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PubMed2006

Comparative analysis of two-component signal transduction systems of Bacillus cereus, Bacillus thuringiensis and Bacillus anthracis.

Members of the Bacillus cereus group are ubiquitously present in the environment and can adapt to a wide range of environmental fluctuations. In bacteria, these adaptive responses are generally mediated by two-component signal transduction systems (TCSs), which consist of a histidine kinase (HK) and its cognate response regulator (RR). With the use of in silico techniques, a complete set of HKs and RRs was recovered from eight completely sequenced B. cereus group genomes. By applying a bidirectional best-hits method combined with gene neighbourhood analysis, a footprint of these proteins was made. Around 40 HK-RR gene pairs were detected in each member of the B. cereus group. In addition, each member contained many HK and RR genes not encoded in pairs ("orphans"). Classification of HKs and RRs based on their enzymic domains together with the analysis of two neighbour-joining trees of these domains revealed putative interaction partners for most of the "orphans". Putative biological functions, including involvement in virulence and host-microbe interactions, were predicted for the B. cereus group HKs and RRs by comparing them with those of B. subtilis and other micro-organisms. Remarkably, B. anthracis appeared to lack specific HKs and RRs and was found to contain many truncated, putatively non-functional, HK and RR genes. It is hypothesized that specialization of B. anthracis as a pathogen could have reduced the range of environmental stimuli to which it is exposed. This may have rendered some of its TCSs obsolete, ultimately resulting in the deletion of some HK and RR genes.

Adaptation, Physiological↗
PubMed2004

Some aspects of the taxonomy and biology of dracunculoid nematodes parasitic in fishes: a review.

The nematode superfamily Dracunculoidea includes 166 recognized species, of which 150 (90%) are parasitic in about 300 species of freshwater, brackish-water and marine fishes. Fish dracunculoids are placed in 31 genera (86% of all dracunculoid genera) belonging to eight of the nine dracunculoid families: Anguillicolidae, Daniconematidae, Guyanemidae, Lucionematidae, Micropleuridae, Philometridae, Skrjabillanidae, and Tetanonematidae; the genus Lockenloia is considered incertae sedis. Because of difficulties in studying fish dracunculoids, associated with their morphological and biological peculiarities, most species of these largely histozoic parasites are poorly known and males of the majority of species and of eight genera have not yet been discovered. It is apparent that the present classification system of dracunculoids as a whole does not reflect phylogenetic relationships and a taxonomic revision of this nematode group, based on detailed morphological (including SEM and TEM), life history and molecular studies of individual species, is quite necessary. Data on the biology of fish dracunculoids is scarce. In known cases, their life cycles involve copepods, ostracods or branchiurids as intermediate hosts and, sometimes, fish paratenic hosts are known to occur in dracunculoid species parasitizing as adults piscivorous definitive hosts. However, nothing is known about the life cycles of representatives of 20 genera. Some species of dracunculoids, particularly of philometrids, are highly pathogenic and are known as agents of serious fish diseases. During recent years, especially the importance of Philometra spp. parasitizing the gonads of many species of marine fishes has increased due in particular to the rapid development of marine aquaculture, because they may significantly decrease fish reproduction or even cause full parasitic castration. Therefore, further detailed studies on fish dracunculoids are significant not only from the theoretical viewpoint, but they may also have practical implications.

Animals↗
PubMed1990

Subgroup classification of porcine group-A rotaviruses, using monoclonal antibodies in an enzyme-linked immunosorbent assay.

Fifty-six samples of feces and intestinal contents from nonvaccinated diarrheal pigs with rotavirus infections were tested, using a subgroup (SGP)-specific ELISA, to determine rotavirus SGP classification. Forty-one percent (23/56) were SGP 1, 25% (14/56) were SGP 2, and 34% (19/56) were not classifiable. For classifiable samples, the geographic distribution for SGP 1 and SGP 2, respectively was: 60%/40% from Ohio (n = 15), 63%/37% from other midwestern states (Iowa, Minnesota, Nebraska, South Dakota; n = 16), and 67%/33% from Canada (n = 6). Thirty-seven SGP-classifiable samples were categorized according to age of pigs. Of pigs less than or equal to 1 week old, 22% of samples were SGP 1 (n = 8), and 14% (n = 5) were SGP 2. Of samples from 1- to 2-week-old pigs, 8% were SGP 1 (n = 3), and 5% were SGP 2 (n = 2). Of samples from 2- to 3-week-old pigs, 5% were SGP 1 (n = 2), and 8% were SGP 2 (n = 3). Of samples from 3- to 4-week-old pigs, 5% were SGP 1 (n = 2), and 3% were SGP 2 (n = 1). Of samples from pigs greater than 4 weeks old, 22% were SGP 1 (n = 8) and 8% were SGP 2 (n = 3). Double-stranded RNA extracted from positive controls and from 10 selected field samples (5 from SGP 1 and 5 from SGP 2) was electrophoresed in polyacrylamide gels to detect correlation between subgroup classification by ELISA and long or short double-stranded RNA electrophoretic-migration patterns. All SGP-1 and -2 rotavirus samples tested had typical long double-stranded RNA electrophoretic-migration patterns.

Age Factors↗
PubMed2000

Pathogenic implications of interleukin-8 activity and bacterial phenotype in antral gastritis associated with Helicobacter pylori.

OBJECTIVE: Helicobacter pylori (Hp) infection is characterized by an intense inflammatory infiltrate in the gastric mucosa, which is chemoattracted by different cytokines. Interleukin-8 (IL-8) seems to play an important role in the recruitment of circulating neutrophils, and modulation of IL-8 secretion seems to be a strain marker. This study was designed to examine IL-8 concentrations in the gastric mucosa and their relationship with H. pylori phenotype and histologic findings. METHODS: Gastric biopsies were obtained from the antrum and corpus in 106 patients (69 Hp-positive and 37 Hp-negative). IL-8 levels in the gastric mucosa were analyzed by ELISA and Hp phenotype was determined with a western blot test. RESULTS: 75% of H. pylori strains were CagA+ and 54.2% were VacA+. The Houston classification was used for histologic findings. No association between gastric atrophy or intestinal metaplasia and Hp phenotype was found. The highest IL-8 levels were found in CagA+ infected gastric mucosa, but the difference with respect to infection by a VacA+ strain was not statistically significant. IL-8 levels were highest when neutrophils were the predominant cell in the gastric inflammatory infiltrate (p < 0.05). IL-8 levels were higher in patients with atrophic gastritis than in patients with nonatrophic gastritis (p < 0.05). CONCLUSIONS: In patients with H. pylori infection, IL-8 levels are higher than in Hp-negative patients regardless of Hp phenotype. There is an association between IL-8 and a neutrophilic infiltrate. Perpetuation of a chronic infiltrate could lead to more severe lesions such as atrophic gastritis or intestinal metaplasia, as deduced from the IL-8 levels found in these types of lesion.

Adolescent↗
PubMedDate not supplied

[May Medically Assisted Procreation (MAP) be relevant for homosexual women? Study among 147 gynaeco-logists involved in MAP techniques].

The second part of the twentieth century has seen societal modifications as well as evolution of medical techniques allowing now thinking human procreation in terms of choices or even rights. Certain voices require sometimes Medically Assisted Procreation (MAP) for lesbians. Even though society did not allow such a possibility in France, it seemed interesting to question about it professionals actively involved in the use of MAP techniques. Through systematic internet queries, we obtained a list of one hundred private or public french medical institutions with a unit for the treatment of sterility. A telephone call to their secretary allowed us to individualize those doctors who did practice MAP. A sample of 147 medical doctors practicing MAP was then drawn. They were questioned with a clinical instrument including 20 ended-questions in order to assess their opinions on: homosexual women with a desire of a child; possibility for these clinicians to intervene with a donor insemination in such situations; developmental risk for such children. One hundred twenty five (85%) accepted to answer. Nine percent of these gynaecologists still consider homosexuality as pathological, and 10% as deviant - contrary to international classifications of mental disorders - and 5% deny good maternal abilities to homosexual women. Before the so-called french laws of bioethics in 1994, none of them had practiced a donor insemination for a lesbian couple, though 4% had realized some for single homosexual women. Two third of them do not agree opening donor insemination to homosexual women though for half of them, the anonymity of a donor is not perceived as prejudicial to the child. Eighty-seven percent of these gynaecologists think that a child brought up by homosexual parents is at risk for developmental disorder, the configuration supposed the most pathogenic being when the birth results from a donor insemination. The supposedly most important risk factors are thought to be the marginality of an homosexual family and the lack of a paternal figure at home. However, for 68% of the clinicians, this role can be taken by another male figure. These reasons make the gynaecologists reluctant to participate actively in the constitution of such a kind of family by the practice of a donor insemination. Even though demands of lesbian couples were not listed as an indication of donor insemination in the laws of bioethics, this does not seem to lessen the number of these demands in this population, and moreover if the law would allow this indication, half of these doctors would agree to practice it. The expression of the desire of a child by homosexual women and their request for its realization through medical techniques places the clinicians at the center of an ethical reflexion fed more by personal affects rather than scientific studies - however available - on the development of children brought up by an homosexual couple. Indeed, these studies indicate that these children suffer more from a societal view than parental sexual orientation, and it seems therefore appropriate to shed light on it in order to alleviate the weight of a stigmatization without any clinical argument founding it until now.

Adult↗
PubMed1993

Experimental murine chronic hepatitis: results following intrahepatic inoculation of human uveitis mycoplasma-like organisms.

Mycoplasma-like organisms (MLO) are non-cultivated intracellular cell-wall deficient pathogenic bacteria with a distinctive ultrastructural appearance. Diagnosis of MLO disease depends on finding the organisms in parasitized cells using a transmission electron microscope. MLO are a well studied cause of transmissible chronic plant disease responsive to antibiotics. MLO have recently been found to cause human chronic uveitis, orbital, and retinal disease with autoimmune features. Ophthalmic leucocytes in these patients display MLO parasitization. Inoculation of human uveitis MLO into mouse eyelids produced chronic uveitis. MLO also disseminated to produce randomly distributed lethal systemic disease including chronic hepatitis. MLO parasitized leucocytes were present in all disease sites. Direct intrahepatic inoculation of human hepatic pathogens is a simple and efficient technique to produce murine hepatitis. This report describes the delayed onset widespread inflammatory liver disease produced by direct intrahepatic inoculation of human chronic uveitis MLO in 12 of 20 mice versus 0 in 40 controls (P < 0.05). The liver disease was accompanied by elevated serum SGOT levels, splenomegaly, and accelerated mortality. All 12 inflamed livers displayed MLO parasitized leucocytes versus 0 of 10 control livers. The resemblance of human chronic active hepatitis, massive hepatic necrosis, and post-necrotic cirrhosis to the MLO induced murine liver disease, the role of molecular biologic techniques in the detection and classification of those bacteria, and in therapy of MLO disease are discussed.

Animals↗
PubMed1965

TAXONOMY OF CLOSTRIDIUM BIFERMENTANS AND CLOSTRIDIUM SORDELLII. 3. AGGLUTINABILITY OF HEAT-RESISTANT SUBSTRAINS OFCLOSTRIDIUM SORDELLII.

Huang, C. T. (Kanazawa University, Kanazawa, Japan), Kenzo Tamai, and Shoki Nishida. Taxonomy of Clostridium bifermentans and Clostridium sordellii, III. Agglutinability of heat-resistant substrains of Clostridium sordellii. J. Bacteriol. 90:391-394. 1965.-By cross-agglutination tests with Clostridium bifermentans and C. sordellii antisera, the heat-resistant substrains from each pathogenic strain of C. sordellii were found to possess antigens of C. bifermentans in addition to displaying changes in biological activities. The agglutinability and biological activities varied with the sporulating potency acquired. Agglutinin-absorption tests further proved that heat-resistant substrains of C. sordellii were immunologically identical to C. bifermentans.

Agglutination↗
PubMed2001

Complete coding sequence of the Alkhurma virus, a tick-borne flavivirus causing severe hemorrhagic fever in humans in Saudi Arabia.

To date, tick-borne flaviviruses responsible for hemorrhagic fever in humans have been isolated in Siberia (Omsk hemorrhagic fever virus), India (Kyasanur Forest disease virus, KFDV), and in Saudi Arabia (Alkhurma virus, ALKV). Prior to this study, only partial coding sequences of these severe pathogens had been determined. We report here the complete coding sequence of ALK virus, which was determined to be 10,248 nucleotides (nt) long, and to encode a single 3,416 amino acid polyprotein. Independent analyses of the complete polyprotein and the envelope protein provided genetic and phylogenetic evidence that ALKV belongs to the tick-borne flavivirus group, within which it is most closely related to KFDV. Analysis of structural genes, genetic distances, and evolutionary relationship indicate that ALKV and KFDV derived from a common phylogenetic ancestor and constitute two genetic subtypes of the same virus species according to current genetic criteria of classification.

Flavivirus↗
PubMed1997

Evaluation of the resolving power of three different DNA fingerprinting methods to discriminate among isolates of a natural Rhizobium meliloti population.

In a comparative study, the PCR-based RAPD and ERIC fingerprint methods were evaluated for their resolving power to discriminate among 21 isolates of a natural Rhizobium meliloti population. PCR fingerprint patterns were analysed by using an automated laser fluorescent (ALF) DNA sequencer, thus allowing the automated on-line storage of data. Results obtained were compared to a classification system using insertion sequence (IS) fingerprinting. Both PCR fingerprint methods were comparable in their ability to resolve differences amongst Rh. meliloti isolates. Grouping of strains on the basis of their RAPD as well as their ERIC fingerprints correlated with grouping of strains according to their IS fingerprints. Moreover, strains displaying identical PCR patterns could be further differentiated according to their IS fingerprints, thus allowing a detailed insight into phylogenetic relationship among strains. The automated evaluation of strain-specific fingerprint patterns has the potential to become a valuable tool for studies of bacterial population genetics. Moreover, the rapid identification of single strains, e.g. pathogens in epidemiological studies seems feasible.

Bacterial Typing Techniques↗
PubMed2000

The genetics of mental illness: implications for practice.

Many of the comfortable and relatively simple models of the nature of mental disorders, their causes and their neural substrates now appear quite frayed. Gone is the idea that symptom clusters, course of illness, family history and treatment response would coalesce in a simple way to yield valid diagnoses. Also too simple was the concept, born of early pharmacological successes, that abnormal levels of one or more neurotransmitters would satisfactorily explain the pathogenesis of depression or schizophrenia. Gone is the notion that there is a single gene that causes any mental disorder or determines any behavioural variant. The concept of the causative gene has been replaced by that of genetic complexity, in which multiple genes act in concert with non-genetic factors to produce a risk of mental disorder. Discoveries in genetics and neuroscience can be expected to lead to better models that provide improved representation of the complexity of the brain and behaviour and the development of both. There are likely to be profound implications for clinical practice. The complex genetics of risk should reinvigorate research on the epidemiology and classification of mental disorders and explain the complex patterns of disease transmission within families. Knowledge of the timing of the expression of risk genes during brain development and of their function should not only contribute to an understanding of gene action and the pathophysiology of disease but should also help to direct the search for modifiable environmental risk factors that convert risk into illness. The function of risk genes can only become comprehensible in the context of advances at the molecular, cellular and systems levels in neuroscience and the behavioural sciences. Genetics should yield new therapies aimed not just at symptoms but also at pathogenic processes, thus permitting the targeting of specific therapies to individual patients.

Genetic Predisposition to Disease↗
PubMed2003

Reticular erythrokeratoderma: a new disorder of cornification.

Heritable disorders of cornification form a large, clinically and genetically heterogeneous group. Recent advances in molecular genetics provide for the first time the opportunity to reliably classify some of these disorders based on their underlying etiology. Many rare phenotypes, however, still remain unclassified and do not fit into established classification schemes. We report here a 12-year-old girl who developed an ichthyosis vulgaris-like skin disorder 6 months after birth. Several years later, the clinical features had changed considerably. The patient had developed streaks of hyperkeratotic, slightly scaling skin with underlying erythema distributed in a reticulate, occasionally annular pattern on the trunk and extremities. The lesions were stable and had not changed significantly in size or distribution over the ensuing years. Histopathologic and ultrastructural findings were nonspecific and there was no evidence for metabolic disorders. The partial clinical overlap with erythrokeratodermia variabilis prompted us to screen several connexin genes but no pathogenic mutations were identified. We believe that this disorder belongs to the group of erythrokeratodermas and represents a novel, previously unrecognized entity.

Child↗
PubMed1999

Variations in etiology of ventilator-associated pneumonia across four treatment sites: implications for antimicrobial prescribing practices.

This retrospective multicenter study compared microorganisms documented by quantitative cultures from bronchoscopic samples in episodes of ventilator-associated pneumonia (VAP) from three different institutions in Barcelona (B), Montevideo (M), and Seville (S). The observations were compared with the findings reported by Trouillet and coworkers (AJRCCM 1998;157:531-539) in Paris (P). The objective was to evaluate whether a classification of etiologies of VAP in four groups, based on the number of ventilation days and previous antimicrobial use, might contribute to establishing generalized guidelines for empirical therapy. Significant variations in etiologies (p < 0.05) were found in all of the microorganisms isolated from VAP episodes across three treatment sites when compared with the reference site (P). In Group 1 (< 7 d and absence of antibiotics), Pseudomonas aeruginosa remained extremely infrequent (3 of 89, 3.3%) in the joint category, whereas the incidence of Acinetobacter baumannii was significantly higher, owing to M findings. On the other hand, one site (B) had a significantly lower incidence of multiresistant pathogens (Methicillin-resistant Staphylococcus aureus [MRSA] and nonfermenters other than P. aeruginosa), even in Group 2 (< 7 d and antibiotics), Group 3 (>/= 7 d and absence of antibiotics), and Group 4 (antibiotics and >/= 7 days). Similar findings were documented when episodes were grouped according to Groups 1 and 3 of the ATS guidelines. We conclude that causes of VAP varied markedly across four treatment sites, resulting in the need for large-scale variations in antimicrobial prescribing practices. Instead of following general recommendations, antimicrobial prescribing practices for VAP should be based on up-to-date information of the pattern of multiresistant isolates from each institution.

Adult↗
PubMed1999

Characteristics of atrophic rhinitis in Thai patients at the Siriraj Hospital.

The common characteristics of primary atrophic rhinitis were studied in 46 Thai patients. From history and demographic data the female to male ratio was found to be 5.6 to 1. The significance of environmental factors was supported by the findings that 69.6% were people from rural areas and 43.5% were industrial workers but a hereditary factor has not been confirmed. The results of the blood tests did not elucidate iron deficiency anemia or nutritional deficiency as the cause of primary atrophic rhinitis. However, all nasal swab cultures yielded pathogenic organisms where Klebsiella species especially, K. ozaena, were the most common bacteria isolated which were 100% susceptible to cephalosporins. This finding together with the evidence of sinusitis seen in 58.7% of either plain x-rays or CT scans, was suggestive of the important role of infection in atrophic rhinitis. Atrophic change of the mucosa and bone with widening of the nasal cavity were constant findings in the CT scans but the developmental anomaly of the maxillary antrum was found in only 15.2%. The histological study showed characteristic changes especially squamous metaplasia and 80% of the cases were compatible with the Type II histopathological classification, i.e. vasodilatation of the capillaries. The mucociliary function was proven to be impaired in accordance with the loss of cilia. The evidence of Type I allergy demonstrated by skin testing, which was obvious in 85%, is highly suggestive of allergic/immunologic disorders. Although many factors have been cited previously as the possible cause of primary atrophic rhinitis, the common characteristics found in our patients indicate that only bacterial infection, environmental factors and allergic/immunologic disorders could be one or more of its multifactorial etiology and should be further investigated.

Adolescent↗
PubMed1992

[Barret's esophagus and acid gastroesophageal reflux. Two-channel pH-metric measurements and manometric study].

Although the pathogenic role of gastroesophageal reflux in Barrett's esophagus (BE) is now widely accepted, the pattern of pH profile in the esophagus of patients with BE is not well documented. The aim of this study was to assess the severity and "extent" of acid exposure in patients with BE using an automated single or two-channel 24-hour pH monitoring system. Eighteen patients with histologically proven BE were compared with 3 other groups: a) 100 patients with clinical symptoms and pHmetrically proven acid reflux divided in 2 sub-groups: 38 patients without esophagitis at endoscopy, and 62 patients with esophagitis (Savary-Miller classification; grade I: n = 24, grade II: n = 27, grade III: n = 8, grade IV: n = 3) and b) 9 healthy volunteers. In 17 patients with BE, and in 14 patients with reflux and healthy volunteers, 2 electrodes were placed 5 (electrode E1) and 10 cm (electrode E2) above the lower esophageal sphincter. In the other patients, pH was monitored using a single pH electrode (E1) only. The mucosal acid exposure at E1 (percentage of time below pH 4 on total period, day and night), the number of reflux episodes longer than 5 min were significantly higher in the BE group when compared with the other groups. The number of patients with abnormal acid exposure at E2 was significantly higher (P less than 0.01) in the BE group (15/17 cases) than in the reflux group (5/14 cases). The mean duration of acid reflux was significantly longer in BE than in other groups at both recording sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2003

The biopersistence of Canadian chrysotile asbestos following inhalation.

Chrysotile asbestos is often included with other asbestos materials in evaluation and classification. However, chrysotile is a serpentine with markedly different physical and chemical characteristics in comparison to amphiboles (e.g., crocidolite, amosite, tremolite). In contrast to amphiboles, which are solid, rodlike fibers, chrysotile is composed like a rope of many fine fibrils, which tend to unwind. In order to quantify the dynamics and rate by which chrysotile is removed from the lung, the biopersistence of a sample of commercial chrysotile from the Eastern Townships area of Quebec, Canada, labeled QS Grade 3-F, which is the longest commercial grade intended for textile use, was studied. As the long fibers have been shown to have the greatest potential for pathogenicity, the chrysotile samples were specifically chosen to have more than 200 fibers/cm3 longer than 20 micro m present in the exposure aerosol. This publication presents the results of this study through 3 mo postexposure. The study design included: (1) Fiber clearance (lung digestions): At 1 day, 2 days, 7 days, 14 days, 1 mo, 3 mo, and 12 mo (to be reported) following a 5-day (6 h/day) inhalation exposure, the lungs from groups of animals were digested by low-temperature plasma ashing and subsequently analyzed by transmission electron microscopy for total chrysotile fibers number in the lungs and chrysotile fiber size (length and diameter) distribution in the lungs. (2) Fiber distribution (confocal microscopy): This procedure was included in order to identify the location of the fibers in the lung. At 1 day, 2 days, 7 days, 14 days, 1 month, and 3 months (to be reported) postexposure, the lungs from groups of animals were analyzed by confocal microscopy to determine the anatomic fate, orientation, and distribution of the retained chrysotile fibrils deposited on airways and in the parenchymal region. Chrysotile was found to be rapidly removed from the lung. Fibers longer than 20 micro m were cleared with T(1/2) = 16 days, most likely by dissolution and disintegration into shorter fibers. The shorter fibers were also rapidly cleared from the lung, with fibers 5-20 micro m clearing even faster (T(1/2) = 29.4 days) than those <5 micro m in length. The fibers <5 micro m in length cleared at a rate (T(1/2) = 107 days) that is within the range of clearance for insoluble nuisance dusts. The breaking apart of the longer fibers would be expected to increase the short fiber pool and therefore could account for this difference in clearance rates. The short fibers were not found clumped together but appeared as separate, fine fibrils, occasionally unwound at one end. Short free fibers appeared in the corners of alveolar septa, and fibers or their fragments were found within alveolar macrophages. The same was true of fibers in lymphatics, as they appeared free or within phagocytic lymphocytes. Neutrophil-mediated inflammatory response did not occur in the presence of chrysotile fibers at the time points examined. Taken in context with the scientific literature to date, this report provides new robust data that clearly support the difference seen epidemiologically between chrysotile and amphibole asbestos.

Animals↗
PubMed2026

Automated patch clamp data improve variant classification and penetrance stratification for SCN5A-Brugada syndrome.

BACKGROUND AND AIMS: Brugada Syndrome (BrS) is an inherited arrhythmia disorder that causes an elevated risk of sudden cardiac death. Approximately 20% of patients with BrS have rare variants in SCN5A, which encodes the cardiac sodium channel NaV1.5. Genetic workup of BrS is often complicated by SCN5A variants of uncertain significance (VUS) and/or incomplete penetrance. This study deployed an SCN5A-BrS functional assay at cohort scale to facilitate the implementation of genetic and precision medicine. METHODS: All 252 missense and in-frame insertion/deletion SCN5A variants from a previously published large cohort of BrS cases (n = 3335 patients) were analysed using a calibrated high-throughput automated patch-clamp (APC) assay. Variant functional Z-scores were assigned evidence levels ranging from BS3_moderate (normal function) to PS3_strong (loss-of-function), as defined by American College of Medical Genetics and Genomics criteria. Functional evidence was combined with population frequency, hotspot, case counts, protein-length changes, and in silico predictions. Odds ratios of BrS case-control enrichment and penetrance for BrS were calculated from variant frequencies in the BrS cohort and in gnomAD. RESULTS: Most variants (146/252) were functionally abnormal (Z &#x2264; -2), with 100 having severe loss-of-function (Z &#x2264; -4). Functional evidence enabled the reclassification of 110 of 225 VUS; 104 to likely pathogenic and 6 to likely benign. SCN5A variants with loss-of-function were mainly localized to the transmembrane domains, especially the regions comprising the central pore. SCN5A variant penetrance was proportional to the severity of loss-of-function; variants with Z &#x2264; -6 had penetrance of 24.5% (15.9%-37.7% CI) and an odds ratio of 501 for BrS. CONCLUSIONS: This cohort-scale APC dataset stratifies SCN5A variants found in BrS patients into normal function 'bystander' variants that have a low risk of BrS and loss-of-function variants that have a high risk for BrS. Functional data can be integrated with other criteria to reclassify a substantial fraction of VUS. The dataset helps clarify the SCN5A-BrS relationship and will improve the diagnosis and clinical management of BrS probands and their families.

Humans↗
PubMed2001

Quality management in neuropathology.

Quality management will have an increasing impact on the field of clinical neurosciences. The neuropathological examination of surgical or autopsy samples obtained from the central nervous system (CNS) and related structures, cerebrospinal fluid, peripheral nerve or skeletal muscle serves three major purposes: to identify a structural correlate of the disease, provide a reliable basis for treatment strategies and to investigate underlying pathogenic mechanisms. In order to achieve histopathological diagnosis at a consistent quality, quality management and control have to be implemented at different levels. At the local site, these concern neuropathological services, such as acquisition of tissue specimens, handling and staining procedures as well as diagnostic examination. Training programs offered in slide seminars and diagnostic workshops are important tools to highlight new developments and maintain high standards. National reference centers for brain tumors, neurodegenerative disorders, prion or muscle and nerve diseases assist with a second opinion in difficult cases and support epidemiological as well as clinical therapy trials. An international panel of neuropathologists has established guidelines for the classification of brain tumors, recently updated during a WHO 2000 consensus conference. Finally, the standardized histopathological and cytological diagnosis of CNS disorders plays also an important role in providing quality control for associated fields of the clinical neurosciences, such as neuroradiology, neurology, psychiatry and neurosurgery.

Brain Neoplasms↗
PubMed1984

Different recombinant murine leukemia viruses use different cell surface receptors.

Retroviruses can be grouped by viral interference measurements into classes which use common cell surface receptors. We previously tested a large number of isolates of mink cell focus-inducing (MCF) murine leukemia viruses (MuLVs), and reported that all of them share a distinct receptor on NIH/3T3 cells (A. Rein, Virology 120, 251, 1982). We now extend this generalization to several additional recombinant isolates, including two (SL3-2 and GPA-V2) which would not be considered MCFs on the basis of host-range data. We note the superiority of interference tests, based on positive, unambiguous data, over host-range tests for virus classification. We also show that in contrast to the MCFs, which are all derived from ecotropic MuLVs, a recombinant derived from wild mouse amphotropic MuLV (S. Rasheed et al., Int. J. Cancer 29, 345, 1982) uses a unique receptor on NIH/3T3 cells. This suggests that (a) mouse cells contain more than one type of endogenous env sequence; and (b) there is some specificity in the generation of recombinants, since ecotropic MuLVs appear to give rise only to MCFs, while amphotropic MuLV has generated a distinct type of recombinant. It also represents a second case (in addition to the MCFs) in which an env gene recombinant is more pathogenic than its exogenous parent. We also show that xenotropic MuLV does not interfere with MCFs in NZB mouse cells; thus, despite the close homology between MCF and xenotropic env sequences, the gp70 of xenotropic MuLV appears to have no detectable affinity for the MCF receptor.

Animals↗