendation for use of this vaccine in persons at increased risk of invasive meningococcal disease (IMD). This background paper summarizes the evidence underlying the recommendation. Bexsero® is based on surface protein antigens expressed by about 80% of circulating serogroup B meningococci in Germany. The paper reviews available data on immunogenicity and safety of Bexsero® in healthy children and adolescents; data in persons with underlying illness and on the effectiveness in preventing clinical outcomes are thus far unavailable.STIKO recommends MenB vaccination for the following persons based on an individual risk assessment: (1) Persons with congenital or acquired immune deficiency or suppression. Among these, persons with terminal complement defects and properdin deficiency, including those under eculizumab therapy, are at highest risk with reported invasive meningococcal disease (IMD) incidences up 10,000-fold higher than in the general population. Persons with asplenia were estimated to have a ~ 20-30-fold increased risk of IMD, while the risk in individuals with other immune defects such as HIV infection or hypogammaglobulinaemia was estimated at no more than 5-10-fold higher than the background risk. (2) Laboratory staff with a risk of exposure to N. meningitidis aerosols, for whom an up to 271-fold increased risk for IMD has been reported. (3) Unvaccinated household (-like) contacts of a MenB IMD index case, who have a roughly 100-200-fold increased IMD risk in the year after the contact despite chemoprophylaxis. Because the risk is highest in the first 3 months and full protective immunity requires more than one dose (particularly in infants and toddlers), MenB vaccine should be administered as soon as possible following identification of the serogroup of the

The relationship between glucocerebrosidase mutations and Parkinson disease.

PubMed

Migdalska-Richards, Anna; Schapira, Anthony H V

2016-10-01

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease, whereas Gaucher disease (GD) is the most frequent lysosomal storage disorder caused by homozygous mutations in the glucocerebrosidase (GBA1) gene. Increased risk of developing PD has been observed in both GD patients and carriers. It has been estimated that GBA1 mutations confer a 20- to 30-fold increased risk for the development of PD, and that at least 7-10% of PD patients have a GBA1 mutation. To date, mutations in the GBA1 gene constitute numerically the most important risk factor for PD. The type of PD associated with GBA1 mutations (PD-GBA1) is almost identical to idiopathic PD, except for a slightly younger age of onset and a tendency to more cognitive impairment. Importantly, the pathology of PD-GBA1 is identical to idiopathic PD, with nigral dopamine cell loss, Lewy bodies, and neurites containing alpha-synuclein. The mechanism by which GBA1 mutations increase the risk for PD is still unknown. However, given that clinical manifestation and pathological findings in PD-GBA1 patients are almost identical to those in idiopathic PD individuals, it is likely that, as in idiopathic PD, alpha-synuclein accumulation, mitochondrial dysfunction, autophagic impairment, oxidative and endoplasmic reticulum stress may contribute to the development and progression of PD-GBA1. Here, we review the GBA1 gene, its role in GD, and its link with PD. The impact of glucocerebrosidase 1 (GBA1) mutations on functioning of endoplasmic reticulum (ER), lysosomes, and mitochondria. GBA1 mutations resulting in production of misfolded glucocerebrosidase (GCase) significantly affect the ER functioning. Misfolded GCase trapped in the ER leads to both an increase in the ubiquitin-proteasome system (UPS) and the ER stress. The presence of ER stress triggers the unfolded protein response (UPR) and/or endoplasmic reticulum-associated degradation (ERAD). The prolonged activation of UPR and ERAD

Endoscopic features and genetic background of inflammatory bowel disease complicated with Takayasu arteritis.

PubMed

Akiyama, Shintaro; Fujii, Toshimitsu; Matsuoka, Katsuyoshi; Yusuke, Ebana; Negi, Mariko; Takenaka, Kento; Nagahori, Masakazu; Ohtsuka, Kazuo; Isobe, Mitsuaki; Watanabe, Mamoru

2017-05-01

Takayasu arteritis (TA) is occasionally complicated with inflammatory bowel disease (IBD). This study assessed the endoscopic and genetic features of IBD complicated with TA (IBD-TA). This study retrospectively reviewed the clinical charts of 142 TA patients (14 men and 128 women; median age 48.5 years [range, 18-97 years]). Human lymphocyte antigen (HLA) types and a single-nucleotide polymorphism rs6871626 in the IL12B gene were assessed in 101 and 81 patients with TA, respectively. Inflammatory bowel disease was diagnosed in 13 (9.2%) of the 142 patients. The endoscopic features of IBD-TA at initial diagnosis (n = 8) showed discontinuous and focal mucosal inflammations (n = 7, 87.5%), and only one case was diagnosed as ulcerative colitis (UC) at the first colonoscopy. In the genetic comparison of HLA class I between TA patients with IBD and those without IBD, HLA-B*52:01 and C*12:02 were more frequent in the IBD-TA group (P = 0.001 and P = 0.009, respectively). Meanwhile, HLA-DRB-1*15:02, DQA-1*01:03, DQB-1*06:01, and DPB-1*09:01 as HLA class II were positively associated with IBD-TA (P = 0.004, P = 0.019, P = 0.019, and P = 0.002, respectively). IL12B rs6871626 did not show an association with IBD-TA compared with that with TA without IBD. The endoscopic findings of IBD-TA at initial diagnosis were atypical for UC or Crohn's disease. IBD-TA possessed the HLA haplotype, which had a susceptible effect on UC. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Unsupervised background-constrained tank segmentation of infrared images in complex background based on the Otsu method.

PubMed

Zhou, Yulong; Gao, Min; Fang, Dan; Zhang, Baoquan

2016-01-01

In an effort to implement fast and effective tank segmentation from infrared images in complex background, the threshold of the maximum between-class variance method (i.e., the Otsu method) is analyzed and the working mechanism of the Otsu method is discussed. Subsequently, a fast and effective method for tank segmentation from infrared images in complex background is proposed based on the Otsu method via constraining the complex background of the image. Considering the complexity of background, the original image is firstly divided into three classes of target region, middle background and lower background via maximizing the sum of their between-class variances. Then, the unsupervised background constraint is implemented based on the within-class variance of target region and hence the original image can be simplified. Finally, the Otsu method is applied to simplified image for threshold selection. Experimental results on a variety of tank infrared images (880 × 480 pixels) in complex background demonstrate that the proposed method enjoys better segmentation performance and even could be comparative with the manual segmentation in segmented results. In addition, its average running time is only 9.22 ms, implying the new method with good performance in real time processing.

Newcastle disease

USGS Publications Warehouse

Docherty, D.E.; Friend, M.

1999-01-01

Newcastle Disease (ND) in domestic poultry is a focus for concern throughout much of the world’s agricultural community because of severe economic losses that have occurred from illness, death, and reduced egg production following infection with pathogenic or disease causing strains. Prior to 1990, this disease had rarely been reported as a cause of mortality in the free-living native birds of the United States or Canada. Repeated large-scale losses of double-crested cormorants from ND in both countries has resulted in a need for enhanced awareness of ND as a disease of wild birds and, therefore, its inclusion within this Manual. Background information about ND in poultry is needed to provide a perspective for understanding the complexity of the disease agent, Newcastle disease virus (NDV). Some general information about ND in other avian species is also provided, but the primary focus for this chapter is the effect of NDV on double-crested cormorants.

Two sides of the coin: patient and provider perceptions of health care delivery to patients from culturally and linguistically diverse backgrounds

PubMed Central

2012-01-01

Background Australia is a culturally diverse nation with one in seven Australians born in a non-English speaking country. Culturally and Linguistically Diverse (CALD) populations are at a high risk of developing preventable chronic diseases such as cardiovascular disease, type 2 diabetes mellitus, renal disease, and chronic respiratory disease, especially communities from the Pacific Islands, the Middle East, North Africa, the Indian subcontinent and China. Previous studies have shown that access to services may be a contributing factor. This study explores the experiences, attitudes and opinions of immigrants from different cultural and linguistic backgrounds and their health care providers with regard to chronic disease care. Methods Five focus groups were conducted comprising participants from an Arabic speaking background, or born in Sudan, China, Vietnam or Tonga. A total of 50 members participated. All focus groups were conducted in the participants’ language and facilitated by a trained multicultural health worker. In addition, 14 health care providers were interviewed by telephone. Interviews were digitally recorded and transcribed. All qualitative data were analysed with the assistance of QSR NVivo 8 software. Results Participants were generally positive about the quality and accessibility of health services, but the costs of health care and waiting times to receive treatment presented significant barriers. They expressed a need for greater access to interpreters and culturally appropriate communication and education. They mentioned experiencing racism and discriminatory practices. Health professionals recommended recruiting health workers from CALD communities to assist them to adequately elicit and address the needs of patients from CALD backgrounds. Conclusions CALD patients, carers and community members as well as health professionals all highlighted the need for establishing culturally tailored programs for chronic disease prevention and management

Functional screening of pharmacological chaperones via restoration of enzyme activity upon denaturation.

PubMed

Shanmuganathan, Meera; Britz-McKibbin, Philip

2012-10-02

Pharmacological chaperones (PCs) are small molecules that stabilize and promote protein folding. Enzyme inhibition is widely used for PC selection; however, it does not accurately reflect chaperone activity. We introduce a functional assay for characterization of PCs based on their capacity to restore enzyme activity that is abolished upon chemical denaturation. Dose-dependent activity curves were performed as a function of urea to assess the chaperone potency of various ligands to β-glucocerebrosidase as a model system. Restoration of enzyme activity upon denaturation allows direct screening of PCs for treatment of genetic disorders associated with protein deficiency, such as Gaucher disease.

Low Background Counting at LBNL

DOE PAGES

Smith, A. R.; Thomas, K. J.; Norman, E. B.; ...

2015-03-24

The Low Background Facility (LBF) at Lawrence Berkeley National Laboratory in Berkeley, California provides low background gamma spectroscopy services to a wide array of experiments and projects. The analysis of samples takes place within two unique facilities; locally within a carefully-constructed, low background cave and remotely at an underground location that historically has operated underground in Oroville, CA, but has recently been relocated to the Sanford Underground Research Facility (SURF) in Lead, SD. These facilities provide a variety of gamma spectroscopy services to low background experiments primarily in the form of passive material screening for primordial radioisotopes (U, Th, K)more » or common cosmogenic/anthropogenic products, as well as active screening via Neutron Activation Analysis for specific applications. The LBF also provides hosting services for general R&D testing in low background environments on the surface or underground for background testing of detector systems or similar prototyping. A general overview of the facilities, services, and sensitivities is presented. Recent activities and upgrades will also be presented, such as the completion of a 3π anticoincidence shield at the surface station and environmental monitoring of Fukushima fallout. The LBF is open to any users for counting services or collaboration on a wide variety of experiments and projects.« less

[Mitochondrial diseases in children including Leigh syndrome--biochemical and molecular background].

PubMed

Pronicka, Ewa; Piekutowska-Abramczuk, Dorota; Pronicki, Maciej

2008-01-01

Mitochondrial diseases in children are more frequently caused by mutations in nuclear DNA then in mtDNA. Special clinical phenotypes are associated with the mutations in SURF1 gene, in SCO2 gene and with mtDNA depletion syndromes. Leigh syndrome is the most common clinical presentation of various mitochondrial disorders during childhood. Elevation of lactate in blood, cerebrospinal fluid and urine is a simple biochemical marker of mitochondrial disorders but its specificity and sensitivity are low. Biochemical investigation of muscle biopsy and search for mitochondrial mutations remain a gold standard in the diagnosis. The standarized diagnostic criteria to establish level of diagnostic certainty (possible, probable, definite) are proposed to be used in practice; these include clinical features, neuroimaging and muscle biopsy investigations. Further research directions to improve our understanding of mitochondrial pathologies in children are suggested.

Genetic background effects in Neuroligin-3 mutant mice: Minimal behavioral abnormalities on C57 background.

PubMed

Jaramillo, Thomas C; Escamilla, Christine Ochoa; Liu, Shunan; Peca, Lauren; Birnbaum, Shari G; Powell, Craig M

2018-02-01

Neuroligin-3 (NLGN3) is a postsynaptic cell adhesion protein that interacts with presynaptic ligands including neurexin-1 (NRXN1) [Ichtchenko et al., Journal of Biological Chemistry, 271, 2676-2682, 1996]. Mice harboring a mutation in the NLGN3 gene (NL3R451C) mimicking a mutation found in two brothers with autism spectrum disorder (ASD) were previously generated and behaviorally phenotyped for autism-related behaviors. In these NL3R451C mice generated and tested on a hybrid C57BL6J/129S2/SvPasCrl background, we observed enhanced spatial memory and reduced social interaction [Tabuchi et al., Science, 318, 71-76, 2007]. Curiously, an independently generated second line of mice harboring the same mutation on a C57BL6J background exhibited minimal aberrant behavior, thereby providing apparently discrepant results. To investigate the origin of the discrepancy, we previously replicated the original findings of Tabuchi et al. by studying the same NL3R451C mutation on a pure 129S2/SvPasCrl genetic background. Here we complete the behavioral characterization of the NL3R451C mutation on a pure C57BL6J genetic background to determine if background genetics play a role in the discrepant behavioral outcomes involving NL3R451C mice. NL3R451C mutant mice on a pure C57BL6J background did not display spatial memory enhancements or social interaction deficits. We only observed a decreased startle response and mildly increased locomotor activity in these mice suggesting that background genetics influences behavioral outcomes involving the NL3R451C mutation. Autism Res 2018, 11: 234-244. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Behavioral symptoms of autism can be highly variable, even in cases that involve identical genetic mutations. Previous studies in mice with a mutation of the Neuroligin-3 gene showed enhanced learning and social deficits. We replicated these findings on the same and different genetic backgrounds. In this study, however, the

Subclinical hypothyroidism in patients with non-alcoholic fatty liver disease at the background of carbohydrate metabolism disorders.

PubMed

Feisa, Snizhana V; Chopei, Ivan V

2018-01-01

Introduction: The prevalence of non-alcoholic fatty liver disease (NAFLD) is 25-30% in the general population and more than 75% among patients with carbohydrate metabolism disorders. One in six patients with NAFLD has concomitant subclinical hypothyroidism. The aim is to compare lipid and carbohydrate metabolism states in patients with NAFLD depending on the functional state of the thyroid gland. Materials and methods:215 patients with NAFLD and type 2 diabetes mellitus (T2-DM) or pre-diabetes (PD) were involved in study and devided into 6 groups according to the functional state of the thyroid gland. Results: In cases of adding subclinical hypothyroidism systolic and diastolic blood pressure are rising. In patients with overt hypothyroidism average HOMA-IR index is 29,98±1,05, which exceeds the corresponding figure in patients with concomitant subclinical hypothyroidism. In patients whose hypothyroidism has been compensated by levothyroxine, HOMA-IR index was reduced to 18,56±1,58, indicating a tendency to restore the sensitivity of peripheral tissues to insulin, on the assumption under the medicatedcorrection of thyroid functional status. Levels of common cholesterol and triglycerides were higher in cases of NAFLD with subclinical or overt hypothyroidism than in patients with NAFLD and normal thyroid function. Replacement therapy by levothyroxine leads to improving of lipid changes in patients with NAFLD and concomitant overt hypothyroidism: the levels of common cholesterol and triglycerides were reducing from 6,04±1,18 mmol/l and 3,96±1,34 mmol/l to 5,97±1,1 mmol/l and 3,45±1,13 mmol/l in accordance. Conclusions: Concomitant subclinical hypothyroidism in patients with NAFLD at the background of carbohydrate metabolism disorders leads to atherogenic dyslipidemia, increasing of blood atherogenicity. The index of lipid accumulated product (LAP) and the resistance of peripheral tissues to insulin also increases.

Background Light Bluer Than Expected

NASA Image and Video Library

2014-11-06

This plot shows data from the Cosmic Infrared Background Experiment, or CIBER, rockets launched in 2010 and 2012. The experiment measures a diffuse glow of infrared light in the sky, known as the cosmic infrared background.

The background in the $$0\

DOE PAGES

Agostini, M.; Allardt, M.; Andreotti, E.; ...

2014-04-04

The GERmanium Detector Array (Gerda) experiment at the Gran Sasso underground laboratory (LNGS) of INFN is searching for neutrinoless double beta (0νββ) decay of 76 Ge. The signature of the signal is a monoenergetic peak at 2039 keV, the Q ββ value of the decay. To avoid bias in the signal search, the present analysis does not consider all those events, that fall in a 40 keV wide region centered around Q ββ. The main parameters needed for the 0νββ analysis are described. A background model was developed to describe the observed energy spectrum. The model contains severalmore » contributions, that are expected on the basis of material screening or that are established by the observation of characteristic structures in the energy spectrum. The model predicts a flat energy spectrum for the blinding window around Qββ with a background index ranging from 17.6 to 23.8 × 10 -3 cts/(keV kg yr). A part of the data not considered before has been used to test if the predictions of the background model are consistent. The observed number of events in this energy region is consistent with the background model. The background at Q ββ is dominated by close sources, mainly due to 42 K, 214 Bi, 228 60 Co and α emitting isotopes from the 226 Ra decay chain. The individual fractions depend on the assumed locations of the contaminants. It is shown, that after removal of the known γ peaks, the energy spectrum can be fitted in an energy range of 200 keV around Q ββ with a constant background. This gives a background index consistent with the full model and uncertainties of the same size.« less

The mathematical limits of genetic prediction for complex chronic disease.

PubMed

Keyes, Katherine M; Smith, George Davey; Koenen, Karestan C; Galea, Sandro

2015-06-01

Attempts at predicting individual risk of disease based on common germline genetic variation have largely been disappointing. The present paper formalises why genetic prediction at the individual level is and will continue to have limited utility given the aetiological architecture of most common complex diseases. Data were simulated on one million populations with 10 000 individuals in each populations with varying prevalences of a genetic risk factor, an interacting environmental factor and the background rate of disease. The determinant risk ratio and risk difference magnitude for the association between a gene variant and disease is a function of the prevalence of the interacting factors that activate the gene, and the background rate of disease. The risk ratio and total excess cases due to the genetic factor increase as the prevalence of interacting factors increase, and decrease as the background rate of disease increases. Germline genetic variations have high predictive capacity for individual disease only under conditions of high heritability of particular genetic sequences, plausible only under rare variant hypotheses. Under a model of common germline genetic variants that interact with other genes and/or environmental factors in order to cause disease, the predictive capacity of common genetic variants is determined by the prevalence of the factors that interact with the variant and the background rate. A focus on estimating genetic associations for the purpose of prediction without explicitly grounding such work in an understanding of modifiable (including environmentally influenced) factors will be limited in its ability to yield important insights about the risk of disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

A Flexible Cosmic Ultraviolet Background Model

NASA Astrophysics Data System (ADS)

McQuinn, Matthew

2016-10-01

HST studies of the IGM, of the CGM, and of reionization-era galaxies are all aided by ionizing background models, which are a critical input in modeling the ionization state of diffuse, 10^4 K gas. The ionization state in turn enables the determination of densities and sizes of absorbing clouds and, when applied to the Ly-a forest, the global ionizing emissivity of sources. Unfortunately, studies that use these background models have no way of gauging the amount of uncertainty in the adopted model other than to recompute their results using previous background models with outdated observational inputs. As of yet there has been no systematic study of uncertainties in the background model and there unfortunately is no publicly available ultraviolet background code. A public code would enable users to update the calculation with the latest observational constraints, and it would allow users to experiment with varying the background model's assumptions regarding emissions and absorptions. We propose to develop a publicly available ionizing background code and, as an initial application, quantify the level of uncertainty in the ionizing background spectrum across cosmic time. As the background model improves, so does our understanding of (1) the sources that dominate ionizing emissions across cosmic time and (2) the properties of diffuse gas in the circumgalactic medium, the WHIM, and the Ly-a forest. HST is the primary telescope for studying both the highest redshift galaxies and low-redshift diffuse gas. The proposed program would benefit HST studies of the Universe at z 0 all the way up to z = 10, including of high-z galaxies observed in the HST Frontier Fields.

Communication and Huntington's Disease: Qualitative Interviews and Focus Groups with Persons with Huntington's Disease, Family Members, and Carers

ERIC Educational Resources Information Center

Hartelius, Lena; Jonsson, Maria; Rickeberg, Anneli; Laakso, Katja

2010-01-01

Background: As an effect of the cognitive, emotional and motor symptoms associated with Huntington's disease, communicative interaction is often dramatically changed. No study has previously included the subjective reports on this subject from individuals with Huntington's disease. Aims: To explore the qualitative aspects of how communication is…

The effectiveness and cost-effectiveness of enzyme and substrate replacement therapies: a longitudinal cohort study of people with lysosomal storage disorders.

PubMed

Wyatt, K; Henley, W; Anderson, L; Anderson, R; Nikolaou, V; Stein, K; Klinger, L; Hughes, D; Waldek, S; Lachmann, R; Mehta, A; Vellodi, A; Logan, S

2012-01-01

To determine natural history and estimate effectiveness and cost of enzyme replacement therapy (ERT) and substrate replacement therapy (SRT) for patients with Gaucher disease, Fabry disease, mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II (MPS II), Pompe disease and Niemann-Pick type C (NPC) disease. Cohort study including prospective and retrospective clinical- and patient-reported data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment. Untreated patients contributed natural history data. National Specialised Commissioning Group-designated lysosomal storage disorder (LSD) treatment centres in England. Consenting adults and children with a diagnosis of Gaucher disease (n = 272), Fabry disease (n = 499), MPS I (n = 126), MPS II (n = 58), NPC (n = 58) or Pompe disease (n = 93) who had attended a treatment centre in England. ERT and SRT. Clinical outcomes chosen by clinicians to reflect disease progression for each disorder; patient-reported quality-of-life (QoL) data; cost of treatment and patient-reported service-use data; numbers of hospitalisations, outpatient and general practitioner appointments; medication use; data pertaining to associated family/carer costs and QoL impacts. Seven hundred and eleven adults and children were recruited. In those with Gaucher disease (n = 175) ERT was associated with improved platelet count, haemoglobin, liver function and reduced risk of enlarged liver or spleen. No association was found between ERT and QoL. In patients with Fabry disease (n = 311) increased time on ERT was associated with small decreases in left ventricular mass and improved glomerular filtration rate, but not with changes in risk of stroke/transient ischaemic attacks or the need for a hearing aid. There was a statistically significant association between duration of ERT use and worsening QoL and fatigue scores. We found no

Susceptibility based upon Chemical Interaction with Disease ...

EPA Pesticide Factsheets

One of the challenges facing toxicology and risk assessment is that numerous host and environmental factors may modulate vulnerability and risk. An area of increasing interest is the potential for chemicals to interact with background aging and disease processes, an interaction that may yield cumulative damage, altered chemical potency, and increased disease incidence. This review outlines the interactions possible between chemicals and background disease and identifies the type of information needed to evaluate such interactions. Key among these is the existence of a clinically relevant and easy to measure biomarker of disease risk which allows the identification of vulnerable individuals based upon the level of risk biomarker. The impact of toxic chemicals on this biomarker can then be used to predict how the chemical modifies disease risk as long as related mechanistic and toxicological data are consistent with toxicant effect on the disease process. Several case studies are briefly presented which describe the toxic chemical, the clinical biomarker and the impacted disease including: fine particulate matter/decreased heart rate variability/increased cardiopulmonary events; cadmium/decreased glomerular filtration rate/increased chronic kidney disease; methyl mercury/decreased paraoxonase-1/increased cardiovascular risk; trichloroethylene/increased anti-nuclear antibody/autoimmunity; dioxin/increased CYP1A1/hypertension. These case studies point o

Two sides of the coin: patient and provider perceptions of health care delivery to patients from culturally and linguistically diverse backgrounds.

PubMed

Komaric, Nera; Bedford, Suzanne; van Driel, Mieke L

2012-09-18

Australia is a culturally diverse nation with one in seven Australians born in a non-English speaking country. Culturally and Linguistically Diverse (CALD) populations are at a high risk of developing preventable chronic diseases such as cardiovascular disease, type 2 diabetes mellitus, renal disease, and chronic respiratory disease, especially communities from the Pacific Islands, the Middle East, North Africa, the Indian subcontinent and China. Previous studies have shown that access to services may be a contributing factor. This study explores the experiences, attitudes and opinions of immigrants from different cultural and linguistic backgrounds and their health care providers with regard to chronic disease care. Five focus groups were conducted comprising participants from an Arabic speaking background, or born in Sudan, China, Vietnam or Tonga. A total of 50 members participated. All focus groups were conducted in the participants' language and facilitated by a trained multicultural health worker. In addition, 14 health care providers were interviewed by telephone. Interviews were digitally recorded and transcribed. All qualitative data were analysed with the assistance of QSR NVivo 8 software. Participants were generally positive about the quality and accessibility of health services, but the costs of health care and waiting times to receive treatment presented significant barriers. They expressed a need for greater access to interpreters and culturally appropriate communication and education. They mentioned experiencing racism and discriminatory practices. Health professionals recommended recruiting health workers from CALD communities to assist them to adequately elicit and address the needs of patients from CALD backgrounds. CALD patients, carers and community members as well as health professionals all highlighted the need for establishing culturally tailored programs for chronic disease prevention and management in CALD populations. Better health care

Field Manual of Wildlife Diseases

USGS Publications Warehouse

Franson, J. Christian; Friend, Milton; Gibbs, Samantha E.J.; Wild, Margaret A.

2015-01-01

We begin this new manual with introductory contextual and historical background about the convergence of wildlife disease with wildlife management as a wildlife conservation concern (section A, chap. 1). The remainder of the publication is focused on pragmatic information and considerations for addressing various aspects of wildlife disease. Section B focuses on concepts associated with disease surveillance and response to outbreaks, and section C deals with specific techniques for disease surveillance and investigation. Section D, “Diseases of Wild Birds,” and others that follow will address diseases of concern in various species groups. Electronic links facilitate timely access to a wide variety of supplemental information and processes relevant to content in this new version of the “Field Manual of Wildlife Diseases.”

Patterns of population differentiation and natural selection on the celiac disease background risk network.

PubMed

Sams, Aaron; Hawks, John

2013-01-01

Celiac disease is a common small intestinal inflammatory condition induced by wheat gluten and related proteins from rye and barley. Left untreated, the clinical presentation of CD can include failure to thrive, malnutrition, and distension in juveniles. The disease can additionally lead to vitamin deficiencies, anemia, and osteoporosis. Therefore, CD potentially negatively affected fitness in past populations utilizing wheat, barley, and rye. Previous analyses of CD risk variants have uncovered evidence for positive selection on some of these loci. These studies also suggest the possibility that risk for common autoimmune conditions such as CD may be the result of positive selection on immune related loci in the genome to fight infection. Under this evolutionary scenario, disease phenotypes may be a trade-off from positive selection on immunity. If this hypothesis is generally true, we can expect to find a signal of natural selection when we survey across the network of loci known to influence CD risk. This study examines the non-HLA autosomal network of gene loci associated with CD risk in Europe. We reject the null hypothesis of neutrality on this network of CD risk loci. Additionally, we can localize evidence of selection in time and space by adding information from the genome of the Tyrolean Iceman. While we can show significant differentiation between continental regions across the CD network, the pattern of evidence is not consistent with primarily recent (Holocene) selection across this network in Europe. Further localization of ancient selection on this network may illuminate the ecological pressures acting on the immune system during this critically interesting phase of our evolution.

[Chronic Disease Self-management Support for People with a Migrant Background: towards a Peer-led Group Program to Improve Equity in Health].

PubMed

Zanoni, S; Gabriel, E; Salis Gross, C; Deppeler, M; Haslbeck, J

2018-03-01

Limited health literacy and language skills are barriers for people with a migrant background (PMB) to access health information and healthcare services, in particular for those living with chronic conditions. During the introduction of a peer-led Stanford chronic disease self-management course in Switzerland, special interest in the program as well as motivation of PMB was observed. In response, we examined if the program can be implemented in German for people with limited language skills. This explorative study is part of the evaluation study on introducing the adapted Stanford program in Switzerland and German-speaking Europe. Following the principles of Grounded Theory, semi-structured focus group and individual interviews were conducted with course participants, leaders and coordinators (n=30) and analyzed thematically. The focus was on the feasibility, satisfaction and course content. In principle, the program seems to have positive value for PMB, may work for them in German, have high relevance for everyday life and give an impetus for social integration. The need for and extent of modification of the program for PMB has to be further explored in order to make it more accessible for vulnerable groups. © Georg Thieme Verlag KG Stuttgart · New York.

47 CFR 215.1 - Background.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 47 Telecommunication 5 2012-10-01 2012-10-01 false Background. 215.1 Section 215.1 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL FEDERAL GOVERNMENT FOCAL POINT FOR ELECTROMAGNETIC PULSE (EMP) INFORMATION § 215.1 Background. (a) The nuclear electromagnetic...

47 CFR 215.1 - Background.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 5 2014-10-01 2014-10-01 false Background. 215.1 Section 215.1 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL FEDERAL GOVERNMENT FOCAL POINT FOR ELECTROMAGNETIC PULSE (EMP) INFORMATION § 215.1 Background. (a) The nuclear electromagnetic...

47 CFR 215.1 - Background.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 5 2010-10-01 2010-10-01 false Background. 215.1 Section 215.1 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL FEDERAL GOVERNMENT FOCAL POINT FOR ELECTROMAGNETIC PULSE (EMP) INFORMATION § 215.1 Background. (a) The nuclear electromagnetic...

47 CFR 215.1 - Background.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 47 Telecommunication 5 2013-10-01 2013-10-01 false Background. 215.1 Section 215.1 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL FEDERAL GOVERNMENT FOCAL POINT FOR ELECTROMAGNETIC PULSE (EMP) INFORMATION § 215.1 Background. (a) The nuclear electromagnetic...

47 CFR 215.1 - Background.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 5 2011-10-01 2011-10-01 false Background. 215.1 Section 215.1 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL FEDERAL GOVERNMENT FOCAL POINT FOR ELECTROMAGNETIC PULSE (EMP) INFORMATION § 215.1 Background. (a) The nuclear electromagnetic...

40 CFR 11.2 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Background. 11.2 Section 11.2 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GENERAL SECURITY CLASSIFICATION REGULATIONS PURSUANT TO EXECUTIVE ORDER 11652 § 11.2 Background. While the Environmental Protection Agency does not...

Waterborne Disease Outbreaks— United States, 2009–2014

EPA Science Inventory

Background: The Centers for Disease Control and Prevention (CDC) has conducted national surveillance for waterborne disease outbreaks since 1971 in partnership with the Council of State and Territorial Epidemiologists and the United States Environmental Protection Agency (USEPA)....

Extragalactic background light measurements and applications.

PubMed

Cooray, Asantha

2016-03-01

This review covers the measurements related to the extragalactic background light intensity from γ-rays to radio in the electromagnetic spectrum over 20 decades in wavelength. The cosmic microwave background (CMB) remains the best measured spectrum with an accuracy better than 1%. The measurements related to the cosmic optical background (COB), centred at 1 μm, are impacted by the large zodiacal light associated with interplanetary dust in the inner Solar System. The best measurements of COB come from an indirect technique involving γ-ray spectra of bright blazars with an absorption feature resulting from pair-production off of COB photons. The cosmic infrared background (CIB) peaking at around 100 μm established an energetically important background with an intensity comparable to the optical background. This discovery paved the way for large aperture far-infrared and sub-millimetre observations resulting in the discovery of dusty, starbursting galaxies. Their role in galaxy formation and evolution remains an active area of research in modern-day astrophysics. The extreme UV (EUV) background remains mostly unexplored and will be a challenge to measure due to the high Galactic background and absorption of extragalactic photons by the intergalactic medium at these EUV/soft X-ray energies. We also summarize our understanding of the spatial anisotropies and angular power spectra of intensity fluctuations. We motivate a precise direct measurement of the COB between 0.1 and 5 μm using a small aperture telescope observing either from the outer Solar System, at distances of 5 AU or more, or out of the ecliptic plane. Other future applications include improving our understanding of the background at TeV energies and spectral distortions of CMB and CIB.

Extragalactic background light measurements and applications

PubMed Central

Cooray, Asantha

2016-01-01

This review covers the measurements related to the extragalactic background light intensity from γ-rays to radio in the electromagnetic spectrum over 20 decades in wavelength. The cosmic microwave background (CMB) remains the best measured spectrum with an accuracy better than 1%. The measurements related to the cosmic optical background (COB), centred at 1 μm, are impacted by the large zodiacal light associated with interplanetary dust in the inner Solar System. The best measurements of COB come from an indirect technique involving γ-ray spectra of bright blazars with an absorption feature resulting from pair-production off of COB photons. The cosmic infrared background (CIB) peaking at around 100 μm established an energetically important background with an intensity comparable to the optical background. This discovery paved the way for large aperture far-infrared and sub-millimetre observations resulting in the discovery of dusty, starbursting galaxies. Their role in galaxy formation and evolution remains an active area of research in modern-day astrophysics. The extreme UV (EUV) background remains mostly unexplored and will be a challenge to measure due to the high Galactic background and absorption of extragalactic photons by the intergalactic medium at these EUV/soft X-ray energies. We also summarize our understanding of the spatial anisotropies and angular power spectra of intensity fluctuations. We motivate a precise direct measurement of the COB between 0.1 and 5 μm using a small aperture telescope observing either from the outer Solar System, at distances of 5 AU or more, or out of the ecliptic plane. Other future applications include improving our understanding of the background at TeV energies and spectral distortions of CMB and CIB. PMID:27069645

Development of a Comprehensive Heart Disease Knowledge Questionnaire

ERIC Educational Resources Information Center

Bergman, Hannah E.; Reeve, Bryce B.; Moser, Richard P.; Scholl, Sarah; Klein, William M. P.

2011-01-01

Background: Heart disease is the number one killer of both men and women in the United States, yet a comprehensive and evidence-based heart disease knowledge assessment is currently not available. Purpose: This paper describes the two-phase development of a novel heart disease knowledge questionnaire. Methods: After review and critique of the…

Mondor's disease of penis: a forgotten disease

PubMed Central

Kumar, B; Narang, T; Radotra, B; Gupta, S

2005-01-01

Background: Mondor's disease of penis is an uncommon genital condition involving the penile sulcus in a circumferential manner. Although this disorder is almost always self limited, it is associated with considerable psychological stress and sexual disharmony. Methods: All patients attending the sexually transmitted disease clinic during 1991–2003 were examined for evidence of Mondor's disease of penis. Detailed history and clinical findings were recorded in a specially designed proforma. Histopathological examination and staining with CD31 and CD34 monoclonal antibodies was also done in 11 patients. Results: 18 out of 1296 patients attending the sexually transmitted diseases (STD) clinic during the study period were found to have penile Mondor's disease, giving an incidence of 1.39%. 17 patients had history of one or more episodes of STDs. Histopathological specimens showed prominent vessels with plump endothelial cells and thickened blood vessel walls. The occasional vessel showed complete occlusion of its lumen. Conclusions: In our study we did not find any evidence of lymphatic involvement. Non-lymphatic vessels, mainly veins, were predominantly involved. In our opinion Mondor's phlebitis of penis or Mondor's disease of penis are better terms to describe the condition rather than non-venereal sclerosing lymphangitis. PMID:16326851

47 CFR 201.0 - Background.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 47 Telecommunication 5 2013-10-01 2013-10-01 false Background. 201.0 Section 201.0 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL EXECUTIVE POLICY § 201.0 Background. National policy with respect to the conservation, allocation and use of the Nation's...

47 CFR 201.0 - Background.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 5 2011-10-01 2011-10-01 false Background. 201.0 Section 201.0 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL EXECUTIVE POLICY § 201.0 Background. National policy with respect to the conservation, allocation and use of the Nation's...

47 CFR 201.0 - Background.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 5 2010-10-01 2010-10-01 false Background. 201.0 Section 201.0 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL EXECUTIVE POLICY § 201.0 Background. National policy with respect to the conservation, allocation and use of the Nation's...

47 CFR 201.0 - Background.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 5 2014-10-01 2014-10-01 false Background. 201.0 Section 201.0 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL EXECUTIVE POLICY § 201.0 Background. National policy with respect to the conservation, allocation and use of the Nation's...

47 CFR 201.0 - Background.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 47 Telecommunication 5 2012-10-01 2012-10-01 false Background. 201.0 Section 201.0 Telecommunication OFFICE OF SCIENCE AND TECHNOLOGY POLICY AND NATIONAL SECURITY COUNCIL EXECUTIVE POLICY § 201.0 Background. National policy with respect to the conservation, allocation and use of the Nation's...

28 CFR 23.2 - Background.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 28 Judicial Administration 1 2011-07-01 2011-07-01 false Background. 23.2 Section 23.2 Judicial Administration DEPARTMENT OF JUSTICE CRIMINAL INTELLIGENCE SYSTEMS OPERATING POLICIES § 23.2 Background. It is... of intelligence data necessary to support control of serious criminal activity may represent...

28 CFR 23.2 - Background.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 28 Judicial Administration 1 2014-07-01 2014-07-01 false Background. 23.2 Section 23.2 Judicial Administration DEPARTMENT OF JUSTICE CRIMINAL INTELLIGENCE SYSTEMS OPERATING POLICIES § 23.2 Background. It is... of intelligence data necessary to support control of serious criminal activity may represent...

28 CFR 23.2 - Background.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 28 Judicial Administration 1 2013-07-01 2013-07-01 false Background. 23.2 Section 23.2 Judicial Administration DEPARTMENT OF JUSTICE CRIMINAL INTELLIGENCE SYSTEMS OPERATING POLICIES § 23.2 Background. It is... of intelligence data necessary to support control of serious criminal activity may represent...

28 CFR 23.2 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Background. 23.2 Section 23.2 Judicial Administration DEPARTMENT OF JUSTICE CRIMINAL INTELLIGENCE SYSTEMS OPERATING POLICIES § 23.2 Background. It is... of intelligence data necessary to support control of serious criminal activity may represent...

28 CFR 23.2 - Background.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 28 Judicial Administration 1 2012-07-01 2012-07-01 false Background. 23.2 Section 23.2 Judicial Administration DEPARTMENT OF JUSTICE CRIMINAL INTELLIGENCE SYSTEMS OPERATING POLICIES § 23.2 Background. It is... of intelligence data necessary to support control of serious criminal activity may represent...

47 CFR 32.1 - Background.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 2 2014-10-01 2014-10-01 false Background. 32.1 Section 32.1 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES UNIFORM SYSTEM OF ACCOUNTS FOR TELECOMMUNICATIONS COMPANIES Preface § 32.1 Background. The revised Uniform System of Accounts (USOA) is a historical...

47 CFR 32.1 - Background.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 47 Telecommunication 2 2013-10-01 2013-10-01 false Background. 32.1 Section 32.1 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES UNIFORM SYSTEM OF ACCOUNTS FOR TELECOMMUNICATIONS COMPANIES Preface § 32.1 Background. The revised Uniform System of Accounts (USOA) is a historical...

47 CFR 32.1 - Background.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 2 2011-10-01 2011-10-01 false Background. 32.1 Section 32.1 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES UNIFORM SYSTEM OF ACCOUNTS FOR TELECOMMUNICATIONS COMPANIES Preface § 32.1 Background. The revised Uniform System of Accounts (USOA) is a historical...

The molecular biology of inflammatory bowel diseases.

PubMed

Corfield, Anthony P; Wallace, Heather M; Probert, Chris S J

2011-08-01

IBDs (inflammatory bowel diseases) are a group of diseases affecting the gastrointestinal tract. The diseases are multifactorial and cover genetic aspects: susceptibility genes, innate and adaptive responses to inflammation, and structure and efficacy of the mucosal protective barrier. Animal models of IBD have been developed to gain further knowledge of the disease mechanisms. These topics form an overlapping background to enable an improved understanding of the molecular features of these diseases. A series of articles is presented based on the topics covered at the Biochemical Society Focused Meeting The Molecular Biology of Inflammatory Bowel Diseases.

Spectral characterization of natural backgrounds

NASA Astrophysics Data System (ADS)

Winkelmann, Max

2017-10-01

As the distribution and use of hyperspectral sensors is constantly increasing, the exploitation of spectral features is a threat for camouflaged objects. To improve camouflage materials at first the spectral behavior of backgrounds has to be known to adjust and optimize the spectral reflectance of camouflage materials. In an international effort, the NATO CSO working group SCI-295 "Development of Methods for Measurements and Evaluation of Natural Background EO Signatures" is developing a method how this characterization of backgrounds has to be done. It is obvious that the spectral characterization of a background will be quite an effort. To compare and exchange data internationally the measurements will have to be done in a similar way. To test and further improve this method an international field trial has been performed in Storkow, Germany. In the following we present first impressions and lessons learned from this field campaign and describe the data that has been measured.

Stabilization of Glucocerebrosidase by Active Site Occupancy

PubMed Central

2017-01-01

Glucocerebrosidase (GBA) is a lysosomal β-glucosidase that degrades glucosylceramide. Its deficiency results in Gaucher disease (GD). We examined the effects of active site occupancy of GBA on its structural stability. For this, we made use of cyclophellitol-derived activity-based probes (ABPs) that bind irreversibly to the catalytic nucleophile (E340), and for comparison, we used the potent reversible inhibitor isofagomine. We demonstrate that cyclophellitol ABPs improve the stability of GBA in vitro, as revealed by thermodynamic measurements (Tm increase by 21 °C), and introduce resistance to tryptic digestion. The stabilizing effect of cell-permeable cyclophellitol ABPs is also observed in intact cultured cells containing wild-type GBA, N370S GBA (labile in lysosomes), and L444P GBA (exhibits impaired ER folding): all show marked increases in lysosomal forms of GBA molecules upon exposure to ABPs. The same stabilization effect is observed for endogenous GBA in the liver of wild-type mice injected with cyclophellitol ABPs. Stabilization effects similar to those observed with ABPs were also noted at high concentrations of the reversible inhibitor isofagomine. In conclusion, we provide evidence that the increase in cellular levels of GBA by ABPs and by the reversible inhibitor is in part caused by their ability to stabilize GBA folding, which increases the resistance of GBA against breakdown by lysosomal proteases. These effects are more pronounced in the case of the amphiphilic ABPs, presumably due to their high lipophilic potential, which may promote further structural compactness of GBA through hydrophobic interactions. Our study provides further rationale for the design of chaperones for GBA to ameliorate Gaucher disease. PMID:28485919

32 CFR 1292.3 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 6 2010-07-01 2010-07-01 false Background. 1292.3 Section 1292.3 National Defense Other Regulations Relating to National Defense DEFENSE LOGISTICS AGENCY MISCELLANEOUS SECURITY OF DLA ACTIVITIES AND RESOURCES § 1292.3 Background. Section 21 of the Internal Security Act of 1950...

14 CFR 1214.302 - Background.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 5 2012-01-01 2012-01-01 false Background. 1214.302 Section 1214.302 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SPACE FLIGHT Payload Specialists for Space Transportation System (STS) Missions § 1214.302 Background. (a) The Space Transportation System (STS) has been...

14 CFR 1214.302 - Background.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Background. 1214.302 Section 1214.302 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SPACE FLIGHT Payload Specialists for Space Transportation System (STS) Missions § 1214.302 Background. (a) The Space Transportation System (STS) has been...

14 CFR 1214.302 - Background.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Background. 1214.302 Section 1214.302 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SPACE FLIGHT Payload Specialists for Space Transportation System (STS) Missions § 1214.302 Background. (a) The Space Transportation System (STS) has been...

14 CFR 1214.302 - Background.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 5 2013-01-01 2013-01-01 false Background. 1214.302 Section 1214.302 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SPACE FLIGHT Payload Specialists for Space Transportation System (STS) Missions § 1214.302 Background. (a) The Space Transportation System (STS) has been...

32 CFR 1292.3 - Background.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 6 2012-07-01 2012-07-01 false Background. 1292.3 Section 1292.3 National Defense Other Regulations Relating to National Defense DEFENSE LOGISTICS AGENCY MISCELLANEOUS SECURITY OF DLA ACTIVITIES AND RESOURCES § 1292.3 Background. Section 21 of the Internal Security Act of 1950...

32 CFR 1292.3 - Background.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 6 2011-07-01 2011-07-01 false Background. 1292.3 Section 1292.3 National Defense Other Regulations Relating to National Defense DEFENSE LOGISTICS AGENCY MISCELLANEOUS SECURITY OF DLA ACTIVITIES AND RESOURCES § 1292.3 Background. Section 21 of the Internal Security Act of 1950...

32 CFR 1292.3 - Background.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 6 2013-07-01 2013-07-01 false Background. 1292.3 Section 1292.3 National Defense Other Regulations Relating to National Defense DEFENSE LOGISTICS AGENCY MISCELLANEOUS SECURITY OF DLA ACTIVITIES AND RESOURCES § 1292.3 Background. Section 21 of the Internal Security Act of 1950...

32 CFR 1292.3 - Background.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 6 2014-07-01 2014-07-01 false Background. 1292.3 Section 1292.3 National Defense Other Regulations Relating to National Defense DEFENSE LOGISTICS AGENCY MISCELLANEOUS SECURITY OF DLA ACTIVITIES AND RESOURCES § 1292.3 Background. Section 21 of the Internal Security Act of 1950...

32 CFR 3.2 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 1 2010-07-01 2010-07-01 false Background. 3.2 Section 3.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE ACQUISITION TRANSACTIONS OTHER THAN CONTRACTS, GRANTS, OR COOPERATIVE AGREEMENTS FOR PROTOTYPE PROJECTS § 3.2 Background. “Other transactions” is the...

An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues.

PubMed

Corces, M Ryan; Trevino, Alexandro E; Hamilton, Emily G; Greenside, Peyton G; Sinnott-Armstrong, Nicholas A; Vesuna, Sam; Satpathy, Ansuman T; Rubin, Adam J; Montine, Kathleen S; Wu, Beijing; Kathiria, Arwa; Cho, Seung Woo; Mumbach, Maxwell R; Carter, Ava C; Kasowski, Maya; Orloff, Lisa A; Risca, Viviana I; Kundaje, Anshul; Khavari, Paul A; Montine, Thomas J; Greenleaf, William J; Chang, Howard Y

2017-10-01

We present Omni-ATAC, an improved ATAC-seq protocol for chromatin accessibility profiling that works across multiple applications with substantial improvement of signal-to-background ratio and information content. The Omni-ATAC protocol generates chromatin accessibility profiles from archival frozen tissue samples and 50-μm sections, revealing the activities of disease-associated DNA elements in distinct human brain structures. The Omni-ATAC protocol enables the interrogation of personal regulomes in tissue context and translational studies.

32 CFR 763.3 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 5 2010-07-01 2010-07-01 false Background. 763.3 Section 763.3 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY ISLANDS UNDER NAVY JURISDICTION RULES GOVERNING PUBLIC ACCESS Entry Regulations for Kaho'olawe Island, Hawaii § 763.3 Background. (a) Kaho'olawe Island...

32 CFR 735.2 - Background.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 5 2011-07-01 2011-07-01 false Background. 735.2 Section 735.2 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL REPORTING BIRTHS AND DEATHS IN COOPERATION WITH OTHER AGENCIES § 735.2 Background. For Armed Forces members and their dependents on duty overseas...

32 CFR 735.2 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 5 2010-07-01 2010-07-01 false Background. 735.2 Section 735.2 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL REPORTING BIRTHS AND DEATHS IN COOPERATION WITH OTHER AGENCIES § 735.2 Background. For Armed Forces members and their dependents on duty overseas...

Disease-associated variants in different categories of disease located in distinct regulatory elements

PubMed Central

2015-01-01

Background The invention of high throughput sequencing technologies has led to the discoveries of hundreds of thousands of genetic variants associated with thousands of human diseases. Many of these genetic variants are located outside the protein coding regions, and as such, it is challenging to interpret the function of these genetic variants by traditional genetic approaches. Recent genome-wide functional genomics studies, such as FANTOM5 and ENCODE have uncovered a large number of regulatory elements across hundreds of different tissues or cell lines in the human genome. These findings provide an opportunity to study the interaction between regulatory elements and disease-associated genetic variants. Identifying these diseased-related regulatory elements will shed light on understanding the mechanisms of how these variants regulate gene expression and ultimately result in disease formation and progression. Results In this study, we curated and categorized 27,558 Mendelian disease variants, 20,964 complex disease variants, 5,809 cancer predisposing germline variants, and 43,364 recurrent cancer somatic mutations. Compared against nine different types of regulatory regions from FANTOM5 and ENCODE projects, we found that different types of disease variants show distinctive propensity for particular regulatory elements. Mendelian disease variants and recurrent cancer somatic mutations are 22-fold and 10- fold significantly enriched in promoter regions respectively (q<0.001), compared with allele-frequency-matched genomic background. Separate from these two categories, cancer predisposing germline variants are 27-fold enriched in histone modification regions (q<0.001), 10-fold enriched in chromatin physical interaction regions (q<0.001), and 6-fold enriched in transcription promoters (q<0.001). Furthermore, Mendelian disease variants and recurrent cancer somatic mutations share very similar distribution across types of functional effects. We further found that

Aircraft and background noise annoyance effects

NASA Technical Reports Server (NTRS)

Willshire, K. F.

1984-01-01

To investigate annoyance of multiple noise sources, two experiments were conducted. The first experiment, which used 48 subjects, was designed to establish annoyance-noise level functions for three community noise sources presented individually: jet aircraft flyovers, air conditioner, and traffic. The second experiment, which used 216 subjects, investigated the effects of background noise on aircraft annoyance as a function of noise level and spectrum shape; and the differences between overall, aircraft, and background noise annoyance. In both experiments, rated annoyance was the dependent measure. Results indicate that the slope of the linear relationship between annoyance and noise level for traffic is significantly different from that of flyover and air conditioner noise and that further research was justified to determine the influence of the two background noises on overall, aircraft, and background noise annoyance (e.g., experiment two). In experiment two, total noise exposure, signal-to-noise ratio, and background source type were found to have effects on all three types of annoyance. Thus, both signal-to-noise ratio, and the background source must be considered when trying to determine community response to combined noise sources.

The Severity of Retinal Degeneration in Rp1h Gene-Targeted Mice Is Dependent on Genetic Background

PubMed Central

Liu, Qin; Saveliev, Alexei; Pierce, Eric A.

2009-01-01

Purpose The severity of disease in patients with retinitis pigmentosa (RP) can vary significantly, even among patients with the same primary mutations. It is hypothesized that modifier genes play important roles in determining the severity of RP, including the retinitis pigmentosa 1 (RP1) form of disease. To investigate the basis of variation in disease expression for RP1 disease, the authors generated congenic mice with a gene-targeted retinitis pigmentosa 1 homolog (Rp1h) allele (Rp1htm1Eap) on several different genetic backgrounds and analyzed their retinal phenotypes. Methods The Rp1htm1Eap allele was placed onto the C57BL/6J, DBA1/J, and A/J backgrounds. Retinal function of the resultant congenic mice was evaluated using electroretino-graphic analyses. Retinal structure and ultrastructure were evaluated using light and electron microscopy. Rp1h protein location was determined with immunofluorescence microscopy. Results Analysis of the retinal phenotype of incipient congenic (N6) B6.129S-Rp1h+/tm1Eap, DBA.129S(B6)-Rp1h+/tm1Eap, and A.129S(B6)-Rp1h+/tm1Eap mice at 1 year of age showed retinal degeneration only in the A.129S(B6)-Rp1h+/tm1Eap mice. Further analyses revealed that the photoreceptors of the fully congenic A.129S(B6)-Rp1h+/tm1Eap mice show evidence of degeneration at 6 months of age and are almost completely lost by 18 months of age. In contrast, the photoreceptor cells in the fully congenic B6.129S-Rp1h+/tm1Eap mice remain healthy up to 18 months. Conclusions The severity of the retinal degeneration caused by the Rp1htm1Eap allele is notably dependent on genetic background. The development and characterization of the B6.129S-Rp1h+/tm1Eap and A.129S(B6)-Rp1h+/tm1Eap congenic mouse lines will facilitate identification of sequence alterations in genes that modify the severity of RP1 disease. PMID:19060274

The severity of retinal degeneration in Rp1h gene-targeted mice is dependent on genetic background.

PubMed

Liu, Qin; Saveliev, Alexei; Pierce, Eric A

2009-04-01

The severity of disease in patients with retinitis pigmentosa (RP) can vary significantly, even among patients with the same primary mutations. It is hypothesized that modifier genes play important roles in determining the severity of RP, including the retinitis pigmentosa 1 (RP1) form of disease. To investigate the basis of variation in disease expression for RP1 disease, the authors generated congenic mice with a gene-targeted retinitis pigmentosa 1 homolog (Rp1h) allele (Rp1h(tm1Eap)) on several different genetic backgrounds and analyzed their retinal phenotypes. The Rp1h(tm1Eap) allele was placed onto the C57BL/6J, DBA1/J, and A/J backgrounds. Retinal function of the resultant congenic mice was evaluated using electroretinographic analyses. Retinal structure and ultrastructure were evaluated using light and electron microscopy. Rp1h protein location was determined with immunofluorescence microscopy. Analysis of the retinal phenotype of incipient congenic (N6) B6.129S-Rp1h(+/tm1Eap), DBA.129S(B6)-Rp1h(+/tm1Eap), and A.129S(B6)-Rp1h(+/tm1Eap) mice at 1 year of age showed retinal degeneration only in the A.129S(B6)-Rp1h(+/tm1Eap) mice. Further analyses revealed that the photoreceptors of the fully congenic A.129S(B6)-Rp1h(+/tm1Eap) mice show evidence of degeneration at 6 months of age and are almost completely lost by 18 months of age. In contrast, the photoreceptor cells in the fully congenic B6.129S-Rp1h(+/tm1Eap) mice remain healthy up to 18 months. The severity of the retinal degeneration caused by the Rp1h(tm1Eap) allele is notably dependent on genetic background. The development and characterization of the B6.129S-Rp1h(+/tm1Eap) and A.129S(B6)-Rp1h(+/tm1Eap) congenic mouse lines will facilitate identification of sequence alterations in genes that modify the severity of RP1 disease.

32 CFR 732.1 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 5 2010-07-01 2010-07-01 false Background. 732.1 Section 732.1 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL NONNAVAL MEDICAL AND DENTAL CARE General § 732.1 Background. When a U.S. Navy or Marine Corps member or a Canadian Navy or Marine Corps member...

32 CFR 732.1 - Background.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 5 2013-07-01 2013-07-01 false Background. 732.1 Section 732.1 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL NONNAVAL MEDICAL AND DENTAL CARE General § 732.1 Background. When a U.S. Navy or Marine Corps member or a Canadian Navy or Marine Corps member...

32 CFR 732.1 - Background.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 5 2014-07-01 2014-07-01 false Background. 732.1 Section 732.1 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL NONNAVAL MEDICAL AND DENTAL CARE General § 732.1 Background. When a U.S. Navy or Marine Corps member or a Canadian Navy or Marine Corps member...

32 CFR 732.1 - Background.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 5 2011-07-01 2011-07-01 false Background. 732.1 Section 732.1 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL NONNAVAL MEDICAL AND DENTAL CARE General § 732.1 Background. When a U.S. Navy or Marine Corps member or a Canadian Navy or Marine Corps member...

32 CFR 732.1 - Background.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 5 2012-07-01 2012-07-01 false Background. 732.1 Section 732.1 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL NONNAVAL MEDICAL AND DENTAL CARE General § 732.1 Background. When a U.S. Navy or Marine Corps member or a Canadian Navy or Marine Corps member...

12 CFR 408.1 - Background.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Background. 408.1 Section 408.1 Banks and Banking EXPORT-IMPORT BANK OF THE UNITED STATES PROCEDURES FOR COMPLIANCE WITH THE NATIONAL ENVIRONMENTAL POLICY ACT General § 408.1 Background. (a) The National Environmental Policy Act (NEPA) of 1969 (42 U.S.C...

Immunogenetic background of patients with autoimmune fatigue syndrome.

PubMed

Itoh, Y; Igarashi, T; Tatsuma, N; Imai, T; Yoshida, J; Tsuchiya, M; Murakami, M; Fukunaga, Y

2000-10-01

We have previously reported that approximately 50% of children with chronic nonspecific complaints were positive for antinuclear antibodies (ANA), and that a novel autoantibody to a 62 kD protein (anti-Sa) was found in 40% of these ANA-positive patients. Therefore, we proposed a distinct disease entity termed autoimmune fatigue syndrome (AIFS). We hypothesized that if autoimmune mechanisms did play an important role in the pathogenesis of AIFS, it is possible that it is immunogenetically regulated as observed in other autoimmune disorders. In order to examine the immunogenetic background of AIFS patients, HLA-A, -B, -C, and -DR loci were analyzed serologically in 61 AIFS patients. AIFS was found to be positively associated with the class I antigen HLA-B61 and with the class II antigen HLA-DR9, with odds ratios of 2.77 (p = 0.015, Pcorr = 0.48) and 2.60 (p= 0.012, Pcorr = 0.17), respectively. A negative association was also found between AIFS and HLA-DR2 with odds ratio of 0.25 (p = 0.029, Pcorr = 0.041). When comparing anti-Sa positive AIFS patients with healthy controls, the odds ratios associated with HLA-B61, DR9, and DR2 were 3.42 (p = 0.021, Pcorr = 0.22), 3.96 (p = 0.0011, Pcorr = 0.015), and 0.16 (p = 0.0022, Porr = 0.031), respectively. Thus, the HLA associations observed in this study suggested that immunogenetic background might play a role in AIFS.

Background of SAM atom-fraction profiles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ernst, Frank

Atom-fraction profiles acquired by SAM (scanning Auger microprobe) have important applications, e.g. in the context of alloy surface engineering by infusion of carbon or nitrogen through the alloy surface. However, such profiles often exhibit an artifact in form of a background with a level that anti-correlates with the local atom fraction. This article presents a theory explaining this phenomenon as a consequence of the way in which random noise in the spectrum propagates into the discretized differentiated spectrum that is used for quantification. The resulting model of “energy channel statistics” leads to a useful semi-quantitative background reduction procedure, which ismore » validated by applying it to simulated data. Subsequently, the procedure is applied to an example of experimental SAM data. The analysis leads to conclusions regarding optimum experimental acquisition conditions. The proposed method of background reduction is based on general principles and should be useful for a broad variety of applications. - Highlights: • Atom-fraction–depth profiles of carbon measured by scanning Auger microprobe • Strong background, varies with local carbon concentration. • Needs correction e.g. for quantitative comparison with simulations • Quantitative theory explains background. • Provides background removal strategy and practical advice for acquisition.« less

The background in the experiment Gerda

NASA Astrophysics Data System (ADS)

Agostini, M.; Allardt, M.; Andreotti, E.; Bakalyarov, A. M.; Balata, M.; Barabanov, I.; Barnabé Heider, M.; Barros, N.; Baudis, L.; Bauer, C.; Becerici-Schmidt, N.; Bellotti, E.; Belogurov, S.; Belyaev, S. T.; Benato, G.; Bettini, A.; Bezrukov, L.; Bode, T.; Brudanin, V.; Brugnera, R.; Budjáš, D.; Caldwell, A.; Cattadori, C.; Chernogorov, A.; Cossavella, F.; Demidova, E. V.; Domula, A.; Egorov, V.; Falkenstein, R.; Ferella, A.; Freund, K.; Frodyma, N.; Gangapshev, A.; Garfagnini, A.; Gotti, C.; Grabmayr, P.; Gurentsov, V.; Gusev, K.; Guthikonda, K. K.; Hampel, W.; Hegai, A.; Heisel, M.; Hemmer, S.; Heusser, G.; Hofmann, W.; Hult, M.; Inzhechik, L. V.; Ioannucci, L.; Csáthy, J. Janicskó; Jochum, J.; Junker, M.; Kihm, T.; Kirpichnikov, I. V.; Kirsch, A.; Klimenko, A.; Knöpfle, K. T.; Kochetov, O.; Kornoukhov, V. N.; Kuzminov, V. V.; Laubenstein, M.; Lazzaro, A.; Lebedev, V. I.; Lehnert, B.; Liao, H. Y.; Lindner, M.; Lippi, I.; Liu, X.; Lubashevskiy, A.; Lubsandorzhiev, B.; Lutter, G.; Macolino, C.; Machado, A. A.; Majorovits, B.; Maneschg, W.; Nemchenok, I.; Nisi, S.; O'Shaughnessy, C.; Palioselitis, D.; Pandola, L.; Pelczar, K.; Pessina, G.; Pullia, A.; Riboldi, S.; Sada, C.; Salathe, M.; Schmitt, C.; Schreiner, J.; Schulz, O.; Schwingenheuer, B.; Schönert, S.; Shevchik, E.; Shirchenko, M.; Simgen, H.; Smolnikov, A.; Stanco, L.; Strecker, H.; Tarka, M.; Ur, C. A.; Vasenko, A. A.; Volynets, O.; von Sturm, K.; Wagner, V.; Walter, M.; Wegmann, A.; Wester, T.; Wojcik, M.; Yanovich, E.; Zavarise, P.; Zhitnikov, I.; Zhukov, S. V.; Zinatulina, D.; Zuber, K.; Zuzel, G.

2014-04-01

The GERmanium Detector Array ( Gerda) experiment at the Gran Sasso underground laboratory (LNGS) of INFN is searching for neutrinoless double beta () decay of Ge. The signature of the signal is a monoenergetic peak at 2039 keV, the value of the decay. To avoid bias in the signal search, the present analysis does not consider all those events, that fall in a 40 keV wide region centered around . The main parameters needed for the analysis are described. A background model was developed to describe the observed energy spectrum. The model contains several contributions, that are expected on the basis of material screening or that are established by the observation of characteristic structures in the energy spectrum. The model predicts a flat energy spectrum for the blinding window around with a background index ranging from 17.6 to 23.8 cts/(keV kg yr). A part of the data not considered before has been used to test if the predictions of the background model are consistent. The observed number of events in this energy region is consistent with the background model. The background at is dominated by close sources, mainly due to K, Bi, Th, Co and emitting isotopes from the Ra decay chain. The individual fractions depend on the assumed locations of the contaminants. It is shown, that after removal of the known peaks, the energy spectrum can be fitted in an energy range of 200 keV around with a constant background. This gives a background index consistent with the full model and uncertainties of the same size.

Antigen detection based on background fluorescence quenching immunochromatographic assay.

PubMed

Chen, Xiangjun; Xu, Yangyang; Yu, Jinsheng; Li, Jiutong; Zhou, Xuelei; Wu, Chuanyong; Ji, Qiuliang; Ren, Yuan; Wang, Liqun; Huang, Zhengyi; Zhuang, Hanling; Piao, Long; Head, Richard; Wang, Yajie; Lou, Jiatao

2014-09-02

Gold immunochromatographic assay (GICA) has been around for quite a while, but it is qualitative in the vast majority of applications. A fast, simple and quantitative GICA is in call for better medicine. In the current study, we have established a novel, quantitative GICA based on fluorescence quenching and nitrocellulose membrane background signals, called background fluorescence quenching immunochromatographic assay (bFQICA). Using model analyte alpha-fetoprotein (AFP), the present study assessed the performance of bFQICA in numerous assay aspects. With serial dilutions of the international AFP standard, standard curves for the calculation of AFP concentration were successfully established. At 10 and 100ngmL(-1) of the international AFP standard, the assay variability was defined with a coefficient of variance at 10.4% and 15.2%, respectively. For samples with extended range of AFP levels, bFQICA was able to detect AFP at as low as 1ngmL(-1). Fluorescence in bFQICA strips stayed constant over months. A good correlation between the results from bFQICA and from a well-established Roche electrochemiluminescence immunoassay was observed in 27 serum samples (r=0.98, p<0.001). In conclusion, our study has demonstrated distinctive features of bFQICA over conventional GICA, including utilization of a unique fluorescence ratio between nitrocellulose membrane background and specific signals (F1/F2) to ensure accurate measurements, combined qualitative and quantitative capabilities, and exceptionally high sensitivity for detection of very low levels of antigens. All of these features could make bFQICA attractive as a model for antigen-antibody complex based GICA, and could promote bFQICA to a broad range of applications for investigation of a variety of diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

The cosmic microwave background

NASA Technical Reports Server (NTRS)

Silk, Joseph

1991-01-01

Recent limits on spectral distortions and angular anisotropies in the cosmic microwave background are reviewed. The various backgrounds are described, and the theoretical implications are assessed. Constraints on inflationary cosmology dominated by cold dark matter (CDM) and on open cosmological models dominated by baryonic dark matter (BDM), with, respectively, primordial random phase scale-invariant curvature fluctuations or non-gaussian isocurvature fluctuations are described. More exotic theories are addressed, and I conclude with the 'bottom line': what theorists expect experimentalists to be measuring within the next two to three years without having to abandon their most cherished theories.

Characterizing the Background Corona with SDO/AIA

NASA Technical Reports Server (NTRS)

Napier, Kate; Alexander, Caroline; Winebarger, Amy

2014-01-01

Characterizing the nature of the solar coronal background would enable scientists to more accurately determine plasma parameters, and may lead to a better understanding of the coronal heating problem. Because scientists study the 3D structure of the Sun in 2D, any line-of-sight includes both foreground and background material, and thus, the issue of background subtraction arises. By investigating the intensity values in and around an active region, using multiple wavelengths collected from the Atmospheric Imaging Assembly (AIA) on the Solar Dynamics Observatory (SDO) over an eight-hour period, this project aims to characterize the background as smooth or structured. Different methods were employed to measure the true coronal background and create minimum intensity images. These were then investigated for the presence of structure. The background images created were found to contain long-lived structures, including coronal loops, that were still present in all of the wavelengths, 131, 171, 193, 211, and 335 A. The intensity profiles across the active region indicate that the background is much more structured than previously thought.

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

PubMed

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

2004-03-01

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

Novel genetic risk markers for ulcerative colitis in the IL2/IL21 region are in epistasis with IL23R and suggest a common genetic background for ulcerative colitis and celiac disease.

PubMed

Glas, Jürgen; Stallhofer, Johannes; Ripke, Stephan; Wetzke, Martin; Pfennig, Simone; Klein, Wolfram; Epplen, Jörg T; Griga, Thomas; Schiemann, Uwe; Lacher, Martin; Koletzko, Sibylle; Folwaczny, Matthias; Lohse, Peter; Göke, Burkhard; Ochsenkühn, Thomas; Müller-Myhsok, Bertram; Brand, Stephan

2009-07-01

Recently, a genome-wide association study showed that single-nucleotide polymorphisms (SNPs) in the chromosome 4q27 region containing IL2 and IL21 are associated with celiac disease. Given the increased prevalence of inflammatory bowel disease (IBD) among celiac disease patients, we investigated the possible involvement of these SNPs in IBD. Five SNPs strongly associated with celiac disease within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block on chromosome 4q27 and one coding SNP within the IL21 gene were analyzed in a large German IBD cohort. The study population comprised a total of 2,948 Caucasian individuals, including 1,461 IBD patients (ulcerative colitis (UC): n=514, Crohn's disease (CD): n=947) and 1,487 healthy unrelated controls. Three of the five celiac disease risk markers had a protective effect on UC susceptibility, and this effect remained significant after correcting for multiple testing: rs6840978: P=0.0082, P(corr)=0.049, odds ratio (OR) 0.77, 95% confidence interval (CI) 0.63-0.93; rs6822844: P=0.0028, P(corr)=0.017, OR 0.73, 95% CI 0.59-0.90; rs13119723: P=0.0058, P(corr)=0.035, OR 0.75, 95% CI 0.61-0.92. A haplotype consisting of the six SNPs tested was markedly associated with UC susceptibility (P=0.0025, P(corr)=0.015, OR 0.72, 95% CI 0.58-0.89). Moreover, in UC, epistasis was observed between the IL23R SNP rs1004819 and three SNPs in the KIAA1109/TENR/IL2/IL21 block (rs13151961, rs13119723, and rs6822844). Similar to other autoimmune diseases such as celiac disease, rheumatoid arthritis, type 1 diabetes, Graves' disease, and psoriatic arthritis, genetic variation in the chromosome 4q27 region predisposes to UC, suggesting a common genetic background for these diseases.

Cosmic Background Explorer (COBE) press kit

NASA Technical Reports Server (NTRS)

1989-01-01

COBE, the Cosmic Background Explorer spacecraft, and its mission are described. COBE was designed to study the origin and dynamics of the universe including the theory that the universe began with a cataclysmic explosion referred to as the Big Bang. To this end, earth's cosmic background - the infrared radiation that bombards earth from every direction - will be measured by three sophisticated instruments: the Differential Microwave Radiometer (DMR), the Far Infrared Absolute Spectrophotometer (FIRAS), and the Diffuse Infrared Background Experiment (DIRBE).

Characterization and Prediction of the SPI Background

NASA Technical Reports Server (NTRS)

Teegarden, B. J.; Jean, P.; Knodlseder, J.; Skinner, G. K.; Weidenspointer, G.

2003-01-01

The INTEGRAL Spectrometer, like most gamma-ray instruments, is background dominated. Signal-to-background ratios of a few percent are typical. The background is primarily due to interactions of cosmic rays in the instrument and spacecraft. It characteristically varies by +/- 5% on time scales of days. This variation is caused mainly by fluctuations in the interplanetary magnetic field that modulates the cosmic ray intensity. To achieve the maximum performance from SPI it is essential to have a high quality model of this background that can predict its value to a fraction of a percent. In this poster we characterize the background and its variability, explore various models, and evaluate the accuracy of their predictions.

Expected background in the LZ experiment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kudryavtsev, Vitaly A.

2015-08-17

The LZ experiment, featuring a 7-tonne active liquid xenon target, is aimed at achieving unprecedented sensitivity to WIMPs with the background expected to be dominated by astrophysical neutrinos. To reach this goal, extensive simulations are carried out to accurately calculate the electron recoil and nuclear recoil rates in the detector. Both internal (from target material) and external (from detector components and surrounding environment) backgrounds are considered. A very efficient suppression of background rate is achieved with an outer liquid scintillator veto, liquid xenon skin and fiducialisation. Based on the current measurements of radioactivity of different materials, it is shown thatmore » LZ can achieve the reduction of a total background for a WIMP search down to about 2 events in 1000 live days for 5.6 tonne fiducial mass.« less

Expected background in the LZ experiment

NASA Astrophysics Data System (ADS)

Kudryavtsev, Vitaly A.

2015-08-01

The LZ experiment, featuring a 7-tonne active liquid xenon target, is aimed at achieving unprecedented sensitivity to WIMPs with the background expected to be dominated by astrophysical neutrinos. To reach this goal, extensive simulations are carried out to accurately calculate the electron recoil and nuclear recoil rates in the detector. Both internal (from target material) and external (from detector components and surrounding environment) backgrounds are considered. A very efficient suppression of background rate is achieved with an outer liquid scintillator veto, liquid xenon skin and fiducialisation. Based on the current measurements of radioactivity of different materials, it is shown that LZ can achieve the reduction of a total background for a WIMP search down to about 2 events in 1000 live days for 5.6 tonne fiducial mass.

Microbiota-Liver Axis in Hepatic Disease

PubMed Central

Chassaing, Benoit; Etienne-Mesmin, Lucie; Gewirtz, Andrew T.

2014-01-01

Accumulating evidence indicates that the gut microbiota, long appreciated to be a key determinant of intestinal inflammation, is also playing a key role in chronic inflammatory disease of the liver. Such studies have yielded a general central hypothesis whereby microbiota products activate the innate immune system to drive pro-inflammatory gene expression thus promoting chronic inflammatory disease of the liver. This article reviews the background supporting this hypothesis, outlines how it can potentially explain classic and newly emerging epidemiological chronic inflammatory liver disease, and discusses potential therapeutic means to manipulate the microbiota so as to prevent and/or treat liver disease. PMID:23703735

Vaccination for Disease

NASA Astrophysics Data System (ADS)

Oehen, Stephan; Hengartner, Hans; Zinkernagel, Rolf M.

1991-01-01

Recombinant virus vaccines that express a limited number of epitopes are currently being developed to prevent disease by changing the relative balance between viral spread and the immune response. Some circumstances, however, were found in infections with a noncytopathic virus in which vaccination caused disease; sensitive parameters included the genetic background of the host, the time or dose of infection, and the constituents of the vaccine. Thus, immunopathologic damage by T cells may be an unwanted consequence of vaccination with the new types of peptide or recombinant vaccines that are being investigated for the human immunodeficiency viruses and other pathogens.

The Cosmic Background Explorer

NASA Technical Reports Server (NTRS)

Gulkis, Samuel; Lubin, Philip M.; Meyer, Stephan S.; Silverberg, Robert F.

1990-01-01

The Cosmic Background Explorer (CBE), NASA's cosmological satellite which will observe a radiative relic of the big bang, is discussed. The major questions connected to the big bang theory which may be clarified using the CBE are reviewed. The satellite instruments and experiments are described, including the Differential Microwave Radiometer, which measures the difference between microwave radiation emitted from two points on the sky, the Far-Infrared Absolute Spectrophotometer, which compares the spectrum of radiation from the sky at wavelengths from 100 microns to one cm with that from an internal blackbody, and the Diffuse Infrared Background Experiment, which searches for the radiation from the earliest generation of stars.

Chagas disease and systemic autoimmune diseases among Bolivian patients in Switzerland

PubMed Central

Jackson, Yves; Pula, Drenusha Vieira de Mello; Finckh, Axel; Chizzolini, Carlo; Chappuis, François

2018-01-01

BACKGROUND Chronic cardiomyopathy occurs in 20-40% of the patients with Chagas disease. Autoimmune mechanisms may contribute to its pathogenesis. We diagnosed several cases of systemic autoimmune diseases among Bolivian migrants in Geneva with a high prevalence of Chagas disease. OBJECTIVES We tested the hypothesis of a clinical association between systemic autoimmune diseases and Chagas disease, particularly with the development of cardiomyopathy. METHODS We retrospectively searched the medical records of all Bolivian patients visiting Geneva University Hospitals between 2012 and 2015 for diagnosis of Chagas disease or systemic autoimmune diseases. FINDINGS Of the 2,189 eligible patients, 28 [1.3%; 95% confidence interval (CI) = 0.9-1.9%] presented with systemic autoimmune disease. The Chagas status was known in 903 (41.3%) patient, of whom 244 (27.0%; 95% CI = 24.2-30.0%) were positive. Eight (28.6%; 95% CI = 15.3-47.1%) of the 28 cases of systemic autoimmune disease had Chagas disease. We found no association between both entities (p = 1.000) or with Chagasic cardiomyopathy (p = 0.729). Moreover, there was no evidence of a temporal relationship between antiparasitic chemotherapy and the development of systemic autoimmune diseases. CONCLUSIONS Our results do not support a clinical association between chronic Chagas disease and systemic autoimmune diseases. However, prospective studies in areas endemic for Chagas disease should better assess the prevalence of systemic autoimmune diseases and thus a possible relationship with this infection. PMID:29412344

Exocrine pancreatic insufficiency is not a cause of abdominal complaints in patients with Fabry disease.

PubMed

Vujasinovic, Miroslav; Tepes, Bojan; Vujkovac, Bojan; Cokan Vujkovac, Andreja; Tretjak, Martin; Korat, Vesna

2015-12-01

Fabry disease (FD), also called Anderson-Fabry disease, is the second most prevalent lysosomal storage disorder after Gaucher disease. Gastrointestinal (GI) symptoms are very common among male and female individuals, although the age of onset is later among female patients. To our best knowledge, exocrine pancreatic insufficiency (EPI) has not yet been studied in patients with FD as a possible cause of abdominal complaints. The aim of our study was to determine whether exocrine pancreatic function is impaired in patients with FD. We analysed medical records of patients with FD treated in Fabry Center in Slovenj Gradec General Hospital (Slovenian referral centre for FD) by the evaluation of the following features: gender, age, first symptoms before confirmation of FD diagnosis, time interval between first symptoms and diagnosis, therapy and current abdominal complaints. Diagnosis of FD was established by genetic analysis and confirmation of mutation in the α-galactosidase A gene. Faecal elastase-1 (FE-1) measurements were performed using enzyme-linked immunosorbent assay and the commercial kit ScheBo Biotech, Giessen, Germany. There were 28 adult patients (Slovene, Caucasians) with known FD included in the study: 12 male and 16 female; mean age, 45.6 ± 14.3 (range, 19-75) years. Seventeen patients (63%) were on enzyme replacement therapy (ERT). In seven (25.9%) patients, abdominal complaints (diarrhoea, bloating and feeling of satiety) were present before introduction of ERT. In three out of these seven patients, abdominal complaints resolved after ERT, and in four patients, they were still occasionally present. FE-1 was normal in all patients (547.9 ± 104.5 µg/g). Our results show that exocrine pancreatic function is normal in all patients with FD and is most likely not a cause of abdominal complaints in this group of patients. Nevertheless, EPI still could not be completely excluded as an aetiology factor for GI problems in patients with FD because all our

A review on natural background radiation

PubMed Central

Shahbazi-Gahrouei, Daryoush; Gholami, Mehrdad; Setayandeh, Samaneh

2013-01-01

The world is naturally radioactive and approximately 82% of human-absorbed radiation doses, which are out of control, arise from natural sources such as cosmic, terrestrial, and exposure from inhalation or intake radiation sources. In recent years, several international studies have been carried out, which have reported different values regarding the effect of background radiation on human health. Gamma radiation emitted from natural sources (background radiation) is largely due to primordial radionuclides, mainly 232Th and 238U series, and their decay products, as well as 40K, which exist at trace levels in the earth's crust. Their concentrations in soil, sands, and rocks depend on the local geology of each region in the world. Naturally occurring radioactive materials generally contain terrestrial-origin radionuclides, left over since the creation of the earth. In addition, the existence of some springs and quarries increases the dose rate of background radiation in some regions that are known as high level background radiation regions. The type of building materials used in houses can also affect the dose rate of background radiations. The present review article was carried out to consider all of the natural radiations, including cosmic, terrestrial, and food radiation. PMID:24223380

Practice Patterns in Screening for Metabolic Disease in Women with PCOS of Diverse Race-Ethnic Backgrounds.

PubMed

Mott, Melanie M; Kitos, Nicole R; Coviello, Andrea D

2014-09-01

Women with polycystic ovary syndrome (PCOS) are at high risk for metabolic disorders, which prompted the American Association of Clinical Endocrinologists (AACE) to publish a 2005 position statement recommending screening for metabolic disease.The purposes of the present study were to 1) to examine changes in screening rates for obesity, type 2 diabetes (T2D), metabolic syndrome (MetS), hyperlipidemia (HL), nonalcoholic fatty liver disease (NAFLD), and hypertension (HTN) in women with PCOS after publication of the 2005 AACE position statement and 2) to determine if screening rates and metabolic disorders vary by race-ethnicity. PCOS cases in 2006 (n = 547) and 2011 (n = 1,159) and metabolic disorders were identified by International Classification of Diseases, 9th revision (ICD9) code. Screening rates for metabolic disorders were determined by the presence of blood tests (hemoglobin A1c [HbA1c], lipid profile, alanine aminotransferase/aspartate aminotransferase [ALT/AST]). In 2006, ≤25% of PCOS patients underwent recommended screening tests: HbA1c 18%; lipid profile <20%; ALT/AST ≤25%. By 2011, only HbA1c testing had increased (18% to 21%). Obesity increased from 35% to 40%, while other metabolic disorders remained stable. Black women had the highest rates of obesity and HTN in 2011 (Obesity: Black 48%, Hispanic 44%, White 33%, Other 31%, P<.0001; HTN: Black 18%, Hispanic 9%, White 10%, Other 7%, P<.0001). Blacks and Hispanics were screened more often with ALT/AST testing (Black 27/27%, Hispanic 28/27%, White 23/22%, Other 17/18%, P = .02/.03). Screening rates were higher in the endocrine clinic for all metabolic disorders than in other clinics (P<.05). Despite the publication of recommendations in 2005, screening rates for metabolic disease in women with PCOS remained low across all race-ethnicities in 2011.

Compressive Sensing for Background Subtraction

DTIC Science & Technology

2009-12-20

i) reconstructing an image using only a single optical pho- todiode (infrared, hyperspectral, etc.) along with a digital micromirror device (DMD... curves , we use the full images, run the background subtraction algorithm proposed in [19], and obtain baseline background subtracted images. We then...the images to generate the ROC curve . 5.5 Silhouettes vs. Difference Images We have used a multi camera set up for a 3D voxel reconstruction using the

Demonstration of Cosmic Microwave Background Delensing Using the Cosmic Infrared Background.

PubMed

Larsen, Patricia; Challinor, Anthony; Sherwin, Blake D; Mak, Daisy

2016-10-07

Delensing is an increasingly important technique to reverse the gravitational lensing of the cosmic microwave background (CMB) and thus reveal primordial signals the lensing may obscure. We present a first demonstration of delensing on Planck temperature maps using the cosmic infrared background (CIB). Reversing the lensing deflections in Planck CMB temperature maps using a linear combination of the 545 and 857 GHz maps as a lensing tracer, we find that the lensing effects in the temperature power spectrum are reduced in a manner consistent with theoretical expectations. In particular, the characteristic sharpening of the acoustic peaks of the temperature power spectrum resulting from successful delensing is detected at a significance of 16σ, with an amplitude of A_{delens}=1.12±0.07 relative to the expected value of unity. This first demonstration on data of CIB delensing, and of delensing techniques in general, is significant because lensing removal will soon be essential for achieving high-precision constraints on inflationary B-mode polarization.

Gamma-Ray Background Variability in Mobile Detectors

NASA Astrophysics Data System (ADS)

Aucott, Timothy John

Gamma-ray background radiation significantly reduces detection sensitivity when searching for radioactive sources in the field, such as in wide-area searches for homeland security applications. Mobile detector systems in particular must contend with a variable background that is not necessarily known or even measurable a priori. This work will present measurements of the spatial and temporal variability of the background, with the goal of merging gamma-ray detection, spectroscopy, and imaging with contextual information--a "nuclear street view" of the ubiquitous background radiation. The gamma-ray background originates from a variety of sources, both natural and anthropogenic. The dominant sources in the field are the primordial isotopes potassium-40, uranium-238, and thorium-232, as well as their decay daughters. In addition to the natural background, many artificially-created isotopes are used for industrial or medical purposes, and contamination from fission products can be found in many environments. Regardless of origin, these backgrounds will reduce detection sensitivity by adding both statistical as well as systematic uncertainty. In particular, large detector arrays will be limited by the systematic uncertainty in the background and will suffer from a high rate of false alarms. The goal of this work is to provide a comprehensive characterization of the gamma-ray background and its variability in order to improve detection sensitivity and evaluate the performance of mobile detectors in the field. Large quantities of data are measured in order to study their performance at very low false alarm rates. Two different approaches, spectroscopy and imaging, are compared in a controlled study in the presence of this measured background. Furthermore, there is additional information that can be gained by correlating the gamma-ray data with contextual data streams (such as cameras and global positioning systems) in order to reduce the variability in the background

Evidence for somatic gene conversion and deletion in bipolar disorder, Crohn's disease, coronary artery disease, hypertension, rheumatoid arthritis, type-1 diabetes, and type-2 diabetes

PubMed Central

2011-01-01

Background During gene conversion, genetic information is transferred unidirectionally between highly homologous but non-allelic regions of DNA. While germ-line gene conversion has been implicated in the pathogenesis of some diseases, somatic gene conversion has remained technically difficult to investigate on a large scale. Methods A novel analysis technique is proposed for detecting the signature of somatic gene conversion from SNP microarray data. The Wellcome Trust Case Control Consortium has gathered SNP microarray data for two control populations and cohorts for bipolar disorder (BD), cardiovascular disease (CAD), Crohn's disease (CD), hypertension (HT), rheumatoid arthritis (RA), type-1 diabetes (T1D) and type-2 diabetes (T2D). Using the new analysis technique, the seven disease cohorts are analyzed to identify cohort-specific SNPs at which conversion is predicted. The quality of the predictions is assessed by identifying known disease associations for genes in the homologous duplicons, and comparing the frequency of such associations with background rates. Results Of 28 disease/locus pairs meeting stringent conditions, 22 show various degrees of disease association, compared with only 8 of 70 in a mock study designed to measure the background association rate (P < 10-9). Additional candidate genes are identified using less stringent filtering conditions. In some cases, somatic deletions appear likely. RA has a distinctive pattern of events relative to other diseases. Similarities in patterns are apparent between BD and HT. Conclusions The associations derived represent the first evidence that somatic gene conversion could be a significant causative factor in each of the seven diseases. The specific genes provide potential insights about disease mechanisms, and are strong candidates for further study. Please see Commentary: http://www.biomedcentral.com/1741-7015/9/13/abstract. PMID:21291537

Studying extragalactic background fluctuations with the Cosmic Infrared Background ExpeRiment 2 (CIBER-2)

NASA Astrophysics Data System (ADS)

Lanz, Alicia; Arai, Toshiaki; Battle, John; Bock, James; Cooray, Asantha; Hristov, Viktor; Korngut, Phillip; Lee, Dae Hee; Mason, Peter; Matsumoto, Toshio; Matsuura, Shuji; Morford, Tracy; Onishi, Yosuke; Shirahata, Mai; Tsumura, Kohji; Wada, Takehiko; Zemcov, Michael

2014-08-01

Fluctuations in the extragalactic background light trace emission from the history of galaxy formation, including the emission from the earliest sources from the epoch of reionization. A number of recent near-infrared measure- ments show excess spatial power at large angular scales inconsistent with models of z < 5 emission from galaxies. These measurements have been interpreted as arising from either redshifted stellar and quasar emission from the epoch of reionization, or the combined intra-halo light from stars thrown out of galaxies during merging activity at lower redshifts. Though astrophysically distinct, both interpretations arise from faint, low surface brightness source populations that are difficult to detect except by statistical approaches using careful observations with suitable instruments. The key to determining the source of these background anisotropies will be wide-field imaging measurements spanning multiple bands from the optical to the near-infrared. The Cosmic Infrared Background ExpeRiment 2 (CIBER-2) will measure spatial anisotropies in the extra- galactic infrared background caused by cosmological structure using six broad spectral bands. The experiment uses three 2048 x 2048 Hawaii-2RG near-infrared arrays in three cameras coupled to a single 28.5 cm telescope housed in a reusable sounding rocket-borne payload. A small portion of each array will also be combined with a linear-variable filter to make absolute measurements of the spectrum of the extragalactic background with high spatial resolution for deep subtraction of Galactic starlight. The large field of view and multiple spectral bands make CIBER-2 unique in its sensitivity to fluctuations predicted by models of lower limits on the luminosity of the first stars and galaxies and in its ability to distinguish between primordial and foreground anisotropies. In this paper the scientific motivation for CIBER-2 and details of its first flight instrumentation will be discussed, including

The Cosmic Background Explorer.

ERIC Educational Resources Information Center

Gulkis, Samuel; And Others

1990-01-01

Outlines the Cosmic Background Explorer (COBE) mission to measure celestial radiation. Describes the instruments used and experiments involving differential microwave radiometers, and a far infrared absolute spectrophotometer. (YP)

Non-perturbative background field calculations

NASA Astrophysics Data System (ADS)

Stephens, C. R.

1988-01-01

New methods are developed for calculating one loop functional determinants in quantum field theory. Instead of relying on a calculation of all the eigenvalues of the small fluctuation equation, these techniques exploit the ability of the proper time formalism to reformulate an infinite dimensional field theoretic problem into a finite dimensional covariant quantum mechanical analog, thereby allowing powerful tools such as the method of Jacobi fields to be used advantageously in a field theory setting. More generally the methods developed herein should be extremely valuable when calculating quantum processes in non-constant background fields, offering a utilitarian alternative to the two standard methods of calculation—perturbation theory in the background field or taking the background field into account exactly. The formalism developed also allows for the approximate calculation of covariances of partial differential equations from a knowledge of the solutions of a homogeneous ordinary differential equation.

Molecular analysis of the glucocerebrosidase gene locus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Winfield, S.L.; Martin, B.M.; Fandino, A.

1994-09-01

Gaucher disease is due to a deficiency in the activity of the lysosomal enzyme glucocerebrosidase. Both the functional gene for this enzyme and a pseudogene are located in close proximity on chromosome 1q21. Analysis of the mutations present in patient samples has suggested interaction between the functional gene and the pseudogene in the origin of mutant genotypes. To investigate the involvement of regions flanking the functional gene and pseudogene in the origin of mutations found in Gaucher disease, a YAC clone containing DNA from this locus has been subcloned and characterized. The original YAC containing {approximately}360 kb was truncated withmore » the use of fragmentation plasmids to about 85 kb. A lambda library derived from this YAC was screened to obtain clones containing glucocerebrosidase sequences. PCR amplification was used to identify subclones containing 5{prime}, central, or 3{prime} sequences of the functional gene or of the pseudogene. Clones spanning the entire distance from the last exon of the functional gene to intron 1 of the pseudogene, the 5{prime} end of the functional gene and 16 kb of 5{prime} flanking region and approximately 15 kb of 3{prime} flanking region of the pseudogene were sequenced. Sequence data from 48 kb of intergenic and flanking regions of the glucocerebrosidase gene and its pseudogene has been generated. A large number of Alu sequences and several simple repeats have been found. Two of these repeats exhibit fragment length polymorphism. There is almost 100% homology between the 3{prime} flanking regions of the functional gene and the pseudogene, extending to about 4 kb past the termination codons. A much lower degree of homology is observed in the 5{prime} flanking region. Patient samples are currently being screened for polymorphisms in these flanking regions.« less

Gifted Students from Low-Education Backgrounds

ERIC Educational Resources Information Center

Gibbons, Melinda M.; Pelchar, Taylor K.; Cochran, Jeff L.

2012-01-01

Gifted children from low-education backgrounds often experience barriers to educational and career success. This article reviews the growing body of literature regarding gifted students from low-education backgrounds and the related literature on the challenges and characteristics of first-generation college students. A mother and daughter…

Greater risk of parkinsonism associated with non-N370S GBA1 mutations

PubMed Central

Giraldo, P.; Capablo, J. L.; Alfonso, P.; Irun, P.; Garcia-Rodriguez, B.; Pocovi, M.; Pastores, G. M.

2014-01-01

Mutations in β-glucosidase (GBA1) are the most common genetic risk factor for Parkinson disease (PD). There is evidence to suggest that PD risk is greater (1) in GBA1 heterozygotes with non-N370S GBA1 mutations compared to N370S mutations and (2) in GD type 1 (GD1) patients compared to GBA1 heterozygotes. This study aimed to determine the comparative risk of parkin-sonism in individuals who are affected or carriers of Gaucher disease (GD) and to ascertain the influence of different GBA1 mutations on risk/clinical expression. We conducted a secondary analysis of cross-sectional data assessing the prevalence of parkinsonism in a population of GD1 patients and their heterozygote and non-carrier family members. Two logistic regression models, both employing a family-specific random effect, were used to assess (1) the association between GBA1 mutation (N370S or non-N370S) and parkinsonism among GBA1 heterozygotes and (2) the association between GBA1 genotype and parkinsonism. Parkinsonism was present in 8.6 % of GD1 (7/81), 8.7 % of GBA1 heterozygotes (18/207), and 2.2 % of non-carriers (1/45). For those greater than 60 years old, parkinsonism was present in 38.5 % (5/13) of GD1 (5/13), 15.3 % of GBA1 heterozygotes (13/85), and 7.1 % of non-carriers (1/14). Among GBA1 heterozygotes, non-N370S mutations were associated with a significantly increased risk of parkinsonism compared to N370S (OR=22.5; p=0.035; 95%CI: 1.24, 411). In this population, each additional GBA1 mutation was associated with a non-significant two-fold increased risk of parkinsonism. GBA1 heterozygotes with non-N370S mutations associated with Gaucher disease have an increased risk of parkinsonism compared to those with N370S mutations. PMID:22968580

Pharmacogenetics in Neurodegenerative Diseases: Implications for Clinical Trials.

PubMed

Tortelli, Rosanna; Seripa, Davide; Panza, Francesco; Solfrizzi, Vincenzo; Logroscino, Giancarlo

2016-01-01

Pharmacogenetics has become extremely important over the last 20 years for identifying individuals more likely to be responsive to pharmacological interventions. The role of genetic background as a predictor of drug response is a young and mostly unexplored field in neurodegenerative diseases. Mendelian mutations in neurodegenerative diseases have been used as models for early diagnosis and intervention. On the other hand, genetic polymorphisms or risk factors for late-onset Alzheimer's disease (AD) or other neurodegenerative diseases, probably influencing drug response, are hardly taken into account in randomized clinical trial (RCT) design. The same is true for genetic variants in cytochrome P450 (CYP), the principal enzymes influencing drug metabolism. A better characterization of individual genetic background may optimize clinical trial design and personal drug response. This chapter describes the state of the art about the impact of genetic factors in RCTs on neurodegenerative disease, with AD, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease as examples. Furthermore, a brief description of the genetic bases of drug response focusing on neurodegenerative diseases will be conducted. The role of pharmacogenetics in RCTs for neurodegenerative diseases is still a young, unexplored, and promising field. Genetic tools allow increased sophistication in patient profiling and treatment optimization. Pharmaceutical companies are aware of the value of collecting genetic data during their RCTs. Pharmacogenetic research is bidirectional with RCTs: efficacy data are correlated with genetic polymorphisms, which in turn define subjects for treatment stratification. © 2016 S. Karger AG, Basel.

Status of the Simbol-X Background Simulation Activities

NASA Astrophysics Data System (ADS)

Tenzer, C.; Briel, U.; Bulgarelli, A.; Chipaux, R.; Claret, A.; Cusumano, G.; Dell'Orto, E.; Fioretti, V.; Foschini, L.; Hauf, S.; Kendziorra, E.; Kuster, M.; Laurent, P.; Tiengo, A.

2009-05-01

The Simbol-X background simulation group is working towards a simulation based background and mass model which can be used before and during the mission. Using the Geant4 toolkit, a Monte-Carlo code to simulate the detector background of the Simbol-X focal plane instrument has been developed with the aim to optimize the design of the instrument. Achieving an overall low instrument background has direct impact on the sensitivity of Simbol-X and thus will be crucial for the success of the mission. We present results of recent simulation studies concerning the shielding of the detectors with respect to the diffuse cosmic hard X-ray background and to the cosmic-ray proton induced background. Besides estimates of the level and spectral shape of the remaining background expected in the low and high energy detector, also anti-coincidence rates and resulting detector dead time predictions are discussed.

45 CFR 650.16 - Background rights.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 45 Public Welfare 3 2012-10-01 2012-10-01 false Background rights. 650.16 Section 650.16 Public Welfare Regulations Relating to Public Welfare (Continued) NATIONAL SCIENCE FOUNDATION PATENTS § 650.16 Background rights. The Foundation will acquire rights to a research performer's pre-existing technology only...

Multi-talker background and semantic priming effect

PubMed Central

Dekerle, Marie; Boulenger, Véronique; Hoen, Michel; Meunier, Fanny

2014-01-01

The reported studies have aimed to investigate whether informational masking in a multi-talker background relies on semantic interference between the background and target using an adapted semantic priming paradigm. In 3 experiments, participants were required to perform a lexical decision task on a target item embedded in backgrounds composed of 1–4 voices. These voices were Semantically Consistent (SC) voices (i.e., pronouncing words sharing semantic features with the target) or Semantically Inconsistent (SI) voices (i.e., pronouncing words semantically unrelated to each other and to the target). In the first experiment, backgrounds consisted of 1 or 2 SC voices. One and 2 SI voices were added in Experiments 2 and 3, respectively. The results showed a semantic priming effect only in the conditions where the number of SC voices was greater than the number of SI voices, suggesting that semantic priming depended on prime intelligibility and strategic processes. However, even if backgrounds were composed of 3 or 4 voices, reducing intelligibility, participants were able to recognize words from these backgrounds, although no semantic priming effect on the targets was observed. Overall this finding suggests that informational masking can occur at a semantic level if intelligibility is sufficient. Based on the Effortfulness Hypothesis, we also suggest that when there is an increased difficulty in extracting target signals (caused by a relatively high number of voices in the background), more cognitive resources were allocated to formal processes (i.e., acoustic and phonological), leading to a decrease in available resources for deeper semantic processing of background words, therefore preventing semantic priming from occurring. PMID:25400572

Foregrounding the Background.

ERIC Educational Resources Information Center

Robbins, Bruce

1998-01-01

Argues that when introductory activities to the classics begin with background information, it can upstage or confine the life of the story, and shows little faith in the students as readers or in the literature itself. Suggests sometimes letting the literature begin, and then helping students make sense of it. Discusses examples from "To Kill a…

Effects of background stimulation upon eye-movement information.

PubMed

Nakamura, S

1996-04-01

To investigate the effects of background stimulation upon eye-movement information (EMI), the perceived deceleration of the target motion during pursuit eye movement (Aubert-Fleishl paradox) was analyzed. In the experiment, a striped pattern was used as a background stimulus with various brightness contrasts and spatial frequencies for serially manipulating the attributions of the background stimulus. Analysis showed that the retinal-image motion of the background stimulus (optic flow) affected eye-movement information and that the effects of optic flow became stronger when high contrast and low spatial frequency stripes were presented as the background stimulus. In conclusion, optic flow is one source of eye-movement information in determining real object motion, and the effectiveness of optic flow depends on the attributes of the background stimulus.

Background Error Correlation Modeling with Diffusion Operators

DTIC Science & Technology

2013-01-01

RESPONSIBLE PERSON 19b. TELEPHONE NUMBER (Include area code) 07-10-2013 Book Chapter Background Error Correlation Modeling with Diffusion Operators...normalization Unclassified Unclassified Unclassified UU 27 Max Yaremchuk (228) 688-5259 Reset Chapter 8 Background error correlation modeling with diffusion ...field, then a structure like this simulates enhanced diffusive transport of model errors in the regions of strong cur- rents on the background of

Social Background, Composition and Educational Growth.

ERIC Educational Resources Information Center

Mare, Robert D.

1979-01-01

Studies the impact of changes in family background on grade-level attainment for White males between 1907-1951. Findings show that the effects of social background on grade attainment decrease with increasing levels of attainment. Reprint available from Institute for Research on Poverty, University of Wisconsin-Madison, Madison WI 53706. (AM)

The Radio Background below 100 MHz

NASA Astrophysics Data System (ADS)

Dowell, Jayce; Taylor, Greg B.

2018-05-01

The recent detection of the “cosmic dawn” redshifted 21 cm signal at 78 MHz by the Experiment to Detect the Global EoR Signatures (EDGES) differs significantly from theoretical predictions. In particular, the absorption trough is roughly a factor of two stronger than the most optimistic theoretical models. The early interpretations of the origin of this discrepancy fall into two categories. The first is that there is increased cooling of the gas due to interactions with dark matter, while the second is that the background radiation field includes a contribution from a component in addition to the cosmic microwave background (CMB). In this Letter we examine the feasibility of the second idea using new data from the first station of the Long Wavelength Array. The data span 40–80 MHz and provide important constraints on the present-day background in a frequency range where there are few surveys with absolute temperature calibration suitable for measuring the strength of the radio monopole. We find support for a strong, diffuse radio background that was suggested by the ARCARDE 2 results in the 3–10 GHz range. We find that this background is well modeled by a power law with a spectral index of ‑2.58 ± 0.05 and a temperature at the rest frame 21 cm frequency of {603}-92+102 mK.

Developing novel chemical entities for the treatment of lysosomal storage disorders: an academic perspective.

PubMed

Shayman, James A

2015-12-15

Historically, most Federal Drug Administration-approved drugs were the result of "in-house" efforts within large pharmaceutical companies. Over the last two decades, this paradigm has steadily shifted as the drug industry turned to startups, small biotechnology companies, and academia for the identification of novel drug targets and early drug candidates. This strategic pivot has created new opportunities for groups less traditionally associated with the creation of novel therapeutics, including small academic laboratories, for engagement in the drug discovery process. A recent example of the successful development of a drug that had its origins in academia is eliglustat tartrate, an oral agent for Gaucher disease type 1. Copyright © 2015 the American Physiological Society.

Multiple sclerosis: individualized disease susceptibility and therapy response.

PubMed

Pravica, Vera; Markovic, Milos; Cupic, Maja; Savic, Emina; Popadic, Dusan; Drulovic, Jelena; Mostarica-Stojkovic, Marija

2013-02-01

Multiple sclerosis (MS) is a heterogeneous disease in which diverse genetic, pathological and clinical backgrounds lead to variable therapy response. Accordingly, MS care should be tailored to address disease traits unique to each person. At the core of personalized management is the emergence of new knowledge, enabling optimized treatment and disease-modifying therapies. This overview analyzes the promise of genetic and nongenetic biomarkers in advancing decision-making algorithms to assist diagnosis or in predicting the disease course and therapy response in any given MS patient.

New application of intelligent agents in sporadic amyotrophic lateral sclerosis identifies unexpected specific genetic background.

PubMed

Penco, Silvana; Buscema, Massimo; Patrosso, Maria Cristina; Marocchi, Alessandro; Grossi, Enzo

2008-05-30

Few genetic factors predisposing to the sporadic form of amyotrophic lateral sclerosis (ALS) have been identified, but the pathology itself seems to be a true multifactorial disease in which complex interactions between environmental and genetic susceptibility factors take place. The purpose of this study was to approach genetic data with an innovative statistical method such as artificial neural networks to identify a possible genetic background predisposing to the disease. A DNA multiarray panel was applied to genotype more than 60 polymorphisms within 35 genes selected from pathways of lipid and homocysteine metabolism, regulation of blood pressure, coagulation, inflammation, cellular adhesion and matrix integrity, in 54 sporadic ALS patients and 208 controls. Advanced intelligent systems based on novel coupling of artificial neural networks and evolutionary algorithms have been applied. The results obtained have been compared with those derived from the use of standard neural networks and classical statistical analysis Advanced intelligent systems based on novel coupling of artificial neural networks and evolutionary algorithms have been applied. The results obtained have been compared with those derived from the use of standard neural networks and classical statistical analysis. An unexpected discovery of a strong genetic background in sporadic ALS using a DNA multiarray panel and analytical processing of the data with advanced artificial neural networks was found. The predictive accuracy obtained with Linear Discriminant Analysis and Standard Artificial Neural Networks ranged from 70% to 79% (average 75.31%) and from 69.1 to 86.2% (average 76.6%) respectively. The corresponding value obtained with Advanced Intelligent Systems reached an average of 96.0% (range 94.4 to 97.6%). This latter approach allowed the identification of seven genetic variants essential to differentiate cases from controls: apolipoprotein E arg158cys; hepatic lipase -480 C/T; endothelial

14 CFR § 1214.302 - Background.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 5 2014-01-01 2014-01-01 false Background. § 1214.302 Section § 1214.302 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SPACE FLIGHT Payload Specialists for Space Transportation System (STS) Missions § 1214.302 Background. (a) The Space Transportation System (STS) has been...

45 CFR 650.16 - Background rights.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 45 Public Welfare 3 2014-10-01 2014-10-01 false Background rights. 650.16 Section 650.16 Public Welfare Regulations Relating to Public Welfare (Continued) NATIONAL SCIENCE FOUNDATION PATENTS § 650.16 Background rights. The Foundation will acquire rights to a research performer's pre-existing technology only in exceptional circumstances where, du...

45 CFR 650.16 - Background rights.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 3 2010-10-01 2010-10-01 false Background rights. 650.16 Section 650.16 Public Welfare Regulations Relating to Public Welfare (Continued) NATIONAL SCIENCE FOUNDATION PATENTS § 650.16 Background rights. The Foundation will acquire rights to a research performer's pre-existing technology only in exceptional circumstances where, du...

45 CFR 650.16 - Background rights.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 45 Public Welfare 3 2013-10-01 2013-10-01 false Background rights. 650.16 Section 650.16 Public Welfare Regulations Relating to Public Welfare (Continued) NATIONAL SCIENCE FOUNDATION PATENTS § 650.16 Background rights. The Foundation will acquire rights to a research performer's pre-existing technology only in exceptional circumstances where, du...

45 CFR 650.16 - Background rights.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 45 Public Welfare 3 2011-10-01 2011-10-01 false Background rights. 650.16 Section 650.16 Public Welfare Regulations Relating to Public Welfare (Continued) NATIONAL SCIENCE FOUNDATION PATENTS § 650.16 Background rights. The Foundation will acquire rights to a research performer's pre-existing technology only in exceptional circumstances where, du...

Social Background and School Continuation Decisions.

ERIC Educational Resources Information Center

Mare, Robert D.

1980-01-01

Presents a model of the relationship between social background and school continuation decisions among White males born between 1900 and 1950. The model predicts a decline in the effects of social background by the last school transition. Reprint available from Institute for Research on Poverty, University of Wisconsin, Madison, WI 53706. (AM)

Community participation in disease control.

PubMed

Bermejo, A; Bekui, A

1993-05-01

The main determinants of community participation in disease control programmes are identified and a framework with eleven variables is developed. Attention is drawn to the political background, community characteristics, the managerial capacity of the provider and the epidemiology of the disease. The framework is designed to guide health professionals in the systematic assessment and monitoring of participation in disease control programmes. Analysis of the Ghanaian Guinea Worm Eradication Programme and the Nicaraguan Tuberculosis Control Programme are presented as case studies. They show that political support does not guarantee community participation in disease control programmes and stress the importance of other determinants such as commitment to PHC, intersectoral coordination, the project approach and human resources. The relevance of the epidemiology of the disease in determining what degree of community participation will be most effective is highlighted by the case studies.

Notification: Background Investigation Services

EPA Pesticide Factsheets

Project #OA-FY15-0029, February 26, 2015. The Office of Inspector General (OIG) for the U.S. Environmental Protection Agency (EPA) plans to begin field work for our audit of background investigation services.

[Nineteen cases of school-aged children with degenerative or metabolic neurological disorders initially presenting with learning difficulty and/or behavior disturbance].

PubMed

Honzawa, Shiho; Sugai, Kenji; Akaike, Hiroto; Nakayama, Tojo; Fujikawa, Yoshinao; Komaki, Hirofumi; Nakagawa, Eiji; Sasaki, Masayuki

2012-07-01

We reported 19 cases of school-aged children. They were initially judged to have learning difficulty or school maladaptation because of attention deficits, hyperactive behaviors or poor school performance, followed by the diagnosis such as degenerative or metabolic neurological diseases. The patients consisted of 4 cases of adrenoleukodystrophy, 5 cases of dentatorubral-pallidoluysian atrophy, 3 cases of Sanfilippo syndrome, 3 cases of subacute sclerosing panencephalitis, and each one case of juvenile Gaucher disease, juvenile Huntington disease, juvenile metachromatic leukodystrophy and Leigh disease. They had markedly poor school performance, and/or abnormal behaviors, followed by seizures, character disorders or psychomotor regression. The diagnostic clues included brain CT scan and/or MRI, peculiar facial appearance and notable family histories. When the children were indicated to have learning difficulty or maladjustment to school life, we should make deliberate differential diagnoses before concluding that they have a learning disorder and/or attention-deficit/hyperactivity disorder. Instead they should be recommended to visit child neurologists, when they present with any problems as aforesaid.

Physiologic correlates to background noise acceptance

NASA Astrophysics Data System (ADS)

Tampas, Joanna; Harkrider, Ashley; Nabelek, Anna

2004-05-01

Acceptance of background noise can be evaluated by having listeners indicate the highest background noise level (BNL) they are willing to accept while following the words of a story presented at their most comfortable listening level (MCL). The difference between the selected MCL and BNL is termed the acceptable noise level (ANL). One of the consistent findings in previous studies of ANL is large intersubject variability in acceptance of background noise. This variability is not related to age, gender, hearing sensitivity, personality, type of background noise, or speech perception in noise performance. The purpose of the current experiment was to determine if individual differences in physiological activity measured from the peripheral and central auditory systems of young female adults with normal hearing can account for the variability observed in ANL. Correlations between ANL and various physiological responses, including spontaneous, click-evoked, and distortion-product otoacoustic emissions, auditory brainstem and middle latency evoked potentials, and electroencephalography will be presented. Results may increase understanding of the regions of the auditory system that contribute to individual noise acceptance.

The cosmic microwave background radiation

NASA Technical Reports Server (NTRS)

Silk, Joseph

1992-01-01

A review the implications of the spectrum and anisotropy of the cosmic microwave background for cosmology. Thermalization and processes generating spectral distortions are discussed. Anisotropy predictions are described and compared with observational constraints. If the evidence for large-scale power in the galaxy distribution in excess of that predicted by the cold dark matter model is vindicated, and the observed structure originated via gravitational instabilities of primordial density fluctuations, the predicted amplitude of microwave background anisotropies on angular scales of a degree and larger must be at least several parts in 10 exp 6.

Urban Background Study Webinar

EPA Pesticide Factsheets

This webinar presented the methodology developed for collecting a city-wide or urban area background data set, general results of southeastern cities data collected to date, and a case study that used this sampling method.

Characterizing the True Background Corona with SDO/AIA

NASA Technical Reports Server (NTRS)

Napier, Kate; Winebarger, Amy; Alexander, Caroline

2014-01-01

Characterizing the nature of the solar coronal background would enable scientists to more accurately determine plasma parameters, and may lead to a better understanding of the coronal heating problem. Because scientists study the 3D structure of the Sun in 2D, any line of sight includes both foreground and background material, and thus, the issue of background subtraction arises. By investigating the intensity values in and around an active region, using multiple wavelengths collected from the Atmospheric Imaging Assembly (AIA) on the Solar Dynamics Observatory (SDO) over an eight-hour period, this project aims to characterize the background as smooth or structured. Different methods were employed to measure the true coronal background and create minimum intensity images. These were then investigated for the presence of structure. The background images created were found to contain long-lived structures, including coronal loops, that were still present in all of the wavelengths, 193 Angstroms,171 Angstroms,131 Angstroms, and 211 Angstroms. The intensity profiles across the active region indicate that the background is much more structured than previously thought.

[Genetic and epigenetic aspects of celiac disease].

PubMed

Kocsis, Dorottya; Béres, Nóra; Veres, Gábor; Szabó, Dolóresz; Müller, Katalin Eszter; Arató, András; Juhász, Márk

2014-01-19

Genetic background of coeliac disease has been subjects to intensive research since decades. However, only results of HLA phenotyping have been taken over to routine clinical practice. Meanwhile, data on the role of epigenetical factors in the manifestation of diseases have been emerging. In coeliac disease, there are several questions both in the fields of genetics and epigenetics yet to be answered. In this review, a cross section of current knowledge on these issues is presented with special interest regarding the future clinical applications.

Background derivation and image flattening: getimages

NASA Astrophysics Data System (ADS)

Men'shchikov, A.

2017-11-01

Modern high-resolution images obtained with space observatories display extremely strong intensity variations across images on all spatial scales. Source extraction in such images with methods based on global thresholding may bring unacceptably large numbers of spurious sources in bright areas while failing to detect sources in low-background or low-noise areas. It would be highly beneficial to subtract background and equalize the levels of small-scale fluctuations in the images before extracting sources or filaments. This paper describes getimages, a new method of background derivation and image flattening. It is based on median filtering with sliding windows that correspond to a range of spatial scales from the observational beam size up to a maximum structure width Xλ. The latter is a single free parameter of getimages that can be evaluated manually from the observed image ℐλ. The median filtering algorithm provides a background image \\tilde{Bλ} for structures of all widths below Xλ. The same median filtering procedure applied to an image of standard deviations 𝓓λ derived from a background-subtracted image \\tilde{Sλ} results in a flattening image \\tilde{Fλ}. Finally, a flattened detection image I{λD} = \\tilde{Sλ}/\\tilde{Fλ} is computed, whose standard deviations are uniform outside sources and filaments. Detecting sources in such greatly simplified images results in much cleaner extractions that are more complete and reliable. As a bonus, getimages reduces various observational and map-making artifacts and equalizes noise levels between independent tiles of mosaicked images.

Modeled summer background concentration nutrients and ...

EPA Pesticide Factsheets

We used regression models to predict background concentration of four water quality indictors: total nitrogen (N), total phosphorus (P), chloride, and total suspended solids (TSS), in the mid-continent (USA) great rivers, the Upper Mississippi, the Lower Missouri, and the Ohio. From best-model linear regressions of water quality indicators with land use and other stressor variables, we determined the concentration of the indicators when the land use and stressor variables were all set to zero the y-intercept. Except for total P on the Upper Mississippi River and chloride on the Ohio River, we were able to predict background concentration from significant regression models. In every model with more than one predictor variable, the model included at least one variable representing agricultural land use and one variable representing development. Predicted background concentration of total N was the same on the Upper Mississippi and Lower Missouri rivers (350 ug l-1), which was much lower than a published eutrophication threshold and percentile-based thresholds (25th percentile of concentration at all sites in the population) but was similar to a threshold derived from the response of sestonic chlorophyll a to great river total N concentration. Background concentration of total P on the Lower Missouri (53 ug l-1) was also lower than published and percentile-based thresholds. Background TSS concentration was higher on the Lower Missouri (30 mg l-1) than the other ri

The isotropic radio background revisited

NASA Astrophysics Data System (ADS)

Fornengo, Nicolao; Lineros, Roberto A.; Regis, Marco; Taoso, Marco

2014-04-01

We present an extensive analysis on the determination of the isotropic radio background. We consider six different radio maps, ranging from 22 MHz to 2.3 GHz and covering a large fraction of the sky. The large scale emission is modeled as a linear combination of an isotropic component plus the Galactic synchrotron radiation and thermal bremsstrahlung. Point-like and extended sources are either masked or accounted for by means of a template. We find a robust estimate of the isotropic radio background, with limited scatter among different Galactic models. The level of the isotropic background lies significantly above the contribution obtained by integrating the number counts of observed extragalactic sources. Since the isotropic component dominates at high latitudes, thus making the profile of the total emission flat, a Galactic origin for such excess appears unlikely. We conclude that, unless a systematic offset is present in the maps, and provided that our current understanding of the Galactic synchrotron emission is reasonable, extragalactic sources well below the current experimental threshold seem to account for the majority of the brightness of the extragalactic radio sky.

The EPIC-MOS Particle-Induced Background Spectra

NASA Technical Reports Server (NTRS)

Kuntz, K. D.; Sowden, S. L.

2007-01-01

In order to analyse diffuse emission that fills the field of view, one must accurately characterize the instrumental backgrounds. For the XMM-Newton EPIC instrument these backgrounds include a temporally variable "quiescent" component. as well as the strongly variable soft proton contamination. We have characterized the spectral and spatial response of the EPIC detectors to these background components and have developed tools to remove these backgrounds from observations. The "quiescent" component was characterized using a combination of the filter-wheel-closed data and a database of unexposed-region data. The soft proton contamination was characterized by differencing images and spectra taken during flared and flare-free intervals. After application of our modeled backgrounds, the differences between independent observations of the same region of "blank sky" are consistent with the statistical uncertainties except when there is clear spectral evidence of solar wind charge exchange emission. Using a large sample of blank sky data, we show that strong magnetospheric SWCX emission requires elevated solar wind fluxes; observations through the densest part of the magnetosheath are not necessarily strongly contaminated with SWCX emission.

The EPIC-MOS Particle-Induced Background Spectrum

NASA Technical Reports Server (NTRS)

Kuntz, K. D.; Snowden, S. L.

2006-01-01

We have developed a method for constructing a spectrum of the particle-induced instrumental background of the XMM-Newton EPIC MOS detectors that can be used for observations of the diffuse background and extended sources that fill a significant fraction of the instrument field of view. The strength and spectrum of the particle-induced background, that is, the background due to the interaction of particles with the detector and the detector surroundings, is temporally variable as well as spatially variable over individual chips. Our method uses a combination of the filter-wheel-closed data and a database of unexposed-region data to construct a spectrum of the "quiescent" background. We show that, using this method of background subtraction, the differences between independent observations of the same region of "blank sky" are consistent with the statistical uncertainties except when there is clear evidence of solar wind charge exchange emission. We use the blank sky observations to show that contamination by SWCX emission is a strong function of the solar wind proton flux, and that observations through the flanks of the magnetosheath appear to be contaminated only at much higher solar wind fluxes. We have also developed a spectral model of the residual soft proton flares, which allows their effects to be removed to a substantial degree during spectral fitting.

Oxidative DNA damage background estimated by a system model of base excision repair

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sokhansanj, B A; Wilson, III, D M

Human DNA can be damaged by natural metabolism through free radical production. It has been suggested that the equilibrium between innate damage and cellular DNA repair results in an oxidative DNA damage background that potentially contributes to disease and aging. Efforts to quantitatively characterize the human oxidative DNA damage background level based on measuring 8-oxoguanine lesions as a biomarker have led to estimates varying over 3-4 orders of magnitude, depending on the method of measurement. We applied a previously developed and validated quantitative pathway model of human DNA base excision repair, integrating experimentally determined endogenous damage rates and model parametersmore » from multiple sources. Our estimates of at most 100 8-oxoguanine lesions per cell are consistent with the low end of data from biochemical and cell biology experiments, a result robust to model limitations and parameter variation. Our results show the power of quantitative system modeling to interpret composite experimental data and make biologically and physiologically relevant predictions for complex human DNA repair pathway mechanisms and capacity.« less

Adolescents' Sexually Transmitted Disease Protective Attitudes Predict Sexually Transmitted Disease Acquisition in Early Adulthood

ERIC Educational Resources Information Center

Crosby, Richard A.; Danner, Fred

2008-01-01

Background: Estimates suggest that about 48% of nearly 19 million cases of sexually transmitted diseases (STDs) occurring annually in the United States are acquired by persons aged 15-24 years. The purpose of this study was to test the hypothesis that adolescents' attitudes about protecting themselves from STDs predict their laboratory-confirmed…

Equivalent background speed in recovery from motion adaptation.

PubMed

Simpson, W A; Newman, A; Aasland, W

1997-01-01

We measured, in the same observers, (1) the detectability, d, of a small rotational jump following adaptation to rotational motion and (2) the detectability of the same jump when superimposed on one of several background rotation speeds. Following 90 s of motion adaptation the detectability of the jump was impaired, and sensitivity slowly recovered over the course of 60 s. The detectability of the jump was also impaired by the background speed in a way consistent with a quadratic form of Weber's law. We propose that motion adaptation impairs the detectability of the small jump because it is as if an equivalent background speed has been superimposed on the display. We measured the equivalent background by finding the real background speed that produced the same d' at each instant in the recovery from motion adaptation. The equivalent background started at approximately one to two thirds the speed of the adapting motion, declined rapidly, rose to a small peak at 30 s, then disappeared by 60 s. Since the equivalent background speed corresponds to the speed of the motion aftereffect, we have measured the time course of the motion aftereffect with objective psychophysics.

Generative electronic background music system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mazurowski, Lukasz

In this short paper-extended abstract the new approach to generation of electronic background music has been presented. The Generative Electronic Background Music System (GEBMS) has been located between other related approaches within the musical algorithm positioning framework proposed by Woller et al. The music composition process is performed by a number of mini-models parameterized by further described properties. The mini-models generate fragments of musical patterns used in output composition. Musical pattern and output generation are controlled by container for the mini-models - a host-model. General mechanism has been presented including the example of the synthesized output compositions.

Localization of Legionella pneumophila in Tissue Using FITC-Conjugated Specific Antibody and a Background Stain

DTIC Science & Technology

1982-05-01

Legionnaires ’ disease in tissue. N Engi J Med 1977; Manual of Clinical Microbiology. Third edition. Edited by EH 297:1218-1220 Lennette, A Balows, WJ Hausler...Pathologits P6 i U. S . A. Localization of Legionella pneumophila in Tissue Using FITC- Conjuga ted Specific Antibody and a Background Stain BARBARA S . LOWRY...M.D., FILIBERTO G. VEGA, JR., AND KENNETH W. HEDLUND, M.D. Lowry, Barbara S4, Vega, Filibert. G., Jr., and Hedlund, Ken- U. S . Army Medcal Rleserch

Background in X-ray astronomy proportional counters

NASA Technical Reports Server (NTRS)

Bower, C. R.; Dietz, K. L.; Ramsey, B. D.; Weisskopf, M. C.

1991-01-01

The authors report the results of an investigation into the nature of background events in proportional counters sensitive to X-ray photons having energy of less than 150 keV. Even with the use of thick shields composed of high-atomic-number material, a significant flux background in the detector's energy region can result from multiple Compton scattering in the mass surrounding the active region of the detector. The importance of the selection of detector components in the reduction of the background by more than an order of magnitude is emphasized. Experimental results are shown to agree qualitatively with Monte Carlo simulations. It is concluded that escape gating is a powerful means of determining the nature of background in flight detectors: the single/pair ratios reveal whether the detected events are charged particles or photons.

CUORE and Background Reduction Case Studies for CUPID

NASA Astrophysics Data System (ADS)

Sakai, Michinari; Gozlukluoglu, Nihal; Huang, Huan; Cuore Collaboration

2017-09-01

CUORE (Cryogenic Underground Observatory for Rare Events) is a bolometric experiment at cryogenic temperatures currently in operation to search for neutrinoless double beta decay. Successful detection of this extremely rare process requires stringent control of radioactive backgrounds of the experiment as well as the detector itself. Great care was taken in CUORE to select the materials and various parts that comprise the current detector. However next-generation neutrinoless double beta decay experiments face a challenge to further reduce backgrounds in order to probe more deeply into the effective Majorana neutrino mass phase space. In this presentation we will review the sensitivity and background budget for the currently running experiment CUORE, as well as the target sensitivity and background goals for the next generation experiment CUPID that will cover the inverted neutrino mass hierarchy. We will explore simulation based R&D case studies for background reduction and lay out achievable background reduction levels using possible materials and feasible geometries in the context of CUPID. National Science Foundation.

Effects of background motion on eye-movement information.

PubMed

Nakamura, S

1997-02-01

The effect of background stimulus on eye-movement information was investigated by analyzing the underestimation of the target velocity during pursuit eye movement (Aubert-Fleishl paradox). In the experiment, a striped pattern with various brightness contrasts and spatial frequencies was used as a background stimulus, which was moved at various velocities. Analysis showed that the perceived velocity of the pursuit target, which indicated the magnitudes of eye-movement information, decreased when the background stripes moved in the same direction as eye movement at higher velocities and increased when the background moved in the opposite direction. The results suggest that the eye-movement information varied as a linear function of the velocity of the motion of the background retinal image (optic flow). In addition, the effectiveness of optic flow on eye-movement information was determined by the attributes of the background stimulus such as the brightness contrast or the spatial frequency of the striped pattern.

Modeling background radiation in Southern Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haber, Daniel A.; Burnley, Pamela C.; Adcock, Christopher T.

Aerial gamma ray surveys are an important tool for national security, scientific, and industrial interests in determining locations of both anthropogenic and natural sources of radioactivity. There is a relationship between radioactivity and geology and in the past this relationship has been used to predict geology from an aerial survey. The purpose of this project is to develop a method to predict the radiologic exposure rate of the geologic materials by creating a high resolution background model. The intention is for this method to be used in an emergency response scenario where the background radiation envi-ronment is unknown. Two studymore » areas in Southern Nevada have been modeled using geologic data, images from the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER), geochemical data, and pre-existing low resolution aerial surveys from the National Uranium Resource Evaluation (NURE) Survey. Using these data, geospatial areas that are homogenous in terms of K, U, and Th, referred to as background radiation units, are defined and the gamma ray exposure rate is predicted. The prediction is compared to data collected via detailed aerial survey by the Department of Energy's Remote Sensing Lab - Nellis, allowing for the refinement of the technique. By using geologic units to define radiation background units of exposed bedrock and ASTER visualizations to subdivide and define radiation background units within alluvium, successful models have been produced for Government Wash, north of Lake Mead, and for the western shore of Lake Mohave, east of Searchlight, NV.« less

Modeling background radiation in Southern Nevada

DOE PAGES

Haber, Daniel A.; Burnley, Pamela C.; Adcock, Christopher T.; ...

2017-02-06

Aerial gamma ray surveys are an important tool for national security, scientific, and industrial interests in determining locations of both anthropogenic and natural sources of radioactivity. There is a relationship between radioactivity and geology and in the past this relationship has been used to predict geology from an aerial survey. The purpose of this project is to develop a method to predict the radiologic exposure rate of the geologic materials by creating a high resolution background model. The intention is for this method to be used in an emergency response scenario where the background radiation envi-ronment is unknown. Two studymore » areas in Southern Nevada have been modeled using geologic data, images from the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER), geochemical data, and pre-existing low resolution aerial surveys from the National Uranium Resource Evaluation (NURE) Survey. Using these data, geospatial areas that are homogenous in terms of K, U, and Th, referred to as background radiation units, are defined and the gamma ray exposure rate is predicted. The prediction is compared to data collected via detailed aerial survey by the Department of Energy's Remote Sensing Lab - Nellis, allowing for the refinement of the technique. By using geologic units to define radiation background units of exposed bedrock and ASTER visualizations to subdivide and define radiation background units within alluvium, successful models have been produced for Government Wash, north of Lake Mead, and for the western shore of Lake Mohave, east of Searchlight, NV.« less

Posture Recognition in Alzheimer's Disease

ERIC Educational Resources Information Center

Mozaz, Maria; Garaigordobil, Maite; Rothi, Leslie J. Gonzalez; Anderson, Jeffrey; Crucian, Gregory P.; Heilman, Kenneth M.

2006-01-01

Background: Apraxia is neurologically induced deficit in the ability perform purposeful skilled movements. One of the most common forms is ideomotor apraxia (IMA) where spatial and temporal production errors are most prevalent. IMA can be associated Alzheimer's disease (AD), even early in its course, but is often not identified possibly because…

Providing Counseling for Individuals with Alzheimer's Disease and Their Caregivers

ERIC Educational Resources Information Center

Granello, Paul F.; Fleming, Matthew S.

2008-01-01

Alzheimer's disease is a progressive condition that results in brain wasting and eventual death. With its increasing diagnosis rate, counselors will likely acquire clients with Alzheimer's disease or their caregivers. Important background information and several practical counseling methods are provided that may assist counselors working with this…

Cost Analysis of Chronic Disease Self-Management Programmes Being Delivered in South Florida

ERIC Educational Resources Information Center

Page, Timothy F.; Palmer, Richard C.

2014-01-01

Background: Chronic disease accounts for the majority of healthcare costs. The Chronic Disease Self-Management Programme (CDSMP) has been shown to be effective in reducing the burden of chronic disease. Objectives: The objective of this study was to measure the cost of delivering the Chronic Disease Self-Management Programme (CDSMP) in order to…

Role of Ionizing Radiation in Neurodegenerative Diseases

PubMed Central

Sharma, Neel K.; Sharma, Rupali; Mathur, Deepali; Sharad, Shashwat; Minhas, Gillipsie; Bhatia, Kulsajan; Anand, Akshay; Ghosh, Sanchita P.

2018-01-01

Ionizing radiation (IR) from terrestrial sources is continually an unprotected peril to human beings. However, the medical radiation and global radiation background are main contributors to human exposure and causes of radiation sickness. At high-dose exposures acute radiation sickness occurs, whereas chronic effects may persist for a number of years. Radiation can increase many circulatory, age related and neurodegenerative diseases. Neurodegenerative diseases occur a long time after exposure to radiation, as demonstrated in atomic bomb survivors, and are still controversial. This review discuss the role of IR in neurodegenerative diseases and proposes an association between neurodegenerative diseases and exposure to IR. PMID:29867445

Background modeling for the GERDA experiment

NASA Astrophysics Data System (ADS)

Becerici-Schmidt, N.; Gerda Collaboration

2013-08-01

The neutrinoless double beta (0νββ) decay experiment GERDA at the LNGS of INFN has started physics data taking in November 2011. This paper presents an analysis aimed at understanding and modeling the observed background energy spectrum, which plays an essential role in searches for a rare signal like 0νββ decay. A very promising preliminary model has been obtained, with the systematic uncertainties still under study. Important information can be deduced from the model such as the expected background and its decomposition in the signal region. According to the model the main background contributions around Qββ come from 214Bi, 228Th, 42K, 60Co and α emitting isotopes in the 226Ra decay chain, with a fraction depending on the assumed source positions.

Low background screening capability in the UK

NASA Astrophysics Data System (ADS)

Ghag, Chamkaur

2015-08-01

Low background rare event searches in underground laboratories seeking observation of direct dark matter interactions or neutrino-less double beta decay have the potential to profoundly advance our understanding of the physical universe. Successful results from these experiments depend critically on construction from extremely radiologically clean materials and accurate knowledge of subsequent low levels of expected background. The experiments must conduct comprehensive screening campaigns to reduce radioactivity from detector components, and these measurements also inform detailed characterisation and quantification of background sources and their impact, necessary to assign statistical significance to any potential discovery. To provide requisite sensitivity for material screening and characterisation in the UK to support our rare event search activities, we have re-developed our infrastructure to add ultra-low background capability across a range of complementary techniques that collectively allow complete radioactivity measurements. Ultra-low background HPGe and BEGe detectors have been installed at the Boulby Underground Laboratory, itself undergoing substantial facility re-furbishment, to provide high sensitivity gamma spectroscopy in particular for measuring the uranium and thorium decay series products. Dedicated low-activity mass spectrometry instrumentation has been developed at UCL for part per trillion level contaminant identification to complement underground screening with direct U and Th measurements, and meet throughput demands. Finally, radon emanation screening at UCL measures radon background inaccessible to gamma or mass spectrometry techniques. With this new capability the UK is delivering half of the radioactivity screening for the LZ dark matter search experiment.

Numerical chromosomal aberrations in Hodgkin's disease detected by in situ hybridisation on routine paraffin sections.

PubMed Central

Pringle, J H; Shaw, J A; Gillies, A; Lauder, I

1997-01-01

AIMS: To visualise directly numerical chromosomal aberrations and polyploidy in both Hodgkin and Reed Sternberg (HRS) cells and background cells from cases of Hodgkin's disease using in situ hybridisation. METHODS: Non-isotopic DNA in situ hybridisation was applied to interphase cell nuclei of Hodgkin's disease within routine paraffin embedded tissue sections. Two a satellite DNA probes, specific for chromosomes 3 and 12, were used to evaluate the feasibility of this approach. Double labelling with immunocytochemical detection of the CD30 antigen was used to identify HRS cells. Cytogenetic normal diploid and triploid placental tissue served as controls. RESULTS: The eight cases of Hodgkin's disease investigated displayed frequent polysomy, while the majority of background cells showed disomy signals. CONCLUSIONS: Numerical chromosomal aberrations were detected in HRS cells from eight cases of Hodgkin's disease by in situ hybridisation. These data show that in Hodgkin's disease HRS cells frequently display polyploidy compared with background cells and are, therefore, probably the only neoplastic component in this disease. Correlations between polysomy and tumour type or grade could not be made from these data owing to the limited number of cases examined and to problems with interpreting data from truncated nuclei. Images PMID:9306933

Optimal Background Estimators in Single-Molecule FRET Microscopy.

PubMed

Preus, Søren; Hildebrandt, Lasse L; Birkedal, Victoria

2016-09-20

Single-molecule total internal reflection fluorescence (TIRF) microscopy constitutes an umbrella of powerful tools that facilitate direct observation of the biophysical properties, population heterogeneities, and interactions of single biomolecules without the need for ensemble synchronization. Due to the low signal/noise ratio in single-molecule TIRF microscopy experiments, it is important to determine the local background intensity, especially when the fluorescence intensity of the molecule is used quantitatively. Here we compare and evaluate the performance of different aperture-based background estimators used particularly in single-molecule Förster resonance energy transfer. We introduce the general concept of multiaperture signatures and use this technique to demonstrate how the choice of background can affect the measured fluorescence signal considerably. A new, to our knowledge, and simple background estimator is proposed, called the local statistical percentile (LSP). We show that the LSP background estimator performs as well as current background estimators at low molecular densities and significantly better in regions of high molecular densities. The LSP background estimator is thus suited for single-particle TIRF microscopy of dense biological samples in which the intensity itself is an observable of the technique. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Serum Immune Responses Predict Rapid Disease Progression among Children with Crohn’s Disease: Immune Responses Predict Disease Progression

PubMed Central

Dubinsky, Marla C.; Lin, Ying-Chao; Dutridge, Debra; Picornell, Yoana; Landers, Carol J.; Farrior, Sharmayne; Wrobel, Iwona; Quiros, Antonio; Vasiliauskas, Eric A.; Grill, Bruce; Israel, David; Bahar, Ron; Christie, Dennis; Wahbeh, Ghassan; Silber, Gary; Dallazadeh, Saied; Shah, Praful; Thomas, Danny; Kelts, Drew; Hershberg, Robert M.; Elson, Charles O.; Targan, Stephan R.; Taylor, Kent D.; Rotter, Jerome I.; Yang, Huiying

2007-01-01

BACKGROUND AND AIM Crohn’s disease (CD) is a heterogeneous disorder characterized by diverse clinical phenotypes. Childhood-onset CD has been described as a more aggressive phenotype. Genetic and immune factors may influence disease phenotype and clinical course. We examined the association of immune responses to microbial antigens with disease behavior and prospectively determined the influence of immune reactivity on disease progression in pediatric CD patients. METHODS Sera were collected from 196 pediatric CD cases and tested for immune responses: anti-I2, anti-outer membrane protein C (anti-OmpC), anti-CBir1 flagellin (anti-CBir1), and anti-Saccharomyces-cerevisiae (ASCA) using ELISA. Associations between immune responses and clinical phenotype were evaluated. RESULTS Fifty-eight patients (28%) developed internal penetrating and/or stricturing (IP/S) disease after a median follow-up of 18 months. Both anti-OmpC (p < 0.0006) and anti-I2 (p < 0.003) were associated with IP/S disease. The frequency of IP/S disease increased with increasing number of immune responses (p trend = 0.002). The odds of developing IP/S disease were highest in patients positive for all four immune responses (OR (95% CI): 11 (1.5–80.4); p = 0.03). Pediatric CD patients positive for ≥1 immune response progressed to IP/S disease sooner after diagnosis as compared to those negative for all immune responses (p < 0.03). CONCLUSIONS The presence and magnitude of immune responses to microbial antigens are significantly associated with more aggressive disease phenotypes among children with CD. This is the first study to prospectively demonstrate that the time to develop a disease complication in children is significantly faster in the presence of immune reactivity, thereby predicting disease progression to more aggressive disease phenotypes among pediatric CD patients. PMID:16454844

Perfluorocarbon background concentrations in Europe

NASA Astrophysics Data System (ADS)

Straume, Anne Grete; Dietz, Russel N.; Koffı̀, Ernest N.'dri; Nodop, Katrin

Five studies of the background level of several perfluorocarbon compounds in Europe are here presented together with measurements from the European Tracer Experiment (ETEX). The tracers used during the two ETEX tracer releases were the perfluorocarbons (PFCs); perfluoromethylcyclohexane (C 7F 14, PMCH) and perfluoromethylcyclopentane (C 6F 12, PMCP). Their background concentrations were detected by using both passive and active sampling techniques, to define the spatial and temporal variation of the PFCs over Europe. Also the background variations of four isomers of the PFC compound perfluorodimethylcyclohexane (C 8F 16, PDCH) were studied. The results were compared to other PFC tracer studies in the U.S.A. and Europe. The mean and median values of the measured PFCs were found to vary slightly and randomly in space and time. They were found to be higher and to have a larger standard deviation than the measurements from the American studies. The background concentrations were still found to be low and stable enough for PFCs to be highly suitable for use in tracer studies. The following concentrations were found: PMCP; 4.6±0.3 fl ℓ -1, PMCH: 4.6±0.8 fl ℓ -1, ocPDCH: 0.96±0.33 fl ℓ -1, mtPDCH: 9.3±0.8 fl ℓ -1, mcPDCH: 8.8±0.8 fl ℓ -1, ptPDCH: 6.1±0.8 fl ℓ -1. A study of the correlation between the measured PFC compounds showed a significant correlation between most of the compounds, which indicate that there are no major PFC sources in Europe.

Urban enhancement of PM10 bioaerosol tracers relative to background locations in the Midwestern United States

NASA Astrophysics Data System (ADS)

Rathnayake, Chathurika M.; Metwali, Nervana; Baker, Zach; Jayarathne, Thilina; Kostle, Pamela A.; Thorne, Peter S.; O'Shaughnessy, Patrick T.; Stone, Elizabeth A.

2016-05-01

Bioaerosols are well-known immune-active particles that exacerbate respiratory diseases. Human exposures to bioaerosols and their resultant health impacts depend on their ambient concentrations, seasonal and spatial variation, and copollutants, which are not yet widely characterized. In this study, chemical and biological tracers of bioaerosols were quantified in respirable particulate matter (PM10) collected at three urban and three background sites in the Midwestern United States across four seasons in 2012. Endotoxins from Gram-negative bacteria (and a few Gram-positive bacteria), water-soluble proteins, and tracers for fungal spores (fungal glucans, arabitol, and mannitol) were ubiquitous and showed significant seasonal variation and dependence on temperature. Fungal spores were elevated in spring and peaked in summer, following the seasonal growing cycle, while endotoxins peaked in autumn during the row crop harvesting season. Paired comparisons of bioaerosols in urban and background sites revealed significant urban enhancements in PM10, fungal glucans, endotoxins, and water-soluble proteins relative to background locations, such that urban populations have a greater outdoor exposure to bioaerosols. These bioaerosols contribute, in part, to the urban excesses in PM10. Higher bioaerosol mass fractions in urban areas relative to background sites indicate that urban areas serve as a source of bioaerosols. Similar urban enhancements in water-soluble calcium and its correlation with bioaerosol tracers point toward windblown soil as an important source of bioaerosols in urban areas.

Background radiation measurements at high power research reactors

NASA Astrophysics Data System (ADS)

Ashenfelter, J.; Balantekin, B.; Baldenegro, C. X.; Band, H. R.; Barclay, G.; Bass, C. D.; Berish, D.; Bowden, N. S.; Bryan, C. D.; Cherwinka, J. J.; Chu, R.; Classen, T.; Davee, D.; Dean, D.; Deichert, G.; Dolinski, M. J.; Dolph, J.; Dwyer, D. A.; Fan, S.; Gaison, J. K.; Galindo-Uribarri, A.; Gilje, K.; Glenn, A.; Green, M.; Han, K.; Hans, S.; Heeger, K. M.; Heffron, B.; Jaffe, D. E.; Kettell, S.; Langford, T. J.; Littlejohn, B. R.; Martinez, D.; McKeown, R. D.; Morrell, S.; Mueller, P. E.; Mumm, H. P.; Napolitano, J.; Norcini, D.; Pushin, D.; Romero, E.; Rosero, R.; Saldana, L.; Seilhan, B. S.; Sharma, R.; Stemen, N. T.; Surukuchi, P. T.; Thompson, S. J.; Varner, R. L.; Wang, W.; Watson, S. M.; White, B.; White, C.; Wilhelmi, J.; Williams, C.; Wise, T.; Yao, H.; Yeh, M.; Yen, Y.-R.; Zhang, C.; Zhang, X.; Prospect Collaboration

2016-01-01

Research reactors host a wide range of activities that make use of the intense neutron fluxes generated at these facilities. Recent interest in performing measurements with relatively low event rates, e.g. reactor antineutrino detection, at these facilities necessitates a detailed understanding of background radiation fields. Both reactor-correlated and naturally occurring background sources are potentially important, even at levels well below those of importance for typical activities. Here we describe a comprehensive series of background assessments at three high-power research reactors, including γ-ray, neutron, and muon measurements. For each facility we describe the characteristics and identify the sources of the background fields encountered. The general understanding gained of background production mechanisms and their relationship to facility features will prove valuable for the planning of any sensitive measurement conducted therein.

76 FR 79565 - Management Contracts-Background Investigations

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-22

... Management Contracts--Background Investigations AGENCY: National Indian Gaming Commission. ACTION: Notice of... investigation process required for management contracts. The proposed revision may reduce duplication of efforts... to clarify that a management contractor should be required to submit background information when the...

Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis.

PubMed

Sisay, Sofia; Pryce, Gareth; Jackson, Samuel J; Tanner, Carolyn; Ross, Ruth A; Michael, Gregory J; Selwood, David L; Giovannoni, Gavin; Baker, David

2013-01-01

Endocannabinoids and some phytocannabinoids bind to CB1 and CB2 cannabinoid receptors, transient receptor potential vanilloid one (TRPV1) receptor and the orphan G protein receptor fifty-five (GPR55). Studies using C57BL/10 and C57BL/6 (Cnr2 (tm1Zim)) CB2 cannabinoid receptor knockout mice have demonstrated an immune-augmenting effect in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis. However, other EAE studies in Biozzi ABH mice often failed to show any treatment effect of either CB2 receptor agonism or antagonism on inhibition of T cell autoimmunity. The influence of genetic background on the induction of EAE in endocannabinoid system-related gene knockout mice was examined. It was found that C57BL/6.GPR55 knockout mice developed less severe disease, notably in female mice, following active induction with myelin oligodendrocyte glycoprotein 35-55 peptide. In contrast C57BL/6.CB2 (Cnr2 (Dgen)) receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2 (tm1Zim) mice. However, when the knockout gene was bred into the ABH mouse background and EAE induced with spinal cord autoantigens the immune-enhancing effect of CB2 receptor deletion was lost. Likewise CB1 receptor and transient receptor potential vanilloid one knockout mice on the ABH background demonstrated no alteration in immune-susceptibility, in terms of disease incidence and severity of EAE, in contrast to that reported in some C57BL/6 mouse studies. Furthermore the immune-modulating influence of GPR55 was marginal on the ABH mouse background. Whilst sedative doses of tetrahydrocannabinol could induce immunosuppression, this was associated with a CB1 receptor rather than a CB2 receptor-mediated effect. These data support the fact that non-psychoactive doses of medicinal cannabis have a marginal influence on the immune response in MS. Importantly, it adds a note of caution for the translational value of some

Genetic Background is a Key Determinant of Glomerular Extracellular Matrix Composition and Organization.

PubMed

Randles, Michael J; Woolf, Adrian S; Huang, Jennifer L; Byron, Adam; Humphries, Jonathan D; Price, Karen L; Kolatsi-Joannou, Maria; Collinson, Sophie; Denny, Thomas; Knight, David; Mironov, Aleksandr; Starborg, Toby; Korstanje, Ron; Humphries, Martin J; Long, David A; Lennon, Rachel

2015-12-01

Glomerular disease often features altered histologic patterns of extracellular matrix (ECM). Despite this, the potential complexities of the glomerular ECM in both health and disease are poorly understood. To explore whether genetic background and sex determine glomerular ECM composition, we investigated two mouse strains, FVB and B6, using RNA microarrays of isolated glomeruli combined with proteomic glomerular ECM analyses. These studies, undertaken in healthy young adult animals, revealed unique strain- and sex-dependent glomerular ECM signatures, which correlated with variations in levels of albuminuria and known predisposition to progressive nephropathy. Among the variation, we observed changes in netrin 4, fibroblast growth factor 2, tenascin C, collagen 1, meprin 1-α, and meprin 1-β. Differences in protein abundance were validated by quantitative immunohistochemistry and Western blot analysis, and the collective differences were not explained by mutations in known ECM or glomerular disease genes. Within the distinct signatures, we discovered a core set of structural ECM proteins that form multiple protein-protein interactions and are conserved from mouse to man. Furthermore, we found striking ultrastructural changes in glomerular basement membranes in FVB mice. Pathway analysis of merged transcriptomic and proteomic datasets identified potential ECM regulatory pathways involving inhibition of matrix metalloproteases, liver X receptor/retinoid X receptor, nuclear factor erythroid 2-related factor 2, notch, and cyclin-dependent kinase 5. These pathways may therefore alter ECM and confer susceptibility to disease. Copyright © 2015 by the American Society of Nephrology.

Genetic Background is a Key Determinant of Glomerular Extracellular Matrix Composition and Organization

PubMed Central

Randles, Michael J.; Woolf, Adrian S.; Huang, Jennifer L.; Byron, Adam; Humphries, Jonathan D.; Price, Karen L.; Kolatsi-Joannou, Maria; Collinson, Sophie; Denny, Thomas; Knight, David; Mironov, Aleksandr; Starborg, Toby; Korstanje, Ron; Humphries, Martin J.; Long, David A.

2015-01-01

Glomerular disease often features altered histologic patterns of extracellular matrix (ECM). Despite this, the potential complexities of the glomerular ECM in both health and disease are poorly understood. To explore whether genetic background and sex determine glomerular ECM composition, we investigated two mouse strains, FVB and B6, using RNA microarrays of isolated glomeruli combined with proteomic glomerular ECM analyses. These studies, undertaken in healthy young adult animals, revealed unique strain- and sex-dependent glomerular ECM signatures, which correlated with variations in levels of albuminuria and known predisposition to progressive nephropathy. Among the variation, we observed changes in netrin 4, fibroblast growth factor 2, tenascin C, collagen 1, meprin 1-α, and meprin 1-β. Differences in protein abundance were validated by quantitative immunohistochemistry and Western blot analysis, and the collective differences were not explained by mutations in known ECM or glomerular disease genes. Within the distinct signatures, we discovered a core set of structural ECM proteins that form multiple protein–protein interactions and are conserved from mouse to man. Furthermore, we found striking ultrastructural changes in glomerular basement membranes in FVB mice. Pathway analysis of merged transcriptomic and proteomic datasets identified potential ECM regulatory pathways involving inhibition of matrix metalloproteases, liver X receptor/retinoid X receptor, nuclear factor erythroid 2-related factor 2, notch, and cyclin-dependent kinase 5. These pathways may therefore alter ECM and confer susceptibility to disease. PMID:25896609

Thermal background noise limitations

NASA Technical Reports Server (NTRS)

Gulkis, S.

1982-01-01

Modern detection systems are increasingly limited in sensitivity by the background thermal photons which enter the receiving system. Expressions for the fluctuations of detected thermal radiation are derived. Incoherent and heterodyne detection processes are considered. References to the subject of photon detection statistics are given.

Stacked Multilayer Self-Organizing Map for Background Modeling.

PubMed

Zhao, Zhenjie; Zhang, Xuebo; Fang, Yongchun

2015-09-01

In this paper, a new background modeling method called stacked multilayer self-organizing map background model (SMSOM-BM) is proposed, which presents several merits such as strong representative ability for complex scenarios, easy to use, and so on. In order to enhance the representative ability of the background model and make the parameters learned automatically, the recently developed idea of representative learning (or deep learning) is elegantly employed to extend the existing single-layer self-organizing map background model to a multilayer one (namely, the proposed SMSOM-BM). As a consequence, the SMSOM-BM gains several merits including strong representative ability to learn background model of challenging scenarios, and automatic determination for most network parameters. More specifically, every pixel is modeled by a SMSOM, and spatial consistency is considered at each layer. By introducing a novel over-layer filtering process, we can train the background model layer by layer in an efficient manner. Furthermore, for real-time performance consideration, we have implemented the proposed method using NVIDIA CUDA platform. Comparative experimental results show superior performance of the proposed approach.

Comprehension of Complex Discourse in Different Stages of Huntington's Disease

ERIC Educational Resources Information Center

Saldert, Charlotta; Fors, Angelika; Stroberg, Sofia; Hartelius, Lena

2010-01-01

Background: Huntington's disease not only affects motor speech control, but also may have an impact on the ability to produce and understand language in communication. Aims: The ability to comprehend basic and complex discourse was investigated in three different stages of Huntington's disease. Methods & Procedures: In this experimental group…

Background-Modeling-Based Adaptive Prediction for Surveillance Video Coding.

PubMed

Zhang, Xianguo; Huang, Tiejun; Tian, Yonghong; Gao, Wen

2014-02-01

The exponential growth of surveillance videos presents an unprecedented challenge for high-efficiency surveillance video coding technology. Compared with the existing coding standards that were basically developed for generic videos, surveillance video coding should be designed to make the best use of the special characteristics of surveillance videos (e.g., relative static background). To do so, this paper first conducts two analyses on how to improve the background and foreground prediction efficiencies in surveillance video coding. Following the analysis results, we propose a background-modeling-based adaptive prediction (BMAP) method. In this method, all blocks to be encoded are firstly classified into three categories. Then, according to the category of each block, two novel inter predictions are selectively utilized, namely, the background reference prediction (BRP) that uses the background modeled from the original input frames as the long-term reference and the background difference prediction (BDP) that predicts the current data in the background difference domain. For background blocks, the BRP can effectively improve the prediction efficiency using the higher quality background as the reference; whereas for foreground-background-hybrid blocks, the BDP can provide a better reference after subtracting its background pixels. Experimental results show that the BMAP can achieve at least twice the compression ratio on surveillance videos as AVC (MPEG-4 Advanced Video Coding) high profile, yet with a slightly additional encoding complexity. Moreover, for the foreground coding performance, which is crucial to the subjective quality of moving objects in surveillance videos, BMAP also obtains remarkable gains over several state-of-the-art methods.

X-Ray Background Survey Spectrometer (XBSS)

NASA Technical Reports Server (NTRS)

Sanders, W. T. (Principal Investigator); Paulos, R. J.

1996-01-01

The objective of this investigation was to perform a spectral survey of the low energy diffuse X-ray background using the X-ray Background Survey Spectrometer (XBSS) on board the Space Station Freedom (SSF). XBSS obtains spectra of the X-ray diffuse background in the 11-24 A and 44-84 A wavelength intervals over the entire sky with 15 deg spatial resolution. These X-rays are almost certainly from a very hot (10(exp 6) K) component of the interstellar medium that is contained in regions occupying a large fraction of the interstellar volume near the Sun. Astrophysical plasmas near 10(exp 6) K are rich in emission lines, and the relative strengths of these lines, besides providing information about the physical conditions of the emitting gas, also provide information about its history and heating mechanisms.

Background frequency of Bacillus species at the Canberra Airport: A 12 month study.

PubMed

Gahan, Michelle E; Thomas, Rory; Rossi, Rebecca; Nelson, Michelle; Roffey, Paul; Richardson, Michelle M; McNevin, Dennis

2015-12-01

Anthrax, caused by Bacillus anthracis, is a naturally occurring disease in Australia. Whilst mainly limited to livestock in grazing regions of Victoria and New South Wales, movement of people, stock and vehicles means B. anthracis could be present outside this region. Of particular interest is the "background" prevalence of B. anthracis at transport hubs including airports. The aim of this study was to determine the background frequency of B. anthracis and the commonly used hoax agent Bacillus thuringiensis at the Canberra Airport over a 12 month period. Samples were collected daily for seven days each month from August 2011-July 2012 and analyzed using species specific real-time polymerase chain reaction. Fourteen samples (of a total of 575) were positive for the B. anthracis PL3 genomic marker, 24 for the cya (pXO1) plasmid marker and five for the capB (pXO2) plasmid marker. Whilst five samples were positive for both PL3 and cya, no samples were positive for all three markers hence there is no evidence to suggest the presence of pathogenic B. anthracis strains. B. anthracis targets were detected primarily in February 2012 and B. thuringiensis peaked in October and November 2011 and again in April and May 2012. This study provides a rapid method to screen for, and differentiate, Bacillus species. Armed with this information investigators will be able to discriminate a "threat" from "background" frequencies should the need arise. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Taiwan: Background Notes Series.

ERIC Educational Resources Information Center

Reams, Joanne Reppert

Concise background information on Taiwan is provided. The publication begins with a profile of Taiwan, discussing the people, geography, political establishment, and economy. A map of the country is provided. The bulk of the publication then provides more detailed information on Taiwan's people, geography, history, administration, political…

Scientific results from the Cosmic Background Explorer (COBE)

PubMed Central

Bennett, C. L.; Boggess, N. W.; Cheng, E. S.; Hauser, M. G.; Kelsall, T.; Mather, J. C.; Moseley, S. H.; Murdock, T. L.; Shafer, R. A.; Silverberg, R. F.; Smoot, G. F.; Weiss, R.; Wright, E. L.

1993-01-01

The National Aeronautics and Space Administration (NASA) has flown the COBE satellite to observe the Big Bang and the subsequent formation of galaxies and large-scale structure. Data from the Far-Infrared Absolute Spectrophotometer (FIRAS) show that the spectrum of the cosmic microwave background is that of a black body of temperature T = 2.73 ± 0.06 K, with no deviation from a black-body spectrum greater than 0.25% of the peak brightness. The data from the Differential Microwave Radiometers (DMR) show statistically significant cosmic microwave background anisotropy, consistent with a scale-invariant primordial density fluctuation spectrum. Measurements from the Diffuse Infrared Background Experiment (DIRBE) provide new conservative upper limits to the cosmic infrared background. Extensive modeling of solar system and galactic infrared foregrounds is required for further improvement in the cosmic infrared background limits. PMID:11607383

Common periodontal diseases of children and adolescents.

PubMed

Al-Ghutaimel, Hayat; Riba, Hisham; Al-Kahtani, Salem; Al-Duhaimi, Saad

2014-01-01

Background. Since 2000, studies, experiments, and clinical observations revealed high prevalence of periodontal diseases among children and adolescents. Therefore, this paper was designed to provide an update for dental practitioners on epidemiology, microbiology, pathology, prevention, diagnosis, and treatment of periodontal diseases in children and adolescents. Methods. This paper reviews the current literature concerning periodontal diseases in pediatric dentistry. It includes MEDLINE database search using key terms: "periodontal diseases in children," "Periodontal diseasesin adolescents," "periodontal diseases risk factors," "microbiology of periodontal diseases," "classification of periodontal diseases," "epidemiology of periodontal diseases," and "treatment of periodontal diseases." Articles were evaluated by title and/or abstract and relevance to pediatric dentistry. Sixty-five citations were selected by this method and by the references within the chosen articles. A review of the comprehensive textbooks on pediatric dentistry and periodontology was done. Some recommendations were based on the opinions of experienced researchers and clinicians, when data were inconclusive.

X-Ray Background from Early Binaries

NASA Astrophysics Data System (ADS)

Kohler, Susanna

2016-11-01

What impact did X-rays from the first binary star systems have on the universe around them? A new study suggests this radiation may have played an important role during the reionization of our universe.Ionizing the UniverseDuring the period of reionization, the universe reverted from being neutral (as it was during recombination, the previous period)to once again being ionized plasma a state it has remained in since then. This transition, which occurred between 150 million and one billion years after the Big Bang (redshift of 6 z 20), was caused by the formation of the first objects energetic enough to reionize the universes neutral hydrogen.ROSAT image of the soft X-ray background throughout the universe. The different colors represent different energy bands: 0.25 keV (red), 0.75 keV (green), 1.5 keV (blue). [NASA/ROSAT Project]Understanding this time period in particular, determining what sources caused the reionization, and what the properties were of the gas strewn throughout the universe during this time is necessary for us to be able to correctly interpret cosmological observations.Conveniently, the universe has provided us with an interesting clue: the large-scale, diffuse X-ray background we observe all around us. What produced these X-rays, and what impact did this radiation have on the intergalactic medium long ago?The First BinariesA team of scientists led by Hao Xu (UC San Diego) has suggested that the very first generation of stars might be an important contributor to these X-rays.This hypothetical first generation, Population III stars, are thought to have formed before and during reionization from large clouds of gas containing virtually no metals. Studies suggest that a large fraction of Pop III stars formed in binaries and when those stars ended their lives as black holes, ensuing accretion from their companions could produceX-ray radiation.The evolution with redshift of the mean X-ray background intensities. Each curve represents a different

Hormones and arterial stiffness in patients with chronic kidney disease.

PubMed

Gungor, Ozkan; Kircelli, Fatih; Voroneanu, Luminita; Covic, Adrian; Ok, Ercan

2013-01-01

Cardiovascular disease constitutes the major cause of mortality in patients with chronic kidney disease. Arterial stiffness is an important contributor to the occurrence and progression of cardiovascular disease. Various risk factors, including altered hormone levels, have been suggested to be associated with arterial stiffness. Based on the background that chronic kidney disease predisposes individuals to a wide range of hormonal changes, we herein review the available data on the association between arterial stiffness and hormones in patients with chronic kidney disease and summarize the data for the general population.

China: Background Notes Series.

ERIC Educational Resources Information Center

Reams, Joanne Reppert

Concise background information on the People's Republic of China is provided. The publication begins with a profile of the country, outlining the people, geography, economy, and membership in international organizations. The bulk of the document then discusses in more detail China's people, geography, history, government, education, economy, and…

7 CFR 3407.1 - Background and purpose.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 15 2011-01-01 2011-01-01 false Background and purpose. 3407.1 Section 3407.1 Agriculture Regulations of the Department of Agriculture (Continued) NATIONAL INSTITUTE OF FOOD AND AGRICULTURE IMPLEMENTATION OF NATIONAL ENVIRONMENTAL POLICY ACT § 3407.1 Background and purpose. (a) The...

7 CFR 3407.1 - Background and purpose.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 15 2014-01-01 2014-01-01 false Background and purpose. 3407.1 Section 3407.1 Agriculture Regulations of the Department of Agriculture (Continued) NATIONAL INSTITUTE OF FOOD AND AGRICULTURE IMPLEMENTATION OF NATIONAL ENVIRONMENTAL POLICY ACT § 3407.1 Background and purpose. (a) The...

7 CFR 3407.1 - Background and purpose.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 15 2013-01-01 2013-01-01 false Background and purpose. 3407.1 Section 3407.1 Agriculture Regulations of the Department of Agriculture (Continued) NATIONAL INSTITUTE OF FOOD AND AGRICULTURE IMPLEMENTATION OF NATIONAL ENVIRONMENTAL POLICY ACT § 3407.1 Background and purpose. (a) The...

7 CFR 3407.1 - Background and purpose.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 15 2012-01-01 2012-01-01 false Background and purpose. 3407.1 Section 3407.1 Agriculture Regulations of the Department of Agriculture (Continued) NATIONAL INSTITUTE OF FOOD AND AGRICULTURE IMPLEMENTATION OF NATIONAL ENVIRONMENTAL POLICY ACT § 3407.1 Background and purpose. (a) The...

44 CFR 10.1 - Background and purpose.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Background and purpose. 10.1 Section 10.1 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY GENERAL ENVIRONMENTAL CONSIDERATIONS General § 10.1 Background and purpose. (a) This part...

Environmental context effects of background color in free recall.

PubMed

Isarida, Taeo; Isarin, Tosmko K

2007-10-01

In four experiments, we investigated background-color context effects in free recall. A total of 194 undergraduates studied words presented one by one against a background color, and oral free recall was tested after a 30-sec filled retention interval. A signal for recall was presented against a background color throughout the test. Recalled items were classified as same- and different-context items according to whether the background colors at study and test were the same or different. Significant context effects were found in Experiments I and 2, in which two background colors were randomly alternated word by word. No context effects were found in Experiments 3 and 4, in which a common background color was presented for all items (Experiment 3) or for a number of successive items (Experiment 4). The results indicate that a change in background colors is necessary and sufficient to produce context effects. Implications of the present findings are discussed.

Background Model for the Majorana Demonstrator

NASA Astrophysics Data System (ADS)

Cuesta, C.; Abgrall, N.; Aguayo, E.; Avignone, F. T.; Barabash, A. S.; Bertrand, F. E.; Boswell, M.; Brudanin, V.; Busch, M.; Byram, D.; Caldwell, A. S.; Chan, Y.-D.; Christofferson, C. D.; Combs, D. C.; Detwiler, J. A.; Doe, P. J.; Efremenko, Yu.; Egorov, V.; Ejiri, H.; Elliott, S. R.; Fast, J. E.; Finnerty, P.; Fraenkle, F. M.; Galindo-Uribarri, A.; Giovanetti, G. K.; Goett, J.; Green, M. P.; Gruszko, J.; Guiseppe, V. E.; Gusev, K.; Hallin, A. L.; Hazama, R.; Hegai, A.; Henning, R.; Hoppe, E. W.; Howard, S.; Howe, M. A.; Keeter, K. J.; Kidd, M. F.; Kochetov, O.; Konovalov, S. I.; Kouzes, R. T.; LaFerriere, B. D.; Leon, J.; Leviner, L. E.; Loach, J. C.; MacMullin, J.; MacMullin, S.; Martin, R. D.; Meijer, S.; Mertens, S.; Nomachi, M.; Orrell, J. L.; O'Shaughnessy, C.; Overman, N. R.; Phillips, D. G.; Poon, A. W. P.; Pushkin, K.; Radford, D. C.; Rager, J.; Rielage, K.; Robertson, R. G. H.; Romero-Romero, E.; Ronquest, M. C.; Schubert, A. G.; Shanks, B.; Shima, T.; Shirchenko, M.; Snavely, K. J.; Snyder, N.; Suriano, A. M.; Thompson, J.; Timkin, V.; Tornow, W.; Trimble, J. E.; Varner, R. L.; Vasilyev, S.; Vetter, K.; Vorren, K.; White, B. R.; Wilkerson, J. F.; Wiseman, C.; Xu, W.; Yakushev, E.; Young, A. R.; Yu, C.-H.; Yumatov, V.

The Majorana Collaboration is constructing a system containing 40 kg of HPGe detectors to demonstrate the feasibility and potential of a future tonne-scale experiment capable of probing the neutrino mass scale in the inverted-hierarchy region. To realize this, a major goal of the Majorana Demonstrator is to demonstrate a path forward to achieving a background rate at or below 1 cnt/(ROI-t-y) in the 4 keV region of interest around the Q-value at 2039 keV. This goal is pursued through a combination of a significant reduction of radioactive impurities in construction materials with analytical methods for background rejection, for example using powerful pulse shape analysis techniques profiting from the p-type point contact HPGe detectors technology. The effectiveness of these methods is assessed using simulations of the different background components whose purity levels are constrained from radioassay measurements.

Background model for the Majorana Demonstrator

DOE PAGES

Cuesta, C.; Abgrall, N.; Aguayo, E.; ...

2015-01-01

The Majorana Collaboration is constructing a system containing 40 kg of HPGe detectors to demonstrate the feasibility and potential of a future tonne-scale experiment capable of probing the neutrino mass scale in the inverted-hierarchy region. To realize this, a major goal of the Majorana Demonstrator is to demonstrate a path forward to achieving a background rate at or below 1 cnt/(ROI-t-y) in the 4 keV region of interest around the Q-value at 2039 keV. This goal is pursued through a combination of a significant reduction of radioactive impurities in construction materials with analytical methods for background rejection, for example usingmore » powerful pulse shape analysis techniques profiting from the p-type point contact HPGe detectors technology. The effectiveness of these methods is assessed using simulations of the different background components whose purity levels are constrained from radioassay measurements.« less

Background Lamb waves in the Earth's atmosphere

NASA Astrophysics Data System (ADS)

Nishida, K.; Kobayashi, N.; Fukao, Y.

2013-12-01

Lamb waves of the Earth's atmosphere in the millihertz band have been considered as transient phenomena excited only by large events [e.g. the major volcanic eruption of Krakatoa in 1833, the impact of Siberian meteorite in 1908, the testing of large nuclear tests and the huge earthquakes, Garrett1969]. In a case of the solid Earth, observation of background free oscillations in the millihertz band-now known as Earth's background free oscillations or seismic hum, has been firmly established. Above 5 mHz, their dominant excitation sources are oceanic infragravity waves. At 3.7 and 4.4 mHz an elasto-acoustic resonance between the solid Earth and the atmosphere was observed [Nishida et al., 2000]. These seismic observations show that the contribution of atmospheric disturbances to the seismic hum is dominant below 5 mHz. Such contribution implies background excitations of acoustic-gravity waves in this frequency range. For direct detection of the background acoustic-gravity waves, our group conducted observations using an array of barometers [Nishida et al. 2005]. However, the spatial scale of the array of about 10 km was too small to detect acoustic modes below 10 mHz. Since then, no direct observations of these waves have been reported. In 2011, 337 high-resolution microbarometers were installed on a continental scale at USArray Transportable Array. The large and dense array enables us to detect the background atmospheric waves. Here, we show the first evidence of background Lamb waves in the Earth's atmosphere from 0.2 to 10 mHz, based on the array analysis of microbarometer data from the USArray in 2012. The observations suggest that the excitation sources are atmospheric disturbances in the troposphere. Theoretically, their energy in the troposphere tunnels into the thermosphere at a resonant frequency via thermospheric gravity wave, where the observed amplitudes indeed take a local minimum. The energy leak through the frequency window could partly contribute to

Genetics Home Reference: non-alcoholic fatty liver disease

MedlinePlus

... different populations of microorganisms in the intestines (gut microbiota) on the breakdown and absorption of nutrients are ... Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background. Gastroenterol Res Pract. 2016;2016: ...

Perforated Sigmoid Diverticular Disease: a Management Protocol

PubMed Central

Moin, Thajammul

2008-01-01

Background: To develop an evidence-based protocol for the management of perforated sigmoid diverticular disease. Methods: A search of the literature was undertaken. All publications pertaining to perforated sigmoid diverticular disease were analyzed and then categorized according to their level of evidence. Recommendations were then made on the basis of this. Results: Multiple case reports suggest that primary closure of perforation of sigmoid diverticula is safe in the absence of peritoneal contamination. Conclusions: A 2-stage laparoscopic approach incorporating the principles of damage limitation surgery may be a safe strategy in the management of perforated diverticular disease. PMID:18435896

Background Knowledge in Learning-Based Relation Extraction

ERIC Educational Resources Information Center

Do, Quang Xuan

2012-01-01

In this thesis, we study the importance of background knowledge in relation extraction systems. We not only demonstrate the benefits of leveraging background knowledge to improve the systems' performance but also propose a principled framework that allows one to effectively incorporate knowledge into statistical machine learning models for…

Judgments of aircraft noise in a traffic noise background

NASA Technical Reports Server (NTRS)

Powell, C. A.; Rice, C. G.

1975-01-01

An investigation was conducted to determine subjective response to aircraft noise in different road traffic backgrounds. In addition, two laboratory techniques for presenting the aircraft noise with the background noise were evaluated. For one technique, the background noise was continuous over an entire test session; for the other, the background noise level was changed with each aircraft noise during a session. Subjective response to aircraft noise was found to decrease with increasing background noise level, for a range of typical indoor noise levels. Subjective response was found to be highly correlated with the Noise Pollution Level (NPL) measurement scale.

Spatiotemporal models for the simulation of infrared backgrounds

NASA Astrophysics Data System (ADS)

Wilkes, Don M.; Cadzow, James A.; Peters, R. Alan, II; Li, Xingkang

1992-09-01

It is highly desirable for designers of automatic target recognizers (ATRs) to be able to test their algorithms on targets superimposed on a wide variety of background imagery. Background imagery in the infrared spectrum is expensive to gather from real sources, consequently, there is a need for accurate models for producing synthetic IR background imagery. We have developed a model for such imagery that will do the following: Given a real, infrared background image, generate another image, distinctly different from the one given, that has the same general visual characteristics as well as the first and second-order statistics of the original image. The proposed model consists of a finite impulse response (FIR) kernel convolved with an excitation function, and histogram modification applied to the final solution. A procedure for deriving the FIR kernel using a signal enhancement algorithm has been developed, and the histogram modification step is a simple memoryless nonlinear mapping that imposes the first order statistics of the original image onto the synthetic one, thus the overall model is a linear system cascaded with a memoryless nonlinearity. It has been found that the excitation function relates to the placement of features in the image, the FIR kernel controls the sharpness of the edges and the global spectrum of the image, and the histogram controls the basic coloration of the image. A drawback to this method of simulating IR backgrounds is that a database of actual background images must be collected in order to produce accurate FIR and histogram models. If this database must include images of all types of backgrounds obtained at all times of the day and all times of the year, the size of the database would be prohibitive. In this paper we propose improvements to the model described above that enable time-dependent modeling of the IR background. This approach can greatly reduce the number of actual IR backgrounds that are required to produce a

Disease-related and drug-induced skin manifestations in inflammatory bowel disease.

PubMed

Hindryckx, Pieter; Novak, Gregor; Costanzo, Antonio; Danese, Silvio

2017-03-01

Skin manifestations are common in patients with inflammatory bowel diseases (IBD) and can be part of a concomitant illness with a shared genetic background, an extra-intestinal manifestation of the disease, or a drug side-effect. Areas covered: We provide a practical overview of the epidemiology, pathogenesis, diagnosis, therapeutic approach and prognosis of the most frequent disease-related and drug-induced cutaneous manifestations in IBD, illustrated by cases encountered in our clinical practice. Among the most frequently encountered IBD-related lesions are erythema nodosum, pyoderma gangrenosum and Sweet's syndrome. Common skin manifestations with a strong association to TNF antagonists are local injection site reactions, psoriasiform lesions, cutaneous infections, vasculitides and lupus-like syndromes. In addition, we discuss the relation of thiopurines and TNF antagonists with the risk of skin cancer. Expert commentary: We hope this review will help caretakers involved in the management of IBD patients to recognize the lesions and to manage them in close collaboration with a dedicated dermatologist.

32 CFR 770.54 - Background.

Code of Federal Regulations, 2013 CFR

2013-07-01

... ACCESS TO PARTICULAR INSTALLATIONS Entry Regulations for Portsmouth Naval Shipyard, Portsmouth, New Hampshire § 770.54 Background. (a) Portsmouth Naval Shipyard maintains and operates facilities “to provide...

32 CFR 770.54 - Background.

Code of Federal Regulations, 2014 CFR

2014-07-01

... ACCESS TO PARTICULAR INSTALLATIONS Entry Regulations for Portsmouth Naval Shipyard, Portsmouth, New Hampshire § 770.54 Background. (a) Portsmouth Naval Shipyard maintains and operates facilities “to provide...

32 CFR 770.54 - Background.

Code of Federal Regulations, 2011 CFR

2011-07-01

... ACCESS TO PARTICULAR INSTALLATIONS Entry Regulations for Portsmouth Naval Shipyard, Portsmouth, New Hampshire § 770.54 Background. (a) Portsmouth Naval Shipyard maintains and operates facilities “to provide...

32 CFR 770.54 - Background.

Code of Federal Regulations, 2012 CFR

2012-07-01

... ACCESS TO PARTICULAR INSTALLATIONS Entry Regulations for Portsmouth Naval Shipyard, Portsmouth, New Hampshire § 770.54 Background. (a) Portsmouth Naval Shipyard maintains and operates facilities “to provide...

36 CFR 401.3 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... § 401.3 Background. Following World War I many American individuals, organizations and governmental... many issues including host nation approvals, design adequacy, and funding for perpetual maintenance. As...

On the way to commercializing plant cell culture platform for biopharmaceuticals: present status and prospect.

PubMed

Xu, Jianfeng; Zhang, Ningning

2014-12-01

Plant cell culture is emerging as an alternative bioproduction system for recombinant pharmaceuticals. Growing plant cells in vitro under controlled environmental conditions allows for precise control over cell growth and protein production, batch-to-batch product consistency and a production process aligned with current good manufacturing practices. With the recent US FDA approval and commercialization of the world's first plant cell-based recombinant pharmaceutical for human use, β-glucocerebrosidase for treatment of Gaucher's disease, a new era has come in which plant cell culture shows high potential to displace some established platform technologies in niche markets. This review updates the progress in plant cell culture processing technology, highlights recent commercial successes and discusses the challenges that must be overcome to make this platform commercially viable.

Child Care: State Requirements for Background Checks.

ERIC Educational Resources Information Center

Fagnoni, Cynthia

Background checks involve gathering information from state and federal databases to determine if child care providers have a history of child abuse or other criminal convictions that would make them unacceptable for working with children. Background checks include state criminal history checks, state child abuse registry checks, and Federal Bureau…

The diffuse infrared background - COBE and other observations

NASA Technical Reports Server (NTRS)

Hauser, M. G.; Kelsall, T.; Moseley, S. H., Jr.; Silverberg, R. F.; Murdock, T.; Toller, G.; Spiesman, W.; Weiland, J.

1991-01-01

The Diffuse Infrared Background Experiment (DIRBE) on the Cosmic Background Explorer (COBE) satellite is designed to conduct a sensitive search for an isotropic cosmic infrared background radiation over the spectral range from 1 to 300 micrometers. The cumulative emissions of pregalactic, protogalactic, and evolving galactic systems are expected to be recorded in this background. The DIRBE instrument, a 10 spectral band absolute photometer with an 0.7 deg field of view, maps the full sky with high redundancy at solar elongation angles ranging from 64 to 124 degrees to facilitate separation of interplanetary, Galactic, and extragalactic sources of emission. Initial sky maps show the expected character of the foreground emissions, with relative minima at wavelengths of 3.4 micrometers and longward of 100 micrometers. Extensive modelling of the foregrounds, just beginning, will be required to isolate the extragalactic component. In this paper, we summarize the status of diffuse infrared background observations from the DIRBE, and compare preliminary results with those of recent rocket and satellite instruments.