Molecular genetics of syndromic and non-syndromic forms of parathyroid carcinoma.

PubMed

Cardoso, Luís; Stevenson, Mark; Thakker, Rajesh V

2017-12-01

Parathyroid carcinoma (PC) may occur as part of a complex hereditary syndrome or an isolated (i.e., non-syndromic) non-hereditary (i.e., sporadic) endocrinopathy. Studies of hereditary and syndromic forms of PC, which include the hyperparathyroidism-jaw tumor syndrome (HPT-JT), multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2), and familial isolated primary hyperparathyroidism (FIHP), have revealed some genetic mechanisms underlying PC. Thus, cell division cycle 73 (CDC73) germline mutations cause HPT-JT, and CDC73 mutations occur in 70% of sporadic PC, but in only ∼2% of parathyroid adenomas. Moreover, CDC73 germline mutations occur in 20%-40% of patients with sporadic PC and may reveal unrecognized HPT-JT. This indicates that CDC73 mutations are major driver mutations in the etiology of PCs. However, there is no genotype-phenotype correlation and some CDC73 mutations (e.g., c.679_680insAG) have been reported in patients with sporadic PC, HPT-JT, or FIHP. Other genes involved in sporadic PC include germline MEN1 and rearranged during transfection (RET) mutations and somatic alterations of the retinoblastoma 1 (RB1) and tumor protein P53 (TP53) genes, as well as epigenetic modifications including DNA methylation and histone modifications, and microRNA misregulation. This review summarizes the genetics and epigenetics of the familial syndromic and non-syndromic (sporadic) forms of PC. © 2017 The Authors. Human Mutation published by Wiley Periodicals, Inc.

Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease.

PubMed

Ancliff, P J; Gale, R E; Liesner, R; Hann, I M; Linch, D C

2001-11-01

Severe congenital neutropenia (SCN) was originally described as an autosomal recessive disorder. Subsequently, autosomal dominant and sporadic forms of the disease have been recognized. All forms are manifest by persistent severe neutropenia and recurrent bacterial infection. In contrast, cyclical hematopoiesis is characterized by periodic neutropenia inter-spaced with (near) normal neutrophil counts. Recently, linkage analysis on 13 affected pedigrees identified chromosome 19p13.3 as the likely position for mutations in cyclical hematopoiesis. Heterozygous mutations in the ELA2 gene encoding neutrophil elastase were detected in all families studied. Further work also demonstrated mutations in ELA2 in sporadic and autosomal dominant SCN. However, all mutations described to date are heterozygous and thus appear to act in a dominant fashion, which is inconsistent with an autosomal recessive disease. Therefore, the current study investigated whether mutations in ELA2 could account for the disease phenotype in classical autosomal recessive SCN and in the sporadic and autosomal dominant types. All 5 exons of ELA2 and their flanking introns were studied in 18 patients (3 autosomal recessive, 5 autosomal dominant [from 3 kindreds], and 10 sporadic) using direct automated sequencing. No mutations were found in the autosomal recessive families. A point mutation was identified in 1 of 3 autosomal dominant families, and a base substitution was identified in 8 of 10 patients with the sporadic form, though 1 was subsequently shown to be a low-frequency polymorphism. These results suggest that mutations in ELA2 are not responsible for classical autosomal recessive Kostmann syndrome but provide further evidence for the role of ELA2 in SCN.

Comparison of transcriptomic signature of post-Chernobyl and postradiotherapy thyroid tumors.

PubMed

Ory, Catherine; Ugolin, Nicolas; Hofman, Paul; Schlumberger, Martin; Likhtarev, Illya A; Chevillard, Sylvie

2013-11-01

We previously identified two highly discriminating and predictive radiation-induced transcriptomic signatures by comparing series of sporadic and postradiotherapy thyroid tumors (322-gene signature), and by reanalyzing a previously published data set of sporadic and post-Chernobyl thyroid tumors (106-gene signature). The aim of the present work was (i) to compare the two signatures in terms of gene expression deregulations and molecular features/pathways, and (ii) to test the capacity of the postradiotherapy signature in classifying the post-Chernobyl series of tumors and reciprocally of the post-Chernobyl signature in classifying the postradiotherapy-induced tumors. We now explored if postradiotherapy and post-Chernobyl papillary thyroid carcinomas (PTC) display common molecular features by comparing molecular pathways deregulated in the two tumor series, and tested the potential of gene subsets of the postradiotherapy signature to classify the post-Chernobyl series (14 sporadic and 12 post-Chernobyl PTC), and reciprocally of gene subsets of the post-Chernobyl signature to classify the postradiotherapy series (15 sporadic and 12 postradiotherapy PTC), by using conventional principal component analysis. We found that the five genes common to the two signatures classified the learning/training tumors (used to search these signatures) of both the postradiotherapy (seven PTC) and the post-Chernobyl (six PTC) thyroid tumor series as compared with the sporadic tumors (seven sporadic PTC in each series). Importantly, these five genes were also effective for classifying independent series of postradiotherapy (five PTC) and post-Chernobyl (six PTC) tumors compared to independent series of sporadic tumors (eight PTC and six PTC respectively; testing tumors). Moreover, part of each postradiotherapy (32 genes) and post-Chernobyl signature (16 genes) cross-classified the respective series of thyroid tumors. Finally, several molecular pathways deregulated in post-Chernobyl tumors matched those found to be deregulated in postradiotherapy tumors. Overall, our data suggest that thyroid tumors that developed following either external exposure or internal (131)I contamination shared common molecular features, related to DNA repair, oxidative and endoplasmic reticulum stresses, allowing their classification as radiation-induced tumors in comparison with sporadic counterparts, independently of doses and dose rates, which suggests there may be a "general" radiation-induced signature of thyroid tumors.

Sporadic E movement followed with a pencil beam high frequency radar

NASA Astrophysics Data System (ADS)

From, W. R.

1983-12-01

Several types of sporadic E are observed using the 5.80 and 3.84-MHz Bribie Island pencil-beam high-frequency radar. Blanketing Es takes the form of large flat sheets with ripples in them. Non-blanketing Es is observed to be small clouds that drift across the field of view (40 deg). There is continuous gradation of sporadic E structure between these extremes. There are at least four different physical means by which sporadic E clouds may apparently move. It is concluded that non-blanketing sporadic E consists of separate clouds which follow the movement of the constructive interference between internal gravity waves rather than being blown by the background wind.

MicroRNA (miRNA) Signaling in the Human CNS in Sporadic Alzheimer’s Disease (AD)-Novel and Unique Pathological Features

PubMed Central

Zhao, Yuhai; Pogue, Aileen I.; Lukiw, Walter J.

2015-01-01

Of the approximately ~2.65 × 103 mature microRNAs (miRNAs) so far identified in Homo sapiens, only a surprisingly small but select subset—about 35–40—are highly abundant in the human central nervous system (CNS). This fact alone underscores the extremely high selection pressure for the human CNS to utilize only specific ribonucleotide sequences contained within these single-stranded non-coding RNAs (ncRNAs) for productive miRNA–mRNA interactions and the down-regulation of gene expression. In this article we will: (i) consolidate some of our still evolving ideas concerning the role of miRNAs in the CNS in normal aging and in health, and in sporadic Alzheimer’s disease (AD) and related forms of chronic neurodegeneration; and (ii) highlight certain aspects of the most current work in this research field, with particular emphasis on the findings from our lab of a small pathogenic family of six inducible, pro-inflammatory, NF-κB-regulated miRNAs including miRNA-7, miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. This group of six CNS-abundant miRNAs significantly up-regulated in sporadic AD are emerging as what appear to be key mechanistic contributors to the sporadic AD process and can explain much of the neuropathology of this common, age-related inflammatory neurodegeneration of the human CNS. PMID:26694372

The c.301_302delAG PROP1 gene mutation in Romanian patients with multiple pituitary hormone deficiency.

PubMed

Lazea, Cecilia; Grigorescu-Sido, Paula; Popp, Radu; Legendre, Marie; Amselem, Serge; Al-Khzouz, Camelia; Bucerzan, Simona; Creţ, Victoria; Crişan, Mirela; Brad, Cristian

2015-09-01

To establish the frequency of the c.301_302 delAG mutation of the PROP1 gene in Romanian patients with multiple pituitary hormone deficiency (MPHD). Somatic assessment, hormonal test, bone age, magnetic resonance imaging of the pituitary gland, and molecular diagnosis were performed in 26 patients with MPHD (7 patients with familial form of MPHD and 19 patients with sporadic form of MPHD). The c.301_302delAG mutation was detected in the homozygous state in 10 patients belonging to 5 unrelated families (7 patients with familial history of MPHD and 3 patients with sporadic form of MPHD). Those 10 patients presented variable pituitary hormone deficiency and pituitary morphology. The c.301_302delAG homozygous genotype had a high frequency of 38% (10/26), reaching 100% (7/7) in group with familial cases of MPHD and 16% (3/19) in group with sporadic forms of MPHD.

Amyotrophic lateral sclerosis: update and new developments

PubMed Central

Pratt, Ashley J; Getzoff, Elizabeth D; Perry, J Jefferson P

2012-01-01

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease. It is typically characterized by adult-onset degeneration of the upper and lower motor neurons, and is usually fatal within a few years of onset. A subset of ALS patients has an inherited form of the disease, and a few of the known mutant genes identified in familial cases have also been found in sporadic forms of ALS. Precisely how the diverse ALS-linked gene products dictate the course of the disease, resulting in compromised voluntary muscular ability, is not entirely known. This review addresses the major advances that are being made in our understanding of the molecular mechanisms giving rise to the disease, which may eventually translate into new treatment options. PMID:23019386

Spontaneous generation of rapidly transmissible prions in transgenic mice expressing wild-type bank vole prion protein.

PubMed

Watts, Joel C; Giles, Kurt; Stöhr, Jan; Oehler, Abby; Bhardwaj, Sumita; Grillo, Sunny K; Patel, Smita; DeArmond, Stephen J; Prusiner, Stanley B

2012-02-28

Currently, there are no animal models of the most common human prion disorder, sporadic Creutzfeldt-Jakob disease (CJD), in which prions are formed spontaneously from wild-type (WT) prion protein (PrP). Interestingly, bank voles (BV) exhibit an unprecedented promiscuity for diverse prion isolates, arguing that bank vole PrP (BVPrP) may be inherently prone to adopting misfolded conformations. Therefore, we constructed transgenic (Tg) mice expressing WT BVPrP. Tg(BVPrP) mice developed spontaneous CNS dysfunction between 108 and 340 d of age and recapitulated the hallmarks of prion disease, including spongiform degeneration, pronounced astrogliosis, and deposition of alternatively folded PrP in the brain. Brain homogenates of ill Tg(BVPrP) mice transmitted disease to Tg(BVPrP) mice in ∼35 d, to Tg mice overexpressing mouse PrP in under 100 d, and to WT mice in ∼185 d. Our studies demonstrate experimentally that WT PrP can spontaneously form infectious prions in vivo. Thus, Tg(BVPrP) mice may be useful for studying the spontaneous formation of prions, and thus may provide insight into the etiology of sporadic CJD.

Comparison of sporadic and FAP-associated desmoid-type fibromatoses.

PubMed

Koskenvuo, Laura; Ristimäki, Ari; Lepistö, Anna

2017-11-01

Desmoid-type fibromatosis is a rare disease of which 7.5-16% have been reported to be related to familial adenomatous polyposis (FAP). We sought to compare the characteristics and treatment of sporadic and FAP-related desmoid-type fibromatoses. Altogether 220 patients were included in the study after receiving a diagnosis of desmoid-type fibromatosis by the Pathology Department of Helsinki University Hospital, with adequate follow-up. Patients were included from January 1, 1980 until April 30, 2015. FAP-related tumors were found in 22 (10%) patients. FAP-related desmoid-type fibromatoses were larger, more commonly multiple, and more often intra-abdominally situated. Surgery was the treatment of choice for 179 (90%) of the sporadic patients and for 18 (82%) of FAP-related patients. Resections with non-involved margins (R0) were more common in sporadic desmoid-type fibromatoses (55% vs. 23%, P = 0.048). The risk of recurrence was 25% in sporadic- and 44% in the FAP-related group. Three (14%) patients with FAP-related desmoid-type fibromatoses died from the disease. The predictors for FAP occurrence among desmoid tumor patients are large tumor size, intra-abdominal location, multiple tumors, and patient's young age. Desmoid-type fibromatosis patients suffer a high recurrence rate, also among those experiencing sporadic tumors, but the risk of death due to the tumor is low. Conversely, desmoid disease represents a substantial cause of death among FAP patients. © 2017 Wiley Periodicals, Inc.

A Tangled Web – Tau and Sporadic Parkinson's Disease

PubMed Central

Wray, Selina; Lewis, Patrick A.

2010-01-01

Parkinson's disease (PD) represents a major challenge for health care systems around the world: it is the most common degenerative movement disorder of old age, affecting over 100,000 people in the UK alone (Schrag et al., 2000). Despite the remarkable success of treatments directed at potentiating or replacing dopamine within the brain, which can relieve symptoms for over a decade, PD remains an incurable and invariably fatal disorder. As such, efforts to understand the processes that lead to cell death in the brains of patients with PD are a priority for neurodegenerative researchers. A great deal of progress has been made in this regard by taking advantage of advances in genetics, initially by the identification of genes responsible for rare Mendelian forms of PD (outlined in Table 1), and more recently by applying genome wide association studies (GWAS) to the sporadic form of the disease (Hardy et al., 2009). Several such GWAS have now been carried out, with a meta-analysis currently under way. Using over 6000 cases and 10,000 controls, two of these studies have identified variation at a number of loci as being associated with an increased risk of disease (Satake et al., 2009; Simon-Sanchez et al., 2009). Three genes stand out as candidates from these studies – the SNCA gene, coding for α-synuclein, the LRRK2 gene, coding for leucine rich repeat kinase 2, and MAPT, coding for the microtubule-associated protein tau. Mutations at all three of these loci have been associated with Mendelian forms of disease presenting with the clinical syndrome of Parkinsonism, however only SNCA and LRRK2 have been previously associated with pathologically defined PD (Hardy et al., 2009). Point mutations in α-synuclein, along with gene multiplication events, result in autosomal dominant PD, often with a significant dementia component. In addition to this, α-synuclein is the principle component of the main pathological hallmark of idiopathic PD, the Lewy body, making it an unsurprising hit in the GWAS (Spillantini et al., 1997). Mutations in LRRK2 are the most common genetic cause of PD, and so again made this gene a likely candidate as a susceptibility locus for the sporadic form of disease (Kumari and Tan, 2009). More surprising, perhaps, was the identification of tau as a susceptibility factor for Parkinson's. In this review we will outline the role of tau in neurodegeneration and in different forms of Parkinsonism, and speculate as to what the functional basis of the association between MAPT and PD might be. PMID:21423457

A tangled web - tau and sporadic Parkinson's disease.

PubMed

Wray, Selina; Lewis, Patrick A

2010-01-01

Parkinson's disease (PD) represents a major challenge for health care systems around the world: it is the most common degenerative movement disorder of old age, affecting over 100,000 people in the UK alone (Schrag et al., 2000). Despite the remarkable success of treatments directed at potentiating or replacing dopamine within the brain, which can relieve symptoms for over a decade, PD remains an incurable and invariably fatal disorder. As such, efforts to understand the processes that lead to cell death in the brains of patients with PD are a priority for neurodegenerative researchers. A great deal of progress has been made in this regard by taking advantage of advances in genetics, initially by the identification of genes responsible for rare Mendelian forms of PD (outlined in Table 1), and more recently by applying genome wide association studies (GWAS) to the sporadic form of the disease (Hardy et al., 2009). Several such GWAS have now been carried out, with a meta-analysis currently under way. Using over 6000 cases and 10,000 controls, two of these studies have identified variation at a number of loci as being associated with an increased risk of disease (Satake et al., 2009; Simon-Sanchez et al., 2009). Three genes stand out as candidates from these studies - the SNCA gene, coding for α-synuclein, the LRRK2 gene, coding for leucine rich repeat kinase 2, and MAPT, coding for the microtubule-associated protein tau. Mutations at all three of these loci have been associated with Mendelian forms of disease presenting with the clinical syndrome of Parkinsonism, however only SNCA and LRRK2 have been previously associated with pathologically defined PD (Hardy et al., 2009). Point mutations in α-synuclein, along with gene multiplication events, result in autosomal dominant PD, often with a significant dementia component. In addition to this, α-synuclein is the principle component of the main pathological hallmark of idiopathic PD, the Lewy body, making it an unsurprising hit in the GWAS (Spillantini et al., 1997). Mutations in LRRK2 are the most common genetic cause of PD, and so again made this gene a likely candidate as a susceptibility locus for the sporadic form of disease (Kumari and Tan, 2009). More surprising, perhaps, was the identification of tau as a susceptibility factor for Parkinson's. In this review we will outline the role of tau in neurodegeneration and in different forms of Parkinsonism, and speculate as to what the functional basis of the association between MAPT and PD might be.

TDP-43 Is Not a Common Cause of Sporadic Amyotrophic Lateral Sclerosis

PubMed Central

Guerreiro, Rita J.; Schymick, Jennifer C.; Crews, Cynthia; Singleton, Andrew; Hardy, John; Traynor, Bryan J.

2008-01-01

Background TAR DNA binding protein, encoded by TARDBP, was shown to be a central component of ubiquitin-positive, tau-negative inclusions in frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). Recently, mutations in TARDBP have been linked to familial and sporadic ALS. Methodology/Principal Findings To further examine the frequency of mutations in TARDBP in sporadic ALS, 279 ALS cases and 806 neurologically normal control individuals of European descent were screened for sequence variants, copy number variants, genetic and haplotype association with disease. An additional 173 African samples from the Human Gene Diversity Panel were sequenced as this population had the highest likelihood of finding changes. No mutations were found in the ALS cases. Several genetic variants were identified in controls, which were considered as non-pathogenic changes. Furthermore, pathogenic structural variants were not observed in the cases and there was no genetic or haplotype association with disease status across the TARDBP locus. Conclusions Our data indicate that genetic variation in TARDBP is not a common cause of sporadic ALS in North American. PMID:18545701

Genetic Relatedness among Nontypeable Pneumococci Implicated in Sporadic Cases of Conjunctivitis

PubMed Central

Barker, Jason H.; Musher, Daniel M.; Silberman, Ronald; Phan, Hoang M.; Watson, David A.

1999-01-01

Nontypeable Streptococcus pneumoniae is a common cause of epidemic conjunctivitis. A previous molecular fingerprinting study identified a clone of nontypeable pneumococcus that was responsible for a recent outbreak of conjunctivitis. In the present study, we examined the extent to which pneumococci that cause sporadic cases of conjunctivitis are related to this epidemic strain. Using arbitrarily primed BOX-PCR, we have determined that, of 10 nontypeable pneumococci causing sporadic conjunctivitis, 5 were clonal and closely related to a previous outbreak strain, whereas 5 others were genetically diverse. PMID:10565927

A Cybrid Cell Model for the Assessment of the Link Between Mitochondrial Deficits and Sporadic Parkinson’s Disease

PubMed Central

Arduíno, Daniela M.; Esteves, A. Raquel; Swerdlow, Russell H.; Cardoso, Sandra M.

2015-01-01

Parkinson’s disease (PD) is a multifactorial and clinically complex age-related movement disorder. The cause of its most common form (sporadic PD, sPD) is unknown, but one prominent causal factor is mitochondrial dysfunction. Although several genetic- and toxin-based models have been developed along the last decades to mimic the pathological cascade of PD, cellular models that reliably recapitulate the pathological features of the neurons that degenerate in PD are scarce. We describe here the generation of cytoplasmic hybrid cells (or cybrids) as a cellular model of sPD. This approach consists on the fusion of platelets harboring mtDNA from sPD patients with cells in which the endogenous mtDNA has been depleted (Rho0 cells). The sPD cybrid model has been successful in recapitulating most of the hallmarks of sPD, constituting now a validated model for addressing the link between mitochondrial dysfunction and sPD pathology. PMID:25634293

A cybrid cell model for the assessment of the link between mitochondrial deficits and sporadic Parkinson's disease.

PubMed

Arduíno, Daniela M; Esteves, A Raquel; Swerdlow, Russell H; Cardoso, Sandra M

2015-01-01

Parkinson's disease (PD) is a multifactorial and clinically complex age-related movement disorder. The cause of its most common form (sporadic PD, sPD) is unknown, but one prominent causal factor is mitochondrial dysfunction. Although several genetic- and toxin-based models have been developed along the last decades to mimic the pathological cascade of PD, cellular models that reliably recapitulate the pathological features of the neurons that degenerate in PD are scarce.We describe here the generation of cytoplasmic hybrid cells (or cybrids) as a cellular model of sPD. This approach consists on the fusion of platelets harboring mtDNA from sPD patients with cells in which the endogenous mtDNA has been depleted (Rho0 cells).The sPD cybrid model has been successful in recapitulating most of the hallmarks of sPD, constituting now a validated model for addressing the link between mitochondrial dysfunction and sPD pathology.

Genetics of recessive cognitive disorders.

PubMed

Musante, Luciana; Ropers, H Hilger

2014-01-01

Most severe forms of intellectual disability (ID) have specific genetic causes. Numerous X chromosome gene defects and disease-causing copy-number variants have been linked to ID and related disorders, and recent studies have revealed that sporadic cases are often due to dominant de novo mutations with low recurrence risk. For autosomal recessive ID (ARID) the recurrence risk is high and, in populations with frequent parental consanguinity, ARID is the most common form of ID. Even so, its elucidation has lagged behind. Here we review recent progress in this field, show that ARID is not rare even in outbred Western populations, and discuss the prospects for improving its diagnosis and prevention. Copyright © 2013 Elsevier Ltd. All rights reserved.

Sporadic-E As Observed with Rockets

NASA Technical Reports Server (NTRS)

Seddon, J. Carl

1961-01-01

Data obtained with rockets flown over New Mexico, U.S.A. and Manitoba, Canada have always shown the sporadic-E layer to be a thin layer with a large electron density gradient. The vertical electron density profiles and the horizontal uniformity of the sporadic-E layer are discussed herein. These layers have a strong tendency to form at preferential altitudes separated by approximately 6 km, and a striking correlation exists with wind- shears and magnetic field variations. In two cases where comparisons with ionograms were possible, the minimum frequency of the F-region echoes was found approximately equal to the plasma frequency of the sporadic-E layer reduced by half the gyrofrequency. On the other hand, the maximum frequency of the sporadic-E echoes as noted on ionograms was sometimes as much as 1 to 2 Mc greater than the plasma frequency.

Sporadic pediatric meningiomas: a neuroradiological and neuropathological study of 15 cases.

PubMed

Huntoon, Kristin; Pluto, Charles P; Ruess, Lynne; Boué, Daniel R; Pierson, Christopher R; Rusin, Jerome A; Leonard, Jeffrey

2017-08-01

OBJECTIVE Sporadic meningiomas have been classified in many different ways. Radiographically, these lesions can be described as occurring in either typical or atypical locations. The purpose of this study was to determine if there are any histopathological differences between sporadic meningiomas that arise in these varying locations in children. METHODS The neuroimaging, histopathological findings, and clinical records in patients with sporadic pediatric meningiomas not associated with neurofibromatosis Type 2 or prior radiation therapy were retrospectively reviewed. Tumors were classified by radiological findings as either typical or atypical, and they were categorized histopathologically by using the latest WHO nomenclature and grading criteria. RESULTS Fifteen sporadic meningiomas in pediatric patients were biopsied or resected at the authors' institution between 1989 and 2013. Five (33%) were typical in radiographic appearance and/or location and 10 (67%) were atypical. Four (80%) typical meningiomas were WHO Grade I tumors. Most (60%) of the atypical meningiomas were WHO Grade II or III. CONCLUSIONS This study is the largest series of sporadic pediatric meningiomas in atypical locations to date. Although sporadic meningiomas are relatively infrequent in children, those with atypical imaging, specifically those with apparently intraparenchymal and intraosseous locations, may be more common than previously recognized. In this study, pediatric sporadic meningiomas arising in atypical locations, in particular intraparenchymal meningiomas, may be of higher histopathological grade. The authors' findings should alert clinicians to the potential for more aggressive clinical behavior in these tumors.

The Enemy within: Innate Surveillance-Mediated Cell Death, the Common Mechanism of Neurodegenerative Disease

PubMed Central

Richards, Robert I.; Robertson, Sarah A.; O'Keefe, Louise V.; Fornarino, Dani; Scott, Andrew; Lardelli, Michael; Baune, Bernhard T.

2016-01-01

Neurodegenerative diseases comprise an array of progressive neurological disorders all characterized by the selective death of neurons in the central nervous system. Although, rare (familial) and common (sporadic) forms can occur for the same disease, it is unclear whether this reflects several distinct pathogenic pathways or the convergence of different causes into a common form of nerve cell death. Remarkably, neurodegenerative diseases are increasingly found to be accompanied by activation of the innate immune surveillance system normally associated with pathogen recognition and response. Innate surveillance is the cell's quality control system for the purpose of detecting such danger signals and responding in an appropriate manner. Innate surveillance is an “intelligent system,” in that the manner of response is relevant to the magnitude and duration of the threat. If possible, the threat is dealt with within the cell in which it is detected, by degrading the danger signal(s) and restoring homeostasis. If this is not successful then an inflammatory response is instigated that is aimed at restricting the spread of the threat by elevating degradative pathways, sensitizing neighboring cells, and recruiting specialized cell types to the site. If the danger signal persists, then the ultimate response can include not only the programmed cell death of the original cell, but the contents of this dead cell can also bring about the death of adjacent sensitized cells. These responses are clearly aimed at destroying the ability of the detected pathogen to propagate and spread. Innate surveillance comprises intracellular, extracellular, non-cell autonomous and systemic processes. Recent studies have revealed how multiple steps in these processes involve proteins that, through their mutation, have been linked to many familial forms of neurodegenerative disease. This suggests that individuals harboring these mutations may have an amplified response to innate-mediated damage in neural tissues, and renders innate surveillance mediated cell death a plausible common pathogenic pathway responsible for neurodegenerative diseases, in both familial and sporadic forms. Here we have assembled evidence in favor of the hypothesis that neurodegenerative disease is the cumulative result of chronic activation of the innate surveillance pathway, triggered by endogenous or environmental danger or damage associated molecular patterns in a progressively expanding cascade of inflammation, tissue damage and cell death. PMID:27242399

Sporadic and genetic forms of paediatric somatotropinoma: a retrospective analysis of seven cases and a review of the literature

PubMed Central

2011-01-01

Background Somatotropinoma, a pituitary adenoma characterised by excessive production of growth hormone (GH), is extremely rare in childhood. A genetic defect is evident in some cases; known genetic changes include: multiple endocrine neoplasia type 1 (MEN1); Carney complex; McCune-Albright syndrome; and, more recently identified, aryl hydrocarbon receptor-interacting protein (AIP). We describe seven children with somatotropinoma with a special focus on the differences between genetic and sporadic forms. Methods Seven children who presented in our regional network between 1992 and 2008 were included in this retrospective analysis. First-type therapy was somatostatin (SMS) analogues or transsphenoidal surgery. Control was defined as when insulin-like growth factor-1 (IGF-1) levels were within the normal range for the patient's age at 6 months after therapy, associated with decreasing tumour volume. Results Patients were aged 5-17 years and the majority (n = 6) were male. Four patients had an identified genetic mutation (McCune-Albright syndrome: n = 1; MEN1: n = 1; AIP: n = 2); the remaining three cases were sporadic. Accelerated growth rate was reported as the first clinical sign in four patients. Five patients presented with macroadenoma; invasion was noted in four of them (sporadic: n = 1; genetic: n = 3). Six patients were treated with SMS analogues; normalisation of IGF-1 occurred in one patient who had a sporadic intrasellar macroadenoma. Multiple types of therapy were necessary in all patients with an identified genetic mutation (4 types: n = 1; 3 types: n = 2; 2 types: n = 1), whereas two of the three patients with sporadic somatotropinoma required only one type of therapy. Conclusions This is the first series that analyzes the therapeutic response of somatotropinoma in paediatric patients with identified genetic defects. We found that, in children, genetic somatotropinomas are more invasive than sporadic somatotropinomas. Furthermore, SMS analogues appear to be less effective for treating genetic somatotropinoma than sporadic somatotropinoma. PMID:22024364

Sporadic inclusion-body myositis: conformational multifactorial ageing-related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid-β42 oligomers and phosphorylated tau.

PubMed

Askanas, Valerie; Engel, W King

2011-04-01

The pathogenesis of sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is complex and multifactorial. Both the muscle fiber degeneration and the mononuclear-cell inflammation are components of the s-IBM pathology, but how each relates to the pathogenesis remains unsettled. We consider that the intramuscle fiber degenerative component plays the primary and the major pathogenic role leading to muscle fiber destruction and clinical weakness. In this article we review the newest research advances that provide a better understanding of the s-IBM pathogenesis. Cellular abnormalities occurring in s-IBM muscle fibers are discussed, including: several proteins that are accumulated in the form of aggregates within muscle fibers, including amyloid-β42 and its oligomers, and phosphorylated tau in the form of paired helical filaments, and we consider their putative detrimental influence; cellular mechanisms leading to protein misfolding and aggregation, including evidence of their inadequate disposal; pathogenic importance of endoplasmic reticulum stress and the unfolded protein response demonstrated in s-IBM muscle fibers; and decreased deacetylase activity of SIRT1. All these factors are combined with, and perhaps provoked by, an ageing intracellular milieu. Also discussed are the intriguing phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer and Parkinson's disease patients, the two most common neurodegenerative diseases associated with ageing. Muscle biopsy diagnostic criteria are also described and illustrated. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Association of SNCA with Parkinson: replication in the Harvard NeuroDiscovery Center Biomarker Study

PubMed Central

Ding, Hongliu; Sarokhan, Alison K.; Roderick, Sarah S.; Bakshi, Rachit; Maher, Nancy E.; Ashourian, Paymon; Kan, Caroline G.; Chang, Sunny; Santarlasci, Andrea; Swords, Kyleen E.; Ravina, Bernard M.; Hayes, Michael T.; Sohur, U. Shivraj; Wills, Anne-Marie; Flaherty, Alice W.; Unni, Vivek K.; Hung, Albert Y.; Selkoe, Dennis J.; Schwarzschild, Michael A.; Schlossmacher, Michael G.; Sudarsky, Lewis R.; Growdon, John H.; Ivinson, Adrian J.; Hyman, Bradley T.; Scherzer, Clemens R.

2011-01-01

Background Mutations in the α-synuclein gene (SNCA) cause autosomal dominant forms of Parkinson’s disease, but the substantial risk conferred by this locus to the common sporadic disease has only recently emerged from genome-wide association studies. Methods Here we genotyped a prioritized non-coding variant in SNCA intron-4 in 344 patients with Parkinson’s and 275 controls from the longitudinal Harvard NeuroDiscovery Center Biomarker Study. Results The common minor allele of rs2736990 was associated with elevated disease susceptibility (odds ratio = 1.40, P value = 0.0032). Conclusions This result increases confidence in the notion that in many clinically well-characterized patients genetic variation in SNCA contributes to “sporadic” disease. PMID:21953863

Creutzfeldt-Jakob disease lookback study: 21 years of surveillance for transfusion transmission risk.

PubMed

Crowder, Lauren A; Schonberger, Lawrence B; Dodd, Roger Y; Steele, Whitney R

2017-08-01

Transfusion transmission of human prion diseases has been observed for variant Creutzfeldt-Jakob disease (vCJD), but not for the classic forms of prion disease (CJD: sporadic, genetic, and iatrogenic). Although the presence of prions or misfolded prion proteins in blood has been documented in some patients with the most common form of CJD, sporadic CJD, no transfusion-transmitted cases of CJD have been recognized. Since 1995, the American Red Cross has conducted a lookback study of the recipients of blood products from donors who develop CJD to assess the risk of blood-borne CJD transmission in the United States. Blood donors subsequently diagnosed with confirmed or probable CJD were enrolled and the consignees were asked to identify the recipients of their blood products. These donors' transfusion recipients are traced annually with the National Death Index to see if they subsequently die of CJD. To date, 65 CJD donors have been enrolled along with 826 of their blood recipients. These recipients have contributed 3934 person-years of follow-up and no transfusion-transmitted cases of CJD have been recognized. From this study, as well as other epidemiologic studies, there is no evidence of CJD transfusion transmission; this risk remains theoretical. © 2017 AABB.

The Identification of Alpha-Synuclein as the First Parkinson Disease Gene

PubMed Central

Nussbaum, Robert L.

2017-01-01

In this Commentary, I describe the events that led from an NINDS-sponsored Workshop on Parkinson Disease Research in 1995, where I was asked to speak about the genetics of Parkinson disease, to the identification a mere two years later of a mutation in alpha-synuclein as the cause of autosomal dominant Parkinson disease in the Contursi kindred. I review the steps we took to first map and then find the mutation in the alpha-synuclein locus and describe the obstacles and the role of serendipity in facilitating the work. Although alpha-synuclein mutations are a rare cause of hereditary PD, the importance of this finding goes far beyond the rare families with hereditary disease because it pinpointed alpha-synuclein as a key contributor to the far more common sporadic form of Parkinson disease. This work confirms William Harvey’s observation from 350 years ago that studying rarer forms of a disease is an excellent way to understand the more common forms of that disease. The identification of synuclein’s role in hereditary Parkinson disease has opened new avenues of research into the pathogenesis and potential treatments of the common form of Parkinson disease that affects many millions of Americans and tens of millions of human beings worldwide. PMID:28282812

The Identification of Alpha-Synuclein as the First Parkinson Disease Gene.

PubMed

Nussbaum, Robert L

2017-01-01

In this Commentary, I describe the events that led from an NINDS-sponsored Workshop on Parkinson Disease Research in 1995, where I was asked to speak about the genetics of Parkinson disease, to the identification a mere two years later of a mutation in alpha-synuclein as the cause of autosomal dominant Parkinson disease in the Contursi kindred. I review the steps we took to first map and then find the mutation in the alpha-synuclein locus and describe the obstacles and the role of serendipity in facilitating the work. Although alpha-synuclein mutations are a rare cause of hereditary PD, the importance of this finding goes far beyond the rare families with hereditary disease because it pinpointed alpha-synuclein as a key contributor to the far more common sporadic form of Parkinson disease. This work confirms William Harvey's observation from 350 years ago that studying rarer forms of a disease is an excellent way to understand the more common forms of that disease. The identification of synuclein's role in hereditary Parkinson disease has opened new avenues of research into the pathogenesis and potential treatments of the common form of Parkinson disease that affects many millions of Americans and tens of millions of human beings worldwide.

Pathogenesis of Germline and Somatic NF1 Rearrangements

DTIC Science & Technology

1999-10-01

de novo DNA deletion in a patient with sporadic neurofibromatosis 1, mental retardation, and dysmorphism . J Med Genet 29:686-90. Leppig, K., Kaplan...a patient with sporadic neurofibromatosis 1, mental retardation, and dysmorphism . J. Med. Genet., 29, 686-690. 13. Kayes, L.M., Burke, W., Riccardi...gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay. Hum. Genet

Age and Diet: Major interacting factors that drive sporadic intestinal cancer | Division of Cancer Prevention

Cancer.gov

Age and diet are the two most clearly recognized risk factors for common sporadic colon cancer, responsible for >90% of cases in developed countries. We will make use of an important technical advance for whole genome sequencing of single cells recently reported by co-investigator Vijg that can uniquely detect rare mutational events to define the mutational load and spectrum

Paracoccidioidomycosis.

PubMed

Ramos-E-Silva, Marcia; Saraiva, Luciana do Espirito Santo

2008-04-01

Paracoccidioidomycosis is a fungal infection that is relatively common in Brazil, Venezuela, Colombia, Ecuador, and Argentina. Sporadic cases can also be seen in some other countries. It is caused by a dimorphic fungus, Paracoccidioides brasiliensis, which affects mainly the skin, lymph nodes, lungs, and oral, nasal, and gastrointestinal mucous membranes. Depending on the specific immunity of the host, the infection can assume many forms and affect single or multiple organs, eventually becoming a severe and even fatal disease. It is very important for dermatologists of all over the world to know about paracoccidioidomycosis because sometimes the disease only manifests many years after the individual has left the endemic area.

Alpha-cardiac myosin heavy chain (MYH6) mutations affecting myofibril formation are associated with congenital heart defects.

PubMed

Granados-Riveron, Javier T; Ghosh, Tushar K; Pope, Mark; Bu'Lock, Frances; Thornborough, Christopher; Eason, Jacqueline; Kirk, Edwin P; Fatkin, Diane; Feneley, Michael P; Harvey, Richard P; Armour, John A L; David Brook, J

2010-10-15

Congenital heart defects (CHD) are collectively the most common form of congenital malformation. Studies of human cases and animal models have revealed that mutations in several genes are responsible for both familial and sporadic forms of CHD. We have previously shown that a mutation in MYH6 can cause an autosomal dominant form of atrial septal defect (ASD), whereas others have identified mutations of the same gene in patients with hypertrophic and dilated cardiomyopathy. In the present study, we report a mutation analysis of MYH6 in patients with a wide spectrum of sporadic CHD. The mutation analysis of MYH6 was performed in DNA samples from 470 cases of isolated CHD using denaturing high-performance liquid chromatography and sequence analysis to detect point mutations and small deletions or insertions, and multiplex amplifiable probe hybridization to detect partial or complete copy number variations. One non-sense mutation, one splicing site mutation and seven non-synonymous coding mutations were identified. Transfection of plasmids encoding mutant and non-mutant green fluorescent protein-MYH6 fusion proteins in mouse myoblasts revealed that the mutations A230P and A1366D significantly disrupt myofibril formation, whereas the H252Q mutation significantly enhances myofibril assembly in comparison with the non-mutant protein. Our data indicate that functional variants of MYH6 are associated with cardiac malformations in addition to ASD and provide a novel potential mechanism. Such phenotypic heterogeneity has been observed in other genes mutated in CHD.

Immunohistochemical Analysis Supports a Role for INI1/SMARCB1 in Hereditary Forms of Schwannomas, But Not in Solitary, Sporadic Schwannomas

PubMed Central

Patil, Sushama; Perry, Arie; MacCollin, Mia; Dong, Shumin; Betensky, Rebecca A.; Yeh, Tu-Hsueh; Gutmann, David H.; Stemmer-Rachamimov, Anat O.

2009-01-01

The INI1/SMARCB1 protein product (INI1), a component of a transcription complex, was recently implicated in the pathogenesis of schwannomas in two members of a single family with familial schwannomatosis1. Tumors were found to have both constitutional and somatic mutations of the SMARCB1 gene and showed a mosaic pattern of loss of INI1 expression by immunohistochemistry, suggesting a tumor composition of mixed null and haploinsufficient cells. To determine if this finding could be extended to all tumors arising in familial schwannomatosis, and how it compares to other multiple schwannoma syndromes (sporadic schwannomatosis and neurofibromatosis 2) as well as to sporadic, solitary schwannomas, we performed an immunohistochemistry analysis on 45 schwannomas from patients with multiple schwannoma syndromes and on 38 solitary, sporadic schwannomas from non-syndromic patients. A mosaic pattern of INI1 expression was seen in 93% of tumors from familial schwannomatosis patients, 55% of tumors from sporadic schwannomatosis, 83% of NF2-associated tumors and only 5% of solitary, sporadic schwannomas. These results confirm a role for INI1/SMARCB1 in multiple schwannoma syndromes and suggest that a different pathway of tumorigenesis occurs in solitary, sporadic tumors. PMID:18422762

Endo-lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?

PubMed

Whyte, Lauren S; Lau, Adeline A; Hemsley, Kim M; Hopwood, John J; Sargeant, Timothy J

2017-03-01

Alzheimer's disease (AD) is the most common cause of dementia, and its prevalence will increase significantly in the coming decades. Although important progress has been made, fundamental pathogenic mechanisms as well as most hereditary contributions to the sporadic form of the disease remain unknown. In this review, we examine the now substantial links between AD pathogenesis and lysosomal biology. The lysosome hydrolyses and processes cargo delivered by multiple pathways, including endocytosis and autophagy. The endo-lysosomal and autophagic networks are central to clearance of cellular macromolecules, which is important given there is a deficit in clearance of amyloid-β in AD. Numerous studies show prominent lysosomal dysfunction in AD, including perturbed trafficking of lysosomal enzymes and accumulation of the same substrates that accumulate in lysosomal storage disorders. Examination of the brain in lysosomal storage disorders shows the accumulation of amyloid precursor protein metabolites, which further links lysosomal dysfunction with AD. This and other evidence leads us to hypothesise that genetic variation in lysosomal genes modifies the disease course of sporadic AD. © 2016 International Society for Neurochemistry.

Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer's disease.

PubMed

Carmona-Iragui, María; Balasa, Mircea; Benejam, Bessy; Alcolea, Daniel; Fernández, Susana; Videla, Laura; Sala, Isabel; Sánchez-Saudinós, María Belén; Morenas-Rodriguez, Estrella; Ribosa-Nogué, Roser; Illán-Gala, Ignacio; Gonzalez-Ortiz, Sofía; Clarimón, Jordi; Schmitt, Frederick; Powell, David K; Bosch, Beatriz; Lladó, Albert; Rafii, Michael S; Head, Elizabeth; Molinuevo, José Luis; Blesa, Rafael; Videla, Sebastián; Lleó, Alberto; Sánchez-Valle, Raquel; Fortea, Juan

2017-11-01

We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]). Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid β (Aβ) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aβ040 levels between groups or between subjects with and without CAA. CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aβ40 levels are not a useful biomarker for CAA in AD. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

PVRL1 Variants Contribute to Non-Syndromic Cleft Lip and Palate in Multiple Populations

PubMed Central

Avila, Joseph R.; Jezewski, Peter A.; Vieira, Alexandre R.; Orioli, Iêda M.; Castilla, Eduardo E.; Christensen, Kaare; Daack-Hirsch, Sandra; Romitti, Paul A.; Murray, Jeffrey C.

2007-01-01

Poliovirus Receptor Like-1 (PVRL1) is a member of the immunoglobulin super family that acts in the initiation and maintenance of epithelial adherens junctions and is mutated in the cleft lip and palate/ectodermal dysplasia 1 syndrome (CLPED1, OMIM #225000). In addition, a common non-sense mutation in PVRL1 was discovered more often among non-syndromic sporadic clefting cases in Northern Venezuela in a previous case-control study. The present work sought to ascertain the role of PVRL1 in the sporadic forms of orofacial clefting in multiple populations. Multiple rare and common variants from all three splice isoforms were initially ascertained by sequencing 92 Iowan and 86 Filipino cases and CEPH controls. Using a family-based analysis to examine these variants, the common glycine allele of the G361V coding variant was significantly overtransmitted among all orofacial clefting phenotypes (P = 0.005). This represented G361V genotyping from over 800 Iowan, Danish, and Filipino families. Among four rare amino acid changes found within the V1 and C1 domains, S112T and T131A were found adjacent to critical amino acid positions within the V1 variable domain, regions previously shown to mediate cell-to-cell and cell-to-virus adhesion. The T131A variant was not found in over 1,300 non-affected control samples although the alanine is found in other species. The serine of the S112T variant position is conserved across all known PVRL1 sequences. Together these data suggest that both rare and common mutations within PVRL1 make a minor contribution to disrupting the initiation and regulation of cell-to-cell adhesion and downstream morphogenesis of the embryonic face. PMID:17089422

Update on Novel CCM Gene Mutations in Patients with Cerebral Cavernous Malformations.

PubMed

Scimone, Concetta; Bramanti, Placido; Alafaci, Concetta; Granata, Francesca; Piva, Francesco; Rinaldi, Carmela; Donato, Luigi; Greco, Federica; Sidoti, Antonina; D'Angelo, Rosalia

2017-02-01

Cerebral cavernous malformations (CCMs) are lesions affecting brain microvessels. The pathogenesis is not clearly understood. Conventional classification criterion is based on genetics, and thus, familial and sporadic forms can be distinguished; however, classification of sporadic cases with multiple lesions still remains uncertain. To date, three CCM causative genes have been identified: CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10. In our previous mutation screening, performed in a cohort of 95 Italian patients, with both sporadic and familial cases, we identified several mutations in CCM genes. This study represents further molecular screening in a cohort of 19 Italian patients enrolled by us in the few last years and classified into familial, sporadic and sporadic with multiple lesions cases. Direct sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis were performed to detect point mutations and large genomic rearrangements, respectively. Effects of detected mutations and single-nucleotide polymorphisms (SNPs) were evaluated by an in silico approach and by western blot analysis. A novel nonsense mutation in CCM1 and a novel missense mutation in CCM2 were detected; moreover, several CCM2 gene polymorphisms in sporadic CCM patients were reported. We believe that these data enrich the mutation spectrum of CCM genes, which is useful for genetic counselling to identify both familial and sporadic CCM cases, as early as possible.

[Physical urticaria].

PubMed

Fleischer, M; Grabbe, J

2004-04-01

The different types of physical urticaria are triggered by mechanical and thermal stimuli, as well as electromagnetic waves. Localized forms restricted to the skin and mucous membranes are most common, but generalized urticaria with variable extracutaneous manifestations can also occur. Physical urticaria is usually sporadic but may rarely have a familial form; it is often associated with chronic urticaria. In most instances, the short time interval between the physical stimulus and reaction points to a causal relationship, but in delayed types the exact diagnosis may be missed without provocation tests. The clinical implication of physical urticaria is demonstrated by investigations showing a greater degree of disability in affected patients as compared to other types of urticaria. There is still an incomplete understanding of the crucial pathophysiological aspects; most likely inflammatory reactions involving leukocytes, endothelial cells and nerves stimulated by various mediators play an important role in this form of urticaria.

Sporadic E-Layers and Meteor Activity

NASA Astrophysics Data System (ADS)

Alimov, Obid

2016-07-01

In average width it is difficult to explain variety of particularities of the behavior sporadic layer Es ionospheres without attraction long-lived metallic ion of the meteoric origin. Mass spectrometric measurements of ion composition using rockets indicate the presence of metal ions Fe+, Mg+, Si+, Na+, Ca+, K+, Al+ and others in the E-region of the ionosphere. The most common are the ions Fe+, Mg+, Si+, which are primarily concentrated in the narrow sporadic layers of the ionosphere at altitudes of 90-130 km. The entry of meteoric matter into the Earth's atmosphere is a source of meteor atoms (M) and ions (M +) that later, together with wind shear, produce midlatitude sporadic Es layer of the ionosphere. To establish the link between sporadic Es layer and meteoroid streams, we proceeded from the dependence of the ionization coefficient of meteors b on the velocity of meteor particles in different meteoroid streams. We investigated the dependence of the critical frequency f0Es of sporadic E on the particle velocity V of meteor streams and associations. It was established that the average values of f0Es are directly proportional to the velocity V of meteor streams and associations, with the correlation coefficient of 0.53 < R < 0.74. Thus, the critical frequency of the sporadic layer Es increases with the increase of particle velocity V in meteor streams, which indicates the direct influence of meteor particles on ionization of the lower ionosphere and formation of long-lived metal atoms M and ions M+ of meteoric origin.

Investigation on the relationship among sporadic Na, sporadic E, Field aligned irregularities and neutral winds

NASA Astrophysics Data System (ADS)

Sundararajan, Sridharan; Patra, Amit Kumar; Pant, Tarun; Gurubaran, Subramanian; Raghunath, Karnam

In the Mesosphere and Lower Thermosphere region (80-100 km), metallic atoms, namely, sodium, potassium, lithium, Iron etc are formed due to ablation of meteors. The lidars based on resonance fluorescence principle has been used to study the vertical distribution of sodium atoms, because of their large abundance than other metals. The profiles of sodium density sometimes show enhancement by a factor of 2 than the normal layer in a narrow altitude region of 2 km and on these occasions, they are called sporadic sodium layer, or briefly Ns. On the other hand, there are observations on sporadic E and radar observations of Field Aligned Irregularities (FAI) associated with these sporadic E. Some investigations have been made to understand the relationship between sporadic E and FAI. Considering that sporadic E is composed of metallic ions and the time of metallic ions are larger compared to other ions, the sodium observations in the same height region would be of significant importance to understand the process involved. Despite a few past observations, no clear picture has emerged due to lack of simultaneous measurements of these parameters. The simultaneous observations of FAI echoes by the Indian MST radar and sodium concentration by the sodium lidar at Gadanki (13.5o N, 79.2o E) are being used to investigate the above mentioned relationship. The Sporadic E and neutral wind information are obtained from the ionosonde, meteor/MF radar observations from Trivandrum (8.5o N, 77E) and Tirunelveli (8.7o N, 77.8o E). The results obtained will be presented during the meeting.

Hereditary pancreatic adenocarcinoma. A clinical perspective.

PubMed

Brand, R E; Lynch, H T

2000-05-01

Although the total number of patients in these various high-risk groups is relatively small, they nevertheless provide excellent models for studying the cause, natural history, pathogenesis, and treatment of pancreatic cancer. These patients would also benefit greatly from procedures capable of detecting cancer at an early stage. This knowledge would be useful for the much commoner sporadic form of pancreatic cancer, in which diagnosis is almost always late and prognosis fatal. With early diagnosis, surgical resection before the cancer's extension beyond the organ's anatomic confines could be curative. The establishment of a National Familial Pancreatic Cancer Registry is essential and would increase the availability of these invaluable families for medical research.

Mutations in FUS are the most frequent genetic cause in juvenile sporadic ALS patients of Chinese origin.

PubMed

Zou, Zhang-Yu; Liu, Ming-Sheng; Li, Xiao-Guang; Cui, Li-Ying

2016-01-01

Juvenile onset ALS is a very rare form of motor neuron disease, with the first symptoms of motor neuron degeneration manifested before 25 years of age. Mutations in the alsin (ALS2), senataxin (SETX), and spatacsin (SPG11) genes have been associated with familial ALS with juvenile onset and slow progression, whereas the genetic architecture of sporadic juvenile ALS remains unclear. We screened mutations in C9orf72, SOD1, FUS, TARDBP, ANG, VCP and PFN1 in 16 juvenile sporadic ALS patients. Four cases (25%) carrying FUS mutations and one individual (6%) harbouring a SOD1 mutation were identified. All cases had an aggressive disease course. Our results suggest that FUS mutations are the most frequent genetic cause in early-onset sporadic ALS patients of Chinese origin. Genetic testing of FUS should be performed in early-onset ALS patients especially those with an aggressive disease course.

Model Simulation of Ionosphere Electron Density with Dynamic Transportation and Mechanism of Sporadic E Layers in Lower Part of Ionosphere

NASA Astrophysics Data System (ADS)

Lin, Y. C.; Chu, Y. H.

2015-12-01

There are many physical theories responsible for explanation the generation mechanism of sporadic E (Es) plasma irregularities. In middle latitude, it's generally believed that sporadic E layers occur in vertical ion convergent areas driven by horizontal neutral wind shear. The sporadic E layers appear characteristic of abundant metallic ion species (i.e., Fe+, Mg+, Na+), that lifetime are longer than molecular ions by a factor of several orders, have been demonstrated by rocket-borne mass spectrometric measurements. On the basic of the GPS Radio Occultation (RO), using the scintillations of the GPS signal-to-noise ratio and intense fluctuation of excess phase, the global and seasonal sporadic E layers occurrence rates could be retrieved. In our previous study we found there is averaged 10 kilometers shift in height between the COSMIC-retrieved sporadic E layer occurrence rate and the sporadic E occurrence rate modeled from considering the convergence/divergence of Fe+ vertical flux. There are many reasons that maybe result in the altitude differences, e.g., tidal wind with phase shift, electric field driven force, iron species distributions. In this research, the quantitative analyses for electric field drives Es layers translations in vertical direction are presented. The tidal wind driven sporadic E layers have been simulating by modeling several nonmetallic ions (O+(4S), O+(2D), O+(2p), N+, N2+, O2+, NO+) and metallic ions (Fe+, FeO2+, FeN2+, FeO+) with wind shear transportation. The simulation result shows the Fe+ particles accumulate at zonal wind shear convergent regions and form the thin sporadic E layers. With the electric field taking into account, the whole shape of sporadic E layers vertical shift 2~5 km that depending on what magnitude and direction of electric field is added.

Significance of common variants on human chromosome 8q24 in relation to the risk of prostate cancer in native Japanese men

PubMed Central

Liu, Miao; Kurosaki, Takayuki; Suzuki, Motofumi; Enomoto, Yutaka; Nishimatsu, Hiroaki; Arai, Tomio; Sawabe, Motoji; Hosoi, Takayuki; Homma, Yukio; Kitamura, Tadaichi

2009-01-01

Background Common variants on human chromosome 8q24, rs1447295 (C/A) and rs6983267 (T/G), have been recently linked to the prevalence of prostate cancer in European and American populations. Here, we evaluated whether the single-nucleotide polymorphisms rs1447295 and rs6983267 were associated with the risk of sporadic prostate cancer as well as latent prostate cancer in a native Japanese population. Results We analyzed genomic DNA samples from 391 sporadic prostate cancer patients, 323 controls who had died from causes unrelated to cancer and 112 Japanese men who were diagnosed as having latent prostate cancer based on autopsy results. The polymorphisms were determined by allelic discrimination using a fluorescent-based TaqMan assay. The A allele of rs1447295 was significantly associated with the risk of sporadic prostate cancer (p = 0.04; age-adjusted OR, 1.34), while the G allele of rs6983267 showed a trend towards being a high-risk allele (p = 0.06; age-adjusted OR, 1.27). No significant difference between these two polymorphisms and the risk of latent prostate cancer was observed in the present Japanese population. Conclusion Known variants on human chromosome 8q24 may be risk factors for sporadic prostate cancer in native Japanese men. PMID:19602258

Impaired proteasome function in sporadic amyotrophic lateral sclerosis.

PubMed

Kabashi, Edor; Agar, Jeffrey N; Strong, Michael J; Durham, Heather D

2012-06-01

Abstract The ubiquitin-proteasome system, important for maintaining protein quality control, is compromised in experimental models of familial ALS. The objective of this study was to determine if proteasome function is impaired in sporadic ALS. Proteasomal activities and subunit composition were evaluated in homogenates of spinal cord samples obtained at autopsy from sporadic ALS and non-neurological control cases, compared to cerebellum as a clinically spared tissue. The level of 20S α structural proteasome subunits was assessed in motor neurons by immunohistochemistry. Catalysis of peptide substrates of the three major proteasomal activities was substantially reduced in ALS thoracic spinal cord, but not in cerebellum, accompanied by alterations in the constitutive proteasome machinery. Chymotrypsin-like activity was decreased to 60% and 65% of control in ventral and dorsal spinal cord, respectively, concomitant with reduction in the β5 subunit with this catalytic activity. Caspase- and trypsin-like activities were reduced to a similar extent (46% - 68% of control). Proteasome levels, although generally maintained, appeared reduced specifically in motor neurons by immunolabelling. In conclusion, there are commonalities of findings in sporadic ALS patients and presymptomatic SOD1-G93A transgenic mice and these implicate inadequate proteasome function in the pathogenesis of both familial and sporadic ALS.

Genome-wide association study of sporadic brain arteriovenous malformations.

PubMed

Weinsheimer, Shantel; Bendjilali, Nasrine; Nelson, Jeffrey; Guo, Diana E; Zaroff, Jonathan G; Sidney, Stephen; McCulloch, Charles E; Al-Shahi Salman, Rustam; Berg, Jonathan N; Koeleman, Bobby P C; Simon, Matthias; Bostroem, Azize; Fontanella, Marco; Sturiale, Carmelo L; Pola, Roberto; Puca, Alfredo; Lawton, Michael T; Young, William L; Pawlikowska, Ludmila; Klijn, Catharina J M; Kim, Helen

2016-09-01

The pathogenesis of sporadic brain arteriovenous malformations (BAVMs) remains unknown, but studies suggest a genetic component. We estimated the heritability of sporadic BAVM and performed a genome-wide association study (GWAS) to investigate association of common single nucleotide polymorphisms (SNPs) with risk of sporadic BAVM in the international, multicentre Genetics of Arteriovenous Malformation (GEN-AVM) consortium. The Caucasian discovery cohort included 515 BAVM cases and 1191 controls genotyped using Affymetrix genome-wide SNP arrays. Genotype data were imputed to 1000 Genomes Project data, and well-imputed SNPs (>0.01 minor allele frequency) were analysed for association with BAVM. 57 top BAVM-associated SNPs (51 SNPs with p<10(-05) or p<10(-04) in candidate pathway genes, and 6 candidate BAVM SNPs) were tested in a replication cohort including 608 BAVM cases and 744 controls. The estimated heritability of BAVM was 17.6% (SE 8.9%, age and sex-adjusted p=0.015). None of the SNPs were significantly associated with BAVM in the replication cohort after correction for multiple testing. 6 SNPs had a nominal p<0.1 in the replication cohort and map to introns in EGFEM1P, SP4 and CDKAL1 or near JAG1 and BNC2. Of the 6 candidate SNPs, 2 in ACVRL1 and MMP3 had a nominal p<0.05 in the replication cohort. We performed the first GWAS of sporadic BAVM in the largest BAVM cohort assembled to date. No GWAS SNPs were replicated, suggesting that common SNPs do not contribute strongly to BAVM susceptibility. However, heritability estimates suggest a modest but significant genetic contribution. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Comparison of sporadic cases of Salmonella Typhimurium with other Salmonella serotypes in Castellon (Spain): case-case study.

PubMed

Arnedo-Pena, Alberto; Vivas-Fornas, Iraya; Meseguer-Ferrer, Noemi; Tirado-Balaguer, María Dolores; Yagüe-Muñoz, Alberto; Herrera-León, Silvia; Sabater-Vidal, Susana; Romeu-García, María Ángeles; Vizcaino Batllés, Ana; Bellido-Blasco, Juan Bautista; Moreno-Muñoz, Rosario

2017-10-07

Salmonella infections (SI) are common in Spain. The aim of this study was to appraise risk factors and the clinical characteristics of sporadic Salmonella Typhimurium infections compared with other sporadic salmonella serotype infections (OSI). From September 2014 to August 2015, a case-case study was carried out by the Epidemiology Division of the Public Health Centre of Castellon. Case 1 consisted of patients with sporadic S. Typhimurium infections, while case 2 comprised OSI patients, assessed according to the stool cultures analyzed by the Microbiology Laboratories of Hospital General de Castellon and Hospital de La Plana in Vila-real. Patients from detected outbreaks were not included. The salmonella serotype was identified by the National Centre of Microbiology (Madrid). The total number of SI patients reported was 327, 242 of whom were studied (74.0%). 148 patients had sporadic S. Typhimurium infection and 64 had OSI, with median ages of 4 and 8.5 years, respectively. Sporadic S. Typhimurium infection patients presented more blood in feces and diarrhea episodes. Consumption of pork meat (OR=2.22; 95% CI 1.12-4.43), cold pork meats (OR=2.49; 95% CI 1.32-4.68) and playing in the dirt (OR=3.02; 95% CI 1.55-5.88), were associated with sporadic S. Typhimurium infection. In the 0-4 year-old group, the associated factors were consumption of cold pork meats, omelets and female gender. In the 5-year-old and over group, only playing in soil was associated with sporadic S. Typhimurium infection. The consumption of pork and omelets, as well as playing in the dirt, were the main factors associated with infection. Children were most affected by sporadic S. Typhimurium infection. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Defects in optineurin- and myosin VI-mediated cellular trafficking in amyotrophic lateral sclerosis.

PubMed

Sundaramoorthy, Vinod; Walker, Adam K; Tan, Vanessa; Fifita, Jennifer A; Mccann, Emily P; Williams, Kelly L; Blair, Ian P; Guillemin, Gilles J; Farg, Manal A; Atkin, Julie D

2015-07-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder primarily affecting motor neurons. Mutations in optineurin cause a small proportion of familial ALS cases, and wild-type (WT) optineurin is misfolded and forms inclusions in sporadic ALS patient motor neurons. However, it is unknown how optineurin mutation or misfolding leads to ALS. Optineurin acts an adaptor protein connecting the molecular motor myosin VI to secretory vesicles and autophagosomes. Here, we demonstrate that ALS-linked mutations p.Q398X and p.E478G disrupt the association of optineurin with myosin VI, leading to an abnormal diffuse cytoplasmic distribution, inhibition of secretory protein trafficking, endoplasmic reticulum (ER) stress and Golgi fragmentation in motor neuron-like NSC-34 cells. We also provide further insight into the role of optineurin as an autophagy receptor. WT optineurin associated with lysosomes and promoted autophagosome fusion to lysosomes in neuronal cells, implying that it mediates trafficking of lysosomes during autophagy in association with myosin VI. However, either expression of ALS mutant optineurin or small interfering RNA-mediated knockdown of endogenous optineurin blocked lysosome fusion to autophagosomes, resulting in autophagosome accumulation. Together these results indicate that ALS-linked mutations in optineurin disrupt myosin VI-mediated intracellular trafficking processes. In addition, in control human patient tissues, optineurin displayed its normal vesicular localization, but in sporadic ALS patient tissues, vesicles were present in a significantly decreased proportion of motor neurons. Optineurin binding to myosin VI was also decreased in tissue lysates from sporadic ALS spinal cords. This study therefore links several previously described pathological mechanisms in ALS, including defects in autophagy, fragmentation of the Golgi and induction of ER stress, to disruption of optineurin function. These findings also indicate that optineurin-myosin VI dysfunction is a common feature of both sporadic and familial ALS. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Gene expression profiling for human iPS-derived motor neurons from sporadic ALS patients reveals a strong association between mitochondrial functions and neurodegeneration

PubMed Central

Alves, Chrystian J.; Dariolli, Rafael; Jorge, Frederico M.; Monteiro, Matheus R.; Maximino, Jessica R.; Martins, Roberto S.; Strauss, Bryan E.; Krieger, José E.; Callegaro, Dagoberto; Chadi, Gerson

2015-01-01

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that leads to widespread motor neuron death, general palsy and respiratory failure. The most prevalent sporadic ALS form is not genetically inherited. Attempts to translate therapeutic strategies have failed because the described mechanisms of disease are based on animal models carrying specific gene mutations and thus do not address sporadic ALS. In order to achieve a better approach to study the human disease, human induced pluripotent stem cell (hiPSC)-differentiated motor neurons were obtained from motor nerve fibroblasts of sporadic ALS and non-ALS subjects using the STEMCCA Cre-Excisable Constitutive Polycistronic Lentivirus system and submitted to microarray analyses using a whole human genome platform. DAVID analyses of differentially expressed genes identified molecular function and biological process-related genes through Gene Ontology. REVIGO highlighted the related functions mRNA and DNA binding, GTP binding, transcription (co)-repressor activity, lipoprotein receptor binding, synapse organization, intracellular transport, mitotic cell cycle and cell death. KEGG showed pathways associated with Parkinson's disease and oxidative phosphorylation, highlighting iron homeostasis, neurotrophic functions, endosomal trafficking and ERK signaling. The analysis of most dysregulated genes and those representative of the majority of categorized genes indicates a strong association between mitochondrial function and cellular processes possibly related to motor neuron degeneration. In conclusion, iPSC-derived motor neurons from motor nerve fibroblasts of sporadic ALS patients may recapitulate key mechanisms of neurodegeneration and may offer an opportunity for translational investigation of sporadic ALS. Large gene profiling of differentiated motor neurons from sporadic ALS patients highlights mitochondrial participation in the establishment of autonomous mechanisms associated with sporadic ALS. PMID:26300727

A Single Lineage of Hepatitis E Virus Causes both Outbreaks and Sporadic Hepatitis in Sudan

PubMed Central

Elduma, Adel Hussein; Zein, Mai Mohammed Adam; Karlsson, Marie; Elkhidir, Isam M.E.; Norder, Heléne

2016-01-01

Few studies have reported sporadic hepatitis E virus (HEV) infections during non-outbreak periods in Africa. In this study, the prevalence of HEV infection in Sudan was investigated in 432 patients with acute hepatitis from 12 localities in North Kordofan, and from 152 patients involved in smaller outbreaks of hepatitis in the neighbouring Darfur. HEV infection was diagnosed in 147 (25%) patients: 98 from Kordofan and 49 from Darfur. The mortality was 10%; six of the patients who died from the infection were pregnant women. HEV RNA was detected by quantitative real-time polymerase chain reaction (RT-qPCR) in 38 (26%) patients: 22 from Kordofan and 16 from Darfur. Partial open reading frame (ORF) 1 and ORF2 were sequenced from HEV from nine and three patients, respectively. Phylogenetic analysis showed that the Sudanese strains belonged to genotype 1 (HEV1), and confirmed the segregation of African HEV1 strains into one branch divergent from Asian HEV1. It also revealed that the Sudanese strains from this study and from an outbreak in 2004 formed a separate clade with a common ancestor, distinct from strains from the neighbouring Chad and Egypt. This HEV strain has thus spread in a large area of Sudan, where it has caused both sporadic hepatitis E and outbreaks from at least 2004 and onwards. These data demonstrate that hepatitis E is a constant, on-going public health problem in Sudan and that there is a need for hepatitis E surveillance, outbreak preparedness, and general improvements of the sanitation in these remote areas of the country. PMID:27782061

DNA mismatch repair protein deficient non-neoplastic colonic crypts: a novel indicator of Lynch syndrome.

PubMed

Pai, Rish K; Dudley, Beth; Karloski, Eve; Brand, Randall E; O'Callaghan, Neil; Rosty, Christophe; Buchanan, Daniel D; Jenkins, Mark A; Thibodeau, Stephen N; French, Amy J; Lindor, Noralane M; Pai, Reetesh K

2018-06-08

Lynch syndrome is the most common form of hereditary colorectal carcinoma. However, establishing the diagnosis of Lynch syndrome is challenging, and ancillary studies that distinguish between sporadic DNA mismatch repair (MMR) protein deficiency and Lynch syndrome are needed, particularly when germline mutation studies are inconclusive. The aim of this study was to determine if MMR protein-deficient non-neoplastic intestinal crypts can help distinguish between patients with and without Lynch syndrome. We evaluated the expression of MMR proteins in non-neoplastic intestinal mucosa obtained from colorectal surgical resection specimens from patients with Lynch syndrome-associated colorectal carcinoma (n = 52) and patients with colorectal carcinoma without evidence of Lynch syndrome (n = 70), including sporadic MMR protein-deficient colorectal carcinoma (n = 30), MMR protein proficient colorectal carcinoma (n = 30), and "Lynch-like" syndrome (n = 10). MMR protein-deficient non-neoplastic colonic crypts were identified in 19 of 122 (16%) patients. MMR protein-deficient colonic crypts were identified in 18 of 52 (35%) patients with Lynch syndrome compared to only 1 of 70 (1%) patients without Lynch syndrome (p < 0.001). This one patient had "Lynch-like" syndrome and harbored two MSH2-deficient non-neoplastic colonic crypts. MMR protein-deficient non-neoplastic colonic crypts were not identified in patients with sporadic MMR protein-deficient or MMR protein proficient colorectal carcinoma. Our findings suggest that MMR protein-deficient colonic crypts are a novel indicator of Lynch syndrome, and evaluation for MMR protein-deficient crypts may be a helpful addition to Lynch syndrome diagnostics.

Genetically engineered mouse models and human osteosarcoma

PubMed Central

2012-01-01

Osteosarcoma is the most common form of bone cancer. Pivotal insight into the genes involved in human osteosarcoma has been provided by the study of rare familial cancer predisposition syndromes. Three kindreds stand out as predisposing to the development of osteosarcoma: Li-Fraumeni syndrome, familial retinoblastoma and RecQ helicase disorders, which include Rothmund-Thomson Syndrome in particular. These disorders have highlighted the important roles of P53 and RB respectively, in the development of osteosarcoma. The association of OS with RECQL4 mutations is apparent but the relevance of this to OS is uncertain as mutations in RECQL4 are not found in sporadic OS. Application of the knowledge or mutations of P53 and RB in familial and sporadic OS has enabled the development of tractable, highly penetrant murine models of OS. These models share many of the cardinal features associated with human osteosarcoma including, importantly, a high incidence of spontaneous metastasis. The recent development of these models has been a significant advance for efforts to improve our understanding of the genetics of human OS and, more critically, to provide a high-throughput genetically modifiable platform for preclinical evaluation of new therapeutics. PMID:23036272

Hyperthyroidism and atrial myxoma--an intriguing cardio-endocrine association.

PubMed

Kumar, Gautam; Chow, John T; Klarich, Kyle W; Dean, Diana S

2007-12-01

A 65-year-old woman presented with dyspnea and bilateral leg edema for 1 week, worsening fatigue for 1 month, and a 7-lb weight loss over the last summer. She was clinically and biochemically hyperthyroid. Echocardiography revealed a left atrial myxoma measuring 6.2 x 3.3 cm protruding into the mitral orifice and left ventricle during diastole. She was treated for Graves' disease with Iodine-131. Six weeks later, her left atrial myxoma measuring 10.1 x 6.2 x 2.4 cm was resected. She became euthyroid before surgery and then biochemically hypothyroid 6 weeks after radioiodine treatment, for which she subsequently required thyroxine replacement. Atrial myxomas are the most common primary cardiac neoplasms. At least 5% to 10% can be attributed to Carney's complex. More than two-thirds of patients with Carney's complex develop one or more cardiac myxomas. Although atrial myxomas in Carney's complex are histologically indistinguishable from the sporadic form, their clinical presentation and course is distinct. This is the first case of newly diagnosed Graves' disease that has been reported in association with an atrial myxoma. The features discussed in this article help differentiate between syndromic and sporadic atrial myxomas.

Reduced expression of fumarate hydratase in clear cell renal cancer mediates HIF-2α accumulation and promotes migration and invasion.

PubMed

Sudarshan, Sunil; Shanmugasundaram, Karthigayan; Naylor, Susan L; Lin, Shu; Livi, Carolina B; O'Neill, Christine F; Parekh, Dipen J; Yeh, I-Tien; Sun, Lu-Zhe; Block, Karen

2011-01-01

Germline mutations of FH, the gene that encodes for the tricarboxylic acid TCA (TCA) cycle enzyme fumarate hydratase, are associated with an inherited form of cancer referred to as Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). Individuals with HLRCC are predisposed to the development of highly malignant and lethal renal cell carcinoma (RCC). The mechanisms of tumorigenesis proposed have largely focused on the biochemical consequences of loss of FH enzymatic activity. While loss of the tumor suppressor gene von Hippel Lindau (VHL) is thought to be an initiating event for the majority of RCCs, a role for FH in sporadic renal cancer has not been explored. Here we report that FH mRNA and protein expression are reduced in clear cell renal cancer, the most common histologic variant of kidney cancer. Moreover, we demonstrate that reduced FH leads to the accumulation of hypoxia inducible factor- 2α (HIF-2α), a transcription factor known to promote renal carcinogenesis. Finally, we demonstrate that overexpression of FH in renal cancer cells inhibits cellular migration and invasion. These data provide novel insights into the tumor suppressor functions of FH in sporadic kidney cancer.

RNF43 is mutated less frequently in Lynch Syndrome compared with sporadic microsatellite unstable colorectal cancers.

PubMed

Fennell, Lochlan J; Clendenning, Mark; McKeone, Diane M; Jamieson, Saara H; Balachandran, Samanthy; Borowsky, Jennifer; Liu, John; Kawamata, Futoshi; Bond, Catherine E; Rosty, Christophe; Burge, Matthew E; Buchanan, Daniel D; Leggett, Barbara A; Whitehall, Vicki L J

2018-01-01

The WNT signaling pathway is commonly altered during colorectal cancer development. The E3 ubiquitin ligase, RNF43, negatively regulates the WNT signal through increased ubiquitination and subsequent degradation of the Frizzled receptor. RNF43 has recently been reported to harbor frequent truncating frameshift mutations in sporadic microsatellite unstable (MSI) colorectal cancers. This study assesses the relative frequency of RNF43 mutations in hereditary colorectal cancers arising in the setting of Lynch syndrome. The entire coding region of RNF43 was Sanger sequenced in 24 colorectal cancers from 23 patients who either (i) carried a germline mutation in one of the DNA mismatch repair genes (MLH1, MSH6, MSH2, PMS2), or (ii) showed immunohistochemical loss of expression of one or more of the DNA mismatch repair proteins, was BRAF wild type at V600E, were under 60 years of age at diagnosis, and demonstrated no promoter region methylation for MLH1 in tumor DNA. A validation cohort of 44 colorectal cancers from mismatch repair germline mutation carriers from the Australasian Colorectal Cancer Family Registry (ACCFR) were sequenced for the most common truncating mutation hotspots (X117 and X659). RNF43 mutations were found in 9 of 24 (37.5%) Lynch syndrome colorectal cancers. The majority of mutations were frameshift deletions in the G659 G7 repeat tract (29%); 2 cancers (2/24, 8%) from the one patient harbored frameshift mutations at codon R117 (C6 repeat tract) within exon 3. In the ACCFR validation cohort, RNF43 hotspot mutations were identified in 19/44 (43.2%) of samples, which was not significantly different to the initial series. The proportion of mutant RNF43 in Lynch syndrome related colorectal cancers is significantly lower than the previously reported mutation rate found in sporadic MSI colorectal cancers. These findings identify further genetic differences between sporadic and hereditary colorectal cancers. This may be because Lynch Syndrome cancers commonly arise in colorectal adenomas already bearing the APC mutation, whereas sporadic microsatellite unstable colorectal cancers arise from serrated polyps typically lacking APC mutation, decreasing the selection pressure on other WNT signaling related loci in Lynch syndrome.

Mismatch repair deficiency commonly precedes adenoma formation in Lynch Syndrome-Associated colorectal tumorigenesis.

PubMed

Sekine, Shigeki; Mori, Taisuke; Ogawa, Reiko; Tanaka, Masahiro; Yoshida, Hiroshi; Taniguchi, Hirokazu; Nakajima, Takeshi; Sugano, Kokichi; Yoshida, Teruhiko; Kato, Mamoru; Furukawa, Eisaku; Ochiai, Atsushi; Hiraoka, Nobuyoshi

2017-08-01

Lynch syndrome is a cancer predisposition syndrome caused by germline mutations in mismatch repair (MMR) genes. MMR deficiency is a ubiquitous feature of Lynch syndrome-associated colorectal adenocarcinomas; however, it remains unclear when the MMR-deficient phenotype is acquired during tumorigenesis. To probe this issue, the present study examined genetic alterations and MMR statuses in Lynch syndrome-associated colorectal adenomas and adenocarcinomas, in comparison with sporadic adenomas. Among the Lynch syndrome-associated colorectal tumors, 68 of 86 adenomas (79%) and all adenocarcinomas were MMR-deficient, whereas all the sporadic adenomas were MMR-proficient, as determined by microsatellite instability testing and immunohistochemistry for MMR proteins. Sequencing analyses identified APC or CTNNB1 mutations in the majority of sporadic adenomas (58/84, 69%) and MMR-proficient Lynch syndrome-associated adenomas (13/18, 72%). However, MMR-deficient Lynch syndrome-associated adenomas had less APC or CTNNB1 mutations (25/68, 37%) and frequent frameshift RNF43 mutations involving mononucleotide repeats (45/68, 66%). Furthermore, frameshift mutations affecting repeat sequences constituted 14 of 26 APC mutations (54%) in MMR-deficient adenomas whereas these frameshift mutations were rare in MMR-proficient adenomas in patients with Lynch syndrome (1/12, 8%) and in sporadic adenomas (3/52, 6%). Lynch syndrome-associated adenocarcinomas exhibited mutation profiles similar to those of MMR-deficient adenomas. Considering that WNT pathway activation sufficiently drives colorectal adenoma formation, the distinct mutation profiles of WNT pathway genes in Lynch syndrome-associated adenomas suggest that MMR deficiency commonly precedes adenoma formation.

Familial Gastric Cancers

PubMed Central

Setia, Namrata; Clark, Jeffrey W.; Duda, Dan G.; Hong, Theodore S.; Kwak, Eunice L.; Mullen, John T.

2015-01-01

Although the majority of gastric carcinomas are sporadic, approximately 10% show familial aggregation, and a hereditary cause is determined in 1%–3% cases. Of these, hereditary diffuse gastric cancer is the most recognized predisposition syndrome. Although rare, the less commonly known syndromes also confer a markedly increased risk for development of gastric cancer. Identification and characterization of these syndromes require a multidisciplinary effort involving oncologists, surgeons, genetic counselors, biologists, and pathologists. This article reviews the molecular genetics, clinical and pathologic features, surveillance guidelines, and preventive measures of common and less common hereditary gastric cancer predisposition syndromes. Implications for Practice: Although the majority of gastric adenocarcinomas are sporadic with many of those related to chronic Helicobacter pylori infection, approximately 10% of the cases show familial aggregation, and a specific hereditary cause is determined in 1%–3% cases. This review describes the molecular genetics, clinical and pathologic features, surveillance guidelines, and preventive measures of common and less common hereditary gastric cancer predisposition syndromes. Ultimately, a better understanding of the biology of these conditions should allow early identification and intervention as part of a multidisciplinary approach involving oncologists, surgeons, genetic counselors, and pathologists. PMID:26424758

[Food-borne botulism].

PubMed

Nakamura, Yuko; Sawada, Mikio; Ikeguchi, Kunihiko; Nakano, Imaharu

2012-08-01

Botulism is a neuroparalytic disease caused by neurotoxins produced by Clostridium botulinum, and classically presents as palsies of cranial nerves and acute descending flaccid paralysis. Food-borne botulism is the most common form of botulism, and caused by preformed neurotoxins produced by Clostridium botulinum. Electrophysiological studies play an important role in the early diagnosis. Confirmation of the diagnosis is based on the detection of botulinum toxins in the patient's serum or stool. In Japan, decades ago, botulism type E occurred, though only sporadically, almost every year, but in recent years, has dramatically decreased in frequency. Botulism is a curable disease when treated early and adequately. Differential diagnosis of cranial nerves and limb muscle palsies with rapid exacerbation should include food-borne botulism.

Brainstem and cerebellar cavernous malformations.

PubMed

Atwal, Gursant S; Sarris, Christina E; Spetzler, Robert F

2017-01-01

Cavernous malformations are vascular lesions that occur throughout the central nervous system, most commonly in the supratentorial location, with brainstem and cerebellar cavernous malformations occurring more rarely. Cavernous malformations are associated with developmental venous anomalies that occur sporadically or in familial form. Patients with a cavernous malformation can present with headaches, seizures, sensorimotor disturbances, or focal neurologic deficits based on the anatomic location of the lesion. Patients with infratentorial lesions present more commonly with a focal neurologic deficit. Cavernous malformations are increasingly discovered incidentally due to the increasing use of magnetic resonance imaging. Understanding the natural history of these lesions is essential to their management. Observation and surgical resection are both reasonable options in the treatment of patients with these lesions. The clinical presentation of the patient, the location of the lesion, and the surgical risk assessment all play critical roles in management decision-making. © 2017 Elsevier B.V. All rights reserved.

Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis.

PubMed

Smith, Miriam J; Wallace, Andrew J; Bowers, Naomi L; Rustad, Cecilie F; Woods, C Geoff; Leschziner, Guy D; Ferner, Rosalie E; Evans, D Gareth R

2012-05-01

Mutations of the SMARCB1 gene have been implicated in several human tumour predisposing syndromes. They have recently been identified as an underlying cause of the tumour suppressor syndrome schwannomatosis. There is a much higher rate of mutation detection in familial disease than in sporadic disease. We have carried out extensive genetic testing on a cohort of familial and sporadic patients who fulfilled clinical diagnostic criteria for schwannomatosis. In our current cohort, we identified novel mutations within the SMARCB1 gene and detected several mutations that have been previously identified in other schwannomatosis cohorts. Of the schwannomatosis screens reported to date, including our current dataset, SMARCB1 mutations have been found in 45 % of familial probands and 7 % of sporadic patients. The exon 1 mutation, c.41C >A, and the 3' untranslated region mutation, c.*82C >T, are the most common changes reported in schwannomatosis disease so far, indicating mutation hotspots at both 5' and 3' portions of the gene. SMARCB1 mutations are found in a significant proportion of schwannomatosis patients, but there remains the possibility that further causative genes remain to be found.

Novel aspects in the life cycle and biotrophic interactions in Pezizomycetes (Ascomycota, Fungi).

PubMed

Tedersoo, Leho; Arnold, A Elizabeth; Hansen, Karen

2013-03-01

The ascomycete class Pezizomycetes (single order Pezizales)is known for its cup-shaped fruit bodies and the evolution of edible truffles and morels, but little is known about the ontogeny and ecology of this large and ecologically diverse fungal group. In this issue of Molecular Ecology, Healy et al. (2013) make a great leap forward by describing and identifying asexual, anamorphic structures that produce mitotic spores in many ectomycorrhiza-forming truffle and nontruffle species on soil surfaces worldwide(Fig. 1). Although such anamorphic forms have been reported sporadically from certain ectomycorrhizal and saprotrophic Pezizomycetes (e.g. Warcup 1990), Healy et al. (2013) demonstrate that these terricolous asexual forms are both taxonomically and geographically more widespread and, in fact, much more common than previously understood. We anticipate that deeper insight into other substrates, provided by molecular analyses of materials such as dead wood and seeds, is likely to reveal numerous anamorphs of saprotrophic and pathogenic Pezizomycetes as well (see Marek et al. 2009).

RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis

PubMed Central

Le Masson, Gwendal

2018-01-01

Amyotrophic lateral sclerosis (ALS) is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS. PMID:29342921

RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis.

PubMed

Mathis, Stéphane; Le Masson, Gwendal

2018-01-15

Amyotrophic lateral sclerosis (ALS) is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS.

Specific mutations in the beta-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors.

PubMed

Lazar, Alexander J F; Tuvin, Daniel; Hajibashi, Shohrae; Habeeb, Sultan; Bolshakov, Svetlana; Mayordomo-Aranda, Empar; Warneke, Carla L; Lopez-Terrada, Dolores; Pollock, Raphael E; Lev, Dina

2008-11-01

Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Molecular determinants of desmoid recurrence remain obscure. beta-Catenin deregulation has been commonly identified in sporadic desmoids although the incidence of CTNNB1 (the gene encoding beta-catenin) mutations is uncertain. Consequently, we evaluated the prevalence of CTNNB1 mutations in a large cohort of sporadic desmoids and examined whether mutation type was relevant to desmoid outcome. Desmoid specimens (195 tumors from 160 patients, 1985 to 2005) and control dermal scars were assembled into a clinical data-linked tissue microarray. CTNNB1 genotyping was performed on a 138-sporadic desmoid subset. Immunohistochemical scoring was performed per standard criteria and data were analyzed using Kaplan-Meier and other indicated methods. CTNNB1 mutations were observed in 117 of 138 (85%) of desmoids. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: 41A (59%), 45F (33%), and 45P (8%, excluded from further analysis because of rarity). Five-year recurrence-free survival was significantly poorer in 45F-mutated desmoids (23%, P < 0.0001) versus either 41A (57%) or nonmutated tumors (65%). Nuclear beta-catenin expression was observed in 98% of specimens and intensity was inversely correlated with incidence of desmoid recurrence (P < 0.01). In conclusion, CTNNB1 mutations are highly common in desmoid tumors. Furthermore, patients harboring CTNNB1 (45F) mutations are at particular risk for recurrence and therefore may especially benefit from adjuvant therapeutic approaches.

Observations of peculiar sporadic sodium structures and their relation with wind variations

NASA Astrophysics Data System (ADS)

Sridharan, S.; Prasanth, P. Vishnu; Kumar, Y. Bhavani; Ramkumar, Geetha; Sathishkumar, S.; Raghunath, K.

2009-04-01

Resonance lidar observations of sodium density in the upper mesosphere region over Gadanki (13.5°N, 79.2°E) rarely show complex structures with rapid enhancements of sodium density, completely different from normal sporadic sodium structures. The hourly averaged meteor radar zonal winds over Trivandrum (8.5°N, 76.5°E) show an eastward shear with altitude during the nights, when these events are formed. As suggested by Kane et al. [2001. Joint observations of sodium enhancements and field-aligned ionospheric irregularities. Geophysical Research Letters 28, 1375-1378], our observations show that the complex structures may be formed due to Kelvin-Helmholtz instability, which can occur in the region of strong wind shear.

Genetic instability in inherited and sporadic leukemias.

PubMed

Popp, Henning D; Bohlander, Stefan K

2010-12-01

Genetic instability due to increased DNA damage and altered DNA repair is of central significance in the initiation and progression of inherited and sporadic human leukemias. Although very rare, some inherited DNA repair insufficiency syndromes (e.g., Fanconi anemia, Bloom's syndrome) have added substantially to our understanding of crucial mechanisms of leukemogenesis in recent years. Conversely, sporadic leukemias account for the main proportion of leukemias and here DNA damaging reactive oxygen species (ROS) play a central role. Although the exact mechanisms of increased ROS production remain largely unknown and no single pathway has been detected thus far, some oncogenic proteins (e.g., the activated tyrosine kinases BCR-ABL1 and FLT3-ITD) seem to play a key role in driving genetic instability by increased ROS generation which influences the disease course (e.g., blast crisis in chronic myeloid leukemia or relapse in FLT3-ITD positive acute myeloid leukemia). Of course other mechanisms, which promote genetic instability in leukemia also exist. A newly emerging mechanism is the genome-wide alteration of epigenetic marks (e.g., hypomethylation of histone H3K79), which promotes chromosomal instability. Taken together genetic instability plays a critical role both in inherited and sporadic leukemias and emerges as a common theme in both inherited and sporadic leukemias. Beyond its theoretical impact, the analysis of genetic instability may lead the way to the development of innovative therapy strategies. © 2010 Wiley-Liss, Inc.

Aggressive fibromatosis (desmoid tumors): definition, occurrence, pathology, diagnostic problems, clinical behavior, genetic background.

PubMed

Ferenc, Tomasz; Sygut, Jacek; Kopczyński, Janusz; Mayer, Magdalena; Latos-Bieleńska, Anna; Dziki, Adam; Kulig, Andrzej

2006-01-01

Aggressive fibromatosis, usually called desmoid tumor develops from muscle connective tissue, fasciae and aponeuroses. This neoplasm is composed of spindle (fibrocyte-like) cells. As regards the site, aggressive fibromatoses can be divided into: extra-abdominal in the area of the shoulder and pelvic girdle or chest and neck wall; abdominal in abdominal wall muscles; intra-abdominal concerning pelvis, mesentery connective tissue or retroperitoneal space. Desmoid tumor is a neoplasm which rarely turns malignant and is non-metastasizing but demonstrates ability to local infiltration into tissue and is characterized by high risk of recurrence (25-65%) after surgical treatment. Desmoid tumor etiology is uncertain. This neoplasm occurs in sporadic (idiopathic) form and is also associated with some familial neoplastic syndromes. Most sporadic cases of aggressive fibromatosis contain a somatic mutation in either the adenomatous polyposis coli (APC) or beta-catenin genes. Sporadic tumors are more frequent in women than in men from 2 : 1 to 5 : 1. In about 10-15 per cent of patients with familial adenomatous polyposis (FAP), aggressive fibromatosis is a parenteral manifestation of this familial syndrome conditioned by APC gene mutation. Abdomen injury--most frequently due to surgery is said to play an important role in the initiation of fibrous tissue proliferative process in the cases of abdominal and intra abdominal forms. High cells growth potential with relatively high local malignancy is observed in about 10% of cases with sporadic tumors as well as in those FAP-associated.

Case study of simultaneous observations of sporadic sodium layer, E-region field-aligned irregularities and sporadic E layer at low latitude of China

NASA Astrophysics Data System (ADS)

Xie, H. Y.; Ning, B. Q.; Zhao, X. K.; Hu, L. H.

2017-03-01

Using the Na lidar at Haikou (20.0°N, 110.3°E), the VHF coherent radar and the digital ionosonde both at Sanya (18.4°N, 109.6°E), cases of simultaneous observations of sporadic sodium layer (SSL), E-region field-aligned irregularities (FAI) and sporadic E layer (Es) in the mesosphere and lower thermosphere (MLT) region at low latitude of China are studied. It is found that SSL occurs simultaneously or follows the enhancement of Es and FAI. The Es, FAI and SSL descend slowly with time which is mostly controlled by the diurnal tide (DT). Besides, the interaction of gravity wave (GW) with tides can cause oscillations in FAI and SSL. Our observations support the neutralization of ions for SSL formation: when the metallic ions layer descents to the altitudes where models predict, the sodium ions convert rapidly to atomic Na that may form an SSL event. Moreover, the SSL peak density will increase (decrease) in the convergence (divergence) vertical shear region of zonal wind.

Rates of loss of heterozygosity and mitotic recombination in NF2 schwannomas, sporadic vestibular schwannomas and schwannomatosis schwannomas.

PubMed

Hadfield, K D; Smith, M J; Urquhart, J E; Wallace, A J; Bowers, N L; King, A T; Rutherford, S A; Trump, D; Newman, W G; Evans, D G

2010-11-25

Biallelic inactivation of the NF2 gene occurs in the majority of schwannomas. This usually involves a combination of a point mutation or multiexon deletion, in conjunction with either a second point mutation or loss of heterozygosity (LOH). We have performed DNA sequence and dosage analysis of the NF2 gene in a panel of 239 schwannoma tumours: 97 neurofibromatosis type 2 (NF2)-related schwannomas, 104 sporadic vestibular schwannomas (VS) and 38 schwannomatosis-related schwannomas. In total, we identified germline NF2 mutations in 86 out of 97 (89%) NF2 patients and a second mutational event in 77 out of 97 (79%). LOH was by far the most common form of second hit. A combination of microsatellite analysis with either conventional comparative genomic hybridization (CGH) or multiplex ligation-dependent probe amplification (MLPA) identified mitotic recombination (MR) as the cause of LOH in 14 out of 72 (19%) total evaluable tumours. Among sporadic VS, at least one NF2 mutation was identified by sequence analysis or MLPA in 65 out of 98 (66%) tumours. LOH occurred in 54 out of 96 (56%) evaluable tumours, but MR only accounted for 5 out of 77 (6%) tested. LOH was present in 28 out of 34 (82%) schwannomatosis-related schwannomas. In all eight patients who had previously tested positive for a germline SMARCB1 mutation, this involved loss of the whole, or part of the long arm, of chromosome 22. In contrast, 5 out of 22 (23%) tumours from patients with no germline SMARCB1 mutation exhibited MR. High-resolution Affymetrix SNP6 genotyping and copy number (CN) analysis (Affymetrix, Santa Clara, CA, USA) were used to determine the chromosomal breakpoint locations in tumours with MR. A range of unique recombination sites, spanning approximately 11.4 Mb, were identified. This study shows that MR is a mechanism of LOH in NF2 and SMARCB1-negative schwannomatosis-related schwannomas, occurring less frequently in sporadic VS. We found no evidence of MR in SMARCB1-positive schwannomatosis, suggesting that susceptibility to MR varies according to the disease context.

A novel heterozygous SOX2 mutation causing anophthalmia/microphthalmia with genital anomalies.

PubMed

Pedace, Lucia; Castori, Marco; Binni, Francesco; Pingi, Alberto; Grammatico, Barbara; Scommegna, Salvatore; Majore, Silvia; Grammatico, Paola

2009-01-01

Anophthalmia/microphthalmia is a rare developmental craniofacial defect, which recognizes a wide range of causes, including chromosomal abnormalities, single-gene mutations as well as environmental factors. Heterozygous mutations in the SOX2 gene are the most common monogenic form of anophthalmia/microphthalmia, as they are reported in up to 10-15% cases. Here, we describe a sporadic patient showing bilateral anophthalmia/microphthalmia and micropenis caused by a novel mutation (c.59_60insGG) in the SOX2 gene. Morphological and endocrinological evaluations excluded any anomaly of the hypothalamus-pituitary axis. Our finding supports the hypothesis that SOX2 is particularly prone to slipped-strand mispairing, which results in a high frequency of point deletions/insertions.

Sporadic Burkitt’s lymphoma/acute B-cell leukaemia presenting with progressive proptosis and orbital mass in a child

PubMed Central

Borreggine, Carmela; Ladogana, Saverio; De Santis, Raffaela; Delle Noci, Nicola; Grilli, Gianpaolo; Macarini, Luca

2016-01-01

Burkitt’s lymphoma (BL) is an aggressive B-cell non-Hodgkin lymphoma that is found predominantly in children, with the highest incidence occurring in Africa. The sporadic form occurs in non-endemic areas and typically involves the ileo-caecum and the bowel, whereas orbital and paranasal sinus involvement is rare. Here, we present an unusual case of sporadic BL in a Caucasian male child with rapidly progressive painful proptosis of the right eye. Magnetic resonance imaging showed an oval-shaped, extraconal mass in the supero-lateral part of the right orbit that deformed and dislocated the eyeball antero-inferiorly. The patient underwent anterior orbitotomy, and a biopsy of the excised tissue revealed a starry-sky appearance characteristic of BL. Postoperative aggressive chemotherapy was initiated with a good response after one week. PMID:27006106

Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder

PubMed Central

Zong, Liang; Guan, Jing; Ealy, Megan; Zhang, Qiujing; Wang, Dayong; Wang, Hongyang; Zhao, Yali; Shen, Zhirong; Campbell, Colleen A; Wang, Fengchao; Yang, Ju; Sun, Wei; Lan, Lan; Ding, Dalian; Xie, Linyi; Qi, Yue; Lou, Xin; Huang, Xusheng; Shi, Qiang; Chang, Suhua; Xiong, Wenping; Yin, Zifang; Yu, Ning; Zhao, Hui; Wang, Jun; Wang, Jing; Salvi, Richard J; Petit, Christine; Smith, Richard J H; Wang, Qiuju

2015-01-01

Background Auditory neuropathy spectrum disorder (ANSD) is a form of hearing loss in which auditory signal transmission from the inner ear to the auditory nerve and brain stem is distorted, giving rise to speech perception difficulties beyond that expected for the observed degree of hearing loss. For many cases of ANSD, the underlying molecular pathology and the site of lesion remain unclear. The X-linked form of the condition, AUNX1, has been mapped to Xq23-q27.3, although the causative gene has yet to be identified. Methods We performed whole-exome sequencing on DNA samples from the AUNX1 family and another small phenotypically similar but unrelated ANSD family. Results We identified two missense mutations in AIFM1 in these families: c.1352G>A (p.R451Q) in the AUNX1 family and c.1030C>T (p.L344F) in the second ANSD family. Mutation screening in a large cohort of 3 additional unrelated families and 93 sporadic cases with ANSD identified 9 more missense mutations in AIFM1. Bioinformatics analysis and expression studies support this gene as being causative of ANSD. Conclusions Variants in AIFM1 gene are a common cause of familial and sporadic ANSD and provide insight into the expanded spectrum of AIFM1-associated diseases. The finding of cochlear nerve hypoplasia in some patients was AIFM1-related ANSD implies that MRI may be of value in localising the site of lesion and suggests that cochlea implantation in these patients may have limited success. PMID:25986071

Exon dosage analysis of parkin gene in Chinese sporadic Parkinson's disease.

PubMed

Guo, Ji-Feng; Dong, Xiao-Li; Xu, Qian; Li, Nan; Yan, Xin-Xiang; Xia, Kun; Tang, Bei-Sha

2015-09-14

Parkin gene mutations are by far the most common mutations in both familial Parkinson's disease (PD) and sporadic PD. Approximately, 50% of parkin mutations is exon dosage mutations (i.e., deletions and duplications of entire exons). Here, we first established a MLPA assay for quick detection of parkin exon rearrangements. Then, we studied parkin exon dosage mutations in 755 Chinese sporadic PDdisease patients using the established MLPA assay. We found that there were 25 (3.3%) patients with exon dosage alterations including deletions and duplications, 20 (11.4%) patients with exon rearrangements in 178 early-onset patients, and 5 (0.86%) patients with exon rearrangement mutations in 579 later-onset patients. The percentage of individuals with parkin dosage mutations is more than 33% when the age at onset is less than 30 years old, but less than 7% when the age at onset is more than 30. In these mutations, deletion is the main mutational style, especially in exon 2-5. Our results indicated that exon dosage mutations in parkin gene might be the main cause for sporadic PD, especially in EOP. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Influence of Sporadic E layers on Mesospheric Na and Fe Layers over Arecibo

NASA Astrophysics Data System (ADS)

Raizada, S.; Tepley, C. A.; Zhou, Q.; Sarkhel, S.; Mathews, J. D.; Aponte, N.; Kerr, R.

2014-12-01

Arecibo offers unique opportunity to investigate the structure of the mesospheric metal layers and their response to Sporadic E as observed by the incoherent scatter radar data. Previous studies have shown higher occurrences of sporadic activity in the neutral Fe layers as compared to Na at mid-latitudes. Other studies demonstrated that Sporadic Na (NaS) layers are more common at low and high latitudes as compared to FeS. It is important to note that case studies based on a few nights of observations are significant as they can shed more light on factors that are important on short term scales. These efforts can also help in evaluation of the role played by these factors in the climatological or global studies. In this study, we have used two adjacent nights of simultaneous Na and Fe data obtained using resonance lidars at Arecibo, while the co-located Incoherent Scatter Radar (ISR) provides information about Sporadic E (ES). On both the nights (17 and 18 March 2004) ES was observed with electron densities exceeding 3000 electrons/cc. Some interesting observations are worth noting: The Fe main layer (below 90 km) was stronger than the corresponding sporadic layer around 95 km. However, Na data displayed a weaker main layer below 90 km with stronger NaS activity. Hence, the ratio of densities determined within layers of 3 km thickness centered at 97 km and at 87 km are less than 1 for Fe and exceeds 1 in the case of Na. A correlation analysis between Na/Ne and Fe/Ne also displays dissimilarities in the 94-100 km altitude range. An onsite all-sky imager recorded similar wave activities on both the nights with both ripple and band type structures that were observed in the 557.7 nm airglow. We will discuss the dissimilar response of Na and Fe to Sporadic E activity in relation to neutralization lifetimes of their respective ions and their sensitivity to temperatures.

Transmission of sporadic Creutzfeldt-Jakob disease by blood transfusion: risk factor or possible biases.

PubMed

Puopolo, Maria; Ladogana, Anna; Vetrugno, Vito; Pocchiari, Maurizio

2011-07-01

The occurrence of transfusion transmissions of variant Creutzfeldt-Jakob disease (CJD) cases has reawakened attention to the possible similar risk posed by other forms of CJD. CJD with a definite or probable diagnosis (sporadic CJD, n = 741; genetic CJD, n = 175) and no-CJD patients with definite alternative diagnosis (n = 482) with available blood transfusion history were included in the study. The risk of exposure to blood transfusion occurring more than 10 years before disease onset and for some possible confounding factors was evaluated by calculating crude odds ratios (ORs). Variables with significant ORs in univariate analyses were included in multivariate logistic regression analyses. In the univariate model, blood transfusion occurring more than 10 years before clinical onset is 4.1-fold more frequent in sporadic CJD than in other neurologic disorders. This significance is lost when the 10-year lag time was not considered. Multivariate analyses show that the risk of developing sporadic CJD after transfusion increases (OR, 5.05) after adjusting for possible confounding factors. Analysis conducted on patients with genetic CJD did not reveal any significant risk factor associated with transfusion. This is the first case-control study showing a significant risk of transfusion occurring more than 10 years before clinical onset in sporadic CJD patients. It remains questionable whether the significance of these data is biologically plausible or the consequence of biases in the design of the study, but they counterbalance previous epidemiologic negative reports that might have overestimated the assessment of blood safety in sporadic CJD. © 2010 American Association of Blood Banks.

The influence of PRNP polymorphisms on human prion disease susceptibility: an update.

PubMed

Kobayashi, Atsushi; Teruya, Kenta; Matsuura, Yuichi; Shirai, Tsuyoshi; Nakamura, Yoshikazu; Yamada, Masahito; Mizusawa, Hidehiro; Mohri, Shirou; Kitamoto, Tetsuyuki

2015-08-01

Two normally occurring polymorphisms of the human PRNP gene, methionine (M)/valine (V) at codon 129 and glutamic acid (E)/lysine (K) at codon 219, can affect the susceptibility to prion diseases. It has long been recognized that 129M/M homozygotes are overrepresented in sporadic Creutzfeldt-Jakob disease (CJD) patients and variant CJD patients, whereas 219E/K heterozygotes are absent in sporadic CJD patients. In addition to these pioneering findings, recent progress in experimental transmission studies and worldwide surveillance of prion diseases have identified novel relationships between the PRNP polymorphisms and the prion disease susceptibility. For example, although 219E/K heterozygosity confers resistance against the development of sporadic CJD, this genotype is not entirely protective against acquired forms (iatrogenic CJD and variant CJD) or genetic forms (genetic CJD and Gerstmann-Sträussler-Scheinker syndrome) of prion diseases. In addition, 129M/V heterozygotes predispose to genetic CJD caused by a pathogenic PRNP mutation at codon 180. These findings show that the effects of the PRNP polymorphisms may be more complicated than previously thought. This review aims to summarize recent advances in our knowledge about the influence of the PRNP polymorphisms on the prion disease susceptibility.

Clinical characteristics and PRRT2 gene mutation analysis of sporadic patients with paroxysmal kinesigenic dyskinesia in China.

PubMed

Zhang, Yu; Li, Lin; Chen, Wei; Gan, Jing; Liu, Zhen Guo

2017-08-01

As a rare type of movement disorder, paroxysmal kinesigenic dyskinesia mainly affects children and is associated with PRRT2 gene mutation. The objective of our study is to identify whether the sporadic patients share the same genotype-phenotype correlations as familial patients in China. We investigated the clinical characteristics and PRRT2 gene mutations of 15 sporadic patients with paroxysmal kinesigenic dyskinesia in china. The clinical and investigational data of our patients was recorded and analyzed meticulously. We have summarized the clinical characteristics and PRRT2 gene mutation of Chinese sporadic patients with paroxysmal kinesigenic dyskinesia. Male patients have a high incidence of paroxysmal kinesigenic dyskinesia. The age of onset is between 6 and 16 years (average 10.27±3.43 years; median 10 years) and the course of disease is between 0.3 and 14 years (average 5.95±4.55years; median 6 years). The attack usually begins in childhood or adolescence and diminishing with age. Paroxysmal dystonia on the limbs is the predominant clinical manifestation of our patients. Tremor on two hands might be a common combined symptom. Carbamazepine is an effective drug for our patients. Two variants PRRT2c.412C>G, PRRT2c.439G>C and one mutation PRRT2 c.649dupC was identified in our patients. Genotype-phenotype correlations in sporadic patients with paroxysmal kinesigenic dyskinesia remain unclear in China. Further studies involving larger patients on the clinical characteristics should be carry out. Carbamazepine is the first-choice drug and PRRT2 c.649dupC mutation is a hot-spot mutation in Chinese sporadic patients with paroxysmal kinesigenic dyskinesia. Copyright © 2017 Elsevier B.V. All rights reserved.

Meteoroid Environment Modeling: the Meteoroid Engineering Model and Shower Forecasting

NASA Technical Reports Server (NTRS)

Moorhead, Althea V.

2017-01-01

INTRODUCTION: The meteoroid environment is often divided conceptually into meteor showers and the sporadic meteor background. It is commonly but incorrectly assumed that meteoroid impacts primarily occur during meteor showers; instead, the vast majority of hazardous meteoroids belong to the sporadic complex. Unlike meteor showers, which persist for a few hours to a few weeks, sporadic meteoroids impact the Earth's atmosphere and spacecraft throughout the year. The Meteoroid Environment Office (MEO) has produced two environment models to handle these cases: the Meteoroid Engineering Model (MEM) and an annual meteor shower forecast. The sporadic complex, despite its year-round activity, is not isotropic in its directionality. Instead, their apparent points of origin, or radiants, are organized into groups called "sources". The speed, directionality, and size distribution of these sporadic sources are modeled by the Meteoroid Engineering Model (MEM), which is currently in its second major release version (MEMR2) [Moorhead et al., 2015]. MEM provides the meteoroid flux relative to a user-provided spacecraft trajectory; it provides the total flux as well as the flux per angular bin, speed interval, and on specific surfaces (ram, wake, etc.). Because the sporadic complex dominates the meteoroid flux, MEM is the most appropriate model to use in spacecraft design. Although showers make up a small fraction of the meteoroid environment, they can produce significant short-term enhancements of the meteoroid flux. Thus, it can be valuable to consider showers when assessing risks associated with vehicle operations that are brief in duration. To assist with such assessments, the MEO issues an annual forecast that reports meteor shower fluxes as a function of time and compares showers with the time-averaged total meteoroid flux. This permits missions to do quick assessments of the increase in risk posed by meteor showers.

Localization of a Susceptibility Gene for Familial Nonmedullary Thyroid Carcinoma to Chromosome 2q21

PubMed Central

McKay, James D.; Lesueur, Fabienne; Jonard, Laurence; Pastore, Alessandro; Williamson, Jan; Hoffman, Linda; Burgess, John; Duffield, Anne; Papotti, Mauro; Stark, Markus; Sobol, Hagay; Maes, Béatrice; Murat, Arnaud; Kääriäinen, Helena; Bertholon-Grégoire, Mireille; Zini, Michele; Rossing, Mary Anne; Toubert, Marie-Elisabeth; Bonichon, Françoise; Cavarec, Marie; Bernard, Anne-Marie; Boneu, Andrée; Leprat, Frédéric; Haas, Oskar; Lasset, Christine; Schlumberger, Martin; Canzian, Federico; Goldgar, David E.; Romeo, Giovanni

2001-01-01

The familial form of nonmedullary thyroid carcinoma (NMTC) is a complex genetic disorder characterized by multifocal neoplasia and a higher degree of aggressiveness than its sporadic counterpart. In a large Tasmanian pedigree (Tas1) with recurrence of papillary thyroid carcinoma (PTC), the most common form of NMTC, an extensive genomewide scan revealed a common haplotype on chromosome 2q21 in seven of the eight patients with PTC. To verify the significance of the 2q21 locus, we performed linkage analysis in an independent sample set of 80 pedigrees, yielding a multipoint heterogeneity LOD score (HLOD) of 3.07 (α=0.42), nonparametric linkage (NPL) 3.19, (P=.001) at marker D2S2271. Stratification based on the presence of at least one case of the follicular variant of PTC, the phenotype observed in the Tas1 family, identified 17 such pedigrees, yielding a maximal HLOD score of 4.17 (α=0.80) and NPL=4.99 (P=.00002) at markers AFMa272zg9 and D2S2271, respectively. These results indicate the existence of a susceptibility locus for familial NMTC on chromosome 2q21. PMID:11438887

Drawing Disorders in Alzheimer's Disease and Other Forms of Dementia.

PubMed

Trojano, Luigi; Gainotti, Guido

2016-04-21

Drawing is a multicomponential process that can be impaired by many kinds of brain lesions. Drawing disorders are very common in Alzheimer's disease and other forms of dementia, and can provide clinical information for the distinction of the different dementing diseases. In our review we started from an overview of the neural and cognitive bases of drawing, and from a recollection of the drawing tasks more frequently used for assessing individuals with dementia. Then, we analyzed drawing disorders in dementia, paying special attention to those observed in Alzheimer's disease, from the prodromal stages of the amnesic mild cognitive impairment to the stages of full-blown dementia, both in the sporadic forms with late onset in the entorhino-hippocampal structures and in those with early onset in the posterior neocortical structures. We reviewed the drawing features that could differentiate Alzheimer's disease from vascular dementia and from the most frequent forms of degenerative dementia, namely frontotemporal dementia and Lewy body disease. Finally, we examined some peculiar aspects of drawing disorders in dementia, such as perseverations, rotations, and closing-in. We argue that a careful analysis of drawing errors helps to differentiate the different forms of dementia more than overall accuracy in drawing.

Distinct Histopathologic and Molecular Alterations in Inflammatory Bowel Disease-Associated Intestinal Adenocarcinoma: c-MYC Amplification is Common and Associated with Mucinous/Signet Ring Cell Differentiation.

PubMed

Hartman, Douglas J; Binion, David G; Regueiro, Miguel D; Miller, Caitlyn; Herbst, Cameron; Pai, Reetesh K

2018-05-17

Chronic idiopathic inflammatory bowel disease (IBD) is a significant risk factor for the development of intestinal adenocarcinoma. The underlying molecular alterations in IBD-associated intestinal adenocarcinoma remain largely unknown. We compared the clinicopathologic and molecular features of 35 patients with 47 IBD-associated intestinal adenocarcinomas with a consecutive series of 451 patients with sporadic colorectal carcinoma identified at our institution and published data on sporadic colorectal carcinoma. c-MYC amplification was the most frequent molecular alteration identified in 33% of IBD-associated intestinal adenocarcinoma that is a significantly higher frequency than in sporadic colorectal carcinoma (8%) (P = 0.0001). Compared to sporadic colorectal carcinoma, IBD-associated intestinal adenocarcinomas more frequently demonstrated mucinous differentiation (60% vs 25%, P < 0.001) and signet ring cell differentiation (28% vs 4%, P < 0.001). Mucinous and signet ring cell differentiation were significantly associated with the presence of c-MYC amplification (both with P < 0.05). HER2 positivity (11%), KRAS exon 2 or 3 mutation (10%), and IDH1 mutation (7%) were less commonly observed in IBD-associated intestinal adenocarcinoma. There was an association between poor survival and HER2 status with 3 of 4 patients having HER2-positive adenocarcinoma dead of disease at last clinical follow-up; however, no statistically significant survival effect was identified for any of the molecular alterations identified. We demonstrate that IBD-associated intestinal adenocarcinomas have a high frequency of c-MYC amplification that is associated with mucinous and signet ring cell differentiation. Many of the identified molecular alterations have potential therapeutic relevance, including HER2 amplification, IDH1 mutation, and low frequency KRAS mutation.

Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome).

PubMed

Bresler, Scott C; Padwa, Bonnie L; Granter, Scott R

2016-06-01

Nevoid basal cell carcinoma syndrome, or basal cell nevus syndrome (Gorlin syndrome), is a rare autosomal dominantly inherited disorder that is characterized by development of basal cell carcinomas from a young age. Other distinguishing clinical features are seen in a majority of patients, and include keratocystic odontogenic tumors (formerly odontogenic keratocysts) as well as dyskeratotic palmar and plantar pitting. A range of skeletal and other developmental abnormalities are also often seen. The disorder is caused by defects in hedgehog signaling which result in constitutive pathway activity and tumor cell proliferation. As sporadic basal cell carcinomas also commonly harbor hedgehog pathway aberrations, therapeutic agents targeting key signaling constituents have been developed and tested against advanced sporadically occurring tumors or syndromic disease, leading in 2013 to FDA approval of the first hedgehog pathway-targeted small molecule, vismodegib. The elucidation of the molecular pathogenesis of nevoid basal cell carcinoma syndrome has resulted in further understanding of the most common human malignancy.

Neurofibromatosis type 2.

PubMed

Evans, D G; Sainio, M; Baser, M E

2000-12-01

Neurofibromatosis type 2 is an often devastating autosomal dominant disorder which, until relatively recently, was confused with its more common namesake neurofibromatosis type 1. Subjects who inherit a mutated allele of the NF2 gene inevitably develop schwannomas, affecting particularly the superior vestibular branch of the 8th cranial nerve, usually bilaterally. Meningiomas and other benign central nervous system tumours such as ependymomas are other common features. Much of the morbidity from these tumours results from their treatment. It is now possible to identify the NF2 mutation in most families, although about 20% of apparently sporadic cases are actually mosaic for their mutation. As a classical tumour suppressor, inactivation of the NF2 gene product, merlin/schwannomin, leads to the development of both NF2 associated and sporadic tumours. Merlin/schwannomin associates with proteins at the cell cytoskeleton near the plasma membrane and it inhibits cell proliferation, adhesion, and migration.

[Personal genome research and neurological diseases: overview].

PubMed

Toda, Tatsushi

2013-03-01

Neurological diseases include those caused by a single defective gene,e.g., Huntington's disease, other polyglutamine diseases, and muscular dystrophies, and those that are mostly sporadic but rarely show Mendelian inheritance in some families, e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and epilepsy. The latter diseases are considered polygenic disorders. Both sporadic and Mendelian cases of these diseases are believed to share some common pathological mechanisms. Since the detection of causal genes for the Mendelian cases, studies have been initiated on disease pathology. SNPs and rare gene variants play important roles in common neurological diseases. From a technological perspective, next-generation sequencers have become widely available and have contributed to the advancement of research based on individual genome sequences (personal genome). This paper presents an overview, as well as a historical context, of the contribution of personal genome research to neurological disease studies.

A Tale of Two Cysts: Steatocystoma Multiplex and Eruptive Vellus Hair Cysts-Two Case Reports and a Review of the Literature.

PubMed

Waldemer-Streyer, Rachel J; Jacobsen, Ellen

2017-01-01

Background . Steatocystoma multiplex (SM) and eruptive vellus hair cysts (EVHC) are uncommon benign tumors of the pilosebaceous unit. Both SM and EVHC are characterized by smooth, asymptomatic papules or nodules, most commonly presenting on the chest, limbs, and abdomen. Most cases of SM and EVHC are sporadic, although less common autosomal dominant inherited forms have been reported. Main Observation . In this report we present two cases of cutaneous cysts exhibiting characteristics of either SM or EVHC. Both patients presented with numerous 1-2 mm asymptomatic papules and responded well to surgical expression by incision and drainage (I&D). Conclusion . SM and EVHC are similar in clinical presentation and management. Previously reported "hybrid-type" tumors present strong evidence for a relationship between the two lesions pathologically. Due to potential similarity of EVHC and SM cyst contents, I&D and subsequent microscopic examination cannot definitely differentiate between EVHC, SM, and hybrid cysts.

No genetic effect of {alpha}{sub 1}-antichymotrypsin in Alzheimer disease

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

Haines, J.L.; Pritchard, M.L.; Saunders, A.M.

1996-04-01

Alzheimer disease (AD) is the most common neurodegenerative disorder for individuals over the age of 40.AD has a complex etiology, and it is likely that multiple genes, acting independently and/or interacting, affect the risk of developing AD. Several genes involved with AD have been described already, but only the APOE gene on chromosome 19q has been shown to affect the risk of the common late onset form of AD. {alpha}{sub 1}-Antichymotrypsin (AACT) is a major component of the amyloid plaques found in the brains of AD patients, and an allele in its gene has been proposed to increase the riskmore » of developing AD when also associated with the APOE-4 allele. We have examined the role of this AACT polymorphism in a large set of families and sporadic cases, and do not see any effect, either alone or in combination with the APOE-4 allele. 18 refs., 3 tabs.« less

Immunohistochemical Pitfalls: Common Mistakes in the Evaluation of Lynch Syndrome.

PubMed

Markow, Michael; Chen, Wei; Frankel, Wendy L

2017-12-01

At least 15% of colorectal cancers diagnosed in the United States are deficient in mismatch repair mechanisms. Most of these are sporadic, but approximately 3% of colorectal cancers result from germline alterations in mismatch repair genes and represent Lynch syndrome. It is critical to identify patients with Lynch syndrome to institute appropriate screening and surveillance for patients and their families. Exclusion of Lynch syndrome in sporadic cases is equally important because it reduces anxiety for patients and prevents excessive spending on unnecessary surveillance. Immunohistochemistry is one of the most widely used screening tools for identifying patients with Lynch syndrome. Copyright © 2017 Elsevier Inc. All rights reserved.

[Epidemiology of Leishmania (L.) infantum, L. major and L. killicki in Tunisia: results and analysis of the identification of 226 human and canine isolates].

PubMed

Aoun, K; Amri, F; Chouihi, E; Haouas, N; Bedoui, K; Benikhlef, R; Ghrab, J; Babba, H; Chahed, M K; Harrat, Z; Bouratbine, A

2008-10-01

The epidemiological situation of leishmaniasis in Tunisia is characterised by the co-existence in a very limited territory (165,000 km2, Sahara included), of 4 clinical forms: the infantile visceral leishmaniasis (VL) and 3 cutaneous leishmaniasis (CL) forms (sporadic, zoonotic and chronic). In addition to the useful epidemiological data, identification of the causative parasitic species is essential to determine the geographic distribution of each form and to select appropriate therapeutic procedure and suitable control measures. 226 Leishmania isolates, 135 human's coming from 59 VL cases and 76 CL cases and 91 canine's were identified by the isoenzyme electrophoresis reference technique. Results confirm the endemicity of the 4 forms mentioned above. The sporadic CL, confined to the North of the country is principally caused by L. infantum MON-24 (72.2%). VL which has reached the southern ridge in the central area of Tunisia, in the governorate of Kairouan (36 typed isolates), presents an unusual high proportion of L. infantum MON-24. In fact, this zymodeme, rather dermotropic is responsible for 47.2% of the cases vs 13% in the other regions of the country where L. infantum MON-1 remains predominant with 78.3% of typed isolates, the difference being statistically significant (P < 0.01). A third zymodeme, L. infantum MON-80 is sporadically pointed out during VL or in sporadic CL. Despite the high number of canine isolates (n=91) coming from 6 governorates, only the zymodeme L. infantum MON-1 was identified, letting hypothetic the reservoir of the 2 other zymodemes of the species identified in humans. Those absences may be related to cross infections, with a low sensitivity to L. infantum MON-24 leading to a selection of MON-1 at the time of culture passages. Hence it is important to develop molecular tools of direct identification on initial biological samples without going through cultures. Zoonotic CL remains the predominant cutaneous form in the central and southern area of Tunisia. However L. killicki, agent of the chronic CL, is confirming its presence out of its original focus of Tataouine in the southern-east of the country in both zoonotic CL and VL areas.

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer

PubMed Central

Forsberg, Lars A.; Rasi, Chiara; Pekar, Gyula; Davies, Hanna; Piotrowski, Arkadiusz; Absher, Devin; Razzaghian, Hamid Reza; Ambicka, Aleksandra; Halaszka, Krzysztof; Przewoźnik, Marcin; Kruczak, Anna; Mandava, Geeta; Pasupulati, Saichand; Hacker, Julia; Prakash, K. Reddy; Dasari, Ravi Chandra; Lau, Joey; Penagos-Tafurt, Nelly; Olofsson, Helena M.; Hallberg, Gunilla; Skotnicki, Piotr; Mituś, Jerzy; Skokowski, Jaroslaw; Jankowski, Michal; Śrutek, Ewa; Zegarski, Wojciech; Tiensuu Janson, Eva; Ryś, Janusz; Tot, Tibor; Dumanski, Jan P.

2015-01-01

Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1–14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer. PMID:26430163

Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer's disease.

PubMed

Grimm, Amandine; Friedland, Kristina; Eckert, Anne

2016-04-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease that represents the most common form of dementia among the elderly. Despite the fact that AD was studied for decades, the underlying mechanisms that trigger this neuropathology remain unresolved. Since the onset of cognitive deficits occurs generally within the 6th decade of life, except in rare familial case, advancing age is the greatest known risk factor for AD. To unravel the pathogenesis of the disease, numerous studies use cellular and animal models based on genetic mutations found in rare early onset familial AD (FAD) cases that represent less than 1 % of AD patients. However, the underlying process that leads to FAD appears to be distinct from that which results in late-onset AD. As a genetic disorder, FAD clearly is a consequence of malfunctioning/mutated genes, while late-onset AD is more likely due to a gradual accumulation of age-related malfunction. Normal aging and AD are both marked by defects in brain metabolism and increased oxidative stress, albeit to varying degrees. Mitochondria are involved in these two phenomena by controlling cellular bioenergetics and redox homeostasis. In the present review, we compare the common features observed in both brain aging and AD, placing mitochondrial in the center of pathological events that separate normal and pathological aging. We emphasize a bioenergetic model for AD including the inverse Warburg hypothesis which postulates that AD is a consequence of mitochondrial deregulation leading to metabolic reprogramming as an initial attempt to maintain neuronal integrity. After the failure of this compensatory mechanism, bioenergetic deficits may lead to neuronal death and dementia. Thus, mitochondrial dysfunction may represent the missing link between aging and sporadic AD, and represent attractive targets against neurodegeneration.

Spinocerebellar ataxia type 12 identified in two Italian families may mimic sporadic ataxia.

PubMed

Brussino, Alessandro; Graziano, Claudio; Giobbe, Dario; Ferrone, Marina; Dragone, Elisa; Arduino, Carlo; Lodi, Raffaele; Tonon, Caterina; Gabellini, Anna; Rinaldi, Rita; Miccoli, Sara; Grosso, Enrico; Bellati, Maria Cristina; Orsi, Laura; Migone, Nicola; Brusco, Alfredo

2010-07-15

SCA12 is an autosomal dominant cerebellar ataxia characterized by onset in the fourth decade of life with action tremor of arms and head, mild ataxia, dysmetria, and hyperreflexia. The disease is caused by an expansion of >or=51 CAGs in the 5' region of the brain- specific phosphatase 2 regulatory subunit B-beta isoform (PPP2R2B) gene. SCA12 is very rare, except for a single ethnic group in India. We screened 159 Italian ataxic patients for SCA12 and identified two families that segregated an expanded allele of 57 to 58 CAGs, sharing a common haplotype. The age at onset, phenotype, and variability of symptoms were compatible with known cases. In one family, the disease was apparently sporadic due to possible incomplete penetrance and/or late age at onset. Our data indicate that SCA12 is also present in Italian patients, and its genetic testing should be applied to both sporadic and familial ataxias.

Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease.

PubMed

Hook, Paul W; McClymont, Sarah A; Cannon, Gabrielle H; Law, William D; Morton, A Jennifer; Goff, Loyal A; McCallion, Andrew S

2018-03-01

Genetic variation modulating risk of sporadic Parkinson disease (PD) has been primarily explored through genome-wide association studies (GWASs). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal time points. These data facilitated unbiased identification of DA neuron subpopulations through their unique transcriptional profiles, including a postnatal neuroblast population and substantia nigra (SN) DA neurons. We use these population-specific data to develop a scoring system to prioritize candidate genes in all 49 GWAS intervals implicated in PD risk, including genes with known PD associations and many with extensive supporting literature. As proof of principle, we confirm that the nigrostriatal pathway is compromised in Cplx1-null mice. Ultimately, this systematic approach establishes biologically pertinent candidates and testable hypotheses for sporadic PD, informing a new era of PD genetic research. Copyright © 2018 American Society of Human Genetics. All rights reserved.

Patterns of Weakness, Classification of Motor Neuron Disease & Clinical Diagnosis of Sporadic ALS

PubMed Central

Statland, Jeffrey M.; Barohn, Richard J.; McVey, April L.; Katz, Jonathan; Dimachkie, Mazen M.

2015-01-01

Synopsis When approaching the patient with suspected motor neuron disease (MND) the pattern of weakness on exam helps distinguish MND from other diseases of peripheral nerves, the neuromuscular junction, or muscle. MND is a clinical diagnosis supported by findings on electrodiagnostic testing, in the absence of other abnormalities on neuroimaging or serological testing. MNDs exist on a spectrum: from a pure lower motor neuron; to mixed upper and lower motor neuron; to a pure upper motor neuron variant in addition to regional variants restricted to the arms, legs or bulbar region. Amyotrophic lateral sclerosis (ALS) is a progressive mixed upper and lower motor neuron disorder, most commonly sporadic (~85%), which is invariably fatal. The only FDA approved treatments for ALS are riluzole, which prolongs life by about 3 months, and dextromethorphan/quinidine which provides symptomatic relief for pseudobulbar affect (inappropriate bouts of laughter or crying). Here we describe a pattern approach to identifying motor neuron disease, and clinical features of sporadic ALS. PMID:26515618

What lysosomes actually tell us about Parkinson's disease?

PubMed

Bourdenx, Mathieu; Dehay, Benjamin

2016-12-01

Parkinson's disease is a common neurodegenerative disorder of unknown origin mainly characterized by the loss of neuromelanin-containing dopaminergic neurons in the substantia nigra pars compacta and the presence of intraneuronal proteinaceous inclusions called Lewy bodies. Lysosomes are dynamic organelles that degrade, in a controlled manner, cellular components delivered via the secretory, endocytic, autophagic and phagocytic membrane-trafficking pathways. Increasing amounts of evidence suggest a central role of lysosomal impairment in PD aetiology. This review provides an update on how genetic evidence support this connection and highlights how the neuropathologic and mechanistic evidence might relate to the disease process in sporadic forms of Parkinson's disease. Finally, we discuss the influence of ageing on lysosomal impairment and PD aetiology and therapeutic strategies targeting lysosomal function. Copyright © 2016 Elsevier B.V. All rights reserved.

A rapid analysis of water for anatoxin a, the unstable toxic alkaloid from Anabaena flos-aquae, the stable non-toxic alkaloids left after bioreduction and a related amine which may be nature's precursor to anatoxin a.

PubMed

Smith, R A; Lewis, D

1987-04-01

Poisoning of animals by Anabaena Flos-Aquae alkaloid is a common, but sporadic event (1). Anatoxin A is the toxic principle responsible for acute fatalities (2), and tends to disappear along with the toxicity within a few days of the event, thus complicating diagnosis. This report reveals our simplified analytical methodology for Anatoxin A (2-acetyl-9-azabicyclo[4.2.1] non-2,3-ene), for the non-toxic compounds into which it bioreduces, the chair and boat forms of 2-acetyl-9-azabicyclo[4.2.1] nonane, and for an as yet uncharacterized amine C10H15N.

Different Angiogenic Potential in Low and High Grade Sporadic Clear Cell Renal Cell Carcinoma Is Not Related to Alterations in the von Hippel–Lindau Gene

PubMed Central

Baldewijns, Marcella M.; van Vlodrop, Iris J. H.; Smits, Kim M.; Vermeulen, Peter B.; Van den Eynden, Gert G.; Schot, Fiona; Roskams, Tania; van Poppel, Hein; van Engeland, Manon; de Bruïne, Adriaan P.

2009-01-01

Background: von Hippel–Lindau (VHL) inactivation is common in sporadic clear cell renal cell carcinomas (ccRCC). pVHL is part of the ubiquitin ligase complex that targets the alpha subunits of hypoxia-inducible transcription factor (HIF) for degradation under well-oxygenated conditions. In the absence of wild-type pVHL, as observed in VHL patients and most sporadic ccRCCs, constitutive upregulation of HIF results in transcriptional activation of angiogenesis-related genes, such as VEGF. Differences in angiogenic activity within the group of ccRCCs were reported and strong genotype-phenotype correlations were found in patients with VHL disease, raising a question about the importance of VHL inactivation status in angiogenic behaviour and tumour progression. Methods: To address this question, we investigated the influence of VHL mutation (direct sequencing)/hypermethylation (methylation-specific PCR) on angiogenesis/tumour parameters (immunohistochemistry) in 150 patients with sporadic ccRCC. Results: We found no significant association between VHL mutation or methylation and angiogenesis/tumour parameters. Conclusions: These data indicate that tumour progression and angiogenesis are not directly influenced by VHL alterations and that additional genetic/epigenetic events should be considered to explain the diverse angiogenic and proliferative behaviour during tumour progression. PMID:19759417

Solid-state NMR studies of metal-free SOD1 fibrillar structures.

PubMed

Banci, Lucia; Blaževitš, Olga; Cantini, Francesca; Danielsson, Jens; Lang, Lisa; Luchinat, Claudio; Mao, Jiafei; Oliveberg, Mikael; Ravera, Enrico

2014-06-01

Copper-zinc superoxide dismutase 1 (SOD1) is present in the protein aggregates deposited in motor neurons of amyotrophic lateral sclerosis (ALS) patients. ALS is a neurodegenerative disease that can be either sporadic (ca. 90%) or familial (fALS). The most widely studied forms of fALS are caused by mutations in the sequence of SOD1. Ex mortuo SOD1 aggregates are usually found to be amorphous. In vitro SOD1, in its immature reduced and apo state, forms fibrillar aggregates. Previous literature data have suggested that a monomeric SOD1 construct, lacking loops IV and VII, (apoSODΔIV-VII), shares the same fibrillization properties of apoSOD1, both proteins having the common structural feature of the central β-barrel. In this work, we show that structural information can be obtained at a site-specific level from solid-state NMR. The residues that are sequentially assignable are found to be located at the putative nucleation site for fibrillar species formation in apoSOD, as detected by other experimental techniques.

Dopamine-dependent neurodegeneration in Drosophila models of familial and sporadic Parkinson's disease.

PubMed

Bayersdorfer, Florian; Voigt, Aaron; Schneuwly, Stephan; Botella, José A

2010-10-01

Parkinson's disease has been found to be caused by both, genetic and environmental factors. Despite the diversity of causes involved, a convergent pathogenic mechanism might underlie the special vulnerability of dopaminergic neurons in different forms of Parkinsonism. In recent years, a number of reports have proposed dopamine as a common player responsible in the loss of dopaminergic neurons independent of its etiology. Using RNAi lines we were able to generate flies with drastically reduced dopamine levels in the dopaminergic neurons. Combining these flies with a chemically induced Parkinson model (rotenone) and a familial form of Parkinson (mutant alpha-synuclein) we were able to show a strong reduction of neurotoxicity and a protection of the dopaminergic neurons when cellular dopamine levels were reduced. These results show that dopamine homeostasis plays a central role for the susceptibility of dopaminergic neurons to environmental and genetic factors in in vivo models of Parkinson disease. (c) 2010 Elsevier Inc. All rights reserved.

[Hepatitis E: a Third World's hepatitis found in Belgium].

PubMed

Seivert, M; Belaiche, J; Delwaide, J

2008-09-01

Hepatitis E virus is the second cause of acute viral hepatitis of oral-fecal origin in the world. This virus has a vast distribution throughout the world and manifests itself either in epidemic or endemic-sporadic form in many developing countries. Usually, the cases of HEV infection in industrialized countries are observed after a history of travel in an endemic area. However, an increasing number of cases have been attributed to a HEV zoonotic form transmitted by swine. HEV infection can lead to deadly fulminant hepatic failure in 1-4% in the common population, but the mortality incidence reaches 20% in case of third trimester pregnant women infection. The diagnosis of HEV infection can be made using serological tests but today, RT-PCR is considered as the gold standard test. Unfortunately, this technique is not widely available in Belgium yet. There is no treatment for HEV infection, only prophylactic measures as hygiene and sewage treatment can stop epidemics. Recently, a new vaccine, still in research phase, has showed promising outcomes.

Giardiasis in NSW: Identification of Giardia duodenalis assemblages contributing to human and cattle cases, and an epidemiological assessment of sporadic human giardiasis.

PubMed

Asher, A J; Hose, G; Power, M L

2016-10-01

Two genetic assemblages (A and B) of the protozoan parasite species, Giardia duodenalis, infect humans, domestic animals and wildlife. In New South Wales, Australia, over 2000 sporadic human giardiasis cases are reported annually, but parasite sources and links between sporadic cases are unknown. This study describes G. duodenalis assemblages contributing to human and cattle cases in NSW, and examines demographic, spatial, and temporal distributions of NSW human infections and G. duodenalis assemblages. Genotyping by PCR-restriction fragment length polymorphism of the glutamate dehydrogenase (gdh) gene identified G. duodenalis assemblage B as the most common (86%) cause of infection among human cases (n=165). Approximately 37% of cattle DNA samples were PCR positive (18S rRNA, gdh), and G. duodenalis assemblages E (69%) or B (31%) were identified from these samples. Human assemblage A was more common among older age groups, and seasonality in the geographic dispersal of human assemblage A was observed. The results of this study indicate G. duodenalis assemblage B is highly prevalent among humans in NSW, and the potential for cross-species transmission exists between humans and cattle in this region. Spatio-temporal and demographic distributions of human assemblage A and B are highlighted, and risk factors associated with these dispersal patterns warrants further research. Copyright © 2016 Elsevier B.V. All rights reserved.

Caspase-6 Activation in Familial Alzheimer Disease Brains Carrying Amyloid Precursor Protein, Presenilin I or Presenilin II Mutations

PubMed Central

Albrecht, Steffen; Bogdanovic, Nenad; Ghetti, Bernardino; Winblad, Bengt; LeBlanc, Andréa C.

2010-01-01

We previously demonstrated the activation of Caspase-6 in the hippocampus and cortex in cases of mild, moderate, severe and very severe Alzheimer disease (AD). To determine whether Caspase-6 is also activated in familial AD, we performed an immunohistochemical analysis of active Caspase-6 and Tau cleaved by Caspase-6 in temporal cortex and hippocampal tissue sections from cases of familial AD. The cases included 5 carrying the amyloid precursor protein K670N, M671L Swedish mutation, 1 carrying the amyloid precursor protein E693G Arctic mutation, 2 each carrying the Presenilin I M146V, F105L, A431E, V261F, Y115C mutations, and 1 with the Presenilin II N141I mutation. Active Caspase-6 immunoreactivity was found in all cases. Caspase-6 immunoreactivity was observed in neuritic plaques or cotton wool plaques in some cases, neuropil threads and neurofibrillary tangles. These results indicate that Caspase-6 is activated in familial forms of AD, as previously observed in sporadic forms. Since sporadic and familial AD cases have similar pathological features, these results support a fundamental role of Caspase-6 in the pathophysiology of both familial and sporadic AD. PMID:19915487

Microvascular Pathology and Morphometrics of Sporadic and Hereditary Small Vessel Diseases of the Brain

PubMed Central

Craggs, Lucinda JL; Yamamoto, Yumi; Deramecourt, Vincent; Kalaria, Raj N

2014-01-01

Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology. PMID:25323665

Six cases of sporadic schwannomatosis: Topographic distribution and outcomes of peripheral nerve tumors.

PubMed

Chick, G; Victor, J; Hollevoet, N

2017-10-01

The diagnosis of schwannomatosis is often overestimated and is based on the existence of multiple peripheral nerve tumors composed exclusively of schwannomas, in the absence of clinical signs of neurofibromatosis type 2 (NF2). Sporadic forms are much more frequent than familial forms. The objective of this study was to describe the distribution of peripheral nerve tumors and investigate the outcomes of schwannomas in the context of sporadic schwannomatosis. We conducted a retrospective study of patients who fulfilled clinical diagnostic criteria for sporadic schwannomatosis. Six patients were reviewed with a mean follow-up of 38.5months (27-60months). Patients' demographic, clinical, radiographic, and pathologic data were extracted. All patients underwent slit-lamp examination, enhanced brain magnetic resonance imaging (MRI) and a spinal MRI. Enucleation that preserved nerve continuity was performed in symptomatic patients. On average, patients were 36years of age at the time of diagnosis with no sex predominance. The topographic distribution of the peripheral nerve tumors was always unilateral and most frequently targeted the upper limb. In four cases, the tumors involved the same peripheral nerve exclusively. The average number of nerve tumors observed per patient was 4.7 (2-8). The outcome after enucleation was marked by the systematic appearance of new tumors. After enucleation, no recurrence or malignant transformation was observed at the final follow-up. There was no transition to a NF2 configuration. The absence of neurofibroma and NF2 criteria makes schwannomatosis a diagnosis of exclusion. While a good prognosis can be expected following enucleation, two risks related to neurofibromatosis type 3 (NF3) are worth monitoring: the transition to NF2, particularly in young patients, and the appearance of new tumors. Copyright © 2017 SFCM. Published by Elsevier Masson SAS. All rights reserved.

Familial Paroxysmal Exercise-Induced Dystonia: Atypical Presentation of Autosomal Dominant GTP-Cyclohydrolase 1 Deficiency

ERIC Educational Resources Information Center

Dale, Russell C.; Melchers, Anna; Fung, Victor S. C.; Grattan-Smith, Padraic; Houlden, Henry; Earl, John

2010-01-01

Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced…

High genotypic and phenotypic similarity among Shiga toxin-producing Escherichia coli O111 environmental and outbreak strains.

PubMed

Diodati, Michelle E; Bates, Anne H; Cooley, Michael B; Walker, Samarpita; Mandrell, Robert E; Brandl, Maria T

2015-03-01

Escherichia coli serogroup O111 is among the six most commonly reported non-O157:H7 Shiga toxin-producing E. coli (STEC), which are emerging as important foodborne pathogens. We have assembled a collection of environmental and clinical strains of E. coli O111 from diverse sources and investigated various genotypic and phenotypic characteristics of these strains to gain a better understanding of the epidemiology and biology of this serogroup. Sixty-three percent of the strains (24/38) were of H-type 8, which dominated the environmental- and outbreak-strains group, whereas the sporadic-case strains were more heterogeneous in H-type. All of the environmental and outbreak strains harbored the Shiga toxin 1 gene (stx1), eae, and ehx, and a subset of these also carried the Shiga toxin 2 gene (stx2). Only 9 of 16 sporadic-case strains produced stx1 and/or stx2, and these were mostly of H-type 8 and 10. Pulsed-field gel electrophoresis analysis revealed a cluster of environmental, outbreak, and sporadic illness strains with high phylogenetic similarity. Strains in this pulsogroup were all of the H8 type and STEC pathotype, and carried eae and ehx. Smaller clusters of highly similar STEC O111 strains included outbreak and sporadic illness strains isolated during different time periods or from different geographical locations. A distinct aggregative behavior was observed in the cultures of all environmental and outbreak STEC O111 strains, but not in those of sporadic-case strains. Among environmental and outbreaks strains, aggregation was positively correlated with production of curli fimbriae and RpoS function, and negatively with cellulose synthesis, while the nonaggregative behavior of sporadic-case strains correlated (positively) only with cellulose production. Our results indicate that STEC O111 strains sharing high genotypic similarity and important phenotypic traits with STEC O111 outbreak strains are present in the agricultural environment and may contribute to the burden of foodborne disease.

Meteoroid Environment Modeling: The Meteoroid Engineering Model and Shower Forecasting

NASA Technical Reports Server (NTRS)

Moorhead, Althea V.

2017-01-01

The meteoroid environment is often divided conceptually into meteor showers and the sporadic meteor background. It is commonly but incorrectly assumed that meteoroid impacts primarily occur during meteor showers; instead, the vast majority of hazardous meteoroids belong to the sporadic complex. Unlike meteor showers, which persist for a few hours to a few weeks, sporadic meteoroids impact the Earth's atmosphere and spacecraft throughout the year. The Meteoroid Environment Office (MEO) has produced two environment models to handle these cases: the Meteoroid Engineering Model (MEM) and an annual meteor shower forecast. The sporadic complex, despite its year-round activity, is not isotropic in its directionality. Instead, their apparent points of origin, or radiants, are organized into groups called "sources". The speed, directionality, and size distribution of these sporadic sources are modeled by the Meteoroid Engineering Model (MEM), which is currently in its second major release version (MEMR2) [Moorhead et al., 2015]. MEM provides the meteoroid flux relative to a user-provided spacecraft trajectory; it provides the total flux as well as the flux per angular bin, speed interval, and on specific surfaces (ram, wake, etc.). Because the sporadic complex dominates the meteoroid flux, MEM is the most appropriate model to use in spacecraft design. Although showers make up a small fraction of the meteoroid environment, they can produce significant short-term enhancements of the meteoroid flux. Thus, it can be valuable to consider showers when assessing risks associated with vehicle operations that are brief in duration. To assist with such assessments, the MEO issues an annual forecast that reports meteor shower fluxes as a function of time and compares showers with the time-averaged total meteoroid flux. This permits missions to do quick assessments of the increase in risk posed by meteor showers. Section II describes MEM in more detail and describes our current efforts to improve its characteristics for a future release. Section III describes the annual shower forecast and highlights recent improvements made to its algorithm and inputs.

A Case for Microtubule Vulnerability in Amyotrophic Lateral Sclerosis: Altered Dynamics During Disease.

PubMed

Clark, Jayden A; Yeaman, Elise J; Blizzard, Catherine A; Chuckowree, Jyoti A; Dickson, Tracey C

2016-01-01

Amyotrophic lateral sclerosis (ALS) is an aggressive multifactorial disease converging on a common pathology: the degeneration of motor neurons (MNs), their axons and neuromuscular synapses. This vulnerability and dysfunction of MNs highlights the dependency of these large cells on their intracellular machinery. Neuronal microtubules (MTs) are intracellular structures that facilitate a myriad of vital neuronal functions, including activity dependent axonal transport. In ALS, it is becoming increasingly apparent that MTs are likely to be a critical component of this disease. Not only are disruptions in this intracellular machinery present in the vast majority of seemingly sporadic cases, recent research has revealed that mutation to a microtubule protein, the tubulin isoform TUBA4A, is sufficient to cause a familial, albeit rare, form of disease. In both sporadic and familial disease, studies have provided evidence that microtubule mediated deficits in axonal transport are the tipping point for MN survivability. Axonal transport deficits would lead to abnormal mitochondrial recycling, decreased vesicle and mRNA transport and limited signaling of key survival factors from the neurons peripheral synapses, causing the characteristic peripheral "die back". This disruption to microtubule dependant transport in ALS has been shown to result from alterations in the phenomenon of microtubule dynamic instability: the rapid growth and shrinkage of microtubule polymers. This is accomplished primarily due to aberrant alterations to microtubule associated proteins (MAPs) that regulate microtubule stability. Indeed, the current literature would argue that microtubule stability, particularly alterations in their dynamics, may be the initial driving force behind many familial and sporadic insults in ALS. Pharmacological stabilization of the microtubule network offers an attractive therapeutic strategy in ALS; indeed it has shown promise in many neurological disorders, ALS included. However, the pathophysiological involvement of MTs and their functions is still poorly understood in ALS. Future investigations will hopefully uncover further therapeutic targets that may aid in combating this awful disease.

Glucose-6-phosphate dehydrogenase deficiency and Alzheimer's disease: Partners in crime? The hypothesis.

PubMed

Ulusu, N Nuray

2015-08-01

Alzheimer's disease is a multifaceted brain disorder which involves various coupled irreversible, progressive biochemical reactions that significantly reduce quality of life as well as the actual life expectancy. Aging, genetic predispositions, head trauma, diabetes, cardiovascular disease, deficiencies in insulin signaling, dysfunction of mitochondria-associated membranes, cerebrovascular changes, high cholesterol level, increased oxidative stress and free radical formation, DNA damage, disturbed energy metabolism, and synaptic dysfunction, high blood pressure, obesity, dietary habits, exercise, social engagement, and mental stress are noted among the risk factors of this disease. In this hypothesis review I would like to draw the attention on glucose-6-phosphate dehydrogenase deficiency and its relationship with Alzheimer's disease. This enzymopathy is the most common human congenital defect of metabolism and defined by decrease in NADPH+H(+) and reduced form of glutathione concentration and that might in turn, amplify oxidative stress due to essentiality of the enzyme. This most common enzymopathy may manifest itself in severe forms, however most of the individuals with this deficiency are not essentially symptomatic. To understand the sporadic Alzheimer's disease, the writer of this paper thinks that, looking into a crystal ball might not yield much of a benefit but glucose-6-phosphate dehydrogenase deficiency could effortlessly give some clues. Copyright © 2015 Elsevier Ltd. All rights reserved.

Clinical endpoints for developing pharmaceuticals to manage patients with sporadic or genetic risk of colorectal cancer

PubMed Central

Rial, Nathaniel S.; Zell, Jason A.; Cohen, Alfred M.; Gerner, Eugene W.

2013-01-01

To reduce the morbidity and mortality from colorectal cancer, current clinical practice focuses on screening for early detection and polypectomy as a form of secondary prevention, complemented with surgical interventions when appropriate. No pharmaceutical agent is currently approved for use in clinical practice for the management of patients with risk of colorectal cancer. This article will review earlier attempts to develop pharmaceuticals for use in managing patients with sporadic or genetic risk of colorectal cancer. It will also discuss therapeutic endpoints under evaluation in current efforts to develop drugs for treating colorectal cancer risk factors. PMID:22928902

Polyradiculopathies from schwannomatosis.

PubMed

Jia, Yuxia; Kraus, James A; Reddy, Hasini; Groff, Michael; Wong, Eric T

2011-01-01

We describe a case of schwannomatosis presenting as radicular pain and numbness in multiple radicular nerve distributions. There were multiple peripheral nerve tumors detected by magnetic resonance imaging (MRI) at the left vestibular nerve, cauda equina, right radial nerve, thoracic paraspinal nerve, and brachial plexi. Several resected tumors have features of schwannomas, including hypercellular Antoni A areas, hypocellular Antoni B areas, Verocay bodies, and hyalinized blood vessels. The specimens are also positive for immunohistochemical staining for INI1 with diffuse nuclear staining. The findings are consistent with sporadic form of schwannomatosis. This case highlights the importance of using MRI and INI1 immunohistochemistry to differentiate familial schwannomatosis, neurofibromatosis 2 (NF2)-associated schwannomatosis, and sporadic schwannomatosis.

Neurofibromatosis type 2

PubMed Central

Evans, D; Sainio, M; Baser, M.

2000-01-01

Neurofibromatosis type 2 is an often devastating autosomal dominant disorder which, until relatively recently, was confused with its more common namesake neurofibromatosis type 1. Subjects who inherit a mutated allele of the NF2 gene inevitably develop schwannomas, affecting particularly the superior vestibular branch of the 8th cranial nerve, usually bilaterally. Meningiomas and other benign central nervous system tumours such as ependymomas are other common features. Much of the morbidity from these tumours results from their treatment. It is now possible to identify the NF2 mutation in most families, although about 20% of apparently sporadic cases are actually mosaic for their mutation. As a classical tumour suppressor, inactivation of the NF2 gene product, merlin/schwannomin, leads to the development of both NF2 associated and sporadic tumours. Merlin/schwannomin associates with proteins at the cell cytoskeleton near the plasma membrane and it inhibits cell proliferation, adhesion, and migration.


Keywords: NF2; vestibular schwannomma; meningioma; mosaic PMID:11106352

Absence of Evidence for a Causal Link between Bovine Spongiform Encephalopathy Strain Variant L-BSE and Known Forms of Sporadic Creutzfeldt-Jakob Disease in Human PrP Transgenic Mice.

PubMed

Jaumain, Emilie; Quadrio, Isabelle; Herzog, Laetitia; Reine, Fabienne; Rezaei, Human; Andréoletti, Olivier; Laude, Hubert; Perret-Liaudet, Armand; Haïk, Stéphane; Béringue, Vincent

2016-12-01

Prions are proteinaceous pathogens responsible for subacute spongiform encephalopathies in animals and humans. The prions responsible for bovine spongiform encephalopathy (BSE) are zoonotic agents, causing variant Creutzfeldt-Jakob disease (CJD) in humans. The transfer of prions between species is limited by a species barrier, which is thought to reflect structural incompatibilities between the host cellular prion protein (PrP C ) and the infecting pathological PrP assemblies (PrP Sc ) constituting the prion. A BSE strain variant, designated L-BSE and responsible for atypical, supposedly spontaneous forms of prion diseases in aged cattle, demonstrates zoonotic potential, as evidenced by its capacity to propagate more easily than classical BSE in transgenic mice expressing human PrP C and in nonhuman primates. In humanized mice, L-BSE propagates without any apparent species barrier and shares similar biochemical PrP Sc signatures with the CJD subtype designated MM2-cortical, thus opening the possibility that certain CJD cases classified as sporadic may actually originate from L-type BSE cross-transmission. To address this issue, we compared the biological properties of L-BSE and those of a panel of CJD subtypes representative of the human prion strain diversity using standard strain-typing criteria in human PrP transgenic mice. We found no evidence that L-BSE causes a known form of sporadic CJD. Since the quasi-extinction of classical BSE, atypical BSE forms are the sole BSE variants circulating in cattle worldwide. They are observed in rare cases of old cattle, making them difficult to detect. Extrapolation of our results suggests that L-BSE may propagate in humans as an unrecognized form of CJD, and we urge both the continued utilization of precautionary measures to eliminate these agents from the human food chain and active surveillance for CJD phenotypes in the general population. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Histological variations in juvenile polyp phenotype correlate with genetic defect underlying juvenile polyposis

PubMed Central

van Hattem, W. Arnout; Langeveld, Danielle; de Leng, Wendy W. J.; Morsink, Folkert H.; van Diest, Paul J.; Iacobuzio-Donahue, Christine A.; Giardiello, Francis M.; Offerhaus, G. Johan A.; Brosens, Lodewijk A. A.

2011-01-01

Background Juvenile polyps are distinct hamartomatous malformations of the gastrointestinal tract that may occur in the heritable juvenile polyposis syndrome (JPS) or sporadically. Histologically, juvenile polyps are characterised by a marked increase of the stromal cell compartment but, an epithelial phenotype has also been reported. JPS has an increased risk of colorectal cancer but sporadic juvenile polyps do not. In 50–60% of JPS patients a germline mutation of the TGF-β/BMP pathway genes SMAD4 or BMPR1A is found. This study compares the histological phenotype of juvenile polyps with a SMAD4 or BMPR1A germline mutation and sporadic juvenile polyps. Methods H&E slides of 65 JPS polyps and 25 sporadic juvenile polyps were reviewed for histological features and dysplasia. Systematic random crypt and stroma counts were obtained by count stereology and a crypt-stroma ratio was determined. All polyps were subsequently categorised as type A (crypt-stroma ratio <1.00) or type B (crypt-stroma ratio ≥1.00), the latter referring to the epithelial phenotype. Cell cycle activity was assessed using immunohistochemistry of the proliferation marker Ki67, and mutation analysis was conducted for KRAS and APC to determine the involvement of the adenoma-carcinoma sequence. Results Juvenile polyps with a SMAD4 germline mutation were predominantly type B, whereas, type A was more common among juvenile polyps with a BMPR1A germline mutation, but this distinction could not be ascribed to differences in cell cycle activity. Dysplasia was equally common in JPS polyps with either a SMAD4 or BMPR1A germline mutation, where the involvement of the adenoma-carcinoma sequence does not seem to play a distinct role. Conclusion juvenile polyps in the setting of JPS exhibit distinct phenotypes correlating with the underlying genetic defect. PMID:21412070

Fast magnetic reconnection supported by sporadic small-scale Petschek-type shocks

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

Shibayama, Takuya, E-mail: shibayama@stelab.nagoya-u.ac.jp; Nakabou, Takashi; Kusano, Kanya

2015-10-15

Standard magnetohydrodynamic (MHD) theory predicts reconnection rate that is far too slow to account for a wide variety of reconnection events observed in space and laboratory plasmas. Therefore, it was commonly accepted that some non-MHD (kinetic) effects play a crucial role in fast reconnection. A recently renewed interest in simple MHD models is associated with the so-called plasmoid instability of reconnecting current sheets. Although it is now evident that this effect can significantly enhance the rate of reconnection, many details of the underlying multiple-plasmoid process still remain controversial. Here, we report results of a high-resolution computer simulation which demonstrate thatmore » fast albeit intermittent magnetic reconnection is sustained by numerous small-scale Petschek-type shocks spontaneously formed in the current sheet due to its plasmoid instability.« less

Clinicopathologic implications of DNA mismatch repair status in endometrial carcinomas.

PubMed

Shikama, Ayumi; Minaguchi, Takeo; Matsumoto, Koji; Akiyama-Abe, Azusa; Nakamura, Yuko; Michikami, Hiroo; Nakao, Sari; Sakurai, Manabu; Ochi, Hiroyuki; Onuki, Mamiko; Satoh, Toyomi; Oki, Akinori; Yoshikawa, Hiroyuki

2016-02-01

Endometrial carcinoma is the most common malignancy in women with Lynch syndrome caused by mismatch repair (MMR) deficiency. We investigated the clinicopathologic significance of deficient MMR and Lynch syndrome presumed by MMR analyses in unselected endometrial carcinomas. We analyzed immunohistochemistry of MMR proteins (MLH1/MSH2/MSH6/PMS2) and MLH1 promoter methylation in primary endometrial carcinomas from 221 consecutive patients. Based on these results, tumors were categorized as sporadic or probable Lynch syndrome (PLS). Clinicopathologic variables and prognosis were compared according to MMR status and sporadic/PLS classification. Deficient MMR showed only trends towards favorable overall survival (OS) compared with intact MMR (p=0.13), whereas PLS showed significantly better OS than sporadic (p=0.038). Sporadic was significantly associated with older age, obesity, deep myometrial invasion, and advanced stage (p=0.008, 0.01, 0.02 and 0.03), while PLS was significantly associated with early stage and Lynch syndrome-associated multiple cancer (p=0.04 and 0.001). The trend towards favorable OS of PLS was stronger in advanced stage than in early stage (hazard ratio, 0.044 [95% CI 0-25.6] vs. 0.49 [0.063-3.8]). In the subset receiving adjuvant therapies, PLS showed trends towards favorable disease-free survival compared to sporadic by contrast with patients receiving no adjuvant therapies showing no such trend (hazard ratio, 0.045 [95% CI 0-20.3] vs. 0.81 [0.095-7.0]). The current findings suggest that analyzing MMR status and searching for Lynch syndrome may identify a subset of patients with favorable survival and high sensitivity to adjuvant therapies, providing novel and useful implications for formulating the precision medicine in endometrial carcinoma. Copyright © 2015 Elsevier Inc. All rights reserved.

Genetic and epigenetic mutations of tumor suppressive genes in sporadic pituitary adenoma

PubMed Central

Zhou, Yunli; Zhang, Xun; Klibanski, Anne

2013-01-01

Human pituitary adenomas are the most common intracranial neoplasms. Approximately 5% of them are familial adenomas. Patients with familial tumors carry germline mutations in predisposition genes, including AIP, MEN1 and PRKAR1A. These mutations are extremely rare in sporadic pituitary adenomas, which therefore are caused by different mechanisms. Multiple tumor suppressive genes linked to sporadic tumors have been identified. Their inactivation is caused by epigenetic mechanisms, mainly promoter hypermethylation, and can be placed into two groups based on their functional interaction with tumor suppressors RB or p53. The RB group includes CDKN2A, CDKN2B, CDKN2C, RB1, BMP4, CDH1, CDH13, GADD45B and GADD45G; AIP and MEN1 genes also belong to this group. The p53 group includes MEG3, MGMT, PLAGL1, RASSF1, RASSF3 and SOCS1. We propose that the tumor suppression function of these genes is mainly mediated by the RB and p53 pathways. We also discuss possible tumor suppression mechanisms for individual genes. PMID:24035864

Population genetic approaches to neurological disease: Parkinson's disease as an example

PubMed Central

Gandhi, S; Abou-Sleiman, P.M; Healy, D.G; Weale, M; Gilks, W; Ahmadi, K; Goldstein, D.B; Wood, N.W

2005-01-01

Parkinson's disease (PD) is a common, progressive, incurable disabling condition. The cause is unknown but over the past few years tremendous progress in our understanding of the genetic bases of this condition has been made. To date, this has almost exclusively come from the study of relatively rare Mendelian forms of the disease and there are no currently, widely accepted common variants known to increase susceptibility. The role that the ‘Mendelian’ genes play in common sporadic forms of PD is unknown. Moreover, most studies in PD can really be described as candidate polymorphism studies rather than true and complete assessments of the genes themselves. We provide a model of how one might tackle some of these issues using Parkinson's disease as an illustration. One of the emerging hypotheses of gene environment interaction in Parkinson's disease is based on drug metabolizing (or xenobiotic) enzymes and their interaction with putative environmental toxins. This motivated us to describe a tagging approach for an extensive but not exhaustive list of 55 drug metabolizing enzyme genes. We use these data to illustrate the power, and some of the limitations of a haplotype tagging approach. We show that haplotype tagging is extremely efficient and works well with only a modest increase in effort through different populations. The tagging approach works much less well if the minor allele frequency is below 5%. However, it will now be possible using these tags to evaluate these genes comprehensively in PD and other neurodegenerative conditions. PMID:16096106

Population genetic approaches to neurological disease: Parkinson's disease as an example.

PubMed

Gandhi, S; Abou-Sleiman, P M; Healy, D G; Weale, M; Gilks, W; Ahmadi, K; Goldstein, D B; Wood, N W

2005-08-29

Parkinson's disease (PD) is a common, progressive, incurable disabling condition. The cause is unknown but over the past few years tremendous progress in our understanding of the genetic bases of this condition has been made. To date, this has almost exclusively come from the study of relatively rare Mendelian forms of the disease and there are no currently, widely accepted common variants known to increase susceptibility. The role that the "Mendelian" genes play in common sporadic forms of PD is unknown. Moreover, most studies in PD can really be described as candidate polymorphism studies rather than true and complete assessments of the genes themselves. We provide a model of how one might tackle some of these issues using Parkinson's disease as an illustration. One of the emerging hypotheses of gene environment interaction in Parkinson's disease is based on drug metabolizing (or xenobiotic) enzymes and their interaction with putative environmental toxins. This motivated us to describe a tagging approach for an extensive but not exhaustive list of 55 drug metabolizing enzyme genes. We use these data to illustrate the power, and some of the limitations of a haplotype tagging approach. We show that haplotype tagging is extremely efficient and works well with only a modest increase in effort through different populations. The tagging approach works much less well if the minor allele frequency is below 5%. However, it will now be possible using these tags to evaluate these genes comprehensively in PD and other neurodegenerative conditions.

Parkinson’s Disease

PubMed Central

Boyd, James T.; Hamill, Robert W.; Maguire-Zeiss, Kathleen A.

2015-01-01

Parkinson’s disease (PD) is the most common age-related motoric neurodegenerative disease initially described in the 1800’s by James Parkinson as the ‘Shaking Palsy’. Loss of the neurotransmitter dopamine was recognized as underlying the pathophysiology of the motor dysfunction; subsequently discovery of dopamine replacement therapies brought substantial symptomatic benefit to PD patients. However, these therapies do not fully treat the clinical syndrome nor do they alter the natural history of this disorder motivating clinicians and researchers to further investigate the clinical phenotype, pathophysiology/pathobiology and etiology of this devastating disease. Although the exact cause of sporadic PD remains enigmatic studies of familial and rare toxicant forms of this disorder have laid the foundation for genome wide explorations and environmental studies. The combination of methodical clinical evaluation, systematic pathological studies and detailed genetic analyses have revealed that PD is a multifaceted disorder with a wide-range of clinical symptoms and pathology that include regions outside the dopamine system. One common thread in PD is the presence of intracytoplasmic inclusions that contain the protein, α-synuclein. The presence of toxic aggregated forms of α-synuclein (e.g., amyloid structures) are purported to be a harbinger of subsequent pathology. In fact, PD is both a cerebral amyloid disease and the most common synucleinopathy, that is, diseases that display accumulations of α-synuclein. Here we present our current understanding of PD etiology, pathology, clinical symptoms and therapeutic approaches with an emphasis on misfolded α-synuclein. PMID:23225012

Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases.

PubMed

Migliore, Lucia; Coppedè, Fabio

2009-07-10

In the present review we summarize recent advances in the understanding of the interaction between genetics and environmental factors involved in complex multi-factorial neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS). The discovery of several genes responsible for the familial forms has led to a better comprehension of the molecular pathways involved in the selective neuronal degeneration which is specific for each of these disorders. However, the vast majority of the cases occurs as sporadic forms, likely resulting from complex gene-gene and gene-environment interplay. Several environmental factors, including, pesticides, metals, head injuries, lifestyles and dietary habits have been associated with increased disease risk or even with protection. Hundreds of genetic variants have been investigated as possible risk factors for the sporadic forms, but results are often conflicting, not repeated or inconclusive. New approaches to environmental health research are revealing us that at the basis there could be chemically induced changes in gene regulation and emphasise the importance of understanding the susceptibility of the human epigenome to dietary and other environmental effects.

Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer

PubMed Central

Tezcan, Gulcin; Tunca, Berrin; Ak, Secil; Cecener, Gulsah; Egeli, Unal

2016-01-01

Colorectal cancer (CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC (EOCRC) cases are heterogeneous population that includes both hereditary and sporadic forms of the CRC. Although EOCRC cases have some distinguishing clinical and pathological features than elder age CRC, the molecular mechanism underlying the EOCRC is poorly clarified. Given the significance of CRC in the world of medicine, the present review will focus on the recent knowledge in the molecular basis of genetic and epigenetic mechanism of the hereditary forms of EOCRC, which includes Lynch syndrome, Familial CRC type X, Familial adenomatous polyposis, MutYH-associated polyposis, Juvenile polyposis syndrome, Peutz-Jeghers Syndrome and sporadic forms of EOCRC. Recent findings about molecular genetics and epigenetic basis of EOCRC gave rise to new alternative therapy protocols. Although exact diagnosis of these cases still remains complicated, the present review paves way for better predictions and contributes to more accurate diagnostic and therapeutic strategies into clinical approach. PMID:26798439

Splenic abscess due to chronic melioidosis in a patient previously misdiagnosed as tuberculosis

PubMed Central

Kunnathuparambil, Sojan George; Sathar, Shanid Abdul; Tank, Devang Chandrakanth; Sreesh, Srijaya; Mukunda, Madhav; Narayanan, Premaletha; Vinayakumar, Kattoor Ramakrishnan

2013-01-01

Melioidosis is endemic in Southeast Asia and Northern Australia. Sporadic cases have been reported from many parts of the world where it has an epidemic potential with high-rate fatality cases. In non-endemic areas, melioidosis may be misdiagnosed with common diseases and this may prove fatal. Sporadic cases of melioidosis are mistaken for tuberculosis in India. We report a case of splenic abscess due to chronic melioidosis who was earlier misdiagnosed as tuberculosis and underwent anti-tuberculosis therapy. Following treatment of melioidosis his symptoms subsided. This case is reported because of the rarity of the disease and to highlight the importance of looking for melioidosis in patients with splenic abscess even in non-endemic areas. PMID:24714690

Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis

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

Palmer, S.E.; Dale, D.C.

Cyclic hematopoiesis (CH, or cyclic neutropenia) is a rare disease manifested by transient severe neutropenia that recurs approximately every 21 days. The hematologic profile of families with the autosomal dominant form (ADCH) has not been well characterized, and it is unknown if the phenotype is distinct from the more common sporadic congenital or acquired forms of CH. We studied nine ADCH families whose children displayed typical CH blood patterns. Pedigrees confirmed dominant inheritance without evidence of heterogeneity or decreased penetrance; three pedigrees suggested new mutations. Families were Caucasian with exception of one with a Cherokee Native American founder. A widemore » spectrum of symptom severity, ranging from asymptomatic to life-threatening illness, was observed within families. The phenotype changed with age. Children displayed typical neutrophil cycles with symptoms of mucosal ulceration, lymphadenopathy, and infections. Adults often had fewer and milder symptoms, sometimes accompanied by mild chronic neutropenia without distinct cycles. While CH is commonly described as {open_quotes}benign{close_quotes}, four children in three of the nine families died of Clostridium or E. coli colitis, documenting the need for urgent evaluation of abdominal pain. Misdiagnosis with other neutropenias was common but can be avoided by serial blood counts in index cases. Genetic counseling requires specific histories and complete blood counts in relatives at risk to assess status regardless of symptoms, especially to determine individuals with new mutations. We propose diagnostic criteria for ADCH in affected children and adults. Recombinant human granulocyte colony-stimulating factor treatment resulted in dramatic improvement of neutropenia and morbidity. The differential diagnosis from other forms of familial neutropenia is reviewed. 45 refs., 4 figs., 1 tab.« less

Features of the amplitude-height-frequency characteristics of midlatitude sporadic-E layer

NASA Astrophysics Data System (ADS)

Yusupov, Kamil; Akchurin, Adel

2012-07-01

At early investigation of an ionosphere the vertical pulse sounding was without separation magnetoionic components and such conditions allowed to observe interferential beatings or polarized fading over frequencies where traces of various magnetoionic component was crossing (overlapping). The beatings in F layer traces are often observed and their origin easily are explain by an interference o - and x-mode whereas in sporadic-E layer traces even observability of beatings of o- and x-modes is in doubt. Absence of experimental evidences of beatings is explain that measurements did not manage to be performed over the necessary time moment because of randomness and a rarity of occurrence high-intensity sporadic-E layers (without properties of scattering on small scale irregularities) and because of high labour input at recording and processing of amplitude-frequency characteristics. The direct observation of interferential beatings became problematic when ionosondes with separations of magnetoionic components appeared. Moreover because of relative vicinity of gyro and background plasma frequencies and also the steep electron profile gradient the beatings in sporadic-E traces should occur between two o-modes because in typical diurnal low-intensity sporadic-E layers (foEs<5MHz) x-mode will be strongly absorbed and the steep gradient on the bottom of sporadic-E layer will strengthen magnetoionic coupling (between o- and x-modes) and lead occurrence of so-called z-mode. The z-mode (extraordinary mode with ordinary polarization) reflected in higher height again takes the form of ordinary mode after passage of height of reflection of ordinary mode and interferes with ordinary mode. However our observations show that beating in sporadic-E traces mostly occur because of interference about o- and x-modes. For detailed research of interference conditions the approximation of width of interference fringes (distance between consecutive minima in interference pattern) as a function of sounding frequency was performed. This information can be also applied to determination of parameters of the height electron profile used in IRI model. For exact profile restoration it is necessary to use all information from ionogram. Besides the specified approximation of width of interference fringes it is necessary to determine also frequency dependences of the virtual height of reflection of sporadic-E layers for o- and x-modes accurate within 300 m. First of all it concerns to cusp in the beginning of sporadic-E traces. For approximation of this dependence the modernized model of a parabolic layer for o- and x-modes with various half-thickness of layer has been used. Comparison with experimental data gives half-thickness are approximately equal 5 and 25 km accordingly. All three approximations of interference fringe widths and of reflection heights will be used for determination of height electron density profile with improved precision below maximum of sporadic-E layer.

Lewis's Woodpecker (Melanerpes lewis): A technical conservation assessment

Treesearch

Stephen C. Abele; Victoria A. Saab; Edward O. Garton

2004-01-01

Lewis's woodpecker (Melanerpes lewis) is a locally common but patchily distributed woodpecker species usually seen in open forests of western North America. The combination of its sporadic distribution, its diet of adult-stage free-living insects (primarily aerial), its preference to nest in burned landscapes, and its variable migratory behavior...

Molecular studies of achondroplasia

PubMed Central

Nahar, Risha; Saxena, Renu; Kohli, Sudha; Puri, Ratna; Verma, Ishwar Chandra

2009-01-01

Background: Achondroplasia (ACH) is the most frequent form of short-limbed dwarfism, caused by mutations in the FGFR3 gene. It follows an autosomal dominant inheritance, though most cases are sporadic. The molecular techniques are the only available methods to confirm the diagnosis of a skeletal dysplasia. Clinical and radiological features are only suggestive and not confirmatory. The present study was conducted to find out how often the clinical diagnosis of achondroplasia is verified on molecular studies. Materials and Methods: From 1998 through 2007, we carried out molecular analysis for the two common mutations in the FGFR3 gene in 130 cases clinically suspected to have ACH. Results: A diagnostic mutation was identified in 53 (40.8%) cases. The common mutation (1138G>A) was present in 50 (94.7%) of the positive cases, while the rare 1138 G>C substitution was found in three (5.3%). Conclusion: This study shows that confirmation of clinical diagnosis of ACH by molecular genetic testing is essential to distinguish it from other skeletal dysplasias, to plan therapeutic options, and to offer genetic counseling. Management (medical and surgical) in patients confirmed to have ACH, is briefly discussed. PMID:19838370

Polyradiculopathies from Schwannomatosis

PubMed Central

Jia, Yuxia; Kraus, James A.; Reddy, Hasini; Groff, Michael; Wong, Eric T

2011-01-01

We describe a case of schwannomatosis presenting as radicular pain and numbness in multiple radicular nerve distributions. There were multiple peripheral nerve tumors detected by magnetic resonance imaging (MRI) at the left vestibular nerve, cauda equina, right radial nerve, thoracic paraspinal nerve, and brachial plexi. Several resected tumors have features of schwannomas, including hypercellular Antoni A areas, hypocellular Antoni B areas, Verocay bodies, and hyalinized blood vessels. The specimens are also positive for immunohistochemical staining for INI1 with diffuse nuclear staining. The findings are consistent with sporadic form of schwannomatosis. This case highlights the importance of using MRI and INI1 immunohistochemistry to differentiate familial schwannomatosis, neurofibromatosis 2 (NF2)-associated schwannomatosis, and sporadic schwannomatosis. PMID:21643503

Familial Gastric Cancers.

PubMed

Setia, Namrata; Clark, Jeffrey W; Duda, Dan G; Hong, Theodore S; Kwak, Eunice L; Mullen, John T; Lauwers, Gregory Y

2015-12-01

Although the majority of gastric carcinomas are sporadic, approximately 10% show familial aggregation, and a hereditary cause is determined in 1%-3% cases. Of these, hereditary diffuse gastric cancer is the most recognized predisposition syndrome. Although rare, the less commonly known syndromes also confer a markedly increased risk for development of gastric cancer. Identification and characterization of these syndromes require a multidisciplinary effort involving oncologists, surgeons, genetic counselors, biologists, and pathologists. This article reviews the molecular genetics, clinical and pathologic features, surveillance guidelines, and preventive measures of common and less common hereditary gastric cancer predisposition syndromes. ©AlphaMed Press.

Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy.

PubMed Central

de Lonlay, P; Fournet, J C; Rahier, J; Gross-Morand, M S; Poggi-Travert, F; Foussier, V; Bonnefont, J P; Brusset, M C; Brunelle, F; Robert, J J; Nihoul-Fékété, C; Saudubray, J M; Junien, C

1997-01-01

Sporadic persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or nesidioblastosis is a heterogeneous disorder characterized by profound hypoglycemia due to inappropriate hypersecretion of insulin. An important diagnostic goal is to distinguish patients with a focal hyperplasia of islet cells of the pancreas (FoPHHI) from those with a diffuse abnormality of islets (DiPHHI) because management strategies differ significantly. 16 infants with sporadic PHHI resistant to diazoxide and who underwent pancreatectomy were investigated. Selective pancreatic venous sampling coupled with peroperative surgical examination and analysis of extemporaneous frozen sections allowed us to identify 10 cases with FoPHHI and 6 cases with DiPHHI. We show here that in cases of FoPHHI, but not those of DiPHHI, there was specific loss of maternal alleles of the imprinted chromosome region 11p15 in cells of the hyperplastic area of the pancreas but not in normal pancreatic cells. This somatic event is consistent with a proliferative monoclonal lesion. It involves disruption of the balance between monoallelic expression of several maternally and paternally expressed genes. Thus, we provide the first molecular explanation of the heterogeneity of sporadic forms of PHHI such that it is possible to perform only partial pancreatectomy, limited to the focal somatic lesion, so as to avoid iatrogenic diabetes in patients with focal adenomatous hyperplasia. PMID:9259578

Recurrent Somatic PDGFRB Mutations in Sporadic Infantile/Solitary Adult Myofibromas But Not in Angioleiomyomas and Myopericytomas.

PubMed

Agaimy, Abbas; Bieg, Matthias; Michal, Michael; Geddert, Helene; Märkl, Bruno; Seitz, Jan; Moskalev, Evgeny A; Schlesner, Matthias; Metzler, Markus; Hartmann, Arndt; Wiemann, Stefan; Michal, Michal; Mentzel, Thomas; Haller, Florian

2017-02-01

Infantile myofibroma (MF) is an uncommon benign myofibroblastic tumor of infancy and childhood. Solitary adult MF shares similar features with infantile MF. The lesions occur in 3 clinicopathologic settings: solitary, multicentric, and generalized and can be either sporadic or familial. Traditionally, infantile MF has been included in the spectrum of infantile hemangiopericytoma. The recent World Health Organization classification listed MF, angioleiomyoma, and myopericytoma under the general heading of perivascular tumors in the sense of a morphologic spectrum of perivascular myoid cell neoplasms. Although activating germline PDGFRB mutations have recently been linked to familial infantile MF, the molecular pathogenesis of sporadic infantile and adult solitary MF remained unclear. In this study, we analyzed 25 solitary MFs without evidence of familial disease (9 infantile and 16 adult MFs) to address the question whether somatic PDGFRB mutations might be responsible for the sporadic form of the disease. Given the presumed histogenetic link of MF to myopericytoma and angioleiomyoma, we additionally analyzed a control group of 6 myopericytomas and 9 angioleiomyomas for PDGFRB mutations. We detected PDGFRB mutations in 6/8 (75%) analyzable infantile and in 11/16 (69%) adult MFs but in none of the angioleiomyomas or myopericytomas. In 2 infantile MFs, additional sequencing of the germline confirmed the somatic nature of PDGFRB mutations. To our knowledge, this is the first study reporting apparently somatic recurrent PDGFRB mutations as molecular driver events in the majority of sporadic infantile and adult solitary MFs. Our results suggest molecular distinctness of MF as compared with angioleiomyoma/myopericytoma. Investigation of more cases including those with atypical and worrisome features, as well as other mimickers in the heterogenous morphologic spectrum of MF, is mandatory for validating the potential diagnostic value of PDGFRB mutation testing as a possible surrogate in difficult-to-classify lesions.

The Role of Iron In Sporadic E Layers

NASA Astrophysics Data System (ADS)

Vondrak, T.; Woodcock, K. R. I.; Plane, J. M. C.

Sporadic E layers in the lower thermosphere are mostly composed of metallic ions, of which Fe+ is the most abundant. Because dielectric recombination (Fe+ + elec- tron) is very slow, the lifetime of Fe+ above about 100 km is at least several days. However, below this height molecular ions such as FeO+, FeO2+ and FeN2+ form in- creasingly rapidly through reactions with O3, O2 and N2, respectively. These undergo rapid dissociative recombination with electrons, causing Fe+ to be neutralised increas- ingly rapidly as a sporadic E layer descends. Indeed, this is the most likely mechanism for the formation of the sporadic neutral Fe layers that are observed by lidar. However, atomic O plays a very important role in reducing these molecular ions back to Fe+, competing with dissociative recombination and thus slowing the rate at which Fe+ is neutralised and a sporadic E layer dissipates. This paper will discuss a laboratory and modelling study of the reactions of FeO+, FeO2+ and FeN2+ with atomic O. These reactions were studied (for the first time) in a fast flow tube, using the pulsed laser ablation of a rotating iron rod as the source of Fe+ ions in the upstream section of the tube. Reactants were then added to produce molecular ions, and atomic O further downstream through a movable injector. Fe+ and the molecular ions were detected at the downstream end of the tube using a two-stage quadrupole mass spectrometer. The spectroscopy of the FeO+ ion, observed by laser induced fluorescence, will also be discussed as a candidate for future ground-based lidar studies of the ion chemistry of the lower thermosphere.

Common NOTCH3 Variants and Cerebral Small-Vessel Disease.

PubMed

Rutten-Jacobs, Loes C A; Traylor, Matthew; Adib-Samii, Poneh; Thijs, Vincent; Sudlow, Cathie; Rothwell, Peter M; Boncoraglio, Giorgio; Dichgans, Martin; Bevan, Steve; Meschia, James; Levi, Christopher; Rost, Natalia S; Rosand, Jonathan; Hassan, Ahamad; Markus, Hugh S

2015-06-01

The most common monogenic cause of cerebral small-vessel disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by NOTCH3 gene mutations. It has been hypothesized that more common variants in NOTCH3 may also contribute to the risk of sporadic small-vessel disease. Previously, 4 common variants (rs10404382, rs1043994, rs10423702, and rs1043997) were found to be associated with the presence of white matter hyperintensity in hypertensive community-dwelling elderly. We investigated the association of common single nucleotide polymorphisms (SNPs) in NOTCH3 in 1350 patients with MRI-confirmed lacunar stroke and 7397 controls, by meta-analysis of genome-wide association study data sets. In addition, we investigated the association of common SNPs in NOTCH3 with MRI white matter hyperintensity volumes in 3670 white patients with ischemic stroke. In each analysis, we considered all SNPs within the NOTCH3 gene, and within 50-kb upstream and downstream of the coding region. A total of 381 SNPs from the 1000 genome population with a mean allele frequency>0.01 were included in the analysis. A significance level of P<0.0015 was used, adjusted for the effective number of independent SNPs in the region using the Galwey method. We found no association of any common variants in NOTCH3 (including rs10404382, rs1043994, rs10423702, and rs1043997) with lacunar stroke or white matter hyperintensity volume. We repeated our analysis stratified for hypertension but again found no association. Our study does not support a role for common NOTCH3 variation in the risk of sporadic small-vessel disease. © 2015 The Authors.

Uncovering the Rare Variants of DLC1 Isoform 1 and Their Functional Effects in a Chinese Sporadic Congenital Heart Disease Cohort

PubMed Central

Wang, Zhen; Tan, Huilian; Kong, Xianghua; Shu, Yang; Zhang, Yuchao; Huang, Yun; Zhu, Yufei; Xu, Heng; Wang, Zhiqiang; Wang, Ping; Ning, Guang; Kong, Xiangyin; Hu, Guohong; Hu, Landian

2014-01-01

Congenital heart disease (CHD) is the most common birth defect affecting the structure and function of fetal hearts. Despite decades of extensive studies, the genetic mechanism of sporadic CHD remains obscure. Deleted in liver cancer 1 (DLC1) gene, encoding a GTPase-activating protein, is highly expressed in heart and essential for heart development according to the knowledge of Dlc1-deficient mice. To determine whether DLC1 is a susceptibility gene for sporadic CHD, we sequenced the coding region of DLC1 isoform 1 in 151 sporadic CHD patients and identified 13 non-synonymous rare variants (including 6 private variants) in the case cohort. Importantly, these rare variants (8/13) were enriched in the N-terminal region of the DLC1 isoform 1 protein. Seven of eight amino acids at the N-terminal variant positions were conserved among the primates. Among the 9 rare variants that were predicted as “damaging”, five were located at the N-terminal region. Ensuing in vitro functional assays showed that three private variants (Met360Lys, Glu418Lys and Asp554Val) impaired the ability of DLC1 to inhibit cell migration or altered the subcellular location of the protein compared to wild-type DLC1 isoform 1. These data suggest that DLC1 might act as a CHD-associated gene in addition to its role as a tumor suppressor in cancer. PMID:24587289

Screening of SOD1, FUS and TARDBP genes in patients with amyotrophic lateral sclerosis in central-southern China.

PubMed

Hou, Lihua; Jiao, Bin; Xiao, Tingting; Zhou, Lu; Zhou, Zhifan; Du, Juan; Yan, Xinxiang; Wang, Junling; Tang, Beisha; Shen, Lu

2016-09-08

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons of the brain, brainstem and spinal cord. To date, mutations in more than 30 genes have been linked to the pathogenesis of ALS. Among them, SOD1, FUS and TARDBP are ranked as the three most common genes associated with ALS. However, no mutation analysis has been reported in central-southern China. In this study, we sequenced SOD1, FUS and TARDBP in a central-southern Chinese cohort of 173 patients with ALS (15 familial ALS and 158 sporadic ALS) to detect mutations. As a result, five missense mutations in SOD1, namely, p.D101N, p.D101G, p.C111Y, p.N86S and p.V87A, were identified in three unrelated familial probands and three sporadic cases; two mutations in FUS were found in two unrelated familial probands, including an insertion mutation (p.P525_Y526insY) and a missense mutation (p.R521H); no variants of TARDBP were observed in patients. Therefore, SOD1 mutations were present in 20.0% of familial ALS patients and 1.9% of sporadic ALS patients, while FUS mutations were responsible for 13.3% of familial ALS cases, and TARDBP mutations were rare in either familial or sporadic ALS cases. This study broadens the known mutational spectrum in patients with ALS and further demonstrates the necessity for genetic screening in ALS patients from central-southern China.

Patterns and severity of vascular amyloid in Alzheimer's disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer's disease.

PubMed

Mann, David M A; Davidson, Yvonne S; Robinson, Andrew C; Allen, Nancy; Hashimoto, Tadafumi; Richardson, Anna; Jones, Matthew; Snowden, Julie S; Pendleton, Neil; Potier, Marie-Claude; Laquerrière, Annie; Prasher, Vee; Iwatsubo, Takeshi; Strydom, Andre

2018-05-16

In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, between APP genetic causes of AD (APPdup, APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer's disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vascular disease, we additionally aimed to explore the role of APOE genotype in CAA severity and subtypes. Plaque formation was greater in DS and missense APP mutations than in APPdup, sEOAD and sLOAD cases. Conversely, CAA was more severe in APPdup and missense APP mutations, and in DS, compared to sEOAD and sLOAD. When stratified by CAA subtype from 1 to 4, there were no differences in plaque scores between the groups, though in patients with APPdup, APP mutations and sEOAD, types 2 and 3 CAA were more common than type 1. Conversely, in DS, sLOAD and controls, type 1 CAA was more common than types 2 and 3. APOE ε4 allele frequency was greater in sEOAD and sLOAD compared to APPdup, missense APP mutations, DS and controls, and varied between each of the CAA phenotypes with APOE ε4 homozygosity being more commonly associated with type 3 CAA than types 1 and 2 CAA in sLOAD and sEOAD. The differing patterns in CAA within individuals of each group could be a reflection of variations in the efficiency of perivascular drainage, this being less effective in types 2 and 3 CAA leading to a greater burden of CAA in parenchymal arteries and capillaries. Alternatively, as suggested by immunostaining using carboxy-terminal specific antibodies, it may relate to the relative tissue burdens of the two major forms of Aβ, with higher levels of Aβ 40 promoting a more 'aggressive' form of CAA, and higher levels of Aβ 42(3) favouring a greater plaque burden. Possession of APOE ε4 allele, especially ε4 homozygosity, favours development of CAA generally, and as type 3 particularly, in sEOAD and sLOAD.

Comparative Incidence of Conformational, Neurodegenerative Disorders

PubMed Central

de Pedro-Cuesta, Jesús; Rábano, Alberto; Martínez-Martín, Pablo; Ruiz-Tovar, María; Alcalde-Cabero, Enrique; Almazán-Isla, Javier; Avellanal, Fuencisla; Calero, Miguel

2015-01-01

Background The purpose of this study was to identify incidence and survival patterns in conformational neurodegenerative disorders (CNDDs). Methods We identified 2563 reports on the incidence of eight conditions representing sporadic, acquired and genetic, protein-associated, i.e., conformational, NDD groups and age-related macular degeneration (AMD). We selected 245 papers for full-text examination and application of quality criteria. Additionally, data-collection was completed with detailed information from British, Swedish, and Spanish registries on Creutzfeldt-Jakob disease (CJD) forms, amyotrophic lateral sclerosis (ALS), and sporadic rapidly progressing neurodegenerative dementia (sRPNDd). For each condition, age-specific incidence curves, age-adjusted figures, and reported or calculated median survival were plotted and examined. Findings Based on 51 valid reported and seven new incidence data sets, nine out of eleven conditions shared specific features. Age-adjusted incidence per million person-years increased from ≤1.5 for sRPNDd, different CJD forms and Huntington's disease (HD), to 1589 and 2589 for AMD and Alzheimer's disease (AD) respectively. Age-specific profiles varied from (a) symmetrical, inverted V-shaped curves for low incidences to (b) those increasing with age for late-life sporadic CNDDs and for sRPNDd, with (c) a suggested, intermediate, non-symmetrical inverted V-shape for fronto-temporal dementia and Parkinson's disease. Frequently, peak age-specific incidences from 20–24 to ≥90 years increased with age at onset and survival. Distinct patterns were seen: for HD, with a low incidence, levelling off at middle age, and long median survival, 20 years; and for sRPNDd which displayed the lowest incidence, increasing with age, and a short median disease duration. Interpretation These results call for a unified population view of NDDs, with an age-at-onset-related pattern for acquired and sporadic CNDDs. The pattern linking age at onset to incidence magnitude and survival might be explained by differential pathophysiological mechanisms associated with specific misfolded protein deposits. PMID:26335347

A novel microsatellite DNA marker at locus D7S1870 detects hemizygosity in 75% of patients with Williams syndrome

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

Gilbert-Dussardier, B.; Bonneau, D.; Gigarel, N.

1995-02-01

Williams syndrome (WS) is a predominantly sporadic developmental disorder characterized by dysmorphic facial features, infantile hypercalcemia, premature aging of skin, mental retardation and gregarious personality. Supravalvular aortic stenosis (SVAS) and other vascular diseases caused by the narrowing of large elastic arteries are present in almost 80% of cases. Recently, hemizygosity at the elastin locus has been shown in sporadic WS, suggesting that this disease is caused by deletions encompassing the elastin gene on chromosome 7q11.23. Taking advantage of a large series of sporadic WS (27 cases), we have explored the potential application of novel microsatellite DNA markers in the rapidmore » detection of hemizygosity in WS. We report here a highly informative marker at locus D7S1870, which detected failure of parental inheritance in almost 75% of cases of WS in our series. This marker can be regarded therefore as a reliable and useful diagnostic tool in suspected cases of WS as well as in complicated forms of supravalvular aortic stenosis. 10 refs., 2 figs.« less

LRRK2 G2385R and R1628P Mutations Are Associated with an Increased Risk of Parkinson's Disease in the Malaysian Population

PubMed Central

Chua, Jing Yi; Lim, Thien Thien; Mohamed Ibrahim, Norlinah; Tan, Ai Huey; Eow, Gaik Bee; Abdul Aziz, Zariah; Puvanarajah, Santhi Datuk; Viswanathan, Shanthi; Lim, Soo Kun; Tan, Li Ping; Chong, Yip Boon; Tan, Chong Tin; Zhao, Yi; Tan, E. K.

2014-01-01

The LRRK2 gene has been associated with both familial and sporadic forms of Parkinson's disease (PD). The G2019S variant is commonly found in North African Arab and Caucasian PD patients, but this locus is monomorphic in Asians. The G2385R and R1628P variants are associated with a higher risk of developing PD in certain Asian populations but have not been studied in the Malaysian population. Therefore, we screened the G2385R and R1628P variants in 1,202 Malaysian subjects consisting of 695 cases and 507 controls. The G2385R and R1628P variants were associated with a 2.2-fold (P = 0.019) and 1.2-fold (P = 0.054) increased risk of PD, respectively. Our data concur with other reported findings in Chinese, Taiwanese, Singaporean, and Korean studies. PMID:25243190

Drosophila Models of Parkinson's Disease: Discovering Relevant Pathways and Novel Therapeutic Strategies

PubMed Central

Muñoz-Soriano, Verónica; Paricio, Nuria

2011-01-01

Parkinson's disease (PD) is the second most common neurodegenerative disorder and is mainly characterized by the selective and progressive loss of dopaminergic neurons, accompanied by locomotor defects. Although most PD cases are sporadic, several genes are associated with rare familial forms of the disease. Analyses of their function have provided important insights into the disease process, demonstrating that three types of cellular defects are mainly involved in the formation and/or progression of PD: abnormal protein aggregation, oxidative damage, and mitochondrial dysfunction. These studies have been mainly performed in PD models created in mice, fruit flies, and worms. Among them, Drosophila has emerged as a very valuable model organism in the study of either toxin-induced or genetically linked PD. Indeed, many of the existing fly PD models exhibit key features of the disease and have been instrumental to discover pathways relevant for PD pathogenesis, which could facilitate the development of therapeutic strategies. PMID:21512585

Mitochondrial dynamics in Parkinson's disease: a role for α-synuclein?

PubMed Central

Pozo Devoto, Victorio M.

2017-01-01

ABSTRACT The distinctive pathological hallmarks of Parkinson's disease are the progressive death of dopaminergic neurons and the intracellular accumulation of Lewy bodies enriched in α-synuclein protein. Several lines of evidence from the study of sporadic, familial and pharmacologically induced forms of human Parkinson's disease also suggest that mitochondrial dysfunction plays an important role in disease progression. Although many functions have been proposed for α-synuclein, emerging data from human and animal models of Parkinson's disease highlight a role for α-synuclein in the control of neuronal mitochondrial dynamics. Here, we review the α-synuclein structural, biophysical and biochemical properties that influence relevant mitochondrial dynamic processes such as fusion-fission, transport and clearance. Drawing on current evidence, we propose that α-synuclein contributes to the mitochondrial defects that are associated with the pathology of this common and progressive neurodegenerative disease. PMID:28883016

Mitochondrial dynamics in Parkinson's disease: a role for α-synuclein?

PubMed

Pozo Devoto, Victorio M; Falzone, Tomas L

2017-09-01

The distinctive pathological hallmarks of Parkinson's disease are the progressive death of dopaminergic neurons and the intracellular accumulation of Lewy bodies enriched in α-synuclein protein. Several lines of evidence from the study of sporadic, familial and pharmacologically induced forms of human Parkinson's disease also suggest that mitochondrial dysfunction plays an important role in disease progression. Although many functions have been proposed for α-synuclein, emerging data from human and animal models of Parkinson's disease highlight a role for α-synuclein in the control of neuronal mitochondrial dynamics. Here, we review the α-synuclein structural, biophysical and biochemical properties that influence relevant mitochondrial dynamic processes such as fusion-fission, transport and clearance. Drawing on current evidence, we propose that α-synuclein contributes to the mitochondrial defects that are associated with the pathology of this common and progressive neurodegenerative disease. © 2017. Published by The Company of Biologists Ltd.

The Role of Fragile Sites in Sporadic Papillary Thyroid Carcinoma

PubMed Central

Dillon, Laura W.; Lehman, Christine E.; Wang, Yuh-Hwa

2012-01-01

The incidence of thyroid cancer is increasing, especially papillary thyroid carcinoma (PTC), making it currently the fastest-growing cancer among women. Reasons for this increase remain unclear, but several risk factors including radiation exposure and improved detection techniques have been suggested. Recently, the induction of chromosomal fragile site breakage was found to result in the formation of RET/PTC1 rearrangements, a common cause of PTC. Chromosomal fragile sites are regions of the genome with a high susceptibility to forming DNA breaks and are often associated with cancer. Exposure to a variety of external agents can induce fragile site breakage, which may account for some of the observed increase in PTC. This paper discusses the role of fragile site breakage in PTC development, external fragile site-inducing agents that may be potential risk factors for PTC, and how these factors are especially targeting women. PMID:22762011

Predicting the risk of multiple endocrine neoplasia type 1 for patients with commonly occurring endocrine tumors.

PubMed

de Laat, Joanne M; Tham, Emma; Pieterman, Carolina R C; Vriens, Menno R; Dorresteijn, Johannes A N; Bots, Michiel L; Nordenskjöld, Magnus; van der Luijt, Rob B; Valk, Gerlof D

2012-08-01

Endocrine diseases that can be part of the rare inheritable syndrome multiple endocrine neoplasia type 1 (MEN1) commonly occur in the general population. Patients at risk for MEN1, and consequently their families, must be identified to prevent morbidity through periodic screening for the detection and treatment of manifestations in an early stage. The aim of the study was to develop a model for predicting MEN1 in individual patients with sporadically occurring endocrine tumors. Cross-sectional study. In a nationwide study in The Netherlands, patients with sporadically occurring endocrine tumors in whom the referring physician suspected the MEN1 syndrome were identified between 1998 and 2011 (n=365). Logistic regression analysis with internal validation using bootstrapping and external validation with a cohort from Sweden was used. A MEN1 mutation was found in 15.9% of 365 patients. Recurrent primary hyperparathyroidism (pHPT; odds ratio (OR) 162.40); nonrecurrent pHPT (OR 25.78); pancreatic neuroendocrine tumors (pNETs) and duodenal NETs (OR 17.94); pituitary tumor (OR 4.71); NET of stomach, thymus, or bronchus (OR 25.84); positive family history of NET (OR 4.53); and age (OR 0.96) predicted MEN1. The c-statistic of the prediction model was 0.86 (95% confidence interval (95% CI) 0.81-0.90) in the derivation cohort and 0.77 (95% CI 0.66-0.88) in the validation cohort. With the prediction model, the risk of MEN1 can be calculated in patients suspected for MEN1 with sporadically occurring endocrine tumors.

NOVEL EFFECTS OF DIOXIN ON BREAST DEVELOPMENT, FUNCTION, AND SUSCEPTIBILITY TO CANCER

EPA Science Inventory

Breast cancer is the most common type of non-dermal cancer among women in this country. Breast cancer risk in women is known to be significantly influenced by genetics, but over 70% of the women that are diagnosed with breast cancer have non-inherited or sporadic cancer. The ris...

Greenhouse thrips, Heliothrips haemorrhoidalis, in California avocado orchards: biological control studies

Treesearch

James A. McMurtry; Mohammad H. Badii

1991-01-01

Greenhouse thrips, Heliothrips haemorrhoidalis (Bouche), on avocado in California, is another case, like pear thrips, of a species being present for many decades but only recently increasing to major pest status. Damaging infestations, previously occurring only sporadically and mainly in areas within a few kilometers of the coast, now are common in...

Prevalence, antimicrobial resistance, and molecular characterization of Campylobacter spp. in bulk tank milk and milk filters from US dairies

USDA-ARS?s Scientific Manuscript database

Campylobacter spp. are frequently isolated from dairy cows as commensal organisms. While sporadic Campylobacter infections in humans in the US are generally attributed to poultry, outbreaks (defined as 2 or more affected people) are commonly associated with dairy products, particularly nonpasteurize...

[Dipylidium caninum, a rare parasite in man].

PubMed

Brandstetter, W; Auer, H

1994-01-01

Dipylidium caninum, the dog tapeworm, is a common cosmopolitan parasite of dogs and cats. Infestations of man are observed only sporadically. We report the case of a 22 months-old child living in Upper Austria with dipylidiasis. The parasite is briefly outlined with respect to biology, epidemiology, clinical features, diagnosis, therapy and prevention.

The dynamics of herpesvirus and polyomavirus reactivation and shedding in healthy adults: a 14-month longitudinal study

NASA Technical Reports Server (NTRS)

Ling, Paul D.; Lednicky, John A.; Keitel, Wendy A.; Poston, David G.; White, Zoe S.; Peng, RongSheng; Liu, Zhensheng; Mehta, Satish K.; Pierson, Duane L.; Rooney, Cliona M.;

A comprehensive review of amyotrophic lateral sclerosis

PubMed Central

Zarei, Sara; Carr, Karen; Reiley, Luz; Diaz, Kelvin; Guerra, Orleiquis; Altamirano, Pablo Fernandez; Pagani, Wilfredo; Lodin, Daud; Orozco, Gloria; Chinea, Angel

2015-01-01

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease affecting motor neurons with an incidence of about 1/100,000. Most ALS cases are sporadic, but 5–10% of the cases are familial ALS. Both sporadic and familial ALS (FALS) are associated with degeneration of cortical and spinal motor neurons. The etiology of ALS remains unknown. However, mutations of superoxide dismutase 1 have been known as the most common cause of FALS. In this study, we provide a comprehensive review of ALS. We cover all aspects of the disease including epidemiology, comorbidities, environmental risk factor, molecular mechanism, genetic factors, symptoms, diagnostic, treatment, and even the available supplement and management of ALS. This will provide the reader with an advantage of receiving a broad range of information about the disease. PMID:26629397

Investigating Bacterial Sources of Toxicity as an Environmental Contributor to Dopaminergic Neurodegeneration

PubMed Central

Caldwell, Kim A.; Tucci, Michelle L.; Armagost, Jafa; Hodges, Tyler W.; Chen, Jue; Memon, Shermeen B.; Blalock, Jeana E.; DeLeon, Susan M.; Findlay, Robert H.; Ruan, Qingmin; Webber, Philip J.; Standaert, David G.; Olson, Julie B.; Caldwell, Guy A.

2009-01-01

Parkinson disease (PD) involves progressive neurodegeneration, including loss of dopamine (DA) neurons from the substantia nigra. Select genes associated with rare familial forms of PD function in cellular pathways, such as the ubiquitin-proteasome system (UPS), involved in protein degradation. The misfolding and accumulation of proteins, such as α-synuclein, into inclusions termed Lewy Bodies represents a clinical hallmark of PD. Given the predominance of sporadic PD among patient populations, environmental toxins may induce the disease, although their nature is largely unknown. Thus, an unmet challenge surrounds the discovery of causal or contributory neurotoxic factors that could account for the prevalence of sporadic PD. Bacteria within the order Actinomycetales are renowned for their robust production of secondary metabolites and might represent unidentified sources of environmental exposures. Among these, the aerobic genera, Streptomyces, produce natural proteasome inhibitors that block protein degradation and may potentially damage DA neurons. Here we demonstrate that a metabolite produced by a common soil bacterium, S. venezuelae, caused DA neurodegeneration in the nematode, Caenorhabditis elegans, which increased as animals aged. This metabolite, which disrupts UPS function, caused gradual degeneration of all neuronal classes examined, however DA neurons were particularly vulnerable to exposure. The presence of DA exacerbated toxicity because neurodegeneration was attenuated in mutant nematodes depleted for tyrosine hydroxylase (TH), the rate-limiting enzyme in DA production. Strikingly, this factor caused dose-dependent death of human SH-SY5Y neuroblastoma cells, a dopaminergic line. Efforts to purify the toxic activity revealed that it is a highly stable, lipophilic, and chemically unique small molecule. Evidence of a robust neurotoxic factor that selectively impacts neuronal survival in a progressive yet moderate manner is consistent with the etiology of age-associated neurodegenerative diseases. Collectively, these data suggest the potential for exposures to the metabolites of specific common soil bacteria to possibly represent a contributory environmental component to PD. PMID:19806188

Novel mutation in the TMEM127 gene associated with phaeochromocytoma.

PubMed

Elston, M S; Meyer-Rochow, G Y; Prosser, D; Love, D R; Conaglen, J V

2013-04-01

Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours that arise from the adrenal glands or paraganglia (paragangliomas) within the abdomen, thorax and neck. Although it was originally suggested that approximately 10% of these tumours were inherited, it is now recognised that up to approximately 30% of these tumours are associated with a germline mutation in one of the phaeochromocytoma/paraganglioma susceptibility genes. Of the 12 currently known genes predisposing to these tumours, the TMEM127 gene is one of the more recently identified and appears to be present in approximately 2% of apparently sporadic phaeochromocytomas. We report a 33-year-old man who presented with an apparently sporadic adrenal phaeochromocytoma and was identified as carrying a novel TMEM127 germline mutation, p.Gln139X. Patients harbouring a germline TMEM127 mutation most commonly present with an apparently sporadic solitary adrenal phaeochromocytoma. Testing patients who present with a phaeochromocytoma or paraganglioma for an underlying germline mutation needs to be considered in all patients due to implications for family members, but a strategy based on clinical and immunohistochemical findings would be prudent to limit costs. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

Comparative genomic analysis identifies a Campylobacter clade deficient in selenium metabolism

USDA-ARS?s Scientific Manuscript database

The non-thermotolerant Campylobacter species C. fetus, C. hyointestinalis, C. iguaniorum and C. lanienae form a distinct phylogenetic cluster within the genus. These species are primarily isolated from foraging (swine) or grazing (e.g. cattle, sheep) animals and cause sporadic and infrequent human i...

Severity of cough in idiopathic pulmonary fibrosis is associated with MUC5 B genotype

PubMed Central

2014-01-01

Background A polymorphism (rs35705950) in the promoter region of the mucin MUC5B is associated with both familial and sporadic forms of idiopathic pulmonary fibrosis. (IPF) We hypothesize that this common MUC5B variant will impact the expression of cough, a frequent disabling symptom seen in subjects with IPF. Methods We genotyped 136 subjects with IPF. All living subjects were provided with a Leicester Cough Questionnaire (LCQ) to measure cough severity. We assessed allele effects of the MUC5B polymorphism on the LCQ scores using SAS General Linear Models (GLM) in the patients with IPF. Results In the 68 of the total 136 IPF patients who returned the LCQ, MUC5B minor allele frequency (T) is consistent with prior published studies (31%). We found a significant independent effect of the T allele on the LCQ score (p = 0.002 for subjects with IPF). This effect is independent of other common causes of cough, including gastroesophogeal reflux disease and upper airway cough syndrome. Conclusions Cough severity, a common disabling phenotypic component of IPF, is significantly associated with the presence of the minor allele of a MUC5B promoter polymorphism. This study highlights a possible genetic mechanism for phenotypic heterogeneity in pulmonary fibrosis. PMID:24667072

Sporadic adult onset dystonia: sensory abnormalities as an endophenotype in unaffected relatives

PubMed Central

Walsh, Richard; O'Dwyer, John P; Sheikh, Ifthikar H; O'Riordan, Sean; Lynch, Tim; Hutchinson, Michael

2007-01-01

Background Most patients with adult onset primary torsion dystonia (AOPTD) have the sporadic form of the disease. They may however be the only manifesting family members of a poorly penetrant genetic disorder. Sensory changes, including structural abnormalities of the primary sensory cortex, are found in AOPTD. Spatial discrimination threshold (SDT), a measure of sensory cortical organisation, is abnormal in AOPTD and in unaffected relatives of patients with familial AOPTD. Our hypothesis was that abnormal SDTs might be found in unaffected relatives of patients with sporadic AOPTD. Methods SDTs were assessed at the index finger bilaterally by a grating orientation task. Normal age related SDTs were derived from 141 control subjects aged 20–64 years. SDTs were considered abnormal when greater than 2.5 SD above the control mean. In total, 105 of 171 (61%) eligible unaffected siblings and offspring of patients with cervical dystonia had SDT examined. Results Fourteen of 48 siblings (29%) and 10 of 57 (18%) offspring were found to have an abnormal SDT. Only five of the 20 patients examined had abnormal SDTs. In 11 of the 25 families, no abnormality was found in an unaffected relative. In the 14 families where at least one unaffected relative had an abnormal SDT, 14 of 37 siblings (38%) and 10 of 33 offspring (30%) had abnormal SDTs. Conclusion Sensory abnormalities found in unaffected relatives of patients with apparently sporadic AOPTD may be a surrogate marker for the carriage of an abnormal gene. PMID:17702779

Retinoblastoma Treatment (PDQ®)—Health Professional Version

Cancer.gov

Retinoblastoma is a tumor that occurs in heritable and sporadic forms. Heritable disease is defined by the presence of a germline mutation of the RB1 gene. Get detailed information about screening, genetic testing, diagnosis, prognosis, and treatment of newly diagnosed and recurrent retinoblastoma in this summary for clinicians.

Is adermatoglyphia an additional feature of Kindler Syndrome?

PubMed

Almeida, Hiram Larangeira de; Goetze, Fernanda Mendes; Fong, Kenneth; Lai-Cheong, Joey; McGrath, John

2015-01-01

A typical feature of Kindler Syndrome is skin fragility; this condition in currently classified as a form of epidermolysis bullosa. We describe a rarely reported feature of two cases, one sporadic and one familial; both patients noticed acquired adermatoglyphia. The loss of dermatoglyphics could be an additional feature of this syndrome.

Palatization in Japanese Mimetics: Response to Mester and Ito.

ERIC Educational Resources Information Center

Schourup, Lawrence; Tamori, Ikuhiro

1992-01-01

Mester and Ito's evidence for the phonological theory of Restricted Underspecification (RU) is refuted. Attention is focused on reduplicated forms; and it is concluded that, if there is only a rough and sporadic sound-syllable meaning association with palatization, the argument for RU is untenable. (12 references) (LB)

Meteoroid Environment Modeling: the Meteoroid Engineering Model and Shower Forecasting

NASA Technical Reports Server (NTRS)

Moorhead, Althea V.

2017-01-01

The meteoroid environment is often divided conceptually into meteor showers plus a sporadic background component. The sporadic complex poses the bulk of the risk to spacecraft, but showers can produce significant short-term enhancements of the meteoroid flux. The Meteoroid Environment Office (MEO) has produced two environment models to handle these cases: the Meteoroid Engineering Model (MEM) and an annual meteor shower forecast. Both MEM and the forecast are used by multiple manned spaceflight projects in their meteoroid risk evaluation, and both tools are being revised to incorporate recent meteor velocity, density, and timing measurements. MEM describes the sporadic meteoroid complex and calculates the flux, speed, and directionality of the meteoroid environment relative to a user-supplied spacecraft trajectory, taking the spacecraft's motion into account. MEM is valid in the inner solar system and offers near-Earth and cis-lunar environments. While the current version of MEM offers a nominal meteoroid environment corresponding to a single meteoroid bulk density, the next version of MEMR3 will offer both flux uncertainties and a density distribution in addition to a revised near-Earth environment. We have updated the near-Earth meteor speed distribution and have made the first determination of uncertainty in this distribution. We have also derived a meteor density distribution from the work of Kikwaya et al. (2011). The annual meteor shower forecast takes the form of a report and data tables that can be used in conjunction with an existing MEM assessment. Fluxes are typically quoted to a constant limiting kinetic energy in order to comport with commonly used ballistic limit equations. For the 2017 annual forecast, the MEO substantially revised the list of showers and their characteristics using 14 years of meteor flux measurements from the Canadian Meteor Orbit Radar (CMOR). Defunct or insignificant showers were removed and the temporal profiles of many showers were improved. In 2016 the MEO also adapted the forecast to the cislunar environment for the first time. We plan to make additional improvements to the model in the next two years using optical meteor flux measurements and mass indices.

A low molecular-weight ferroxidase is increased in the CSF of sCJD cases: CSF ferroxidase and transferrin as diagnostic biomarkers for sCJD

USDA-ARS?s Scientific Manuscript database

Imbalance of brain iron homeostasis is a common feature of neurodegenerative conditions that include sporadic Creutzfeldt-Jakob disease (sCJD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease, among others. However, the mechanisms underlying this change are unclear. In s...

Avian botulism: geographic expansion of a historic disease

USGS Publications Warehouse

Locke, Louis N.; Friend, Milton

1989-01-01

Avian botulism is a paralytic, often fatal disease of birds resulting from ingestion of toxin produced by the bacterium Clostridium botulinum. Waterfowl die-offs from the botulism are usually caused by type C toxin; sporadic die-offs among fish-eating birds, such as common loons (Gavia immer) and gulls, have been caused by type E toxin.

Orthogonal typing methods identify genetic diversity among Belgian Campylobacter jejuni strains isolated over a decade from poultry and cases of sporadic human illness

USDA-ARS?s Scientific Manuscript database

Campylobacter jejuni is a zoonotic pathogen commonly associated with human gastroenteritis. Retail poultry meat is a major food-related transmission source of C. jejuni to humans. The present study investigated the genetic diversity, clonal relationship, and strain risk-ranking of 403 representativ...

Risk factors for sporadic Giardia infection in the USA: a case-control study in Colorado and Minnesota.

PubMed

Reses, H E; Gargano, J W; Liang, J L; Cronquist, A; Smith, K; Collier, S A; Roy, S L; Vanden Eng, J; Bogard, A; Lee, B; Hlavsa, M C; Rosenberg, E S; Fullerton, K E; Beach, M J; Yoder, J S

2018-05-09

Giardia duodenalis is the most common intestinal parasite of humans in the USA, but the risk factors for sporadic (non-outbreak) giardiasis are not well described. The Centers for Disease Control and Prevention and the Colorado and Minnesota public health departments conducted a case-control study to assess risk factors for sporadic giardiasis in the USA. Cases (N = 199) were patients with non-outbreak-associated laboratory-confirmed Giardia infection in Colorado and Minnesota, and controls (N = 381) were matched by age and site. Identified risk factors included international travel (aOR = 13.9; 95% CI 4.9-39.8), drinking water from a river, lake, stream, or spring (aOR = 6.5; 95% CI 2.0-20.6), swimming in a natural body of water (aOR = 3.3; 95% CI 1.5-7.0), male-male sexual behaviour (aOR = 45.7; 95% CI 5.8-362.0), having contact with children in diapers (aOR = 1.6; 95% CI 1.01-2.6), taking antibiotics (aOR = 2.5; 95% CI 1.2-5.0) and having a chronic gastrointestinal condition (aOR = 1.8; 95% CI 1.1-3.0). Eating raw produce was inversely associated with infection (aOR = 0.2; 95% CI 0.1-0.7). Our results highlight the diversity of risk factors for sporadic giardiasis and the importance of non-international-travel-associated risk factors, particularly those involving person-to-person transmission. Prevention measures should focus on reducing risks associated with diaper handling, sexual contact, swimming in untreated water, and drinking untreated water.

The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder.

PubMed

Smith, Bradley N; Newhouse, Stephen; Shatunov, Aleksey; Vance, Caroline; Topp, Simon; Johnson, Lauren; Miller, Jack; Lee, Younbok; Troakes, Claire; Scott, Kirsten M; Jones, Ashley; Gray, Ian; Wright, Jamie; Hortobágyi, Tibor; Al-Sarraj, Safa; Rogelj, Boris; Powell, John; Lupton, Michelle; Lovestone, Simon; Sapp, Peter C; Weber, Markus; Nestor, Peter J; Schelhaas, Helenius J; Asbroek, Anneloor Alm Ten; Silani, Vincenzo; Gellera, Cinzia; Taroni, Franco; Ticozzi, Nicola; Van den Berg, Leonard; Veldink, Jan; Van Damme, Phillip; Robberecht, Wim; Shaw, Pamela J; Kirby, Janine; Pall, Hardev; Morrison, Karen E; Morris, Alex; de Belleroche, Jacqueline; Vianney de Jong, J M B; Baas, Frank; Andersen, Peter M; Landers, John; Brown, Robert H; Weale, Michael E; Al-Chalabi, Ammar; Shaw, Christopher E

2013-01-01

A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.

Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia.

PubMed

Churchman, Michelle L; Qian, Maoxiang; Te Kronnie, Geertruy; Zhang, Ranran; Yang, Wenjian; Zhang, Hui; Lana, Tobia; Tedrick, Paige; Baskin, Rebekah; Verbist, Katherine; Peters, Jennifer L; Devidas, Meenakshi; Larsen, Eric; Moore, Ian M; Gu, Zhaohui; Qu, Chunxu; Yoshihara, Hiroki; Porter, Shaina N; Pruett-Miller, Shondra M; Wu, Gang; Raetz, Elizabeth; Martin, Paul L; Bowman, W Paul; Winick, Naomi; Mardis, Elaine; Fulton, Robert; Stanulla, Martin; Evans, William E; Relling, Mary V; Pui, Ching-Hon; Hunger, Stephen P; Loh, Mignon L; Handgretinger, Rupert; Nichols, Kim E; Yang, Jun J; Mullighan, Charles G

2018-05-14

Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique variants in 45 children. The majority of variants adversely affected IKZF1 function and drug responsiveness of leukemic cells. These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL. Copyright © 2018 Elsevier Inc. All rights reserved.

Mosaic parental germline mutations causing recurrent forms of malformations of cortical development

PubMed Central

Zillhardt, Julia Lauer; Poirier, Karine; Broix, Loïc; Lebrun, Nicolas; Elmorjani, Adrienne; Martinovic, Jelena; Saillour, Yoann; Muraca, Giuseppe; Nectoux, Juliette; Bessieres, Bettina; Fallet-Bianco, Catherine; Lyonnet, Stanislas; Dulac, Olivier; Odent, Sylvie; Rejeb, Imen; Jemaa, Lamia Ben; Rivier, Francois; Pinson, Lucile; Geneviève, David; Musizzano, Yuri; Bigi, Nicole; Leboucq, Nicolas; Giuliano, Fabienne; Philip, Nicole; Vilain, Catheline; Van Bogaert, Patrick; Maurey, Hélène; Beldjord, Cherif; Artiguenave, François; Boland, Anne; Olaso, Robert; Masson, Cécile; Nitschké, Patrick; Deleuze, Jean-François; Bahi-Buisson, Nadia; Chelly, Jamel

2016-01-01

To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of cortical development (MCD). Interestingly, four families with parental germline variants, out of 18, were identified by whole-exome sequencing (WES), including a variant in a new candidate gene, syntaxin 7. In view of this high frequency, revision of diagnostic strategies and reoccurrence risk should be considered not only for the recurrent forms, but also for the sporadic cases of MCD. PMID:26395554

FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis

PubMed Central

Deng, Han-Xiang; Zhai, Hong; Bigio, Eileen H.; Yan, Jianhua; Fecto, Faisal; Ajroud, Kaouther; Mishra, Manjari; Ajroud-Driss, Senda; Heller, Scott; Sufit, Robert; Siddique, Nailah; Mugnaini, Enrico; Siddique, Teepu

2014-01-01

Objective Amyotrophic lateral sclerosis (ALS) is a fatal disorder of motor neuron degeneration. Most cases of ALS are sporadic (SALS), but about 5-10% of ALS cases are familial (FALS). Recent studies have shown that mutations in FUS are causal in approximately 4-5% of FALS and some apparent SALS cases. The pathogenic mechanism of the mutant FUS-mediated ALS and potential roles of FUS in non-FUS ALS remain to be investigated. Methods Immunostaining was performed on postmortem spinal cords from 78 ALS cases, including SALS (n=52), ALS with dementia (ALS/dementia, n=10) and FALS (n=16). In addition, postmortem brains or spinal cords from 22 cases with or without frontotemporal lobar degeneration (FTLD) were also studied. In total, 100 cases were studied. Results FUS-immunoreactive inclusions were observed in spinal anterior horn neurons in all sporadic and familial ALS cases, except for those with SOD1 mutations. The FUS-containing inclusions were also immunoreactive with antibodies to TDP43, p62 and ubiquitin. A fraction of tested FUS antibodies recognized FUS inclusions and an unusual antigen retrieval appeared to be important for detection of the skein-like FUS inclusions. Interpretation Although mutations in FUS account for only a small fraction of FALS and SALS, our data suggest that FUS protein may be a common component of the cellular inclusions in non-SOD1 ALS and some other neurodegenerative conditions, implying a shared pathogenic pathway underlying SALS, non-SOD1 FALS, ALS/dementia and related disorders. Our data also indicate that SOD1-linked ALS may have a distinct pathogenic pathway from SALS and other types of FALS. PMID:20517935

Amyotrophic lateral sclerosis immunoglobulins increase Ca2+ currents in a motoneuron cell line.

PubMed

Mosier, D R; Baldelli, P; Delbono, O; Smith, R G; Alexianu, M E; Appel, S H; Stefani, E

1995-01-01

The sporadic form of amyotrophic lateral sclerosis (ALS) is an idiopathic and eventually lethal disorder causing progressive degeneration of cortical and spinal motoneurons. Recent studies have shown that the majority of patients with sporadic ALS have serum antibodies that bind to purified L-type voltage-gated calcium channels and that antibody titer correlates with the rate of disease progression. Furthermore, antibodies purified from ALS patient sera have been found to alter the physiologic function of voltage-gated calcium channels in nonmotoneuron cell types. Using whole-cell patch-clamp techniques, immunoglobulins purified from sera of 5 of 6 patients with sporadic ALS are now shown to increase calcium currents in a hybrid motoneuron cell line, VSC4.1. These calcium currents are blocked by the polyamine funnel-web spider toxin FTX, which has previously been shown to block Ca2+ currents and evoked transmitter release at mammalian motoneuron terminals. These data provide additional evidence linking ALS to an autoimmune process and suggest that antibody-induced increases in calcium entry through voltage-gated calcium channels may occur in motoneurons in this disease, with possible deleterious effects in susceptible neurons.

Gentle Heating by Mixing in Cooling Flow Clusters

NASA Astrophysics Data System (ADS)

Hillel, Shlomi; Soker, Noam

2017-08-01

We analyze 3D hydrodynamical simulations of the interaction of jets and the bubbles they inflate with the intracluster medium (ICM) and show that the heating of the ICM by mixing hot bubble gas with the ICM operates over tens of millions of years and hence can smooth the sporadic activity of the jets. The inflation process of hot bubbles by propagating jets forms many vortices, and these vortices mix the hot bubble gas with the ICM. The mixing, and hence the heating of the ICM, starts immediately after the jets are launched, but continues for tens of millions of years. We suggest that the smoothing of the active galactic nucleus (AGN) sporadic activity by the long-lived vortices accounts for the recent finding of a gentle energy coupling between AGN heating and the ICM.

Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning.

PubMed

Dodson, Mark W; Zhang, Ting; Jiang, Changan; Chen, Shengdi; Guo, Ming

2012-03-15

LRRK2 (PARK8) is the most common genetic determinant of Parkinson's disease (PD), with dominant mutations in LRRK2 causing inherited PD and sequence variation at the LRRK2 locus associated with increased risk for sporadic PD. Although LRRK2 has been implicated in diverse cellular processes encompassing almost all cellular compartments, the precise functions of LRRK2 remain unclear. Here, we show that the Drosophila homolog of LRRK2 (Lrrk) localizes to the membranes of late endosomes and lysosomes, physically interacts with the crucial mediator of late endosomal transport Rab7 and negatively regulates rab7-dependent perinuclear localization of lysosomes. We also show that a mutant form of lrrk analogous to the pathogenic LRRK2(G2019S) allele behaves oppositely to wild-type lrrk in that it promotes rather than inhibits rab7-dependent perinuclear lysosome clustering, with these effects of mutant lrrk on lysosome position requiring both microtubules and dynein. These data suggest that LRRK2 normally functions in Rab7-dependent lysosomal positioning, and that this function is disrupted by the most common PD-causing LRRK2 mutation, linking endolysosomal dysfunction to the pathogenesis of LRRK2-mediated PD.

Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning

PubMed Central

Dodson, Mark W.; Zhang, Ting; Jiang, Changan; Chen, Shengdi; Guo, Ming

2012-01-01

LRRK2 (PARK8) is the most common genetic determinant of Parkinson's disease (PD), with dominant mutations in LRRK2 causing inherited PD and sequence variation at the LRRK2 locus associated with increased risk for sporadic PD. Although LRRK2 has been implicated in diverse cellular processes encompassing almost all cellular compartments, the precise functions of LRRK2 remain unclear. Here, we show that the Drosophila homolog of LRRK2 (Lrrk) localizes to the membranes of late endosomes and lysosomes, physically interacts with the crucial mediator of late endosomal transport Rab7 and negatively regulates rab7-dependent perinuclear localization of lysosomes. We also show that a mutant form of lrrk analogous to the pathogenic LRRK2G2019S allele behaves oppositely to wild-type lrrk in that it promotes rather than inhibits rab7-dependent perinuclear lysosome clustering, with these effects of mutant lrrk on lysosome position requiring both microtubules and dynein. These data suggest that LRRK2 normally functions in Rab7-dependent lysosomal positioning, and that this function is disrupted by the most common PD-causing LRRK2 mutation, linking endolysosomal dysfunction to the pathogenesis of LRRK2-mediated PD. PMID:22171073

Is adermatoglyphia an additional feature of Kindler Syndrome?*

PubMed Central

de Almeida Jr, Hiram Larangeira; Goetze, Fernanda Mendes; Fong, Kenneth; Lai-Cheong, Joey; McGrath, John

2015-01-01

A typical feature of Kindler Syndrome is skin fragility; this condition in currently classified as a form of epidermolysis bullosa. We describe a rarely reported feature of two cases, one sporadic and one familial; both patients noticed acquired adermatoglyphia. The loss of dermatoglyphics could be an additional feature of this syndrome. PMID:26375235

Role of Genetic Factors in the Pathogenesis of Radial Deficiencies in Humans

PubMed Central

Elmakky, Amira; Stanghellini, Ilaria; Landi, Antonio; Percesepe, Antonio

2015-01-01

Radial deficiencies (RDs), defined as under/abnormal development or absence of any of the structures of the forearm, radial carpal bones and thumb, occur with a live birth incidence ranging from 1 out of 30,000 to 1 out 6,000 newborns and represent about one third/one fourth of all the congenital upper limb anomalies. About half of radial disorders have a mendelian cause and pattern of inheritance, whereas the remaining half appears sporadic with no known gene involved. In sporadic forms certain anomalies, such as thumb or radial hypoplasia, may occur either alone or in association with systemic conditions, like vertebral abnormalities or renal defects. All the cases with a mendelian inheritance are syndromic forms, which include cardiac defects (in Holt-Oram syndrome), bone marrow failure (in Fanconi anemia), platelet deficiency (in thrombocytopenia-absent-radius syndrome), ocular motility impairment (in Okihiro syndrome). The genetics of radial deficiencies is complex, characterized by genetic heterogeneity and high inter- and intra-familial clinical variability: this review will analyze the etiopathogenesis and the genotype/phenotype correlations of the main radial deficiency disorders in humans. PMID:26962299

Hashimoto thyroiditis: clinical and diagnostic criteria.

PubMed

Caturegli, P; De Remigis, A; Rose, N R

2014-01-01

Hashimoto thyroiditis (HT), now considered the most common autoimmune disease, was described over a century ago as a pronounced lymphoid goiter affecting predominantly women. In addition to this classic form, several other clinico-pathologic entities are now included under the term HT: fibrous variant, IgG4-related variant, juvenile form, Hashitoxicosis, and painless thyroiditis (sporadic or post-partum). All forms are characterized pathologically by the infiltration of hematopoietic mononuclear cells, mainly lymphocytes, in the interstitium among the thyroid follicles, although specific features can be recognized in each variant. Thyroid cells undergo atrophy or transform into a bolder type of follicular cell rich in mitochondria called Hürthle cell. Most HT forms ultimately evolve into hypothyroidism, although at presentation patients can be euthyroid or even hyperthyroid. The diagnosis of HT relies on the demonstration of circulating antibodies to thyroid antigens (mainly thyroperoxidase and thyroglobulin) and reduced echogenicity on thyroid sonogram in a patient with proper clinical features. The treatment remains symptomatic and based on the administration of synthetic thyroid hormones to correct the hypothyroidism as needed. Surgery is performed when the goiter is large enough to cause significant compression of the surrounding cervical structures, or when some areas of the thyroid gland mimic the features of a nodule whose cytology cannot be ascertained as benign. HT remains a complex and ever expanding disease of unknown pathogenesis that awaits prevention or novel forms of treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

Outbreak bias in illness reporting and case confirmation in ciguatera fish poisoning surveillance in south Florida.

PubMed

Begier, Elizabeth M; Backer, Lorraine C; Weisman, Richard S; Hammond, Roberta M; Fleming, Lora E; Blythe, Donna

2006-01-01

Ciguatera fish poisoning is a potentially life-threatening disease caused by eating coral reef fish contaminated with ciguatoxins and is the most common marine poisoning. However, existing surveillance systems capture few cases. To improve regional ciguatera surveillance in South Florida, this study compared ciguatera illnesses in the Florida Poison Information Center-Miami (FPICM) call database to ciguatera cases in the Florida Department of Health (FDOH) disease surveillance systems. Univariate and multivariate logistic regression were used to identify predictors of when FPICM reported ciguatera illnesses to FDOH and whether FDOH confirmed reported ciguatera cases. FPICM staff preferentially reported ciguatera illnesses that were of shorter duration (adjusted odds ratio [AOR] = 0.84 per additional illness day; 95% confidence interval [CI] 0.74, 0.97); outbreak-associated (AOR = 7.0; 95% CI 2.5, 19.5); and clinically more severe (AOR = 21.6; 95% CI 2.3, 198.5). Among ciguatera illnesses reported to FDOH, outbreak-associated illnesses were more likely than single, sporadic illnesses to become confirmed surveillance cases (crude OR = 11.1; 95% CI 2.0, 62.5). The over-representation of outbreak-associated ciguatera cases underestimates the true contribution of sporadic illnesses to ciguatera disease burden. This bias should be considered when evaluating surveillance systems that include both outbreak-associated and sporadic illness reports.

A qualitative examination of the effects of international counter-drug interdictions.

PubMed

Toth, Alexander G; Mitchell, Ojmarrh

2018-05-01

The purpose of this study is to utilize unique qualitative data to determine the effects of sporadic international drug interdictions on drug trafficking, and to assess whether the responses of drug traffickers align with rational choice theory. Qualitative data obtained from 23 high-level United States Drug Enforcement Administration (DEA) informants, who are embedded in international drug trafficking groups, are examined to identify common responses to drug interdiction operations. The findings indicate that sporadic counter-drug interdictions do not a have permanent deterrent effect on transnational drug smuggling operations. However, these types of law enforcement operations produce temporary alterations in drug trafficking, as traffickers adopted a variety of methods to thwart the efforts of law enforcement-often by relying on information acquired from corrupt local law enforcement. The results also indicate that while interdiction operations displaced trafficking activities (temporally, spatially, and methodological), there is little evidence that drug traffickers responded to such operations by moving into new areas (i.e., malign spatial displacement). Sporadic international drug interdiction programs do little to deter drug trafficking organizations (DTOs) from engaging in their illicit trade. Instead, DTOs adjust in a calculating manner to these operations to ensure that their illegal products reach consumer marketplaces, which is congruent with the rational choice theoretical perspective. Copyright © 2018 Elsevier B.V. All rights reserved.

Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain

PubMed Central

Andriani, Grasiella A.; Vijg, Jan; Montagna, Cristina

2017-01-01

Aneuploidy and polyploidy are a form of Genomic Instability (GIN) known as Chromosomal Instability (CIN) characterized by sporadic abnormalities in chromosome copy numbers. Aneuploidy is commonly linked to pathological states. It is a hallmark of spontaneous abortions and birth defects and it is observed virtually in every human tumor, therefore being generally regarded as detrimental for the development or the maturation of tissues under physiological conditions. Polyploidy however, occurs as part of normal physiological processes during maturation and differentiation of some mammalian cell types. Surprisingly, high levels of aneuploidy are present in the brain, and their frequency increases with age suggesting that the brain is able to maintain its functionality in the presence of high levels of mosaic aneuploidy. Because somatic aneuploidy with age can reach exceptionally high levels, it is likely to have long-term adverse effects in this organ. We describe the mechanisms accountable for an abnormal DNA content with a particular emphasis on the CNS where cell division is limited. Next, we briefly summarize the types of GIN known to date and discuss how they interconnect with CIN. Lastly we highlight how several forms of CIN may contribute to genetic variation, tissue degeneration and disease in the CNS. PMID:27013377

Meteoric metal layers in the atmosphere of Mars

NASA Astrophysics Data System (ADS)

Plane, John; Whalley, Charlotte

Radio occultation measurements from several spacecraft (e.g., Mars Express, Mars Global Sur-veyor) have revealed the presence of a "third" ion layer in the Martian atmosphere, which occurs sporadically around 90 km. Because this is the aerobraking region of the atmosphere, and the layers resemble sporadic E layers observed in the terrestrial atmosphere, it has been proposed that these layers consist of metallic ions (principally Fe+ and Mg+ ). A major problem with this hypothesis is that we have shown recently that metallic ions re-combine rapidly in a CO2 -rich atmosphere, both because of the efficiency of CO2 as the "third body" and because of the very low temperatures (about 140 K). In fact, both Fe+ and Mg+ form CO2 cluster ions about 200 times faster than current Mars models predict. These cluster ions should rapidly be destroyed by dissociative recombination with electrons, so that sporadic layers containing metallic ions would have lifetimes of only minutes. We will present a new laboratory study of all the reactions that appear to be required to solve this problem. Most importantly, we will show that the reactions of molecular magnesium ions (Mg+ .CO2 , MgO2 + and MgO+ ) with atomic O are about 20 times faster than expected. The laboratory will then be used to construct a new model of the Martian upper atmosphere, which demonstrates that the sporadic third layers must largely be composed of Mg+ and not Fe+ . These layers should then have lifetimes of more than 10 hours, in accord with observations from Mars Express made on successive orbits.

Sequencing of sporadic Attention-Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder.

PubMed

Kim, Daniel Seung; Burt, Amber A; Ranchalis, Jane E; Wilmot, Beth; Smith, Joshua D; Patterson, Karynne E; Coe, Bradley P; Li, Yatong K; Bamshad, Michael J; Nikolas, Molly; Eichler, Evan E; Swanson, James M; Nigg, Joel T; Nickerson, Deborah A; Jarvik, Gail P

2017-06-01

Attention-Deficit Hyperactivity Disorder (ADHD) has high heritability; however, studies of common variation account for <5% of ADHD variance. Using data from affected participants without a family history of ADHD, we sought to identify de novo variants that could account for sporadic ADHD. Considering a total of 128 families, two analyses were conducted in parallel: first, in 11 unaffected parent/affected proband trios (or quads with the addition of an unaffected sibling) we completed exome sequencing. Six de novo missense variants at highly conserved bases were identified and validated from four of the 11 families: the brain-expressed genes TBC1D9, DAGLA, QARS, CSMD2, TRPM2, and WDR83. Separately, in 117 unrelated probands with sporadic ADHD, we sequenced a panel of 26 genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD) to evaluate whether variation in ASD/ID-associated genes were also present in participants with ADHD. Only one putative deleterious variant (Gln600STOP) in CHD1L was identified; this was found in a single proband. Notably, no other nonsense, splice, frameshift, or highly conserved missense variants in the 26 gene panel were identified and validated. These data suggest that de novo variant analysis in families with independently adjudicated sporadic ADHD diagnosis can identify novel genes implicated in ADHD pathogenesis. Moreover, that only one of the 128 cases (0.8%, 11 exome, and 117 MIP sequenced participants) had putative deleterious variants within our data in 26 genes related to ID and ASD suggests significant independence in the genetic pathogenesis of ADHD as compared to ASD and ID phenotypes. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Family history of cancer and risk of sporadic differentiated thyroid carcinoma.

PubMed

Xu, Li; Li, Guojun; Wei, Qingyi; El-Naggar, Adel K; Sturgis, Erich M

2012-03-01

Thyroid cancer incidence in the United States, particularly in women, has increased dramatically since the 1980s. Although the causes of thyroid cancer in most patients remain largely unknown, evidence suggests the existence of an inherited predisposition to development of differentiated thyroid carcinoma (DTC). Therefore, the authors explored the association between sporadic DTC and family history of cancer. In a retrospective hospital-based case-control study of prospectively recruited subjects who completed the study questionnaire upon enrollment, unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as estimates of the DTC risk associated with first-degree family history of cancer. The study included 288 patients with sporadic DTC and 591 cancer-free controls. Family history of thyroid cancer in first-degree relatives was associated with increased DTC risk (adjusted OR, 4.1; 95% CI, 1.7-9.9). All DTC cases in patients with a first-degree family history of thyroid cancer were cases of papillary thyroid carcinoma (PTC) (adjusted OR, 4.6; 95% CI, 1.9-11.1). Notably, the risk of PTC was highest in subjects with a family history of thyroid cancer in siblings (OR, 7.4; 95% CI, 1.8-30.4). In addition, multifocal primary tumor was more common among PTC patients with first-degree family history of thyroid cancer than among PTC patients with no first-degree family history of thyroid cancer (68.8% vs 35.5%, P = .01). The study suggests that family history of thyroid cancer in first-degree relatives, particularly in siblings, is associated with an increased risk of sporadic PTC. Copyright © 2011 American Cancer Society.

Family History of Cancer and Risk of Sporadic Differentiated Thyroid Carcinoma

PubMed Central

Xu, Li; Li, Guojun; Wei, Qingyi; El-Naggar, Adel K.; Sturgis, Erich M.

2011-01-01

BACKGROUND Thyroid cancer incidence in the United States, particularly in women, has increased dramatically since 1980s. While the causes of thyroid cancer in most patients remain largely unknown, evidence suggests the existence of an inherited predisposition to development of differentiated thyroid cancer (DTC). Therefore, we explored the association between sporadic DTC and family history of cancer. METHODS In a retrospective hospital-based case-control study of prospectively recruited subjects who completed the study questionnaire upon enrollment, unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as estimates of the DTC risk associated with first-degree family history of cancer. RESULTS The study included 288 patients with sporadic DTC and 591 cancer-free controls. Family history of thyroid cancer in first-degree relatives was associated with increased DTC risk (adjusted OR = 4.1, 95% CI: 1.7–9.9). All DTC cases in patients with a first-degree family history of thyroid cancer were cases of papillary thyroid carcinoma (PTC) (adjusted OR = 4.6, 95 CI%: 1.9–11.1). Notably, the risk of PTC was highest in subjects with a family history of thyroid cancer in siblings (OR = 7.4, 95% CI: 1.8–30.4). In addition, multifocal primary tumor was more common among PTC patients with first-degree family history of thyroid cancer than among PTC patients with no first-degree family history of thyroid cancer (68.8% vs. 35.5%, p = 0.01). CONCLUSIONS Our study suggests that family history of thyroid cancer in first-degree relatives, particularly in siblings, is associated with an increased risk of sporadic PTC. PMID:21800288

Exome Sequencing in the Clinical Diagnosis of Sporadic or Familial Cerebellar Ataxia

PubMed Central

Fogel, Brent L.; Lee, Hane; Deignan, Joshua L.; Strom, Samuel P.; Kantarci, Sibel; Wang, Xizhe; Quintero-Rivera, Fabiola; Vilain, Eric; Grody, Wayne W.; Perlman, Susan; Geschwind, Daniel H.; Nelson, Stanley F.

2015-01-01

IMPORTANCE Cerebellar ataxias are a diverse collection of neurologic disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established. OBJECTIVE To investigate the contribution of genetic disease in a population of patients with predominantly adult- and sporadic-onset cerebellar ataxia. DESIGN, SETTING, AND PARTICIPANTS We examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia. MAIN OUTCOMES AND MEASURES Next-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation. RESULTS We identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias. CONCLUSIONS AND RELEVANCE This study demonstrated that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high-yield test, providing a definitive diagnosis in more than one-fifth of patients and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Therefore, clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia. PMID:25133958

Inclusion Body Myositis

PubMed Central

Dimachkie, Mazen M.; Barohn, Richard J.

2012-01-01

The idiopathic inflammatory myopathies are a group of rare disorders that share many similarities. These include dermatomyositis (DM), polymyositis (PM), necrotizing myopathy (NM), and sporadic inclusion body myositis (IBM). Inclusion body myositis is the most common idiopathic inflammatory myopathy after age 50 and it presents with chronic proximal leg and distal arm asymmetric mucle weakness. Despite similarities with PM, it is likely that IBM is primarily a degenerative disorder rather than an inflammatory muscle disease. Inclusion body myositis is associated with a modest degree of creatine kinase (CK) elevation and an abnormal electromyogram demonstrating an irritative myopathy with some chronicity. The muscle histopathology demonstrates inflammatory exudates surrounding and invading nonnecrotic muscle fibers often times accompanied by rimmed vacuoles. In this chapter, we review sporadic IBM. We also examine past, essentially negative, clinical trials in IBM and review ongoing clinical trials. For further details on DM, PM, and NM, the reader is referred to the idiopathic inflammatory myopathies chapter. PMID:23117948

Association study between XRCC1 gene polymorphisms and sporadic amyotrophic lateral sclerosis.

PubMed

Coppedè, Fabio; Migheli, Francesca; Lo Gerfo, Annalisa; Fabbrizi, Maria Rita; Carlesi, Cecilia; Mancuso, Michelangelo; Corti, Stefania; Mezzina, Nicoletta; del Bo, Roberto; Comi, Giacomo P; Siciliano, Gabriele; Migliore, Lucia

2010-01-01

The aim of the present study was to investigate the possible contribution of three common functional polymorphisms in the DNA repair protein X-ray repair cross-complementing group 1 (XRCC1), namely Arg194Trp (rs1799782), Arg280His (rs25489) and Arg399Gln (rs25487), to sporadic amyotrophic lateral sclerosis (SALS). We genotyped 206 Italian SALS patients and 203 matched controls for XRCC1 Arg194Trp, Arg280His and Arg399Gln polymorphisms by means of PCR/RFLP technique, searching for association between any of the studied polymorphisms and disease risk, age and site of onset. We observed a statistically significant difference in XRCC1 Gln399 allele frequencies between SALS cases and controls (0.39/0.28; p=0.001). The present study suggests that the XRCC1 Arg399Gln polymorphism might contribute to SALS risk.

The Genomic Architecture of Sporadic Heart Failure

PubMed Central

Dorn, Gerald W

2011-01-01

Common or sporadic systolic heart failure (heart failure) is the clinical syndrome of insufficient forward cardiac output resulting from myocardial disease. Most heart failure is the consequence of ischemic or idiopathic cardiomyopathy. There is a clear familial predisposition to heart failure, with a genetic component estimated to confer between 20 and 30% of overall risk. The multifactorial etiology of this syndrome has complicated identification of its genetic underpinnings. Until recently, almost all genetic studies of heart failure were designed and deployed according to the common disease-common variant hypothesis, in which individual risk alleles impart a small positive or negative effect and overall genetic risk is the cumulative impact of all functional genetic variations. Early studies employed a candidate gene approach, focused mainly on factors within adrenergic and renin-angiotensin pathways that affect heart failure progression and are targeted by standard pharmacotherapeutics. Many of these reported allelic associations with heart failure have not been replicated. However, the preponderance of data support risk-modifier effects for the Arg389Gly polymorphism of β1-adrenergic receptors and the intron 16 in/del polymorphism of angiotensin converting enzyme. Recent unbiased studies using genome-wide single nucleotide polymorphism (SNP) microarrays have shown fewer positive results than when these platforms were applied to hypertension, myocardial infarction, or diabetes, possibly reflecting the complex etiology of heart failure. A new cardiovascular gene-centric sub-genome SNP array identified a common heat failure risk allele at 1p36 in multiple independent cohorts, but the biological mechanism for this association is still uncertain. It is likely that common gene polymorphisms account for only a fraction of individual genetic heart failure risk, and future studies using deep resequencing are likely to identify rare gene variants with larger biological effects. PMID:21566223

Epigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma

PubMed Central

Mehdi, Ali; Riazalhosseini, Yasser

2017-01-01

Clear cell renal cell carcinoma (ccRCC), the most common form of Kidney cancer, is characterized by frequent mutations of the von Hippel-Lindau (VHL) tumor suppressor gene in ~85% of sporadic cases. Loss of pVHL function affects multiple cellular processes, among which the activation of hypoxia inducible factor (HIF) pathway is the best-known function. Constitutive activation of HIF signaling in turn activates hundreds of genes involved in numerous oncogenic pathways, which contribute to the development or progression of ccRCC. Although VHL mutations are considered as drivers of ccRCC, they are not sufficient to cause the disease. Recent genome-wide sequencing studies of ccRCC have revealed that mutations of genes coding for epigenome modifiers and chromatin remodelers, including PBRM1, SETD2 and BAP1, are the most common somatic genetic abnormalities after VHL mutations in these tumors. Moreover, recent research has shed light on the extent of abnormal epigenome alterations in ccRCC tumors, including aberrant DNA methylation patterns, abnormal histone modifications and deregulated expression of non-coding RNAs. In this review, we discuss the epigenetic modifiers that are commonly mutated in ccRCC, and our growing knowledge of the cellular processes that are impacted by them. Furthermore, we explore new avenues for developing therapeutic approaches based on our knowledge of epigenome aberrations of ccRCC. PMID:28812986

Epigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma.

PubMed

Mehdi, Ali; Riazalhosseini, Yasser

2017-08-16

Clear cell renal cell carcinoma (ccRCC), the most common form of Kidney cancer, is characterized by frequent mutations of the von Hippel-Lindau ( VHL ) tumor suppressor gene in ~85% of sporadic cases. Loss of pVHL function affects multiple cellular processes, among which the activation of hypoxia inducible factor (HIF) pathway is the best-known function. Constitutive activation of HIF signaling in turn activates hundreds of genes involved in numerous oncogenic pathways, which contribute to the development or progression of ccRCC. Although VHL mutations are considered as drivers of ccRCC, they are not sufficient to cause the disease. Recent genome-wide sequencing studies of ccRCC have revealed that mutations of genes coding for epigenome modifiers and chromatin remodelers, including PBRM1 , SETD2 and BAP1 , are the most common somatic genetic abnormalities after VHL mutations in these tumors. Moreover, recent research has shed light on the extent of abnormal epigenome alterations in ccRCC tumors, including aberrant DNA methylation patterns, abnormal histone modifications and deregulated expression of non-coding RNAs. In this review, we discuss the epigenetic modifiers that are commonly mutated in ccRCC, and our growing knowledge of the cellular processes that are impacted by them. Furthermore, we explore new avenues for developing therapeutic approaches based on our knowledge of epigenome aberrations of ccRCC.

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

PubMed Central

Smith, Bradley N; Newhouse, Stephen; Shatunov, Aleksey; Vance, Caroline; Topp, Simon; Johnson, Lauren; Miller, Jack; Lee, Younbok; Troakes, Claire; Scott, Kirsten M; Jones, Ashley; Gray, Ian; Wright, Jamie; Hortobágyi, Tibor; Al-Sarraj, Safa; Rogelj, Boris; Powell, John; Lupton, Michelle; Lovestone, Simon; Sapp, Peter C; Weber, Markus; Nestor, Peter J; Schelhaas, Helenius J; Asbroek, Anneloor ALM ten; Silani, Vincenzo; Gellera, Cinzia; Taroni, Franco; Ticozzi, Nicola; Van den Berg, Leonard; Veldink, Jan; Van Damme, Phillip; Robberecht, Wim; Shaw, Pamela J; Kirby, Janine; Pall, Hardev; Morrison, Karen E; Morris, Alex; de Belleroche, Jacqueline; Vianney de Jong, J M B; Baas, Frank; Andersen, Peter M; Landers, John; Brown, Robert H; Weale, Michael E; Al-Chalabi, Ammar; Shaw, Christopher E

2013-01-01

A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/−FTD from five European cohorts (total n=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/−FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/−FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10−8). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe. PMID:22692064

Clinical and Imaging Presentation of a Patient with Beta-Propeller Protein-Associated Neurodegeneration, a Rare and Sporadic form of Neurodegeneration with Brain Iron Accumulation (NBIA).

PubMed

Hattingen, Elke; Handke, Nikolaus; Cremer, Kirsten; Hoffjan, Sabine; Kukuk, Guido Matthias

2017-12-01

Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of inherited neurologic disorders with iron accumulation in the basal ganglia, which share magnetic resonance (MR) imaging characteristics, histopathologic and clinical features. According to the affected basal nuclei, clinical features include extrapyramidal movement disorders and varying degrees of intellectual disability status. The most common NBIA subtype is caused by pathogenic variants in PANK2. The hallmark of MR imaging in patients with PANK2 mutations is an eye-of-the-tiger sign in the globus pallidus. We report a 33-year-old female with a rare subtype of NBIA, called beta-propeller protein-associated neurodegeneration (BPAN) with a hitherto unknown missense variant in WDR45. She presented with BPAN's particular biphasic course of neurological symptoms and with a dominant iron accumulation in the midbrain that enclosed a spotty T2-hyperintensity.

Familial polythelia over three generations with polymastia in the youngest girl.

PubMed

Galli-Tsinopoulou, A; Krohn, C; Schmidt, H

2001-06-01

Supernumerary nipples or polythelia are developmental abnormalities located along the embryonic mammary lines. It is the most common form of accessory breast tissue malformation and usually occurs sporadically but familial aggregation has been reported. Polythelia has been reported in association with congenital malformations, in particular with renal anomalies. Polymastia in female patients has been reported to manifest usually during pregnancy or lactation. We report on a pedigree with six cases of polythelia over three generations and one case of polythelia and polymastia in the youngest member of this family. The girl (11 years old ) had in addition to six supernumerary nipples, an accessory breast gland located under the normal left breast. No other congenital malformations could be detected. This girl will remain under follow-up until the end of puberty when the accessory breast gland will be removed. Manifestation of polymastia during puberty rarely has been reported. Polymastia may appear with familial polythelia even without renal anomalies.

Anesthesia and Tau Pathology

PubMed Central

Whittington, Robert A.; Bretteville, Alexis; Dickler, Maya F.; Planel, Emmanuel

2013-01-01

Alzheimer’s disease (AD) is the most common form of dementia and remains a growing worldwide health problem. As life expectancy continues to increase, the number of AD patients presenting for surgery and anesthesia will steadily rise. The etiology of sporadic AD is thought to be multifactorial, with environmental, biological and genetic factors interacting together to influence AD pathogenesis. Recent reports suggest that general anesthetics may be such a factor and may contribute to the development and exacerbation of this neurodegenerative disorder. Intra-neuronal neurofibrillary tangles (NFT), composed of hyperphosphorylated and aggregated tau protein are one of the main neuropathological hallmarks of AD. Tau pathology is important in AD as it correlates very well with cognitive dysfunction. Lately, several studies have begun to elucidate the mechanisms by which anesthetic exposure might affect the phosphorylation, aggregation and function of this microtubule-associated protein. Here, we specifically review the literature detailing the impact of anesthetic administration on aberrant tau hyperphosphorylation as well as the subsequent development of neurofibrillary pathology and degeneration. PMID:23535147

New ALS-Related Genes Expand the Spectrum Paradigm of Amyotrophic Lateral Sclerosis.

PubMed

Sabatelli, Mario; Marangi, Giuseppe; Conte, Amelia; Tasca, Giorgio; Zollino, Marcella; Lattante, Serena

2016-03-01

Amyotrophic Lateral Sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons. Clinical heterogeneity is a well-recognized feature of the disease as age of onset, site of onset and the duration of the disease can vary greatly among patients. A number of genes have been identified and associated to familial and sporadic forms of ALS but the majority of cases remains still unexplained. Recent breakthrough discoveries have demonstrated that clinical manifestations associated with ALS-related genes are not circumscribed to motor neurons involvement. In this view, ALS appears to be linked to different conditions over a continuum or spectrum in which overlapping phenotypes may be identified. In this review, we aim to examine the increasing number of spectra, including ALS/Frontotemporal Dementia and ALS/Myopathies spectra. Considering all these neurodegenerative disorders as different phenotypes of the same spectrum can help to identify common pathological pathways and consequently new therapeutic targets in these incurable diseases. © 2016 International Society of Neuropathology.

Left hand polydactyly: a case report.

PubMed

Mumoli, Nicola; Gandini, Daniele; Wamala, Edris Kalanzi; Cei, Marco

2008-11-24

Polydactyly is a congenital anomaly with a wide range of manifestations that occurs in many forms, ranging from varying degrees of mere splitting to completely duplicated thumb. When duplication occurs alone, it is usually unilateral and sporadic. In this case report we describe an otherwise healthy 19-year-old woman of Tibetan heritage with isolated left hand preaxial polydactyly. She experienced working related difficulties in her daily yak's milking. She subsequently underwent surgical correction, and the over number thumb was removed with associated meticulous skeletal and soft tissue reconstruction. Polydactyly is the most common congenital digital anomaly of the hand and foot. It can occur in isolation or as part of a syndrome. Surgery is necessary to create a single, functioning thumb and is indicated to improve cosmesis. Skin, nail, bone, ligament, and musculoskeletal elements must be combined to reconstruct an optimal digit. In this case (Tibetan society is almost exclusively a sheep-breeding one) surgery was necessary to leave a single, functioning thumb for her work as yak milkmaid.

[Clinicopathological characteristics of hereditary ovarian cancer syndrome].

PubMed

Zhong, Yan; Sheng, Xiu-gui; Ma, Zhi-fang; Ma, Yue-bing; Liu, Nai-fu; Chen, Yue-ting; Gao, Rong; Wang, Ying-ying; Sun, Li

2009-09-01

To explore the clinicopathological characteristics of hereditary ovarian cancer syndrome (HOCS). From Jan. 2000 to Jan. 2007, among 580 cases of primary ovarian cancer, 42 cases (hereditary group), who had a positive family history of ovarian cancer and met the diagnostic criteria of HOCS, were analyzed retrospectively. One hundred cases without a family history of ovarian cancer were enrolled randomizely as control group (sporadic group). The incidence of HOCS was 7.2% (42/580). Forty-two cases associated tumors affected at least 2 successive generations in 31 families and affected 1 generation in 8 families. Eighty-seven percent (27/31) was from maternal lineage, while 13% (4/31) from paternal lineage. Earlier age of onset was significantly difference between two groups [(49 +/- 10) years vs. (55 +/- 10) years, P < 0.05]. There were 90% belong to serous adenocarcinoma in the hereditary group, while 84% in the sporadic group. There was statistical difference in the proportion of mucinous adenocarcinoma (0 vs. 11%, P < 0.05). The most common clinical manifestations were abdominal distention and anorexia (64% vs. 70%, P > 0.05), International Federational of Gynecology Obstetrics (FIGO) stage III (62% vs. 63%, P > 0.05) between two groups. Fourteen cases (33%,14/42) were previously untreated in the hereditary group, while 40 cases (40%, 40/100) in the sporadic group. There were 15 cases (36%, 15/42) underwent secondary surgery and 15 cases (36%, 15/42) underwent third surgery or more in hereditary group, while 50 cases (50%,50/100) and 27 cases (27%, 27/100) in the sporadic group. The mean number of chemotherapy cycles received in two groups was 13.3 and 11.8 (P > 0.05). The 3-year and 5-year survival rate in hereditary group were 73.6% and 54.9% respectively, compared with 47.4% and 21.2% (P < 0.05) in sporadic group. Hereditary ovarian cancer mostly from maternal lineage are featuring in early age of onset, serous adenocarcinoma, advanced stage (stage III), and better prognosis after the comprehensive treated by cytoreductive surgery plus with chemotherapy.

The 116G > A MSH6 and IVS1-1121C > T PMS2 Genes Polymorphisms Modulate the Risk of the Sporadic Colorectal Cancer Development in Polish Population.

PubMed

Zelga, Piotr; Przybyłowska-Sygut, Karolina; Zelga, Marta; Dziki, Adam; Majsterek, Ireneusz

2018-04-01

Colorectal cancer (CRC) is one of the most common cancers worldwide. DNA mismatch repair (MMR) is an evolutionarily conserved process that corrects mismatches generated during DNA replication. MMR defects were found to be associated with hereditary non-polyposis colorectal cancer (HNPCC) and a subset of sporadic colon cancers. The inheritance of common variations in MMR genes may influences individual susceptibility to the development of colorectal cancer. The purpose of the study was to evaluate the association between gene polymorphisms Glu39Gly (c.116G > A) of MSH6 gene and IVS1-1121C > T of PMS2 gene and sporadic colorectal cancer risk, in a case-control study comprising 200 patients and 200 controls origination from polish population. DNA was isolated from peripheral blood lymphocytes of enrolled patients, and gene polymorphisms were analysed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) for MSH6 and TaqMan for PMS2. G/A variant of Glu39Gly (c.116G > A) genotype was associated with an increased risk of colorectal cancer (OR 1,65 95%CI:1,01-2,69 p = 0.44). Presence of A allele was also significantly higher in patient with CRC (OR 1,57 95% CI: 1,04-2,38 p = 0.032). Prevalence of this genotype was also markedly higher in females and patients above 60 years in CRC group (OR 2.25 95%CI: 1.22-4.14 p = 0.0098 and OR 2.74 95% CI: 1.27-5.93 p = 0.0097 respectively). None of such correlations was observed for genotype variants of IVS1-1121C > T PMS2. In conclusion, our data suggests thatMSH6 Glu39Gly polymorphism is associated with the risk of developing sporadic colorectal cancer in polish population. Linkage to the female gender, onset above 60 years old and further increase of risk when combined with wild-type allele of PMS2 IVS1-1121C > T polymorphism indicates defective mismatch repair system.

Etiogenic factors present in the cerebrospinal fluid from amyotrophic lateral sclerosis patients induce predominantly pro-inflammatory responses in microglia.

PubMed

Mishra, Pooja-Shree; Vijayalakshmi, K; Nalini, A; Sathyaprabha, T N; Kramer, B W; Alladi, Phalguni Anand; Raju, T R

2017-12-16

Microglial cell-associated neuroinflammation is considered as a potential contributor to the pathophysiology of sporadic amyotrophic lateral sclerosis. However, the specific role of microglia in the disease pathogenesis remains to be elucidated. We studied the activation profiles of the microglial cultures exposed to the cerebrospinal fluid from these patients which recapitulates the neurodegeneration seen in sporadic amyotrophic lateral sclerosis. This was done by investigating the morphological and functional changes including the expression levels of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), TNF-α, IL-6, IFN-γ, IL-10, inducible nitric oxide synthase (iNOS), arginase, and trophic factors. We also studied the effect of chitotriosidase, the inflammatory protein found upregulated in the cerebrospinal fluid from amyotrophic lateral sclerosis patients, on these cultures. We report that the cerebrospinal fluid from amyotrophic lateral sclerosis patients could induce an early and potent response in the form of microglial activation, skewed primarily towards a pro-inflammatory profile. It was seen in the form of upregulation of the pro-inflammatory cytokines and factors including IL-6, TNF-α, iNOS, COX-2, and PGE2. Concomitantly, a downregulation of beneficial trophic factors and anti-inflammatory markers including VEGF, glial cell line-derived neurotrophic factor, and IFN-γ was seen. In addition, chitotriosidase-1 appeared to act specifically via the microglial cells. Our findings demonstrate that the cerebrospinal fluid from amyotrophic lateral sclerosis patients holds enough cues to induce microglial inflammatory processes as an early event, which may contribute to the neurodegeneration seen in the sporadic amyotrophic lateral sclerosis. These findings highlight the dynamic role of microglial cells in the pathogenesis of the disease, thus suggesting the need for a multidimensional and temporally guarded therapeutic approach targeting the inflammatory pathways for its treatment.

Comparing Characteristics of Sporadic and Outbreak-Associated Foodborne Illnesses, United States, 2004–2011

PubMed Central

Ebel, Eric D.; Cole, Dana; Travis, Curtis C.; Klontz, Karl C.; Golden, Neal J.; Hoekstra, Robert M.

2016-01-01

Outbreak data have been used to estimate the proportion of illnesses attributable to different foods. Applying outbreak-based attribution estimates to nonoutbreak foodborne illnesses requires an assumption of similar exposure pathways for outbreak and sporadic illnesses. This assumption cannot be tested, but other comparisons can assess its veracity. Our study compares demographic, clinical, temporal, and geographic characteristics of outbreak and sporadic illnesses from Campylobacter, Escherichia coli O157, Listeria, and Salmonella bacteria ascertained by the Foodborne Diseases Active Surveillance Network (FoodNet). Differences among FoodNet sites in outbreak and sporadic illnesses might reflect differences in surveillance practices. For Campylobacter, Listeria, and Escherichia coli O157, outbreak and sporadic illnesses are similar for severity, sex, and age. For Salmonella, outbreak and sporadic illnesses are similar for severity and sex. Nevertheless, the percentage of outbreak illnesses in the youngest age category was lower. Therefore, we do not reject the assumption that outbreak and sporadic illnesses are similar. PMID:27314510

Combined Treatment of an Amyotrophic Lateral Sclerosis Rat Model with Recombinant GOT1 and Oxaloacetic Acid: A Novel Neuroprotective Treatment.

PubMed

Ruban, Angela; Malina, Katayun Cohen-Kashi; Cooper, Itzik; Graubardt, Nadine; Babakin, Leonid; Jona, Ghil; Teichberg, Vivian I

2015-01-01

The sporadic form of the disease affects the majority of amyotrophic lateral sclerosis (ALS) patients. The role of glutamate (Glu) excitotoxicity in ALS has been extensively documented and remains one of the prominent hypotheses of ALS pathogenesis. In light of this evidence, the availability of a method to remove excess Glu from brain and spinal cord extracellular fluids without the need to deliver drugs across the blood-brain barrier and with minimal or no adverse effects may provide a major therapeutic asset, which is the primary aim of this study. The therapeutic efficacy of the combined treatment with recombinant Glu-oxaloacetate-transaminase (rGOT) and its co-factor oxaloacetic acid (OxAc) has been tested in an animal model of sporadic ALS. We found that OxAc/rGOT treatment provides significant neuroprotection to spinal cord motor neurons. It also slows down the development of motor weakness and prolongs survival. In this study we bring evidence that the administration of Glu scavengers to rats with sporadic ALS inhibited the massive death of spinal cord motor neurons, slowed the onset of motor weakness and prolonged survival. This treatment may be of high clinical significance for the future treatment of chronic neurodegenerative diseases. © 2015 S. Karger AG, Basel.

SEPT9 Mutations and a Conserved 17q25 Sequence in Sporadic and Hereditary Brachial Plexus Neuropathy

PubMed Central

Klein, Christopher J.; Wu, Yanhong; Cunningham, Julie M.; Windebank, Anthony J.; Dyck, P. James B.; Friedenberg, Scott M.; Klein, Diane M.; Dyck, Peter J.

2009-01-01

Background The clinical characteristics of sporadic brachial plexus neuropathy (S-BPN) and hereditary brachial plexus neuropathy (H-BPN) are similar. At times of attack inflammation in brachial plexus nerves has been identified in both conditions. SEPT-9 mutations (Arg88Trp, Ser93Phe, 5UTR-131G to C) occur in some families with H-BPN. These mutations were not found in American H-BPN kindreds with a conserved 500 Kb sequence of DNA at 17q25 (the location of SEPT-9) where a founder mutation has been suggested. Objective To study 17q25 and SEPT-9 in S-BPN (56 patients) and H-BPN (13 kindreds). Methods Allele analysis at 17q25, SEPT-9 DNA sequencing and mRNA analysis from lymphoblast cultures. Results A conserved 17q25 sequence was found in 5 of 13 H-BPN kindreds and one S-BPN patient. This conserved sequence was not found in the family with a SEPT-9 mutation (Arg88Trp) or controls (182). SEPT-9 mRNA expression did not differ between forms of H-BPN and controls. No known mutations of SEPT-9 were found in S-BPN. Conclusions/Relevance Rare S-BPN patients have the same conserved 17q25 sequence found in many American H-BPN kindreds. BPN patients with this conserved sequence do not appear to have SEPT-9 mutations or alterations of its mRNA expression levels in lymphoblast cultures. BPN patients with this conserved sequence may have the most common genetic cause in the Americas by a founder effect mutation. PMID:19204161

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease.

PubMed

Chaudhury, Sultan; Patel, Tulsi; Barber, Imelda S; Guetta-Baranes, Tamar; Brookes, Keeley J; Chappell, Sally; Turton, James; Guerreiro, Rita; Bras, Jose; Hernandez, Dena; Singleton, Andrew; Hardy, John; Mann, David; Morgan, Kevin

2018-02-01

Sporadic early-onset Alzheimer's disease (sEOAD) exhibits the symptoms of late-onset Alzheimer's disease but lacks the familial aspect of the early-onset familial form. The genetics of Alzheimer's disease (AD) identifies APOEε4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and multiple genetic loci. Polygenic risk scores (PRSs) accumulate the total risk of a phenotype in an individual based on variants present in their genome. We determined whether sEOAD cases had a higher PRS compared to controls. A cohort of sEOAD cases was genotyped on the NeuroX array, and PRSs were generated using PRSice. The target data set consisted of 408 sEOAD cases and 436 controls. The base data set was collated by the International Genomics of Alzheimer's Project consortium, with association data from 17,008 late-onset Alzheimer's disease cases and 37,154 controls, which can be used for identifying sEOAD cases due to having shared phenotype. PRSs were generated using all common single nucleotide polymorphisms between the base and target data set, PRS were also generated using only single nucleotide polymorphisms within a 500 kb region surrounding the APOE gene. Sex and number of APOE ε2 or ε4 alleles were used as variables for logistic regression and combined with PRS. The results show that PRS is higher on average in sEOAD cases than controls, although there is still overlap among the whole cohort. Predictive ability of identifying cases and controls using PRSice was calculated with 72.9% accuracy, greater than the APOE locus alone (65.2%). Predictive ability was further improved with logistic regression, identifying cases and controls with 75.5% accuracy. Copyright © 2017 Elsevier Inc. All rights reserved.

Searching for a link between the L-BMAA neurotoxin and amyotrophic lateral sclerosis: a study protocol of the French BMAALS programme

PubMed Central

Delzor, Aurélie; Couratier, Philippe; Boumédiène, Farid; Nicol, Marie; Druet-Cabanac, Michel; Paraf, François; Méjean, Annick; Ploux, Olivier; Leleu, Jean-Philippe; Brient, Luc; Lengronne, Marion; Pichon, Valérie; Combès, Audrey; El Abdellaoui, Saïda; Bonneterre, Vincent; Lagrange, Emmeline; Besson, Gérard; Bicout, Dominique J; Boutonnat, Jean; Camu, William; Pageot, Nicolas; Juntas-Morales, Raul; Rigau, Valérie; Masseret, Estelle; Abadie, Eric; Preux, Pierre-Marie; Marin, Benoît

2014-01-01

Introduction Amyotrophic lateral sclerosis (ALS) is the most common motor neurone disease. It occurs in two forms: (1) familial cases, for which several genes have been identified and (2) sporadic cases, for which various hypotheses have been formulated. Notably, the β-N-methylamino-L-alanine (L-BMAA) toxin has been postulated to be involved in the occurrence of sporadic ALS. The objective of the French BMAALS programme is to study the putative link between L-BMAA and ALS. Methods and analysis The programme covers the period from 1 January 2003 to 31 December 2011. Using multiple sources of ascertainment, all the incident ALS cases diagnosed during this period in the area under study (10 counties spread over three French regions) were collected. First, the standardised incidence ratio will be calculated for each municipality under concern. Then, by applying spatial clustering techniques, overincidence and underincidence zones of ALS will be sought. A case–control study, in the subpopulation living in the identified areas, will gather information about patients’ occupations, leisure activities and lifestyle habits in order to assess potential risk factors to which they are or have been exposed. Specimens of drinking water, food and biological material (brain tissue) will be examined to assess the presence of L-BMAA in the environment and tissues of ALS cases and controls. Ethics and dissemination The study has been reviewed and approved by the French ethical committee of the CPP SOOM IV (Comité de Protection des Personnes Sud-Ouest & Outre-Mer IV). The results will be published in peer-reviewed journals and presented at national and international conferences. PMID:25180055

Orbit characteristics of the tristatic EISCAT UHF meteors

NASA Astrophysics Data System (ADS)

Szasz, C.; Kero, J.; Meisel, D. D.; Pellinen-Wannberg, A.; Wannberg, G.; Westman, A.

2008-07-01

The tristatic EISCAT 930-MHz UHF system is used to determine the absolute geocentric velocities of meteors detected with all three receivers simultaneously at 96 km, the height of the common radar volume. The data used in this study were taken between 2002 and 2005, during four 24-h runs at summer/winter solstice and vernal/autumnal equinox to observe the largest seasonal difference. The observed velocities of 410 tristatic meteors are integrated back through the Earth atmosphere to find their atmospheric entry velocities using an ablation model. Orbit calculations are performed by taking zenith attraction, Earth rotation as well as obliquity of the ecliptic into account. The results are presented in the form of different orbital characteristics. None of the observed meteors appears to be of extrasolar or asteroidal origin; comets, particularly short-period (<200 yr) ones, may be the dominant source for the particles observed. About 40 per cent of the radiants can be associated with the north apex sporadic meteor source and 58 per cent of the orbits are retrograde. There is evidence of resonance gaps at semimajor axis values corresponding to commensurabilities with Jupiter, which may be the first convincing evidence of Jupiter's gravitational influence on the population of small sporadic meteoroids surveyed by radar. The geocentric velocity distribution is bimodal with a prograde population centred around 38 kms-1 and a retrograde population peaking at 59 kms-1. The EISCAT radar system is located close to the Arctic Circle, which means that the North Ecliptic Pole (NEP) is near zenith once every 24 h, i.e. during each observational period. In this particular geometry, the local horizon coincides with the ecliptic plane. The meteoroid influx should therefore be directly comparable throughout the year.

Timing and Distribution of Single-Layered Ejecta Craters Imply Sporadic Preservation of Tropical Subsurface Ice on Mars

NASA Astrophysics Data System (ADS)

Kirchoff, Michelle R.; Grimm, Robert E.

2018-01-01

Determining the evolution of tropical subsurface ice is a key component to understanding Mars's climate and geologic history. Study of an intriguing crater type on Mars—layered ejecta craters, which likely form by tapping subsurface ice—may provide constraints on this evolution. Layered ejecta craters have a continuous ejecta deposit with a fluidized-flow appearance. Single-layered ejecta (SLE) craters are the most common and dominate at tropical latitudes and therefore offer the best opportunity to derive new constraints on the temporal evolution of low-latitude subsurface ice. We estimate model formation ages of 54 SLE craters with diameter (D) ≥ 5 km using the density of small, superposed craters with D < 1 km on their continuous ejecta deposits. These model ages indicate that SLE craters have formed throughout the Amazonian and at a similar rate expected for all Martian craters. This suggests that tropical ice has remained at relatively shallow depths at least where these craters formed. In particular, the presence of equatorial SLE craters with D 1 km indicates that ice could be preserved as shallow as 100 m or less at those locations. Finally, there is a striking spatial mixing in an area of highlands near the equator of layered and radial (lunar-like ballistic) ejecta craters; the latter form where there are insufficient concentrations of subsurface ice. This implies strong spatial heterogeneity in the concentration of tropical subsurface ice.

Loss of nuclear TDP-43 in amyotrophic lateral sclerosis (ALS) causes altered expression of splicing machinery and widespread dysregulation of RNA splicing in motor neurones.

PubMed

Highley, J Robin; Kirby, Janine; Jansweijer, Joeri A; Webb, Philip S; Hewamadduma, Channa A; Heath, Paul R; Higginbottom, Adrian; Raman, Rohini; Ferraiuolo, Laura; Cooper-Knock, Johnathan; McDermott, Christopher J; Wharton, Stephen B; Shaw, Pamela J; Ince, Paul G

2014-10-01

Loss of nuclear TDP-43 characterizes sporadic and most familial forms of amyotrophic lateral sclerosis (ALS). TDP-43 (encoded by TARDBP) has multiple roles in RNA processing. We aimed to determine whether (1) RNA splicing dysregulation is present in lower motor neurones in ALS and in a motor neurone-like cell model; and (2) TARDBP mutations (mtTARDBP) are associated with aberrant RNA splicing using patient-derived fibroblasts. Affymetrix exon arrays were used to study mRNA expression and splicing in lower motor neurones obtained by laser capture microdissection of autopsy tissue from individuals with sporadic ALS and TDP-43 proteinopathy. Findings were confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and in NSC34 motor neuronal cells following shRNA-mediated TDP-43 depletion. Exon arrays and immunohistochemistry were used to study mRNA splicing and TDP-43 expression in fibroblasts from patients with mtTARDBP-associated, sporadic and mutant SOD1-associated ALS. We found altered expression of spliceosome components in motor neurones and widespread aberrations of mRNA splicing that specifically affected genes involved in ribonucleotide binding. This was confirmed in TDP-43-depleted NSC34 cells. Fibroblasts with mtTARDBP showed loss of nuclear TDP-43 protein and demonstrated similar changes in splicing and gene expression, which were not present in fibroblasts from patients with sporadic or SOD1-related ALS. Loss of nuclear TDP-43 is associated with RNA processing abnormalities in ALS motor neurones, patient-derived cells with mtTARDBP, and following artificial TDP-43 depletion, suggesting that splicing dysregulation directly contributes to disease pathogenesis. Key functional pathways affected include those central to RNA metabolism. © 2014 British Neuropathological Society.

Human microRNA expression in sporadic and FAP-associated desmoid tumors and correlation with beta-catenin mutations.

PubMed

Cavallini, Aldo; Rotelli, Maria Teresa; Lippolis, Catia; Piscitelli, Domenico; Digennaro, Rosa; Covelli, Claudia; Carella, Nicola; Accetturo, Matteo; Altomare, Donato Francesco

2017-06-27

Desmoid tumors (DT) are rare, benign, fibroblastic neoplasm with challenging histological diagnosis. DTs can occur sporadically or associated with the familial adenomatous polyposis coli (FAP). Most sporadic DTs are associated with β-catenin gene (CTNNB1) mutations, while mutated APC gene causes FAP disease. microRNAs (miRNAs) are involved in many human carcinogenesis.The miRNA profile was analyzed by microarray in formalin-fixed, paraffin-embedded (FFPE) specimens of 12 patients (8 sporadic, 4 FAP-associated) and 4 healthy controls. One hundred and one mRNAs resulted dysregulated, of which 98 in sporadic DTs and 8 in FAP-associated DTs, 5 were shared by both tumors. Twenty-six miRNAs were then validated by RT-qPCR in 23 sporadic and 7 FAP-associated DT samples matched with healthy controls. The qPCR method was also used to evaluate the CTNNB1 mutational status in sporadic DTs. The correlation between sporadic DTs and miRNA expression showed that miR-21-3p increased in mutated versus wild-type DTs, while miR-197-3p was decreased. The mRNA expression of Tetraspanin3 and Serpin family A member 3, as miR-21-3p targets, and L1 Cell Adhesion Molecule, as miR-197-3p target, was also evaluate. CTNNB1 mutations associated to miRNA dysregulation could affect the genesis and the progression of this disease and help histological diagnosis of sporadic DTs.

The expanding universe of prion diseases.

PubMed

Watts, Joel C; Balachandran, Aru; Westaway, David

2006-03-01

Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrP(C). Several mammalian species are affected by the diseases, and in the case of "mad cow disease" (BSE) the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases--including human diseases variant Creutzfeldt-Jakob disease (vCJD) and sporadic fatal insomnia (sFI), bovine amyloidotic spongiform encephalopathy (BASE), and Nor98 of sheep--have been identified in the last ten years, and chronic wasting disease (CWD) of North American deer (Odocoileus Specis) and Rocky Mountain elk (Cervus elaphus nelsoni) is undergoing a dramatic spread across North America. While amplification (BSE) and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk) can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of "sporadic" disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded.

Sporadic Fatal Insomnia in an Adolescent

PubMed Central

Blase, Jennifer L.; Cracco, Laura; Schonberger, Lawrence B.; Maddox, Ryan A.; Cohen, Yvonne; Cali, Ignazio

2014-01-01

The occurrence of sporadic prion disease among adolescents is extremely rare. A prion disease was confirmed in an adolescent with disease onset at 13 years of age. Genetic, neuropathologic, and biochemical analyses of the patient’s autopsy brain tissue were consistent with sporadic fatal insomnia, a type of sporadic prion disease. There was no evidence of an environmental source of infection, and this patient represents the youngest documented case of sporadic prion disease. Although rare, a prion disease diagnosis should not be discounted in adolescents exhibiting neurologic signs. Brain tissue testing is necessary for disease confirmation and is particularly beneficial in cases with an unusual clinical presentation. PMID:24488737

[Generalized congenital fibromatosis (author's transl)].

PubMed

Larrègue, M; Poitou, C; Bressieux, J P; de Giacomoni, P; Vant, F

1977-05-01

About a spontaneously regressive case of osteo-cutaneous congenital fibromatosis, the authors describe the characteristics of the disease (32 observations). Although the majority of cases are sporadic, 3 familial observations are in favour of a dominant autosomal transmission of low penetrance. Study of the familial cases and analysis of the different localisations demonstrate the unicity of the so-called diffuse forms with visceral involvement and of the so-called generalized forms without visceral involvement congenital fibromatosis is characterized by several fibromas at birth: in two-thirds of the cases, it is a purely cutaneous or osteocutaneous form, which disappears spontaneously; in one third of the cases, it is a cutaneous or osteo-cutaneous form with lethal visceral involvement.

Breeding biologies, pollinators, and seed beetles of two prairie-clovers, Dalea ornata and Dalea searlsiae (Fabaceae: Amorpheae), from the Intermountain West, USA

Treesearch

James H. Cane; Melissa Weber; Stephanie Miller

2012-01-01

Two prairie-clovers, Dalea ornata (Douglas ex Hook.) Eaton & J. Wright and Dalea searlsiae (A. Gray) Barneby, are perennial forbs found sporadically in the U.S. Intermountain West. Their seed is desirable for use in rangeland restoration. We experimentally characterized the breeding biologies of D. ornata and D. searlsiae in a common garden, surveyed their...

Multifactor-Dimensionality Reduction Reveals High-Order Interactions among Estrogen-Metabolism Genes in Sporadic Breast Cancer

PubMed Central

Ritchie, Marylyn D.; Hahn, Lance W.; Roodi, Nady; Bailey, L. Renee; Dupont, William D.; Parl, Fritz F.; Moore, Jason H.

2001-01-01

One of the greatest challenges facing human geneticists is the identification and characterization of susceptibility genes for common complex multifactorial human diseases. This challenge is partly due to the limitations of parametric-statistical methods for detection of gene effects that are dependent solely or partially on interactions with other genes and with environmental exposures. We introduce multifactor-dimensionality reduction (MDR) as a method for reducing the dimensionality of multilocus information, to improve the identification of polymorphism combinations associated with disease risk. The MDR method is nonparametric (i.e., no hypothesis about the value of a statistical parameter is made), is model-free (i.e., it assumes no particular inheritance model), and is directly applicable to case-control and discordant-sib-pair studies. Using simulated case-control data, we demonstrate that MDR has reasonable power to identify interactions among two or more loci in relatively small samples. When it was applied to a sporadic breast cancer case-control data set, in the absence of any statistically significant independent main effects, MDR identified a statistically significant high-order interaction among four polymorphisms from three different estrogen-metabolism genes. To our knowledge, this is the first report of a four-locus interaction associated with a common complex multifactorial disease. PMID:11404819

A familial case of Keratitis-Ichthyosis-Deafness (KID) syndrome with the GJB2 mutation G45E.

PubMed

Jonard, Laurence; Feldmann, Delphine; Parsy, Christophe; Freitag, Sylvie; Sinico, Martine; Koval, Céleste; Grati, Mhamed; Couderc, Remy; Denoyelle, Françoise; Bodemer, Christine; Marlin, Sandrine; Hadj-Rabia, Smail

2008-01-01

Keratitis-Ichthyosis-Deafness (KID) syndrome (OMIM 148210) is a congenital ectodermal defect. KID consists of an atypical ichthyosiform erythroderma associated with congenital sensorineural deafness. A rare form of the KID syndrome is a fatal course in the first year of life due to severe skin lesion infections and septicaemia. KID appears to be genetically heterogeneous and may be caused by mutations in connexin 26 or connexin 30 genes. GJB2 mutations in the connexin 26 gene are the main cause of the disease. Most of the cases caused by GJB2 mutations are sporadic, but dominant transmission has also been described. To date, the rare lethal form of the disease has been only observed in two Caucasian sporadic patients with the GJB2 mutation, with the p.Gly45Glu (G45E) arising de novo. We have reported an African family with dizygotic twins suffering from a lethal form of KID. The dizygosity of the twins was confirmed by microsatellite markers. The two patients were heterozygous for the G45E mutation of GJB2, whereas the mutation was not detected in the two parents. The unusual transmission of the disease observed in this family could be explained by the occurrence of a somatic or more probably a germinal mosaic in one of the parents.

A family with X-linked optic atrophy linked to the OPA2 locus Xp11.4-Xp11.2.

PubMed

Katz, Bradley J; Zhao, Yu; Warner, Judith E A; Tong, Zongzhong; Yang, Zhenglin; Zhang, Kang

2006-10-15

Autosomal dominant optic atrophy (ADOA) is the most common inherited optic atrophy. Clinical features of ADOA include a slowly progressive bilateral loss of visual acuity, constriction of peripheral visual fields, central scotomas, and color vision abnormalities. Although ADOA is the most commonly inherited optic atrophy, autosomal recessive, X-linked, mitochondrial, and sporadic forms have also been reported. Four families with X-linked optic atrophy (XLOA) were previously described. One family was subsequently linked to Xp11.4-Xp11.2 (OPA2). This investigation studied one multi-generation family with an apparently X-linked form of optic atrophy and compared their clinical characteristics with those of the previously described families, and determined whether this family was linked to the same genetic locus. Fifteen individuals in a three-generation Idaho family underwent complete eye examination, color vision testing, automated perimetry, and fundus photography. Polymorphic markers were used to genotype each individual and to determine linkage. Visual acuities ranged from 20/30 to 20/100. All affected subjects had significant optic nerve pallor. Obligate female carriers were clinically unaffected. Preliminary linkage analysis (LOD score = 1.8) revealed that the disease gene localized to the OPA2 locus on Xp11.4-Xp11.2. Four forms of inherited optic neuropathy, ADOA, autosomal recessive optic atrophy (Costeff Syndrome), Leber hereditary optic neuropathy, and Charcot-Marie-Tooth disease with optic atrophy, are associated with mitochondrial dysfunction. Future identification of the XLOA gene will reveal whether this form of optic atrophy is also associated with a mitochondrial defect. Identification of the XLOA gene will advance our understanding of the inherited optic neuropathies and perhaps suggest treatments for these diseases. An improved understanding of inherited optic neuropathies may in turn advance our understanding of acquired optic nerve diseases, such as glaucoma and ischemic optic neuropathy. (c) 2006 Wiley-Liss, Inc.

A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy.

PubMed

Milillo, Annamaria; La Carpia, Francesca; Costanzi, Stefano; D'Urbano, Vanessa; Martini, Maurizio; Lanuti, Paola; Vischini, Gisella; Larocca, Luigi M; Marchisio, Marco; Miscia, Sebastiano; Amoroso, Antonio; Gurrieri, Fiorella; Sangiorgi, Eugenio

2015-12-01

IgA nephropathy (IgAN) represents the most common primary glomerulonephritis worldwide with a prevalence of 25-50% among patients with primary glomerulopathies. In ~5-10% of the patients the disease segregates with an autosomal dominant (AD) pattern. Association studies identified loci on chromosomes 1q32, 6p21, 8p23, 17p13, 22q12, whereas classical linkage studies on AD families identified loci on chromosomes 2q36, 4q26-31, 6q22, 17q12-22. We have studied a large Sicilian family where IgAN segregates with an AD transmission. To identify the causal gene, the exomes of two affected and one unaffected individual have been sequenced. From the bioinformatics analysis a p.(Arg119Trp) variant in the SPRY2 gene was identified as the probable disease-causing mutation. Moreover, functional characterization of this variant showed that it is responsible for the inhibition of the MAPK/ERK1/2 pathway. The same effect was observed in two sporadic IgAN patients carriers of wild-type SPRY2, suggesting that downregulation of the MAPK/ERK1/2 pathway represents a common mechanism leading to IgAN.

Heterozygous Deletion of FOXA2 Segregates with Disease in a Family with Heterotaxy, Panhypopituitarism, and Biliary Atresia

PubMed Central

Tsai, Ellen A.; Grochowski, Christopher M.; Falsey, Alexandra M.; Rajagopalan, Ramakrishnan; Wendel, Danielle; Devoto, Marcella; Krantz, Ian D.; Loomes, Kathleen M.; Spinner, Nancy B.

2015-01-01

Biliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. Most cases are sporadic, although reports of familial cases have led to the hypothesis of genetic susceptibility in some patients. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal microarray analysis demonstrated a 277kb heterozygous deletion on chromosome 20 which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. The proband and her father share a common diagnosis of heterotaxy, but they also each presented with a variety of other issues. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism (rs1904589; p.His165Arg) in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband. PMID:25765999

Clinical implications of recent breakthroughs in amyotrophic lateral sclerosis.

PubMed

Van Damme, Philip; Robberecht, Wim

2013-10-01

This review examines the clinical implications of recent breakthroughs in amyotrophic lateral sclerosis (ALS). ALS has been found to be a highly variable condition at the clinical, genetic and mechanistic level. The study of newly discovered genetic causes for ALS has demonstrated that in addition to the effect of toxic mutant proteins, abnormalities of RNA householding contribute to motor neuron degeneration. Furthermore, the classic distinction between gain of function and loss of function may be an oversimplification of the biological reality. The most important clinical breakthrough was the finding of intronic hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) as a common cause of ALS, frontotemporal lobar degeneration (FTLD) and ALS with concomitant FTLD. This provides unambiguous evidence that ALS and FTLD represent the ends of one spectrum of neurodegenerative diseases. The high prevalence of C9orf72 mutations in patients without family history further blurs the distinction between sporadic and familial forms of ALS and FTLD. It also opens opportunities for stratified clinical trials in ALS and for the development of targeted therapies. ALS is a heterogeneous disorder that overlaps with FTLD. C9orf72 mutations are the most common cause of ALS, and add to the evidence that disturbances in RNA householding contribute to ALS.

Characterization of hepatitis E virus from sporadic hepatitis cases and sewage samples from Vellore, south India

PubMed Central

Vivek, Rosario; Zachariah, Uday G.; Ramachandran, Jeyamani; Eapen, Chundamannil E.; Rajan, Deva P.; Kang, Gagandeep

2017-01-01

Background Hepatitis E virus (HEV) is endemic in India and causes epidemics and sporadic cases. However, the exact transmission route for sporadic hepatitis E remains unclear. This study investigated HEV in sporadic hepatitis cases and sewage samples, as sewage is the major source of contamination of water in developing countries. Methods Monthly sampling and testing for HEV in sewage samples from Vellore, India was carried out for 1 year (November 2009–October 2010) and plasma and/or fecal samples from sporadic hepatitis cases presenting to a hospital in Vellore during 2006–2010 were tested for HEV RNA. A total of 144 raw sewage samples and 94 samples from sporadic hepatitis cases were tested for HEV RNA using RT-PCR. Results The prevalence of HEV RNA in sewage and sporadic cases was 55.6% and 9.6%, respectively. HEV strains isolated from sewage showed 94–100% nucleotide sequence similarity with the HEV strains isolated from the sporadic hepatitis cases. HEV RNA in sewage was identified more often during the summer (81.2%) than the monsoon season (14.5%) (p < 0.001). Conclusion This study indicates that sewage may be a source of contamination for sporadic hepatitis and also underscores the need for preventive measures to protect drinking water from sewage contamination, particularly in the summer. GenBank accession numbers HEV strains isolated from this study were deposited in GenBank under accession numbers JF972766–JF972773, JN705651–JN705659 and JN705660–JN705662. PMID:23677583

Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans.

PubMed

Tuijnenburg, Paul; Lango Allen, Hana; Burns, Siobhan O; Greene, Daniel; Jansen, Machiel H; Staples, Emily; Stephens, Jonathan; Carss, Keren J; Biasci, Daniele; Baxendale, Helen; Thomas, Moira; Chandra, Anita; Kiani-Alikhan, Sorena; Longhurst, Hilary J; Seneviratne, Suranjith L; Oksenhendler, Eric; Simeoni, Ilenia; de Bree, Godelieve J; Tool, Anton T J; van Leeuwen, Ester M M; Ebberink, Eduard H T M; Meijer, Alexander B; Tuna, Salih; Whitehorn, Deborah; Brown, Matthew; Turro, Ernest; Thrasher, Adrian J; Smith, Kenneth G C; Thaventhiran, James E; Kuijpers, Taco W

2018-03-02

The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort. In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21 low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Familial Cerebral Cavernous Malformations Are Associated with Adrenal Calcifications on CT Scans: An Imaging Biomarker for a Hereditary Cerebrovascular Condition.

PubMed

Strickland, Corinne D; Eberhardt, Steven C; Bartlett, Mary R; Nelson, Jeffrey; Kim, Helen; Morrison, Leslie A; Hart, Blaine L

2017-08-01

Purpose To determine if adrenal calcifications seen at computed tomography (CT) are associated with familial cerebral cavernous malformations (fCCMs) in carriers of the CCM1 Common Hispanic Mutation. Materials and Methods This study was approved by the institutional review board. The authors retrospectively reviewed abdominal CT scans in 38 patients with fCCM, 38 unaffected age- and sex-matched control subjects, and 13 patients with sporadic, nonfamilial cerebral cavernous malformation (CCM). The size, number, and laterality of calcifications and the morphologic characteristics of the adrenal gland were recorded. Brain lesion count was recorded from brain magnetic resonance (MR) imaging in patients with fCCM. The prevalence of adrenal calcifications in patients with fCCM was compared with that in unaffected control subjects and those with sporadic CCM by using the Fisher exact test. Additional analyses were performed to determine whether age and brain lesion count were associated with adrenal findings in patients with fCCM. Results Small focal calcifications (SFCs) (≤5 mm) were seen in one or both adrenal glands in 19 of the 38 patients with fCCM (50%), compared with 0 of the 38 unaffected control subjects (P < .001) and 0 of the 13 subjects with sporadic CCM (P = .001). Adrenal calcifications in patients with fCCM were more frequently left sided, with 17 of 19 patients having more SFCs in the left adrenal gland than the right adrenal gland and 50 of the 61 observed SFCs (82%) found in the left adrenal gland. No subjects had SFCs on the right side only. In patients with fCCM, the presence of SFCs showed a positive correlation with age (P < .001) and number of brain lesions (P < .001). Conclusion Adrenal calcifications identified on CT scans are common in patients with fCCM and may be a clinically silent manifestation of disease. © RSNA, 2017.

Copy number variability in Parkinson's disease: assembling the puzzle through a systems biology approach.

PubMed

La Cognata, Valentina; Morello, Giovanna; D'Agata, Velia; Cavallaro, Sebastiano

2017-01-01

Parkinson's disease (PD), the second most common progressive neurodegenerative disorder of aging, was long believed to be a non-genetic sporadic origin syndrome. The proof that several genetic loci are responsible for rare Mendelian forms has represented a revolutionary breakthrough, enabling to reveal molecular mechanisms underlying this debilitating still incurable condition. While single nucleotide polymorphisms (SNPs) and small indels constitute the most commonly investigated DNA variations accounting for only a limited number of PD cases, larger genomic molecular rearrangements have emerged as significant PD-causing mutations, including submicroscopic Copy Number Variations (CNVs). CNVs constitute a prevalent source of genomic variations and substantially participate in each individual's genomic makeup and phenotypic outcome. However, the majority of genetic studies have focused their attention on single candidate-gene mutations or on common variants reaching a significant statistical level of acceptance. This gene-centric approach is insufficient to uncover the genetic background of polygenic multifactorial disorders like PD, and potentially masks rare individual CNVs that all together might contribute to disease development or progression. In this review, we will discuss literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will analyze the most frequent copy number changes in familiar PD genes and provide a "systems biology" overview of rare individual rearrangements that could functionally act on commonly deregulated molecular pathways. Assessing the global genome-wide burden of CNVs in PD patients may reveal new disease-related molecular mechanisms, and open the window to a new possible genetic scenario in the unsolved PD puzzle.

Soluble Aβ aggregates can inhibit prion propagation.

PubMed

Sarell, Claire J; Quarterman, Emma; Yip, Daniel C-M; Terry, Cassandra; Nicoll, Andrew J; Wadsworth, Jonathan D F; Farrow, Mark A; Walsh, Dominic M; Collinge, John

2017-11-01

Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) and consist of multi-chain assemblies of misfolded cellular prion protein (PrP C ). Ligands that bind to PrP C can inhibit prion propagation and neurotoxicity. Extensive prior work established that certain soluble assemblies of the Alzheimer's disease (AD)-associated amyloid β-protein (Aβ) can tightly bind to PrP C , and that this interaction may be relevant to their toxicity in AD. Here, we investigated whether such soluble Aβ assemblies might, conversely, have an inhibitory effect on prion propagation. Using cellular models of prion infection and propagation and distinct Aβ preparations, we found that the form of Aβ assemblies which most avidly bound to PrP in vitro also inhibited prion infection and propagation. By contrast, forms of Aβ which exhibit little or no binding to PrP were unable to attenuate prion propagation. These data suggest that soluble aggregates of Aβ can compete with prions for binding to PrP C and emphasize the bidirectional nature of the interplay between Aβ and PrP C in Alzheimer's and prion diseases. Such inhibitory effects of Aβ on prion propagation may contribute to the apparent fall-off in the incidence of sporadic CJD at advanced age where cerebral Aβ deposition is common. © 2017 The Authors.

Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain.

PubMed

Andriani, Grasiella A; Vijg, Jan; Montagna, Cristina

2017-01-01

Aneuploidy and polyploidy are a form of Genomic Instability (GIN) known as Chromosomal Instability (CIN) characterized by sporadic abnormalities in chromosome copy numbers. Aneuploidy is commonly linked to pathological states. It is a hallmark of spontaneous abortions and birth defects and it is observed virtually in every human tumor, therefore being generally regarded as detrimental for the development or the maturation of tissues under physiological conditions. Polyploidy however, occurs as part of normal physiological processes during maturation and differentiation of some mammalian cell types. Surprisingly, high levels of aneuploidy are present in the brain, and their frequency increases with age suggesting that the brain is able to maintain its functionality in the presence of high levels of mosaic aneuploidy. Because somatic aneuploidy with age can reach exceptionally high levels, it is likely to have long-term adverse effects in this organ. We describe the mechanisms accountable for an abnormal DNA content with a particular emphasis on the CNS where cell division is limited. Next, we briefly summarize the types of GIN known to date and discuss how they interconnect with CIN. Lastly we highlight how several forms of CIN may contribute to genetic variation, tissue degeneration and disease in the CNS. Copyright © 2016. Published by Elsevier B.V.

The dysregulation of intracellular calcium in Alzheimer disease.

PubMed

Supnet, Charlene; Bezprozvanny, Ilya

2010-02-01

Alzheimer disease (AD) is the most common neurodegenerative disorder worldwide and is at present, incurable. The accumulation of toxic amyloid-beta (Abeta) peptide aggregates in AD brain are thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline, an idea that underlies the 'amyloid hypothesis' of AD etiology in both the familal (FAD) and sporadic forms of the disease. Mutations causing FAD also result in the dysregulation of neuronal calcium (Ca2+) handling and may contribute to AD pathogenesis, an idea termed the 'calcium hypothesis' of AD. In particular, Ca2+ dysregulation by the endoplasmic reticulum (ER) in AD mouse models results in augmented cytosolic Ca2+ levels which can trigger signalling cascades that are detrimental to neuronal function and health. However, there is growing evidence to suggest that not all forms of Ca2+ dysregulation in AD neurons are harmful and some of them instead may be compensatory. These changes may help modulate neuronal excitability and slow AD pathology, especially in the early stages of the disease. Clearly, a better understanding of how dysregulation of neuronal Ca2+ handling contributes to neurodegeneration and neuroprotection in AD is needed as Ca2+ signalling modulators are targets of great interest as potential AD therapeutics. 2010 Elsevier Ltd. All rights reserved.

The dysregulation of intracellular calcium in Alzheimer disease

PubMed Central

Supnet, Charlene; Bezprozvanny, Ilya

2010-01-01

Alzheimer disease (AD) is the most common neurodegenerative disorder worldwide and is at present, incurable. The accumulation of toxic amyloid-beta (Aβ) peptide aggregates in AD brain are thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline, an idea that underlies the ‘amyloid hypothesis’ of AD etiology in both the familal (FAD) and sporadic forms of the disease. Mutations causing FAD also result in the dysregulation of neuronal calcium (Ca2+) handling and may contribute to AD pathogenesis, an idea termed the ‘calcium hypothesis’ of AD. In particular, Ca2+ dysregulation by the endoplasmic reticulum (ER) in AD mouse models results in augmented cytosolic Ca2+ levels which can trigger signaling cascades that are detrimental to neuronal function and health. However, there is growing evidence to suggest that not all forms of Ca2+ dysregulation in AD neurons are harmful and some of them instead may be compensatory. These changes may help modulate neuronal excitability and slow AD pathology, especially in the early stages of the disease. Clearly, a better understanding of how dysregulation of neuronal Ca2+ handling contributes to neurodegeneration and neuroprotection in AD is needed as Ca2+ signaling modulators are targets of great interest as potential AD therapeutics. PMID:20080301

Sporadic Visual Acuity Loss in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)

PubMed Central

Kim, Benjamin J.; Ying, Gui-Shuang; Huang, Jiayan; Levy, Nicole E.; Maguire, Maureen G.

2014-01-01

Purpose To evaluate transient, large visual acuity (VA) decreases, termed sporadic vision loss, during anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration (AMD). Design Cohort within a randomized clinical trial. Methods Setting Comparison of AMD Treatments Trials (CATT). Study Population 1185 CATT patients. Main Outcome Measures incidence of sporadic vision loss and odds ratio (OR) for association with patient and ocular factors. Sporadic vision loss was a decline of ≥ 15 letters from the previous visit, followed by a return at the next visit to no more than 5 letters worse than the visit before the VA loss. Results There were 143 sporadic vision loss events in 122/1185 (10.3%) patients. Mean VA at two years for those with and without sporadic vision loss was 58.5 (~20/63) and 68.4 (~20/40) letters, respectively (P < 0.001). Among patients treated pro re nata, no injection was given for 27.6% (27/98) of sporadic vision loss events. Multivariate analysis demonstrated that baseline predictors for sporadic vision loss included worse baseline VA (OR 2.92, 95%CI:1.65–5.17 for ≤ 20/200 compared with ≥ 20/40), scar (OR 2.21, 95%CI:1.22–4.01), intraretinal foveal fluid on optical coherence tomography (OR 1.80, 95%CI:1.11–2.91), and medical history of anxiety (OR 1.90, 95%CI:1.12–3.24) and syncope (OR 2.75, 95%CI:1.45–5.22). Refraction decreased the likelihood of sporadic vision loss (OR 0.62, 95%CI:0.42–0.91). Conclusions Approximately 10% of CATT patients had sporadic vision loss. Baseline predictors included AMD-related factors and factors independent of AMD. These data are relevant for clinicians in practice and those involved in clinical trials. PMID:24727261

Sporadic visual acuity loss in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).

PubMed

Kim, Benjamin J; Ying, Gui-Shuang; Huang, Jiayan; Levy, Nicole E; Maguire, Maureen G

2014-07-01

To evaluate transient, large visual acuity (VA) decreases, termed sporadic vision loss, during anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration (AMD). Cohort within a randomized clinical trial. setting: Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). study population: Total of 1185 CATT patients. main outcome measures: Incidence of sporadic vision loss and odds ratio (OR) for association with patient and ocular factors. Sporadic vision loss was a decline of ≥15 letters from the previous visit, followed by a return at the next visit to no more than 5 letters worse than the visit before the VA loss. There were 143 sporadic vision loss events in 122 of 1185 patients (10.3%). Mean VA at 2 years for those with and without sporadic vision loss was 58.5 (∼20/63) and 68.4 (∼20/40) letters, respectively (P < .001). Among patients treated pro re nata, no injection was given for 27.6% (27/98) of sporadic vision loss events. Multivariate analysis demonstrated that baseline predictors for sporadic vision loss included worse baseline VA (OR 2.92, 95% confidence interval [CI]:1.65-5.17 for ≤20/200 compared with ≥20/40), scar (OR 2.21, 95% CI:1.22-4.01), intraretinal foveal fluid on optical coherence tomography (OR 1.80, 95% CI:1.11-2.91), and medical history of anxiety (OR 1.90, 95% CI:1.12-3.24) and syncope (OR 2.75, 95% CI:1.45-5.22). Refraction decreased the likelihood of sporadic vision loss (OR 0.62, 95%CI: 0.42-0.91). Approximately 10% of CATT patients had sporadic vision loss. Baseline predictors included AMD-related factors and factors independent of AMD. These data are relevant for clinicians in practice and those involved in clinical trials. Copyright © 2014 Elsevier Inc. All rights reserved.

Structure and sources of the sporadic meteor background from video observations

NASA Astrophysics Data System (ADS)

Jakšová, Ivana; Porubčan, Vladimír; Klačka, Jozef

2015-10-01

We investigate and discuss the structure of the sporadic meteor background population in the near-Earth space based on video meteor orbits from the SonotaCo database (SonotaCo 2009, WGN, 37, 55). The selection of the shower meteors was done by the Southworth-Hawkins streams-search criterion (Southworth & Hawkins 1963, Smithson. Contr. Astrophys., 7, 261). Of a total of 117786 orbits, 69.34% were assigned to sporadic background meteors. Our analysis revealed all the known sporadic sources, such as the dominant apex source which is splitting into the northern and southern branch. Part of a denser ring structure about the apex source connecting the antihelion and north toroidal sources is also evident. We showed that the annual activity of the apex source is similar to the annual variation in activity of the whole sporadic background. The antihelion source exhibits a very broad maximum from July until January and the north toroidal source shows three maxima similar to the radar observations by the Canadian Meteor Orbit Radar (CMOR). Potential parent bodies of the sporadic population were searched for by comparison of the distributions of the orbital elements of sporadic meteors, minor planets and comets.

Aging Impacts Transcriptome but not Genome of Hormone-dependentBreast Cancers

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

Yau, Christina; Fedele, Vita; Roydasgupta, Ritu

Age is one of the most important risk factors for human malignancies, including breast cancer; in addition, age-at-diagnosis has been shown to be an independent indicator of breast cancer prognosis. However, except for inherited forms of breast cancer, there is little genetic or epigenetic understanding of the biological basis linking aging with sporadic breast cancer incidence and its clinical behavior.

Update on Sporadic Colorectal Cancer Genetics.

PubMed

Hardiman, Karin M

2018-05-01

Our understanding of the genetics of colorectal cancer has changed dramatically over recent years. Colorectal cancer can be classified in multiple different ways. Along with the advent of whole-exome sequencing, we have gained an understanding of the scale of the genetic changes found in sporadic colorectal cancer. We now know that there are multiple pathways that are commonly involved in the evolution of colorectal cancer including Wnt/β-catenin, RAS, EGFR, and PIK3 kinase. Another recent leap in our understanding of colorectal cancer genetics is the recognition that many, if not all tumors, are actually genetically heterogeneous within individual tumors and also between tumors. Recent research has revealed the prognostic and possibly therapeutic implications of various specific mutations, including specific mutations in BRAF and KRAS . There is increasing interest in the use of mutation testing for screening and surveillance through stool and circulating DNA testing. Recent advances in translational research in colorectal cancer genetics are dramatically changing our understanding of colorectal cancer and will likely change therapy and surveillance in the near future.

Germline BAP1 mutations predispose to malignant mesothelioma

PubMed Central

Testa, Joseph R.; Cheung, Mitchell; Pei, Jianming; Below, Jennifer E.; Tan, Yinfei; Sementino, Eleonora; Cox, Nancy J.; Dogan, A. Umran; Pass, Harvey I.; Trusa, Sandra; Hesdorffer, Mary; Nasu, Masaki; Powers, Amy; Rivera, Zeyana; Comertpay, Sabahattin; Tanji, Mika; Gaudino, Giovanni; Yang, Haining; Carbone, Michele

2011-01-01

Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma1, and because mesothelioma clustering is observed in some families1, we searched for genetic predisposing factors. We discovered germline mutations in BAP1 (BRCA1-associated protein 1) in two families with a high incidence of mesothelioma. Somatic alterations affecting BAP1 were observed in familial mesotheliomas, indicating biallelic inactivation. Besides mesothelioma, some BAP1 mutation carriers developed uveal melanoma. Germline BAP1 mutations were also found in two of 26 sporadic mesotheliomas: both patients with mutant BAP1 were previously diagnosed with uveal melanoma. Truncating mutations and aberrant BAP1 expression were common in sporadic mesotheliomas without germline mutations. These results reveal a BAP1-related cancer syndrome characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved, and that mesothelioma predominates upon asbestos exposure. These findings will help identify individuals at high risk of mesothelioma who could be targeted for early intervention. PMID:21874000

Inclusion body myositis.

PubMed

Dimachkie, Mazen M; Barohn, Richard J

2012-07-01

The idiopathic inflammatory myopathies are a group of rare disorders that share many similarities. These include dermatomyositis (DM), polymyositis (PM), necrotizing myopathy (NM), and sporadic inclusion body myositis (IBM). Inclusion body myositis is the most common idiopathic inflammatory myopathy after age 50 and it presents with chronic proximal leg and distal arm asymmetric mucle weakness. Despite similarities with PM, it is likely that IBM is primarily a degenerative disorder rather than an inflammatory muscle disease. Inclusion body myositis is associated with a modest degree of creatine kinase (CK) elevation and an abnormal electromyogram demonstrating an irritative myopathy with some chronicity. The muscle histopathology demonstrates inflammatory exudates surrounding and invading nonnecrotic muscle fibers often times accompanied by rimmed vacuoles. In this chapter, we review sporadic IBM. We also examine past, essentially negative, clinical trials in IBM and review ongoing clinical trials. For further details on DM, PM, and NM, the reader is referred to the idiopathic inflammatory myopathies chapter. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Lack of association between the APEX1 Asp148Glu polymorphism and sporadic amyotrophic lateral sclerosis.

PubMed

Coppedè, Fabio; Lo Gerfo, Annalisa; Carlesi, Cecilia; Piazza, Selina; Mancuso, Michelangelo; Pasquali, Livia; Murri, Luigi; Migliore, Lucia; Siciliano, Gabriele

2010-02-01

Impairments in DNA repair enzymes have been observed in amyotrophic lateral sclerosis (ALS) tissues, particularly in the activity of the apurinic/apyrimidinic endonuclease 1 (APEX1). Moreover, it was suggested that the common APEX1 Asp148Glu polymorphism might be associated with ALS risk. To further address this question we performed the present study aimed at evaluating the contribution of the APEX1 Asp148Glu polymorphism in sporadic ALS (sALS) risk and clinical presentation, including age and site of onset and disease progression. We screened 134 sALS Italian patients and 129 matched controls for the presence of the APEX1 Asp148Glu polymorphism. No difference in APEX1 Asp148Glu allele and genotype frequencies was found between the groups, nor was the polymorphism associated with age and site of onset or disease progression. Present results do not support a role for the APEX1 Asp148Glu polymorphism in sALS pathogenesis in the Italian population.

Sporadic E ionization layers observed with radar imaging and ionospheric modification

NASA Astrophysics Data System (ADS)

Hysell, D. L.; Munk, J.; McCarrick, M.

2014-10-01

Sporadic E ionization layers have been observed in the daytime subauroral ionospheric E layer by a 30 MHz radar in Alaska. The radar detects coherent backscatter from meter-scale field-aligned plasma density irregularities. The irregularities were generated by ionospheric modification—by the emission of strong HF electromagnetic waves directly beneath the layers—making the layers visible to the radar. Aperture-synthesis methods are used to generate imagery of the layers from the radar data. The layers are patchy, with patches organized along fronts spaced by tens of kilometers and propagating slowly toward the southwest. Similar, naturally occurring layers are commonly observed at middle latitudes at night in the absence of ionospheric modification. That the patchy layers can be found at high magnetic latitudes during the day argues that they are most likely produced through the interaction of the ionospheric layer with neutral atmospheric waves and instabilities. Attenuation of the radar echoes when the HF emission frequency exceeded the third harmonic of the electron gyrofrequency was observed and is discussed.

Lidar Probing of the Mesosphere: Simultaneous Observations of Sporadic Sodium and Iron Formations, Calcium Ion Layers, Neutral Temperature and Winds

NASA Technical Reports Server (NTRS)

Kane, Timothy J.; Qian, Jun; Scherrer, Daniel R.; Senft, Daniel C.; Pfenninger, W. Matthew; Papen, George C.; Gardner, Chester S.

1992-01-01

Meteoritic ablation in the upper atmosphere is the commonly accepted source of the mesospheric metals between 80 and 105 km. The vertical and temporal behavior of some of these metals can be probed with high accuracy and resolution using resonance fluorescence lidar techniques. Of considerable interest in recent years has been the sporadic and rapid formation of thin, dense enhancements in these metallic layers. Since late Mar. 1991, the UIUC CEDAR lidar system, located at the Urbana Atmospheric Observatory, has been routinely operating at the Fe resonance line of 372 nm in order to probe the mesospheric Fe layer. In Nov. 1991, the capability to investigate mesospheric Ca(+) at the resonance line of 393.4 nm was added. The lidar's eximer-pumped dye laser uses Exciton QUI laser dye dissolved in p-dioxane, which can lase at both the Fe and Ca(+) frequencies. Various aspects of this investigation are discussed.

Field epidemiology to manage BRD risk in beef cattle production systems.

PubMed

Smith, David R

2014-12-01

Field disease investigations can help to identify patterns of disease that lead to causal hypotheses and, hopefully, effective disease risk management strategies. The most common way of doing this would be to characterize the outbreak by subject, time, and space. One of the perplexing animal health problems on some beef cattle ranches is the occurrence of pneumonia in calves prior to weaning in conditions of little stress and relative isolation. Field investigation of outbreaks of pneumonia in ranch calves prior to weaning has revealed patterns of sporadic illness in calves less than 30 days of age, and rapidly occurring outbreaks in calves 90-150 days of age. We speculate that the causes of these two patterns may be failure of passive transfer resulting in more sporadic cases in very young calves, or a large proportion of the population losing maternal antibody protection (i.e. losing herd immunity) resulting in rapid and widespread onset of pneumonia in older calves.

Genome Sequences of 228 Shiga Toxin-Producing Escherichia coli Isolates and 12 Isolates Representing Other Diarrheagenic E. coli Pathotypes

PubMed Central

Strockbine, Nancy; Changayil, Shankar; Ranganathan, Satishkumar; Zhao, Kun; Weil, Ryan; MacCannell, Duncan; Sabol, Ashley; Schmidtke, Amber; Martin, Haley; Stripling, Devon; Ribot, Efrain M.; Gerner-Smidt, Peter

2014-01-01

Shiga toxin-producing Escherichia coli (STEC) are a common cause for food-borne diarrheal illness outbreaks and sporadic cases. Here, we report the availability of the draft genome sequences of 228 STEC strains representing 32 serotypes with known pulsed-field gel electrophoresis (PFGE) types and epidemiological relationships, as well as 12 strains representing other diarrheagenic E. coli pathotypes. PMID:25103754

Clinical and Functional Analyses of p73R1 Mutations in Prostate Cancer

DTIC Science & Technology

2005-02-01

mutations in several genes (BRCA 1, BRCA2, and CHEK2) whose products are involved in this pathway have been associated with increased risk for this...screened this gene for mutations in prostate cancer. Two germline truncating mutations were identified. Genotyping of 403 men with sporadic prostate...based on mutation screening of candidate genes involved in the DNA damage- signaling pathway. Genomic instability is a common feature of all human

An Australian case of Streptococcus suis toxic shock syndrome associated with occupational exposure to animal carcasses.

PubMed

Tramontana, Adrian R; Graham, Maryza; Sinickas, Vincent; Bak, Narin

2008-05-05

Streptococcus suis is known to cause sporadic infections in people who have occupational exposure to pigs and pig meat. A large outbreak occurred in China in 2005, where there was 62% mortality among those who developed toxic shock syndrome. Despite S. suis being common in pigs, this is the first published report of a human case of S. suis toxic shock syndrome in Australia.

Novel Genetic Variants of Sporadic Atrial Septal Defect (ASD) in a Chinese Population Identified by Whole-Exome Sequencing (WES)

PubMed Central

Liu, Yong; Cao, Yu; Li, Yaxiong; Lei, Dongyun; Li, Lin; Hou, Zong Liu; Han, Shen; Meng, Mingyao; Shi, Jianlin; Zhang, Yayong; Wang, Yi; Niu, Zhaoyi; Xie, Yanhua; Xiao, Benshan; Wang, Yuanfei; Li, Xiao; Yang, Lirong

2018-01-01

Background Recently, mutations in several genes have been described to be associated with sporadic ASD, but some genetic variants remain to be identified. The aim of this study was to use whole-exome sequencing (WES) combined with bioinformatics analysis to identify novel genetic variants in cases of sporadic congenital ASD, followed by validation by Sanger sequencing. Material/Methods Five Han patients with secundum ASD were recruited, and their tissue samples were analyzed by WES, followed by verification by Sanger sequencing of tissue and blood samples. Further evaluation using blood samples included 452 additional patients with sporadic secundum ASD (212 male and 240 female patients) and 519 healthy subjects (252 male and 267 female subjects) for further verification by a multiplexed MassARRAY system. Bioinformatic analyses were performed to identify novel genetic variants associated with sporadic ASD. Results From five patients with sporadic ASD, a total of 181,762 genomic variants in 33 exon loci, validated by Sanger sequencing, were selected and underwent MassARRAY analysis in 452 patients with ASD and 519 healthy subjects. Three loci with high mutation frequencies, the 138665410 FOXL2 gene variant, the 23862952 MYH6 gene variant, and the 71098693 HYDIN gene variant were found to be significantly associated with sporadic ASD (P<0.05); variants in FOXL2 and MYH6 were found in patients with isolated, sporadic ASD (P<5×10−4). Conclusions This was the first study that demonstrated variants in FOXL2 and HYDIN associated with sporadic ASD, and supported the use of WES and bioinformatics analysis to identify disease-associated mutations. PMID:29505555

Novel Genetic Variants of Sporadic Atrial Septal Defect (ASD) in a Chinese Population Identified by Whole-Exome Sequencing (WES).

PubMed

Liu, Yong; Cao, Yu; Li, Yaxiong; Lei, Dongyun; Li, Lin; Hou, Zong Liu; Han, Shen; Meng, Mingyao; Shi, Jianlin; Zhang, Yayong; Wang, Yi; Niu, Zhaoyi; Xie, Yanhua; Xiao, Benshan; Wang, Yuanfei; Li, Xiao; Yang, Lirong; Wang, Wenju; Jiang, Lihong

2018-03-05

BACKGROUND Recently, mutations in several genes have been described to be associated with sporadic ASD, but some genetic variants remain to be identified. The aim of this study was to use whole-exome sequencing (WES) combined with bioinformatics analysis to identify novel genetic variants in cases of sporadic congenital ASD, followed by validation by Sanger sequencing. MATERIAL AND METHODS Five Han patients with secundum ASD were recruited, and their tissue samples were analyzed by WES, followed by verification by Sanger sequencing of tissue and blood samples. Further evaluation using blood samples included 452 additional patients with sporadic secundum ASD (212 male and 240 female patients) and 519 healthy subjects (252 male and 267 female subjects) for further verification by a multiplexed MassARRAY system. Bioinformatic analyses were performed to identify novel genetic variants associated with sporadic ASD. RESULTS From five patients with sporadic ASD, a total of 181,762 genomic variants in 33 exon loci, validated by Sanger sequencing, were selected and underwent MassARRAY analysis in 452 patients with ASD and 519 healthy subjects. Three loci with high mutation frequencies, the 138665410 FOXL2 gene variant, the 23862952 MYH6 gene variant, and the 71098693 HYDIN gene variant were found to be significantly associated with sporadic ASD (P<0.05); variants in FOXL2 and MYH6 were found in patients with isolated, sporadic ASD (P<5×10^-4). CONCLUSIONS This was the first study that demonstrated variants in FOXL2 and HYDIN associated with sporadic ASD, and supported the use of WES and bioinformatics analysis to identify disease-associated mutations.

SFE/SFHTA/AFCE consensus on primary aldosteronism, part 5: Genetic diagnosis of primary aldosteronism.

PubMed

Zennaro, Maria-Christina; Jeunemaitre, Xavier

2016-07-01

While the majority of cases of primary aldosteronism (PA) are sporadic, four forms of autosomal-dominant inheritance have been described: familial hyperaldosteronism (FH) types I to IV. FH-I, also called glucocorticoid-remediable aldosteronism, is characterized by early and severe hypertension, usually before the age of 20 years. It is due to the formation of a chimeric gene between the adjacent CYP11B2 and CYP11B1 genes (coding for aldosterone synthase and 11β-hydroxylase, respectively). FH-I is often associated with family history of stroke before 40years of age. FH-II is clinically and biochemically indistinguishable from sporadic forms of PA and is only diagnosed on the basis of two or more affected family members. No causal genes have been identified so far and no genetic test is available. FH-III is characterized by severe and early-onset hypertension in children and young adults, resistant to treatment and associated with severe hypokalemia. Mild forms, resembling FH-II, have been described. FH-III is due to gain-of-function mutations in the KCNJ5 gene. Recently, a new autosomal-dominant form of familial PA, FH-IV, associated with mutations in the CACNA1H gene, was described in patients with hypertension and PA before the age of 10years. In rare cases, PA may be associated with complex neurologic disorder involving epileptic seizures and cerebral palsy (Primary Aldosteronism, Seizures, and Neurologic Abnormalities [PASNA]) due to de novo germline CACNA1D mutations. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Visual art therapy in sporadic Creutzfeldt-Jakob disease: a case study.

PubMed

Shrestha, Rajeet; Trauger-Querry, Barbara; Loughrin, Athena; Appleby, Brian S

2016-01-01

This paper describes the diagnostic and treatment utility of visual art therapy in a case of sporadic Creutzfeldt-Jakob disease. Visual art therapy was compared longitudinally with clinical and neuroimaging data over five-month period in an autopsy-confirmed case of sporadic Creutzfeldt-Jakob disease of MM2-cortical subtype. Art therapy sessions and content were useful in ascertaining neuropsychiatric symptoms during the course of her illness. Art therapy offered a unique emotional and cognitive outlet as illness progressed. Patients and families affected by sporadic Creutzfeldt-Jakob disease may benefit from art therapy despite the rapidly progressive nature of the illness. Art therapy can also be useful for assessment of patients with sporadic Creutzfeldt-Jakob disease by healthcare professionals.

Rocket/Radar Investigation of Lower Ionospheric Electrodynamics Associated with Intense Midlatitude Sporadic-E Layers

NASA Technical Reports Server (NTRS)

Heelis, R. A.

1998-01-01

Sporadic layers, which appear in the region from 100 km to 120 km are thought to be formed by convergent Pedersen drifts induced by altitude gradients in the zonal neutral wind. In this altitude region NO+ and 02+ are the major ions produced by photoionization and charge exchange of atmospheric and ionospheric species. The relative composition of atmospheric ions and meteoric ions in sporadic layers is important in determining their persistence, the time scales for formation, and the electrical conductivity of the layers. This rocket investigation will include a diagnosis of the neutral wind field and the electric field distribution. Coupled with ion composition measurements we will be able to expose the relevant formation mechanisms and the electrodynamic consequences of their existence. A rocket trajectory has been chosen to provide substantial horizontal sampling of the layer properties and knowledge of the horizontal gradients in composition and density are essential to determine the polarization electric fields that may be associated with ionospheric layers. The University of Texas at Dallas (UTD) is responsible for designing, building, and operating the ion mass spectrometers included on these rockets. The following provides a summary of the UTD accomplishments in the second year of the project as well as a description of the plans for the third year's activities. The UTD mass spectrometer acronym has been coined as PRIMS for Puerto Rico Ion Mass Spectrometer.

S-Nitrosylation of parkin as a novel regulator of p53-mediated neuronal cell death in sporadic Parkinson’s disease

PubMed Central

2013-01-01

Background Mutations in the gene encoding parkin, a neuroprotective protein with dual functions as an E3 ubiquitin ligase and transcriptional repressor of p53, are linked to familial forms of Parkinson’s disease (PD). We hypothesized that oxidative posttranslational modification of parkin by environmental toxins may contribute to sporadic PD. Results We first demonstrated that S-nitrosylation of parkin decreased its activity as a repressor of p53 gene expression, leading to upregulation of p53. Chromatin immunoprecipitation as well as gel-shift assays showed that parkin bound to the p53 promoter, and this binding was inhibited by S-nitrosylation of parkin. Additionally, nitrosative stress induced apoptosis in cells expressing parkin, and this death was, at least in part, dependent upon p53. In primary mesencephalic cultures, pesticide-induced apoptosis was prevented by inhibition of nitric oxide synthase (NOS). In a mouse model of pesticide-induced PD, both S-nitrosylated (SNO-)parkin and p53 protein levels were increased, while administration of a NOS inhibitor mitigated neuronal death in these mice. Moreover, the levels of SNO-parkin and p53 were simultaneously elevated in postmortem human PD brain compared to controls. Conclusions Taken together, our data indicate that S-nitrosylation of parkin, leading to p53-mediated neuronal cell death, contributes to the pathophysiology of sporadic PD. PMID:23985028

Identification of two novel mutations in the PHEX gene in Chinese patients with hypophosphatemic rickets/osteomalacia.

PubMed

Yue, Hua; Yu, Jin-bo; He, Jin-wei; Zhang, Zeng; Fu, Wen-zhen; Zhang, Hao; Wang, Chun; Hu, Wei-wei; Gu, Jie-mei; Hu, Yun-qiu; Li, Miao; Liu, Yu-juan; Zhang, Zhen-Lin

2014-01-01

X-linked dominant hypophosphatemia (XLH) is the most prevalent form of inherited rickets/osteomalacia in humans. The aim of this study was to identify PHEX gene mutations and describe the clinical features observed in 6 unrelated Chinese families and 3 sporadic patients with hypophosphatemic rickets/osteomalacia. For this study, 45 individuals from 9 unrelated families of Chinese Han ethnicity (including 16 patients and 29 normal phenotype subjects), and 250 healthy donors were recruited. All 22 exons and exon-intron boundaries of the PHEX gene were amplified by polymerase chain reaction (PCR) and directly sequenced. The PHEX mutations were detected in 6 familial and 3 sporadic hypophosphatemic rickets/osteomalacia. Altogether, 2 novel mutations were detected: 1 missense mutation c.1183G>C in exon 11, resulting in p.Gly395Arg and 1 missense mutation c.1751A>C in exon 17, resulting in p.His584Pro. No mutations were found in the 250 healthy controls. Our study increases knowledge of the PHEX gene mutation types and clinical phenotypes found in Chinese patients with XLH, which is important for understanding the genetic basis of XLH. The molecular diagnosis of a PHEX genetic mutation is of great importance for confirming the clinical diagnosis of XLH, conducting genetic counseling, and facilitating prenatal intervention, especially in the case of sporadic patients.

Screening LGI1 in a cohort of 26 lateral temporal lobe epilepsy patients with auditory aura from Turkey detects a novel de novo mutation.

PubMed

Kesim, Yesim F; Uzun, Gunes Altiokka; Yucesan, Emrah; Tuncer, Feyza N; Ozdemir, Ozkan; Bebek, Nerses; Ozbek, Ugur; Iseri, Sibel A Ugur; Baykan, Betul

2016-02-01

Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is an autosomal dominant epileptic syndrome characterized by focal seizures with auditory or aphasic symptoms. The same phenotype is also observed in a sporadic form of lateral temporal lobe epilepsy (LTLE), namely idiopathic partial epilepsy with auditory features (IPEAF). Heterozygous mutations in LGI1 account for up to 50% of ADLTE families and only rarely observed in IPEAF cases. In this study, we analysed a cohort of 26 individuals with LTLE diagnosed according to the following criteria: focal epilepsy with auditory aura and absence of cerebral lesions on brain MRI. All patients underwent clinical, neuroradiological and electroencephalography examinations and afterwards they were screened for mutations in LGI1 gene. The single LGI1 mutation identified in this study is a novel missense variant (NM_005097.2: c.1013T>C; p.Phe338Ser) observed de novo in a sporadic patient. This is the first study involving clinical analysis of a LTLE cohort from Turkey and genetic contribution of LGI1 to ADLTE phenotype. Identification of rare LGI1 gene mutations in sporadic cases supports diagnosis as ADTLE and draws attention to potential familial clustering of ADTLE in suggestive generations, which is especially important for genetic counselling. Copyright © 2015 Elsevier B.V. All rights reserved.

Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy.

PubMed

van Waning, Jaap I; Caliskan, Kadir; Hoedemaekers, Yvonne M; van Spaendonck-Zwarts, Karin Y; Baas, Annette F; Boekholdt, S Matthijs; van Melle, Joost P; Teske, Arco J; Asselbergs, Folkert W; Backx, Ad P C M; du Marchie Sarvaas, Gideon J; Dalinghaus, Michiel; Breur, Johannes M P J; Linschoten, Marijke P M; Verlooij, Laura A; Kardys, Isabella; Dooijes, Dennis; Lekanne Deprez, Ronald H; IJpma, Arne S; van den Berg, Maarten P; Hofstra, Robert M W; van Slegtenhorst, Marjon A; Jongbloed, Jan D H; Majoor-Krakauer, Danielle

2018-02-20

The clinical outcomes of noncompaction cardiomyopathy (NCCM) range from asymptomatic to heart failure, arrhythmias, and sudden cardiac death. Genetics play an important role in NCCM. This study investigated the correlations among genetics, clinical features, and outcomes in adults and children diagnosed with NCCM. A retrospective multicenter study from 4 cardiogenetic centers in the Netherlands classified 327 unrelated NCCM patients into 3 categories: 1) genetic, with a mutation in 32% (81 adults; 23 children) of patients; 2) probably genetic, familial cardiomyopathy without a mutation in 16% (45 adults; 8 children) of patients; or 3) sporadic, no family history, without mutation in 52% (149 adults; 21 children) of patients. Clinical features and major adverse cardiac events (MACE) during follow-up were compared across the children and adults. MYH7, MYBPC3, and TTN mutations were the most common mutations (71%) found in genetic NCCM. The risk of having reduced left ventricular (LV) systolic dysfunction was higher for genetic patients compared with the probably genetic and sporadic cases (p = 0.024), with the highest risk in patients with multiple mutations and TTN mutations. Mutations were more frequent in children (p = 0.04) and were associated with MACE (p = 0.025). Adults were more likely to have sporadic NCCM. High risk for cardiac events in children and adults was related to LV systolic dysfunction in mutation carriers, but not in sporadic cases. Patients with MYH7 mutations had low risk for MACE (p = 0.03). NCCM is a heterogeneous condition, and genetic stratification has a role in clinical care. Distinguishing genetic from nongenetic NCCM complements prediction of outcome and may lead to management and follow-up tailored to genetic status. Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Value of surgery in patients with negative imaging and sporadic Zollinger-Ellison syndrome.

PubMed

Norton, Jeffrey A; Fraker, Douglas L; Alexander, H Richard; Jensen, Robert T

2012-09-01

To address the value of surgery in patients with sporadic Zollinger-Ellison syndrome (ZES) with negative imaging studies. Medical control of acid hypersecretion in patients with sporadic ZES is highly effective. This has led to these patients frequently not being sent to surgery, especially if preoperative imaging studies are negative, due, in large part, to existence of almost no data on the success of surgery in this group. Fifty-eight prospectively studied patients with sporadic ZES (17% of total studied) had negative imaging studies, and their surgical outcome was compared with 117 patients with positive imaging results. Thirty-five patients had negative imaging studies in the pre-somatostatin receptor scintigraphy (SRS) era, and 23 patients in the post-SRS era. Patients with negative imaging studies had long disease histories before surgery [mean ± SEM (from onset) = 7.9 ± 1 [range, -0.25 to 35 years]) and 25% were followed for 2 or more years from diagnosis. At surgery, gastrinoma was found in 57 of 58 patients (98%). Tumors were small (mean = 0.8 cm, 60% <1 cm). The most common primary sites were duodenal 64%, pancreatic 17%, and lymph node (10%). Fifty percent had a primary-only, 41% primary + lymph node, and 7% had liver metastases. Thirty-five of 58 patients (60%) were cured immediately postoperatively, and at last follow-up [mean = -9.4 years; range, 0.2-22 years], 27 patients (46%) remained cured. During follow-up, 3 patients died, each had liver metastases at surgery. In comparison to positive imaging patients, those with negative imaging studies had lower preoperative fasting gastrin levels; had a longer delay before surgery; more frequently had a small duodenal tumor; less frequently had a pancreatic tumor, multiple tumors, or developed a new lesion postoperatively; and had a longer survival. Sporadic ZES patients with negative imaging studies are not rare even in the post-SRS period. An experienced surgeon can find gastrinoma in almost every patient (98%) and nearly one half (46%) are cured, a rate similar to patients with positive imaging findings. Because liver metastases were found in 7%, which may have been caused by a long delay in surgery and all the disease-related deaths occurred in this group, surgery should be routinely undertaken early in ZES patients despite negative imaging studies.

Value of Surgery In Patients With Negative Imaging And Sporadic Zollinger-Ellison Syndrome (ZES)

PubMed Central

Norton, Jeffrey A.; Fraker, Douglas L.; Alexander, H. Richard; Jensen, Robert T

2012-01-01

Objectives To address the value of surgery in sporadic Zollinger-Ellison syndrome (ZES) patients with negative imaging studies. Background Medical control of acid hypersecretion in patients with sporadic Zollinger-Ellison syndrome (ZES) is highly effective. This has led to these patients frequently not sent to surgery, especially if preoperative imaging studies are negative, due in large part because almost no data exists on the success of surgery in this group. Methods 58 prospectively studied sporadic ZES patients (17% of total studied) had negative imaging studies and their surgical outcome was compared to 117 patients with positive imaging results. Results 35 patients had negative imaging in the pre-somatostatin receptor scintigraphy era (SRS) and 23 in the post-SRS era. The image negative patients had long disease histories prior to surgery (mean±SEM, from onset=7.9±1[range −0.25-35 yrs]) and 25% were followed ≥2yrs from diagnosis. At surgery, gastrinoma was found in 57/58 patients (98%). Tumors were small (mean=0.8cm, 60% < 1 cm). The most common primary sites were: duodenal 64%, pancreatic 17%, and lymph node (LN)(10%). 50% had a primary only, 41% primary + LN, and 7% had liver metastases. 35/58(60%) were cured immediately postoperatively and at last follow-up [mean-9.4yrs, range 0.2-22yrs], 27 patients (46%) remained cured. During follow-up 3 patients died, each was found to have liver metastases at surgery. In comparison to the image positive patients, those with negative imaging had lower preop fasting gastrin levels; a longer delay prior to surgery; more frequently had a small duodenal tumors; less frequently had a pancreatic tumor, multiple tumors or developed a new lesion postoperatively and had a longer survival. Conclusions Imaging negative sporadic ZES patients are not rare even in the post-SRS period. An experienced surgeon can find gastrinoma in almost every patient (98%) and nearly one-half (46%) are cured, a rate similar to imaging positive tumor patients. Because liver metastases were found in 7%, which may have been caused by a long delay in surgery and all the disease-related deaths occurred in this group, surgery should be routinely undertaken early in ZES patients despite negative imaging studies. PMID:22868363

Granulosa cell cycle regulation and steroidogenesis in a high androstenedione follicular microenvironment

USDA-ARS?s Scientific Manuscript database

Anovulatory infertility (either chronic or sporadic anovulation) affects up to 40% of infertile women. In fact, sporadic anovulation in humans may often go undetected. Recent literature has reported that 8-13% of normally menstruating women (250 total, two reproductive cycles) exhibit sporadic anovu...

Allelic loss and linkage studies in prostate cancer

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

Johnson, D.R.; Bale, A.E.; Lytton, B.

1994-09-01

Prostate cancer is the most common malignancy in U.S. males. Many examples of familial aggregation have been reported, and segregration analysis suggests that an autosomal dominant gene with a penetrance of 88% by age 85 accounts for 9% of all cases. Because many dominant cancer predisposition syndromes are related to germline mutations in tumor suppressor genes, we analyzed a series of sporadic and hereditary tumors for allelic loss. High grade sporadic, paraffin-embedded, primary prostate tumors were obtained from the archival collection in the Department of Pathology at Yale and hereditary tumors from three families were obtained by an advertisement inmore » the New York Times and from referrals by urologists. PCR analysis showed loss in 4/7 informative sporadic prostate tumors with NEFL (8p21), in 8/22 informative tumors with D10S169 (10q26-qter), in 2/8 informative tumors with D10S108 (10q) and in 4/23 informative tumors with D10S89 (10p) in agreement with previous studies. PYGM on chromosome 11 and D9S127 on chromosome 9 showed no loss. Linkage analysis with NEFL in 3 prostate cancer families gave strongly negative results for close linkage (Z=-2.1 at {theta}=0.01) but LOD scores were very dependent on parameters, e.g. gene frequency, phenocopy rate, and penetrance. Linkage analysis with chromosome 10 markers and systematic analysis of the genome for other area of allelic loss are underway.« less

Effect of β-catenin alterations in the prognosis of patients with sporadic colorectal cancer.

PubMed

Rafael, Sara; Veganzones, Silvia; Vidaurreta, Marta; de la Orden, Virginia; Maestro, Maria Luisa

2014-01-01

Wnt pathway activation represents a critical step in the etiology of most of colorectal cancer (CRC) and it is commonly due to mutations in the APC gene, which originates the loss of β-catenin regulatory function. It has been suggested that APC inactivation or β-catenin alteration have similar effects in tumor progression in CRC tumorigenesis. The aim of this study was to analyze the frequency of β-catenin gene mutation in patients with sporadic CRC and to determine its effect in prognosis. This was a prospective cohort study, which included 345 patients with sporadic CRC. β-Catenin gene mutations in exon 3 were detected by single strand conformation polymorphism (SSCP). Exon 3 deletion was studied by identifying differences in fragment length of specific amplification products. All the altered samples were confirmed by direct sequencing. In our population, point mutations were detected in 1.8% of the samples and 4.9% of the samples showed deletion. We observed association between exon 3 mutations and increased levels of Carcinoenbryonic Antigen (CEA). In these patients, clinically relevant improvement in overall survival was also observed. Frequency of point mutations in exon 3 β-catenin gene is low in our population. It would be interesting to increase the population size to test the clinically relevant influence in the prognosis found, and to test the relation of these events with Microsatellite Instabillity (MSI) pathway. If these findings were confirmed, β-catenin determination would help in the selection of patients with different prognosis.

Identification of three novel LRRK2 mutations associated with Parkinson's disease in a Calabrian population.

PubMed

Anfossi, Maria; Colao, Rosanna; Gallo, Maura; Bernardi, Livia; Conidi, M Elena; Frangipane, Francesca; Vasso, Franca; Puccio, Gianfranco; Clodomiro, Alessandra; Mirabelli, Maria; Curcio, Sabrina A M; Torchia, Giusi; Smirne, Nicoletta; Di Lorenzo, Raffaele; Maletta, Raffaele; Bruni, Amalia C

2014-01-01

LRRK2 mutations are common in familial and sporadic Parkinson's disease (PD) cases. We present a screening of the most frequently mutated exons of LRRK2 in Calabrian population. Eighty-eight PD patients diagnosed according to standard criteria, underwent screening for LRRK2 mutations in exons 19, 21, 24, 25, 27, 29, 31, 32, 33, 35, 38, 40, 41, and 48. Eight LRRK2 variations were identified in nine patients affected by PD, including three novel missense variations (p.Phe1227Leu, p.Gly1520Ala, p.Ile2020Ser) and five previously identified mutations (p.Ala1151Thr, IVS31+3A>G, p.Arg1514Gln, p.Gly2019Ser, p.Thr2356Ile). LRRK2 frequency mutations were approximately 10.2% in all PD patients, 12% in familial, 8% in sporadic cases. The p.Gly2019Ser mutation was found in 2.3% of the total cohort and in 3.2% of sporadic cases. The clinical features of LRRK2-associated with PD in our patients were similar to those of idiopathic PD although most LRRK2 mutated patients presented with bradykinesia instead of tremor; 33.3% developed dementia. We identified three novel LRRK2 mutations and reported a higher frequency in Calabria compared to previously reported data possibly due to the relative genetic isolation of the Calabrian population. These findings contribute to the understanding of the role of LRKK2 variations in PD and provide additional genetic insight into this disease.

Homozygous HAX1 mutations in severe congenital neutropenia patients with sporadic disease: a novel mutation in two unrelated British kindreds.

PubMed

Smith, Bradley N; Ancliff, Phil J; Pizzey, Arnold; Khwaja, Asim; Linch, David C; Gale, Rosemary E

2009-03-01

Patients with autosomal dominant (AD), sporadic and X-linked severe congenital neutropenia (SCN) may have mutations in the elastase 2 (ELA2) or Wiskott-Aldrich syndrome (WAS) genes. Homozygous mutations in the HAX1 gene have recently been reported in autosomal recessive (AR) cases of primarily Middle-Eastern descent and the original Kostmann family. We screened 109 predominantly Caucasian SCN kindreds for mutations in these genes; 33 (30%) had 24 different ELA2 mutations, five of them novel, two kindreds (2%) had WAS mutations and four kindreds (4%) had three different HAX1 mutations, two of them novel. One HAX1 mutation (p.Ser43LeufsX11) was found in an AR Ashkenazi Jewish kindred, the other (p.Glu31LysfsX54) in two unrelated British patients with sporadic disease. Microsatellite analysis of the HAX1 locus revealed a common haplotype (maximum distance 4.1 Megabases) for the p.Glu31LysfsX54 patients, suggesting a possible ancestral founder. In functional assays, the level of spontaneous and staurosporine-induced apoptosis was increased in neutrophils from both p.Ser43LeufsX11 patients but not a p.Glu31LysfsX54 patient, suggesting the possible presence of modifying factors. The low incidence of HAX1 mutations in our study suggests that the frequency may vary between racial groups but suggests that irrespective of inheritance or racial origin, SCN patients should be screened for HAX1 mutations.

Estimation of ionospheric sporadic E intensities from GPS radio occultation measurements

NASA Astrophysics Data System (ADS)

Arras, C.; Wickert, J.

2018-06-01

The radio occultation experiment aboard the FORMOSAT-3/COSMIC satellites enables the observation of phenomena in Earth's ionosphere on a global scale. Numerous radio occultation profiles are used to analyse the occurrence of sporadic E layers as well as its properties. We will present a new method to approach additionally to the presence of sporadic E also its intensity which is closely related to the blanketing frequency (fbEs) provided by ionosondes. We observed that the sporadic E occurrence and its intensity show a highly developed annual cycle with high occurrence rates and intensities in the actual summer hemisphere. The global latitude/longitude distribution of both parameters is strongly related to Earth's magnetic field which is reflected by the missing of sporadic E observations along the magnetic equator.

Detection and partial discrimination of atypical and classical bovine spongiform encephalopathies in cattle and primates using real-time quaking-induced conversion assay.

PubMed

Levavasseur, Etienne; Biacabe, Anne-Gaëlle; Comoy, Emmanuel; Culeux, Audrey; Grznarova, Katarina; Privat, Nicolas; Simoneau, Steve; Flan, Benoit; Sazdovitch, Véronique; Seilhean, Danielle; Baron, Thierry; Haïk, Stéphane

2017-01-01

The transmission of classical bovine spongiform encephalopathy (C-BSE) through contaminated meat product consumption is responsible for variant Creutzfeldt-Jakob disease (vCJD) in humans. More recent and atypical forms of BSE (L-BSE and H-BSE) have been identified in cattle since the C-BSE epidemic. Their low incidence and advanced age of onset are compatible with a sporadic origin, as are most cases of Creutzfeldt-Jakob disease (CJD) in humans. Transmissions studies in primates and transgenic mice expressing a human prion protein (PrP) indicated that atypical forms of BSE may be associated with a higher zoonotic potential than classical BSE, and require particular attention for public health. Recently, methods designed to amplify misfolded forms of PrP have emerged as promising tools to detect prion strains and to study their diversity. Here, we validated real-time quaking-induced conversion assay for the discrimination of atypical and classical BSE strains using a large series of bovine samples encompassing all the atypical BSE cases detected by the French Centre of Reference during 10 years of exhaustive active surveillance. We obtained a 100% sensitivity and specificity for atypical BSE detection. In addition, the assay was able to discriminate atypical and classical BSE in non-human primates, and also sporadic CJD and vCJD in humans. The RT-QuIC assay appears as a practical means for a reliable detection of atypical BSE strains in a homologous or heterologous PrP context.

Immunohistochemical expression of SP-NK-1R-EGFR pathway and VDR in colonic inflammation and neoplasia

PubMed Central

Isidro, Raymond A; Cruz, Myrella L; Isidro, Angel A; Baez, Axel; Arroyo, Axel; González-Marqués, William A; González-Keelan, Carmen; Torres, Esther A; Appleyard, Caroline B

2015-01-01

AIM: To determine the expression of neurokinin-1 receptor (NK-1R), phosphorylated epidermal growth factor receptor (pEGFR), cyclooxygenase-2 (Cox-2), and vitamin D receptor (VDR) in normal, inflammatory bowel disease (IBD), and colorectal neoplasia tissues from Puerto Ricans. METHODS: Tissues from patients with IBD, colitis-associated colorectal cancer (CAC), sporadic dysplasia, and sporadic colorectal cancer (CRC), as well as normal controls, were identified at several centers in Puerto Rico. Archival formalin-fixed, paraffin-embedded tissues were de-identified and processed by immunohistochemistry for NK-1R, pEGFR, Cox-2, and VDR. Pictures of representative areas of each tissues diagnosis were taken and scored by three observers using a 4-point scale that assessed intensity of staining. Tissues with CAC were further analyzed by photographing representative areas of IBD and the different grades of dysplasia, in addition to the areas of cancer, within each tissue. Differences in the average age between the five patient groups were assessed with one-way analysis of variance and Tukey-Kramer multiple comparisons test. The mean scores for normal tissues and tissues with IBD, dysplasia, CRC, and CAC were calculated and statistically compared using one-way analysis of variance and Dunnett’s multiple comparisons test. Correlations between protein expression patterns were analyzed with the Pearson’s product-moment correlation coefficient. Data are presented as mean ± SE. RESULTS: On average, patients with IBD were younger (34.60 ± 5.81) than normal (63.20 ± 6.13, P < 0.01), sporadic dysplasia (68.80 ± 4.42, P < 0.01), sporadic cancer (74.80 ± 4.91, P < 0.001), and CAC (57.50 ± 5.11, P < 0.05) patients. NK-1R in cancer tissue (sporadic CRC, 1.73 ± 0.34; CAC, 1.57 ± 0.53) and sporadic dysplasia (2.00 ± 0.45) were higher than in normal tissues (0.73 ± 0.19). pEGFR was significantly increased in sporadic CRC (1.53 ± 0.43) and CAC (2.25 ± 0.47) when compared to normal tissue (0.07 ± 0.25, P < 0.05, P < 0.001, respectively). Cox-2 was significantly increased in sporadic colorectal cancer (2.20 ± 0.23 vs 0.80 ± 0.37 for normal tissues, P < 0.05). In comparison to normal (2.80 ± 0.13) and CAC (2.50 ± 0.33) tissues, VDR was significantly decreased in sporadic dysplasia (0.00 ± 0.00, P < 0.001 vs normal, P < 0.001 vs CAC) and sporadic CRC (0.47 ± 0.23, P < 0.001 vs normal, P < 0.001 vs CAC). VDR levels negatively correlated with NK-1R (r = -0.48) and pEGFR (r = -0.56) in normal, IBD, sporadic dysplasia and sporadic CRC tissue, but not in CAC. CONCLUSION: Immunohistochemical NK-1R and pEGFR positivity with VDR negativity can be used to identify areas of sporadic colorectal neoplasia. VDR immunoreactivity can distinguish CAC from sporadic cancer. PMID:25684939

Modeling Chemical and Isotopic Variations in Lab Formed Hydrothermal Carbonates

NASA Technical Reports Server (NTRS)

Niles, P. B.; Leshin, L. A.; Golden, D. C.; Socki, R. A.; Guan, Y.; Ming, D. W.

2005-01-01

Chemical and mineralogical data (e.g. [1]) from Mars suggest that the history of liquid water on the planet was more sporadic in nature than long-lived. The non-equilibrium chemical and isotopic compositions of the carbonates preserved in the martian meteorite ALH84001 are direct evidence of ancient secondary minerals that have not undergone significant diagenesis or stabilization processes typical of long-lived aqueous systems on Earth. Thus secondary minerals and sediments on Mars may primarily record the characteristics of the aqueous environment in which they formed without being significantly overprinted by subsequent diagenetic processes during burial.

Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center.

PubMed

Chadi, Gerson; Maximino, Jessica Ruivo; Jorge, Frederico Mennucci de Haidar; Borba, Fabrício Castro de; Gilio, Joyce Meire; Callegaro, Dagoberto; Lopes, Camila Galvão; Santos, Samantha Nakamura Dos; Rebelo, Gabriela Natania Sales

2017-05-01

To investigate gene mutations in familial form (FALS) and sporadic form (SALS) of amyotrophic lateral sclerosis (ALS) in a highly miscegenated population. Frequencies of mutations in the C9orfF72, TARDBP, SOD1, FUS and VAPB genes were investigated in a cohort of FALS (n = 39) and SALS (n = 189) subjects from the Research Centre of the University of São Paulo School of Medicine. All patients were subjected to C9orf72 and TARDBP analyses. SOD1, FUS and VAPB were also evaluated in FALS subjects. Mutations were identified in FALS (61.3%) and SALS (5.3%) patients. Mutations in C9orf72 (12.8%, >45 GGGGCC hexanucleotide repeats), VAPB (43.6%, P56S) and SOD1 (7.7%, L145S) were identified in FALS subjects. Pathogenic C9orf72 expansions (2.64%) were identified in some SALS patients. Similar changes of TARDBP were found in SALS (2.64%) but not in FALS subjects. No FUS mutations were seen in any FALS subjects. TARDBP and C9orf72 mutations in this cohort were similar to those found in other centres worldwide. VAPB mutation (P56S) was highly prevalent in Brazilian FALS patients.

Gas hydrate characterization and grain-scale imaging of recovered cores from the Mount Elbert Gas Hydrate Stratigraphic Test Well, Alaska North Slope

USGS Publications Warehouse

Stern, Laura A.; Lorenson, T.D.; Pinkston, John C.

2011-01-01

Using cryogenic scanning electron microscopy (CSEM), powder X-ray diffraction, and gas chromatography methods, we investigated the physical states, grain characteristics, gas composition, and methane isotopic composition of two gas-hydrate-bearing sections of core recovered from the BPXA–DOE–USGS Mount Elbert Gas Hydrate Stratigraphic Test Well situated on the Alaska North Slope. The well was continuously cored from 606.5 m to 760.1 m depth, and sections investigated here were retrieved from 619.9 m and 661.0 m depth. X-ray analysis and imaging of the sediment phase in both sections shows it consists of a predominantly fine-grained and well-sorted quartz sand with lesser amounts of feldspar, muscovite, and minor clays. Cryogenic SEM shows the gas-hydrate phase forming primarily as a pore-filling material between the sediment grains at approximately 70–75% saturation, and more sporadically as thin veins typically several tens of microns in diameter. Pore throat diameters vary, but commonly range 20–120 microns. Gas chromatography analyses of the hydrate-forming gas show that it is comprised of mainly methane (>99.9%), indicating that the gas hydrate is structure I. Here we report on the distribution and articulation of the gas-hydrate phase within the cores, the grain morphology of the hydrate, the composition of the sediment host, and the composition of the hydrate-forming gas.

Gas hydrate characterization and grain-scale imaging of recovered cores from the Mount Elbert Gas Hydrate Stratigraphic Test Well, Alaska North Slope

USGS Publications Warehouse

Stern, L.A.; Lorenson, T.D.; Pinkston, J.C.

2011-01-01

Using cryogenic scanning electron microscopy (CSEM), powder X-ray diffraction, and gas chromatography methods, we investigated the physical states, grain characteristics, gas composition, and methane isotopic composition of two gas-hydrate-bearing sections of core recovered from the BPXA-DOE-USGS Mount Elbert Gas Hydrate Stratigraphic Test Well situated on the Alaska North Slope. The well was continuously cored from 606.5. m to 760.1. m depth, and sections investigated here were retrieved from 619.9. m and 661.0. m depth. X-ray analysis and imaging of the sediment phase in both sections shows it consists of a predominantly fine-grained and well-sorted quartz sand with lesser amounts of feldspar, muscovite, and minor clays. Cryogenic SEM shows the gas-hydrate phase forming primarily as a pore-filling material between the sediment grains at approximately 70-75% saturation, and more sporadically as thin veins typically several tens of microns in diameter. Pore throat diameters vary, but commonly range 20-120 microns. Gas chromatography analyses of the hydrate-forming gas show that it is comprised of mainly methane (>99.9%), indicating that the gas hydrate is structure I. Here we report on the distribution and articulation of the gas-hydrate phase within the cores, the grain morphology of the hydrate, the composition of the sediment host, and the composition of the hydrate-forming gas. ?? 2009.

Association Studies of Sporadic Parkinson’s Disease in the Genomic Era

PubMed Central

Labbé, Catherine; Ross, Owen A

2014-01-01

Parkinson’s disease is a common age-related progressive neurodegenerative disorder. Over the last 10 years, advances have been made in our understanding of the etiology of the disease with the greatest insights perhaps coming from genetic studies, including genome-wide association approaches. These large scale studies allow the identification of genomic regions harboring common variants associated to disease risk. Since the first genome-wide association study on sporadic Parkinson’s disease performed in 2005, improvements in study design, including the advent of meta-analyses, have allowed the identification of ~21 susceptibility loci. The first loci to be nominated were previously associated to familial PD (SNCA, MAPT, LRRK2) and these have been extensively replicated. For other more recently identified loci (SREBF1, SCARB2, RIT2) independent replication is still warranted. Cumulative risk estimates of associated variants suggest that more loci are still to be discovered. Additional association studies combined with deep re-sequencing of known genome-wide association study loci are necessary to identify the functional variants that drive disease risk. As each of these associated genes and variants are identified they will give insight into the biological pathways involved the etiology of Parkinson’s disease. This will ultimately lead to the identification of molecules that can be used as biomarkers for diagnosis and as targets for the development of better, personalized treatment. PMID:24653658

Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease

PubMed Central

Hamza, Taye H; Zabetian, Cyrus P; Tenesa, Albert; Laederach, Alain; Montimurro, Jennifer; Yearout, Dora; Kay, Denise M; Doheny, Kimberly F; Paschall, Justin; Pugh, Elizabeth; Kusel, Victoria I; Collura, Randall; Roberts, John; Griffith, Alida; Samii, Ali; Scott, William K; Nutt, John; Factor, Stewart A; Payami, Haydeh

2010-01-01

Parkinson disease (PD) is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study (GWAS) with 2000 PD and 1986 control Caucasian subjects from NeuroGenetics Research Consortium.1–5 We confirmed SNCA2,6–8 and MAPT3,7–9; replicated GAK9 (PPankratz+NGRC=3.2×10−9); and detected a novel association with HLA (PNGRC=2.9×10−8) which replicated in two datasets (PMeta-analysis=1.9×10−10). We designate the new PD genes PARK17 (GAK) and PARK18 (HLA). PD-HLA association was uniform across genetic and environmental risk strata, and strong in sporadic (P=5.5×10−10) and late-onset (P=2.4×10−8) PD. The association peak was at rs3129882, a non-coding variant in HLA-DRA. Two studies suggested rs3129882 influences expression of HLA-DR and HLA-DQ.10,11 PD brains exhibit up-regulation of DR antigens and presence of DR-positive reactive microglia.12 Moreover, non-steroidal anti-inflammatory drugs (NSAID) reduce PD risk.4,13 The genetic association with HLA coalesces the evidence for involvement of the immune system and offers new targets for drug development and pharmacogenetics. PMID:20711177

Two Novel Mutations in the GDAP1 and PRX Genes in Early Onset Charcot-Marie-Tooth Syndrome

PubMed Central

Auer-Grumbach, M.; Fischer, C.; Papić, L.; John, E.; Plecko, B.; Bittner, R. E.; Bernert, G.; Pieber, T. R.; Miltenberger, G.; Schwarz, R.; Windpassinger, C.; Grill, F.; Timmerman, V.; Speicher, M. R.; Janecke, A. R.

2011-01-01

Autosomal recessive Charcot-Marie-Tooth syndrome (AR-CMT) is often characterised by an infantile disease onset and a severe phenotype. Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene are thought to be a common cause of AR-CMT. Mutations in the periaxin (PRX) gene are rare. They are associated with severe demyelination of the peripheral nerves and sometimes lead to prominent sensory disturbances. To evaluate the frequency of GDAP1 and PRX mutations in early onset CMT, we examined seven AR-CMT families and 12 sporadic CMT patients, all presenting with progressive distal muscle weakness and wasting. In one family also prominent sensory abnormalities and sensory ataxia were apparent from early childhood. In three families we detected four GDAP1 mutations (L58LfsX4, R191X, L239F and P153L), one of which is novel and is predicted to cause a loss of protein function. In one additional family with prominent sensory abnormalities a novel homozygous PRX mutation was found (A700PfsX17). No mutations were identified in 12 sporadic cases. This study suggests that mutations in the GDAP1 gene are a common cause of early-onset AR-CMT. In patients with early-onset demyelinating AR-CMT and severe sensory loss PRX is one of the genes to be tested. PMID:18504680

Study of sporadical properties of crosslinked polyelectrolyte multilayers

NASA Astrophysics Data System (ADS)

Balu, Deebika

Polyelectrolyte multilayers (PEM) have become a highly studied class of materials due to the range of their applicability in many areas of research, including biology, chemistry and materials science. Recent advances in surface coatings have enabled modification of PEM surfaces to provide desirable properties such as controlled release, super-hydrophobicity, biocompatibility, antifouling and antibacterial properties. In the past decade, antimicrobial PEM coatings have been investigated as a safer alternative to the traditional disinfection methods that usually involve application of hazardous chemicals onto the surface to be cleaned. These antimicrobial coatings could be applied to common surfaces prone to colonization of bacteria (such as bench tops, faucet handles, etc) to supplement routine sanitization protocols by providing sustained antimicrobial activity. Vegetative bacteria (such as Escherichia coli) are more susceptible to antimicrobial agents than bacterial species that form spores. Hence, the antimicrobial activity of PEM coatings fabricated using Layer by Layer (LbL) technique were assayed using Bacillus anthracis spores (Sterne strain). In this thesis, the sporicidal effect of various polyelectrolyte multilayer coatings containing cross-linked polymers immersed in bleach have been evaluated as potential augmentation to existing disinfection methods.

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 nitric oxide synthase 690 C/T and glu298asp; vitamin K-dependent coagulation factor seven arg353glu, glycoprotein Ia/IIa 873 G/A and E-selectin ser128arg. This study provides an alternative and reliable method to approach complex diseases. Indeed, the application of a novel artificial intelligence-based method offers a new insight into genetic markers of sporadic ALS pointing out the existence of a strong genetic background.

Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche.

PubMed

Davis, Hayley; Irshad, Shazia; Bansal, Mukesh; Rafferty, Hannah; Boitsova, Tatjana; Bardella, Chiara; Jaeger, Emma; Lewis, Annabelle; Freeman-Mills, Luke; Giner, Francesc Castro; Rodenas-Cuadrado, Pedro; Mallappa, Sreelakshmi; Clark, Susan; Thomas, Huw; Jeffery, Rosemary; Poulsom, Richard; Rodriguez-Justo, Manuel; Novelli, Marco; Chetty, Runjan; Silver, Andrew; Sansom, Owen James; Greten, Florian R; Wang, Lai Mun; East, James Edward; Tomlinson, Ian; Leedham, Simon John

2015-01-01

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.

Terminal changes in hereditary sensory and autonomic neuropathy: a long-term follow-up of a sporadic case.

PubMed

Lee, Sang-Soo; Lee, Sung-Hyun; Han, Seol-Heui

2003-07-01

We describe terminal changes in a long-term follow-up of a 51-year-old man with sporadic hereditary sensory and autonomic neuropathy (HSAN). From the age of 15 years onwards, he suffered from multiple painless ulcers of his feet and fingers, necessitating amputation. Neurological studies revealed almost complete sensory loss affecting all modalities in the upper and lower limbs, minimal involvement of motor fibers, and areflexia. A neurophysiological abnormality involved an absence of sensory action potentials with relatively normal motor nerve conduction velocities. Biopsy of the sural nerve showed almost total loss of myelinated fibers with a mild decrease in unmyelinated fibers. Despite the late onset of the disease, the progressive course, and the lancinating pain, the terminal features of this patient, which involved a selective loss of myelinated fibers and widespread sensory loss, seem to be symptomatic of HSAN II, the progressive form of autosomal recessive sensory neuropathy, and emphasize the clinical heterogeneity of HSAN.

Far East Scarlet-Like Fever: A Review of the Epidemiology, Symptomatology, and Role of Superantigenic Toxin: Yersinia pseudotuberculosis-Derived Mitogen A

PubMed Central

Amphlett, A.

2016-01-01

Far East scarlet-like fever (FESLF) is a severe inflammatory disease that occurs sporadically and in outbreaks in Russia and Japan. Far East scarlet-like fever is caused by Yersinia pseudotubuclosis infection, an organism that typically causes self-limiting gastroenteritis in Europe. Studies suggest the ability of Far Eastern strains to produce superantigen toxin Y pseudotuberculosis-derived mitogen A is integral to FESLF pathogenesis. In Europe, human Y pseudotuberculosis infection typically occurs sporadically, in the form of a self-limiting gastroenteritis. In Russia and Japan, outbreaks of Y pseudotuberculosis infection cause severe systemic inflammatory symptoms. This disease variant is called FESLF. Geographical heterogeneity exists between virulence factors produced by European and Far Eastern Y pseudotuberculosis strains, implicating superantigen Y pseudotuberculosis-derived mitogen A (YPMa) in the pathogenesis of FESLF. This article describes the epidemiology and clinical features of FESLF, and it presents the evidence for the role of YPMa in FESLF pathogenesis. PMID:26819960

Far East Scarlet-Like Fever: A Review of the Epidemiology, Symptomatology, and Role of Superantigenic Toxin: Yersinia pseudotuberculosis-Derived Mitogen A.

PubMed

Amphlett, A

2016-01-01

Far East scarlet-like fever (FESLF) is a severe inflammatory disease that occurs sporadically and in outbreaks in Russia and Japan. Far East scarlet-like fever is caused by Yersinia pseudotubuclosis infection, an organism that typically causes self-limiting gastroenteritis in Europe. Studies suggest the ability of Far Eastern strains to produce superantigen toxin Y pseudotuberculosis-derived mitogen A is integral to FESLF pathogenesis. In Europe, human Y pseudotuberculosis infection typically occurs sporadically, in the form of a self-limiting gastroenteritis. In Russia and Japan, outbreaks of Y pseudotuberculosis infection cause severe systemic inflammatory symptoms. This disease variant is called FESLF. Geographical heterogeneity exists between virulence factors produced by European and Far Eastern Y pseudotuberculosis strains, implicating superantigen Y pseudotuberculosis-derived mitogen A (YPMa) in the pathogenesis of FESLF. This article describes the epidemiology and clinical features of FESLF, and it presents the evidence for the role of YPMa in FESLF pathogenesis.

Transmission Characteristics of Variably Protease-Sensitive Prionopathy

PubMed Central

Notari, Silvio; Xiao, Xiangzhu; Espinosa, Juan Carlos; Cohen, Yvonne; Qing, Liuting; Aguilar-Calvo, Patricia; Kofskey, Diane; Cali, Ignazio; Cracco, Laura; Kong, Qingzhong; Torres, Juan Maria

2014-01-01

Variably protease-sensitive prionopathy (VPSPr), a recently identified and seemingly sporadic human prion disease, is distinct from Creutzfeldt-Jakob disease (CJD) but shares features of Gerstmann-Sträussler-Scheinker disease (GSS). However, contrary to exclusively inherited GSS, no prion protein (PrP) gene variations have been detected in VPSPr, suggesting that VPSPr might be the long-sought sporadic form of GSS. The VPSPr atypical features raised the issue of transmissibility, a prototypical property of prion diseases. We inoculated VPSPr brain homogenate into transgenic mice expressing various levels of human PrP (PrPC). On first passage, 54% of challenged mice showed histopathologic lesions, and 34% harbored abnormal PrP similar to that of VPSPr. Surprisingly, no prion disease was detected on second passage. We concluded that VPSPr is transmissible; thus, it is an authentic prion disease. However, we speculate that normal human PrPC is not an efficient conversion substrate (or mouse brain not a favorable environment) and therefore cannot sustain replication beyond the first passage. PMID:25418590

Clinical and Epidemiological Characteristics of Burkitt Lymphomas in Pediatric Patients from Two Defined Socioeconomic Regions in Mexico.

PubMed

Enrique Rendón-Macías, Mario; Alfonso Valencia-Ramón, Edwin; Fajardo-Gutiérrez, Arturo

2017-08-01

We analyzed clinical and epidemiological characteristics of Burkitt lymphoma (BL) in two defined socioeconomic regions in Mexico: high socioeconomic region (HSER; with two political jurisdictions) and low socioeconomic region (LSER; with three jurisdictions). Of the 63 cases registered in the Childhood Cancer Registry (1996-2013), 45 (71.4%) were from HSER and 18 (28.6%) from LSER. The incidence was higher in the LSER (3.1 vs. 1.4 cases per million children/year). The sporadic form and Stages III/IV predominated in both regions. Only one post-renal transplant (HSER) was found. The male/female ratio was higher in the LSER (5.0 vs. 1.4). The peak incidence was in the 1-4 age group for LSER, and in the 5-9 age group for HSER. This difference in the sporadic BL by socioeconomic regions may be related to different exposure factors. © The Author [2016]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Case-Control Studies of Sporadic Enteric Infections: A Review and Discussion of Studies Conducted Internationally from 1990 to 2009

PubMed Central

Fullerton, Kathleen E.; Scallan, Elaine; Kirk, Martyn D.; Mahon, Barbara E.; Angulo, Frederick J.; de Valk, Henriette; van Pelt, Wilfrid; Gauci, Charmaine; Hauri, Anja M.; Majowicz, Shannon; O’Brien, Sarah J.

2015-01-01

Epidemiologists have used case-control studies to investigate enteric disease outbreaks for many decades. Increasingly, case-control studies are also used to investigate risk factors for sporadic (not outbreak-associated) disease. While the same basic approach is used, there are important differences between outbreak and sporadic disease settings that need to be considered in the design and implementation of the case-control study for sporadic disease. Through the International Collaboration on Enteric Disease “Burden of Illness” Studies (the International Collaboration), we reviewed 79 case-control studies of sporadic enteric infections caused by nine pathogens that were conducted in 22 countries and published from 1990 through to 2009. We highlight important methodological and study design issues (including case definition, control selection, and exposure assessment) and discuss how approaches to the study of sporadic enteric disease have changed over the last 20 years (e.g., making use of more sensitive case definitions, databases of controls, and computer-assisted interviewing). As our understanding of sporadic enteric infections grows, methods and topics for case-control studies are expected to continue to evolve; for example, advances in understanding of the role of immunity can be used to improve control selection, the apparent protective effects of certain foods can be further explored, and case-control studies can be used to provide population-based measures of the burden of disease. PMID:22443481

Oestrogen receptor beta isoform expression in sporadic colorectal cancer, familial adenomatous polyposis and progressive stages of colorectal cancer.

PubMed

Stevanato Filho, Paulo Roberto; Aguiar Júnior, Samuel; Begnami, Maria Dirlei; Kuasne, Hellen; Spencer, Ranyell Matheus; Nakagawa, Wilson Toshihiko; Bezerra, Tiago Santoro; Kupper, Bruna Catin; Takahashi, Renata Maymi; Barros Filho, Mateus; Rogatto, Silvia Regina; Lopes, Ademar

2017-11-13

Among the sex hormones, oestrogen may play a role in colorectal cancer, particularly in conjunction with oestrogen receptor-β (ERβ). The expression of ERβ isoform variants and their correlations with familial adenomatous polyposis (FAP) syndrome and sporadic colorectal carcinomas are poorly described. This study aimed to investigate the expression levels of the ERβ1, ERβ2, ERβ4 and ERβ5 isoform variants using quantitative RT-PCR (921 analyses) in FAP, normal mucosa, adenomatous polyps and sporadic colorectal carcinomas. Decreased expression of ERβ isoforms was identified in sporadic polyps and in sporadic colorectal cancer as well as in polyps from FAP syndrome patients compared with normal tissues (p < 0.001). In FAP patients, ERβ1 and ERβ5 isoforms showed significant down-expression in polyps (p < 0.001) compared with matched normal tissues. However, no differences were observed when sporadic colorectal carcinomas were compared to normal mucosa tissues. These findings suggest an association of the ERβ isoform variants in individuals affected by germline mutations of the APC gene. Progressively decreased expression of ERβ was found in polyps at early stages of low-grade dysplasia, followed by T1-T2 and T3-T4 tumours (p < 0.05). In sporadic colorectal cancer, the loss of expression was an independent predictor of recurrence, and ERβ1 and ERβ5 expression levels were associated with better disease-free survival (p = 0.002). These findings may provide a better understanding of oestrogens and their potential preventive and therapeutic effects on sporadic colorectal cancer and cancers associated with FAP syndrome.

Unraveling ALS due to SOD1 mutation through the combination of brain and cervical cord MRI.

PubMed

Agosta, Federica; Spinelli, Edoardo Gioele; Marjanovic, Ivan V; Stevic, Zorica; Pagani, Elisabetta; Valsasina, Paola; Salak-Djokic, Biljana; Jankovic, Milena; Lavrnic, Dragana; Kostic, Vladimir S; Filippi, Massimo

2018-02-20

To explore structural and functional changes of the brain and cervical cord in patients with amyotrophic lateral sclerosis (ALS) due to mutation in the superoxide dismutase ( SOD1 ) gene compared with sporadic ALS. Twenty patients with SOD1 ALS, 11 with sporadic ALS, and 33 healthy controls underwent clinical evaluation and brain MRI. Cortical thickness analysis, diffusion tensor MRI of the corticospinal tracts (CST) and corpus callosum, and resting-state functional connectivity were performed. Patients with ALS also underwent cervical cord MRI to evaluate cord cross-sectional area and magnetization transfer ratio (MTR). Patients with SOD1 ALS showed longer disease duration and slower rate of functional decline relative to those with sporadic ALS. No cortical thickness abnormalities were found in patients with ALS compared with controls. Fractional anisotropy showed that sporadic ALS patients had significant CST damage relative to both healthy controls ( p = 0.001-0.02) and SOD1-related ALS ( p = 0.05), although the latter showed alterations that were intermediate between controls and sporadic ALS. Functional hyperconnectivity of the motor cortex in the sensorimotor network was observed in patients with sporadic ALS relative to controls. Conversely, patients with SOD1 ALS showed lower cord cross-sectional area along the whole cervical cord relative to those with sporadic ALS ( p < 0.001). No cord MTR differences were found between patient groups. Patients with SOD1 ALS showed cervical cord atrophy relative to those with sporadic ALS and a relative preservation of brain motor structural and functional networks. Neurodegeneration in SOD1 ALS is likely to occur primarily in the spinal cord. An objective and accurate estimate of spinal cord damage has potential in the future assessment of preventive SOD1 ALS therapies. © 2018 American Academy of Neurology.

SNCA polymorphisms, smoking, and sporadic Parkinson's disease in Japanese.

PubMed

Miyake, Yoshihiro; Tanaka, Keiko; Fukushima, Wakaba; Kiyohara, Chikako; Sasaki, Satoshi; Tsuboi, Yoshio; Yamada, Tatsuo; Oeda, Tomoko; Shimada, Hiroyuki; Kawamura, Nobutoshi; Sakae, Nobutaka; Fukuyama, Hidenao; Hirota, Yoshio; Nagai, Masaki

2012-06-01

Several case-control studies and genome-wide association studies have examined the relationships between single nucleotide polymorphisms (SNPs) in the SNCA gene and Parkinson's disease (PD), and have provided inconsistent results. We investigated the relationships between SNPs rs356229, rs356219, rs356220, rs7684318, and rs2736990 and the risk of sporadic PD in Japan using data from a multicenter hospital-based case-control study. Included were 229 cases within 6 years of onset of PD as defined according to the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 357 inpatients and outpatients without neurodegenerative disease. Adjustment was made for sex, age, region of residence, and smoking. Based on the recessive model, compared with subjects with the CC or CT genotype of SNP rs356220, those with the TT genotype had a significantly increased risk of sporadic PD: the adjusted OR was 1.42 (95% CI: 1.002-2.02). In the additive model, SNP rs2736990 was significantly related to the risk of sporadic PD: the adjusted OR was 1.30 (95% CI: 1.002-1.68). There were no significant relationships between SNP rs356229, rs356219, or rs7684318 and the risk of sporadic PD in any genetic model. The additive interactions between SNPs rs356219 and rs356220 and smoking with respect to sporadic PD were significant although the multiplicative interactions were not significant. This study suggests that SNCA SNPs rs356220 and rs2736990 are significantly associated with the risk of sporadic PD in Japanese. We also present new evidence for biological interactions between SNPs rs356219 and rs356220 and smoking that affect sporadic PD. Copyright © 2012 Elsevier Ltd. All rights reserved.

Family history is under-estimated in children with isolated hypospadias: a French multicenter report of 88 families.

PubMed

Ollivier, Margot; Paris, Francoise; Philibert, Pascal; Garnier, Sarah; Coffy, Amandine; Fauconnet-Servant, Nadège; Haddad, Mirna; Guys, Jean Michel; Reynaud, Rachel; Faure, Alice; Merrot, Thierry; Wagner, Kathy; Bréaud, Jean; Valla, Jean Stéphane; Dobremez, Eric; Gaspari, Laura; Daures, Jean-Pierre; Sultan, Charles; Kalfa, Nicolas

2018-04-30

Whereas familial forms of complex disorders/differences of sex development have been widely reported, data regarding isolated hypospadias are sparse and a family history is thought to be less frequent. We aimed 1-to determine the frequency of hypospadias in families of hypospadiac boys 2-to determine if theses familial forms exhibit a particular phenotype 3-to evaluate the prevalence of genetic defects of the main candidate genes. A prospective inclusion of 395 hypospadiac boys screened for family history with a standardized questionnaire, extensive clinical description, family tree and sequencing of AR, SF1, SRD5A2 and MAMLD1 was performed. Family history of hypospadias was more frequent than expected (22.3%, n=88). In 19.3% of cases, the familial cases were multiple (n=17). Familial hypospadias were related to the paternal side in 59.1% of cases including the father himself (30.7%), paternal uncles and cousins. Prematurity, assisted-reproductive techniques, other congenital abnormalities and growth retardation were not more frequent in familial hypospadias than in sporadic cases. The severity of phenotype was similar in both groups. The results of the genetic analysis combined to previous data on AR sequencing showed that familial cases tend to reveal more frequently genetic defects than sporadic cases (5.68% vs 1,63%, p=0,048). Familial forms of hypospadias are far more frequent than previously reported. Even minor and isolated hypospadias justify a full clinical investigation of the family history. Detecting these hereditary forms may help to find out the underlying genetic defects and may improve the follow-up and counseling of these patients. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Prion Diseases: Update on Mad Cow Disease, Variant Creutzfeldt-Jakob Disease, and the Transmissible Spongiform Encephalopathies.

PubMed

Janka, Jacqueline; Maldarelli, Frank

2004-08-01

Transmissible spongiform encephalopathies (TSEs) are a group of progressive, fatal neurodegenerative disorders that share a common spongiform histopathology. TSEs may be transmitted in a sporadic, familial, iatrogenic, or zoonotic fashion. The putative infectious agent of TSE, the prion, represents a novel paradigm of infectious disease with disease transmission in the absence of nucleic acid. Several small but spectacular epidemics of TSEs in man have prompted widespread public health and food safety concerns. Although TSEs affect a comparatively small number of individuals, prion research has revealed fascinating insights of direct relevance to common illnesses. This paper reviews recent advances that have shed new light on the nature of prions and TSEs.

Legionnaire's Disease Since Philadelphia: Lessons Learned and Continued Progress.

PubMed

Cunha, Cheston B; Cunha, Burke A

2017-03-01

Legionnaire's disease has been recognized as a cause of severe community-acquired pneumonia (CAP). Legionnaire's disease has characteristic extrapulmonary findings that are the basis for a presumptive clinical diagnosis. The widespread use of Legionella culture, sputum DFA, serology, urinary antigen testing, and polymerase chain reaction have allowed earlier diagnosis of Legionnaire's disease. Excluding common source outbreaks, CAP caused by Legionnaire's disease is manifested as sporadic cases. In contrast, nosocomial Legionnaire's disease occurs in clusters or outbreaks from common Legionella species-contaminated water sources. Improved diagnostic tests have permitted accurate diagnosis. Bacterial coinfections with Legionnaire's disease are uncommon, but when present, are most often associated with bacteremia pneumococcal pneumonia. Copyright © 2016 Elsevier Inc. All rights reserved.

Mosaicism for dominant collagen 6 mutations as a cause for intrafamilial phenotypic variability.

PubMed

Donkervoort, Sandra; Hu, Ying; Stojkovic, Tanya; Voermans, Nicol C; Foley, A Reghan; Leach, Meganne E; Dastgir, Jahannaz; Bolduc, Véronique; Cullup, Thomas; de Becdelièvre, Alix; Yang, Lin; Su, Hai; Meilleur, Katherine; Schindler, Alice B; Kamsteeg, Erik-Jan; Richard, Pascale; Butterfield, Russell J; Winder, Thomas L; Crawford, Thomas O; Weiss, Robert B; Muntoni, Francesco; Allamand, Valérie; Bönnemann, Carsten G

2015-01-01

Collagen 6-related dystrophies and myopathies (COL6-RD) are a group of disorders that form a wide phenotypic spectrum, ranging from severe Ullrich congenital muscular dystrophy, intermediate phenotypes, to the milder Bethlem myopathy. Both inter- and intrafamilial variable expressivity are commonly observed. We present clinical, immunohistochemical, and genetic data on four COL6-RD families with marked intergenerational phenotypic heterogeneity. This variable expression seemingly masquerades as anticipation is due to parental mosaicism for a dominant mutation, with subsequent full inheritance and penetrance of the mutation in the heterozygous offspring. We also present an additional fifth simplex patient identified as a mosaic carrier. Parental mosaicism was confirmed in the four families through quantitative analysis of the ratio of mutant versus wild-type allele (COL6A1, COL6A2, and COL6A3) in genomic DNA from various tissues, including blood, dermal fibroblasts, and saliva. Consistent with somatic mosaicism, parental samples had lower ratios of mutant versus wild-type allele compared with the fully heterozygote offspring. However, there was notable variability of the mutant allele levels between tissues tested, ranging from 16% (saliva) to 43% (fibroblasts) in one mosaic father. This is the first report demonstrating mosaicism as a cause of intrafamilial/intergenerational variability of COL6-RD, and suggests that sporadic and parental mosaicism may be more common than previously suspected. © 2014 WILEY PERIODICALS, INC.

Heterozygous deletion of FOXA2 segregates with disease in a family with heterotaxy, panhypopituitarism, and biliary atresia.

PubMed

Tsai, Ellen A; Grochowski, Christopher M; Falsey, Alexandra M; Rajagopalan, Ramakrishnan; Wendel, Danielle; Devoto, Marcella; Krantz, Ian D; Loomes, Kathleen M; Spinner, Nancy B

2015-06-01

Biliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. Most cases are sporadic, although reports of familial cases have led to the hypothesis of genetic susceptibility in some patients. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal microarray analysis demonstrated a 277 kb heterozygous deletion on chromosome 20, which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. The proband and her father share a common diagnosis of heterotaxy, but they also each presented with a variety of other issues. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism (rs1904589; p.His165Arg) in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband. © 2015 WILEY PERIODICALS, INC.

Molecular factors in migraine

PubMed Central

Kowalska, Marta; Prendecki, Michał; Kozubski, Wojciech; Lianeri, Margarita; Dorszewska, Jolanta

2016-01-01

Migraine is a common neurological disorder that affects 11% of adults worldwide. This disease most likely has a neurovascular origin. Migraine with aura (MA) and more common form - migraine without aura (MO) – are the two main clinical subtypes of disease. The exact pathomechanism of migraine is still unknown, but it is thought that both genetic and environmental factors are involved in this pathological process. The first genetic studies of migraine were focused on the rare subtype of MA: familial hemiplegic migraine (FHM). The genes analysed in familial and sporadic migraine are: MTHFR, KCNK18, HCRTR1, SLC6A4, STX1A, GRIA1 and GRIA3. It is possible that migraine is a multifactorial disease with polygenic influence. Recent studies have shown that the pathomechanisms of migraine involves both factors responsible for immune response and oxidative stress such as: cytokines, tyrosine metabolism, homocysteine; and factors associated with pain transmission and emotions e.g.: serotonin, hypocretin-1, calcitonin gene-related peptide, glutamate. The correlations between genetic variants of the HCRTR1 gene, the polymorphism 5-HTTLPR and hypocretin-1, and serotonin were observed. It is known that serotonin inhibits the activity of hypocretin neurons and may affect the appearance of the aura during migraine attack. The understanding of the molecular mechanisms of migraine, including genotype-phenotype correlations, may contribute to finding markers important for the diagnosis and treatment of this disease. PMID:27191890

UBE2QL1 is Disrupted by a Constitutional Translocation Associated with Renal Tumor Predisposition and is a Novel Candidate Renal Tumor Suppressor Gene

PubMed Central

Wake, Naomi C; Ricketts, Christopher J; Morris, Mark R; Prigmore, Elena; Gribble, Susan M; Skytte, Anne-Bine; Brown, Michael; Clarke, Noel; Banks, Rosamonde E; Hodgson, Shirley; Turnell, Andrew S; Maher, Eamonn R; Woodward, Emma R

2013-01-01

Investigation of rare familial forms of renal cell carcinoma (RCC) has led to the identification of genes such as VHL and MET that are also implicated in the pathogenesis of sporadic RCC. In order to identify a novel candidate renal tumor suppressor gene, we characterized the breakpoints of a constitutional balanced translocation, t(5;19)(p15.3;q12), associated with familial RCC and found that a previously uncharacterized gene UBE2QL1 was disrupted by the chromosome 5 breakpoint. UBE2QL1 mRNA expression was downregulated in 78.6% of sporadic RCC and, although no intragenic mutations were detected, gene deletions and promoter region hypermethylation were detected in 17.3% and 20.3%, respectively, of sporadic RCC. Reexpression of UBE2QL1 in a deficient RCC cell line suppressed anchorage-independent growth. UBE2QL1 shows homology to the E2 class of ubiquitin conjugating enzymes and we found that (1) UBE2QL1 possesses an active-site cysteine (C88) that is monoubiquitinated in vivo, and (2) UBE2QL1 interacts with FBXW7 (an F box protein providing substrate recognition to the SCF E3 ubiquitin ligase) and facilitates the degradation of the known FBXW7 targets, CCNE1 and mTOR. These findings suggest UBE2QL1 as a novel candidate renal tumor suppressor gene. PMID:24000165

A Novel Tau Mutation in Exon 12, p.Q336H, Causes Hereditary Pick Disease

PubMed Central

Tacik, Pawel; DeTure, Michael; Hinkle, Kelly M.; Lin, Wen-Lang; Sanchez-Contreras, Monica; Carlomagno, Yari; Pedraza, Otto; Rademakers, Rosa; Ross, Owen A.; Wszolek, Zbigniew K.; Dickson, Dennis W.

2015-01-01

Pick disease (PiD) is a frontotemporal lobar degeneration with distinctive neuronal inclusions (Pick bodies) that are enriched in 3-repeat (3R) tau. Although mostly sporadic, mutations in the tau gene (MAPT) have been reported. We screened 24 cases of neuropathologically confirmed PiD for MAPT mutations and found a novel mutation (c.1008G>C, p.Q336H) in one patient. Pathogenicity was confirmed on microtubule assembly and tau filament formation assays. The patient was compared to sporadic PiD and PiD associated with MAPT mutations from a review of the literature. The patient had behavioral changes at 55 years of age, followed by reduced verbal fluency, parkinsonism and death at 63 years of age. His mother and maternal uncle had similar symptoms. Recombinant tau with p.Q336H mutation formed filaments faster than wild type tau, especially with 3R tau. It also promoted more microtubule assembly than wild type tau. We conclude that mutations in MAPT, including p.Q336H, can be associated with clinical, pathologic, and biochemical features that are similar to those in sporadic PiD. The pathomechanism of p.Q336H, and another previously reported variant at the same codon (p.Q336R), appears to be unique to MAPT mutations in that they not only predispose to abnormal tau filament formation but also facilitate microtubule assembly in a 3R tau-dependent manner. PMID:26426266

Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms.

PubMed

Cruchaga, Carlos; Del-Aguila, Jorge L; Saef, Benjamin; Black, Kathleen; Fernandez, Maria Victoria; Budde, John; Ibanez, Laura; Deming, Yuetiva; Kapoor, Manav; Tosto, Giuseppe; Mayeux, Richard P; Holtzman, David M; Fagan, Anne M; Morris, John C; Bateman, Randall J; Goate, Alison M; Harari, Oscar

2018-02-01

To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer's Disease (sLOAD), familial late-onset AD (fLOAD), sporadic early-onset AD (sEOAD), and autosomal dominant early-onset AD (eADAD). Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk. We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10 -7 ) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10 -7 ) and sLOAD (OR = 1.40; P = 1.21 × 10 -3 ). The PRS was associated with cerebrospinal fluid ptau 181 -Aβ 42 on eADAD (P = 4.36 × 10 -2 ). Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Outbreak of tularaemia in brown hares (Lepus europaeus) in France, January to March 2011.

PubMed

Decors, A; Lesage, C; Jourdain, E; Giraud, P; Houbron, P; Vanhem, P; Madani, N; Madani, M

2011-07-14

We report an outbreak of tularaemia in brown hares (Lepus europaeus) in France, which occurred from January to March 2011 and was characterised by a high mortality rate in the local hare population. In France, hare tularaemia is usually sporadic and does not significantly affect hare populations. The epizootic form of the outbreak reported here led us to reconsider the potential associated risks for hare populations and public health.

Peritoneal dialysis glossary 2009.

PubMed

Liakopoulos, Vassilios; Stefanidis, Ioannis; Dombros, Nicholas V

2010-06-01

A number of attempts to create a commonly accepted terminology regarding definitions and terms used for clinical entities, methods, problems, and materials encountered by health professionals involved in peritoneal dialysis (PD) were undertaken in the past, the last one in 1990. Later on, some relevant sporadic attempts in a number of textbooks have been made, but they did not include the whole spectrum of PD. This glossary is an attempt to address the need for a universally accepted PD terminology including the latest advances in PD connection systems and fluids.

Diagnosis and Management of Hereditary Meningioma and Vestibular Schwannoma.

PubMed

Shaw, Adam

2016-01-01

Bilateral vestibular schwannomata and meningiomata are the tumours most commonly associated with neurofibromatosis type II (NF2). These tumours may also be seen in patients with schwannomatosis and familial meningioma, but these phenotypes are usually easy to distinguish. The main diagnostic challenge when managing these tumours is distinguishing between sporadic disease which carries low risk of subsequent tumours or NF2 with its associated morbidities and reduced life expectancy. This chapter outlines some of the diagnostic and management considerations along with associated evidence.

Constitutional aneuploidy and cancer predisposition†

PubMed Central

Ganmore, Ithamar; Smooha, Gil; Izraeli, Shai

2009-01-01

Constitutional aneuploidies are rare syndromes associated with multiple developmental abnormalities and the alterations in the risk for specific cancers. Acquired somatic chromosomal aneuploidies are the most common genetic aberrations in sporadic cancers. Thus studies of these rare constitutional aneuploidy syndromes are important not only for patient counseling and clinical management, but also for deciphering the mechanisms by which chromosomal aneuploidy affect cancer initiation and progression. Here we review the major constitutional aneuploidy syndromes and suggest some general mechanisms for the associated cancer predisposition. PMID:19297405

Constitutional aneuploidy and cancer predisposition.

PubMed

Ganmore, Ithamar; Smooha, Gil; Izraeli, Shai

2009-04-15

Constitutional aneuploidies are rare syndromes associated with multiple developmental abnormalities and the alterations in the risk for specific cancers. Acquired somatic chromosomal aneuploidies are the most common genetic aberrations in sporadic cancers. Thus studies of these rare constitutional aneuploidy syndromes are important not only for patient counseling and clinical management, but also for deciphering the mechanisms by which chromosomal aneuploidy affect cancer initiation and progression. Here we review the major constitutional aneuploidy syndromes and suggest some general mechanisms for the associated cancer predisposition.

Mitochondrial Debris as a Discriminator Between Inflammatory and Infectious Complications of Blast Injuries: The Enemy Within

DTIC Science & Technology

2012-01-01

adult respiratory distress syndrome (ALI/ARDS) occur after fractures in a sporadic entity often termed ‘‘ fat embolism syndrome.’’ Fat embolism ...We then went on to evaluate the role of fracture injuries in mobilizing mtDNA from human tissue trauma. As proposed, we used discarded human samples...to show that long bone fractures (very common in combatants) and their repair by clinical reamed nailing operations mobilized huge amounts of mtDNA

Comparison of Observations of Sporadic-E Layers in the Nighttime and Daytime Mid-Latitude Ionosphere

NASA Technical Reports Server (NTRS)

Pfaff, R.; Freudenreich, H.; Rowland, D.; Klenzing, J.; Clemmons, J.; Larsen, M.; Kudeki, E.; Franke, S.; Urbina, J.; Bullett, T.

2012-01-01

A comparison of numerous rocket experiments to investigate mid-latitude sporadic-E layers is presented. Electric field and plasma density data gathered on sounding rockets launched in the presence of sporadic-E layers and QP radar echoes reveal a complex electrodynamics including both DC parameters and plasma waves detected over a large range of scales. We show both DC and wave electric fields and discuss their relationship to intense sporadic-E layers in both nighttime and daytime conditions. Where available, neutral wind observations provide the complete electrodynamic picture revealing an essential source of free energy that both sets up the layers and drives them unstable. Electric field data from the nighttime experiments reveal the presence of km-scale waves as well as well-defined packets of broadband (10's of meters to meters) irregularities. What is surprising is that in both the nighttime and daytime experiments, neither the large scale nor short scale waves appear to be distinctly organized by the sporadic-E density layer itself. The observations are discussed in the context of current theories regarding sporadic-E layer generation and quasi-periodic echoes.

Candidate SNP Markers of Familial and Sporadic Alzheimer's Diseases Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters

PubMed Central

Ponomarenko, Petr; Chadaeva, Irina; Rasskazov, Dmitry A.; Sharypova, Ekaterina; Kashina, Elena V.; Drachkova, Irina; Zhechev, Dmitry; Ponomarenko, Mikhail P.; Savinkova, Ludmila K.; Kolchanov, Nikolay

2017-01-01

While year after year, conditions, quality, and duration of human lives have been improving due to the progress in science, technology, education, and medicine, only eight diseases have been increasing in prevalence and shortening human lives because of premature deaths according to the retrospective official review on the state of US health, 1990-2010. These diseases are kidney cancer, chronic kidney diseases, liver cancer, diabetes, drug addiction, poisoning cases, consequences of falls, and Alzheimer's disease (AD) as one of the leading pathologies. There are familial AD of hereditary nature (~4% of cases) and sporadic AD of unclear etiology (remaining ~96% of cases; i.e., non-familial AD). Therefore, sporadic AD is no longer a purely medical problem, but rather a social challenge when someone asks oneself: “What can I do in my own adulthood to reduce the risk of sporadic AD at my old age to save the years of my lifespan from the destruction caused by it?” Here, we combine two computational approaches for regulatory SNPs: Web service SNP_TATA_Comparator for sequence analysis and a PubMed-based keyword search for articles on the biochemical markers of diseases. Our purpose was to try to find answers to the question: “What can be done in adulthood to reduce the risk of sporadic AD in old age to prevent the lifespan reduction caused by it?” As a result, we found 89 candidate SNP markers of familial and sporadic AD (e.g., rs562962093 is associated with sporadic AD in the elderly as a complication of stroke in adulthood, where natural marine diets can reduce risks of both diseases in case of the minor allele of this SNP). In addition, rs768454929, and rs761695685 correlate with sporadic AD as a comorbidity of short stature, where maximizing stature in childhood and adolescence as an integral indicator of health can minimize (or even eliminate) the risk of sporadic AD in the elderly. After validation by clinical protocols, these candidate SNP markers may become interesting to the general population [may help to choose a lifestyle (in childhood, adolescence, and adulthood) that can reduce the risks of sporadic AD, its comorbidities, and complications in the elderly]. PMID:28775688

Characterization of Patients with Amyotrophic Lateral Sclerosis attending the Muscular Dystrophy Association-Supported Clinics in Puerto Rico.

PubMed

Deliz, Brenda; Ramos, Kathya; Pérez, Cynthia M

2018-03-01

To evaluate the sociodemographic characteristics and clinical and functional profile of amyotrophic lateral sclerosis (ALS) patients evaluated at Puerto Rico's Muscular Dystrophy Association-supported (MDA) clinics. A retrospective review of 76 medical records of ALS patients evaluated at any of four MDA-sponsored clinics in Puerto Rico. The mean age of diagnosis was 57.4 ± 11.1 yrs. Most of the patients (52.3%) were women. The majority of the cases were sporadic (48.7%). Over 40% of the patients were diagnosed at one year or earlier. Patients with initial upper extremity involvement (63.2%) were diagnosed earlier (≤ 6 months) than any of the others. The most common presentation of the disease overall was lower extremity weakness (34.2%), which was followed by a bulbar presentation (31.6%). There was a marked difference between men and women in disease presentation, with bulbar involvement in 75% of the women. This study characterized a sample of ALS patients in Puerto Rico who are receiving services at the MDA-sponsored clinics. Puerto Rican patients have similarities with published data from the United States and other countries, including: sporadic pattern, initial symptoms in extremities, and time to diagnosis. Major differences are that the disease was more common in women than in men and that a higher than expected percentage of patients presented with bulbar onset. This may partly account for the overall predominance of the disease in women over men as found in our study, since the bulbar presentation has been reported to be more common in women. Studies with a greater number of patients are needed to determine whether our findings are reproducible. This study will serve as a basis for designing future analytic studies regarding etiology or the factors that might modulate disease progression.

Ciguatera poisoning: a global issue with common management problems.

PubMed

Ting, J Y; Brown, A F

2001-12-01

Ciguatera poisoning, a toxinological syndrome comprising an enigmatic mixture of gastrointestinal, neurocutaneous and constitutional symptoms, is a common food-borne illness related to contaminated fish consumption. As many as 50000 cases worldwide are reported annually, and the condition is endemic in tropical and subtropical regions of the Pacific Basin, Indian Ocean and Caribbean. Isolated outbreaks occur sporadically but with increasing frequency in temperate areas such as Europe and North America. Increase in travel between temperate countries and endemic areas and importation of susceptible fish has led to its encroachment into regions of the world where ciguatera has previously been rarely encountered. In the developed world, ciguatera poses a public health threat due to delayed or missed diagnosis. Ciguatera is frequently encountered in Australia. Sporadic cases are often misdiagnosed or not medically attended to, leading to persistent or recurrent debilitating symptoms lasting months to years. Without treatment, distinctive neurologic symptoms persist, occasionally being mistaken for multiple sclerosis. Constitutional symptoms may be misdiagnosed as chronic fatigue syndrome. A common source outbreak is easier to recognize and therefore notify to public health organizations. We present a case series of four adult tourists who developed ciguatera poisoning after consuming contaminated fish in Vanuatu. All responded well to intravenous mannitol. This is in contrast to a fifth patient who developed symptoms suggestive of ciguatoxicity in the same week as the index cases but actually had staphylococcal endocarditis with bacteraemia. In addition to a lack of response to mannitol, clinical and laboratory indices of sepsis were present in this patient. Apart from ciguatera, acute gastroenteritis followed by neurological symptoms may be due to paralytic or neurotoxic shellfish poisoning, scombroid and pufferfish toxicity, botulism, enterovirus 71, toxidromes and bacteraemia. Clinical aspects of ciguatera toxicity, its pathophysiology, diagnostic difficulties and epidemiology are discussed.

TBX6 Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis

PubMed Central

Wu, N.; Ming, X.; Xiao, J.; Wu, Z.; Chen, X.; Shinawi, M.; Shen, Y.; Yu, G.; Liu, J.; Xie, H.; Gucev, Z.S.; Liu, S.; Yang, N.; Al-Kateb, H.; Chen, J.; Zhang, Jian; Hauser, N.; Zhang, T.; Tasic, V.; Liu, P.; Su, X.; Pan, X.; Liu, C.; Wang, L.; Shen, Joseph; Shen, Jianxiong; Chen, Y.; Zhang, T.; Zhang, Jianguo; Choy, K.W.; Wang, Jun; Wang, Q.; Li, S.; Zhou, W.; Guo, J.; Wang, Y.; Zhang, C.; Zhao, H.; An, Y.; Zhao, Y.; Wang, Jiucun; Liu, Z.; Zuo, Y.; Tian, Y.; Weng, X.; Sutton, V.R.; Wang, H.; Ming, Y.; Kulkarni, S.; Zhong, T.P.; Giampietro, P.F.; Dunwoodie, S.L.; Cheung, S.W.; Zhang, X.; Jin, L.; Lupski, J.R.; Qiu, G.; Zhang, F.

2015-01-01

BACKGROUND Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis. METHODS We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multi-center series of 42 persons with 16p11.2 deletions. RESULTS We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10−6). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10−6). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis. CONCLUSIONS Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed. PMID:25564734

Population Structure of Listeria monocytogenes Serotype 4b Isolates from Sporadic Human Listeriosis Cases in the United States from 2003 to 2008

PubMed Central

Ward, Todd J.; Graves, Lewis M.; Tarr, Cheryl L.; Siletzky, Robin M.; Kathariou, Sophia

2014-01-01

Listeria monocytogenes can cause severe food-borne disease (listeriosis). Numerous outbreaks have involved three serotype 4b epidemic clones (ECs): ECI, ECII, and ECIa. However, little is known about the population structure of L. monocytogenes serotype 4b from sporadic listeriosis in the United States, even though most cases of human listeriosis are in fact sporadic. Here we analyzed 136 serotype 4b isolates from sporadic cases in the United States, 2003 to 2008, utilizing multiple tools including multilocus genotyping, pulsed-field gel electrophoresis, and sequence analysis of the inlAB locus. ECI, ECII, and ECIa were frequently encountered (32, 17, and 7%, respectively). However, annually 30 to 68% of isolates were outside these ECs, and several novel clonal groups were identified. An estimated 33 and 17% of the isolates, mostly among the ECs, were resistant to cadmium and arsenic, respectively, but resistance to benzalkonium chloride was uncommon (3%) among the sporadic isolates. The frequency of clonal groups fluctuated within the 6-year study period, without consistent trends. However, on several occasions, temporal clusters of isolates with indistinguishable genotypes were detected, suggesting the possibility of hidden multistate outbreaks. Our analysis suggests a complex population structure of serotype 4b L. monocytogenes from sporadic disease, with important contributions by ECs and several novel clonal groups. Continuous monitoring will be needed to assess long-term trends in clonality patterns and population structure of L. monocytogenes from sporadic listeriosis. PMID:24705322

Population structure of Listeria monocytogenes serotype 4b isolates from sporadic human listeriosis cases in the United States from 2003 to 2008.

PubMed

Lee, Sangmi; Ward, Todd J; Graves, Lewis M; Tarr, Cheryl L; Siletzky, Robin M; Kathariou, Sophia

2014-06-01

Listeria monocytogenes can cause severe food-borne disease (listeriosis). Numerous outbreaks have involved three serotype 4b epidemic clones (ECs): ECI, ECII, and ECIa. However, little is known about the population structure of L. monocytogenes serotype 4b from sporadic listeriosis in the United States, even though most cases of human listeriosis are in fact sporadic. Here we analyzed 136 serotype 4b isolates from sporadic cases in the United States, 2003 to 2008, utilizing multiple tools including multilocus genotyping, pulsed-field gel electrophoresis, and sequence analysis of the inlAB locus. ECI, ECII, and ECIa were frequently encountered (32, 17, and 7%, respectively). However, annually 30 to 68% of isolates were outside these ECs, and several novel clonal groups were identified. An estimated 33 and 17% of the isolates, mostly among the ECs, were resistant to cadmium and arsenic, respectively, but resistance to benzalkonium chloride was uncommon (3%) among the sporadic isolates. The frequency of clonal groups fluctuated within the 6-year study period, without consistent trends. However, on several occasions, temporal clusters of isolates with indistinguishable genotypes were detected, suggesting the possibility of hidden multistate outbreaks. Our analysis suggests a complex population structure of serotype 4b L. monocytogenes from sporadic disease, with important contributions by ECs and several novel clonal groups. Continuous monitoring will be needed to assess long-term trends in clonality patterns and population structure of L. monocytogenes from sporadic listeriosis.

Genetic screening in adolescents with steroid-resistant nephrotic syndrome.

PubMed

Lipska, Beata S; Iatropoulos, Paraskevas; Maranta, Ramona; Caridi, Gianluca; Ozaltin, Fatih; Anarat, Ali; Balat, Ayse; Gellermann, Jutta; Trautmann, Agnes; Erdogan, Ozlem; Saeed, Bassam; Emre, Sevinc; Bogdanovic, Radovan; Azocar, Marta; Balasz-Chmielewska, Irena; Benetti, Elisa; Caliskan, Salim; Mir, Sevgi; Melk, Anette; Ertan, Pelin; Baskin, Esra; Jardim, Helena; Davitaia, Tinatin; Wasilewska, Anna; Drozdz, Dorota; Szczepanska, Maria; Jankauskiene, Augustina; Higuita, Lina Maria Serna; Ardissino, Gianluigi; Ozkaya, Ozan; Kuzma-Mroczkowska, Elzbieta; Soylemezoglu, Oguz; Ranchin, Bruno; Medynska, Anna; Tkaczyk, Marcin; Peco-Antic, Amira; Akil, Ipek; Jarmolinski, Tomasz; Firszt-Adamczyk, Agnieszka; Dusek, Jiri; Simonetti, Giacomo D; Gok, Faysal; Gheissari, Alaleh; Emma, Francesco; Krmar, Rafael T; Fischbach, Michel; Printza, Nikoleta; Simkova, Eva; Mele, Caterina; Ghiggeri, Gian Marco; Schaefer, Franz

2013-07-01

Genetic screening paradigms for congenital and infantile nephrotic syndrome are well established; however, screening in adolescents has received only minor attention. To help rectify this, we analyzed an unselected adolescent cohort of the international PodoNet registry to develop a rational screening approach based on 227 patients with nonsyndromic steroid-resistant nephrotic syndrome aged 10-20 years. Of these, 21% had a positive family history. Autosomal dominant cases were screened for WT1, TRPC6, ACTN4, and INF2 mutations. All other patients had the NPHS2 gene screened, and WT1 was tested in sporadic cases. In addition, 40 sporadic cases had the entire coding region of INF2 tested. Of the autosomal recessive and the sporadic cases, 13 and 6%, respectively, were found to have podocin-associated nephrotic syndrome, and 56% of them were compound heterozygous for the nonneutral p.R229Q polymorphism. Four percent of the sporadic and 10% of the autosomal dominant cases had a mutation in WT1. Pathogenic INF2 mutations were found in 20% of the dominant but none of the sporadic cases. In a large cohort of adolescents including both familial and sporadic disease, NPHS2 mutations explained about 7% and WT1 4% of cases, whereas INF2 proved relevant only in autosomal dominant familial disease. Thus, screening of the entire coding sequence of NPHS2 and exons 8-9 of WT1 appears to be the most rational and cost-effective screening approach in sporadic juvenile steroid-resistant nephrotic syndrome.

[Gluten Ataxia: Anti-Transglutaminase-6 Antibody as a New Biomarker].

PubMed

Sato, Kenji; Nanri, Kazunori

2017-08-01

Gluten-related disorders (GRDs) are conditions that develop in response to the common trigger of gluten ingestion and manifest as a variety of clinical symptoms. GRDs have been considered rare in Asian countries, including Japan, because of lower consumption of wheat products than in Europe and the U.S.A. and differences in genetic background. Recently, however, GRDs, such as celiac disease and gluten ataxia, have been reported in Japan, albeit sporadically and their presence is now recognized in this country. Gluten ataxia is defined as an anti-gliadin antibody positive sporadic ataxia. Recently, it was reported that the presence of anti-transglutaminase-6 (TG6) antibody can be used to diagnose gluten ataxia. Herein, we will review evidence relating to gluten ataxia and report two cases of anti-TG6 antibody positive gluten ataxia. In patients with gluten ataxia, sensory disturbance is generally considered to be so mild that it contributes minimally to ataxia. However, our patients showed a positive Romberg sign. Deep sensory disturbance, in addition to cerebellar disturbance, may have been involved in the clinical symptoms of our cases.

[Botulism. Summary based on six cases].

PubMed

Adorján, T; Farkas, M; Boros, L; Czeglédi, Z

1998-10-18

Botulism is a rare neuroparalytic disease caused by neurotoxins of Clostridium species. In Hungary it most commonly occurs as a foodborne illness with ocular and bulbar paralysis, muscle weakness and gastrointestinal symptoms. Six cases of botulism were observed by the authors, first in 1993 five members of a family, then in 1997 a patient with sporadic illness. The diagnosis was confirmed by toxin tests in addition to the symptoms and food history. Recognition of the epidemiologic associations proved very useful in the confirmation of outbreak-related cases. The illness was moderately serious at three patients and mild at two patients. One of the patients had a cirrhosis of the liver, and her status became critical because of the repeated bleeding from oesophagus varicose vein. The patient with sporadic illness had a serious gastric dilatation and palsy of bowels causing paralytic ileus at the start of the illness. The symptoms regressed slowly, roughly in three weeks, at all patients. Death did not happened. After the case reports the authors review the disease-microorganism, toxin, clinical entities, incidence, symptoms, diagnosis, differential-diagnosis, and finally the treatment.

Taeniases and cysticercosis in Indonesia: past and present situations.

PubMed

Wandra, Toni; Ito, Akira; Swastika, Kadek; Dharmawan, Nyoman S; Sako, Yasuhito; Okamoto, Munehiro

2013-11-01

The main aim of this study is to overview the past and present situations of human taeniases and cysticercosis in Indonesia and including future perspectives. Through joint projects from 1996, we have confirmed the occurrence of Taenia saginata (beef tapeworm) in Bali, of Taenia solium (pork tapeworm) mainly in Papua and sporadically in Bali, and of Taenia asiatica in North Sumatra. These taeniases were caused through eating uncooked pork and pig viscera for T. solium and T. asiatica, respectively, and beef for T. saginata. The distribution of these tapeworms in Indonesia is basically highly restricted by the traditional cultural and religious backgrounds in each island. T. saginata is relatively common in Bali although people consume pork 'lawar' more than beef 'lawar'. Taeniases due to T. saginata or T. asiatica and T. solium and cysticercosis due to T. solium have also been sporadically reported in some other islands. Among these species, T. solium is exceptional since humans can be infected not only by larval stages (cysticerci) in pork but also by eggs released from human tapeworm carriers. Cysticercosis has been confirmed in Indonesia in humans, pigs and even dogs.

Continuing challenges in influenza

PubMed Central

Webster, Robert G.; Govorkova, Elena A.

2014-01-01

Influenza is an acute respiratory disease in mammals and domestic poultry that emerges from zoonotic reservoirs in aquatic birds and bats. Although influenza viruses are among the most intensively studied pathogens, existing control options require further improvement. Influenza vaccines must be regularly updated because of continuous antigenic drift and sporadic antigenic shifts in the viral surface glycoproteins. Currently, influenza therapeutics are limited to neuraminidase inhibitors; novel drugs and vaccine approaches are therefore urgently needed. Advances in vaccinology and structural analysis have revealed common antigenic epitopes on hemagglutinins across all influenza viruses and suggest that a universal influenza vaccine is possible. In addition, various immunomodulatory agents and signaling pathway inhibitors are undergoing preclinical development. Continuing challenges in influenza include the emergence of pandemic H1N1 influenza in 2009, human infections with avian H7N9 influenza in 2013, and sporadic human cases of highly pathogenic avian H5N1 influenza. Here, we review the challenges facing influenza scientists and veterinary and human public health officials; we also discuss the exciting possibility of achieving the ultimate goal of controlling influenza’s ability to change its antigenicity. PMID:24891213

Analysis of wave-like oscillations in parameters of sporadic E layer and neutral atmosphere

NASA Astrophysics Data System (ADS)

Mošna, Z.; Koucká Knížová, P.

2012-12-01

The present study mainly concerns the wave-like activity in the ionospheric sporadic E layer (Es) and in the lower lying stratosphere. The proposed analysis involves parameters describing the state of plasma in the sporadic E layer. Critical frequencies foEs and layer heights hEs were measured at the Pruhonice station (50°N, 14.5°E) during summer campaigns 2004, 2006 and 2008. Further, we use neutral atmosphere (temperature data at 10 hPa) data from the same time interval. The analysis concentrates on vertically propagating wave-like structures within distant atmospheric regions. By means of continuous wavelet transform (CWT) we have detected significant wave-like oscillation at periods covering tidal and planetary oscillation domains both in the Es layer parameters (some of them were reported earlier, for instance in works of Abdu et al., 2003; Pancheva and Mitchel, 2004; Pancheva et al., 2003; Šauli and Bourdillon, 2008) and in stratospheric temperature variations. Further analyses using cross wavelet transform (XWT) and wavelet coherence analysis (WTC) show that despite high wave-like activity in a wide period range, there are only limited coherent wave-like bursts present in both spectra. Such common coherent wave bursts occur on periods close to eigen-periods of the terrestrial atmosphere. We suppose that vertical coupling between atmospheric regions realized by vertically propagating planetary waves occurs predominantly on periods close to those of Rossby modes. Analysis of the phase shift between data from distant atmospheric regions reveals high variability and very likely supports the non-linear scenario of the vertical coupling provided by planetary waves.

Array CGH Analysis of Paired Blood and Tumor Samples from Patients with Sporadic Wilms Tumor

PubMed Central

del Carmen Crespo, María; Vallespín, Elena; Palomares-Bralo, María; Martin-Arenas, Rubén; Rueda-Arenas, Inmaculada; Silvestre de Faria, Paulo Antonio; García-Miguel, Purificación; Lapunzina, Pablo; Regla Vargas, Fernando; Seuanez, Hector N.; Martínez-Glez, Víctor

2015-01-01

Wilms tumor (WT), the most common cancer of the kidney in infants and children, has a complex etiology that is still poorly understood. Identification of genomic copy number variants (CNV) in tumor genomes provides a better understanding of cancer development which may be useful for diagnosis and therapeutic targets. In paired blood and tumor DNA samples from 14 patients with sporadic WT, analyzed by aCGH, 22% of chromosome abnormalities were novel. All constitutional alterations identified in blood were segmental (in 28.6% of patients) and were also present in the paired tumor samples. Two segmental gains (2p21 and 20q13.3) and one loss (19q13.31) present in blood had not been previously described in WT. We also describe, for the first time, a small, constitutive partial gain of 3p22.1 comprising 2 exons of CTNNB1, a gene associated to WT. Among somatic alterations, novel structural chromosomal abnormalities were found, like gain of 19p13.3 and 20p12.3, and losses of 2p16.1-p15, 4q32.5-q35.1, 4q35.2-q28.1 and 19p13.3. Candidate genes included in these regions might be constitutively (SIX3, SALL4) or somatically (NEK1, PIAS4, BMP2) operational in the development and progression of WT. To our knowledge this is the first report of CNV in paired blood and tumor samples in sporadic WT. PMID:26317783

Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer’s disease

PubMed Central

Shinohara, Mitsuru; Fujioka, Shinsuke; Murray, Melissa E.; Wojtas, Aleksandra; Baker, Matthew; Rovelet-Lecrux, Anne; Rademakers, Rosa; Das, Pritam; Parisi, Joseph E.; Graff-Radford, Neill R.; Petersen, Ronald C.; Dickson, Dennis W.

2014-01-01

Recent studies suggest that subcortical structures, including striatum, are vulnerable to amyloid-β accumulation and other neuropathological features in familial Alzheimer’s disease due to autosomal dominant mutations. We explored differences between familial and sporadic Alzheimer’s disease that might shed light on their respective pathogenic mechanisms. To this end, we analysed 12 brain regions, including neocortical, limbic and subcortical areas, from post-mortem brains of familial Alzheimer’s disease (n = 10; age at death: 50.0 ± 8.6 years) with mutations in amyloid precursor protein (APP) or presenilin 1 (PSEN1), sporadic Alzheimer’s disease (n = 19; age at death: 84.7 ± 7.8 years), neurologically normal elderly without amyloid-β accumulation (normal ageing; n = 13, age at death: 82.9 ± 10.8 years) and neurologically normal elderly with extensive cortical amyloid-β deposits (pathological ageing; n = 15; age at death: 92.7 ± 5.9 years). The levels of amyloid-β40, amyloid-β42, APP, apolipoprotein E, the synaptic marker PSD95 (now known as DLG4), the astrocyte marker GFAP, other molecules related to amyloid-β metabolism, and tau were determined by enzyme-linked immunosorbent assays. We observed that familial Alzheimer’s disease had disproportionate amyloid-β42 accumulation in subcortical areas compared with sporadic Alzheimer’s disease, whereas sporadic Alzheimer’s disease had disproportionate amyloid-β42 accumulation in cortical areas compared to familial Alzheimer’s disease. Compared with normal ageing, the levels of several proteins involved in amyloid-β metabolism were significantly altered in both sporadic and familial Alzheimer’s disease; however, such changes were not present in pathological ageing. Among molecules related to amyloid-β metabolism, the regional distribution of PSD95 strongly correlated with the regional pattern of amyloid-β42 accumulation in sporadic Alzheimer’s disease and pathological ageing, whereas the regional distribution of APP as well as β-C-terminal fragment of APP were strongly associated with the regional pattern of amyloid-β42 accumulation in familial Alzheimer’s disease. Apolipoprotein E and GFAP showed negative regional association with amyloid-β (especially amyloid-β40) accumulation in both sporadic and familial Alzheimer’s disease. Familial Alzheimer’s disease had greater striatal tau pathology than sporadic Alzheimer’s disease. In a retrospective medical record review, atypical signs and symptoms were more frequent in familial Alzheimer’s disease compared with sporadic Alzheimer’s disease. These results suggest that disproportionate amyloid-β42 accumulation in cortical areas in sporadic Alzheimer’s disease may be mediated by synaptic processes, whereas disproportionate amyloid-β42 accumulation in subcortical areas in familial Alzheimer’s disease may be driven by APP and its processing. Region-specific amyloid-β42 accumulation might account for differences in the relative amounts of tau pathology and clinical symptoms in familial and sporadic Alzheimer’s disease. PMID:24625695

Update: Dura Mater Graft-Associated Creutzfeldt-Jakob Disease - Japan, 1975-2017.

PubMed

Ae, Ryusuke; Hamaguchi, Tsuyoshi; Nakamura, Yosikazu; Yamada, Masahito; Tsukamoto, Tadashi; Mizusawa, Hidehiro; Belay, Ermias D; Schonberger, Lawrence B

2018-03-09

Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder that, according to the most well accepted hypothesis (1), is caused by replicating, transmissible, abnormal forms of a host-encoded prion protein (prions). Most CJD cases occur spontaneously (sporadic CJD) or are inherited (genetic CJD). Iatrogenic CJD can occur after exposure to prion-contaminated instruments or products in medical/surgical settings. Cadaveric dura mater graft-associated CJD (dCJD) accounts for a common form of iatrogenic CJD. This report summarizes the epidemiologic features of 154 cases of dCJD identified in Japan during 1975-2017; these cases account for >60% of dCJD cases reported worldwide (1,2). The unusually high prevalence of dCJD in Japan was first reported in 1997 (3). In 2008, a single brand of graft (Lyodura [B. Braun Melsungen AG, Melsungen, Germany]), frequently used as a patch in neurosurgical procedures, was identified as the probable vehicle of transmission (4). No international recall of the implicated Lyodura occurred, the product had a relatively long shelf life, and the grafts were used frequently in Japanese patients with non-life-threatening conditions (4,5). Since 2008, additional cases have been ascertained, reflecting the identification of previously missed cases and the occurrence of new cases with longer latency periods (interval from exposure to symptom onset) for dCJD (up to 30 years), underscoring the importance of maintaining surveillance for dCJD.

Molecular Typing of Legionella pneumophila Isolates in the Province of Quebec from 2005 to 2015.

PubMed

Lévesque, Simon; Lalancette, Cindy; Bernard, Kathryn; Pacheco, Ana Luisa; Dion, Réjean; Longtin, Jean; Tremblay, Cécile

2016-01-01

Legionella is found in natural and man-made aquatic environments, such as cooling towers and hot water plumbing infrastructures. Legionella pneumophila serogroup 1 (Lp1) is the most common etiological agent causing waterborne disease in the United States and Canada. This study reports the molecular characterization of Lp strains during a 10 year period. We conducted sequence-based typing (SBT) analysis on a large set of Lp isolates (n = 284) to investigate the province of Quebec sequence types (STs) distribution in order to identify dominant clusters. From 2005 to 2015, 181 clinical Lp isolates were typed by SBT (141 sporadic cases and 40 outbreak related cases). From the same period of time, 103 environmental isolates were also typed. Amongst the 108 sporadic cases of Lp1 typed, ST-62 was the most frequent (16.6%), followed by ST-213 (10.2%), ST-1 (8.3%) and ST-37 (8.3%). Amongst other serogroups (SG), ST-1327 (SG5) (27.3%) and ST-378 (SG10) (12.2%) were the most frequent. From the environmental isolates, ST-1 represent the more frequent SBT type (26.5%). Unweighted pair group method with arithmetic mean (UPGMA) dendrogram from the 108 sporadic cases of SG1 contains 4 major clusters (A to D) of related STs. Cluster B contains the majority of the strains (n = 61) and the three most frequent STs in our database (ST-62, ST-213 and ST-1). During the study period, we observed an important increase in the incidence rate in Quebec. All the community associated outbreaks, potentially or confirmed to be associated with a cooling tower were caused by Lp1 strains, by opposition to hospital associated outbreaks that were caused by serogroups of Lp other than SG1. The recent major Quebec City outbreak caused by ST-62, and the fact that this genotype is the most common in the province supports whole genome sequencing characterization of this particular sequence type in order to understand its evolution and associated virulence factors.

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.

PubMed

Majounie, Elisa; Renton, Alan E; Mok, Kin; Dopper, Elise G P; Waite, Adrian; Rollinson, Sara; Chiò, Adriano; Restagno, Gabriella; Nicolaou, Nayia; Simon-Sanchez, Javier; van Swieten, John C; Abramzon, Yevgeniya; Johnson, Janel O; Sendtner, Michael; Pamphlett, Roger; Orrell, Richard W; Mead, Simon; Sidle, Katie C; Houlden, Henry; Rohrer, Jonathan D; Morrison, Karen E; Pall, Hardev; Talbot, Kevin; Ansorge, Olaf; Hernandez, Dena G; Arepalli, Sampath; Sabatelli, Mario; Mora, Gabriele; Corbo, Massimo; Giannini, Fabio; Calvo, Andrea; Englund, Elisabet; Borghero, Giuseppe; Floris, Gian Luca; Remes, Anne M; Laaksovirta, Hannu; McCluskey, Leo; Trojanowski, John Q; Van Deerlin, Vivianna M; Schellenberg, Gerard D; Nalls, Michael A; Drory, Vivian E; Lu, Chin-Song; Yeh, Tu-Hsueh; Ishiura, Hiroyuki; Takahashi, Yuji; Tsuji, Shoji; Le Ber, Isabelle; Brice, Alexis; Drepper, Carsten; Williams, Nigel; Kirby, Janine; Shaw, Pamela; Hardy, John; Tienari, Pentti J; Heutink, Peter; Morris, Huw R; Pickering-Brown, Stuart; Traynor, Bryan J

2012-04-01

We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. Full funding sources listed at end of paper (see Acknowledgments). Copyright © 2012 Elsevier Ltd. All rights reserved.

New insights into genotype-phenotype correlations for the doublecortin-related lissencephaly spectrum.

PubMed

Bahi-Buisson, Nadia; Souville, Isabelle; Fourniol, Franck J; Toussaint, Aurelie; Moores, Carolyn A; Houdusse, Anne; Lemaitre, Jean Yves; Poirier, Karine; Khalaf-Nazzal, Reham; Hully, Marie; Leger, Pierre Louis; Elie, Caroline; Boddaert, Nathalie; Beldjord, Cherif; Chelly, Jamel; Francis, Fiona

2013-01-01

X-linked isolated lissencephaly sequence and subcortical band heterotopia are allelic human disorders associated with mutations of doublecortin (DCX), giving both familial and sporadic forms. DCX encodes a microtubule-associated protein involved in neuronal migration during brain development. Structural data show that mutations can fall either in surface residues, likely to impair partner interactions, or in buried residues, likely to impair protein stability. Despite the progress in understanding the molecular basis of these disorders, the prognosis value of the location and impact of individual DCX mutations has largely remained unclear. To clarify this point, we investigated a cohort of 180 patients who were referred with the agyria-pachygyria subcortical band heterotopia spectrum. DCX mutations were identified in 136 individuals. Analysis of the parents' DNA revealed the de novo occurrence of DCX mutations in 76 cases [62 of 70 females screened (88.5%) and 14 of 60 males screened (23%)], whereas in the remaining cases, mutations were inherited from asymptomatic (n = 14) or symptomatic mothers (n = 11). This represents 100% of families screened. Female patients with DCX mutation demonstrated three degrees of clinical-radiological severity: a severe form with a thick band (n = 54), a milder form (n = 24) with either an anterior thin or an intermediate thickness band and asymptomatic carrier females (n = 14) with normal magnetic resonance imaging results. A higher proportion of nonsense and frameshift mutations were identified in patients with de novo mutations. An analysis of predicted effects of missense mutations showed that those destabilizing the structure of the protein were often associated with more severe phenotypes. We identified several severe- and mild-effect mutations affecting surface residues and observed that the substituted amino acid is also critical in determining severity. Recurrent mutations representing 34.5% of all DCX mutations often lead to similar phenotypes, for example, either severe in sporadic subcortical band heterotopia owing to Arg186 mutations or milder in familial cases owing to Arg196 mutations. Taken as a whole, these observations demonstrate that DCX-related disorders are clinically heterogeneous, with severe sporadic and milder familial subcortical band heterotopia, each associated with specific DCX mutations. There is a clear influence of the individual mutated residue and the substituted amino acid in determining phenotype severity.

Exclusion of the GNAS Locus in PHP-Ib Patients With Broad GNAS Methylation Changes: Evidence for an Autosomal Recessive Form of PHP-Ib?

PubMed Central

Fernández-Rebollo, Eduardo; de Nanclares, Guiomar Pérez; Lecumberri, Beatriz; Turan, Serap; Anda, Emma; Pérez-Nanclares, Gustavo; Feig, Denice; Nik-Zainal, Serena; Bastepe, Murat; Jüppner, Harald

2013-01-01

Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) carry maternally inherited microdeletions upstream of GNAS that are associated with loss of methylation restricted to GNAS exon A/B. Only few AD-PHP-Ib patients carry microdeletions within GNAS that are associated with loss of all maternal methylation imprints. These epigenetic changes are often indistinguishable from those observed in patients affected by an apparently sporadic PHP-Ib form that has not yet been defined genetically. We have now investigated six female patients affected by PHP-Ib (four unrelated and two sisters) with complete or almost complete loss of GNAS methylation, whose healthy children (11 in total) showed no epigenetic changes at this locus. Analysis of several microsatellite markers throughout the 20q13 region made it unlikely that PHP-Ib is caused in these patients by large deletions involving GNAS or by paternal uniparental isodisomy or heterodisomy of chromosome 20 (patUPD20). Microsatellite and single-nucleotide variation (SNV) data revealed that the two affected sisters share their maternally inherited GNAS alleles with unaffected relatives that lack evidence for abnormal GNAS methylation, thus excluding linkage to this locus. Consistent with these findings, healthy children of two unrelated sporadic PHP-Ib patients had inherited different maternal GNAS alleles, also arguing against linkage to this locus. Based on our data, it appears plausible that some forms of PHP-Ib are caused by homozygous or compound heterozygous mutation(s) in an unknown gene involved in establishing or maintaining GNAS methylation. PMID:21523828

Biomarkers in Sporadic and Familial Alzheimer's Disease.

PubMed

Lista, Simone; O'Bryant, Sid E; Blennow, Kaj; Dubois, Bruno; Hugon, Jacques; Zetterberg, Henrik; Hampel, Harald

2015-01-01

Most forms of Alzheimer's disease (AD) are sporadic (sAD) or inherited in a non-Mendelian fashion, and less than 1% of cases are autosomal-dominant. Forms of sAD do not exhibit familial aggregation and are characterized by complex genetic and environmental interactions. Recently, the expansion of genomic methodologies, in association with substantially larger combined cohorts, has resulted in various genome-wide association studies that have identified several novel genetic associations of AD. Currently, the most effective methods for establishing the diagnosis of AD are defined by multi-modal pathways, starting with clinical and neuropsychological assessment, cerebrospinal fluid (CSF) analysis, and brain-imaging procedures, all of which have significant cost- and access-to-care barriers. Consequently, research efforts have focused on the development and validation of non-invasive and generalizable blood-based biomarkers. Among the modalities conceptualized by the systems biology paradigm and utilized in the "exploratory biomarker discovery arena", proteome analysis has received the most attention. However, metabolomics, lipidomics, transcriptomics, and epigenomics have recently become key modalities in the search for AD biomarkers. Interestingly, biomarker changes for familial AD (fAD), in many but not all cases, seem similar to those for sAD. The integration of neurogenetics with systems biology/physiology-based strategies and high-throughput technologies for molecular profiling is expected to help identify the causes, mechanisms, and biomarkers associated with the various forms of AD. Moreover, in order to hypothesize the dynamic trajectories of biomarkers through disease stages and elucidate the mechanisms of biomarker alterations, updated and more sophisticated theoretical models have been proposed for both sAD and fAD.

Clinical and genetic characteristics of Pseudohypoparathyroidism in the Chinese population.

PubMed

Chu, Xueying; Zhu, Yan; Wang, Ou; Nie, Min; Quan, Tingting; Xue, Yu; Wang, Wenbo; Jiang, Yan; Li, Mei; Xia, Weibo; Xing, Xiaoping

2018-02-01

Pseudohypoparathyroidism (PHP) is caused by mutations and epimutations in the GNAS locus, and characterized by the possibility of resistance to multiple hormones and Albright's hereditary osteodystrophy. PHP can be classified into the forms 1A/C, sporadic 1B and familial 1B. To obtain an overall view of the clinical and genetic characteristics of the Chinese PHP patient population. From 2000 to 2016, 120 patients were recruited and studied using Sanger sequencing, methylation-specific multiple ligation-dependent probe amplification (MS-MLPA) and combined bisulfite restriction analysis (COBRA). Of these patients, 104 had positive molecular alterations indicative of certain forms of PHP and were included in data analysis. Clinical and laboratory features were compared between PHP1A/C and PHP1B patients. Ten PHP1A/C, 21 familial PHP1B and 73 sporadic PHP1B patients were identified. Four novel GNAS mutations were discovered in these patients, including c.1038+1G>T, c.530+2T>C, c.880_883delCAAG and c.311_312delAAG, insT. The most common symptoms in this series were recurrent tetany (89.4%) and epilepsy (47.1%). The prevalence of weight excess increased with age for PHP1B (10%-35%) and PHP1A/C (50%-75%). Intracranial calcification had a prevalence of 94.6% and correlated with seizures (r = .227, P = .029). Cataracts occurred in 56.2% PHP patients, and there was a trend towards longer disease duration in patients with cataracts (P = .051). Statistically significant differences (P < .05) were observed when comparing certain clinical characteristics between PHP1B and PHP1A/C patients, including age of onset (10 vs 7 year), short stature (21.3% vs 70%), rounded face (60.6% vs 100%), brachydactyly (25.5% vs 100%), ectopic ossification (1.1% vs 40%) and TSH resistance (44.6% vs 90%), respectively. This study is the largest single-centre series of PHP patients and summarizes the clinical and genetic features of the Chinese PHP population. While there was substantial clinical overlap between PHP1A/C and PHP1B, differences in disease progression were observed. © 2017 John Wiley & Sons Ltd.

Identification of Norovirus as the Top Enteric Viruses Detected in Adult Cases with Acute Gastroenteritis

PubMed Central

Liu, Li-Juan; Liu, Wei; Liu, Yun-Xi; Xiao, Hong-Jv; Jia, Ning; Liu, Gang; Tong, Yi-Gang; Cao, Wu-Chun

2010-01-01

To elucidate the importance of the norovirus and other enteric viruses, and the difference of the genetic relatedness on norovirus between the outbreak and sporadic cases, a total of 557 stool samples, consisting of 503 sporadic cases and 54 samples of 4 outbreaks were collected and tested for norovirus and other enteric viruses in Beijing, China, July 2007–June 2008. The data showed norovirus, rotavirus, astrovirus, and sapovirus, were detected in 26.6%, 6.1%, 1.8%, and 0.5%, respectively. Norovirus was detected almost throughout the surveillance period, norovirus co-infecting with rotavirus, astrovirus, and sapovirus, respectively, were identified both in outbreak and the sporadic cases. GII.4/2006 was identified as the predominant strain circulating both in outbreak and sporadic cases. The results showed that norovirus was rather the important agent than other enteric viruses affected adults with acute gastroenteritis; no significant genetic relatedness of the dominant strains was found between the outbreak and sporadic cases. PMID:20348525

Genomic Alterations Observed in Colitis-Associated Cancers Are Distinct From Those Found in Sporadic Colorectal Cancers and Vary by Type of Inflammatory Bowel Disease.

PubMed

Yaeger, Rona; Shah, Manish A; Miller, Vincent A; Kelsen, Judith R; Wang, Kai; Heins, Zachary J; Ross, Jeffrey S; He, Yuting; Sanford, Eric; Yantiss, Rhonda K; Balasubramanian, Sohail; Stephens, Philip J; Schultz, Nikolaus; Oren, Moshe; Tang, Laura; Kelsen, David

2016-08-01

Patients with inflammatory bowel diseases, such as Crohn's disease (CD) and ulcerative colitis (UC), are at increased risk for small bowel or colorectal cancers (colitis-associated cancers [CACs]). We compared the spectrum of genomic alterations in CACs with those of sporadic colorectal cancers (CRCs) and investigated differences between CACs from patients with CD vs UC. We studied tumor tissues from patients with CACs treated at Memorial Sloan Kettering Cancer Center or Weill Cornell Medical College from 2003 through 2015. We performed hybrid capture-based next-generation sequencing analysis of >300 cancer-related genes to comprehensively characterize genomic alterations. We performed genomic analyses of 47 CACs (from 29 patients with UC and 18 with CD; 43 primary tumors and 4 metastases). Primary tumors developed in the ileum (n = 2), right colon (n = 18), left colon (n = 6), and rectosigmoid or rectum (n = 21). We found genomic alterations in TP53, IDH1, and MYC to be significantly more frequent, and mutations in APC to be significantly less frequent, than those reported in sporadic CRCs by The Cancer Genome Atlas or Foundation Medicine. We identified genomic alterations that might be targeted by a therapeutic agent in 17 of 47 (36%) CACs. These included the mutation encoding IDH1 R132; amplification of FGFR1, FGFR2, and ERBB2; and mutations encoding BRAF V600E and an EML4-ALK fusion protein. Alterations in IDH1 and APC were significantly more common in CACs from patients with CD than UC. In an analysis of CACs from 47 patients, we found significant differences in the spectrum of genomic alterations in CACs compared with sporadic CRCs. We observed a high frequency of IDH1 R132 mutations in patients with CD but not UC, as well as a high frequency of MYC amplification in CACs. Many genetic alterations observed in CACs could serve as therapeutic targets. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Genomic Alterations Observed in Colitis-associated Cancers are Distinct from Those Found in Sporadic Colorectal Cancers and Vary by Type of Inflammatory Bowel Disease

PubMed Central

Yaeger, Rona; Shah, Manish A.; Miller, Vincent A.; Kelsen, Judith R.; Wang, Kai; Heins, Zachary J.; Ross, Jeffrey S.; He, Yuting; Sanford, Eric; Yantiss, Rhonda K.; Balasubramanian, Sohail; Stephens, Philip J.; Schultz, Nikolaus; Oren, Moshe; Tang, Laura; Kelsen, David

2016-01-01

Background & Aims Patients with inflammatory bowel diseases such as Crohn's disease (CD) or ulcerative colitis (UC) are at increased risk for small bowel or colorectal cancers (colitis-associated cancers, CACs). We compared the spectrum of genomic alterations in CACs with those of sporadic colorectal cancers (CRCs) and investigated differences between CACs from patients with CD vs UC. Methods We studied tumor tissues from patients with CACs, treated at Memorial Sloan Kettering Cancer Center or Weill Cornell Medical College from 2003 through 2015. We performed hybrid capture based next-generation sequencing analysis of over 300 cancer-related genes to comprehensively characterize genomic alterations. Results We performed genomic analyses of 47 CACs (from 29 patients with UC and 18 with CD; 43 primary tumors and 4 metastases). Primary tumors developed in the ileum (n=2), right colon (n=18), left colon (n=6) and rectosigmoid or rectum (n=21). We found genomic alterations in TP53, IDH1, and MYC to be significantly more frequent, and mutations in APC to be significantly less frequent, than those reported in sporadic CRCs by The Cancer Genome Atlas or Foundation Medicine. We identified genomic alterations that might be targeted by a therapeutic agent in 17/47 (36%) of CACs. These included the mutation encoding IDH1 R132; amplification of FGFR1, FGFR2, and ERBB2; and mutations encoding BRAF V600E and an EML4-ALK fusion protein. Alterations in IDH1 and APC were significantly more common in CACs from patients with CD than UC. Conclusions In an analysis of CACs from 47 patients, we found significant differences in the spectrum of genomic alterations in CACs compared to sporadic CRCs. We observed a high frequency of IDH1 R132 mutations in patients with CD but not UC, as well as a high frequency of MYC amplification in CACs. Many genetic alterations observed in CACs could serve as therapeutic targets. PMID:27063727

Screening for susceptibility genes in hereditary non-polyposis colorectal cancer.

PubMed

Yu, Li; Yin, Bo; Qu, Kaiying; Li, Jingjing; Jin, Qiao; Liu, Ling; Liu, Chunlan; Zhu, Yuxing; Wang, Qi; Peng, Xiaowei; Zhou, Jianda; Cao, Peiguo; Cao, Ke

2018-06-01

In the present study, hereditary non-polyposis colorectal cancer (HNPCC) susceptibility genes were screened for using whole exome sequencing in 3 HNPCC patients from 1 family and using single nucleotide polymorphism (SNP) genotyping assays in 96 other colorectal cancer and control samples. Peripheral blood was obtained from 3 HNPCC patients from 1 family; the proband and the proband's brother and cousin. High-throughput sequencing was performed using whole exome capture technology. Sequences were aligned against the HAPMAP, dbSNP130 and 1,000 Genome Project databases. Reported common variations and synonymous mutations were filtered out. Non-synonymous single nucleotide variants in the 3 HNPCC patients were integrated and the candidate genes were identified. Finally, SNP genotyping was performed for the genes in 96 peripheral blood samples. In total, 60.4 Gb of data was retrieved from the 3 HNPCC patients using whole exome capture technology. Subsequently, according to certain screening criteria, 15 candidate genes were identified. Among the 96 samples that had been SNP genotyped, 92 were successfully genotyped for 15 gene loci, while genotyping for HTRA1 failed in 4 sporadic colorectal cancer patient samples. In 12 control subjects and 81 sporadic colorectal cancer patients, genotypes at 13 loci were wild-type, namely DDX20, ZFYVE26, PIK3R3, SLC26A8, ZEB2, TP53INP1, SLC11A1, LRBA, CEBPZ, ETAA1, SEMA3G, IFRD2 and FAT1 . The CEP290 genotype was mutant in 1 sporadic colorectal cancer patient and was wild-type in all other subjects. A total of 5 of the 12 control subjects and 30 of the 81 sporadic colorectal cancer patients had a mutant HTRA1 genotype. In all 3 HNPCC patients, the same mutant genotypes were identified at all 15 gene loci. Overall, 13 potential susceptibility genes for HNPCC were identified, namely DDX20, ZFYVE26, PIK3R3, SLC26A8, ZEB2, TP53INP1, SLC11A1, LRBA, CEBPZ, ETAA1, SEMA3G, IFRD2 and FAT1 .

Genetic variants of TREML2 are associated with HLA-B27-positive ankylosing spondylitis.

PubMed

Feng, Yuan; Hong, Yaqiang; Zhang, Xin; Cao, Chunwei; Yang, Xichao; Lai, Shujuan; Fan, Chunmei; Cheng, Feng; Yan, Mei; Li, Chaohua; Huang, Wan; Chen, Wei; Zhu, Ping; Zeng, Changqing

2018-08-20

Although ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the precise genetic mechanism underlying the disease remains elusive. Here, we investigate the disease-causing mutations in a large AS family with distinguished complexity, consisting of 23 patients covering four generations and exhibiting a mixed HLA-B27 (+) and (-) status. Linkage analysis with 32 members using three methods and whole-exome sequencing analysis with three HLA-B27 (+) patients, one HLA-B27 (-) patient, and one healthy individual did not identify a mutation common to all of the patients, strongly suggesting the existence of genetic heterogeneity in this large pedigree. However, if only B27-positive patients were analyzed, the linkage analysis located a 22-Mb region harboring the HLA gene cluster in chromosome 6 (LOD = 4.2), and the subsequent exome analysis identified two non-synonymous mutations in the TREML2 and IP6K3 genes. These genes were resequenced among 370 sporadic AS patients and 487 healthy individuals. A significantly higher mutation frequency of TREML2 was observed in AS patients (1.51% versus 0.21%). The results obtained for the AS pedigree and sporadic patients suggest that mutation of TREML2 is a major factor leading to AS for HLA-B27 (+) members in this large family and that TREML2 is also a susceptibility gene promoting the development of ankylosing spondylitis in HLA-B27 (+) individuals. Copyright © 2018 Elsevier B.V. All rights reserved.

High prevalence of exon 8 G533C mutation in apparently sporadic medullary thyroid carcinoma in Greece.

PubMed

Sarika, H L; Papathoma, A; Garofalaki, M; Vasileiou, V; Vlassopoulou, B; Anastasiou, E; Alevizaki, M

2012-12-01

Genetic screening for ret mutation has become routine practice in the evaluation of medullary thyroid carcinoma (MTC). Approximately 25% of these tumours are familial, and they occur as components of the multiple endocrine neoplasia type 2 syndromes (MEN 2A and 2B) or familial MTC. In familial cases, the majority of mutations are found in exons 10, 11, 13, 14 or 15 of the ret gene. A rare mutation involving exon 8 (G533C) has recently been reported in familial cases of MTC in Brazil and Greece; some of these cases were originally thought to be sporadic. The aim of this study was to re-evaluate a series of sporadic cases of MTC, with negative family history, and screen them for germline mutations in exon 8. Genomic DNA was extracted from peripheral lymphocytes in 129 unrelated individuals who had previously been characterized as 'sporadic' based on the negative family history and negative screening for ret gene mutations. Samples were analysed in Applied Biosystems 7500 real-time PCR and confirmed by sequencing. The G533C exon 8 mutation was identified in 10 of 129 patients with sporadic MTC. Asymptomatic gene carriers were subsequently identified in other family members. In our study, we found that 7·75% patients with apparently sporadic MTC do carry G533C mutation involving exon 8 of ret. We feel that there is now a need to include exon 8 mutation screening in all patients diagnosed as sporadic MTC, in Greece. © 2012 Blackwell Publishing Ltd.

HLA-DRB1 Alleles Are Associated with the Susceptibility to Sporadic Parkinson’s Disease in Chinese Han Population

PubMed Central

Sun, Congcong; Wei, Lei; Luo, Feifei; Li, Yi; Li, Jiaobiao; Zhu, Feiqi; Kang, Ping; Xu, Rensi; Xiao, LuLu; Liu, Zhuolin; Xu, Pingyi

2012-01-01

Immune disorders may play an important role in the pathogenesis of Parkinson's disease (PD). Recently, polymorphisms in the HLA-DR region have been found to be associated with sporadic PD in European ancestry populations. However, polymorphisms in the HLA complex are highly variable with ethnic and geographic origin. To explore the relationships between polymorphisms of the HLA-DR region and sporadic PD in Chinese Han population, we genotyped 567 sporadic PD patients and 746 healthy controls in two independent series for the HLA-DRB1 locus with Polymerase chain reaction-sequence based typing(PCR-SBT). The χ2 test was used to evaluate the distribution of allele frequencies between the patients and healthy controls. The impact of HLA-DRB1 alleles on PD risk was estimated by unconditional logistic regression. We found a significant higher frequency of HLA-DRB1*0301 in sporadic PD patients than in healthy controls and a positive association, which was independent of onset age, between HLA-DRB1*0301 and PD risk. Conversely, a lower frequency of HLA-DRB1*0406 was found in sporadic PD patients than in healthy controls, with a negative association between HLA-DRB1*0406 and PD risk. Furthermore, a meta-analysis involving 195205 individuals was conducted to summarize the frequencies of these two alleles in populations from various ethnic regions, we found a higher frequency of HLA-DRB1*0301, but a lower frequency of HLA-DRB1*0406 in European ancestry populations than that in Asians, this was consistent with the higher prevalence of sporadic PD in European ancestry populations. Based on these results, we speculate that HLA-DRB1 alleles are associated with the susceptibility to sporadic PD in Chinese Han population, among them HLA-DRB1*0301 is a risk allele while the effect of HLA-DRB1*0406 deserves debate. PMID:23139797

MEN1 mutations and potentially MEN1-targeting miRNAs are responsible for menin deficiency in sporadic and MEN1 syndrome-associated primary hyperparathyroidism.

PubMed

Grolmusz, Vince Kornél; Borka, Katalin; Kövesdi, Annamária; Németh, Kinga; Balogh, Katalin; Dékány, Csaba; Kiss, András; Szentpéteri, Anna; Sármán, Beatrix; Somogyi, Anikó; Csajbók, Éva; Valkusz, Zsuzsanna; Tóth, Miklós; Igaz, Péter; Rácz, Károly; Patócs, Attila

2017-09-01

Inherited, germline mutations of menin-coding MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), while somatic MEN1 mutations are the sole main driver mutations in sporadic primary hyperparathyroidism (PHPT), suggesting that menin deficiency has a central role in the pathogenesis of PHPT. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to investigate both the role of MEN1 mutations and potentially MEN1-targeting miRNAs as the underlying cause of menin deficiency in MEN1-associated and sporadic PHPT tissues. Fifty six PHPT tissues, including 16 MEN1-associated tissues, were evaluated. Diagnosis of MEN1 syndrome was based on identification of germline MEN1 mutations. In silico target prediction was used to identify miRNAs potentially targeting MEN1. Menin expression was determined by immunohistochemistry while expression of miRNAs was analyzed by quantitative real-time PCR. Sporadic PHPT tissues were subjected to somatic MEN1 mutation analysis as well. Lack of nuclear menin was identified in all MEN1-associated and in 28% of sporadic PHPT tissues. Somatic MEN1 mutations were found in 25% of sporadic PHPTs. The sensitivity and specificity of menin immunohistochemistry to detect a MEN1 mutation were 86 and 87%, respectively. Expression levels of hsa-miR-24 and hsa-miR-28 were higher in sporadic compared to MEN1-associated PHPT tissues; however, no difference in miRNA levels occurred between menin-positive and menin-negative PHPT tissues. Menin deficiency is the consequence of a MEN1 mutation in most menin-negative PHPT tissues. Elevated expression of hsa-miR-24 and hsa-miR-28 mark the first epigenetic changes observed between sporadic and MEN1-associated PHPT.

DJ-1 is a redox sensitive adapter protein for high molecular weight complexes involved in regulation of catecholamine homeostasis

PubMed Central

Piston, Dominik; Alvarez-Erviti, Lydia; Bansal, Vikas; Gargano, Daniela; Yao, Zhi; Szabadkai, Gyorgy; Odell, Mark; Puno, M Rhyan; Björkblom, Benny; Maple-Grødem, Jodi; Breuer, Peter; Kaut, Oliver; Larsen, Jan Petter; Bonn, Stefan; Møller, Simon Geir; Wüllner, Ullrich; Schapira, Anthony H V

2017-01-01

Abstract DJ-1 is an oxidation sensitive protein encoded by the PARK7 gene. Mutations in PARK7 are a rare cause of familial recessive Parkinson’s disease (PD), but growing evidence suggests involvement of DJ-1 in idiopathic PD. The key clinical features of PD, rigidity and bradykinesia, result from neurotransmitter imbalance, particularly the catecholamines dopamine (DA) and noradrenaline. We report in human brain and human SH-SY5Y neuroblastoma cell lines that DJ-1 predominantly forms high molecular weight (HMW) complexes that included RNA metabolism proteins hnRNPA1 and PABP1 and the glycolysis enzyme GAPDH. In cell culture models the oxidation status of DJ-1 determined the specific complex composition. RNA sequencing indicated that oxidative changes to DJ-1 were concomitant with changes in mRNA transcripts mainly involved in catecholamine metabolism. Importantly, loss of DJ-1 function upon knock down (KD) or expression of the PD associated form L166P resulted in the absence of HMW DJ-1 complexes. In the KD model, the absence of DJ-1 complexes was accompanied by impairment in catecholamine homeostasis, with significant increases in intracellular DA and noraderenaline levels. These changes in catecholamines could be rescued by re-expression of DJ-1. This catecholamine imbalance may contribute to the particular vulnerability of dopaminergic and noradrenergic neurons to neurodegeneration in PARK7-related PD. Notably, oxidised DJ-1 was significantly decreased in idiopathic PD brain, suggesting altered complex function may also play a role in the more common sporadic form of the disease. PMID:29016861

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

Baumbach, L.; Schiavi, A.

The proximal spinal muscular atrophies (PSMA), one of the most common forms of lower motor neuron disease in children, are characterized by progressive muscle weakness due to loss of anterior horn cells. All three autosomal recessive forms have been mapped to chromosome 5q11.2-11.3, implying an allelic association between these disorders. Recent evidence from our laboratories, as well as others, suggests that a distinct form of lethal neonatal spinal muscular atrophy, associated with early onset contractures, is determined by a gene on the X chromosome. We report our efforts in mapping this disease locus. Our original studies have focused on twomore » unrelated multigenerational families with similar clinical presentations of severe hypotonia, muscle weakness, and a disease course similar to Werdnig Hoffman except for the additional finding of congenital or early onset contractures. Muscle biopsy and/or autopsy were indicative of anterior horn cell loss in affected males. Disease occurrence in each of the families was consistent with an X-linked recessive mode of inheritance. Subsequently, two additional families have been identified, as well as several sporadic male cases. Linkage analysis has been completed in one of these families using highly polymorphic repeats dispersed 10 cM on the X chromosome. Interpretation of results was achieved using an automated data acquisition program. Analysis of over 300 haplotypes generated using PCR-based DNA markers have identified two 16 cM regions on Xp with complete concordance to the disease phenotype. Our currents efforts are focused on the region surrounding the Kallman gene, in attempts to better define a candidate region, as well as analyze possible candidate genes within this region.« less

Methods for culturing saltwater rotifers (Brachionus plicatilis) for rearing larval zebrafish.

PubMed

Lawrence, Christian; Sanders, Erik; Henry, Eric

2012-09-01

The saltwater rotifer, Brachionus plicatilis, is widely used in the aquaculture industry as a prey item for first-feeding fishes due to its ease of culture, small size, rapid reproductive rate, and amenability to enrichment with nutrients. Despite the distinct advantages of this approach, rotifers have only been sporadically utilized for rearing larval zebrafish, primarily because of the common misconception that maintaining cultures of rotifers is difficult and excessively time-consuming. Here we present simple methods for maintaining continuous cultures of rotifers capable of supporting even the very largest zebrafish aquaculture facility, with minimal investments in materials, time, labor, and space. Examples of the methods' application in one large, existing facility is provided, and troubleshooting of common problems is discussed.

Is there a conclusive evidence on lightning-related effects on sporadic E layers?

NASA Astrophysics Data System (ADS)

Haldoupis, Christos

2018-07-01

In recent years, there have been a few studies claiming that thunderstorm cloud-to-ground lightning discharges affect sporadic E layers existing over the storm. In this brief paper, we consider and critically evaluate the results of these studies in the context of our present knowledge on sporadic E layers and the coupling processes of thunderstorm and lightning wave energy into the upper atmosphere and lower ionosphere. It is shown that the reported findings and their implications raise questions and cast doubts, therefore the conclusions of the existing studies are not substantiated and thus need to be treated with caution. We reason that, the anticipated occurrence of lighting-related effects on midlatitude sporadic E lacks at present firm verification.

Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside of the crypt base stem cell niche

PubMed Central

Bansal, Mukesh; Rafferty, Hannah; Boitsova, Tatjana; Bardella, Chiara; Jaeger, Emma; Lewis, Annabelle; Freeman-Mills, Luke; Giner, Francesc Castro; Rodenas-Cuadrado, Pedro; Mallappa, Sreelakshmi; Clark, Susan; Thomas, Huw; Jeffery, Rosemary; Poulsom, Richard; Rodriguez-Justo, Manuel; Novelli, Marco; Chetty, Runjan; Silver, Andrew; Sansom, Owen James; Greten, Florian R; Wang, Lai Mun; East, James Edward; Tomlinson, Ian; Leedham, Simon John

2015-01-01

Hereditary mixed polyposis syndrome (HMPS) is characterised by the development of mixed morphology colorectal tumours and is caused by a 40 kb duplication that results in aberrant epithelial expression of the mesenchymal Bone Morphogenetic Protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell-fate, that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem-cell properties in Lgr5 negative (non-expressing) progenitor cells that have exited the stem-cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem-cell is not the sole cell-of-origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic pre-malignant lesions with a hitherto unknown pathogenesis and these lesions can be considered the sporadic equivalents of HMPS polyps. PMID:25419707

Adherence of Clostridium perfringens spores to human intestinal epithelial Caco-2 cells.

PubMed

Sakanoue, Hideyo; Nakano, Takashi; Sano, Kouichi; Yasugi, Mayo; Monma, Chie; Miyake, Masami

2018-03-01

Clostridium perfringens is a gram-positive, spore-forming bacillus, and is a causative agent of foodborne infection, antibiotic-associated diarrhoea and sporadic diarrhoea in humans. In cases of antibiotic-associated and sporadic diarrhoea, C. perfringens colonises the intestine, proliferates and causes disease. However, bacterial colonisation of the intestine is not considered necessary in the pathogenesis of foodborne illness, because such pathogenesis can be explained by anchorage-independent production of diarrhoeic toxin by the bacterium in the intestine. In this study, we used an in vitro adherence assay to examine the adherence of C. perfringens spores to human intestinal Caco-2 cells. Adherence of spores from isolates of foodborne illness and nosocomial infection was observed within 15 min, and plateaued 60 min after inoculation. Electron microscopy revealed a tight association of spores with the surface of Caco-2 cells. The adherence of vegetative cells could not be confirmed by the same method, however. These results suggest that C. perfringens spores may adhere to intestinal epithelial cells in vivo, although its biological significance remains to be determined.

Modeling Late-Onset Sporadic Alzheimer's Disease through BMI1 Deficiency.

PubMed

Flamier, Anthony; El Hajjar, Jida; Adjaye, James; Fernandes, Karl J; Abdouh, Mohamed; Bernier, Gilbert

2018-05-29

Late-onset sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but its origin remains poorly understood. The Bmi1/Ring1 protein complex maintains transcriptional repression of developmental genes through histone H2A mono-ubiquitination, and Bmi1 deficiency in mice results in growth retardation, progeria, and neurodegeneration. Here, we demonstrate that BMI1 is silenced in AD brains, but not in those with early-onset familial AD, frontotemporal dementia, or Lewy body dementia. BMI1 expression was also reduced in cortical neurons from AD patient-derived induced pluripotent stem cells but not in neurons overexpressing mutant APP and PSEN1. BMI1 knockout in human post-mitotic neurons resulted in amyloid beta peptide secretion and deposition, p-Tau accumulation, and neurodegeneration. Mechanistically, BMI1 was required to repress microtubule associated protein tau (MAPT) transcription and prevent GSK3beta and p53 stabilization, which otherwise resulted in neurodegeneration. Restoration of BMI1 activity through genetic or pharmaceutical approaches could represent a therapeutic strategy against AD. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Acute Necrotizing Encephalopathy: An Underrecognized Clinicoradiologic Disorder

PubMed Central

Wu, Xiujuan; Wu, Wei; Pan, Wei; Wu, Limin; Liu, Kangding; Zhang, Hong-Liang

2015-01-01

Acute necrotizing encephalopathy (ANE) is a rare but distinctive type of acute encephalopathy with global distribution. Occurrence of ANE is usually preceded by a virus-associated febrile illness and ensued by rapid deterioration. However, the causal relationship between viral infections and ANE and the exact pathogenesis of ANE remain unclear; both environmental and host factors might be involved. Most cases of ANE are sporadic and nonrecurrent, namely, isolated or sporadic ANE; however, few cases are recurrent and with familial episodes. The recurrent and familial forms of ANE were found to be incompletely autosomal-dominant. Further the missense mutations in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2) were identified. Although the clinical course and the prognosis of ANE are diverse, the hallmark of neuroradiologic manifestation of ANE is multifocal symmetric brain lesions which are demonstrated by computed tomography (CT) or magnetic resonance imaging (MRI). The treatment of ANE is still under investigation. We summarize the up-to-date knowledge on ANE, with emphasis on prompt diagnosis and better treatment of this rare but fatal disease. PMID:25873770

Mutation analysis for DJ-1 in sporadic and familial parkinsonism: screening strategy in parkinsonism.

PubMed

Tomiyama, Hiroyuki; Li, Yuanzhe; Yoshino, Hiroyo; Mizuno, Yoshikuni; Kubo, Shin-Ichiro; Toda, Tatsushi; Hattori, Nobutaka

2009-05-22

DJ-1 mutations cause autosomal recessive parkinsonism (ARP). Although some reports of DJ-1 mutations have been published, there is lack of information on the prevalence of these mutations in large-scale studies of both familial and sporadic parkinsonism. In this genetic screening study, we analyzed the distribution and frequency of DJ-1 mutations by direct nucleotide sequencing of coding exons and exon-intron boundaries of DJ-1, in 386 parkin-negative parkinsonism patients (371 index cases: 67 probands of autosomal recessive parkinsonism families, 90 probands of autosomal dominant parkinsonism families, 201 patients with sporadic parkinsonism, and 13 with unknown family histories) from 12 countries (Japan 283, China 27, Taiwan 22, Korea 22, Israel 16, Turkey 5, Philippines 2, Bulgaria 2, Greece 2, Tunisia 1, USA 2, Ukraine 1, unknown 1). None had causative mutation in DJ-1, suggesting DJ-1 mutation is very rare among patients with familial and sporadic parkinsonism from Asian countries and those with other ethnic background. This is in contrast to the higher frequencies and worldwide distribution of parkin- and PINK1-related parkinsonism in ARP and sporadic parkinsonism. Thus, after obtaining clinical information, screening for mutations in (1) parkin, (2) PINK1, (3) DJ-1, (4) ATP13A2 should be conducted in that order, in ARP and sporadic parkinsonism, based on their reported frequencies. In addition, haplotype analysis should be employed to check for homozygosity of 1p36, which harbors a cluster of causative genes for ARP such as DJ-1, PINK1 and ATP13A2 in ARP and sporadic parkinsonism, especially in parkinsonism with consanguinity.

Variable interstellar absorption lines in young stellar aggregates

NASA Astrophysics Data System (ADS)

Krełowski, J.; Strobel, A.; Vješnica, S.; Melekh, D.; Bondar, A.

2018-06-01

The variability of interstellar atomic lines, sporadically reported in the astronomical literature, has been confirmed both in the case of the nearby hot star δ Ori and the very young and violent star-forming region η Carinae, using high-resolution echelle spectra. The presented variability concerns the intensities and profiles of Na I, K I and Ca II. The time-scale of the above-mentioned variations clearly suggests very local phenomena as their cause. It is important to say that not all interstellar lines vary in unison.

Secondary lymphangiectasia of the small bowel: utility of double balloon enteroscopy for diagnosis and management.

PubMed

Safatle-Ribeiro, Adriana Vaz; Iriya, Kiyoshi; Couto, Décio Sampaio; Kawaguti, Fábio Shiguehiss; Retes, Felipe; Ribeiro, Ulysses; Sakai, Paulo

2008-01-01

Sporadic lymphangiectasias are commonly found throughout the small bowel and are considered to be normal. Not uncommonly, lymphangiectasias are pathologic and can lead to mid-gastrointestinal bleeding, abdominal pain and protein-losing enteropathy. Pathologic lymphangiectasias of the small bowel include primary lymphangiectasia, secondary lymphangiectasia and lymphaticovenous malformations. In this report we present three different cases of small bowel lymphangiectasia detected by double balloon enteroscopy. The patients were diagnosed with South American blastomycosis, tuberculosis and primary small bowel lymphangioma. 2009 S. Karger AG, Basel

[Protein-losing enteropathy due to intestinal lymphangiectasis: a rare disease. Report of two cases].

PubMed

Sommaruga, Horacio; Santarcángelo, Salomé Catalina; Quintana, Carlos; Navacchia, Daniel

2015-03-01

Congenital intestinal lymphangiectasis (LIP) is a protein-losing enteropathy that appears sporadically in children. It begins with edema due to hypoproteinemia and hypoalbuminemia, and in some cases with ascites, immunodeficience and hypocalcemic tetania. The purpose of this report is to present two patients with LIP which appeared during the first year of life. The diagnosis was certificated by upper gastrointestinal videoendoscopy and histological findings. Both patients were treated with a new formula containing mean chain triglycerides with an adequate response, not obtained before with a common semielemental formula.

Polymorphism of MSH2 Gly322Asp and MLH1 –93G>A in non-familial colon cancer – a case-controlled study

PubMed Central

Dziki, Lukasz; Malinowska, Katarzyna; Trzcinski, Radzislaw; Majsterek, Ireneusz; Dziki, Adam

2017-01-01

Introduction Our aim was to determine the effect of the single nucleotide polymorphisms (SNP) –93G>A of the MLH1 gene (rs1800734) and Gly322Asp of the MSH2 gene (rs4987188) on the risk of colon cancer (CC) and identify any relationship with clinical factors. Material and methods The study included 144 unrelated patients with sporadic CC (71 males; mean age: 61.7 ±11 years) and 151 control patients (74 males; mean age: 63 ±11 years). DNA was extracted from peripheral blood lymphocytes, and genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. Results In our population, the homozygous G/G genotype of the –93G>AMLH1 gene increased the risk of sporadic CC (OR = 2.07; 95% CI: 1.11–3.83; p < 0.02). For A/G and A/A genotypes, the MLH1-93G>A polymorphism was significantly more common in women (p = 0.034). The SNP demonstrated differences in allele distribution according to the location of the tumor, i.e. right vs. left side (p = 0.014), and disease recurrence (p = 0.022). Significant differences were found in the occurrence of Gly322Asp of MSH2 with regard to primary and recurrent disease (p = 0.001). Conclusions The –93G>AMLH1 polymorphism plays an important role in evaluating the risk of sporadic CC. It can also be used as an indicator in some patients with left-sided and recurrent tumors. MSH2 Gly322Asp is a potential marker in patients with risk of recurrence. PMID:29181059

In vivo signatures of nonfluent/agrammatic primary progressive aphasia caused by FTLD pathology

PubMed Central

Caso, Francesca; Mandelli, Maria Luisa; Henry, Maya; Gesierich, Benno; Bettcher, Brianne M.; Ogar, Jennifer; Filippi, Massimo; Comi, Giancarlo; Magnani, Giuseppe; Sidhu, Manu; Trojanowski, John Q.; Huang, Eric J.; Grinberg, Lea T.; Miller, Bruce L.; Dronkers, Nina; Seeley, William W.

2014-01-01

Objective: To identify early cognitive and neuroimaging features of sporadic nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) caused by frontotemporal lobar degeneration (FTLD) subtypes. Methods: We prospectively collected clinical, neuroimaging, and neuropathologic data in 11 patients with sporadic nfvPPA with FTLD-tau (nfvPPA-tau, n = 9) or FTLD–transactive response DNA binding protein pathology of 43 kD type A (nfvPPA-TDP, n = 2). We analyzed patterns of cognitive and gray matter (GM) and white matter (WM) atrophy at presentation in the whole group and in each pathologic subtype separately. We also considered longitudinal clinical data. Results: At first evaluation, regardless of pathologic FTLD subtype, apraxia of speech (AOS) was the most common cognitive feature and atrophy involved the left posterior frontal lobe. Each pathologic subtype showed few distinctive features. At presentation, patients with nfvPPA-tau presented with mild to moderate AOS, mixed dysarthria with prominent hypokinetic features, clear agrammatism, and atrophy in the GM of the left posterior frontal regions and in left frontal WM. While speech and language deficits were prominent early, within 3 years of symptom onset, all patients with nfvPPA-tau developed significant extrapyramidal motor signs. At presentation, patients with nfvPPA-TDP had severe AOS, dysarthria with spastic features, mild agrammatism, and atrophy in left posterior frontal GM only. Selective mutism occurred early, when general neurologic examination only showed mild decrease in finger dexterity in the right hand. Conclusions: Clinical features in sporadic nfvPPA caused by FTLD subtypes relate to neurodegeneration of GM and WM in frontal motor speech and language networks. We propose that early WM atrophy in nfvPPA is suggestive of FTLD-tau pathology while early selective GM loss might be indicative of FTLD-TDP. PMID:24353332

Prospectively-Identified Incident Testicular Cancer Risk in a Familial Testicular Cancer Cohort

PubMed Central

Pathak, Anand; Adams, Charleen D.; Loud, Jennifer T.; Nichols, Kathryn; Stewart, Douglas R.; Greene, Mark H.

2015-01-01

Background Human testicular germ cell tumors (TGCT) have a strong genetic component and a high familial relative risk. However, linkage analyses have not identified a rare, highly-penetrant familial TGCT (FTGCT) susceptibility locus. Currently, multiple low-penetrance genes are hypothesized to underlie the familial multiple-case phenotype. The observation that two is the most common number of affected individuals per family presents an impediment to FTGCT gene discovery. Clinically, the prospective TGCT risk in the multiple-case family context is unknown. Methods We performed a prospective analysis of TGCT incidence in a cohort of multiple-affected-person families and sporadic-bilateral-case families; 1,260 men from 140 families (10,207 person-years of follow-up) met our inclusion criteria. Age-, gender-, and calendar time-specific standardized incidence ratios (SIR) for TGCT relative to the general population were calculated using SEER*Stat. Results Eight incident TGCTs occurred during prospective FTGCT cohort follow-up (versus 0.67 expected; SIR=11.9; 95% confidence interval [CI]=5.1–23.4; excess absolute risk=7.2/10,000). We demonstrate that the incidence rate of TGCT is greater among bloodline male relatives from multiple-case testicular cancer families than that expected in the general population, a pattern characteristic of adult-onset Mendelian cancer susceptibility disorders. Two of these incident TGCTs occurred in relatives of sporadic-bilateral cases (0.15 expected; SIR=13.4; 95%CI=1.6–48.6). Conclusions Our data are the first indicating that despite relatively low numbers of affected individuals per family, members of both multiple-affected-person FTGCT families and sporadic-bilateral TGCT families comprise high-risk groups for incident testicular cancer. Impact Men at high TGCT risk might benefit from tailored risk stratification and surveillance strategies. PMID:26265202

Prospectively Identified Incident Testicular Cancer Risk in a Familial Testicular Cancer Cohort.

PubMed

Pathak, Anand; Adams, Charleen D; Loud, Jennifer T; Nichols, Kathryn; Stewart, Douglas R; Greene, Mark H

2015-10-01

Human testicular germ cell tumors (TGCT) have a strong genetic component and a high familial relative risk. However, linkage analyses have not identified a rare, highly penetrant familial TGCT (FTGCT) susceptibility locus. Currently, multiple low-penetrance genes are hypothesized to underlie the familial multiple-case phenotype. The observation that two is the most common number of affected individuals per family presents an impediment to FTGCT gene discovery. Clinically, the prospective TGCT risk in the multiple-case family context is unknown. We performed a prospective analysis of TGCT incidence in a cohort of multiple-affected-person families and sporadic-bilateral-case families; 1,260 men from 140 families (10,207 person-years of follow-up) met our inclusion criteria. Age-, gender-, and calendar time-specific standardized incidence ratios (SIR) for TGCT relative to the general population were calculated using SEER*Stat. Eight incident TGCTs occurred during prospective FTGCT cohort follow-up (versus 0.67 expected; SIR = 11.9; 95% CI, 5.1-23.4; excess absolute risk = 7.2/10,000). We demonstrate that the incidence rate of TGCT is greater among bloodline male relatives from multiple-case testicular cancer families than that expected in the general population, a pattern characteristic of adult-onset Mendelian cancer susceptibility disorders. Two of these incident TGCTs occurred in relatives of sporadic-bilateral cases (0.15 expected; SIR = 13.4; 95% CI, 1.6-48.6). Our data are the first to indicate that despite relatively low numbers of affected individuals per family, members of both multiple-affected-person FTGCT families and sporadic-bilateral TGCT families comprise high-risk groups for incident testicular cancer. Men at high TGCT risk might benefit from tailored risk stratification and surveillance strategies. ©2015 American Association for Cancer Research.

Mutations in both KRAS and BRAF may contribute to the methylator phenotype in colon cancer

PubMed Central

Nagasaka, Takeshi; Koi, Minoru; Kloor, Matthias; Gebert, Johannes; Vilkin, Alex; Nishida, Naoshi; Shin, Sung Kwan; Sasamoto, Hiromi; Tanaka, Noriaki; Matsubara, Nagahide; Boland, C. Richard; Goel, Ajay

2008-01-01

Background Colorectal cancers (CRCs) with the CpG island methylator phenotype (CIMP) often associate with epigenetic silencing of hMLH1 and an activating mutation in the BRAF gene. However, the current CIMP criteria are ambiguous, and often result in an underestimation of CIMP frequencies in CRCs. Since BRAF and KRAS belong to same signaling pathway, we hypothesized that not only mutations in BRAF, but mutant KRAS, may also associate with CIMP in CRC. Methods We determined the methylation status of a panel of 14 markers (7 canonical CIMP-related loci, and 7 new loci), MSI status, and BRAF/KRAS mutations in a cohort of 487 colorectal tissues that included both sporadic and Lynch syndrome patients. Results Methylation analysis of seven CIMP-related markers revealed that the mean number of methylated loci was highest in BRAF mutated CRCs [3.6], versus KRAS-mutated [1.2; P<0.0001] or BRAF/KRAS wild-type tumors [0.7; P<0.0001]. However, analyses with seven additional markers showed that the mean number of methylated loci in BRAF mutant tumors [4.4] was the same as in KRAS mutant CRCs [4.3; P=0.8610]. Although sporadic MSI-H tumors had the most average number of methylated markers [8.4], surprisingly Lynch syndrome CRCs also demonstrated frequent methylation [5.1]. Conclusions CIMP in CRC may result from activating mutations in either BRAF or KRAS, and the inclusion of additional methylation markers that correlate with mutant KRAS may help clarify CIMP in future studies. Additionally, aberrant DNA methylation is a common event not only in sporadic CRC, but also in Lynch syndrome CRCs. PMID:18435933

Longitudinal changes in seizure outcomes after resection of cerebral cavernous malformations in patients presenting with seizures: a long-term follow-up of 46 patients.

PubMed

Kim, Jiha; Kim, Chi Heon; Chung, Chun Kee

2014-08-01

Seizure is the most common presentation in patients with cerebral cavernous malformations (CCMs). Although many articles have documented seizure outcomes after resection of CCM, few have conducted long-term follow-ups; thus, the fluctuating seizure outcomes have been neglected. The purpose of this study is to describe long-term postoperative seizure outcomes in patients with CCM and to compare seizure outcomes between patients with sporadic seizures and those with chronic seizures. Forty-six patients with CCM presenting with seizures underwent surgery. The male-to-female ratio was 1:1, and the average age at initial seizure onset was 27.6 years. The mean preoperative seizure duration was 42.7 months. Patients were divided into two groups: a chronic group (N = 20) and a sporadic group (N = 26) according to seizure frequency and duration. The mean postoperative follow-up duration was 96.3 months, and the postoperative seizure outcomes were checked annually based upon Engel's classification. After the first year of follow-up, 80.8 % of the sporadic group and 75.0 % of the chronic group were evaluated as Engel class I. These rates increased to 100.0 % and 90.0 %, respectively, at the eighth year of follow-up. Overall, 29 (63.0 %) of the 46 patients experienced changes in seizure outcomes over the follow-up period. Despite their delayed improvements, the chronic group showed less favorable outcomes throughout follow-up (p = 0.025). Long-term follow-up is indispensable for accurately assessing postoperative seizure outcomes because these outcomes change continuously. We recommend earlier surgery to achieve seizure-free status in patients with CCM. However, even in the chronic group, surgery is recommended, considering the overall delayed improvement.

Luteal phase hyperprolactinemia.

PubMed

Falk, R J; Anderson, L

1994-01-01

To determine the incidence of both isolated and repetitive prolactin elevations in the luteal phase of otherwise normoprolactinemic women. To see if sporadic luteal-phase hyperprolactinemia is associated with progesterone deficiency, and to explore a possible physiological basis for sporadic hyperprolactinemia by TRH challenge. Hospital-based reproductive endocrinology/infertility service. Prospective measurement of luteal phase serum progesterone and prolactin in normoprolactinemic ovulatory women. TRH stimulation testing in volunteers with repetitive luteal phase hyperprolactinemia and normoprolactinemic controls. 133 sequentially selected infertile, ovulatory women with normal prolactin levels in the proliferative phase of the cycle. Measurement of serum progesterone and prolactin during the luteal phase, based on the day of the LH surge. TRH testing in the midluteal phase of the cycle in patients with two or more luteal phase prolactin elevations, and in five normoprolactinemic volunteers in both the preovulatory and midluteal phase. Of 133 subjects, 85 (64%) had no prolactin level exceeding 20 ng/mL in the luteal phase. Thirty-three (25%) had two or more elevated levels, and were considered to have repetitive luteal phase hyperprolactinemia (LPH). TRH testing in control subjects resulted in a greater prolactin response in the preovulatory phase. The group with LPH demonstrated an initial elevation of prolactin greater than that of the normoprolactinemic controls, but a subsequent drop to levels lower than both preovulatory and midluteal normoprolactinemic controls by 45 minutes. Sporadic luteal-phase hyperprolactinemia is a relatively common event (36% of 133 subjects in the present series). Of these 48 women, 33 (69%) had repetitive elevations, suggesting the elevation in these subjects to be more than a random event. The physiological validity of this observation is further demonstrated by an abnormal response to TRH stimulation, but the normal levels of luteal phase progesterone leave questions as to its pathological importance.

Familial cancer associated with a polymorphism in ARLTS1.

PubMed

Calin, George Adrian; Trapasso, Francesco; Shimizu, Masayoshi; Dumitru, Calin Dan; Yendamuri, Sai; Godwin, Andrew K; Ferracin, Manuela; Bernardi, Guido; Chatterjee, Devjani; Baldassarre, Gustavo; Rattan, Shashi; Alder, Hansjuerg; Mabuchi, Hideaki; Shiraishi, Takeshi; Hansen, Lise Lotte; Overgaard, Jens; Herlea, Vlad; Mauro, Francesca Romana; Dighiero, Guillaume; Movsas, Benjamin; Rassenti, Laura; Kipps, Thomas; Baffa, Raffaele; Fusco, Alfredo; Mori, Masaki; Russo, Giandomenico; Liu, Chang-Gong; Neuberg, Donna; Bullrich, Florencia; Negrini, Massimo; Croce, Carlo M

2005-04-21

The finding of hemizygous or homozygous deletions at band 14 on chromosome 13 in a variety of neoplasms suggests the presence of a tumor-suppressor locus telomeric to the RB1 gene. We studied samples from 216 patients with various types of sporadic tumors or idiopathic pancytopenia, peripheral-blood samples from 109 patients with familial cancer or multiple cancers, and control blood samples from 475 healthy people or patients with diseases other than cancer. We performed functional studies of cell lines lacking ARLTS1 expression with the use of both the full-length ARLTS1 gene and a truncated variant. We found a gene at 13q14, ARLTS1, a member of the ADP-ribosylation factor family, with properties of a tumor-suppressor gene. We analyzed 800 DNA samples from tumors and blood cells from patients with sporadic or familial cancer and controls and found that the frequency of a nonsense polymorphism, G446A (Trp149Stop), was similar in controls and patients with sporadic tumors but was significantly more common among patients with familial cancer than among those in the other two groups (P=0.02; odds ratio, 5.7; 95 percent confidence interval, 1.3 to 24.8). ARLTS1 was down-regulated by promoter methylation in 25 percent of the primary tumors we analyzed. Transfection of wild-type ARLTS1 into A549 lung-cancer cells suppressed tumor formation in immunodeficient mice and induced apoptosis, whereas transfection of truncated ARLTS1 had a limited effect on apoptosis and tumor suppression. Microarray analysis revealed that the wild-type and Trp149Stop-transfected clones had different expression profiles. A genetic variant of ARLTS1 predisposes patients to familial cancer. Copyright 2005 Massachusetts Medical Society.

SMARCB1 mutations in schwannomatosis and genotype correlations with rhabdoid tumors.

PubMed

Smith, Miriam J; Wallace, Andrew J; Bowers, Naomi L; Eaton, Helen; Evans, D Gareth R

2014-09-01

Mutations in the SMARCB1 gene are involved in several human tumor-predisposing syndromes. They were established as an underlying cause of the tumor suppressor syndrome schwannomatosis in 2008. There is a much higher rate of mutation detection in familial disease than in sporadic disease. We have performed extensive genetic testing on a cohort of familial and sporadic patients who fulfilled clinical diagnostic criteria for schwannomatosis. In our updated cohort, we identified novel mutations within the SMARCB1 gene as well as several recurrent mutations. Of the schwannomatosis screens reported to date, including those in our updated cohort, SMARCB1 mutations have been found in 45% of familial probands and 9% of sporadic patients. The exon 1 mutation, c.41C>A p.Pro14His (10% in our series), and the 3' untranslated region mutation, c.*82C>T (27%), are the most common changes reported in patients with schwannomatosis to date, indicating the presence of mutation hot spots at both 5' and 3' portions of the gene. Comparison with germline SMARCB1 mutations in patients with rhabdoid tumors showed that the schwannomatosis mutations were significantly more likely to occur at either end of the gene and be nontruncating mutations (P < 0.0001). SMARCB1 mutations are found in a significant proportion of schwannomatosis patients, and an even higher proportion of rhabdoid patients. Whereas SMARCB1 alone seems to account for rhabdoid disease, there is likely to be substantial heterogeneity in schwannomatosis even for familial disease. There is a clear genotype-phenotype correlation, with germline rhabdoid mutations being significantly more likely to be centrally placed, involve multiple exon deletions, and be truncating mutations. Copyright © 2014 Elsevier Inc. All rights reserved.

Bornholm disease in Upper Silesia

PubMed Central

Gibiński, Kornel; Makower, Henryk; Skurska, Zofia; Bara, Boleslaw; Sypułowa, Alicja

1960-01-01

Bornholm disease is generally attributed to infection with Coxsackie viruses of the B group, but in 1954-56 a number of sporadic cases occurred in Bytom, Upper Silesia, which were shown on virological examination to be caused by Coxsackie A4. In 1957, however, in the same area, an epidemic of Bornholm disease broke out for which Coxsackie B virus was clearly responsible. Re-examination of stocked material from the earlier sporadic cases to make sure that no B-type virus was present confirmed that these cases had been caused by A4. Clinically, the epidemic cases showed a preponderance of abdominal pains and comparatively infrequent chest pain, whereas the reverse was true of the sporadic cases; vomiting was also considerably less frequent in the sporadic than in the epidemic cases. PMID:13827939

Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime.

PubMed

McBrayer, MaryKate; Nixon, Ralph A

2013-12-01

Early-onset FAD (familial Alzheimer's disease) is caused by mutations of PS1 (presenilin 1), PS2 (presenilin 2) and APP (amyloid precursor protein). Beyond the effects of PS1 mutations on proteolytic functions of the γ-secretase complex, mutant or deficient PS1 disrupts lysosomal function and Ca2+ homoeostasis, both of which are considered strong pathogenic factors in FAD. Loss of PS1 function compromises assembly and proton-pumping activity of the vacuolar-ATPase on lysosomes, leading to defective lysosomal acidification and marked impairment of autophagy. Additional dysregulation of cellular Ca2+ by mutant PS1 in FAD has been ascribed to altered ion channels in the endoplasmic reticulum; however, rich stores of Ca2+ in lysosomes are also abnormally released in PS1-deficient cells secondary to the lysosomal acidification defect. The resultant rise in cytosolic Ca2+ activates Ca2+-dependent enzymes, contributing substantially to calpain overactivation that is a final common pathway leading to neurofibrillary degeneration in all forms of AD (Alzheimer's disease). In the present review, we discuss the close inter-relationships among deficits of lysosomal function, autophagy and Ca2+ homoeostasis as a pathogenic process in PS1-related FAD and their relevance to sporadic AD.

NOTCH3 variants in patients with subcortical vascular cognitive impairment: a comparison with typical CADASIL patients.

PubMed

Yoon, Cindy W; Kim, Young-Eun; Seo, Sang Won; Ki, Chang-Seok; Choi, Seong Hye; Kim, Jong-Won; Na, Duk L

2015-08-01

Although cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is thought to be a common form of hereditary subcortical vascular cognitive impairment (SVCI), there is little data on the frequency of NOTCH3 variants in SVCI patients. We prospectively screened for NOTCH3 variants in consecutive SVCI patients who underwent brain magnetic resonance imaging and amyloid positron emission tomography as well as sequence analysis for mutational hotspots in the NOTCH3 gene. Among 117 patients with SVCI, 16 patients had either known mutations or variants of unknown significance in the NOTCH3 gene. There were no differences in clinical and neuroimaging features between SVCI patients with and without NOTCH3 variants, only except for a higher number of deep microbleeds in SVCI patients with NOTCH3 variants. Our findings suggest that there is a phenotypic entity of NOTCH3 variant that is similar to that of sporadic SVCI but not of typical CADASIL. Notably, 2 SVCI patients with NOTCH3 mutations showed significant amyloid burden, which challenges the prevailing concept that CADASIL represents the genetic model of pure small vessel disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Forms of vitality play in infancy.

PubMed

Español, Silvia; Martínez, Mauricio; Bordoni, Mariana; Camarasa, Rosario; Carretero, Soledad

2014-12-01

In this paper we report a qualitative study based on the constant comparative method to initiate the systematic study of forms of vitality play. This is an unnoticed non-figurative play frame linked to early social play and temporal arts in which child and adult elaborate the dynamics of their own movements and sounds in a repetition-variation form. In the introduction we present the theoretical underpinnings and the sporadic observations we have done in previous studies. Then, by the iterative observations of the recorded material of a longitudinal case study on play during the third year of life, we generated the general category of forms of vitality play and four subcategories of display modes of forms of vitality play (improvised forms of vitality play, ritualized forms of vitality play, forms of vitality play combined with pretend play, and forms of vitality play combined with role playing) which are illustrated with descriptive narratives. We discuss the properties of the developed categories, the limits of the present study, and the need to continue systematizing the research on this playful activity.

Allele doses of apolipoprotein E type {epsilon}4 in sporadic late-onset Alzheimer`s disease

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

Lucotte, G.; Aouizerate, A.; Gerard, N.

1995-12-18

Apoliprotein E, type {epsilon}4 allele (ApoE-{epsilon}4) is associated with late-onset sporadic Alzheimer`s disease (AD). We have found that the cumulative probability of remaining unaffected over time decreases for each dose of ApoE-{epsilon}4 in sporadic, late-onset French AD. The effect of genotypes on age at onset of AD was analyzed using the product limit method, to compare unaffected groups during aging. 26 refs., 2 figs., 1 tab.

All-time high tularaemia incidence in Norway in 2011: report from the national surveillance.

PubMed

Larssen, K W; Bergh, K; Heier, B T; Vold, L; Afset, J E

2014-11-01

Tularaemia has mainly been a sporadic disease in Norway. In 2011, 180 persons (3.7 per 100,000 population) were diagnosed with tularaemia. This article describes the epidemiological and clinical features of tularaemia cases during a year with exceptionally high tularaemia incidence. Data from the national reference laboratory for tularaemia combined with epidemiological data from the Norwegian Surveillance System for Communicable Diseases (MSIS) were used. The incidence of tularaemia varied greatly between counties, but almost every county was involved. The majority (77.8 %) of the cases were diagnosed during the autumn and winter months. The geographic distribution also showed seasonal patterns. Overall, oropharyngeal tularaemia (41.1 %) was the most common clinical presentation, followed by glandular (14.4 %), typhoidal (14.4 %), respiratory (13.3 %) and ulceroglandular (12.8 %) tularaemia. From January to April, oropharyngeal tularaemia dominated, from May to September, ulceroglandular tularaemia was most common, whereas from October to December, there was an almost even distribution between several clinical forms of tularaemia. Eighty-five (47.2 %) of all tularaemia cases were admitted to, or seen as outpatients in, hospitals. An unexpectedly high number (3.9 %) of the patients had positive blood culture with Francisella tularensis. The clinical manifestations of tularaemia in Norway in 2011 were diverse, and changing throughout the year. Classification was sometimes difficult due to uncharacteristic symptoms and unknown mode of transmission. In rodent years, tularaemia is an important differential diagnosis to keep in mind at all times of the year for a variety of clinical symptoms.

Multiple endocrine neoplasia type 1

PubMed Central

Marini, Francesca; Falchetti, Alberto; Monte, Francesca Del; Sala, Silvia Carbonell; Gozzini, Alessia; Luzi, Ettore; Brandi, Maria Luisa

2006-01-01

Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary cancer syndrome presented mostly by tumours of the parathyroids, endocrine pancreas and anterior pituitary, and characterised by a very high penetrance and an equal sex distribution. It occurs in approximately one in 30,000 individuals. Two different forms, sporadic and familial, have been described. The sporadic form presents with two of the three principal MEN1-related endocrine tumours (parathyroid adenomas, entero-pancreatic tumours and pituitary tumours) within a single patient, while the familial form consists of a MEN1 case with at least one first degree relative showing one of the endocrine characterising tumours. Other endocrine and non-endocrine lesions, such as adrenal cortical tumours, carcinoids of the bronchi, gastrointestinal tract and thymus, lipomas, angiofibromas, collagenomas have been described. The responsible gene, MEN1, maps on chromosome 11q13 and encodes a 610 aminoacid nuclear protein, menin, with no sequence homology to other known human proteins. MEN1 syndrome is caused by inactivating mutations of the MEN1 tumour suppressor gene. This gene is probably involved in the regulation of several cell functions such as DNA replication and repair and transcriptional machinery. The combination of clinical and genetic investigations, together with the improving of molecular genetics knowledge of the syndrome, helps in the clinical management of patients. Treatment consists of surgery and/or drug therapy, often in association with radiotherapy or chemotherapy. Currently, DNA testing allows the early identification of germline mutations in asymptomatic gene carriers, to whom routine surveillance (regular biochemical and/or radiological screenings to detect the development of MEN1-associated tumours and lesions) is recommended. PMID:17014705

Evaluating the levels of interleukin-1 family cytokines in sporadic amyotrophic lateral sclerosis.

PubMed

Italiani, Paola; Carlesi, Cecilia; Giungato, Paola; Puxeddu, Ilaria; Borroni, Barbara; Bossù, Paola; Migliorini, Paola; Siciliano, Gabriele; Boraschi, Diana

2014-05-23

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease leading to the death of affected individuals within years. The involvement of inflammation in the pathogenesis of neurodegenerative diseases, including ALS, is increasingly recognized but still not well understood. The aim of this study is to evaluate the levels of inflammation-related IL-1 family cytokines (IL-1β, IL-18, IL-33, IL-37) and their endogenous inhibitors (IL-1Ra, sIL-1R2, IL-18BP, sIL-1R4) in patients with sporadic ALS (sALS), METHODS: Sera were collected from 144 patients (125 patients were characterized by disease form, duration, and disability, using the revised ALS functional rating scale (ALSFRS-R) and from 40 matched controls. Cerebrospinal fluid (CSF) was collected from 54 patients with sALS and 65 patients with other non-infectious non-oncogenic diseases as controls. Cytokines and inhibitors were measured by commercial ELISA. Among the IL-1 family cytokines tested total IL-18, its endogenous inhibitor IL-18BP, and the active form of the cytokine (free IL-18) were significantly higher in the sALS sera than in controls. No correlation between these soluble mediators and different clinical forms of sALS or the clinical setting of the disease was found. IL-18BP was the only mediator detectable in the CSF of patients. Among the IL-1 family cytokines, only IL-18 correlates with this disease and may therefore have a pathological role in sALS. The increase of total IL-18 suggests the activation of IL-18-cleaving inflammasome. Whether IL-18 upregulation in circulation of sALS patients is a consequence of inflammation or one of the causes of the pathology still needs to be addressed.

Evaluating the levels of interleukin-1 family cytokines in sporadic amyotrophic lateral sclerosis

PubMed Central

2014-01-01

Background Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease leading to the death of affected individuals within years. The involvement of inflammation in the pathogenesis of neurodegenerative diseases, including ALS, is increasingly recognized but still not well understood. The aim of this study is to evaluate the levels of inflammation-related IL-1 family cytokines (IL-1β, IL-18, IL-33, IL-37) and their endogenous inhibitors (IL-1Ra, sIL-1R2, IL-18BP, sIL-1R4) in patients with sporadic ALS (sALS), Methods Sera were collected from 144 patients (125 patients were characterized by disease form, duration, and disability, using the revised ALS functional rating scale (ALSFRS-R) and from 40 matched controls. Cerebrospinal fluid (CSF) was collected from 54 patients with sALS and 65 patients with other non-infectious non-oncogenic diseases as controls. Cytokines and inhibitors were measured by commercial ELISA. Results Among the IL-1 family cytokines tested total IL-18, its endogenous inhibitor IL-18BP, and the active form of the cytokine (free IL-18) were significantly higher in the sALS sera than in controls. No correlation between these soluble mediators and different clinical forms of sALS or the clinical setting of the disease was found. IL-18BP was the only mediator detectable in the CSF of patients. Conclusions Among the IL-1 family cytokines, only IL-18 correlates with this disease and may therefore have a pathological role in sALS. The increase of total IL-18 suggests the activation of IL-18-cleaving inflammasome. Whether IL-18 upregulation in circulation of sALS patients is a consequence of inflammation or one of the causes of the pathology still needs to be addressed. PMID:24884937

Exclusion of the GNAS locus in PHP-Ib patients with broad GNAS methylation changes: evidence for an autosomal recessive form of PHP-Ib?

PubMed

Fernández-Rebollo, Eduardo; Pérez de Nanclares, Guiomar; Lecumberri, Beatriz; Turan, Serap; Anda, Emma; Pérez-Nanclares, Gustavo; Feig, Denice; Nik-Zainal, Serena; Bastepe, Murat; Jüppner, Harald

2011-08-01

Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) carry maternally inherited microdeletions upstream of GNAS that are associated with loss of methylation restricted to GNAS exon A/B. Only few AD-PHP-Ib patients carry microdeletions within GNAS that are associated with loss of all maternal methylation imprints. These epigenetic changes are often indistinguishable from those observed in patients affected by an apparently sporadic PHP-Ib form that has not yet been defined genetically. We have now investigated six female patients affected by PHP-Ib (four unrelated and two sisters) with complete or almost complete loss of GNAS methylation, whose healthy children (11 in total) showed no epigenetic changes at this locus. Analysis of several microsatellite markers throughout the 20q13 region made it unlikely that PHP-Ib is caused in these patients by large deletions involving GNAS or by paternal uniparental isodisomy or heterodisomy of chromosome 20 (patUPD20). Microsatellite and single-nucleotide variation (SNV) data revealed that the two affected sisters share their maternally inherited GNAS alleles with unaffected relatives that lack evidence for abnormal GNAS methylation, thus excluding linkage to this locus. Consistent with these findings, healthy children of two unrelated sporadic PHP-Ib patients had inherited different maternal GNAS alleles, also arguing against linkage to this locus. Based on our data, it appears plausible that some forms of PHP-Ib are caused by homozygous or compound heterozygous mutation(s) in an unknown gene involved in establishing or maintaining GNAS methylation. Copyright © 2011 American Society for Bone and Mineral Research.

Histophilosis as a Natural Disease.

PubMed

O'Toole, D; Sondgeroth, K S

2016-01-01

Histophilus somni is responsible for sporadic disease worldwide in cattle and, to a lesser extent, in small ruminants, bighorn sheep (Ovis canadensis), and North American bison (Bison bison). The importance of H. somni diseases can be attributed to improved clinical and laboratory recognition, combined with the growth in intensive management practices for cattle. Although outbreaks of bovine histophilosis can occur year-round, in northern and southern hemispheres, it is most frequent in late fall and early winter. Weather, stress, dietary changes, and comingling of cattle are likely to be major triggers for outbreaks. The most frequent clinical expressions of histophilosis include undifferentiated fever, fibrinosuppurative pneumonia, encephalitis-leptomeningitis, necrotizing myocarditis, and diffuse pleuritis. Neurological disease occurs either as thrombotic meningoencephalitis (TME) or as suppurative meningitis with ventriculitis. Acute myocarditis is characteristically necrotizing and generally involves one or both papillary muscles in the left ventricular myocardium. Biofilm-like aggregates of bacteria occur in capillaries and veins in myocardium, in the central nervous system, and on endocardial surfaces. H. somni is a component of bovine respiratory disease (BRD) complex. In our experience, it is most commonly diagnosed in subacute-to-chronic polymicrobial pulmonary infections in combination with Mannheimia haemolytica, Trueperella pyogenes, Pasteurella multocida, or Mycoplasma bovis. Other, less common forms of H. somni disease present as polyarthritis/tenosynovitis, abortion with placentitis and fetal septicemia, epididymitis-orchitis, and ocular infections. It is likely that H. somni is under-recognized clinically and diagnostically. Most state and provincial laboratories in North America rely on bacterial isolation to confirm infection. The use of more sensitive detection methods on field cases of histophilosis will help resolve the pathogenesis of H. somni in natural outbreaks, and whether the disease is as common elsewhere as it is in Canada.

De novo and inherited private variants in MAP1B in periventricular nodular heterotopia.

PubMed

Heinzen, Erin L; O'Neill, Adam C; Zhu, Xiaolin; Allen, Andrew S; Bahlo, Melanie; Chelly, Jamel; Chen, Ming Hui; Dobyns, William B; Freytag, Saskia; Guerrini, Renzo; Leventer, Richard J; Poduri, Annapurna; Robertson, Stephen P; Walsh, Christopher A; Zhang, Mengqi

2018-05-01

Periventricular nodular heterotopia (PVNH) is a malformation of cortical development commonly associated with epilepsy. We exome sequenced 202 individuals with sporadic PVNH to identify novel genetic risk loci. We first performed a trio-based analysis and identified 219 de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27x10-7), suggesting a role for rare new alleles in genes yet to be associated with the condition. Using a gene-level collapsing analysis comparing cases and controls, we identified a genome-wide significant signal driven by four ultra-rare loss-of-function heterozygous variants in MAP1B, including one de novo variant. In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH. The PVNH was frontally predominant and associated with perisylvian polymicrogyria. These results implicate MAP1B in PVNH. More broadly, our findings suggest that detrimental mutations likely arising in immediately preceding generations with incomplete penetrance may also be responsible for some apparently sporadic diseases.

Facing and managing natural disasters in the Sporades islands, Greece

NASA Astrophysics Data System (ADS)

Karanikola, P.; Panagopoulos, T.; Tampakis, S.; Karantoni, M. I.; Tsantopoulos, G.

2014-04-01

The region of the Sporades islands located in central Greece is at the mercy of many natural phenomena, such as earthquakes due to the marine volcano Psathoura and the rift of Anatolia, forest fires, floods, landslides, storms, hail, snowfall and frost. The present work aims at studying the perceptions and attitudes of the residents regarding how they face and manage natural disasters. A positive public response during a hazard crisis depends not only upon the availability and good management of a civil defense plan but also on the knowledge and perception of the possible hazards by the local population. It is important for the stakeholders to know what the citizens expect so that the necessary structures can be developed in the phase of preparation and organization. The residents were asked their opinion about what they think should be done by the stakeholders after a catastrophic natural disaster, particularly about the immediate response of stakeholders and their involvement and responsibilities at different, subsequent intervals of time following the disaster. The residents were also asked about the most common disasters that happen in their region and about the preparation activities of the stakeholders.

Viral infections and breast cancer - A current perspective.

PubMed

Gannon, O M; Antonsson, A; Bennett, I C; Saunders, N A

2018-04-28

Sporadic human breast cancer is the most common cancer to afflict women. Since the discovery, decades ago, of the oncogenic mouse mammary tumour virus, there has been significant interest in the potential aetiologic role of infectious agents in sporadic human breast cancer. To address this, many studies have examined the presence of viruses (e.g. papillomaviruses, herpes viruses and retroviruses), endogenous retroviruses and more recently, microbes, as a means of implicating them in the aetiology of human breast cancer. Such studies have generated conflicting experimental and clinical reports of the role of infection in breast cancer. This review evaluates the current evidence for a productive oncogenic viral infection in human breast cancer, with a focus on the integration of sensitive and specific next generation sequencing technologies with pathogen discovery. Collectively, the majority of the recent literature using the more powerful next generation sequencing technologies fail to support an oncogenic viral infection being involved in disease causality in breast cancer. In balance, the weight of the current experimental evidence supports the conclusion that viral infection is unlikely to play a significant role in the aetiology of breast cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

Contribution of GLC3A locus to Primary Congenital Glaucoma in Pakistani population.

PubMed

Bashir, Rasheeda; Sanai, Mahrukh; Azeem, Adnan; Altaf, Imran; Saleem, Faiza; Naz, Sadaf

2014-01-01

To check the contribution of GLC3A locus to primary congenital glaucoma in the Pakistani population. We enrolled twenty-nine sporadic cases and three families with multiple individuals affected with recessive primary congenital glaucoma in the year 2013. It was a genetic linkage study accomplished jointly in Department of Biotechnology of Lahore College for Women University and School of Biological Sciences, University of the Punjab, Lahore. Samples from all affected individuals were checked for homozygosity for alleles of microsatellite markers spanning CYP1B1 at GLC3A locus. Genotyping was performed with fluorescently labeled primers by capillary electrophoresis. For familial cases, linkage was evaluated by checking the co-segregation of the phenotype with the genotypes. Two-point LOD score was calculated for each microsatellite marker with MLINK. Our study revealed that GLCA3 may contribute to glaucoma in 17% of the sporadic cases and patients in 2 of the 3 families. This data suggests that the GLC3A may make an important contribution to autosomal recessive primary congenital glaucoma in the Pakistani population. Genotyping and Sequencing of more families will be helpful to identify the common mutations in CYP1B1 in future.

and Sporadic Breast Cancer Patients in Rwanda

PubMed

Habyarimana, Thierry; Attaleb, Mohammed; Mugenzi, Pacifique; Mazarati, Jean Baptiste; Bakri, Youssef; El Mzibri, Mohammed

2018-02-26

Worldwide, breast cancer is the most frequent neoplasm and the second leading cause of cancer death among females. It dominates in both developed and developing countries and represents a major public health problem. The etiology is multifactorial and involves exogenous agents as well as endogenous factors. Although they account for only a small fraction of the breast cancer burden, mutations in the BRCA1 and BRCA2 genes are known to confer a high risk predisposition. Mutations in moderate/low-penetrance genes may also contribute to breast cancer risk. Previous studies have shown that mutations in the CHEK2 gene are involved in breast cancer susceptibility due to its impact on DNA repair processes and replication checkpoints. This study was conducted to evaluate the frequencies of three germline mutations in CHEK2 gene (c.1100delC, R145W and I157T) in breast cancers in Rwanda. Using direct DNA sequencing, we analyzed 41 breast cancer patients and 42 normal breast controls but could not detect any positives. CHEK2 mutations may be a rare event in Rwandan population and may only play a minor if an role in breast cancer predisposition among familial and sporadic cases. Creative Commons Attribution License

Video Meteor Fluxes

NASA Technical Reports Server (NTRS)

Campbell-Brown, M. D.; Braid, D.

2011-01-01

The flux of meteoroids, or number of meteoroids per unit area per unit time, is critical for calibrating models of meteoroid stream formation and for estimating the hazard to spacecraft from shower and sporadic meteors. Although observations of meteors in the millimetre to centimetre size range are common, flux measurements (particularly for sporadic meteors, which make up the majority of meteoroid flux) are less so. It is necessary to know the collecting area and collection time for a given set of observations, and to correct for observing biases and the sensitivity of the system. Previous measurements of sporadic fluxes are summarized in Figure 1; the values are given as a total number of meteoroids striking the earth in one year to a given limiting mass. The Gr n et al. (1985) flux model is included in the figure for reference. Fluxes for sporadic meteoroids impacting the Earth have been calculated for objects in the centimeter size range using Super-Schmidt observations (Hawkins & Upton, 1958); this study used about 300 meteors, and used only the physical area of overlap of the cameras at 90 km to calculate the flux, corrected for angular speed of meteors, since a large angular speed reduces the maximum brightness of the meteor on the film, and radiant elevation, which takes into account the geometric reduction in flux when the meteors are not perpendicular to the horizontal. They bring up corrections for both partial trails (which tends to increase the collecting area) and incomplete overlap at heights other than 90 km (which tends to decrease it) as effects that will affect the flux, but estimated that the two effects cancelled one another. Halliday et al. (1984) calculated the flux of meteorite-dropping fireballs with fragment masses greater than 50 g, over the physical area of sky accessible to the MORP fireball cameras, counting only observations in clear weather. In the micron size range, LDEF measurements of small craters on spacecraft have been used to estimate the flux (Love & Brownlee, 1993); here the physical area of the detector is well known, but the masses depend strongly on the unknown velocity distribution. In the same size range, Thomas & Netherway (1989) used the narrow-beam radar at Jindalee to calculate the flux of sporadics. In between these very large and very small sizes, a number of video and photographic observations were reduced by Ceplecha (2001). These fluxes were calculated (details are given in Ceplecha, 1988) taking the Halliday et al. (1984) MORP fireball fluxes, slightly corrected in mass, as a calibration, and adjusting the flux of small cameras to overlap with the number/mass relation from that work.

Imbalance of mitochondrial dynamics in Drosophila models of amyotrophic lateral sclerosis

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

Altanbyek, Volodya; Cha, Sun-Joo; Kang, Ga-Un

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease, characterized by progressive and selective loss of motor neurons in the brain and spinal cord. DNA/RNA-binding proteins such as TDP-43, FUS, and TAF15 have been linked with the sporadic and familial forms of ALS. However, the exact pathogenic mechanism of ALS is still unknown. Recently, we found that ALS-causing genes such as TDP-43, FUS, and TAF15 genetically interact with mitochondrial dynamics regulatory genes. In this study, we show that mitochondrial fission was highly enhanced in muscles and motor neurons of TDP-43, FUS, and TAF15-induced fly models of ALS. Furthermore, themore » mitochondrial fission defects were rescued by co-expression of mitochondrial dynamics regulatory genes such as Marf, Opa1, and the dominant negative mutant form of Drp1. Moreover, we found that the expression level of Marf was decreased in ALS-induced flies. These results indicate that the imbalance of mitochondrial dynamics caused by instability of Marf is linked to the pathogenesis of TDP-43, FUS, and TAF15-associated ALS. - Highlights: • Mitochondrial fission is highly enhanced in TDP-43, FUS, and TAF15-induced fly models of ALS. • Excessive mitochondrial fragmentation in fly models of ALS is restored by mitochondrial dynamics regulatory genes. • Level of Marf protein is decreased in TDP-43, FUS, and TAF15-mediated ALS. • Imbalance of mitochondrial dynamics caused by Marf instability is linked to the pathogenesis of ALS.« less

Epigenetics of breast cancer: modifying role of environmental and bioactive food compounds

PubMed Central

Romagnolo, Donato F.; Daniels, Kevin D.; Grunwald, Jonathan T.; Ramos, Stephan A.; Propper, Catherine R.; Selmin, Ornella I.

2017-01-01

Scope Reduced expression of tumor suppressor genes (TSG) increases the susceptibility to breast cancer. However, only a small percentage of breast tumors is related to family history and mutational inactivation of TSG. Epigenetics refers to non-mutational events that alter gene expression. Endocrine disruptors found in foods and drinking water may disrupt epigenetically hormonal regulation and increase breast cancer risk. This review centers on the working hypothesis that agonists of the aromatic hydrocarbon receptor (AHR); bisphenol A (BPA); and arsenic compounds, induce in TSG epigenetic signatures that mirror those often seen in sporadic breast tumors. Conversely, it is hypothesized that bioactive food components that target epigenetic mechanisms protect against sporadic breast cancer induced by these disruptors. Methods and results This review highlights 1) overlaps between epigenetic signatures placed in TSG by AHR-ligands, BPA, and arsenic with epigenetic alterations associated with sporadic breast tumorigenesis; and 2) potential opportunities for prevention of sporadic breast cancer with food components that target the epigenetic machinery. Conclusions Characterizing the overlap between epigenetic signatures elicited in TSG by endocrine disruptors with those observed in sporadic breast tumors may afford new strategies for breast cancer prevention with specific bioactive food components or diet. PMID:27144894

MAPT as a predisposing gene for sporadic amyotrophic lateral sclerosis in the Chinese Han population

PubMed Central

Fang, Pu; Xu, Wenyuan; Wu, Chengsi; Zhu, Min; Li, Xiaobing; Hong, Daojun

2013-01-01

A previous study of European Caucasian patients with sporadic amyotrophic lateral sclerosis demonstrated that a polymorphism in the microtubule-associated protein Tau (MAPT) gene was significantly associated with sporadic amyotrophic lateral sclerosis pathogenesis. Here, we tested this association in 107 sporadic amyotrophic lateral sclerosis patients and 100 healthy controls from the Chinese Han population. We screened the mutation-susceptible regions of MAPT – the 3' and 5' untranslated regions as well as introns 9, 10, 11, and 12 – by direct sequencing, and identified 33 genetic variations. Two of these, 105788 A > G in intron 9 and 123972 T > A in intron 11, were not present in the control group. The age of onset in patients with the 105788 A > G and/or the 123972 T > A variant was younger than that in patients without either genetic variation. Moreover, the pa-tients with a genetic variation were more prone to bulbar palsy and breathing difficulties than those with the wild-type genotype. This led to a shorter survival period in patients with a MAPT genetic variant. Our study suggests that the MAPT gene is a potential risk gene for sporadic amyotrophic lateral sclerosis in the Chinese Han population. PMID:25206632

Molecular characterization of wild-type measles viruses in Tamil Nadu, India, during 2005-2006: relationship of genotype D8 strains from Tamil Nadu to global strains.

PubMed

Duraisamy, Raja; Rota, Paul A; Palani, Gunasekaran; Elango, Varalakshmi; Sambasivam, Mohana; Lowe, Luis; Lopareva, Elena; Ramamurty, Nalini

2012-02-01

Molecular characterization of measles viruses is a valuable tool for measuring the effectiveness of measles control and elimination programmes. WHO recommends that virological surveillance be conducted during all phases of measles control to document circulation of indigenous strains and trace future importation. This report describes the genetic characterization of wild type measles viruses from Tamil Nadu, India isolated between January 2005 and January 2006. In the study, 304 suspected measles cases (292 from 56 outbreaks and 12 sporadic cases) were investigated. Blood samples were collected from suspected measles outbreaks and 11 suspected sporadic cases and tested for the presence of measles and rubella specific IgM. Based on serological results, 53 outbreaks were confirmed as measles, 2 as a combination of measles and rubella, and 1 negative for both. Eight sporadic cases were confirmed as measles and one as rubella. Throat swab and urine samples were collected for virus isolation and 28 isolates were obtained. Sequencing and analysis showed that 3 isolates belonged to genotype D4 and 25 to genotype D8. Comparison of the genotype D8 sequences from Tamil Nadu with previously reported genotype D8 sequences from India and abroad showed six distinct clusters with Tamil Nadu strains forming two clusters. This study has established baseline molecular data and is the first report that describes genetic diversity of circulating measles strains in Tamil Nadu, a state in India. D8 has multiple lineages and this has been linked with importation of measles into the USA and UK. Copyright © 2011 Wiley Periodicals, Inc.

Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer’s Disease

PubMed Central

Potter, Huntington; Granic, Antoneta; Caneus, Julbert

2017-01-01

Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and increased beta-amyloid (Aβ) peptide production underlie the universal development of Alzheimer’s disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy 21 and other forms of aneuploidy also arise among neurons and peripheral cells in both sporadic and familial AD and in mouse and cell models thereof, reinforcing the conclusion that AD and DS are two sides of the same coin. The demonstration that 90% of the neurodegeneration in AD can be attributed to the selective loss of aneuploid neurons generated over the course of the disease indicates that aneuploidy is an essential feature of the pathogenic pathway leading to the depletion of neuronal cell populations. Trisomy 21 mosaicism also occurs in neurons and other cells from patients with Niemann-Pick C1 disease and from patients with familial or sporadic frontotemporal lobar degeneration (FTLD), as well as in their corresponding mouse and cell models. Biochemical studies have shown that Aβ induces mitotic spindle defects, chromosome mis-segregation, and aneuploidy in cultured cells by inhibiting specific microtubule motors required for mitosis. These data indicate that neuronal trisomy 21 and other types of aneuploidy characterize and likely contribute to multiple neurodegenerative diseases and are a valid target for therapeutic intervention. For example, reducing extracellular calcium or treating cells with lithium chloride (LiCl) blocks the induction of trisomy 21 by Aβ. The latter finding is relevant in light of recent reports of a lowered risk of dementia in bipolar patients treated with LiCl and in the stabilization of cognition in AD patients treated with LiCl. PMID:26651340

Somatic Mosaicism Underlies X-linked Acrogigantism (XLAG) Syndrome in Sporadic Male Subjects

PubMed Central

Daly, Adrian F.; Yuan, Bo; Fina, Frederic; Caberg, Jean-Hubert; Trivellin, Giampaolo; Rostomyan, Liliya; de Herder, Wouter W.; Naves, Luciana A.; Metzger, Daniel; Cuny, Thomas; Rabl, Wolfgang; Shah, Nalini; Jaffrain-Rea, Marie-Lise; Zatelli, Maria Chiara; Faucz, Fabio R; Castermans, Emilie; Nanni-Metellus, Isabelle; Lodish, Maya; Muhammad, Ammar; Palmeira, Leonor; Potorac, Iulia; Mantovani, Giovanna; Neggers, Sebastian J.; Klein, Marc; Barlier, Anne; Liu, Pengfei; Ouafik, L'Houcine; Bours, Vincent; Lupski, James R.; Stratakis, Constantine A.; Beckers., Albert

2016-01-01

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101. We studied XLAG syndrome patients (N=18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome were identified with Xq26.3 duplications using high definition array comparative genome hybridization (HD-aCGH). We noted males with XLAG had a decreased log2 ratio compared with expected values, suggesting potential mosaicism, while females showed no such decrease. As compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1-53.8%. These characteristics were replicated using a novel, personalized breakpoint-junction specific quantification droplet digital PCR (ddPCR) technique. Using a separate ddPCR technique we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism and identified one female gigantism patient that had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes. PMID:26935837

Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects.

PubMed

Daly, Adrian F; Yuan, Bo; Fina, Frederic; Caberg, Jean-Hubert; Trivellin, Giampaolo; Rostomyan, Liliya; de Herder, Wouter W; Naves, Luciana A; Metzger, Daniel; Cuny, Thomas; Rabl, Wolfgang; Shah, Nalini; Jaffrain-Rea, Marie-Lise; Zatelli, Maria Chiara; Faucz, Fabio R; Castermans, Emilie; Nanni-Metellus, Isabelle; Lodish, Maya; Muhammad, Ammar; Palmeira, Leonor; Potorac, Iulia; Mantovani, Giovanna; Neggers, Sebastian J; Klein, Marc; Barlier, Anne; Liu, Pengfei; Ouafik, L'Houcine; Bours, Vincent; Lupski, James R; Stratakis, Constantine A; Beckers, Albert

2016-04-01

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101 We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes. © 2016 Society for Endocrinology.

Drivers: A Biologically Contextualized, Cross-Inferential View of the Epidemiology of Neurodegenerative Disorders

PubMed Central

de Pedro-Cuesta, Jesús; Martínez-Martín, Pablo; Rábano, Alberto; Alcalde-Cabero, Enrique; José García López, Fernando; Almazán-Isla, Javier; Ruiz-Tovar, María; Medrano, Maria-José; Avellanal, Fuencisla; Calero, Olga; Calero, Miguel

2016-01-01

Background: Sutherland et al. (2011) suggested that, instead of risk factors for single neurodegenerative disorders (NDDs), there was a need to identify specific “drivers”, i.e., risk factors with impact on specific deposits, such as amyloid-β, tau, or α-synuclein, acting across entities. Objectives and Methods: Redefining drivers as “neither protein/gene- nor entity-specific features identifiable in the clinical and general epidemiology of conformational NDDs (CNDDs) as potential footprints of templating/spread/transfer mechanisms”, we conducted an analysis of the epidemiology of ten CNDDs, searching for patterns. Results: We identified seven potential drivers, each of which was shared by at least two CNDDs: 1) an age-at-exposure-related susceptibility to Creutzfeldt-Jakob disease (CJD) and several late-life CNDDs; 2) a relationship between age at onset, survival, and incidence; 3) shared genetic risk factors for CJD and late-life CNNDs; 4) partly shared personal (diagnostic, educational, behavioral, and social risk factors) predating clinical onset of late-life CNDDs; 5) two environmental risk factors, namely, surgery for sporadic CJD and amyotrophic lateral sclerosis, and Bordetella pertussis infection for Parkinson’s disease; 6) reticulo-endothelial system stressors or general drivers (andropause or premenopausal estrogen deficiency, APOEɛ4, and vascular risk factors) for late-life CNDDs such as dementia/Alzheimer’s disease, type-2 diabetes mellitus, and some sporadic cardiac and vascular degenerative diseases; and 7) a high, invariant incidence ratio of sporadic to genetic forms of mid- and late-life CNDDs, and type-2 diabetes mellitus. Conclusion: There might be a systematic epidemiologic pattern induced by specific proteins (PrP, TDP-43, SOD1, α-synuclein, amyloid-β, tau, Langerhans islet peptide, and transthyretin) or established combinations of these. PMID:26923014

The Heterogeneity Between Lynch-Associated and Sporadic MMR Deficiency in Colorectal Cancers.

PubMed

Liu, Guo-Chen; Liu, Ran-Yi; Yan, Jun-Ping; An, Xin; Jiang, Wu; Ling, Yi-Hong; Chen, Jie-Wei; Bei, Jin-Xin; Zuo, Xiao-Yu; Cai, Mu-Yan; Liu, Ze-Xian; Zuo, Zhi-Xiang; Liu, Ji-Hong; Pan, Zhi-Zhong; Ding, Pei-Rong

2018-02-20

Previous studies demonstrated that prognosis of germline deficiency in mismatch repair protein (dMMR) was different from that of sporadic dMMR. The underlying mechanism has not been studied. From a prospectively maintained database, we collected dMMR colorectal cancer (CRC) patients identified by postoperative immunohistochemistry screening. According to genetic test, patients were grouped as Lynch-associated or sporadic dMMR. We compared the clinical-pathological features, prognosis, and immunoreactive differences between the two groups. By whole-exome sequencing and neoantigen detection pipeline, mutational frequencies and neoantigen burdens were also compared. All statistical tests were two-sided. Sixty-seven sporadic dMMR and 85 Lynch-associated CRC patients were included in the study. Sporadic dMMR patients were older (P < .001) and their tumors were poorly differentiated (P = .03). The survival was better in the Lynch-associated group (P = .001). After adjustment, the difference still remained statistically significant (hazard ratio = 0.29, 95% confidence interval = 0.09 to 0.95, P = .04). The scores of Crohn's-like reaction (CRO; P < .001), immunoreactions in the invasive margin (IM; P = .01), tumor stroma (TS; P = .009), and cancer nest (CN; P = .02) of the Lynch-associated group were statistically significantly higher. The numbers of CD3+, CD8+, Foxp3+ tumor-infiltrating lymphocytes (TILs) in IM; CD3+, CD4+ TILs in TS; and CD3+, CD4+, CD8+ TILs in CN were statistically significantly higher in Lynch-associated dMMR patients. Based on the 16 patients who under went whole-exome sequencing, there were also more somatic mutations and neoantigen burdens in the Lynch-associated group compared with the sporadic dMMR group (439/pt vs 68/pt, P = .006; 628/pt vs 97/pt, P = .009). There are heterogeneities in dMMR CRCs. Lynch-associated dMMR patients present with more somatic mutations and neoantigens compared with sporadic dMMR, which probably results in stronger immunoreactions and survival improvement.

Near Earth space sporadic radio emission busts occurring during sunrise

NASA Technical Reports Server (NTRS)

Dudnik, A. V.; Zaljubovsky, I. I.; Kartashev, V. M.; Lasarev, A. V.; Shmatko, E. S.

1985-01-01

During the period of low solar activity at sunrise the effect of sporadic high frequency near Earth space radio emission was experimentally discovered at middle latitudes. The possible mechanism of its origin is discussed.

Midlatitude sporadic-E layers

NASA Technical Reports Server (NTRS)

Miller, K. L.; Smith, L. G.

1976-01-01

The partially transparent echo from midlatitude sporadic E layers was recorded by ionosondes between the blanketing frequency and the maximum frequency. The theory that the midlatitude sporadic E layers are not uniform in the horizontal plane but contain localized regions of high electron density was evaluated using data obtained by incoherent scatter radar and found to provide a satisfactory explanation. The main features of midlatitude sporadic E layers are consistent with the convergence of metallic ions as described by the wind shear theory applied to gravity waves and tides. The interference of gravity waves with other gravity waves and tides can be recognized in the altitudes of occurrence and the structure of the layers. Small scale horizontal irregularities are attributed in some cases to critical level effects and in others to fluid instabilities. The convergence of a meteor trail can, under some circumstances, account for localized enhancement of the electron density in the layer.

Kuru prions and sporadic Creutzfeldt–Jakob disease prions have equivalent transmission properties in transgenic and wild-type mice

PubMed Central

Wadsworth, Jonathan D. F.; Joiner, Susan; Linehan, Jacqueline M.; Desbruslais, Melanie; Fox, Katie; Cooper, Sharon; Cronier, Sabrina; Asante, Emmanuel A.; Mead, Simon; Brandner, Sebastian; Hill, Andrew F.; Collinge, John

2008-01-01

Kuru provides our principal experience of an epidemic human prion disease and primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. Kuru was transmitted by the practice of consuming dead relatives as a mark of respect and mourning (transumption). To date, detailed information of the prion strain type propagated in kuru has been lacking. Here, we directly compare the transmission properties of kuru prions with sporadic, iatrogenic, and variant Creutzfeldt–Jakob disease (CJD) prions in Prnp-null transgenic mice expressing human prion protein and in wild-type mice. Molecular and neuropathological data from these transmissions show that kuru prions are distinct from variant CJD and have transmission properties equivalent to those of classical (sporadic) CJD prions. These findings are consistent with the hypothesis that kuru originated from chance consumption of an individual with sporadic CJD. PMID:18316717

Hydrotectonics; principles and relevance

USGS Publications Warehouse

Kopf, R.W.

1982-01-01

Hydrotectonics combines the principles of hydraulics and rock mechanics. The hypothesis assumes that: (1) no faults are truly planar, (2) opposing noncongruent wavy wallrock surfaces form chambers and bottlenecks along the fault, and (3) most thrusting occurs beneath the water table. These physical constraints permit the following dynamics. Shear displacement accompanying faulting must constantly change the volume of each chamber. Addition of ground water liquefies dry fault breccia to a heavy incompressible viscous muddy breccia I call fault slurry. When the volume of a chamber along a thrust fault decreases faster than its fault slurry can escape laterally, overpressurized slurry is hydraulically injected into the base of near-vertical fractures in the otherwise impervious overriding plate. Breccia pipes commonly form where such fissures intersect. Alternating decrease and increase in volume of the chamber subjects this injection slurry to reversible surges that not only raft and abrade huge clasts sporadically spalled from the walls of the conduit but also act as a forceful hydraulic ram which periodically widens the conduit and extends its top. If the pipe perforates a petroleum reservoir, leaking hydrocarbons float to its top. Sudden faulting may generate a powerful water hammer that can be amplified at some distal narrow ends of the anastomosing plumbing system, where the shock may produce shatter cones. If vented on the Earth's surface, the muddy breccia, now called extrusion slurry, forms a mud volcano. This hypothesis suggests that many highly disturbed features presently attributed to such catastrophic processes as subsurface explosions or meteorite impacts are due to the rheology of tectonic slurry in an intermittently reactivated pressure-relief tube rooted in a powerful reciprocating hydrotectonic pump activated by a long-lived deep-seated thrust fault.

Haplotype defined by the MLH1-93G/A polymorphism is associated with MLH1 promoter hypermethylation in sporadic colorectal cancers.

PubMed

Miyakura, Yasuyuki; Tahara, Makiko; Lefor, Alan T; Yasuda, Yoshikazu; Sugano, Kokichi

2014-11-24

Methylation of the MLH1 promoter region has been suggested to be a major mechanism of gene inactivation in sporadic microsatellite instability-positive (MSI-H) colorectal cancers (CRCs). Recently, single-nucleotide polymorphism (SNP) in the MLH1 promoter region (MLH1-93G/A; rs1800734) has been proposed to be associated with MLH1 promoter methylation, loss of MLH1 protein expression and MSI-H tumors. We examined the association of MLH1-93G/A and six other SNPs surrounding MLH1-93G/A with the methylation status in 210 consecutive sporadic CRCs in Japanese patients. Methylation of the MLH1 promoter region was evaluated by Na-bisulfite polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) analysis. The genotype frequencies of SNPs located in the 54-kb region surrounding the MLH1-93G/A SNP were examined by SSCP analysis. Methylation of the MLH1 promoter region was observed in 28.6% (60/210) of sporadic CRCs. The proportions of MLH1-93G/A genotypes A/A, A/G and G/G were 26% (n=54), 51% (n=108) and 23% (n=48), respectively, and they were significantly associated with the methylation status (p=0.01). There were no significant associations between genotype frequency of the six other SNPs and methylation status. The A-allele of MLH1-93G/A was more common in cases with methylation than the G-allele (p=0.0094), especially in females (p=0.0067). In logistic regression, the A/A genotype of the MLH1-93G/A SNP was shown to be the most significant risk factor for methylation of the MLH1 promoter region (odds ratio 2.82, p=0.003). Furthermore, a haplotype of the A-allele of rs2276807 located -47 kb upstream from the MLH1-93G/A SNP and the A-allele of MLH1-93G/A SNP was significantly associated with MLH1 promoter methylation. These results indicate that individuals, and particularly females, carrying the A-allele at the MLH1-93G/A SNP, especially in association with the A-allele of rs2276807, may harbor an increased risk of methylation of the MLH1 promoter region.

Cholesterol, endocrine and metabolic disturbances in sporadic anovulatory women with regular menstruation

PubMed Central

Mumford, Sunni L.; Schisterman, Enrique F.; Siega-Riz, Anna Maria; Gaskins, Audrey J.; Steiner, Anne Z.; Daniels, Julie L.; Olshan, Andrew F.; Hediger, Mary L.; Hovey, Kathleen; Wactawski-Wende, Jean; Trevisan, Maurizio; Bloom, Michael S.

2011-01-01

BACKGROUND Sporadic anovulation among regularly menstruating women is not well understood. It is hypothesized that cholesterol abnormalities may lead to hormone imbalances and incident anovulation. The objective was to evaluate the association between lipoprotein cholesterol levels and endocrine and metabolic disturbances and incident anovulation among ovulatory and anovulatory women reporting regular menstruation. METHODS The BioCycle Study was a prospective cohort study conducted at the University at Buffalo from September 2005 to 2007, which followed 259 self-reported regularly menstruating women aged 18–44 years, for one or two complete menstrual cycles. Sporadic anovulation was assessed across two menstrual cycles. RESULTS Mean total and low-density lipoprotein cholesterol and triglycerides levels across the menstrual cycles were higher during anovulatory cycles (mean difference: 4.6 (P = 0.01), 3.0 (P = 0.06) and 6.4 (P = 0.0002) mg/dl, respectively, adjusted for age and BMI). When multiple total cholesterol (TC) measures prior to expected ovulation were considered, we observed a slight increased risk of anovulation associated with increased levels of TC (odds ratio per 5 mg/dl increase, 1.07; 95% confidence interval, 0.99, 1.16). Sporadic anovulation was associated with an increased LH:FSH ratio (P = 0.002), current acne (P = 0.02) and decreased sex hormone-binding globulin levels (P = 0.005). CONCLUSIONS These results do not support a strong association between lipoprotein cholesterol levels and sporadic anovulation. However, sporadic anovulation among regularly menstruating women is associated with endocrine disturbances which are typically observed in women with polycystic ovary syndrome. PMID:21115506

Surgical cure rates of sporadic medullary thyroid cancer in the era of calcitonin screening.

PubMed

Machens, Andreas; Dralle, Henning

2016-09-01

Time trends of the extent of disease at first diagnosis and biochemical cure remain ill-defined for sporadic medullary thyroid cancer (MTC). This investigation aimed to delineate time trends and biochemical cure rates for sporadic MTC. This was an observational study of consecutive patients operated on for sporadic MTC between 1995 and 2015. Time trends of clinical and histopathological variables indicative of the extent of disease and biochemical cure were calculated for 600 patients with sporadic MTC, 322 of whom had initial neck surgery and 278 of whom had neck reoperation at a tertiary surgical center in Germany. From 1995-2000 to 2011-2015, significant declines (all P<0.001) were noted in the percentage of node-positive tumors (from 73 to 49%), mediastinal lymph node metastasis (from 21 to 6%) and distant metastasis (from 23 to 6%). These changes were paralleled by significant increases (all P<0.001) in mean patient age (from 49.1 to 57.3years) and the percentage of MTC ≤10mm (from 19 to 39%) and biochemical cure (from 28 to 62%). When only patients with primary tumors >10mm were considered, the decreasing percentage of mediastinal lymph node metastasis and distant metastasis, and rising mean patient age and biochemical cure rates remained statistically significant. Significant reductions in the extent of the disease and improved biochemical cure rates pointed toward increasing therapeutic control of sporadic MTC. The independent contribution of routine calcitonin screening to these time-dependent changes warrants more research. © 2016 European Society of Endocrinology.

Frequent NF2 gene transcript mutations in sporadic meningiomas and vestibular schwannomas

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

Deprez, R.H.L.; Groen, N.A.; Zwarthoff, E.C.

1994-06-01

The gene for the hereditary disorder neurofibromatosis type 2 (NF2), which predisposes for benign CNS tumors such as vestibular schwannomas and meningiomas, has been assigned to chromosome 22 and recently has been isolated. Mutations in the NF2 gene were found in both sporadic meningiomas and vestibular schwannomas. However, so far only 6 of the 16 exons of the gene have been analyzed. In order to extend the analysis of an involvement of the NF2 gene in the sporadic counterparts of these NF2-related tumors, the authors have used reverse transcriptase-PCR amplification followed by SSCP and DNA sequence analysis to screen formore » mutations in the coding region of the NF2 gene. Analysis of the NF2 gene transcript in 53 unrelated patients with meningiomas and vestibular schwannomas revealed mutations in 32% of the sporadic meningiomas (n = 44), in 50% of the sporadic vestibular schwannomas (n = 4), in 100% of the tumors found in NF2 patients (n = 2), and in one of three tumors from multiple-meningioma patients. Of the 18 tumors in which a mutation in the NF2 gene transcript was observed and the copy number of chromosome 22 could be established, 14 also showed loss of (parts of) chromosome 22. This suggests that in sporadic meningiomas and NF2-associated tumors the NF2 gene functions as a recessive tumor-suppressor gene. The mutations detected resulted mostly in frameshifts, predicting truncations starting within the N-terminal half of the putative protein. 23 refs., 2 figs. 3 tabs.« less

TGFbeta and miRNA regulation in familial and sporadic breast cancer

PubMed Central

Pinto, Rosamaria; Pilato, Brunella; Palumbo, Orazio; Carella, Massimo; Popescu, Ondina; Digennaro, Maria; Lacalamita, Rosanna; Tommasi, Stefania

2017-01-01

The term ‘BRCAness’ was introduced to identify sporadic malignant tumors sharing characteristics similar to those germline BRCA-related. Among all mechanisms attributable to BRCA1 expression silencing, a major role has been assigned to microRNAs. MicroRNAs role in familial and sporadic breast cancer has been explored but few data are available about microRNAs involvement in homologous recombination repair control in these breast cancer subgroups. Our aim was to seek microRNAs associated to pathways underlying DNA repair dysfunction in breast cancer according to a family history of the disease. Affymetrix GeneChip microRNA Arrays were used to perform microRNA expression analysis in familial and sporadic breast cancer. Pathway enrichment analysis and microRNA target prediction was carried out using DIANA miRPath v.3 web-based computational tool and miRWalk v.2 database. We analyzed an external gene expression dataset (E-GEOD-49481), including both familial and sporadic breast cancers. For microRNA validation, an independent set of 19 familial and 10 sporadic breast cancers was used. Microarray analysis identified a signature of 28 deregulated miRNAs. For our validation analyses by real time PCR, we focused on miR-92a-1*, miR-1184 and miR-943 because associated to TGF-β signalling pathway, ATM and BRCA1 genes expression. Our results highlighted alterations in miR-92a-1*, miR-1184 and miR-943 expression levels suggesting their involvement in repair of DNA double-strand breaks through TGF-beta pathway control. PMID:28881597

Disseminated Hemangiosarcoma in a Juvenile Rhesus Macaque (Macaca mulatta)

PubMed Central

Beck, Amanda P; Gray, Stanton B; Chaffee, Beth K

2016-01-01

Hemangiosarcoma is a malignant tumor of vascular endothelial origin that is sporadically reported in rhesus macaques. This report describes the clinicopathologic features of a 1-y-old rhesus macaque with spontaneous disseminated hemangiosarcoma that originally presented as a focal cutaneous mass. Histopathologic examination of multiple tumor foci revealed regions in which the neoplastic cells formed diffuse sheets, as well as the well-defined vascular channels typically associated with hemangiosarcoma. Multiple endothelial cell immunomarkers were used to confirm the diagnosis in this rhesus macaque. The tumor exhibited staining properties consistent with those seen in domestic animals and humans. In addition, to our knowledge, this animal represents the youngest case of any form of spontaneous hemangiosarcoma reported in the rhesus macaque to date. PMID:27298251

Disseminated Hemangiosarcoma in a Juvenile Rhesus Macaque (Macaca mulatta).

PubMed

Beck, Amanda P; Gray, Stanton B; Chaffee, Beth K

2016-01-01

Hemangiosarcoma is a malignant tumor of vascular endothelial origin that is sporadically reported in rhesus macaques. This report describes the clinicopathologic features of a 1-y-old rhesus macaque with spontaneous disseminated hemangiosarcoma that originally presented as a focal cutaneous mass. Histopathologic examination of multiple tumor foci revealed regions in which the neoplastic cells formed diffuse sheets, as well as the well-defined vascular channels typically associated with hemangiosarcoma. Multiple endothelial cell immunomarkers were used to confirm the diagnosis in this rhesus macaque. The tumor exhibited staining properties consistent with those seen in domestic animals and humans. In addition, to our knowledge, this animal represents the youngest case of any form of spontaneous hemangiosarcoma reported in the rhesus macaque to date.

Integrable cosmological potentials

NASA Astrophysics Data System (ADS)

Sokolov, V. V.; Sorin, A. S.

2017-09-01

The problem of classification of the Einstein-Friedman cosmological Hamiltonians H with a single scalar inflaton field φ, which possess an additional integral of motion polynomial in momenta on the shell of the Friedman constraint H=0, is considered. Necessary and sufficient conditions for the existence of the first-, second- and third-degree integrals are derived. These conditions have the form of ODEs for the cosmological potential V(φ). In the case of linear and quadratic integrals we find general solutions of the ODEs and construct the corresponding integrals explicitly. A new wide class of Hamiltonians that possess a cubic integral is derived. The corresponding potentials are represented in parametric form in terms of the associated Legendre functions. Six families of special elementary solutions are described, and sporadic superintegrable cases are discussed.

Inclusion body myositis.

PubMed

Dimachkie, Mazen M; Barohn, Richard J

2014-08-01

The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare disorders that share many similarities. In addition to sporadic inclusion body myositis (IBM), these include dermatomyositis, polymyositis, and autoimmune necrotizing myopathy. IBM is the most common IIM after age 50 years. Muscle histopathology shows endomysial inflammatory exudates surrounding and invading nonnecrotic muscle fibers often accompanied by rimmed vacuoles and protein deposits. It is likely that IBM is has a prominent degenerative component. This article reviews the evolution of knowledge in IBM, with emphasis on recent developments in the field, and discusses ongoing clinical trials. Copyright © 2014 Elsevier Inc. All rights reserved.

Avian botulism

USGS Publications Warehouse

Rocke, T.E.; Friend, M.

1999-01-01

Avian botulism is a paralytic, often fatal, disease of birds that results when they ingest toxin produced by the bacterium, Clostridium botulinum. Seven distinct types of toxin designated by the letters A to G have been identified (Table 38.1). Waterfowl die-offs due to botulism are usually caused by type C toxin; sporadic die-offs among fish-eating birds, such as common loons and gulls, have been caused by type E toxin. Type A botulinum toxin has also caused disease in birds, most frequently in domestic chickens. Types B, D, F, and G are not known to cause avian botulism in North America.

Acquired Methemoglobinemia - A Sporadic Holi Disaster.

PubMed

Masavkar, Sanjeevani Satish; Mauskar, Anupama; Patwardhan, Gaurav; Bhat, Vasudeva; Manglani, Mamta V

2017-06-15

To study clinical profile and outcome in patients with methemoglobinemia following exposure to toxic colors during Holi festival. This retrospective study included 112 children (5 to 12 years) admitted with methemoglobinemia after playing Holi. Clinical and treatment details were reviewed. The common symptoms were giddiness, vomiting and headache. Treatment included thorough skin wash, intravenous fluid and methylene blue in 111 children. Age 7-9 and > 11 years, vomiting, giddiness, cyanosis, PaO2 < 80 mm Hg and oxygen saturation < 95% were associated with higher need for methylene blue. All children had a good outcome. Timely diagnosis and management of acquired methemoglobinemia can save lives.

Sporadic Kindler syndrome with a novel mutation.

PubMed

Almeida, Hiram Larangeira de; Heckler, Gláucia Thomas; Fong, Kenneth; Lai-Cheong, Joey; McGrath, John

2013-01-01

We report the case of a 28-year-old woman with Kindler syndrome, a rare form of epidermolysis bullosa. Clinically, since childhood, she had widespread pigmentary changes in her skin as well as photosensitivity and fragility of the skin and mucous membranes. The mucosal involvement led to an erosive stomatitis as well as esophageal, anal and vaginal stenoses, requiring surgical intervention. The diagnosis of Kindler syndrome was confirmed by DNA sequencing with compound heterozygosity for a nonsense/frameshift combination of mutations (p.Arg110X; p.Ala289GlyfsX7) in the FERMT1 gene.

Implications of Martian Phyllosilicate Formation Conditions to the Early Climate on Mars

NASA Astrophysics Data System (ADS)

Bishop, J. L.; Baker, L.; Fairén, A. G.; Michalski, J. R.; Gago-Duport, L.; Velbel, M. A.; Gross, C.; Rampe, E. B.

2017-12-01

We propose that short-term warmer and wetter environments, occurring sporadically in a generally cold early Mars, enabled formation of phyllosilicate-rich outcrops on the surface of Mars without requiring long-term warm and wet conditions. We are investigating phyllosilicate formation mechanisms including CO2 and H2O budgets to provide constraints on the early martian climate. We have evaluated the nature and stratigraphy of phyllosilicate-bearing surface units on Mars based on i) phyllosilicate-forming environments on Earth, ii) phyllosilicate reactions in the lab, and iii) modeling experiments involving phyllosilicates and short-range ordered (SRO) materials. The type of phyllosilicates that form on Mars depends on temperature, water/rock ratio, acidity, salinity and available ions. Mg-rich trioctahedral smectite mixtures are more consistent with subsurface formation environments (crustal, hydrothermal or alkaline lakes) up to 400 °C and are not associated with martian surface environments. In contrast, clay profiles dominated by dioctahedral Al/Fe-smectites are typically formed in subaqueous or subaerial surface environments. We propose models describing formation of smectite-rich outcrops and laterally extensive vertical profiles of Fe/Mg-smectites, sulfates, and Al-rich clay assemblages formed in surface environments. Further, the presence of abundant SRO materials without phyllosilicates could mark the end of the last warm and wet episode on Mars supporting smectite formation. Climate Implications for Early Mars: Clay formation reactions proceed extremely slowly at cool temperatures. The thick smectite outcrops observed on Mars through remote sensing would require standing water on Mars for hundreds of millions of years if they formed in waters 10-15 °C. However, warmer temperatures could have enabled faster production of these smectite-rich beds. Sporadic warming episodes to 30-40 °C could have enabled formation of these smectites over only tens or hundreds of thousands of years instead. Our analyses of the phyllosilicate record on Mars point to a scenario of brief warm and wet conditions that accounts for formation of substantial smectite clays in many locations, geologic features resulting from liquid water across the planet, and a generally cold and dry climate.

The characteristics of hydrogeochemical zonation of groundwater in inland plain

NASA Astrophysics Data System (ADS)

Xin-yu, HOU; Li-ting, XING; Yi, YANG; Wen-jing, ZHANG; Guang-yao, CHI

2018-05-01

To find out the hydrochemical zoning of groundwaterin the inland plain, taking Jiyang plain as an example, based on mathematical statistics, ion ratio coefficient and isotopic analysis method, the characteristics of water chemical composition and its zoning at different depths of 500m were studied. The result shows: ①The groundwater flow system in the study area can be divided into local flow system, intermediate flow system and regional flow system. ②The hydrochemical type of shallow groundwater is complex. The hydrochemical types of middle confined water are mainly ClṡSO4—MgṡNa and SO4ṡCl—NaṡMg. The deep confined water is mainly HCO3. ③The TDS of shallow groundwater increases gradually along the direction of groundwater flow. ④The shallow saltwater and freshwater are alternately distributed in horizontal direction, and saltwater is distributed sporadically in the interfluve area with sporadic punctate or banded, and hydrochemical types are mainly ClṡSO4—NaṡMgṡCa. Conclusion: Groundwater in the study area is affected by complicated hydrogeochemical action, mainly in the form of filtration, cation exchange and evaporation. The inland plain area is characterized by hydrogeochemical zonation in horizontal and vertical.

Biomonitoring chromium III or VI soluble pollution by moss chlorophyll fluorescence.

PubMed

Chen, Yang-Er; Mao, Hao-Tian; Ma, Jie; Wu, Nan; Zhang, Chao-Ming; Su, Yan-Qiu; Zhang, Zhong-Wei; Yuan, Ming; Zhang, Huai-Yu; Zeng, Xian-Yin; Yuan, Shu

2018-03-01

We systematically compared the impacts of four Cr salts (chromic chloride, chromic nitrate, potassium chromate and potassium bichromate) on physiological parameters and chlorophyll fluorescence in indigenous moss Taxiphyllum taxirameum. Among the four Cr salts, K 2 Cr 2 O 7 treatment resulted in the most significant decrease in photosynthetic efficiency and antioxidant enzymes, increase in reactive oxygen species (ROS), and obvious cell death. Different form the higher plants, although hexavalent Cr(VI) salt treatments resulted in higher accumulation levels of Cr and were more toxic than Cr(III) salts, Cr(III) also induced significant changes in moss physiological parameters and chlorophyll fluorescence. Our results showed that Cr(III) and Cr(VI) could be monitored distinguishably according to the non-photochemical quenching (NPQ) fluorescence of sporadic purple and sporadic lavender images respectively. Then, the valence states and concentrations of Cr contaminations could be evaluated according to the image of maximum efficiency of PSII photochemistry (Fv/Fm) and the quantum yield of PSII electron transport (ΦPSII). Therefore, this study provides new ideas of moss's sensibility to Cr(III) and a new method to monitor Chromium contaminations rapidly and non-invasively in water. Copyright © 2017 Elsevier Ltd. All rights reserved.

Single chain variable fragment antibodies block aggregation and toxicity induced by familial ALS-linked mutant forms of SOD1.

PubMed

Ghadge, Ghanashyam D; Pavlovic, John D; Koduvayur, Sujatha P; Kay, Brian K; Roos, Raymond P

2013-08-01

Approximately 10% of amyotrophic lateral sclerosis (ALS) cases are familial (known as FALS) with an autosomal dominant inheritance pattern, and ~25% of FALS cases are caused by mutations in Cu/Zn superoxide dismutase (SOD1). There is convincing evidence that mutant SOD1 (mtSOD1) kills motor neurons (MNs) because of a gain-of-function toxicity, most likely related to aggregation of mtSOD1. A number of recent reports have suggested that antibodies can be used to treat mtSOD1-induced FALS. To follow up on the use of antibodies as potential therapeutics, we generated single chain fragments of variable region antibodies (scFvs) against SOD1, and then expressed them as 'intrabodies' within a motor neuron cell line. In the present study, we describe isolation of human scFvs that interfere with mtSOD1 in vitro aggregation and toxicity. These scFvs may have therapeutic potential in sporadic ALS, as well as FALS, given that sporadic ALS may also involve abnormalities in the SOD1 protein or activity. Copyright © 2013 Elsevier Inc. All rights reserved.

SOVRaD - A Digest of Recent Soviet R and D Articles. Volume 2, Number 2, 1976

DTIC Science & Technology

1976-02-01

34""" ■■■I"" ^"■’ " """"^ R-F Heating of Sporadic E-Layer (abstract) Effects of ionospheric heating by powerful r-f emission on the sporadic E-layers are...situation is just the reverse. Here heating by powerful r-f fields decreases its electron density and increases its thickness. At mean latitudes...T - 2, it decreases by 18% [Ignat’yev, Yu. A. Effect on the sporadic E-layer of ionospheric heating by powerful r-f emission. IVUZ

Mutational Analysis of Mismatch Repair Genes, hMLH1 and hMSH2, in Sporadic Endometrial Carcinomas with Microsatellite Instability

PubMed Central

Kobayashi, Kanji; Matsushima, Mieko; Koi, Sumiko; Saito, Hiroko; Sagae, Satoru; Kudo, Ryuichi

1996-01-01

Microsatellite instability, monitored by replication error (RER), bas been observed in both sporadic and hereditary types of endometrial carcinoma. In the hereditary tumors, this instability is considered to be caused by a germline defect in the DNA mismatch‐repair system. We previously reported that nearly one‐quarter of sporadic endometrial carcinomas examined revealed an RER‐positive phenotype at multiple microsatellite loci. To investigate the role of genetic alterations of DNA mismatch‐repair genes in sporadic endometrial carcinomas, we screened 18 RER(+) endometrial carcinomas for mutations of hMLH1 and hMSH2. Although we found no germline mutations, we detected two somatic mutations of hMLH1 in a single endometrial cancer; these two mutations had occurred on different alleles, suggesting that two separate mutational events had affected both copies of hMLH1 in this particular tumor. These data implied that mutations of hMLH1 or hMSH2 play limited roles in the development of sporadic endometrial carcinomas, and that the tumors with genetic instability might have alterations of other mismatch‐repair genes, such as hPMS1 and hPMS2, or of unknown genes related to the mismatch‐repair system. PMID:8609062

Delineation of an endemic tick paralysis zone in southeastern Australia.

PubMed

Whitfield, Zoe; Kelman, Mark; Ward, Michael P

2017-11-30

Tick paralysis has a major impact on pet dog and cat populations in southeastern Australia. It results from envenomation by Ixodes holocyclus and Ixodes cornuatus ticks, the role of Ixodes cornuatus in the epidemiology of this disease in Australia being unclear. The aim of this study was to describe the geographical distribution of tick paralysis cases in southeastern Australia using data from a national disease surveillance system and to compare characteristics of "endemic" cases with those reported outside this endemic zone ("sporadic" cases). Data were collated and a proportional symbol map of all cases by postcode was created. A 15-case isopleth was developed based on descriptive spatial statistics (directional ellipses) and then kernel smoothing to distinguish endemic from sporadic cases. During the study period (January 2010-December 2015) 12,421 cases were reported, and 10,839 of these reported by clinics located in 434 postcodes were included in the study. Endemic cases were predominantly reported from postcodes in coastal southeastern Australia, from southern Queensland to eastern Victoria. Of those cases meeting selection criteria, within the endemic zone 10,767 cases were reported from 351 (88%) postcodes and outside this zone 72 cases were reported from 48 (12%) postcodes. Of these latter 48 postcodes, 18 were in Victoria (26 cases), 16 in New South Wales (28 cases), 7 in Tasmania (9 cases), 5 in South Australia (7 cases) and 2 in Queensland (2 cases). Seasonal distribution in reporting was found: 62% of endemic and 52% of sporadic cases were reported in spring. The number of both endemic and sporadic cases reported peaked in October and November, but importantly a secondary peak in reporting of sporadic cases in April was found. In non-endemic areas, summer was the lowest risk season whilst in endemic areas, autumn was the lowest risk season. Two clusters of sporadic cases were identified, one in South Australia (P=0.022) during the period 22 May to 2 June 2012 and another in New South Wales (P=0.059) during the period 9 October to 29 November 2012. Endemic and sporadic cases did not differ with respect to neuter status (P=0.188), sex (P=0.205), case outcome (P=0.367) or method of diagnosis (P=0.413). However, sporadic cases were 4.2-times more likely to be dogs than cats (P<0.001). The endemic tick paralysis zone described is consistent with previous anecdotal reports. Sporadic cases reported outside this zone might be due to a history of pet travel to endemic areas, small foci of I. holocyclus outside of the endemic zone, or in the case of southern areas, tick paralysis caused by I. cornuatus. Copyright © 2017 Elsevier B.V. All rights reserved.

Cleaning and Disinfection of Biofilms Composed of Listeria monocytogenes and Background Microbiota from Meat Processing Surfaces

PubMed Central

Møretrø, Trond; Heir, Even; Briandet, Romain; Langsrud, Solveig

2017-01-01

ABSTRACT Surfaces of food processing premises are exposed to regular cleaning and disinfection (C&D) regimes, using biocides that are highly effective against bacteria growing as planktonic cells. However, bacteria growing in surface-associated communities (biofilms) are typically more tolerant toward C&D than their individual free-cell counterparts, and survival of pathogens such as Listeria monocytogenes may be affected by interspecies interactions within biofilms. In this study, Pseudomonas and Acinetobacter were the most frequently isolated genera surviving on conveyor belts subjected to C&D in meat processing plants. In the laboratory, Pseudomonas, Acinetobacter, and L. monocytogenes dominated the community, both in suspensions and in biofilms formed on conveyor belts, when cultures were inoculated with eleven-genus cocktails of representative bacterial strains from the identified background flora. When biofilms were exposed to daily C&D cycles mimicking treatments used in food industry, the levels of Acinetobacter and Pseudomonas mandelii diminished, and biofilms were instead dominated by Pseudomonas putida (65 to 76%), Pseudomonas fluorescens (11 to 15%) and L. monocytogenes (3 to 11%). The dominance of certain species after daily C&D correlated with high planktonic growth rates at 12°C and tolerance to C&D. In single-species biofilms, L. monocytogenes developed higher tolerance to C&D over time, for both the peracetic acid and quaternary ammonium disinfectants, indicating that a broad-spectrum mechanism was involved. Survival after C&D appeared to be a common property of L. monocytogenes strains, as persistent and sporadic subtypes showed equal survival rates in complex biofilms. Biofilms established preferentially in surface irregularities of conveyor belts, potentially constituting harborage sites for persistent contamination. IMPORTANCE In the food industry, efficient production hygiene is a key measure to avoid the accumulation of spoilage bacteria and eliminate pathogens. However, the persistence of bacteria is an enduring problem in food processing environments. This study demonstrated that environmental bacteria can survive foam cleaning and disinfection (C&D) at concentrations used in the industrial environment. The phenomenon was replicated in laboratory experiments. Important characteristics of persisting bacteria were a high growth rate at low temperature, a tolerance to the cleaning agent, and the ability to form biofilms. This study also supports other recent research suggesting that strain-to-strain variation cannot explain why certain subtypes of Listeria monocytogenes persist in food processing environments while others are found only sporadically. The present investigation highlights the failure of regular C&D and a need for research on improved agents that efficiently detach the biofilm matrix. PMID:28667108

Cleaning and disinfection of biofilms composed of Listeria monocytogenes and background microbiota from meat processing surfaces.

PubMed

Fagerlund, Annette; Møretrø, Trond; Heir, Even; Briandet, Romain; Langsrud, Solveig

2017-06-30

Surfaces of food processing premises are exposed to regular cleaning and disinfection (C&D) regimes, using biocides that are highly effective against bacteria growing as planktonic cells. However, bacteria growing in surface associated communities (biofilms) are typically more tolerant towards C&D than their individual free cells counterparts, and survival of pathogens such as Listeria monocytogenes may be affected by interspecies interactions within biofilms. In this study, Pseudomonas and Acinetobacter were the most frequently isolated genera surviving on conveyor belts subjected to C&D in meat processing plants. In the laboratory, Pseudomonas , Acinetobacter and L. monocytogenes dominated the community both in suspensions and in biofilms formed on conveyor belts, when cultures were inoculated with eleven-genera cocktails of representative bacterial strains from the identified background flora. When biofilms were exposed to daily C&D cycles, mimicking treatments used in food industry, the levels of Acinetobacter and Pseudomonas mandelii diminished, and biofilms were instead dominated by Pseudomonas putida (65-76%), Pseudomonas fluorescens (11-15%) and L. monocytogenes (3-11%). The dominance of certain species after daily C&D correlated with high planktonic growth rates at 12°C and tolerance to C&D. In single-species biofilms, L. monocytogenes developed higher tolerance to C&D over time, both for the peracetic acid and quaternary ammonium disinfectant, indicating that a broad-spectrum mechanism was involved. Survival after C&D appeared to be a common property of L. monocytogenes strains, as both persistent and sporadic subtypes showed equal survival in complex biofilms. Biofilms established preferentially in surface irregularities of conveyor belts, potentially constituting harborage sites for persistent contamination. IMPORTANCE In food industry, efficient production hygiene is a key measure to avoid accumulation of spoilage bacteria and eliminate pathogens. Persistence of bacteria is however a withstanding problem in food processing environments. This study demonstrated that environmental bacteria can survive foam cleaning and disinfection (C&D) at user concentrations in the industrial environment. The phenomenon was replicated in laboratory experiments. Important characteristics of persisting bacteria were high growth rate at low temperature, tolerance to the cleaning agent and ability to form biofilm. This study also supports other recent research suggesting that strain-to-strain variation cannot explain why certain subtypes of Listeria monocytogenes persist in food processing environments while others are found only sporadically. The present investigation highlights the failure of regular C&D and a need for research on improved agents efficiently detaching the biofilm matrix. Copyright © 2017 American Society for Microbiology.

Mitochondrial dysfunctions in Parkinson's disease.

PubMed

Gautier, C A; Corti, O; Brice, A

2014-05-01

Neurodegenerative disorders (ND) include a wide spectrum of diseases characterized by progressive neuronal dysfunctions or degeneration. With an estimated cost of 135 billion € in 2010 in the European Union (Olesen et al., 2012), they put an enormous economic as well as social burden on modern societies. Hence, they have been the subject of a huge amount of research for the last fifty years. For many of these diseases, our understanding of their profound causes is incomplete and this hinders the discovery of efficient therapies. ND form a highly heterogeneous group of diseases affecting various neuronal subpopulations reflecting different origins and different pathological mechanisms. However, some common themes in the physiopathology of these disorders are emerging. There is growing evidence that mitochondrial dysfunctions play a pivotal role at some point in the course of neurodegeneration. In some cases (e.g. Alzheimer's disease, amyotrophic lateral sclerosis), impairment of mitochondrial functions probably occurs late in the course of the disease. In a subset of ND, current evidence suggests that mitochondrial dysfunctions play a more seminal role in neuronal demise. Parkinson's disease (PD) presents one of the strongest cases based in part on post-mortem studies that have shown mitochondrial impairment (e.g. reduced complex I activity) and oxidative damage in idiopathic PD brains. The occurrence of PD is largely sporadic, but clinical syndromes resembling sporadic PD have been linked to specific environmental insults or to mutations in at least 5 distinct genes (α-synuclein, parkin, DJ-1, PINK1 and LRRK2). It is postulated that the elucidation of the pathogenic mechanisms underlying the selective dopaminergic degeneration in familial and environmental Parkinsonism should provide important clues to the pathogenic mechanisms responsible for idiopathic PD. Hence, numerous cellular and animal models of the disease have been generated that mimic these environmental or genetic insults. The study of these models has yielded valuable information regarding the pathogenic mechanisms underlying dopaminergic degeneration in PD, many of which point towards an involvement of mitochondrial dysfunction. In this short review we will analyze critically the experimental evidence for the mitochondrial origin of PD and evaluate its relevance for our general understanding of the disease. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Diagnosing Sporadic Creutzfeldt-Jakob Disease: Accuracy of CSF 14-3-3 Protein Test of the Spinal Fluid

MedlinePlus

... JAKOB DISEASE: ACCURACY OF THE 14-3-3 PROTEIN TEST OF THE SPINAL FLUID This information sheet ... help you understand how the 14-3-3 protein test helps in diagnosing sporadic Creutzfeldt-Jakob disease ( ...

A Case Based Approach to Clinical Genetics of Thoracic Aortic Aneurysm/Dissection

PubMed Central

Giusti, Betti; Nistri, Stefano; Sticchi, Elena; De Cario, Rosina; Abbate, Rosanna; Gensini, Gian Franco; Pepe, Guglielmina

2016-01-01

Thoracic aortic aneurysm/dissection (TAAD) is a potential lethal condition with a rising incidence. This condition may occur sporadically; nevertheless, it displays familial clustering in >20% of the cases. Family history confers a six- to twentyfold increased risk of TAAD and has to be considered in the identification and evaluation of patients needing an adequate clinical follow-up. Familial TAAD recognizes a number of potential etiologies with a significant genetic heterogeneity, in either syndromic or nonsyndromic forms of the manifestation. The clinical impact and the management of patients with TAAD differ according to the syndromic and nonsyndromic forms of the manifestation. The clinical management of TAAD patients varies, depending on the different forms. Starting from the description of patient history, in this paper, we summarized the state of the art concerning assessment of clinical/genetic profile and therapeutic management of TAAD patients. PMID:27314043

Chemically diverse, sporadic volcanism at seamounts offshore southern and Baja California

USGS Publications Warehouse

Davis, A.S.; Gunn, S.H.; Bohrson, W.A.; Gray, L.-B.; Hein, J.R.

1995-01-01

Compositions of lavas from seven small to medium-sized seamounts offshore southern and Baja California, include low-K2O tholeiitic, transitional, and mildly to moderately alkalic basalt and their differentiates. The seamounts with these MORB-like lavas are inferred to have formed at or near the spreading center. Based on 40Ar/39Ar laser fusion techniques, MORB-like lava from one of the northern edifices is as old as the underlying oceanic crust (>20 Ma), indicating that it originated at a spreading center. Other seamount lava ages are much younger than the oceanic crust on which they reside. Some of the seamounts with transitional and alkalic lavas may have formed as part of a short, age-progressive chain formed by a short-lived mantle plume. Many others, may have resulted from upwelling mantle diapirs in response to localized extension. -from Authors

Equine nasal and paranasal sinus tumours. Part 1: review of the literature and tumour classification.

PubMed

Head, K W; Dixon, P M

1999-05-01

The normal gross and histological anatomy of the equine nasal and paranasal sinuses are reviewed and the relationships between the local anatomy, the occurrence of different tumour types, and of tumour spread are examined. The histological classification of the more common equine sinonasal tumours and tumour-like lesions are discussed. Clinical and pathological descriptions of 50 more recently recorded such tumours are separately tabulated. The literature shows that equine sinonasal tumours, both endemic and sporadic, are relatively uncommon in horses, with non-neoplastic growths such as maxillary (sinus) cysts, progressive ethmoid haematoma and inflammatory nasal polyps more commonly recorded. The equine paranasal sinuses, especially the caudal maxillary sinus, are the most common sites for sinonasal tumours and, in contrast to other species, primary nasal tumours are uncommon. The more common tumour types include squamous cell carcinoma that, in some cases, arise in the oral cavity and spread to the maxillary sinuses; adenocarcinomas; bone and dental tumours; fibrosarcomas and haemangiosarcomas. Except for some benign bone tumours, there are few records of successful treatment of equine sinonasal tumours.

Sporadic adult onset primary torsion dystonia is a genetic disorder by the temporal discrimination test.

PubMed

Kimmich, Okka; Bradley, David; Whelan, Robert; Mulrooney, Nicola; Reilly, Richard B; Hutchinson, Siobhan; O'Riordan, Sean; Hutchinson, Michael

2011-09-01

Adult-onset primary torsion dystonia is an autosomal dominant disorder with markedly reduced penetrance; patients with sporadic adult-onset primary torsion dystonia are much more prevalent than familial. The temporal discrimination threshold is the shortest time interval at which two stimuli are detected to be asynchronous and has been shown to be abnormal in adult-onset primary torsion dystonia. The aim was to determine the frequency of abnormal temporal discrimination thresholds in patients with sporadic adult-onset primary torsion dystonia and their first-degree relatives. We hypothesized that abnormal temporal discrimination thresholds in first relatives would be compatible with an autosomal dominant endophenotype. Temporal discrimination thresholds were examined in 61 control subjects (39 subjects <50 years of age; 22 subjects >50 years of age), 32 patients with sporadic adult-onset primary torsion dystonia (cervical dystonia n = 30, spasmodic dysphonia n = 1 and Meige's syndrome n = 1) and 73 unaffected first-degree relatives (36 siblings, 36 offspring and one parent) using visual and tactile stimuli. Z-scores were calculated for all subjects; a Z > 2.5 was considered abnormal. Abnormal temporal discrimination thresholds were found in 1/61 (2%) control subjects, 27/32 (84%) patients with adult-onset primary torsion dystonia and 32/73 (44%) unaffected relatives [siblings (20/36; 56%), offspring (11/36; 31%) and one parent]. When two or more relatives were tested in any one family, 22 of 24 families had at least one first-degree relative with an abnormal temporal discrimination threshold. The frequency of abnormal temporal discrimination thresholds in first-degree relatives of patients with sporadic adult-onset primary torsion dystonia is compatible with an autosomal dominant disorder and supports the hypothesis that apparently sporadic adult-onset primary torsion dystonia is genetic in origin.

Frequency of Undiagnosed Cystic Lung Disease in Patients With Sporadic Renal Angiomyolipomas

PubMed Central

Hartman, Thomas E.; Torres, Vicente E.; Decker, Paul A.

2012-01-01

Objective: The aim of this study was to assess the frequency of undiagnosed cystic lung lesions suggestive of pulmonary lymphangioleiomyomatosis (LAM) in patients who received a diagnosis of sporadic renal angiomyolipomas (AMLs). Methods: We conducted a retrospective review of CT scans of the chest or abdomen for cystic lung lesions on 176 adult patients who received a diagnosis of sporadic renal AML during a 10-year period, 1997 to 2006, and comparison with chest CT scans of 176 control subjects without renal AML but matched for age, sex, and smoking history. Patients presenting with suspected or known pulmonary LAM and those with underlying tuberous sclerosis were excluded. Results: Sporadic renal AML was diagnosed in 176 patients with a median age of 58 years (range, 20-91 years), the majority of whom were women (81.8%). Renal tumor was an incidental finding on imaging studies for most patients (90.3%). Nineteen patients (10.8%) had one or more cystic lung lesions and included nine patients (5.1%) with four or more cysts, all of whom were women. In comparison, eight control subjects (4.6%) had one to three cystic lung lesions and none of them exhibited four or more cysts. None of the patients with renal AML and cystic lung lesions, including six women with 10 or more cysts, had undergone an evaluation of their cystic lung disease. Conclusions: We conclude that a significant portion of women with sporadic renal AMLs exhibit cystic lung lesions suggestive of pulmonary LAM but may remain undiagnosed. Coexistence of pulmonary LAM should be considered in women incidentally found to have sporadic renal AMLs. PMID:21737494

Magnetic eta index and the ability to forecast sporadic E layer appearance

NASA Astrophysics Data System (ADS)

Dziak-Jankowska, Beata; Stanislawska, Iwona; Pozoga, Mariusz; Tomasik, Lukasz; Ernst, Tomasz

2012-07-01

We analysed the correlation of the changes of the magnetic vertical component with the ionospheric deviations from monthly median of the E layer characteristics. Promising results indicate that the eta parameter can be used to predict sporadic E layer during magnetically quiet days. Our previous work concern the data from only one year - 2004. During the descending phase of solar cycle in 2004 there was not numerous amount of quiet days. We extend our research to other years starting from 1996 and focusing on 2007 - 2009, years of the prolonged solar minimum. The analysis shows that under magnetically quiet circumstances the magnetic index eta indicates large magnetic disturbance, especially in vertical component when other magnetic indices inform about quiet magnetic conditions. The results indicate that the increase of the magnetic eta index (the ratio of the variations of vertical component of the external magnetic field to the horizontal component) is associated with the emergence of sporadic E layer or with increase of foEs critical frequency of sporadic E layer. The appearance of sporadic E layer followed 1-2 h after growth of magnetic index eta. An important conclusion is that the analysis of the hourly ionospheric data does not give 100% correlation between the increase of eta and the emergence of Es layer, however, studies of dense measurement data show that the correlation is almost 100%. An advantage of the eta index is the fact that after eliminating the effect of currents induced within the Earth, eta index bring independent and meaningful information on the system of current in the ionosphere. Hence, the eta index could be an important element of the ionosphere monitoring and can be used to predict such local phenomenon like the appearance of the sporadic E layer.

Two cases of multiple ossifying fibromas in the jaws

PubMed Central

2014-01-01

Background The clinicopathologic characteristics of multiple ossifying fibroma (OF) are unclear due to the condition’s rarity, making diagnosis challenging. Sporadic multiple OFs must be distinguished from hyperparathyroidism-jaw tumour syndrome (HPT-JT) related OF and other fibro-osseous lesions. Methods Multiple OF cases were identified from ossifying fibroma cases. Clinical data including age, sex, anatomic site, radiographic features, clinical impression, treatment and available follow-up data as well as serum calcium, phosphorus, and parathyroid hormone (PTH) were recorded. GNAS and HRPT2 genetic mutations were examined in the two present cases. Case reports of sporadic multiple ossifying fibroma and HPT-JT-related OF were also reviewed. Results The two present cases were confirmed as sporadic multiple OF, with no genetic GNAS and HRPT2 mutations found. The incidence of sporadic multiple ossifying fibroma was 2.0% (2/102). The total 18 sporadic multiform OF cases were characterized as followed: 13 (72.2%) female; 5 (27.8%) male; mean age 28.6 years; 2/16 (11.1%) cases only in the mandible; 4/18 (22.2%) cases only in the maxilla; and 12/18 (66.7%) cases in both the maxilla and mandible. Radiographically, the lesions were radiolucent in 5/18 (27.8%) cases and mixed density in 13/18 (72.2%) cases. Along with 24 cases of HPT-JT related OF were reviewed, sixteen (66.7%) patients were diagnosed with a single lesion, and 8 patients (33.3%) were diagnosed with multiple jaw lesions. Conclusions Sporadic multiple OFs are very rare, but must be distinguished from HPT-JT related OF. We strongly recommend that patients diagnosed with multiple ossifying fibromas receive serum PTH testing and mutation screening of HRPT2. Virtual slides http://www.diagnosticpathology.diagnomx.eu/vs/1194507146115753 PMID:24678936

Increased Frequency of KRAS Mutations in African Americans Compared with Caucasians in Sporadic Colorectal Cancer.

PubMed

Staudacher, Jonas J; Yazici, Cemal; Bul, Vadim; Zeidan, Joseph; Khalid, Ahmer; Xia, Yinglin; Krett, Nancy; Jung, Barbara

2017-10-19

The basis for over-representation of colorectal cancer (CRC) in African-American (AA) populations compared with Caucasians are multifactorial and complex. Understanding the mechanisms for this racial disparity is critical for delivery of better care. Several studies have investigated sporadic CRC for differences in somatic mutations between AAs and Caucasians, but owing to small study sizes and conflicting results to date, no definitive conclusions have been reached. Here, we present the first systematic literature review and meta-analysis investigating the mutational differences in sporadic CRC between AAs and Caucasians focused on frequent driver mutations (APC,TP53, KRAS,PI3CA, FBXW7,SMAD4, and BRAF). Publication inclusion criteria comprised sporadic CRC, human subjects, English language, information on ethnicity (AA, Caucasian, or both), total subject number >20, and information on mutation frequencies. We identified 6,234 publications. Meta-analysis for APC, TP54, FBXW7, or SMAD4 was not possible owing to paucity of data. KRAS mutations were statistically less frequent in non-Hispanic Whites when compared with AAs (odds ratio, 0.640; 95% confidence interval (CI): 0.5342-0.7666; P=0.0001), while the mutational differences observed in BRAF and PI3CA did not reach statistical significance. Here, we report the mutational patterns for KRAS, BRAF, and PI3CA in sporadic CRC of AAs and Caucasians in a systematic meta-analysis of previously published data. We identified an increase in KRAS mutations in sporadic CRC in AAs, which may contribute to worse prognosis and increased mortality of CRC in AAs. Future studies investigating health-care disparities in CRC in AAs should control for KRAS mutational frequency.

Familial Kleine-Levin Syndrome: A Specific Entity?

PubMed

Nguyen, Quang Tuan Remy; Groos, Elisabeth; Leclair-Visonneau, Laurène; Monaca-Charley, Christelle; Rico, Tom; Farber, Neal; Mignot, Emmanuel; Arnulf, Isabelle

2016-08-01

Kleine-Levin syndrome (KLS) is a rare, mostly sporadic disorder, characterized by intermittent episodes of hypersomnia plus cognitive and behavior disorders. Although its cause is unknown, multiplex families have been described. We contrasted the clinical and biological features of familial versus sporadic KLS. Two samples of patients with KLS from the United States and France (n = 260) were studied using clinical interviews and human leukocyte antigen (HLA) genotyping. A multiplex family contained two or more first- or second-degree affected relatives (familial cases). Twenty-one patients from 10 multiplex families (siblings: n = 12, including two pairs of monozygotic twins; parent-child: n = 4; cousins: n = 2; uncle-nephews: n = 3) and 239 patients with sporadic KLS were identified, yielding to 4% multiplex families and 8% familial cases. The simplex and multiplex families did not differ for autoimmune, neurological, and psychiatric disorders. Age, sex ratio, ethnicity, HLA typing, karyotyping, disease course, frequency, and duration of KLS episodes did not differ between groups. Episodes were less frequent in familial versus sporadic KLS (2.3 ± 1.8/y versus 3.8 ± 3.7/y, P = 0.004). Menses triggered more frequently KLS onset in the nine girls with familial KLS (relative risk, RR = 4.12, P = 0.03), but not subsequent episodes. Familial cases had less disinhibited speech (RR = 3.44, P = 0.049), less combined hypophagia/hyperphagia (RR = 4.38, P = 0.006), more abrupt termination of episodes (RR = 1.45, P = 0.04) and less postepisode insomnia (RR = 2.16, P = 0.008). There was similar HLA DQB1 distribution in familial versus sporadic cases and no abnormal karyotypes. Familial KLS is mostly present in the same generation, and is clinically similar to but slightly less severe than sporadic KLS. © 2016 Associated Professional Sleep Societies, LLC.

CpG methylation of APC promoter 1A in sporadic and familial breast cancer patients.

PubMed

Debouki-Joudi, Saoussen; Trifa, Fatma; Khabir, Abdelmajid; Sellami-Boudawara, Tahia; Frikha, Mounir; Daoud, Jamel; Mokdad-Gargouri, Raja

2017-01-01

Tumour suppressor gene (TSG) silencing through promoter hypermethylation plays an important role in cancer initiation. The aim of this study was to assess the extent of methylation of APC gene promoter in 91 sporadic and 44 familial cases of Tunisian patients with breast cancer (BC) in. The frequency of APC promoter methylation is somewhat similar for sporadic and familial breast cancer cases, (52.1%, and 54.5% respectively). For sporadic breast cancer patients, there was a significant correlation of APC promoter hypermethylation with TNM stage (p = 0.024) and 3-year survival (p = 0.025). Regarding the hormonal status (HR), we found significant association between negativity to PR and unmethylated APC (p= 0.005) while ER and Her2/neu are not correlated. Moreover, unmethylated APC promoter is more frequent in tumours expressing at least one out the 3 proteins compared to triple negative cases (p= 0.053). On the other hand, aberrant methylation of APC was associated with tumour size (p = 0.036), lymph node (p = 0.028), distant metastasis (p = 0.031), and 3-year survival (p = 0.046) in the group of patients with familial breast cancer. Moreover, patients with sporadic breast cancer displaying the unmethylated profile have a significant prolonged overall survival compared to those with the methylated pattern of APC promoter (p log rank = 0.008). Epigenetic change at the CpG islands in the APC promoter was associated with the silence of its transcript and the loss of protein expression suggesting that this event is the main mechanism regulating the APC expression in breast cancer. In conclusion, our data showed that the loss of APC through aberrant methylation is associated with the aggressive behavior of both sporadic and familial breast cancer in Tunisian patients.

UCHL1 S18Y variant is a risk factor for Parkinson’s disease in Japan

PubMed Central

2012-01-01

Background A recent meta-analysis on the UCHL1 S18Y variant and Parkinson’s disease (PD) showed a significant inverse association between the Y allele and PD; the individual studies included in that meta-analysis, however, have produced conflicting results. We examined the relationship between UCHL1 S18Y single nucleotide polymorphism (SNP) and sporadic PD in Japan. Methods Included were 229 cases within 6 years of onset of PD, defined according to the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 357 inpatients and outpatients without neurodegenerative disease. Adjustment was made for sex, age, region of residence, smoking, and caffeine intake. Results Compared with subjects with the CC or CA genotype of UCHL1 S18Y SNP, those with the AA genotype had a significantly increased risk of sporadic PD: the adjusted OR was 1.57 (95 % CI: 1.06 − 2.31). Compared with subjects with the CC or CA genotype of UCHL1 S18Y and the CC or CT genotype of SNCA SNP rs356220, those with the AA genotype of UCHL1 S18Y and the TT genotype of SNP rs356220 had a significantly increased risk of sporadic PD; the interaction, however, was not significant. Our previous investigation found significant inverse relationships between smoking and caffeine intake and PD in this population. There were no significant interactions between UCHL1 S18Y and smoking or caffeine intake affecting sporadic PD. Conclusions This study reveals that the UCHL1 S18Y variant is a risk factor for sporadic PD. We could not find evidence for interactions affecting sporadic PD between UCHL1 S18Y and SNCA SNP rs356220, smoking, or caffeine intake. PMID:22839974

Amyotrophic lateral sclerosis

PubMed Central

Wijesekera, Lokesh C; Leigh, P Nigel

2009-01-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence (average 1.89 per 100,000/year) and prevalence (average 5.2 per100,000) are relatively uniform in Western countries, although foci of higher frequency occur in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male prevalence (M:F ratio~1.5:1). Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, where the symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solid or liquids, and limbs symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1–2 years. Paralysis is progressive and leads to death due to respiratory failure within 2–3 years for bulbar onset cases and 3–5 years for limb onset ALS cases. Most ALS cases are sporadic but 5–10% of cases are familial, and of these 20% have a mutation of the SOD1 gene and about 2–5% have mutations of the TARDBP (TDP-43) gene. Two percent of apparently sporadic patients have SOD1 mutations, and TARDBP mutations also occur in sporadic cases. The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. cervical spondylotic myelopathies, multifocal motor neuropathy, Kennedy's disease) by appropriate investigations. The pathological hallmarks comprise loss of motor neurones with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurones and TDP-43 immunoreactive inclusions in degenerating lower motor neurones. Signs of upper motor neurone and lower motor neurone damage not explained by any other disease process are suggestive of ALS. The management of ALS is supportive, palliative, and multidisciplinary. Non-invasive ventilation prolongs survival and improves quality of life. Riluzole is the only drug that has been shown to extend survival. PMID:19192301

Comparative characteristics of primary hyperparathyroidism in pediatric and young adult patients.

PubMed

Nicholson, Kristina J; McCoy, Kelly L; Witchel, Selma F; Stang, Michael T; Carty, Sally E; Yip, Linwah

2016-10-01

Primary hyperparathyroidism is rare in pediatric patients. Our study aim was to compare primary hyperparathyroidism in pediatric (<19 years) and young adult (19-29 years) patients. A prospectively collected database from a single, high-volume institution was queried for all patients age <30 years who had initial parathyroidectomy for primary hyperparathyroidism yielding 126/4,546 (2.7%) primary hyperparathyroidism patients representing 39 pediatric and 87 young adult patients. Presenting symptoms, operative data, and postoperative course were compared for patients age 0-19 years and 20-29 years. Sporadic primary hyperparathyroidism was present in 81.7% and occurred less often in pediatric patients than young adult patients (74.4% vs 86.2%, P = .12). Among patients with hereditary primary hyperparathyroidism, multiple endocrine neoplasia type 1 was the most common type. Multiglandular disease was common in both pediatric (30.7%) and young adult (21.8%) patients. Following parathyroidectomy, 3 (2.3%) patients had permanent hypoparathyroidism and none had permanent recurrent laryngeal nerve paralysis. Biochemical cure at 6 months was equally likely in pediatric and young adult patients (97.1% vs 93.6%, P = .44) with comparable follow-up (78.4 months vs 69.1 months, P = .66) and rates of recurrent disease (5.9% vs 10.3%, P = .46). Recurrence was due to multiple endocrine neoplasia 1-related primary hyperparathyroidism in all cases. Although primary hyperparathyroidism is sporadic in most patients <19 years, they are more likely to have multiple endocrine neoplasia type 1-associated primary hyperparathyroidism (23%). Parathyroidectomy for primary hyperparathyroidism can be performed safely in pediatric patients with a high rate of cure. Follow-up for patients with hereditary disease is necessary. Copyright © 2016 Elsevier Inc. All rights reserved.

Comparison of the clinical and cognitive features of genetically positive ALS patients from the largest tertiary center in Serbia.

PubMed

Marjanović, Ivan V; Selak-Djokić, Biljana; Perić, Stojan; Janković, Milena; Arsenijević, Vladimir; Basta, Ivana; Lavrnić, Dragana; Stefanova, Elka; Stević, Zorica

2017-06-01

Discovering novel mutations in C9orf72, FUS, ANG, and TDP-43 genes in ALS patients arises necessities for better clinical characterizations of these subjects. The aim is to determine clinical and cognitive profile of genetically positive Serbian ALS patients. 241 ALS patients were included in the study (17 familiar and 224 apparently sporadic). The following genes were analyzed: SOD1, C9orf72, ANG, FUS, and TDP-43. An extensive battery of classic neuropsychological tests was used in 27 ALS patients (22 SOD1 positive and 5 SOD1 negative) and 82 healthy controls (HCs). Overall 37 (15.4%) of 241 ALS patients carried mutations in tested genes-among 17 familiar ALS patients 16 (94.1%) were positive and among 224 apparently sporadic 21 (9.4%) had causative mutation. Mutations in SOD1 gene were the most common, representing 27 (73.0%) of all genetically positive ALS patients. The main clinical characteristics of SOD1 positive patients were: spinal onset in lower extremities, common sphincter and sensitive disturbances, and dysexecutive syndrome. Within SOD1 positive patients, we noticed somewhat earlier onset in patients with A145G, sensory and sphincter disturbances were dominant in patients with L144F, while D90A patients had significant sensory involvement. SOD1 negative group consisted of ten (27.0%) patients (six C9orf72, two ANG, one TDP-43, and one patient baring triple FUS, C9orf72 expansion, and ANG variants). Bulbar involvement and more extensive neuropsychological impairment (including executive, visuospatial, and memory difficulties) were the main features of SOD1 negative cohort. Our results suggest that meaningful clinical suspicion of certain ALS genotype might be made based on thorough clinical evaluation of patients.

[A historical survey of diphtheria in the Western World, China and Japan. Part II: Modern age (from sixteenth century to the beginning of nineteenth century)].

PubMed

Nakamura, A

1996-09-01

In Europe and North America, literatures on diphtheritic diseases was increasing from sixteenth to eighteenth century. In New England of North America, diphtheria and scarlet fever occurred epidemically in mingled form from 1735 to the succeeding year. Thereafter, many physicians in Europe and America treated patients of diphtheria and had different opinions about the nature of croup and diphtheria. In China, its own clinical medicine progressed extraordinarily during the modern age. Laryngeal specialists appeared and wrote special monographs about the pharynx and larynx. A physician wrote about "epidemic exanthem", which the author presumes to be a complicated form of scarlet fever and diphtheria. In Japan, diphtheria occurred in sporadic form usually, and in epidemic form occasionally. Japanese physicians studied medicine from China since the ancient age, and also introduced European medicine through the Netherlands in the eighteenth century. So Japanese physicians learned knowledge about throat diseases and diphtheria from Chinese and European medicine.

Thunderstorm related variations of the ionospheric sporadic E layer over Rome

NASA Astrophysics Data System (ADS)

Barta, Veronika; Scotto, Carlo; Pietrella, Marco

2013-04-01

Meteorological events in the lower atmosphere can affect the ionosphere by electromagnetic and mechanical processes. One type of the latter ones is the internal atmospheric gravity waves (AGWs) which can often be generated by thunderstorms. According to a Superposed Epoch Analyses (SEA) using the time series of the critical frequency (foEs) and virtual height (h'Es) of the sporadic E layer and WWLLN (World Wide Lightning Location Network) lightning data over the ionospheric station of Rome (41.9° 12.5°) there is a statistically significant decrease in the foEs of the sporadic E layer after the time of the lightnings. This may indicate a sudden decrease in the electron density of the sporadic E layer associated to lightnings. In order to understand the physical explanation for this phenomenon further studies are performed as follows: a SEA for different seasons and for daytime - nightime lightnings separately. Direction of arrival of thunderstorms is also taken into account.

Pontine hyperperfusion in sporadic hyperekplexia

PubMed Central

Vetrugno, Roberto; Mascalchi, Mario; Vella, Alessandra; Nave, Riccardo Della; Guerrini, Laura; Vattimo, Angelo; del Giudice, Emanuele Miraglia; Plazzi, Giuseppe; D'Angelo, Roberto; Greco, Giovanni; Montagna, Pasquale

2007-01-01

Objective To explore with neuroimaging techniques the anatomical and functional correlates of sporadic hyperekplexia. Methods Two elderly women with sporadic hyperekplexia underwent neurophysiological assessment, MRI of the brain and proton magnetic resonance spectroscopy (1H‐MRS) of the brainstem and frontal lobes. Regional cerebral blood flow was investigated with single photon emission tomography (SPECT) during evoked startles and at rest. Results Both patients showed excessively large and non‐habituating startle responses. In both patients, MRI showed impingement of the brainstem by the vertebrobasilar artery, lack of frontal or brainstem abnormalities on 1H‐MRS and hyperperfusion in the dorsal pons and cingulate cortex, and superior frontal gyrus at SPECT during evoked startles. Conclusions In our patients with hyperekplexia, the vertebrobasilar arteries were found to impinge on the brainstem. Neurophysiological findings and neurofunctional imaging of evoked startles indicated a pontine origin of the movement disorder modulated by activation in cortical, especially frontal, areas. The neurofunctional correlates of evoked startles in human sporadic hyperekplexia are similar to those observed for the startle circuit in animals. PMID:17702784

Pontine hyperperfusion in sporadic hyperekplexia.

PubMed

Vetrugno, Roberto; Mascalchi, Mario; Vella, Alessandra; Della Nave, Riccardo; Guerrini, Laura; Vattimo, Angelo; del Giudice, Emanuele Miraglia; Plazzi, Giuseppe; D'Angelo, Roberto; Greco, Giovanni; Montagna, Pasquale

2007-09-01

To explore with neuroimaging techniques the anatomical and functional correlates of sporadic hyperekplexia. Two elderly women with sporadic hyperekplexia underwent neurophysiological assessment, MRI of the brain and proton magnetic resonance spectroscopy (1H-MRS) of the brainstem and frontal lobes. Regional cerebral blood flow was investigated with single photon emission tomography (SPECT) during evoked startles and at rest. Both patients showed excessively large and non-habituating startle responses. In both patients, MRI showed impingement of the brainstem by the vertebrobasilar artery, lack of frontal or brainstem abnormalities on 1H-MRS and hyperperfusion in the dorsal pons and cingulate cortex, and superior frontal gyrus at SPECT during evoked startles. In our patients with hyperekplexia, the vertebrobasilar arteries were found to impinge on the brainstem. Neurophysiological findings and neurofunctional imaging of evoked startles indicated a pontine origin of the movement disorder modulated by activation in cortical, especially frontal, areas. The neurofunctional correlates of evoked startles in human sporadic hyperekplexia are similar to those observed for the startle circuit in animals.

Relationship between home food-handling practices and sporadic salmonellosis in adults in Louisiana, United States.

PubMed Central

Kohl, K. S.; Rietberg, K.; Wilson, S.; Farley, T. A.

2002-01-01

Salmonellosis is the leading cause of death caused by foodborne bacterial pathogens in the United States. Approximately 90% of salmonella infections are sporadic, but most of what is known about salmonellosis has come from outbreak investigations. We studied the risk for sporadic salmonellosis among 115 persons aged > or = 15 years reported to the Louisiana Office of Public Health during May 1998-April 1999, compared with 115 age-matched controls. Significantly more case-patients than controls had chronic underlying medical conditions [adjusted odds ratio (aOR) = 4.3; 95% confidence interval (CI) = 2.2-8.7]. Although reported consumption of specific food items likely to contain salmonella was not associated with illness, inconsistent handwashing between preparation of meat and non-meat items was associated with illness (aOR = 8.3; CI = 1.1-61.8). Enhanced measures to provide a consistently safe food supply and promote safer food preparation in households will depend on prevention of sporadic salmonellosis. PMID:12403102

Escherichia coli pathotypes in Pakistan from consecutive floods in 2010 and 2011.

PubMed

Bokhari, Habib; Shah, Muhammad Ali; Asad, Saba; Akhtar, Sania; Akram, Muhammad; Wren, Brendan W

2013-03-01

This study compares Escherichia coli pathotypes circulating among children in Pakistan during the floods of 2010 and 2011 and from sporadic cases outside flood affected areas. Using multiplex polymerase chain reaction 115 of 205 stool samples (56.29%) were positive for diarrheagenic E. coli from specimens taken during the floods compared with 50 of 400 (12.5%) stool samples being positive for sporadic cases. The E. coli pathotypes were categorized as Enteropathogenic E. coli 33 (28.69%) and 13 (26%), Enterotoxigenic E. coli 29 (25.21%) and 15 (30%), Enteroaggregative E. coli 21 (18.2%) and 18 (36%), Enterohemorrhagic E. coli 5 (4.34%) and 1 (2%) from flood and sporadic cases, respectively. Furthermore, patients co-infected with more than one pathotype were 26 (22.60%) and 3 (6%) from flood and sporadic cases, respectively. The study shows an unexpectedly high rate of isolation of E. coli pathotypes suggesting Pakistan as an endemic region that requires active surveillance particularly during flood periods.

Escherichia coli Pathotypes in Pakistan from Consecutive Floods in 2010 and 2011

PubMed Central

Bokhari, Habib; Shah, Muhammad Ali; Asad, Saba; Akhtar, Sania; Akram, Muhammad; Wren, Brendan W.

2013-01-01

This study compares Escherichia coli pathotypes circulating among children in Pakistan during the floods of 2010 and 2011 and from sporadic cases outside flood affected areas. Using multiplex polymerase chain reaction 115 of 205 stool samples (56.29%) were positive for diarrheagenic E. coli from specimens taken during the floods compared with 50 of 400 (12.5%) stool samples being positive for sporadic cases. The E. coli pathotypes were categorized as Enteropathogenic E. coli 33 (28.69%) and 13 (26%), Enterotoxigenic E. coli 29 (25.21%) and 15 (30%), Enteroaggregative E. coli 21 (18.2%) and 18 (36%), Enterohemorrhagic E. coli 5 (4.34%) and 1 (2%) from flood and sporadic cases, respectively. Furthermore, patients co-infected with more than one pathotype were 26 (22.60%) and 3 (6%) from flood and sporadic cases, respectively. The study shows an unexpectedly high rate of isolation of E. coli pathotypes suggesting Pakistan as an endemic region that requires active surveillance particularly during flood periods. PMID:23358642

Frequency and spectrum of c-Ki-ras mutations in human sporadic colon carcinoma, carcinomas arising in ulcerative colitis, and pancreatic adenocarcinoma

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

Burmer, G.C.; Rabinovitch, P.S.; Loeb, L.A.

1991-06-01

Sporadic colon carcinomas, carcinomas arising in chronic ulcerative colitis, and pancreatic adenocarcinomas have been analyzed for the presence of c-Ki-ras mutations by a combination of histological enrichment, cell sorting, polymerase chain reaction, and direct sequencing. Although 60% (37/61) of sporadic colon carcinomas contained mutations in codon 12, only 1 of 17 specimens of dysplasia or carcinoma from ulcerative colitis patients contained c-Ki-ras mutations, despite a high frequency of aneuploid tumors. In contrast, a higher percentage (16/20 = 80%) of pancreatic adenocarcinomas contained mutations in c-Ki-ras 2, despite a lower frequency of DNA aneuploidy in these neoplasms. Moreover, the spectrum ofmore » mutations differed between sporadic colon carcinoma, where the predominant mutation was a G to A transition, and pancreatic carcinomas, which predominantly contained G to C or T transversions. These results suggest that the etiology of ras mutations is different in these three human neoplasms.« less

Mutations in FUS cause FALS and SALS in French and French Canadian populations

PubMed Central

Belzil, V. V.; Valdmanis, P. N.; Dion, P. A.; Daoud, H.; Kabashi, E.; Noreau, A.; Gauthier, J.; Hince, P.; Desjarlais, A.; Bouchard, J. -P.; Lacomblez, L.; Salachas, F.; Pradat, P. -F.; Camu, W.; Meininger, V.; Dupré, N.; Rouleau, G. A.

2009-01-01

Background: The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease. Methods: To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported. Results: In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS. Conclusions: Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis. PMID:19741216

Mutations in FUS cause FALS and SALS in French and French Canadian populations.

PubMed

Belzil, V V; Valdmanis, P N; Dion, P A; Daoud, H; Kabashi, E; Noreau, A; Gauthier, J; Hince, P; Desjarlais, A; Bouchard, J-P; Lacomblez, L; Salachas, F; Pradat, P-F; Camu, W; Meininger, V; Dupré, N; Rouleau, G A

2009-10-13

The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease. To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported. In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS. Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis.

Inheritable and sporadic non-autoimmune hyperthyroidism.

PubMed

Ferraz, Carolina; Paschke, Ralf

2017-03-01

Hyperthyroidism is a clinical state that results from high thyroid hormone levels which has multiple etiologies, manifestations, and potential therapies. Excluding the autoimmune Graves disease, autonomic adenomas account for the most import cause of non-autoimmune hyperthyroidism. Activating germline mutations of the TSH receptor are rare etiologies for hyperthyroidism. They can be inherited in an autosomal dominant manner (familial or hereditary, FNAH), or may occur sporadically as a de novo condition, also called: persistent sporadic congenital non-autoimmune hyperthyroidism (PSNAH). These three conditions: autonomic adenoma, FNAH and PSNAH constitute the inheritable and sporadic non-autoimmune hyperthyroidism. Particularities in epidemiology, etiology, molecular and clinical aspects of these three entities will be discussed in this review in order to guide to an accurate diagnosis allowing among others genetic counseling and presymptomatic diagnosis for the affected families. The optimal treatment based on the right diagnosis will avoid consequences of a persistent or relapsing hyperthyroidism. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Optical Meteor Fluxes and Application to the 2015 Perseids

NASA Technical Reports Server (NTRS)

Blaauw, R. C.; Campbell-Brown, M.; Kingery, A.

2016-01-01

This paper outlines new methods to measure optical meteor fluxes for showers and sporadic sources. Many past approaches have found the collecting area of a detector at a fixed 100 km altitude, but this approach considers the full volume, finding the area in two km height intervals based on the position of the shower or sporadic source radiant and the population's velocity. Here, the stellar limiting magnitude is found every 10 minutes during clear periods and converted to a limiting meteor magnitude for the shower or sporadic source having fluxes measured, which is then converted to a limiting mass. The final output is a mass limited flux for meteor showers or sporadic sources. Presented are the results of these flux methods as applied to the 2015 Perseid meteor shower as seen by the Meteoroid Environment Office's eight wide-field cameras. The peak Perseid flux on the night of August 13, 2015, was measured to be 0.002989 meteoroids/km2/hr down to 0.00051 grams, corresponding to a ZHR of 100.7.

Cortical sensorimotor alterations classify clinical phenotype and putative genotype of spasmodic dysphonia.

PubMed

Battistella, G; Fuertinger, S; Fleysher, L; Ozelius, L J; Simonyan, K

2016-10-01

Spasmodic dysphonia (SD), or laryngeal dystonia, is a task-specific isolated focal dystonia of unknown causes and pathophysiology. Although functional and structural abnormalities have been described in this disorder, the influence of its different clinical phenotypes and genotypes remains scant, making it difficult to explain SD pathophysiology and to identify potential biomarkers. We used a combination of independent component analysis and linear discriminant analysis of resting-state functional magnetic resonance imaging data to investigate brain organization in different SD phenotypes (abductor versus adductor type) and putative genotypes (familial versus sporadic cases) and to characterize neural markers for genotype/phenotype categorization. We found abnormal functional connectivity within sensorimotor and frontoparietal networks in patients with SD compared with healthy individuals as well as phenotype- and genotype-distinct alterations of these networks, involving primary somatosensory, premotor and parietal cortices. The linear discriminant analysis achieved 71% accuracy classifying SD and healthy individuals using connectivity measures in the left inferior parietal and sensorimotor cortices. When categorizing between different forms of SD, the combination of measures from the left inferior parietal, premotor and right sensorimotor cortices achieved 81% discriminatory power between familial and sporadic SD cases, whereas the combination of measures from the right superior parietal, primary somatosensory and premotor cortices led to 71% accuracy in the classification of adductor and abductor SD forms. Our findings present the first effort to identify and categorize isolated focal dystonia based on its brain functional connectivity profile, which may have a potential impact on the future development of biomarkers for this rare disorder. © 2016 EAN.

Cortical sensorimotor alterations classify clinical phenotype and putative genotype of spasmodic dysphonia

PubMed Central

Battistella, Giovanni; Fuertinger, Stefan; Fleysher, Lazar; Ozelius, Laurie J.; Simonyan, Kristina

2017-01-01

Background Spasmodic dysphonia (SD), or laryngeal dystonia, is a task-specific isolated focal dystonia of unknown causes and pathophysiology. Although functional and structural abnormalities have been described in this disorder, the influence of its different clinical phenotypes and genotypes remains scant, making it difficult to explain SD pathophysiology and to identify potential biomarkers. Methods We used a combination of independent component analysis and linear discriminant analysis of resting-state functional MRI data to investigate brain organization in different SD phenotypes (abductor vs. adductor type) and putative genotypes (familial vs. sporadic cases) and to characterize neural markers for genotype/phenotype categorization. Results We found abnormal functional connectivity within sensorimotor and frontoparietal networks in SD patients compared to healthy individuals as well as phenotype- and genotype-distinct alterations of these networks, involving primary somatosensory, premotor and parietal cortices. The linear discriminant analysis achieved 71% accuracy classifying SD and healthy individuals using connectivity measures in the left inferior parietal and sensorimotor cortex. When categorizing between different forms of SD, the combination of measures from left inferior parietal, premotor and right sensorimotor cortices achieved 81% discriminatory power between familial and sporadic SD cases, whereas the combination of measures from the right superior parietal, primary somatosensory and premotor cortices led to 71% accuracy in the classification of adductor and abductor SD forms. Conclusions Our findings present the first effort to identify and categorize isolated focal dystonia based on its brain functional connectivity profile, which may have a potential impact on the future development of biomarkers for this rare disorder. PMID:27346568

Variably Protease-Sensitive Prionopathy: A New Sporadic Disease of the Prion Protein

PubMed Central

Zou, Wen-Quan; Puoti, Gianfranco; Xiao, Xiangzhu; Yuan, Jue; Qing, Liuting; Cali, Ignazio; Shimoji, Miyuki; Langeveld, Jan P. M.; Castellani, Rudy; Notari, Silvio; Crain, Barbara; Schmidt, Robert E.; Geschwind, Michael; DeArmond, Stephen J.; Cairns, Nigel J.; Dickson, Dennis; Honig, Lawrence; Torres, Juan Maria; Mastrianni, James; Capellari, Sabina; Giaccone, Giorgio; Belay, Ermias D.; Schonberger, Lawrence B.; Cohen, Mark; Perry, George; Kong, Qingzhong; Parchi, Piero; Tagliavini, Fabrizio; Gambetti, Pierluigi

2011-01-01

Objective The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). Methods Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. Results Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with “variably protease-sensitive prionopathy” (VPSPr). None of the subjects had mutations in the PrP gene coding region. Interpretation Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease. PMID:20695009

Rare Copy Number Variants Are a Common Cause of Short Stature

PubMed Central

Zahnleiter, Diana; Uebe, Steffen; Ekici, Arif B.; Hoyer, Juliane; Wiesener, Antje; Wieczorek, Dagmar; Kunstmann, Erdmute; Reis, André; Doerr, Helmuth-Guenther; Rauch, Anita; Thiel, Christian T.

2013-01-01

Human growth has an estimated heritability of about 80%–90%. Nevertheless, the underlying cause of shortness of stature remains unknown in the majority of individuals. Genome-wide association studies (GWAS) showed that both common single nucleotide polymorphisms and copy number variants (CNVs) contribute to height variation under a polygenic model, although explaining only a small fraction of overall genetic variability in the general population. Under the hypothesis that severe forms of growth retardation might also be caused by major gene effects, we searched for rare CNVs in 200 families, 92 sporadic and 108 familial, with idiopathic short stature compared to 820 control individuals. Although similar in number, patients had overall significantly larger CNVs (p-value<1×10−7). In a gene-based analysis of all non-polymorphic CNVs>50 kb for gene function, tissue expression, and murine knock-out phenotypes, we identified 10 duplications and 10 deletions ranging in size from 109 kb to 14 Mb, of which 7 were de novo (p<0.03) and 13 inherited from the likewise affected parent but absent in controls. Patients with these likely disease causing 20 CNVs were smaller than the remaining group (p<0.01). Eleven (55%) of these CNVs either overlapped with known microaberration syndromes associated with short stature or contained GWAS loci for height. Haploinsufficiency (HI) score and further expression profiling suggested dosage sensitivity of major growth-related genes at these loci. Overall 10% of patients carried a disease-causing CNV indicating that, like in neurodevelopmental disorders, rare CNVs are a frequent cause of severe growth retardation. PMID:23516380

Nonampullary duodenal adenoma: Current understanding of its diagnosis, pathogenesis, and clinical management

PubMed Central

Lim, Chul-Hyun; Cho, Young-Seok

2016-01-01

Nonampullary duodenal adenomas are relatively common in familial adenomatous polyposis (FAP), but nonampullary sporadic duodenal adenomas (SDAs) are rare. Emerging evidence shows that duodenal adenomas, regardless of their anatomic location and whether they are sporadic or FAP-related, share morphologic and molecular features with colorectal adenomas. The available data suggest that duodenal adenomas develop to duodenal adenocarcinomas via similar mechanisms. The optimal approach for management of duodenal adenomas remains to be determined. The techniques for endoscopic resection of duodenal adenoma include snare polypectomy, endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and argon plasma coagulation ablation. EMR may facilitate removal of large duodenal polyps. Although several studies have reported cases of successful ESD for duodenal adenomas, the procedure is technically difficult to perform safely because of the anatomical properties of the duodenum. Although current clinical practice recommends endoscopic resection of all large duodenal adenomas in patients with FAP, endoscopic treatment is usually insufficient to guarantee a polyp-free duodenum. Surgery is indicated for FAP patients with severe polyposis or nonampullary SDAs or FAP-related polyps not amenable to endoscopic resection. Further studies are needed to develop newer endoscopic techniques to guide diagnostic and therapeutic decisions for future management of nonampullary duodenal adenomas. PMID:26811631

Sporadic renal angiomyolipoma in a patient with Birt-Hogg-Dubé: chaperones in pathogenesis.

PubMed

Sager, Rebecca A; Woodford, Mark R; Shapiro, Oleg; Mollapour, Mehdi; Bratslavsky, Gennady

2018-04-24

Birt-Hogg-Dubé (BHD) is an autosomal dominant genetic syndrome caused by germline mutations in the FLCN gene that predisposes patients to develop renal tumors. Renal angiomyolipoma (AML) is not a renal tumor sub-type associated with BHD. AML is, however, a common phenotypic manifestation of Tuberous Sclerosis Complex (TSC) syndrome caused by mutations in either the TSC1 or TSC2 tumor suppressor genes. Previous case reports of renal AML in patients with BHD have speculated on the molecular and clinical overlap of these two syndromes as a result of described involvement of the gene products in the mTOR pathway. Our recent work provided a new molecular link between these two syndromes by identifying FLCN and Tsc2 as clients of the molecular chaperone Hsp90. Folliculin interacting proteins FNIP1/2 and Tsc1 are important for FLCN and Tsc2 stability as new Hsp90 co-chaperones. Here we present a case of sporadic AML as a result of somatic Tsc1/2 loss in a patient with BHD. We further demonstrate that FNIP1 and Tsc1 are capable of compensating for each other in the chaperoning of mutated FLCN tumor suppressor. Our findings demonstrate interconnectivity and compensatory mechanisms between the BHD and TSC pathways.

Distribution of gene mutations in sporadic congenital cataract in a Han Chinese population

PubMed Central

Li, Dan; Wang, Siying; Ye, Hongfei; Tang, Yating; Qiu, Xiaodi; Fan, Qi; Rong, Xianfang; Liu, Xin; Chen, Yuhong; Yang, Jin

2016-01-01

Purpose This study aimed to investigate the genetic effects underlying non-familial sporadic congenital cataract (SCC). Methods We collected DNA samples from 74 patients with SCC and 20 patients with traumatic cataract (TC) in an age-matched group and performed genomic sequencing of 61 lens-related genes with target region capture and next-generation sequencing (NGS). The suspected SCC variants were validated with MassARRAY and Sanger sequencing. DNA samples from 103 healthy subjects were used as additional controls in the confirmation examination. Results By filtering against common variants in public databases and those associated with TC cases, we identified 23 SCC-specific variants in 17 genes from 19 patients, which were predicted to be functional. These mutations were further confirmed by examination of the 103 healthy controls. Among the mutated genes, CRYBB3 had the highest mutation frequency with mutations detected four times in four patients, followed by EPHA2, NHS, and WDR36, the mutation of which were detected two times in two patients. We observed that the four patients with CRYBB3 mutations had three different cataract phenotypes. Conclusions From this study, we concluded the clinical and genetic heterogeneity of SCC. This is the first study to report broad spectrum genotyping for patients with SCC. PMID:27307692

Whole genome sequencing of Salmonella Typhimurium illuminates distinct outbreaks caused by an endemic multi-locus variable number tandem repeat analysis type in Australia, 2014.

PubMed

Phillips, Anastasia; Sotomayor, Cristina; Wang, Qinning; Holmes, Nadine; Furlong, Catriona; Ward, Kate; Howard, Peter; Octavia, Sophie; Lan, Ruiting; Sintchenko, Vitali

2016-09-15

Salmonella Typhimurium (STM) is an important cause of foodborne outbreaks worldwide. Subtyping of STM remains critical to outbreak investigation, yet current techniques (e.g. multilocus variable number tandem repeat analysis, MLVA) may provide insufficient discrimination. Whole genome sequencing (WGS) offers potentially greater discriminatory power to support infectious disease surveillance. We performed WGS on 62 STM isolates of a single, endemic MLVA type associated with two epidemiologically independent, food-borne outbreaks along with sporadic cases in New South Wales, Australia, during 2014. Genomes of case and environmental isolates were sequenced using HiSeq (Illumina) and the genetic distance between them was assessed by single nucleotide polymorphism (SNP) analysis. SNP analysis was compared to the epidemiological context. The WGS analysis supported epidemiological evidence and genomes of within-outbreak isolates were nearly identical. Sporadic cases differed from outbreak cases by a small number of SNPs, although their close relationship to outbreak cases may represent an unidentified common food source that may warrant further public health follow up. Previously unrecognised mini-clusters were detected. WGS of STM can discriminate foodborne community outbreaks within a single endemic MLVA clone. Our findings support the translation of WGS into public health laboratory surveillance of salmonellosis.

Co-existence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection*

PubMed Central

Haldiman, Tracy; Kim, Chae; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Qing, Liuting; Cohen, Mark L.; Langeveld, Jan; Telling, Glenn C.; Kong, Qingzhong; Safar, Jiri G.

2013-01-01

The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrPSc). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrPSc particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease. The protein misfolding cyclic amplification replicates each of the PrPSc particle types independently and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrPC substrate, the dominant PrPSc conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sporadic Creutzfeldt-Jakob disease PrPSc is not a single conformational entity but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrPSc conformers. PMID:23974118

Periodic Fever: A Review on Clinical, Management and Guideline for Iranian Patients - Part II

PubMed Central

Ahmadinejad, Zahra; Mansouri, Sedigeh; Ziaee, Vahid; Aghighi, Yahya; Moradinejad, Mohammad-Hassan; Fereshteh-Mehregan, Fatemeh

2014-01-01

Periodic fever syndromes are a group of diseases characterized by episodes of fever with healthy intervals between febrile episodes. In the first part of this paper, we presented a guideline for approaching patients with periodic fever and reviewed two common disorders with periodic fever in Iranian patients including familial Mediterranean fever (FMF) and periodic fever syndromes except for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA). In this part, we review other autoinflammatory disorders including hyper IgD, tumor necrosis factor receptor–associated periodic syndrome (TRAPS), cryopyrin associated periodic syndromes, autoinflammatory bone disorders and some other rare autoinflammatory disorders such as Sweet’s and Blau syndromes. In cryopyrin associated periodic syndromes group, we discussed chronic infantile neurologic cutaneous and articular (CINCA) syndrome, Muckle-Wells syndrome and familial cold autoinflammatory syndrome. Autoinflammatory bone disorders are categorized to monogenic disorders such as pyogenic arthritis, pyoderma ;gangraenosum and acne (PAPA) syndrome, the deficiency of interleukine-1 receptor antagonist (DIRA) and Majeed syndrome and polygenic background or sporadic group such as chronic recurrent multifocal osteomyelitis (CRMO) or synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome are classified in sporadic group. Other autoinflammatory syndromes are rare causes of periodic fever in Iranian system registry. PMID:25562014

The clinical spectrum of phaeochromocytoma: analysis of 115 patients.

PubMed

Safwat, Ahmed S; Bissada, Nabil K; Seyam, Raouf M; Al Sobhi, Saif; Hanash, Kamal A

2008-06-01

To analyse the presentation, manifestations and outcome in consecutive patients with phaeochromocytoma, as this disease has a wide range of pathological and clinical expressions. The records of 115 patients with phaeochromocytoma were analysed retrospectively, recording the patients' age, sex, presenting symptoms and clinical signs, chemical, radiological and pathological findings and associated conditions. Of the 115 patients, 90 had adrenal tumours, 18 extra-adrenal and seven combined adrenal and extra-adrenal tumours. Ten patients had malignant and 105 had benign phaeochromocytoma. Eighty-six patients had sporadic and 29 had familial phaeochromocytoma, comprising eight with von Hippel-Lindau (VHL) disease, 17 with multiple endocrine neoplasia type II (MEN II) and four with von Recklinghausen disease. Two patients with sporadic phaeochromocytoma had Grave's disease. Ten patients (8.7%) had malignant phaeochromocytoma, of whom two had MEN II. A pregnant woman required prolonged intensive-care management before adrenalectomy and lost a fetus. Phaeochromocytoma is an interesting clinical entity with a wide spectrum of pathological and clinical manifestations. The diagnosis of phaeochromocytoma is confirmed by chemical methods, and located using imaging techniques, with computed tomography, magnetic resonance imaging and (131)I-meta-iodobenzyl guanidine radioisotope scanning being the most common. This series reflects the pathological and clinical spectrum of phaeochromocytoma. The presence of other manifestations of familial phaeochromocytoma influenced the presentation and prognosis of these patients.

Fine-scale spatial distribution of orchid mycorrhizal fungi in the soil of host-rich grasslands.

PubMed

Voyron, Samuele; Ercole, Enrico; Ghignone, Stefano; Perotto, Silvia; Girlanda, Mariangela

2017-02-01

Mycorrhizal fungi are essential for the survival of orchid seedlings under natural conditions. The distribution of these fungi in soil can constrain the establishment and resulting spatial arrangement of orchids at the local scale, but the actual extent of occurrence and spatial patterns of orchid mycorrhizal (OrM) fungi in soil remain largely unknown. We addressed the fine-scale spatial distribution of OrM fungi in two orchid-rich Mediterranean grasslands by means of high-throughput sequencing of fungal ITS2 amplicons, obtained from soil samples collected either directly beneath or at a distance from adult Anacamptis morio and Ophrys sphegodes plants. Like ectomycorrhizal and arbuscular mycobionts, OrM fungi (tulasnelloid, ceratobasidioid, sebacinoid and pezizoid fungi) exhibited significant horizontal spatial autocorrelation in soil. However, OrM fungal read numbers did not correlate with distance from adult orchid plants, and several of these fungi were extremely sporadic or undetected even in the soil samples containing the orchid roots. Orchid mycorrhizal 'rhizoctonias' are commonly regarded as unspecialized saprotrophs. The sporadic occurrence of mycobionts of grassland orchids in host-rich stands questions the view of these mycorrhizal fungi as capable of sustained growth in soil. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Evidence for presumable feline origin of sporadic G6P[9] rotaviruses in humans.

PubMed

Pietsch, Corinna; Liebert, Uwe G

2018-05-31

Species A rotaviruses are highly diverse and impose a substantial burden to human and animal health. Interspecies transmission between livestock, domestic animals and humans is commonly observed, but spread of animal-like rotaviruses within the human population is limited. During the continued monitoring of rotavirus strains in Germany, an unusual G6P[9] rotavirus strain was detected in feces of a child. The complete rotavirus coding sequences revealed a unique G6-P[9]-I2-R2-C2-M2-A3-N2-T3-E2-H3 genotype constellation. The virus was phylogenetically related to feline G3P[9] strains and other human G6P[9] rotaviruses of presumable zoonotic origin. Analysis of primer binding sites of G6 specific genotyping revealed further evidence of a G6P[9] feline reservoir. Moreover, substantial deficits of conventional semi-nested PCR genotyping approaches in detecting contemporary G6P[9] were revealed. Rotavirus strain GER29-14 most likely resulted from a direct or recent interspecies transmission from a cat to human. Further studies could assess nucleic acid sequences and genotype constellations of feline rotavirus to confirm the likely feline origin of sporadic human G6P[9] strains. Copyright © 2018 Elsevier B.V. All rights reserved.

Genetic susceptibility to neuroblastoma: current knowledge and future directions.

PubMed

Ritenour, Laura E; Randall, Michael P; Bosse, Kristopher R; Diskin, Sharon J

2018-05-01

Neuroblastoma, a malignancy of the developing peripheral nervous system that affects infants and young children, is a complex genetic disease. Over the past two decades, significant progress has been made toward understanding the genetic determinants that predispose to this often lethal childhood cancer. Approximately 1-2% of neuroblastomas are inherited in an autosomal dominant fashion and a combination of co-morbidity and linkage studies has led to the identification of germline mutations in PHOX2B and ALK as the major genetic contributors to this familial neuroblastoma subset. The genetic basis of "sporadic" neuroblastoma is being studied through a large genome-wide association study (GWAS). These efforts have led to the discovery of many common susceptibility alleles, each with modest effect size, associated with the development and progression of sporadic neuroblastoma. More recently, next-generation sequencing efforts have expanded the list of potential neuroblastoma-predisposing mutations to include rare germline variants with a predicted larger effect size. The evolving characterization of neuroblastoma's genetic basis has led to a deeper understanding of the molecular events driving tumorigenesis, more precise risk stratification and prognostics and novel therapeutic strategies. This review details the contemporary understanding of neuroblastoma's genetic predisposition, including recent advances and discusses ongoing efforts to address gaps in our knowledge regarding this malignancy's complex genetic underpinnings.

A genome-wide assessment of rare copy number variants in colorectal cancer.

PubMed

Li, Zhenli; Yu, Dan; Gan, Meifu; Shan, Qiaonan; Yin, Xiaoyang; Tang, Shunli; Zhang, Shuai; Shi, Yongyong; Zhu, Yimin; Lai, Maode; Zhang, Dandan

2015-09-22

Colorectal cancer (CRC) is a complex disease with an estimated heritability of approximately 35%. However, known CRC-related common single nucleotide polymorphisms (SNPs) can only explain ~0.65% of the heritability. This "missing heritability" may be explained partially by rare copy number variants (CNVs). In this study, we performed a genome-wide scan using Illumina Human-Omni Express BeadChip, 694 sporadic CRC cases and 1641 controls were eventually included in our analysis after quality control. The global burden analysis revealed a 1.53-fold excess of rare CNVs in CRC cases compared with controls (P < 1 × 10(-6)), and the difference being more pronounced for genic rare CNVs and CNVs overlapped with coding regions (1.65-fold and 1.84-fold, respectively, both P < 1 × 10(-6)). Interestingly, both the cases in the lowest and middle tertile of age carried a higher burden of rare CNVs comparing to the highest tertile. Furthermore, 639 CNV-disrupted genes exclusive to CRC cases were found to be significantly enriched in gene ontology (GO) terms concerning nucleosome assembly and olfactory receptor activity. Our study was the first to evaluate the burden of rare CNVs in sporadic CRC and suggested that rare CNVs contributed to the missing heritability of CRC.

MEN4 and CDKN1B mutations: the latest of the MEN syndromes.

PubMed

Alrezk, Rami; Hannah-Shmouni, Fady; Stratakis, Constantine A

2017-10-01

Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of endocrine and non-endocrine manifestations. The most frequent among these conditions is MEN type 1 (MEN1), which is caused by germline heterozygous loss-of-function mutations in the tumor suppressor gene MEN1 MEN1 is characterized by primary hyperparathyroidism (PHPT) and functional or nonfunctional pancreatic neuroendocrine tumors and pituitary adenomas. Approximately 10% of patients with familial or sporadic MEN1-like phenotype do not have MEN1 mutations or deletions. A novel MEN syndrome was discovered, initially in rats (MENX), and later in humans (MEN4), which is caused by germline mutations in the putative tumor suppressor CDKN1B The most common phenotype of the 19 established cases of MEN4 that have been described to date is PHPT followed by pituitary adenomas. Recently, somatic or germline mutations in CDKN1B were also identified in patients with sporadic PHPT, small intestinal neuroendocrine tumors, lymphoma and breast cancer, demonstrating a novel role for CDKN1B as a tumor susceptibility gene for other neoplasms. In this review, we report on the genetic characterization and clinical features of MEN4. © 2017 Society for Endocrinology.

Sporadic frame dropping impact on quality perception

NASA Astrophysics Data System (ADS)

Pastrana-Vidal, Ricardo R.; Gicquel, Jean Charles; Colomes, Catherine; Cherifi, Hocine

2004-06-01

Over the past few years there has been an increasing interest in real time video services over packet networks. When considering quality, it is essential to quantify user perception of the received sequence. Severe motion discontinuities are one of the most common degradations in video streaming. The end-user perceives a jerky motion when the discontinuities are uniformly distributed over time and an instantaneous fluidity break is perceived when the motion loss is isolated or irregularly distributed. Bit rate adaptation techniques, transmission errors in the packet networks or restitution strategy could be the origin of this perceived jerkiness. In this paper we present a psychovisual experiment performed to quantify the effect of sporadically dropped pictures on the overall perceived quality. First, the perceptual detection thresholds of generated temporal discontinuities were measured. Then, the quality function was estimated in relation to a single frame dropping for different durations. Finally, a set of tests was performed to quantify the effect of several impairments distributed over time. We have found that the detection thresholds are content, duration and motion dependent. The assessment results show how quality is impaired by a single burst of dropped frames in a 10 sec sequence. The effect of several bursts of discarded frames, irregularly distributed over the time is also discussed.

Contribution of GLC3A locus to Primary Congenital Glaucoma in Pakistani population

PubMed Central

Bashir, Rasheeda; Sanai, Mahrukh; Azeem, Adnan; Altaf, Imran; Saleem, Faiza; Naz, Sadaf

2014-01-01

Objectives: To check the contribution of GLC3A locus to primary congenital glaucoma in the Pakistani population. Methods: We enrolled twenty-nine sporadic cases and three families with multiple individuals affected with recessive primary congenital glaucoma in the year 2013. It was a genetic linkage study accomplished jointly in Department of Biotechnology of Lahore College for Women University and School of Biological Sciences, University of the Punjab, Lahore. Samples from all affected individuals were checked for homozygosity for alleles of microsatellite markers spanning CYP1B1 at GLC3A locus. Genotyping was performed with fluorescently labeled primers by capillary electrophoresis. For familial cases, linkage was evaluated by checking the co-segregation of the phenotype with the genotypes. Two-point LOD score was calculated for each microsatellite marker with MLINK. Results: Our study revealed that GLCA3 may contribute to glaucoma in 17% of the sporadic cases and patients in 2 of the 3 families. Conclusions: This data suggests that the GLC3A may make an important contribution to autosomal recessive primary congenital glaucoma in the Pakistani population. Genotyping and Sequencing of more families will be helpful to identify the common mutations in CYP1B1 in future. PMID:25674135

Familial chronic lymphocytic leukemia in Israel: A disproportionate distribution among Ashkenazi Jews.

PubMed

Zada, Mor; Lerner, Daniele; Piltz, Yuval; Perry, Chava; Avivi, Irit; Herishanu, Yair

2017-07-01

Relatives of patients with chronic lymphocytic leukemia (CLL) are at increased risk of developing CLL. Familial CLL is defined as more than one case of CLL among blood relatives, a phenomenon reported in approximately 5%-10% of all CLL patients. Given the known predisposition of CLL among Ashkenazi Jews, we studied the features of familial CLL in an Israeli population. This is a retrospective study, in which we reviewed the demographics, clinical characteristics, and outcomes of a total of 332 patients with CLL/small lymphocytic lymphoma. Familial CLL was recorded in 41 cases (12.3%) of the patients. The age at diagnosis was younger in patients with familial CLL (by almost 3.5 years). Familial CLL was strongly associated with Ashkenazi Jewish origin. Patients with familial CLL more commonly presented with higher hemoglobin and lower serum β-2-microglobulin levels. No significant differences were detected between sporadic and familial CLL in disease stage, time to treatment, second cancers, or overall survival. Familial cases of CLL in an Israeli population show a disproportionate ethnic distribution toward Jews of Ashkenazi origin. The clinical characteristics and the overall outcome are not substantially different from sporadic cases. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Genomic Comparisons and Shiga Toxin Production among Escherichia coli O157:H7 Isolates from a Day Care Center Outbreak and Sporadic Cases in Southeastern Wisconsin

PubMed Central

Gouveia, S.; Proctor, M. E.; Lee, M.-S.; Luchansky, J. B.; Kaspar, C. W.

1998-01-01

Contour-clamped homogeneous electric field pulsed-field gel electrophoresis (CHEF-PFGE) was used to compare Wisconsin isolates of Escherichia coli O157:H7, including 39 isolates from a 1994 day care center outbreak, 28 isolates from 18 individuals from the surrounding geographic area with sporadic cases occurring during the 3 months before the outbreak, and 3 isolates, collected in 1995, from patients with hemolytic-uremic syndrome (HUS) who were from eastern Wisconsin counties other than those inhabited by the day care center and sporadic-case individuals. The technique of CHEF-PFGE using XbaI identified seven highly related restriction endonuclease digestion profiles (REDPs) (93 to 98% similarity) among the 39 day care center isolates and nine XbaI REDPs (63 to 93% similarity) among the 28 isolates from sporadic-case individuals, including REDP 33, which was exhibited by both day care and sporadic-case isolates. PFGE analyses of sequential E. coli O157:H7 isolates from symptomatic day care center attendees revealed that the REDPs of 25 isolates from eight patients were indistinguishable whereas the REDPs of 2 of 6 isolates from two patients differed slightly (93 to 95% similarity). The REDPs of the three isolates from 1995 HUS patients were 78 to 83% similar, with REDP 26 being exhibited by one HUS-associated isolate and an isolate from one day care attendee who did not develop HUS. The genes for both Shiga toxins I and II (stx1 and stx2, respectively) were detected in all but one isolate (sporadic case), and Shiga toxin production by the day care center isolates was not significantly different from that of the other isolates, including the three HUS-associated isolates. Analyses of E. coli O157:H7 isolates from both the day care center outbreak and sporadic cases by CHEF-PFGE permitted us to define the REDP variability of an outbreak and geographic region and demonstrated that the day care center outbreak and a HUS case in 1995 were caused by E. coli O157:H7 strains endemic to eastern Wisconsin. PMID:9508303

Sporadic Jakob-Creutzfeldt Disease Presenting as Primary Progressive Aphasia

PubMed Central

Johnson, David Y.; Dunkelberger, Diana L.; Henry, Maya; Haman, Aissatou; Greicius, Michael D.; Wong, Katherine; DeArmond, Stephen J.; Miller, Bruce L.; Gorno-Tempini, Maria Luisa; Geschwind, Michael D.

2015-01-01

Objective To report the clinical, neuropsychological, linguistic, imaging, and neuropathological features of a unique case of sporadic Jakob-Creutzfeldt disease in which the patient presented with a logopenic variant of primary progressive aphasia. Design Case report. Setting Large referral center for atypical memory and aging disorders, particularly Jakob-Creutzfeldt disease. Patient Patient presenting with logopenic variant primary progressive aphasia initially thought to be due to Alzheimer disease. Results Despite the long, slow 3.5-year course, the patient was shown to have pathology-proven sporadic Jakob-Creutzfeldt disease. Conclusions These findings expand the differential of primary progressive aphasia to include prion disease. PMID:23400721

Neuroendocrine Differentiation in Sporadic CRC and Hereditary Nonpolyosis Colorectal Cancer

PubMed Central

Sun, M. H.

2004-01-01

Extent neuroendocrine differentiation can be encountered in many human neoplasm derived from different organs and systems using immunohistochemistry and ultrastructural techniques. The tumor cells' behaviors resemble those of neurons and neuroendocrine cells. The presence of neuroendocrine differentiation reputedly appears to be associated with a poorer prognosis than the adenocarcinoma counterparts in sporadic human neoplasm. In this review the neuroendocrine carcinoma and the adenocarcinoma with neuroendocrine differentiation of colon and rectum both in sporadic colorectal carcinoma and the hereditary nonpolyposis colorectal cancer, the relationship of neuroendocrine differentiation and some possible molecular pathways in tumorogenesis of colorectal cancer will be discussed. Possible treatment strategy will also be addressed. PMID:15528794

Older paternal age and fresh gene mutation: data on additional disorders.

PubMed

Jones, K L; Smith, D W; Harvey, M A; Hall, B D; Quan, L

1975-01-01

Older paternal age has previously been documented as a factor in sporadic fresh mutational cases of several autosomal dominant disorders. In this collaborative study, an older mean paternal age has been documented in sporadic cases of at least five additional dominantly inheritable disorders; the basal cell nevus syndrome, the Waardenburg syndrome, the Crouzon syndrome, the oculo-dental-digital sysdrome, and the Treacher-Collins syndrome. It was also found to be a factor in acrodysostosis and progeria, suggesting a fresh mutant gene etiology for these two conditions in which virtually all cases have been sporadic and the mode of genetic etiology has been unknown.

S182 and STM2 gene missense mutations in sporadic alzheimer disease

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

Higuchi, Susumu; Matsushita, Sachio; Hasegawa, Yoshio

1996-07-26

The linkage of genes S182 and STM2 to early-onset or late-onset sporadic Alzheimer disease (AD) was not found in a group of 97 clinically-diagnosed AD patients and 46 autopsy-confirmed AD cases, using PCR-RFLP methods. 7 refs.

White matter involvement in sporadic Creutzfeldt-Jakob disease

PubMed Central

Mandelli, Maria Luisa; DeArmond, Stephen J.; Hess, Christopher P.; Vitali, Paolo; Papinutto, Nico; Oehler, Abby; Miller, Bruce L.; Lobach, Irina V.; Bastianello, Stefano; Geschwind, Michael D.; Henry, Roland G.

2014-01-01

Sporadic Creutzfeldt-Jakob disease is considered primarily a disease of grey matter, although the extent of white matter involvement has not been well described. We used diffusion tensor imaging to study the white matter in sporadic Creutzfeldt-Jakob disease compared to healthy control subjects and to correlated magnetic resonance imaging findings with histopathology. Twenty-six patients with sporadic Creutzfeldt-Jakob disease and nine age- and gender-matched healthy control subjects underwent volumetric T1-weighted and diffusion tensor imaging. Six patients had post-mortem brain analysis available for assessment of neuropathological findings associated with prion disease. Parcellation of the subcortical white matter was performed on 3D T1-weighted volumes using Freesurfer. Diffusion tensor imaging maps were calculated and transformed to the 3D-T1 space; the average value for each diffusion metric was calculated in the total white matter and in regional volumes of interest. Tract-based spatial statistics analysis was also performed to investigate the deeper white matter tracts. There was a significant reduction of mean (P = 0.002), axial (P = 0.0003) and radial (P = 0.0134) diffusivities in the total white matter in sporadic Creutzfeldt-Jakob disease. Mean diffusivity was significantly lower in most white matter volumes of interest (P < 0.05, corrected for multiple comparisons), with a generally symmetric pattern of involvement in sporadic Creutzfeldt-Jakob disease. Mean diffusivity reduction reflected concomitant decrease of both axial and radial diffusivity, without appreciable changes in white matter anisotropy. Tract-based spatial statistics analysis showed significant reductions of mean diffusivity within the white matter of patients with sporadic Creutzfeldt-Jakob disease, mainly in the left hemisphere, with a strong trend (P = 0.06) towards reduced mean diffusivity in most of the white matter bilaterally. In contrast, by visual assessment there was no white matter abnormality either on T2-weighted or diffusion-weighted images. Widespread reduction in white matter mean diffusivity, however, was apparent visibly on the quantitative attenuation coefficient maps compared to healthy control subjects. Neuropathological analysis showed diffuse astrocytic gliosis and activated microglia in the white matter, rare prion deposition and subtle subcortical microvacuolization, and patchy foci of demyelination with no evident white matter axonal degeneration. Decreased mean diffusivity on attenuation coefficient maps might be associated with astrocytic gliosis. We show for the first time significant global reduced mean diffusivity within the white matter in sporadic Creutzfeldt-Jakob disease, suggesting possible primary involvement of the white matter, rather than changes secondary to neuronal degeneration/loss. PMID:25367029

Cholesterol metabolism and transport in the pathogenesis of Alzheimer's disease.

PubMed

Martins, Ian J; Berger, Tamar; Sharman, Matthew J; Verdile, Giuseppe; Fuller, Stephanie J; Martins, Ralph N

2009-12-01

Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting millions of people worldwide. Apart from age, the major risk factor identified so far for the sporadic form of AD is possession of the epsilon4 allele of apolipoprotein E (APOE), which is also a risk factor for coronary artery disease (CAD). Other apolipoproteins known to play an important role in CAD such as apolipoprotein B are now gaining attention for their role in AD as well. AD and CAD share other risk factors, such as altered cholesterol levels, particularly high levels of low density lipoproteins together with low levels of high density lipoproteins. Statins--drugs that have been used to lower cholesterol levels in CAD, have been shown to protect against AD, although the protective mechanism(s) involved are still under debate. Enzymatic production of the beta amyloid peptide, the peptide thought to play a major role in AD pathogenesis, is affected by membrane cholesterol levels. In addition, polymorphisms in several proteins and enzymes involved in cholesterol and lipoprotein transport and metabolism have been linked to risk of AD. Taken together, these findings provide strong evidence that changes in cholesterol metabolism are intimately involved in AD pathogenic processes. This paper reviews cholesterol metabolism and transport, as well as those aspects of cholesterol metabolism that have been linked with AD.

Fibrillar Structure and Charge Determine the Interaction of Polyglutamine Protein Aggregates with the Cell Surface*

PubMed Central

Trevino, R. Sean; Lauckner, Jane E.; Sourigues, Yannick; Pearce, Margaret M.; Bousset, Luc; Melki, Ronald; Kopito, Ron R.

2012-01-01

The pathogenesis of most neurodegenerative diseases, including transmissible diseases like prion encephalopathy, inherited disorders like Huntington disease, and sporadic diseases like Alzheimer and Parkinson diseases, is intimately linked to the formation of fibrillar protein aggregates. It is becoming increasingly appreciated that prion-like intercellular transmission of protein aggregates can contribute to the stereotypical spread of disease pathology within the brain, but the mechanisms underlying the binding and uptake of protein aggregates by mammalian cells are largely uninvestigated. We have investigated the properties of polyglutamine (polyQ) aggregates that endow them with the ability to bind to mammalian cells in culture and the properties of the cell surface that facilitate such uptake. Binding and internalization of polyQ aggregates are common features of mammalian cells and depend upon both trypsin-sensitive and trypsin-resistant saturable sites on the cell surface, suggesting the involvement of cell surface proteins in this process. polyQ aggregate binding depends upon the presence of a fibrillar amyloid-like structure and does not depend upon electrostatic interaction of fibrils with the cell surface. Sequences in the huntingtin protein that flank the amyloid-forming polyQ tract also influence the extent to which aggregates are able to bind to cell surfaces. PMID:22753412

Deregulation of E2-EPF Ubiquitin Carrier Protein in Papillary Renal Cell Carcinoma

PubMed Central

Roos, Frederik C.; Evans, Andrew J.; Brenner, Walburgis; Wondergem, Bill; Klomp, Jeffery; Heir, Pardeep; Roche, Olga; Thomas, Christian; Schimmel, Heiko; Furge, Kyle A.; Teh, Bin T.; Thüroff, Joachim W.; Hampel, Christian; Ohh, Michael

2011-01-01

Molecular pathways associated with pathogenesis of sporadic papillary renal cell carcinoma (PRCC), the second most common form of kidney cancer, are poorly understood. We analyzed primary tumor specimens from 35 PRCC patients treated by nephrectomy via gene expression analysis and tissue microarrays constructed from an additional 57 paraffin-embedded PRCC samples via immunohistochemistry. Gene products were validated and further studied by Western blot analyses using primary PRCC tumor samples and established renal cell carcinoma cell lines, and potential associations with pathologic variables and survival in 27 patients with follow-up information were determined. We show that the expression of E2-EPF ubiquitin carrier protein, which targets the principal negative regulator of hypoxia-inducible factor (HIF), von Hippel-Lindau protein, for proteasome-dependent degradation, is markedly elevated in the majority of PRCC tumors exhibiting increased HIF1α expression, and is associated with poor prognosis. In addition, we identified multiple hypoxia-responsive elements within the E2-EPF promoter, and for the first time we demonstrated that E2-EPF is a hypoxia-inducible gene directly regulated via HIF1. These findings reveal deregulation of the oxygen-sensing pathway impinging on the positive feedback mechanism of HIF1-mediated regulation of E2-EPF in PRCC. PMID:21281817

Distribution of Gene Mutations Associated with Familial Normosmic Idiopathic Hypogonadotropic Hypogonadism

PubMed Central

Gürbüz, Fatih; Kotan, L. Damla; Mengen, Eda; Şıklar, Zeynep; Berberoğlu, Merih; Dökmetaş, Sebila; Kılıçlı, Mehmet Fatih; Güven, Ayla; Kirel, Birgül; Saka, Nurçin; Poyrazoğlu, Şükran; Cesur, Yaşar; Doğan, Murat; Özen, Samim; Özbek, Mehmet Nuri; Demirbilek, Hüseyin; Kekil, M. Burcu; Temiz, Fatih; Önenli Mungan, Neslihan; Yüksel, Bilgin; Topaloğlu, Ali Kemal

2012-01-01

Objective: Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is characterized by failure of initiation or maintenance of puberty due to insufficient gonadotropin release, which is not associated with anosmia/hyposmia. The objective of this study was to determine the distribution of causative mutations in a hereditary form of nIHH. Methods: In this prospective collaborative study, 22 families with more than one affected individual (i.e. multiplex families) with nIHH were recruited and screened for genes known or suspected to be strong candidates for nIHH. Results: Mutations were identified in five genes (GNRHR, TACR3, TAC3, KISS1R, and KISS1) in 77% of families with autosomal recessively inherited nIHH. GNRHR and TACR3 mutations were the most common two causative mutations occurring with about equal frequency. Conclusions: Mutations in these five genes account for about three quarters of the causative mutations in nIHH families with more than one affected individual. This frequency is significantly greater than the previously reported rates in all inclusive (familial plus sporadic) cohorts. GNRHR and TACR3 should be the first two genes to be screened for diagnostic purposes. Identification of causative mutations in the remaining families will shed light on the regulation of puberty. Conflict of interest:None declared. PMID:22766261

Role of BRI2 in dementia.

PubMed

Del Campo, Marta; Teunissen, Charlotte E

2014-01-01

Alzheimer's disease (AD), the most common form of dementia, shares clinical and pathological similarities with familial British and Danish dementias (FBD and FDD). Whereas the etiology of sporadic AD remains unclear, familial AD is linked to mutations in amyloid-β protein precursor (AβPP), presenilin 1 (PS1), and presenilin 2 (PS2). Similarly, FBD and FDD originate from mutations in the BRI2 gene (or ITM2b), causing amyloid angiopathy and neurofibrillary tangles analogous to those observed in AD. Recent studies on the role of BRI2 in FBD and FDD have revealed that the three diseases may share pathophysiological pathways leading to dementia. Interestingly, BRI2 is a potential regulator of AβPP processing, and it can inhibit the production and fibrillation of Aβ. This suggests a role of BRI2 in the amyloid cascade, which is the prevailing hypothesis about AD pathogenesis. To understand a possible relationship of BRI2 with AD, we reviewed the relevant studies on this protein. The data included not only the protein's structure, expression pattern, function, and involvement in FBD and FDD, but also its relationship with memory deficits and the main pathological proteins involved in AD. Thus, we highlight and discuss the potential links between BRI2 and AD, leading to the formulation of a modified hypothesis about AD etiology.

Progression to Adrenocortical Tumorigenesis in Mice and Humans through Insulin-Like Growth Factor 2 and β-Catenin

PubMed Central

Heaton, Joanne H.; Wood, Michelle A.; Kim, Alex C.; Lima, Lorena O.; Barlaskar, Ferdous M.; Almeida, Madson Q.; Fragoso, Maria C.B.V.; Kuick, Rork; Lerario, Antonio M.; Simon, Derek P.; Soares, Ibere C.; Starnes, Elisabeth; Thomas, Dafydd G.; Latronico, Ana C.; Giordano, Thomas J.; Hammer, Gary D.

2013-01-01

Dysregulation of the WNT and insulin-like growth factor 2 (IGF2) signaling pathways has been implicated in sporadic and syndromic forms of adrenocortical carcinoma (ACC). Abnormal β-catenin staining and CTNNB1 mutations are reported to be common in both adrenocortical adenoma and ACC, whereas elevated IGF2 expression is associated primarily with ACC. To better understand the contribution of these pathways in the tumorigenesis of ACC, we examined clinicopathological and molecular data and used mouse models. Evaluation of adrenal tumors from 118 adult patients demonstrated an increase in CTNNB1 mutations and abnormal β-catenin accumulation in both adrenocortical adenoma and ACC. In ACC, these features were adversely associated with survival. Mice with stabilized β-catenin exhibited a temporal progression of increased adrenocortical hyperplasia, with subsequent microscopic and macroscopic adenoma formation. Elevated Igf2 expression alone did not cause hyperplasia. With the combination of stabilized β-catenin and elevated Igf2 expression, adrenal glands were larger, displayed earlier onset of hyperplasia, and developed more frequent macroscopic adenomas (as well as one carcinoma). Our results are consistent with a model in which dysregulation of one pathway may result in adrenal hyperplasia, but accumulation of a second or multiple alterations is necessary for tumorigenesis. PMID:22800756

Parkin Regulation and Neurodegenerative Disorders

PubMed Central

Zhang, Cheng-Wu; Hang, Liting; Yao, Tso-Pang; Lim, Kah-Leong

2016-01-01

Parkin is a unique, multifunctional ubiquitin ligase whose various roles in the cell, particularly in neurons, are widely thought to be protective. The pivotal role that Parkin plays in maintaining neuronal survival is underscored by our current recognition that Parkin dysfunction represents not only a predominant cause of familial parkinsonism but also a formal risk factor for the more common, sporadic form of Parkinson’s disease (PD). Accordingly, keen research on Parkin over the past decade has led to an explosion of knowledge regarding its physiological roles and its relevance to PD. However, our understanding of Parkin is far from being complete. Indeed, surprises emerge from time to time that compel us to constantly update the paradigm of Parkin function. For example, we now know that Parkin’s function is not confined to mere housekeeping protein quality control (QC) roles but also includes mitochondrial homeostasis and stress-related signaling. Furthermore, emerging evidence also suggest a role for Parkin in several other major neurodegenerative diseases including Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis (ALS). Yet, it remains truly amazing to note that a single enzyme could serve such multitude of functions and cellular roles. Clearly, its activity has to be tightly regulated. In this review, we shall discuss this and how dysregulated Parkin function may precipitate neuronal demise in various neurodegenerative disorders. PMID:26793099

Chronic Oxidative Damage together with Genome Repair Deficiency in the Neurons is a Double Whammy for Neurodegeneration: Is Damage Response Signaling a Potential Therapeutic Target?

PubMed Central

Wang, Haibo; Dharmalingam, Prakash; Vasquez, Velmarini; Mitra, Joy; Boldogh, Istvan; Rao, K. S.; Kent, Thomas A.; Mitra, Sankar; Hegde, Muralidhar L.

2016-01-01

A foremost challenge for the neurons, which are among the most oxygenated cells, is the genome damage caused by chronic exposure to endogenous reactive oxygen species (ROS), formed as cellular respiratory byproducts. Strong metabolic activity associated with high transcriptional levels in these long lived post-mitotic cells render them vulnerable to oxidative genome damage, including DNA strand breaks and mutagenic base lesions. There is growing evidence for the accumulation of unrepaired DNA lesions in the central nervous system (CNS) during accelerated ageing and progressive neurodegeneration. Several germ line mutations in DNA repair or DNA damage response (DDR) signaling genes are uniquely manifested in the phenotype of neuronal dysfunction and are etiologically linked to many neurodegenerative disorders. Studies in our lab and elsewhere revealed that pro-oxidant metals, ROS and misfolded amyloidogenic proteins not only contribute to genome damage in CNS, but also impede their repair/DDR signaling leading to persistent damage accumulation, a common feature in sporadic neurodegeneration. Here, we have reviewed recent advances in our understanding of the etiological implications of DNA damage vs. repair imbalance, abnormal DDR signaling in triggering neurodegeneration and potential of DDR as a target for the amelioration of neurodegenerative diseases. PMID:27663141

Diurnal, seasonal, and interannual differences in the links of probabilities of derivation of different types Es with solar activity

NASA Astrophysics Data System (ADS)

Petrukhin, Venedict F.; Poddubnaya, I. V.; Ponomarev, Evgenij A.; Sutyrin, Nicolaj A.

2004-12-01

The analysis of the ionospheric data on Irkutsk obtained from 1960 to 1996 was made. Was shown, that the link of probabilities of observation of the sporadic derivations in E-region of ionosphere with solar activity (SA) essentially depends on time of day, season and correlation between solar and geophysical parameters. For different types of sporadic derivations this link has different character and with a different image varies with current of time. It is necessary to mark, that the link of night sporadic derivations (Es such as "f") with solar activity in the summer very high and practically does not vary in time (r=-0.897-/+0.04). The temporary course of coefficients of correlation between solar activity and probability of observation of sporadic stratums (r) of a different type varies depending on the season. Further, for stratums of a type "cl" and "l" the change r happens within increase of SA. At the same time, there is an abnormal behavior of height so f sporadic stratums such as "cl". There is an impression that in a considered time frame there is competition of two factors. One of them - solar activity, which in the norm supports the negative correlation link with frequency of observation and second - a factor of an unknown nature, which has caused evocative anomaly of altitude, becomes dominant above natural negative link.

Modelling the effects of penetrance and family size on rates of sporadic and familial disease.

PubMed

Al-Chalabi, Ammar; Lewis, Cathryn M

2011-01-01

Many complex diseases show a diversity of inheritance patterns ranging from familial disease, manifesting with autosomal dominant inheritance, through to simplex families in which only one person is affected, manifesting as apparently sporadic disease. The role of ascertainment bias in generating apparent patterns of inheritance is often overlooked. We therefore explored the role of two key parameters that influence ascertainment, penetrance and family size, in rates of observed familiality. We develop a mathematical model of familiality of disease, with parameters for penetrance, mutation frequency and family size, and test this in a complex disease: amyotrophic lateral sclerosis. Monogenic, high-penetrance variants can explain patterns of inheritance in complex diseases and account for a large proportion of those with no apparent family history. With current demographic trends, rates of familiality will drop further. For example, a variant with penetrance 0.5 will cause apparently sporadic disease in 12% of families of size 10, but 80% of families of size 1. A variant with penetrance 0.9 has only an 11% chance of appearing sporadic in families of a size similar to those of Ireland in the past, compared with 57% in one-child families like many in China. These findings have implications for genetic counselling, disease classification and the design of gene-hunting studies. The distinction between familial and apparently sporadic disease should be considered artificial. Copyright © 2011 S. Karger AG, Basel.

Clinical Presentation and Outcome of Patients With Optic Pathway Glioma.

PubMed

Robert-Boire, Viviane; Rosca, Lorena; Samson, Yvan; Ospina, Luis H; Perreault, Sébastien

2017-10-01

Optic pathway gliomas (OPGs) occur sporadically or in patients with neurofibromatosis type 1 (NF1). The purpose of this study was to evaluate the clinical presentation at diagnosis and at progression of patients with OPGs. We conducted a chart review of patients with OPGs diagnosed in a single center over a period of 15 years. Demographic data including age, sex, NF1 status, clinical presentation, and outcome were collected. Of the 40 patients who were identified, 23 had sporadic tumors (57.5%) and 17 had NF1-related tumors (42.5%). Among the children with NF1, there was a significant overrepresentation of girls (82.3%) (P = 0.02), while among the children without NF1, there were slightly more boys (56.5%) than girls (43.5%). The presence of nystagmus was strongly associated with sporadic optic pathway gliomas. Poor visual outcome was related to tumor affecting both optic pathways, hydrocephalus at diagnosis, and optic nerve atrophy. Of the 40 patients, five died of OPG complications (12.5%) and all had sporadic tumors. Our cohort is one of the largest with OPGs and a detailed description of the clinical presentation both at diagnosis and at progression. We observed a significant difference between sporadic and NF1 optic pathway gliomas in terms of demographics, clinical presentation, and outcome. Copyright © 2017 Elsevier Inc. All rights reserved.

Cognitive deficits in amyotrophic lateral sclerosis evaluated by event-related potentials.

PubMed

Ogawa, Tomohiro; Tanaka, Hideaki; Hirata, Koichi

2009-04-01

To determine the cognitive profiles in non-demented, relatively less handicapped patients with early-stage sporadic amyotrophic lateral sclerosis (ALS) by using neuropsychological tests, event-related potentials (ERPs) and clinical scale. We recruited 19 patients with sporadic ALS (eight with limb-onset, 11 with bulbar-onset) and 19 controls. In addition to the mini-mental state examination and the Wechsler adult intelligence scale-revised, we assessed the frontal lobe function with Wisconsin card sorting test, Stroop test and trail making test. We used auditory 'oddball' counting paradigm for the ERPs under 20-channel electroencephalogram (EEG) recording. Global field power (GFP) was computed, and its peak amplitudes and latencies of N1/N2/P3 were determined. The results of ERP and neuropsychological tests were correlated with respiratory function and clinical scale. No global cognitive impairment except for subtle frontal dysfunction was detected, although N1/N2/P3 GFP latencies were significantly prolonged in ALS patients than in the controls. Vital capacity correlated with P3 GFP amplitude, and the relative bulbar functional rating scale correlated with P3 GFP latency. Our findings indicated the presence of sub-clinical cognitive deficits in non-demented, sporadic ALS patients. In addition, clinical sub-types and respiratory function dependently influenced cognitive function in patients with sporadic ALS. ERP confirmed cognitive impairment in patients with sporadic ALS.

Non compaction cardiomyopathy: Review of a controversial entity.

PubMed

Lorca, Rebeca; Rozado, José; Martín, María

2018-05-11

Non-compaction cardiomyopathy is a heterogeneous and complex entity concerning which there are still many doubts to be resolved. While the American Heart Association includes it among genetic cardiomyopathies, the European Society of Cardiology treats it as an unclassified cardiomyopathy. It may present in a sporadic or familial form, isolated or associated with other heart diseases, affecting only the left ventricle or both and can sometimes appear as a mixed phenotype in patients with other cardiomyopathies. Different forms of clinical presentation are also associated with its different morphological manifestations, and even non-compaction of the left ventricle may be triggered by other physiological or pathological processes. The purpose of this review is an update of this entity and its controversies. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Absence of mutations in PAX8, NKX2.5, and TSH receptor genes in patients with thyroid dysgenesis.

PubMed

Brust, Ester S; Beltrao, Cristine B; Chammas, Maria C; Watanabe, Tomoco; Sapienza, Marcelo T; Marui, Suemi

2012-04-01

To precisely classify the various forms of TD, and then to screen for mutations in transcription factor genes active in thyroid development. Patients underwent ultrasound, thyroid scan, and serum thyroglobulin measurement to accurately diagnose the form of TD. DNA was extracted from peripheral leukocytes. The PAX8, and NKX2.5 genes were evaluated in all patients, and TSH receptor (TSHR) gene in those with hypoplasia. In 27 nonconsanguineous patients with TD, 13 were diagnosed with ectopia, 11 with hypoplasia, and 3 with athyreosis. No mutations were detected in any of the genes studied. Sporadic cases of TD are likely to be caused by epigenetic factors, rather than mutations in thyroid transcription factors or genes involved in thyroid development.

Expression of miRNA-26b-5p and its target TRPS1 is associated with radiation exposure in post-Chernobyl breast cancer.

PubMed

Wilke, Christina M; Hess, Julia; Klymenko, Sergiy V; Chumak, Vadim V; Zakhartseva, Liubov M; Bakhanova, Elena V; Feuchtinger, Annette; Walch, Axel K; Selmansberger, Martin; Braselmann, Herbert; Schneider, Ludmila; Pitea, Adriana; Steinhilber, Julia; Fend, Falko; Bösmüller, Hans C; Zitzelsberger, Horst; Unger, Kristian

2018-02-01

Ionizing radiation is a well-recognized risk factor for the development of breast cancer. However, it is unknown whether radiation-specific molecular oncogenic mechanisms exist. We investigated post-Chernobyl breast cancers from radiation-exposed female clean-up workers and nonexposed controls for molecular changes. Radiation-associated alterations identified in the discovery cohort (n = 38) were subsequently validated in a second cohort (n = 39). Increased expression of hsa-miR-26b-5p was associated with radiation exposure in both of the cohorts. Moreover, downregulation of the TRPS1 protein, which is a transcriptional target of hsa-miR-26b-5p, was associated with radiation exposure. As TRPS1 overexpression is common in sporadic breast cancer, its observed downregulation in radiation-associated breast cancer warrants clarification of the specific functional role of TRPS1 in the radiation context. For this purpose, the impact of TRPS1 on the transcriptome was characterized in two radiation-transformed breast cell culture models after siRNA-knockdown. Deregulated genes upon TRPS1 knockdown were associated with DNA-repair, cell cycle, mitosis, cell migration, angiogenesis and EMT pathways. Furthermore, we identified the interaction partners of TRPS1 from the transcriptomic correlation networks derived from gene expression data on radiation-transformed breast cell culture models and sporadic breast cancer tissues provided by the TCGA database. The genes correlating with TRPS1 in the radiation-transformed breast cell lines were primarily linked to DNA damage response and chromosome segregation, while the transcriptional interaction partners in the sporadic breast cancers were mostly associated with apoptosis. Thus, upregulation of hsa-miR-26b-5p and downregulation of TRPS1 in radiation-associated breast cancer tissue samples suggests these molecules representing radiation markers in breast cancer. © 2017 UICC.

Evidence-based risk assessment and communication: a new global dengue-risk map for travellers and clinicians#

PubMed Central

Lash, R. Ryan; Johansson, Michael A.; Sharp, Tyler M.; Henry, Ronnie; Brady, Oliver J.; Sotir, Mark J.; Hay, Simon I.; Margolis, Harold S.; Brunette, Gary W.

2016-01-01

Abstract Background: International travel can expose travellers to pathogens not commonly found in their countries of residence, like dengue virus. Travellers and the clinicians who advise and treat them have unique needs for understanding the geographic extent of risk for dengue. Specifically, they should assess the need for prevention measures before travel and ensure appropriate treatment of illness post-travel. Previous dengue-risk maps published in the Centers for Disease Control and Prevention’s Yellow Book lacked specificity, as there was a binary (risk, no risk) classification. We developed a process to compile evidence, evaluate it and apply more informative risk classifications. Methods: We collected more than 839 observations from official reports, ProMED reports and published scientific research for the period 2005–2014. We classified each location as frequent/continuous risk if there was evidence of more than 10 dengue cases in at least three of the previous 10 years. For locations that did not fit this criterion, we classified locations as sporadic/uncertain risk if the location had evidence of at least one locally acquired dengue case during the last 10 years. We used expert opinion in limited instances to augment available data in areas where data were sparse. Results: Initial categorizations classified 134 areas as frequent/continuous and 140 areas as sporadic/uncertain. CDC subject matter experts reviewed all initial frequent/continuous and sporadic/uncertain categorizations and the previously uncategorized areas. From this review, most categorizations stayed the same; however, 11 categorizations changed from the initial determinations. Conclusions: These new risk classifications enable detailed consideration of dengue risk, with clearer meaning and a direct link to the evidence that supports the specific classification. Since many infectious diseases have dynamic risk, strong geographical heterogeneities and varying data quality and availability, using this approach for other diseases can improve the accuracy, clarity and transparency of risk communication. PMID:27625400

Evidence-based risk assessment and communication: a new global dengue-risk map for travellers and clinicians.

PubMed

Jentes, Emily S; Lash, R Ryan; Johansson, Michael A; Sharp, Tyler M; Henry, Ronnie; Brady, Oliver J; Sotir, Mark J; Hay, Simon I; Margolis, Harold S; Brunette, Gary W

2016-06-01

International travel can expose travellers to pathogens not commonly found in their countries of residence, like dengue virus. Travellers and the clinicians who advise and treat them have unique needs for understanding the geographic extent of risk for dengue. Specifically, they should assess the need for prevention measures before travel and ensure appropriate treatment of illness post-travel. Previous dengue-risk maps published in the Centers for Disease Control and Prevention's Yellow Book lacked specificity, as there was a binary (risk, no risk) classification. We developed a process to compile evidence, evaluate it and apply more informative risk classifications. We collected more than 839 observations from official reports, ProMED reports and published scientific research for the period 2005-2014. We classified each location as frequent/continuous risk if there was evidence of more than 10 dengue cases in at least three of the previous 10 years. For locations that did not fit this criterion, we classified locations as sporadic/uncertain risk if the location had evidence of at least one locally acquired dengue case during the last 10 years. We used expert opinion in limited instances to augment available data in areas where data were sparse. Initial categorizations classified 134 areas as frequent/continuous and 140 areas as sporadic/uncertain. CDC subject matter experts reviewed all initial frequent/continuous and sporadic/uncertain categorizations and the previously uncategorized areas. From this review, most categorizations stayed the same; however, 11 categorizations changed from the initial determinations. These new risk classifications enable detailed consideration of dengue risk, with clearer meaning and a direct link to the evidence that supports the specific classification. Since many infectious diseases have dynamic risk, strong geographical heterogeneities and varying data quality and availability, using this approach for other diseases can improve the accuracy, clarity and transparency of risk communication. Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.

Quantifying CNS protein production and clearance rates in humans using in vivo stable isotope labeling, immunoprecipitation, and tandem mass spectrometry

PubMed Central

Bateman, Randall J.; Munsell, Ling Y.; Morris, John C.; Swarm, Robert; Yarasheski, Kevin E.; Holtzman, David M.

2008-01-01

Certain disease states are characterized by disturbances in protein production, accumulation, or clearance. In the central nervous system (CNS), alterations in metabolism of proteins such as amyloid-beta (Aβ), alpha-synuclein, or tau may cause degenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease or fronto-temporal dementias respectively. In AD, dysregulation of Aβ metabolism is indicated by a massive buildup of this protein in the brains of those with AD. In rare, autosomal dominant forms of AD, mutations in the amyloid precursor protein or in components of the enzymes which produce Aβ (presenilin-1 and presenilin-2) appear to result in Aβ overproduction. However, whether dysregulation of Aβ metabolism (increased synthesis or clearance) causes the most common form of AD (sporadic >99%) is not known. Furthermore, there has not been a method available which could determine the synthesis or clearance rate of Aβ or any other protein produced in the CNS. This report describes a method to determine the production rate and clearance rate of proteins produced by the CNS in vivo in humans. We report the first measurements of the fractional production and clearance rates of Aβ in vivo in the human CNS to be 7.6%/hr and 8.2%/hr respectively. This method may be used to search for novel biomarkers of disease, assess underlying differences in protein metabolism that contribute to disease, and to evaluate treatments in terms of their pharmacodynamic properties on proposed disease causing pathways. PMID:16799555

Recurrent pregnancy loss: evaluation and treatment.

PubMed

Shahine, Lora; Lathi, Ruth

2015-03-01

Recurrent pregnancy loss (RPL) is a multifactorial condition. Approximately half of patients with RPL will have no explanation for their miscarriages. De novo chromosome abnormalities are common in sporadic and recurrent pregnancy loss. Testing for embryonic abnormalities can provide an explanation for the miscarriage in many cases and prognostic information. Regardless of the cause of RPL, patients should be reassured that the prognosis for live birth with an evidence-based approach is excellent for most patients. The authors review current evidence for the evaluation and treatment of RPL and explore the proposed use of newer technology for patients with RPL. Copyright © 2015 Elsevier Inc. All rights reserved.

The Genetic Basis of Pheochromocytoma and Paraganglioma: Implications for Management

PubMed Central

Shuch, Brian; Ricketts, Christopher J.; Pacak, Karol; Linehan, W. Marston

2015-01-01

Chromaffin cells are catecholamine-producing cells derived from neural crest tissue. Chromaffin tumors (ChT) are rare tumors arising from these cells and are divided into pheochromocytoma (PCC) arising from adrenal tissue and paraganglioma (PGL) arising from extra-adrenal ganglia. Previously, ∼10% were believed to be hereditary, but advances in genome sequencing has shown roughly 35% of apparently sporadic tumors have a hereditary component. In this review we describe both classic and newly discovered hereditary ChT syndromes and provide recommendations for genetic testing. In many cases the genes associated with these conditions are linked to common kidney cancer pathways familiar to urologic oncologists. PMID:24642075

Down syndrome, RASopathies, and other rare syndromes.

PubMed

Kratz, Christian P; Izraeli, Shai

2017-04-01

In this article we discuss the occurrence of myeloid neoplasms in patients with a range of syndromes that are due to germline defects of the RAS signaling pathway and in patients with trisomy 21. Both RAS mutations and trisomy 21 are common somatic events contributing to leukemogenis. Thus, the increased leukemia risk observed in children affected by these conditions is biologically highly plausible. Children with myeloid neoplasms in the context of these syndromes require different treatments than children with sporadic myeloid neoplasms and provide an opportunity to study the role of trisomy 21 and RAS signaling during leukemogenesis and development. Copyright © 2017 Elsevier Inc. All rights reserved.

Campylobacter in poultry: filling an ecological niche.

PubMed

Lee, Margie D; Newell, Diane G

2006-03-01

Epidemiological studies indicate that Campylobacter species may be responsible for the majority of cases of sporadic gastroenteritis in humans. These studies also suggest that poultry may be one of the most common sources of the bacteria for humans. Campylobacter and related genera in the family Campylobacteraceae are oral and intestinal commensals of vertebrates and some nonvertebrates, a characteristic that complicates rational approaches to controlling Campylobacter contamination of poultry. This review will discuss the phylogeny, genomics, and physiology of campylobacters with the intention of revealing how these organisms have evolved to fill their intestinal ecological niche in poultry and how their physiology must be understood in order to enact effective control strategies.

Urbanization of human visceral leishmaniasis in Morocco.

PubMed

Kahime, Kholoud; Boussaa, Samia; Nhammi, Haddou; Boumezzough, Ali

2017-11-01

Human visceral leishmaniasis one of the seven most neglected tropical diseases in the world. In Morocco, HVL is widespread in all regions; but it is more common in the northern part with sporadic cases observed in the South. During the period between 2004 and 2013, the most affected Moroccan provinces were Taounate province, with 220 cases (16.09% of all cases), followed by Chefchaouen with 13.17% and Taza with 10.46% of the total cases. Children < 5 years old are the most affected age group, most cases registered were male. Geographic distribution of HVL showed predominance in rural areas but we noted that it's opening to be urban.

Schwannomatosis, sporadic schwannomatosis, and familial schwannomatosis: a surgical series with long-term follow-up. Clinical article.

PubMed

Gonzalvo, Augusto; Fowler, Adam; Cook, Raymond John; Little, Nicholas Scott; Wheeler, Helen; McDonald, Kerrie L; Biggs, Michael Thomas

2011-03-01

The aim of this study was to provide disease-specific information about schwannomatosis in its different forms and to present 2 particular cases of malignant schwannomas in the context of familial schwannomatosis (FS). The authors analyzed patients with pathologically defined schwannomas and identified those with varied forms of schwannomatosis. Each case was retrospectively analyzed for patient sex and age, number of operations and tumors excised, symptoms, location and size of tumors, extent of resection, nerve function pre- and postoperatively, complications, other nonsurgically treated tumors, malignancy, results of brain MR imaging, and follow-up data. One hundred fifty-eight patients underwent the excision of 216 schwannomas. One hundred forty-two patients presented with solitary schwannomas, 2 had neurofibromatosis Type 2 (NF2), and 14 presented with schwannomatosis. The average follow-up was 52 months. Six individuals had sporadic schwannomatosis, whereas 8 had the familial form of the disease. These 14 patients had an average age of 28.3 years at the time of disease onset (median 27.5 years) and 35.4 years at the time of the first operation (median 37 years) Thirteen of the 14 patients with schwannomatosis experienced pain as the first symptom. Eight (57%) of the 14 patients presented with at least 1 tumor in the spinal canal or attached to the spinal nerve roots. Malignant schwannomas developed in 2 patients from the same family during the follow-up. Patients suffering from schwannomatosis tend to be younger than those presenting with solitary schwannomas. Therefore, individuals presenting at a young age with multiple schwannomas but not meeting the criteria for NF2 should prompt the physician to suspect schwannomatosis. Patients with schwannomatosis who report pain should be exhaustively examined. The spine is affected in the majority of patients, and MR imaging of the spine should be part of the routine evaluation. Rapid enlargement of schwannomas in the context of FS should raise suspicion of malignant transformation.

[Molecular genetics of familial tumour syndromes of the central nervous system].

PubMed

Murnyák, Balázs; Szepesi, Rita; Hortobágyi, Tibor

2015-02-01

Although most of the central nervous system tumours are sporadic, rarely they are associated with familial tumour syndromes. These disorders usually present with an autosomal dominant inheritance and neoplasia develops at younger age than in sporadic cases. Most of these tumours are bilateral, multiplex or multifocal. The causative mutations occur in genes involved in cell cycle regulation, cell growth, differentiation and DNA repair. Studying these hereditary cancer predisposition syndromes associated with nervous system tumours can facilitate the deeper understanding of the molecular background of sporadic tumours and the development of novel therapeutic agents. This review is an update on hereditary tumour syndromes with nervous system involvement with emphasis on molecular genetic characteristics and their clinical implications.

Small molecule kinase inhibitors for LRRK2 and their application to Parkinson's disease models.

PubMed

Kramer, Thomas; Lo Monte, Fabio; Göring, Stefan; Okala Amombo, Ghislaine Marlyse; Schmidt, Boris

2012-03-21

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Several single gene mutations have been linked to this disease. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) indicate LRRK2 as promising therapeutic target for the treatment of PD. LRRK2 mutations were observed in sporadic as well as familial PD patients and have been investigated intensively. LRRK2 is a large and complex protein, with multiple enzymatic and protein-interaction domains, each of which is effected by mutations. The most common mutation in PD patients is G2019S. Several LRRK2 inhibitors have been reported already, although the crystal structure of LRRK2 has not yet been determined. This review provides a summary of known LRRK2 inhibitors and will discuss recent in vitro and in vivo results of these inhibitors.

Trichoderma theobromicola and T. paucisporum: two new species isolated from cacao in South America.

PubMed

Samuels, Gary J; Suarez, Carmen; Solis, Karina; Holmes, Keith A; Thomas, Sarah E; Ismaiel, Adnan; Evans, Harry C

2006-04-01

Trichoderma theobromicola and T. paucisporum spp. nov. are described. Trichoderma theobromicola was isolated as an endophyte from the trunk of a healthy cacao tree (Theobroma cacao, Malvaceae) in Amazonian Peru; it sporulates profusely on common mycological media. Trichoderma paucisporum is represented by two cultures that were obtained in Ecuador from cacao pods partially infected with frosty pod rot, Moniliophthora roreri; it sporulates sporadically and most cultures remain sterile on common media and autoclaved rice. It sporulates more reliably on synthetic low-nutrient agar (SNA) but produces few conidia. Trichoderma theobromicola was reintroduced into cacao seedlings through shoot inoculation and was recovered from stems but not from leaves, indicating that it is an endophytic species. Both produced a volatile/diffusable antibiotic that inhibited development of M. roreri in vitro and on-pod trials. Neither species demonstrated significant direct in vitro mycoparasitic activity against M. roreri.

Environmental surveillance during an outbreak of tularaemia in hares, the Netherlands, 2015

PubMed Central

Janse, Ingmar; Maas, Miriam; Rijks, Jolianne M; Koene, Miriam; van der Plaats, Rozemarijn QJ; Engelsma, Marc; van der Tas, Peter; Braks, Marieta; Stroo, Arjan; Notermans, Daan W; de Vries, Maaike C; Reubsaet, Frans; Fanoy, Ewout; Swaan, Corien; Kik, Marja JL; IJzer, Jooske; Jaarsma, Ryanne I; van Wieren, Sip; de Roda-Husman, Ana Maria; van Passel, Mark; Roest, Hendrik-Jan; van der Giessen, Joke

2017-01-01

Tularaemia, a disease caused by the bacterium Francisella tularensis, is a re-emerging zoonosis in the Netherlands. After sporadic human and hare cases occurred in the period 2011 to 2014, a cluster of F. tularensis-infected hares was recognised in a region in the north of the Netherlands from February to May 2015. No human cases were identified, including after active case finding. Presence of F. tularensis was investigated in potential reservoirs and transmission routes, including common voles, arthropod vectors and surface waters. F. tularensis was not detected in common voles, mosquito larvae or adults, tabanids or ticks. However, the bacterium was detected in water and sediment samples collected in a limited geographical area where infected hares had also been found. These results demonstrate that water monitoring could provide valuable information regarding F. tularensis spread and persistence, and should be used in addition to disease surveillance in wildlife. PMID:28877846

The epidemiology of supernumerary teeth and the associated molecular mechanism

PubMed Central

Lu, Xi; Yu, Fang; Liu, Junjun; Cai, Wenping; Zhao, Yumei; Zhao, Shouliang; Liu, Shangfeng

2017-01-01

ABSTRACT Supernumerary teeth are common clinical dental anomalies. Although various studies have provided abundant information regarding genes and signaling pathways involved in tooth morphogenesis, which include Wnt, FGF, BMP, and Shh, the molecular mechanism of tooth formation, especially for supernumerary teeth, is still unclear. In the population, some cases of supernumerary teeth are sporadic, while others are syndrome-related with familial hereditary. The prompt and accurate diagnosis of syndrome related supernumerary teeth is quite important for some distinctive disorders. Mice are the most commonly used model system for investigating supernumerary teeth. The upregulation of Wnt and Shh signaling in the dental epithelium results in the formation of multiple supernumerary teeth in mice. Understanding the molecular mechanism of supernumerary teeth is also a component of understanding tooth formation in general and provides clinical guidance for early diagnosis and treatment in the future. PMID:28598258

Effects of over-the-counter analgesic use on reproductive hormones and ovulation in healthy, premenopausal women

PubMed Central

Matyas, R.A.; Mumford, S.L.; Schliep, K.C.; Ahrens, K.A.; Sjaarda, L.A.; Perkins, N.J.; Filiberto, A.C.; Mattison, D.; Zarek, S.M.; Wactawski-Wende, J.; Schisterman, E.F.

2015-01-01

STUDY QUESTION Does use of commonly used over-the-counter (OTC) pain medication affect reproductive hormones and ovulatory function in premenopausal women? SUMMARY ANSWER Few associations were found between analgesic medication use and reproductive hormones, but use during the follicular phase was associated with decreased odds of sporadic anovulation after adjusting for potential confounders. WHAT IS KNOWN ALREADY Analgesic medications are the most commonly used OTC drugs among women, but their potential effects on reproductive function are unclear. STUDY DESIGN, SIZE, DURATION The BioCycle Study was a prospective, observational cohort study (2005–2007) which followed 259 women for one (n = 9) or two (n = 250) menstrual cycles. PARTICIPANTS, SETTING, METHODS Two hundred and fifty-nine healthy, premenopausal women not using hormonal contraception and living in western New York state. Study visits took place at the University at Buffalo. MAIN RESULTS AND THE ROLE OF CHANCE During study participation, 68% (n = 175) of women indicated OTC analgesic use. Among users, 45% used ibuprofen, 33% acetaminophen, 10% aspirin and 10% naproxen. Analgesic use during the follicular phase was associated with decreased odds of sporadic anovulation after adjusting for age, race, body mass index, perceived stress level and alcohol consumption (OR 0.36 [0.17, 0.75]). Results remained unchanged after controlling for potential confounding by indication by adjusting for ‘healthy’ cycle indicators such as amount of blood loss and menstrual pain during the preceding menstruation. Moreover, luteal progesterone was higher (% difference = 14.0, −1.6–32.1, P = 0.08 adjusted) in cycles with follicular phase analgesic use, but no associations were observed with estradiol, LH or FSH. LIMITATIONS, REASONS FOR CAUTION Self-report daily diaries are not validated measures of medication usage, which could lead to some classification error of medication use. We were also limited in our evaluation of aspirin and naproxen which were used by few women. WIDER IMPLICATIONS OF THE FINDINGS The observed associations between follicular phase analgesic use and higher progesterone and a lower probability of sporadic anovulation indicate that OTC pain medication use is likely not harmful to reproduction function, and certain medications possibly improve ovulatory function. STUDY FUNDING/COMPETING INTERESTS This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract # HHSN275200403394C). The authors have no conflicts of interest to disclose. PMID:25954035

Role and Treatment of Mitochondrial DNA-Related Mitochondrial Dysfunction in Sporadic Neurodegenerative Diseases

PubMed Central

Swerdlow, Russell H.

2012-01-01

Several sporadic neurodegenerative diseases display phenomena that directly or indirectly relate to mitochondrial function. Data suggesting altered mitochondrial function in these diseases could arise from mitochondrial DNA (mtDNA) are reviewed. Approaches for manipulating mitochondrial function and minimizing the downstream consequences of mitochondrial dysfunction are discussed. PMID:21902672

Sporadic radio emission connected with a definite manifestation of solar activity in the near Earth space

NASA Technical Reports Server (NTRS)

Dudnic, A. V.; Zaljubovski, I. I.; Kartashev, V. M.; Shmatko, E. S.

1985-01-01

Sporadic radio emission of near Earth space at the frequency of 38 MHz is shown to appear in the event of a rapid development of instabilities in the ionospheric plasma. The instabilities are generated due to primary ionospheric disturbances occurring under the influence of solar chromospheric flares.

Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome.

PubMed Central

Wilkin, D J; Szabo, J K; Cameron, R; Henderson, S; Bellus, G A; Mack, M L; Kaitila, I; Loughlin, J; Munnich, A; Sykes, B; Bonaventure, J; Francomano, C A

1998-01-01

More than 97% of achondroplasia cases are caused by one of two mutations (G1138A and G1138C) in the fibroblast growth factor receptor 3 (FGFR3) gene, which results in a specific amino acid substitution, G380R. Sporadic cases of achondroplasia have been associated with advanced paternal age, suggesting that these mutations occur preferentially during spermatogenesis. We have determined the parental origin of the achondroplasia mutation in 40 sporadic cases. Three distinct 1-bp polymorphisms were identified in the FGFR3 gene, within close proximity to the achondroplasia mutation site. Ninety-nine families, each with a sporadic case of achondroplasia in a child, were analyzed in this study. In this population, the achondroplasia mutation occurred on the paternal chromosome in all 40 cases in which parental origin was unambiguous. This observation is consistent with the clinical observation of advanced paternal age resulting in new cases of achondroplasia and suggests that factors influencing DNA replication or repair during spermatogenesis, but not during oogenesis, may predispose to the occurrence of the G1138 FGFR3 mutations. PMID:9718331

Germline LEMD3 mutations are rare in sporadic patients with isolated melorheostosis.

PubMed

Hellemans, Jan; Debeer, Philippe; Wright, Michael; Janecke, Andreas; Kjaer, Klaus W; Verdonk, Peter C M; Savarirayan, Ravi; Basel, Lina; Moss, Celia; Roth, Johannes; David, Albert; De Paepe, Anne; Coucke, Paul; Mortier, Geert R

2006-03-01

To further explore the allelic heterogeneity within the group of LEMD3-related disorders, we have screened a larger series of patients including 5 probands with osteopoikilosis or Buschke-Ollendorff syndrome (BOS), 2 families with the co-occurrence of melorheostosis and BOS, and 12 unrelated patients with isolated melorheostosis. Seven novel LEMD3 mutations were identified, all predicted to result in loss-of-function of the protein. We confirm that loss-of-function mutations in the LEMD3 gene can result in either osteopoikilosis or BOS. However, LEMD3 germline mutations were only found in two melorheostosis patients belonging to a different BOS family and one sporadic patient with melorheostosis. The additional presence of osteopoikilosis lesions in these patients seemed to distinguish them from the group of sporadic melorheostosis patients where no germline LEMD3 mutation was identified. Somatic mosaicism for a LEMD3 mutation in the latter group was also not observed, and therefore we must conclude that the genetic defect in the majority of sporadic and isolated melorheostosis remains unknown. 2006 Wiley-Liss, Inc.

The APOC3 SstI polymorphism is weakly associated with sporadic Alzheimer's disease in a Chinese population.

PubMed

Sun, Yan; Shi, Jiajun; Zhang, Sizhong; Tang, Mouni; Han, Haiying; Guo, Yangbo; Ma, Cui; Liu, Xiehe; Li, Tao

2005-06-03

In order to clarify the relationship of apolipoprotein CIII (APOC3) polymorphism and sporadic Alzheimer's disease (AD) in Chinese, 165 sporadic AD patients and 174 age-matched elderly individuals were genotyped for the APOC3 SstI and apolipoprotein E (APOE) HhaI polymorphisms. As the result, the APOC3 3017G allele was found to be associated with AD in APOE epsilon4 allele noncarriers (chi2=4.433, P=0.035), and the risk estimate of allele C versus G resulted in an OR of 1.56 (95% CI: 1.03-2.37), although in total no significant differences of allelic or genotypic frequencies between patients and controls were found. Assessment of interaction between APOE epsilon4 and APOC3 3017G status presented an adjusted odds ratio of 0.62 (95% CI: 0.37-1.03) with a borderline significant P-value (P=0.066). Therefore, we conclude that the rare APOC3 G allele may offer some protection against the development of sporadic AD in APOE epsilon4 noncarriers in Chinese.

Expression of microRNAs in human post-mortem amyotrophic lateral sclerosis spinal cords provides insight into disease mechanisms.

PubMed

Figueroa-Romero, Claudia; Hur, Junguk; Lunn, J Simon; Paez-Colasante, Ximena; Bender, Diane E; Yung, Raymond; Sakowski, Stacey A; Feldman, Eva L

2016-03-01

Amyotrophic lateral sclerosis is a late-onset and terminal neurodegenerative disease. The majority of cases are sporadic with unknown causes and only a small number of cases are genetically linked. Recent evidence suggests that post-transcriptional regulation and epigenetic mechanisms, such as microRNAs, underlie the onset and progression of neurodegenerative disorders; therefore, altered microRNA expression may result in the dysregulation of key genes and biological pathways that contribute to the development of sporadic amyotrophic lateral sclerosis. Using systems biology analyses on postmortem human spinal cord tissue, we identified dysregulated mature microRNAs and their potential targets previously implicated in functional process and pathways associated with the pathogenesis of ALS. Furthermore, we report a global reduction of mature microRNAs, alterations in microRNA processing, and support for a role of the nucleotide binding protein, TAR DNA binding protein 43, in regulating sporadic amyotrophic lateral sclerosis-associated microRNAs, thereby offering a potential underlying mechanism for sporadic amyotrophic lateral sclerosis. Copyright © 2015 Elsevier Inc. All rights reserved.

SHOX duplications found in some cases with type I Mayer-Rokitansky-Kuster-Hauser syndrome.

PubMed

Gervasini, Cristina; Grati, Francesca Romana; Lalatta, Faustina; Tabano, Silvia; Gentilin, Barbara; Colapietro, Patrizia; De Toffol, Simona; Frontino, Giada; Motta, Francesca; Maitz, Silvia; Bernardini, Laura; Dallapiccola, Bruno; Fedele, Luigi; Larizza, Lidia; Miozzo, Monica

2010-10-01

The Mayer-Rokitansky-Küster-Hauser syndrome is defined as congenital aplasia of müllerian ducts derived structures in females with a normal female chromosomal and gonadal sex. Most cases with Mayer-Rokitansky-Küster-Hauser syndrome are sporadic, although familial cases have been reported. The genetic basis of Mayer-Rokitansky-Küster-Hauser syndrome is largely unknown and seems heterogeneous, and a small number of cases were found to have mutations in the WNT4 gene. The aim of this study was to identify possible recurrent submicroscopic imbalances in a cohort of familial and sporadic cases with Mayer-Rokitansky-Küster-Hauser syndrome. Multiplex ligation-dependent probe amplification was used to screen the subtelomeric sequences of all chromosomes in 30 patients with Mayer-Rokitansky-Küster-Hauser syndrome (sporadic, n = 27 and familial, n = 3). Segregation analysis and pyrosequencing were applied to validate the MLPA results in the informative family. Partial duplication of the Xpter pseudoautosomal region 1 containing the short stature homeobox (SHOX) gene was detected in five patients with Mayer-Rokitansky-Küster-Hauser syndrome (familial, n = 3 and sporadic, n = 2) and not in 53 healthy controls. The duplications were not overlapping, and SHOX was never entirely duplicated. Haplotyping in the informative family revealed that SHOX gene duplication was inherited from the unaffected father and was absent in two healthy sisters. Partial duplication of SHOX gene is found in some cases with both familial and sporadic Mayer-Rokitansky-Küster-Hauser type I syndrome.

Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism.

PubMed

Gozu, Hulya Iliksu; Lublinghoff, Julia; Bircan, Rifat; Paschke, Ralf

2010-06-30

TSH receptor (TSHR) germline mutations occur as activating mutations in familial non-autoimmune hyperthyroidism (FNAH) or sporadic non-autoimmune hyperthyroidism (SNAH). Up to date 17 constitutively activating TSHR mutations have been reported in 24 families with FNAH. The diagnosis of FNAH should be considered in cases with a positive family history, early onset of hyperthyroidism, goiter, absence of clinical stigmata of autoimmunity and recurrent hyperthyroidism. Moreover, 14 subjects with sporadic non-autoimmune hyperthyroidism and 10 different TSH receptor germline mutations have been reported. The main characteristic of SNAH is a negative family history. Additional consequences of prolonged neonatal hyperthyroidism (mental retardation, speech disturbances and craniosynostosis) have often been reported in SNAH. No genotype-phenotype relationship has been reported in patients with germline TSHR mutations. There is no association of in vitro activities determined by linear regression analysis (LRA) and several clinical indicators of hyperthyroidism activity for SNAH. However, the comparison of the LRA values of sporadic TSHR mutations with LRA values of familial TSHR mutations does show a significantly higher median LRA value for sporadic as compared to familial autosomal dominant hyperthyroidism. This finding is in line with the clinical impression of a more active clinical course in patients with SNAH. However, additional genetic, constitutional or environmental factors are most likely responsible for the phenotypic variations of the disease and the lack of correlation between in vitro activities of the TSHR mutations and the severity of hyperthyroidism. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Novel mutations of ABCB6 associated with autosomal dominant dyschromatosis universalis hereditaria.

PubMed

Cui, Ying-Xia; Xia, Xin-Yi; Zhou, Yang; Gao, Lin; Shang, Xue-Jun; Ni, Tong; Wang, Wei-Ping; Fan, Xiao-Buo; Yin, Hong-Lin; Jiang, Shao-Jun; Yao, Bing; Hu, Yu-An; Wang, Gang; Li, Xiao-Jun

2013-01-01

Dyschromatosis universalis hereditaria (DUH) is a rare heterogeneous pigmentary genodermatosis, which was first described in 1933. The genetic cause has recently been discovered by the discovery of mutations in ABCB6. Here we investigated a Chinese family with typical features of autosomal dominant DUH and 3 unrelated patients with sporadic DUH. Skin tissues were obtained from the proband, of this family and the 3 sporadic patients. Histopathological examination and immunohistochemical analysis of ABCB6 were performed. Peripheral blood DNA samples were obtained from 21 affected, 14 unaffected, 11 spouses in the family and the 3 sporadic patients. A genome-wide linkage scan for the family was carried out to localize the causative gene. Exome sequencing was performed from 3 affected and 1 unaffected in the family. Sanger sequencing of ABCB6 was further used to identify the causative gene for all samples obtained from available family members, the 3 sporadic patients and a panel of 455 ethnically-matched normal Chinese individuals. Histopathological analysis showed melanocytes in normal control's skin tissue and the hyperpigmented area contained more melanized, mature melanosomes than those within the hypopigmented areas. Empty immature melanosomes were found in the hypopigmented melanocytes. Parametric multipoint linkage analysis produced a HLOD score of 4.68, with markers on chromosome 2q35-q37.2. A missense mutation (c.1663 C>A, p.Gln555Lys) in ABCB6 was identified in this family by exome and Sanger sequencing. The mutation perfectly cosegregated with the skin phenotype. An additional mutation (g.776 delC, c.459 delC) in ABCB6 was found in an unrelated sporadic patient. No mutation in ABCB6 was discovered in the other two sporadic patients. Neither of the two mutations was present in the 455 controls. Melanocytes showed positive immunoreactivity to ABCB6. Our data add new variants to the repertoire of ABCB6 mutations with DUH.