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PubMed1996

The variant forms of autoimmune hepatitis.

OBJECTIVES: To review the diagnostic criteria for autoimmune hepatitis, to characterize the variant forms of autoimmune hepatitis, and to indicate appropriate therapies for this condition. DATA SOURCES: A MEDLINE search (1990 to 1995) of the English-language literature, review of a personal library of journals and reprints (1975 to 1995), and review of references selected from the bibliographies of identified articles. Terms used in the MEDLINE search included the names of all autoimmune liver diseases, viral hepatitis and autoimmunity, cryptogenic hepatitis, and overlap syndromes. STUDY SELECTION: All articles that discussed atypical clinical features, mixed diagnostic findings, and variations in treatment response were selected. DATA EXTRACTION: Data were selected from 548 articles. DATA SYNTHESIS: Standardized criteria permit the confident diagnosis of autoimmune hepatitis, but they exclude many patients who have features suggesting autoimmunity. Such patients have findings indicative of both autoimmune hepatitis and another disorder (overlap syndromes) or findings that are inconsistent with the classic definition of autoimmune hepatitis (outlier syndromes). Overlap syndromes include combinations of autoimmune hepatitis and primary biliary cirrhosis, primary sclerosing cholangitis, or chronic viral hepatitis. Treatment of these syndromes requires identification of the predominant disorder and selection of the most appropriate drug regimen. Outlier syndromes include autoimmune cholangitis and cryptogenic chronic hepatitis. Corticosteroids or ursodeoxycholic acid are treatment options for patients with autoimmune cholangitis; corticosteroids can also benefit patients with cryptogenic chronic hepatitis. Grading each clinical feature and developing a composite score can permit comparison of the variants and a determination of the similarity between the variants and autoimmune hepatitis. CONCLUSIONS: Variant forms of autoimmune hepatitis are common. Recognition of them is important in assessing common pathogenic mechanisms, developing effective treatment strategies, and refining classification schemes.

Autoimmune Diseases↗

PubMed2000

[Quasispecies and molecular evolution of viruses].

Ribonucleic acid (RNA) viruses evolve as complex distributions of genetically different but closely related variants termed viral quasispecies. The precise genome of a quasispecies cannot be defined, since the consensus genome is an average of many variants. The dynamics of quasispecies has considerable implications for the understanding of the adaptability and pathogenic potential of viruses, and in addition, for the design of preventive and therapeutic measures for the diseases caused by these viruses. The authors summarise current knowledge on the structure of quasispecies, and the biological implications of this structure.

Adaptation, Biological↗

PubMed2000

Human Herpesvirus 6: an Evolving Story.

First isolated in 1986 from patients with lymphoproliferative disorders, human herpesvirus 6 (HHV-6) is a B-herpesvirus with two variants: HHV-6A and HHV-6B. HHV-6B is the major causal pathogen of exanthem subitum, a predominantly benign exanthematous disease of infants with occasional complications in the central nervous system. Infection with HHV-6 is common among the general population and the virus mainly seems to be transmitted from mother to infant via saliva. Following primary infection, HHV-6 persists latently and can reactivate in immunocompromised hosts, such as in individuals with AIDS or in transplant or multiple sclerosis patients where it possibly causes encephalitis and pneumonitis. Its precise role in these conditions is not well understood and further study is needed.

Journal Article↗

PubMed2002

[The risk of variant Creutzfeldt-Jakob disease in the Netherlands and the effect of preventive measures].

Variant Creutzfeldt-Jakob disease (vCJD) is a fatal and untreatable neurological disease, in which pathogenic prions (PrPSc) are involved. There is convincing epidemiological and experimental evidence that vCJD is a human expression of bovine spongiform encephalopathy (BSE). The risk of transmission of pathogenic prions which cause vCJD to humans is influenced by the species barrier, genetic susceptibility of the host, dose of infection and route of exposure. Transmission of pathogenic prions from bovines to humans is possible through meat products containing nerve and lymphatic tissue, and through medical products derived from bovine material. Human to human transmission is, in principle, also possible via blood and blood-derived products, human organs and tissues for transplantation, and through surgical instruments. Preventive measures to reduce transmission from bovines to humans have been introduced step by step in the Netherlands since 1989. With proper implementation, the current risk of becoming infected by Dutch meat products is small. It is very likely, however, that in the past decade BSE-infected bovines have entered the food chain. The Dutch population has also been exposed to foreign infected meat products. Measures to prevent human to human transmission are currently being improved in the Netherlands. It is expected that cases of vCJD will occur in the Netherlands in the future, but the number cannot be estimated accurately. The presence of PrPSc in both the livestock and in the human population in the Netherlands constitutes a permanent public health threat and is a reason for continued vigilance and active prevention.

Animals↗

PubMed1982

[Clinico-morphologic forms of sepsis (analysis of autopsy material over the past 20 years)].

An analysis of 385 fatal cases of sepsis in therapeutic institutions for the past 20 years was carried out. The septico-pyemic variant was found to be predominant. Bacteriological studies revealed that the predominant causative agent was pathogenic staphylococcus (54.9%), less frequently streptococcus, Escherichia coli, and Pseudomonas aeruginosa. Changes in the spectrum of the causative agents in the last two decades appear to reflect changes in the ecological conditions, immunologic responsiveness of the population, directed natural and therapeutic pathomorphosis. The analysis of the frequency and nature of divergencies in the clinical and pathoanatomic diagnoses indicate certain differences in sepsis diagnosis nowadays.

Adolescent↗

PubMed2005

Impact of genetic diversity of HIV-1 on diagnosis, antiretroviral therapy & vaccine development.

HIV-1 strains have diversified extensively through mutation and recombination since their initial transmission to human beings many decades ago in central Africa. The high error rate of HIV reverse transcriptase combined with the estimated in vivo HIV-1 replication rate of ten billion new virions each day leads to extraordinary genetic diversity of HIV. Twenty seven circulating genetic forms of the HIV-1 group M are presently recognized, including 11 subtypes and sub-subtypes, and 16 circulating recombinant forms (CRF). Genotypic analyses have provided a better understanding of the molecular diversity of HIV-1, enabling the detection of emerging HIV-1 variants and improving the tracking of the epidemic worldwide. The rapid evolution of HIV within infected hosts contributes significantly to the elusiveness of this pathogen from host antiviral responses. The complex nature of HIV envelope glycoprotein that is inherently resistant to neutralization, the selective infection, progressive destruction and impaired regeneration of CD4+ T helper cells, generation of cytotoxic T lymphocyte (CTL) escape mutants, together with high genetic diversity with continually evolving HIV variants worldwide, makes design of an effective vaccine a formidable task. Given the rapidity and unpredictability with which HIV-1 genetic forms may propagate in future, a vaccine protective against all major HIV-1 circulating genetic forms is desirable, which could require multivalent formulations. Understanding the kinetics and directions of this continuing adaptation and its impact on viral fitness, immunogenicity and pathogenicity are crucial to the successful design of effective HIV vaccines. In this review, we focus on extensive diversity of HIV-1, emergence of recombinant forms and their impact on diagnosis, antiretroviral therapy, disease progression, transmission, and vaccine development.

AIDS Vaccines↗

PubMed2000

Studies on linkage and association of atopy with the chromosomal region 12q13-24.

BACKGROUND: Several studies have shown linkage of bronchial asthma, allergic rhinitis and total serum IgE concentration to the chromosomal region 12q13-24 in ethnical diverse populations. This region harbours a number of candidate genes for asthma and atopy, including stem cell factor (SCF), leukotriene A4 hydrolase (LTA4H), thyroid receptor 2 (TR2), and signal transducer and activator of transcription 6 (STAT6). However, the same region was shown as well to be linked to other diseases with inflammatory character. So far no variants in any of these genes have been published which would allow association studies and confirm the pathogenicity of any of these genes. OBJECTIVE: We wanted to test for linkage of the chromosomal region 12q13-24 with the atopic phenotype without regard to clinical manifestations. Furthermore we screened for common nucleotide polymorphisms in candidate genes to enable association studies. METHODS: We employed sib-pair linkage analysis and transmission disequilibrium testing with regard to four highly polymorphic microsatellite markers in 12q13-24 in atopic nuclear families. In addition, we looked for polymorphisms in the genes coding for SCF, LTA4H, TR2 and STAT6 performing SSCP-analysis and direct genomic sequencing. RESULTS: We found no evidence for linkage of the genomic region 12q13-24 to elevated total serum IgE levels, specific sensitization to common inhalant allergens or atopy. Furthermore we identified three nucleotide polymorphisms including one common variant in the gene coding for SCF. No association of this polymorphism and any of the atopic phenotypes was seen. CONCLUSION: We conclude from our data that genes in the chromosomal region 12q13-24 and in particular SCF are unlikely to exert a major effect on the induction of the atopic phenotype in our Caucasian population. However, we did not focus on the asthmatic and thereby inflammatory aspect of atopy which might explain these results in contradiction to previous studies.

Chromosomes, Human, Pair 12↗

PubMed2024

Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci.

The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of ∼2.2-5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci.

Humans↗

PubMed2001

Distribution and structural variation of the she pathogenicity island in enteric bacterial pathogens.

Shigella flexneri serotype 2a carries a chromosomal pathogenicity island (PAI), termed the she PAI, that has been implicated in the pathogenesis of diarrhoeal disease. The complete nucleotide sequence and genetic organisation of the she PAI of S. flexneri 2a strain YSH6000T was determined recently. In the current study the distribution and structure of the she PAI was investigated by PCR and Southern analysis in 65 isolates of enteric pathogens including Shigella spp., enterohaemorrhagic Escherichia coli (EHEC), enteropathogenic E. coli (EPEC), enteroinvasive E. coli (EIEC), Yersinia enterocolitica and Salmonella enterica serovar Typhimurium. The study showed that the she PAI has undergone a variety of structural changes, defined by the presence or absence of specific marker genes in the PAI. The she PAI or structural variants of this element were found in all species of Shigella as well as in EIEC, EHEC and EPEC. No evidence of the PAI was found in Y. enterocolitica or Sal. Typhimurium. The structural form of the she PAI that exists in strain YSH6000T was present in all strains of S. flexneri serotype 2a and in some strains of S. flexneri serotypes 2b and 3c. Variants of the PAI that were missing one or more marker regions were found in all species of Shigella and in pathogenic strains of E. coli. In all strains, the PAIs have inserted into either pheV or a phe tRNA gene in another location on the chromosome. It was concluded that the she PAI is one of several closely related genetic elements that have disseminated throughout Shigella and pathogenic strains of E. coli and diverged into distinct stuctural forms.

DNA-Directed RNA Polymerases↗

PubMed2001

Mechanisms of T cell receptor antagonism: implications in the treatment of disease.

The adaptive immune response is often required for the successful clearing of infectious pathogens. Antigen presenting cells (APC) present peptide antigens derived from pathogens to T cells via major histocompatibility complex (MHC) molecules. T cells then become activated and differentiate into effector cells with the capacity to kill infected cells or to induce an anti-pathogen antibody response. In autoimmunity, this T cell response is directed against self-antigens and often leads to deleterious effects on specific tissues. Likewise, T cell responses to allogeneic MHC molecules in transplants also leads to pathology. By introducing subtle changes in the antigenic peptide amino acid content, T cell activation can be inhibited, thereby preventing T cell effector functions. This strategy of TCR antagonism has been used successfully in vitro and in vivo to inhibit models of autoimmunity and allorecognition. In addition, a variety of pathogens that often result in chronic disease following infection, also have seemingly evolved natural mechanisms to inhibit T cell responses by antagonism. These microorganisms express natural variants of certain proteins, that when presented to T cells have the capacity to specifically inhibit T cell responses by functioning as antagonists or by modulating the nature of the T cell response. The understanding of how pathogens mediate this inhibition in vivo will be beneficial to ongoing studies in both autoimmunity and transplantation aimed at suppressing the harmful immune response, thereby controlling disease. TCR antagonism seems to have the potential to be used therapeutically to prevent or inhibit an undesired T cell response that will ultimately lead to disease.

Animals↗

PubMed1995

Identification and characterization of a locus which regulates multiple functions in Pseudomonas tolaasii, the cause of brown blotch disease of Agaricus bisporus.

Pseudomonas tolaasii, the causal agent of brown blotch disease of Agaricus bisporus, spontaneously gives rise to morphologically distinct stable sectors, referred to as the phenotypic variant form, at the margins of the wild-type colonies. The phenotypic variant form is nonpathogenic and differs from the wild type in a range of biochemical and physiological characteristics. A genomic cosmid clone (pSISG29) from a wild-type P. tolaasii library was shown to be capable of restoring a range of characteristics of the phenotypic variant to those of the wild-type form, when present in trans. Subcloning and saturation mutagenesis analysis with Tn5lacZ localized a 3.0-kb region from pSISG29, designated the pheN locus, required for complementation of the phenotypic variant to the wild-type form. Marker exchange of the Tn5lacZ-mutagenized copy of the pheN locus into the wild-type strain demonstrated that a functional copy of the pheN gene is required to maintain the wild-type pathogenic phenotype and that loss of the pheN gene or its function results in conversion of the wild-type form to the phenotypic variant form. The pheN locus contained a 2,727-bp open reading frame encoding an 83-kDa protein. The predicted amino acid sequence of the PheN protein showed homology to the sensor and regulator domains of the conserved family of two component bacterial sensor regulator proteins. Southern hybridization analysis of pheN genes from the wild type and the phenotypic variant form revealed that DNA rearrangement occurs within the pheN locus during phenotypic variation. Analysis of pheN expression with a pheN::lacZ fusion demonstrated that expression is regulated by environmental factors. These results are related to a model for control for phenotypic variation in P. tolaasii.

Agaricus↗

PubMed2003

Pathophysiology of priapism: dysregulatory erection physiology thesis.

PURPOSE: While a modest amount of medical literature has been written on the topic of priapism, reports heretofore have focused predominantly on diagnostic and management related aspects of the disorder, providing meager information in regard to its pathophysiology. Accordingly the intent of this review was to explore the etiological and pathogenic factors involved in priapism. MATERIALS AND METHODS: The review entailed an overview of traditional and modern concepts that have been applied to the pathophysiology of priapism and an evaluation of assorted observational and experimental data relating to this field of study. The basic exercise consisted of a literature search using the National Library of Medicine PubMed Services, index referencing provided through the Historical Collection of the Institute of Medicine of The Johns Hopkins University and a survey of abstract proceedings from national meetings relevant to priapism. RESULTS: Insight into the pathophysiology of priapism was derived from a synthesis of evolutionary clinical experiences, mythical beliefs, clinical variants and scientific advances associated with the field of priapism. The results can be summarized. 1) Clinicopathological manifestations of priapism support its basic classification into low flow (ischemic) and high flow (nonischemic) hemodynamic categories, commonly attributed to venous outflow occlusion and unregulated arterial overflow of the penis, respectively. 2) Factual information is insufficient to substantiate etiological roles for urethral infection, bladder distention, failed ejaculation, satyriasis and sleep apnea in priapism. 3) Features of the variant forms of priapism invoke changes in nervous system control of erection and penile vascular homeostasis as having pathogenic roles in the disorder. 4) Clinical therapeutic and basic science investigative studies have revealed various effector mechanisms of the erectile tissue response that may act in dysregulated fashion to subserve priapism. CONCLUSIONS: This exercise suggested that, while priapism is commonly defined in terms of adverse mechanical contexts affecting penile circulation, it may also be viewed at least in some situations as an unbalanced erectile response involving derangements in possibly diverse systems of regulatory control. An integrative scientific approach that encompasses tissular, cellular and molecular levels of investigation may allow further understanding of the pathophysiology of the disorder. Ongoing elucidation of this pathophysiology can be expected to promote the development of new priapism therapies.

Greece, Ancient↗

PubMed2004

High reactivation of BK virus variants in Asian Indians with renal disorders and during pregnancy.

There is resurgence of interest in the study of occurrence, genotype and pathogenic associations of human Polyomavirus BK and JC in recent years. In the present study, we have ascertained the presence of BK virus shed in the urine samples of pregnant women and immunocompromised patients, for the first time in Asian Indian population, and have also characterised the prevalent genotypes of the non-coding control regions (NCCRs) of these natural isolates. The results strongly suggest a very high incidence, as well as degree, of BK virus reactivation in this population groups assayed. Approximately 65% of the patients and pregnant women together, tested positive based on polymerase chain reaction (PCR) analysis, and these results were further confirmed by Southern hybridisation and dot blot against BKV specific probes. The NCCRs of the several Indian endemic strains were analysed by sequencing PCR products, amplified directly from urine samples, with oligonucleotide primers designed from the constant region of T-Antigen and VP2 coding sequences. The typical features of the NCCRs of these Indian strains appeared to be comparable and related to the archetypal strain BKV (WW) with some alterations in few key positions. Apart from these subtle alterations, neither any major DNA rearrangement within the NCCR region nor any drastic modification marked BKV strains found in nephropathy and in the healthy subjects (pregnancy). However, in some of the immunocompromised patients studied, the degree of reactivations reflected by viruria, appeared to be much higher compared to other reports.

BK Virus↗

PubMed2025

Mapping genetic and phenotypic diversity of Pseudomonas aeruginosa across clinical and environmental isolation sites.

Pseudomonas aeruginosa is a clinically significant opportunistic pathogen adept at thriving in both host-associated and environmental settings. To define the extent to which P. aeruginosa isolates specialize across niches and identify genotype-phenotype correlates, we performed whole genome sequencing and comprehensive phenotypic characterization of 125 P. aeruginosa isolates from diverse clinical and environmental sites, evaluating virulence-associated traits, including motility, cytotoxicity, biofilm formation, pyocyanin production, and antimicrobial susceptibility. We identify that genomic diversity does not correlate with isolation source or most virulence phenotypes. Instead, we find that the two major P. aeruginosa clades (Groups A and B) delineate phylogeny and cytotoxicity, with Group B strains showing significantly higher cytotoxicity than Group A. Sequence analysis revealed previously uncharacterized alleles of genes encoding type III secretion effector proteins. We observed high variability amongst strains and isolation sources in all four assayed virulence phenotypes. Antimicrobial resistance (AMR) is exclusively observed in clinical isolates, not environmental, reflecting antibiotic exposure-driven selection. Bacterial GWAS revealed a statistically significant association between cytotoxicity and exoU presence, and we identified a novel exoU allelic variant with decreased cytotoxicity, demonstrating that functional diversity within well-characterized virulence factors may still influence pathogenic outcomes. In summary, our analyses of 125 diverse isolates suggest that the ability of P. aeruginosa to thrive across diverse niches is driven by broadly conserved genetic repertoire rather than niche-specific accessory genes.

Journal Article↗

PubMed1991

Ability of a mutagenized virus variant to protect young lambs from Rift Valley fever.

A live attenuated vaccine virus variant of Rift Valley fever (RVF) virus was developed by passaging a human isolate in tissue culture under the influence of the mutagen 5-fluorouracil. This virus variant (MV P12) has been assessed in this study as to its suitability as a vaccine, by testing its pathogenicity in young lambs and measuring its ability to induce a protective immune response. Even high doses of the vaccine virus failed to induce any of the clinical or histopathologic changes associated with classical RVF virus infection. Although the vaccine induced mild pyrexia when given in high doses, viremia was not induced. Neutralizing antibody and a protective immune response was elicited with even low doses of vaccine virus. These data, along with data of other workers on the lack of abortigenicity of this virus variant, indicate that the MV P12 variant of RVF virus is an excellent candidate for a safe and effective vaccine against RVF.

Animals↗

PubMed2006

Oncogenesis of RON receptor tyrosine kinase: a molecular target for malignant epithelial cancers.

Recepteur d'origine nantais (RON) belongs to a subfamily of receptor tyrosine kinases (RTK) with unique expression patterns and biological activities. RON is activated by a serum-derived growth factor macrophage stimulating protein (MSP). The RON gene transcription is essential for embryonic development and critical in regulating certain physiological processes. Recent studies have indicated that altered RON expression contributes significantly to cancer progression and malignancy. In primary tumors, such as colon and breast cancers, overexpression of RON exists in large numbers and is often accompanied by the generation of different splicing variants. These RON variants direct a unique program that controls cell transformation, growth, migration, and invasion, indicating that altered RON expression has the ability to regulate motile/invasive phenotypes. These activities were also seen in transgenic mice, in which targeted expression of RON in lung epithelial cells resulted in numerous tumors with pathological features of human bronchioloalveolar carcinoma. Thus, abnormal RON activation is a pathogenic factor that transduces oncogenic signals leading to uncontrolled cell growth and subsequent malignant transformation. Considering these facts, RON and its variants can be considered as potential targets for therapeutic intervention. Experiments using small interfering RNA and neutralizing monoclonal antibodies demonstrated that suppressing RON expression and activation decreases cancer cell proliferation, increases apoptotic death, prevents tumor formation in nude mice, and reduces malignant phenotypes. Thus, blocking RON expression and activation has clinical significance in reversing malignant phenotypes and controlling tumor growth.

Animals↗

PubMed1994

Immunological variants of the aerobactin-cloacin DF13 outer membrane protein receptor IutA among enteric bacteria.

Mouse monoclonal antibodies (MAbs) were generated against a 76-kDa IutA receptor of pathogenic avian Escherichia coli 15972. Six of the eight IutA-specific MAbs isolated (AB1 to AB6) were shown to be directed toward membrane-exposed conformational epitopes, although they did not interfere with the uptake of ferric aerobactin and cloacin DF13 as assessed by competition experiments with purified ligands. The two remaining IutA MAbs (AB9 and AB10) recognized linear epitopes buried in the IutA molecule. The panel of IutA MAbs was used to characterize IutA variants occurring in strains of E. coli, Klebsiella pneumoniae, Enterobacter spp., and Shigella spp., resulting in the identification of four immunological groups of IutAs. MAb AB9 defined an epitope conserved in all IutA variants. In addition, the panel of IutA MAbs served to identify the presence of IutA in wild-type bacteria grown in the presence of diphenylamine to reduce the expression of O-specific polysaccharide.

Antibodies, Monoclonal↗

PubMed2004

Molecular epidemiology of DFNB1 deafness in France.

BACKGROUND: Mutations in the GJB2 gene have been established as a major cause of inherited non syndromic deafness in different populations. A high number of sequence variations have been described in the GJB2 gene and the associated pathogenic effects are not always clearly established. The prevalence of a number of mutations is known to be population specific, and therefore population specific testing should be a prerequisite step when molecular diagnosis is offered. Moreover, population studies are needed to determine the contribution of GJB2 variants to deafness. We present our findings from the molecular diagnostic screening of the GJB2 and GJB6 genes over a three year period, together with a population-based study of GJB2 variants. METHODS AND RESULTS: Molecular studies were performed using denaturing High Performance Liquid Chromatograghy (DHPLC) and sequencing of the GJB2 gene. Over the last 3 years we have studied 159 families presenting sensorineural hearing loss, including 84 with non syndromic, stable, bilateral deafness. Thirty families were genotyped with causative mutations. In parallel, we have performed a molecular epidemiology study on more than 3000 dried blood spots and established the frequency of the GJB2 variants in our population. Finally, we have compared the prevalence of the variants in the hearing impaired population with the general population. CONCLUSION: Although a high heterogeneity of sequence variation was observed in patients and controls, the 35delG mutation remains the most common pathogenic mutation in our population. Genetic counseling is dependent on the knowledge of the pathogenicity of the mutations and remains difficult in a number of cases. By comparing the sequence variations observed in hearing impaired patients with those sequence variants observed in general population, from the same ethnic background, we show that the M34T, V37I and R127H variants can not be responsible for profound or severe deafness.

Connexin 26↗