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Epidermolysis bullosa acquisita and bullous systemic lupus erythematosus. Diseases of autoimmunity to type VII collagen.

Autoimmunity to C7 is a genetically predisposed condition that results in the production of predominantly IgG class basement membrane autoantibodies that may cause basement membrane damage and subepidermal blisters by at least two pathogenic mechanisms. Autoimmunity to C7 cuts across traditional disease classifications (EBA versus bullous SLE), presents with heterogeneous clinical and pathologic features, mimics other diseases, and may be difficult to diagnose and treat. Autoimmunity to C7 is associated with susceptibility to SLE and perhaps inflammatory bowel disease.

Autoantibodies↗

Classification of Vibrio vulnificus strains by the carbohydrate composition of their capsular polysaccharides.

Pathogenic bacteria are often classified on the basis of the complex polysaccharides found on the surface, usually capsular polysaccharides or lipopolysaccharides. It is common in clinical practice to use reactivity with antisera specific to the various cell surface carbohydrates for this purpose. In this work, we describe a chemotyping method for bacterial capsular polysaccharides which is based on a carbohydrate analysis of an acid hydrolysate of the capsule. High-performance anion-exchange chromatography at high pH (HPAE) with electrochemical detection, which is used for analysis of the hydrolysate, shows preferential sensitivity for sugars. A single acid hydrolysis condition is chosen for screening a large collection of bacterial isolates and a computerized autosampler is used to make possible a large number of rapid analyses. This procedure does not yield a quantitative carbohydrate analysis for the sample but produces a fingerprint which can be used to discriminate among isolates which have different capsular polysaccharide structures. The procedure has been applied to a collection of 120 isolates of Vibrio vulnificus, a water-born species common in shellfish which causes septicemia in immunocompromised individuals, most often from eating of raw oysters. The collection of bacterial isolates includes strains from both clinical cases of septicemia and from such environmental sources such as sea water, sediments, and shellfish. Our results show that a number of unusual sugars including many amino sugars are found in these polysaccharides and that a wide variety of capsular carbotypes in V. vulnificus may be readily distinguished by the HPAE fingerprint.

Anion Exchange Resins↗

Schizophrenia and bipolar disorder: similarities in pathogenic mechanisms but differences in neurodevelopment.

Over the past 100 years, the Kraepelinian classification of psychoses has dominated our approach to schizophrenia and bipolar disorder. However, controversy as to the nature of the illnesses--whether they can be viewed as completely distinct, essentially the same, or occupying different points along a psychosis spectrum--has intensified in recent years. This paper reviews the evidence for these differing opinions, examining both the commonalities between the two diseases and the distinctions. A genetic propensity towards psychotic disorders is widely acknowledged; more recent studies suggest a considerable overlap in genetic susceptibility to schizophrenia and bipolar disorder. The influence of early environmental effects, such as obstetric complications, on schizophrenia is also established but little such evidence exists for bipolar disorder. Structural abnormalities of the brain of developmental origin as well as neuropsychological deficits have been clearly identified in schizophrenia but less evidence has been found in bipolar disorder. The most plausible explanation is that one or more susceptible genes are shared between schizophrenia and bipolar illness, and can be thought of as predisposing individuals to psychosis, perhaps by producing a dysregulation of the dopaminergic response to stress. Other genes and environmental factors are likely to have more specific effects and contribute to producing the patterns that psychiatrists recognize as 'classical' schizophrenia and mania. In particular, genes involved in early cortical development and early neurodevelopmental insults causing developmental impairment may put individuals on a trajectory towards schizophrenia rather than bipolar illness.

Adult↗

Imprecision medicine: Systematic gaps in reporting variants of uncertain significance (VUS) and their reclassifications.

PURPOSE: Variants of uncertain significance (VUS) are frequently encountered during clinical genetic testing. To explore the clinical burden of VUS, we developed the Brotman Baty Institute Clinical Variant Database, which is an electronic health record (EHR)-linked database of clinical germline genetic variant information from patients with rare genetic disorders seen at 2 tertiary academic medical centers. METHODS: We retrospectively reviewed EHRs and genetic testing reports from 5158 patients seen across diverse adult genetics practices at these institutions from 2015 to 2024. We also compared these EHR-based variant classifications with those in ClinVar. RESULTS: The number of reported VUS relative to pathogenic or likely pathogenic variants can vary by over 14-fold depending on the primary indication for genetic testing and 3-fold depending on self-reported race. Furthermore, at least 1.6% of variant classifications used in the EHR for clinical care are outdated based on ClinVar variant classifications, including 26 instances in which the testing lab updated ClinVar, but the reclassification was never communicated to the patient. CONCLUSION: Our findings reveal that the clinical burden of VUS in adult medical genetics is unequally distributed across patients. We also highlight a deficiency in existing systems for communicating variant reclassifications to ClinVar, patients, and providers.

Humans↗

Lupus nephritis. Part II. A clinicopathological correlation and study of outcome.

A 5-year retrospective study of lupus nephritis at Tygerberg Hospital was performed in an attempt to document the clinical and histological spectrum of the disease and to study the outcome of the illness. Activity and chronicity scores were used in addition to the World Health Organisation classification system. Of 55 biopsies from 51 patients reviewed, 6 were class II, 13 class III, 32 class IV and 4 class V. There were 19 deaths and in 15 of these the histological classification was IV. Renal failure and infections, often with uncommon pathogens, were the most important causes of death. Serum creatinine values and creatinine clearance at the time of biopsy or follow-up, and hypertension at follow-up showed a significant relationship with outcome. WHO class IV was associated with a poor outcome (P = 0.048) when compared with the other WHO classes combined. Activity scores showed a significant relationship to the outcome (P = 0.018). The anticardiolipin antibodies IgG and IgM were not associated with WHO class or outcome. The study revealed a spectrum of histological results similar to that of other studies, with a high mortality rate, particularly in class IV disease. Poor renal function, persistent hypertension, histological classification IV, and high activity scores were found to be important prognostic indicators.

Adolescent↗

[Molecular biological analysis of Tinea faciei caused by a clinically anomalous strain of Trichophyton mentagrophytes].

We report a case of Trichophyton mentagrophytes infection. A 27-year-old female dairy worker visited our hospital in August 2001 for evaluation of an erythematous lesion near her right eye. The patient had been treated with antibiotics and an anti-allergic drug at another clinic with no effect on the lesion. KOH preparation of the scale revealed mycelia and T. mentagrophytes was isolated from the culture. The isolated pathogen was identified as T. mentagrophytes animal type 1 by the classification system based on the cluster analysis of nuclear ribosomal internal transcribed spacer 1 (ITS1) DNA sequences. The oral administration of terbinafine at 125 mg/day and antifungal cream was effective. T. mentagrophytes is one of the most common dermatophytes isolated from humans and animals. We should be aware that animals may carry this kind of fungal pathogen.

Administration, Oral↗

[The importance of classifications in psychiatry].

The classifications currently used in psychiatry have different aims: to facilitate communication between researchers and clinicians at national and international levels through the use of a common language, or at least a clearly and precisely defined nomenclature; to provide a nosographical reference system which can be used in practice (diagnosis, prognosis, treatment); to optimize research by ensuring that sample cases are as homogeneous as possible; to facilitate statistical records for public health institutions. A classification is of practical interest only if it is reliable, valid and acceptable to all potential users. In recent decades, there has been a considerable systematic and coordinated effort to improve the methodological approach to classification and categorization in the field of psychiatry, including attempts to create operational definitions, field trials of inter-assessor reliability, attempts to validate the selected nosological categories by analysis of correlation between progression, treatment response, family history and additional examinations. The introduction of glossaries, and particularly of diagnostic criteria, marked a decisive step in this new approach. The key problem remains that of the validity of diagnostic criteria. Ideally, these should be based on demonstrable etiologic or pathogenic data, but such information is rarely available in psychiatry. Current classifications rely on the use of extremely diverse elements in differing degrees: descriptive criteria, evolutive criteria, etiopathogenic criteria, psychopathogenic criteria, etc. Certain syndrome-based classifications such as DSM III and its successors aim to be atheoretical and pragmatic. Others, such as ICD-10, while more eclectic than the different versions of DSM, follow suit by abandoning the terms "disease" and "illness" in favor of the more consensual "disorder". The legitimacy of classifications in the field of psychiatry has been fiercely contested, being variously dubbed "a reductive academic exercise of no relevance to patients", "a dehumanizing labelling system, and a potential source of social and political violence", "a destructive prognostic guide", and so on. Other critics point to various aspects of certain classifications: the abandonment of theoretical concepts, the arbitrary nature of certain categories, the selection of definitions and criteria, the privileged position systematically accorded to the notion of category over that of general dimension. Multiaxial systems such as those proposed in successive versions of DSM or the classifications used in child psychiatry go some way towards meeting these criticisms. They go beyond simple labelling and place the patient in an overall medicopsycho-social setting. Nosographical indicators do not constitute an obstacle to psychopathological understanding. No classifications are capable of satisfactorily fulfilling all needs, namely those of daily practice, research and health statistics. The has led to the development of specialized diagnostic criteria and instruments, as in research for example. It should also be noted in this context that different versions of ICD-10 exist for psychiatrists, general practitioners, researchers and healthcare managers. The greatest danger posed by classifications is the potential reification of hypothetical approaches, arbitrary categorization and the dulling of reflection, all of which have created a need for regular revisions underpinned by field trials.

Humans↗

Classification of Histoplasma capsulatum isolates by restriction fragment polymorphisms.

Twenty isolates of the dimorphic, pathogenic fungus Histoplasma capsulatum were divided into three classes based on comparisons of restriction enzyme digests of their mitochondrial DNA and rDNA. The majority of isolates, including most North American strains and the African H. capsulatum var. duboisii variants, belong to class 2. Isolates from Central America and South America make up class 3. The attenuated Downs strain is the only member of class 1.

Africa↗

Analysis and functional classification of transcripts from the nematode Meloidogyne incognita.

BACKGROUND: Plant parasitic nematodes are major pathogens of most crops. Molecular characterization of these species as well as the development of new techniques for control can benefit from genomic approaches. As an entrée to characterizing plant parasitic nematode genomes, we analyzed 5,700 expressed sequence tags (ESTs) from second-stage larvae (L2) of the root-knot nematode Meloidogyne incognita. RESULTS: From these, 1,625 EST clusters were formed and classified by function using the Gene Ontology (GO) hierarchy and the Kyoto KEGG database. L2 larvae, which represent the infective stage of the life cycle before plant invasion, express a diverse array of ligand-binding proteins and abundant cytoskeletal proteins. L2 are structurally similar to Caenorhabditis elegans dauer larva and the presence of transcripts encoding glyoxylate pathway enzymes in the M. incognita clusters suggests that root-knot nematode larvae metabolize lipid stores while in search of a host. Homology to other species was observed in 79% of translated cluster sequences, with the C. elegans genome providing more information than any other source. In addition to identifying putative nematode-specific and Tylenchida-specific genes, sequencing revealed previously uncharacterized horizontal gene transfer candidates in Meloidogyne with high identity to rhizobacterial genes including homologs of nodL acetyltransferase and novel cellulases. CONCLUSIONS: With sequencing from plant parasitic nematodes accelerating, the approaches to transcript characterization described here can be applied to more extensive datasets and also provide a foundation for more complex genome analyses.

Animals↗

[Basic types of pathogenic infections].

The theory of the pathogenetic basic types renders possible a clinical basic classification of the infectious diseases. The essential qualities and characteristics of the cyclic infectious diseases, of the local infections and of sepsis are again represented in a survey and explained in the light of more recent knowledge.

Humans↗

[Changes in the taxonomy and nomenclature of pathogenic microscopic fungi].

The authors present a survey of medically important microscopic fungi whose classification were critically revised and correctly named in the last few years. The list was adopted from a paper of American mycologists trying to make the nomenclature of mycotic agents more precise and stable. The authors divided the adopted list according to diseases the individual fungi produce and explained less known terms describing mostly non-european mycoses. Notes giving reasons for nomenclature changes supplement the list of names.

Classification↗

Conidiogenesis of fungi pathogenic for man.

Despite an apparent stabilizing of nomenclature and concepts involved in fungal conidiogenesis during the past decade, there is now evidence that a much more complex and demanding approach to the descriptive study of processes involved in conidial formation would allow a more phylogenetically realistic classification of anamorphic fungi. The present review attempts to evaluate data on the human pathogenic molds in light of this new approach and to relate conidiogenesis to the known teleomorph connections of the fungi concerned. It is hoped that by treating the species in groups corresponding to their sexual affinities, it may be possible to infer homologous forms of conidiogenesis by comparative morphology and development.

Arthrodermataceae↗

Uveal Melanoma and the Lynch Syndrome Tumor Spectrum.

IMPORTANCE: To date, no environmental factors and few therapeutic options are known for uveal melanoma (UM), the most common malignant intraocular primary tumor in adults. Identification of new predisposition factors could lead to better monitoring and possibly improved treatments of patients with UM. OBJECTIVE: To identify new genetic alterations predisposing for UM. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study conducted at Institut Curie in Paris, France, among 381 consecutive patients diagnosed with UM between July 2021 and February 2023. UM was diagnosed clinically by ophthalmologists, and a senior pathologist confirmed the diagnosis when tumor or biopsy was available. All participants received genetic counseling and consented to extended genetic testing. A panel of 122 genes predisposing to cancer were analyzed by targeted sequencing on germline DNA from these patients. MAIN OUTCOMES AND MEASURES: Frequency of pathogenic variants (PVs) in genes from a targeted panel, with classification of germline PVs done according to the American College of Medical Genetics and Genomics guidelines and the French Unicancer Genetics Group. RESULTS: A total of 79 PVs were identified in 70 participants (41 female and 29 male; mean [SD] age, 60.6 [15.3] years). Among them, 21 were found in clinically relevant genes, with an enrichment in the mismatch repair (MMR) genes, involved in Lynch syndrome, a frequent predisposition to colon and endometrial cancers. This finding suggested MMR germline PVs could also predispose to UM. One tumor was available from a participant carrying a MLH1 germline PV. The tumor exhibited a monosomy 3 with loss of the wild-type allele of MLH1, located on chromosome 3. Loss of expression of MLH1 was observed by immunohistochemistry, and MMR variant signatures SBS6, ID1, and ID2 were identified from the whole-genome sequencing of this tumor, supporting the possibility that MLH1 contributes to the oncogenesis of this UM. CONCLUSIONS AND RELEVANCE: This prospective germline study on patients with UM provided evidence supporting the notion that MMR germline alterations are enriched among patients with UM and may contribute to oncogenesis of UM, and that UM may therefore be a rare tumor manifestation of Lynch syndrome.

Humans↗

Envelope proteins in Neisseria.

The proteins of the cell envelope of Neisseria sicca strain ATCC 9913 have been examined by SDS - polyacrylamide gel electrophoresis. Some 20 proteins were resolved from the total envelope fraction, and nearly all of these were found to be localized in the outer membrane. Preparations of the "free-endotoxin" fraction differ from the outer membrane only in lacking a few minor proteins. The behavior of several of the envelope proteins on electrophoresis can be modified by changing the temperature of sample solubilization, and also by alteration of the growth medium. Experiments with phosphate-limited cultures showed that certain periplasmic proteins are closely associated with free endotoxin. Mutations which result in altered outer membrane permeability to antibiotics were found to cause changes in cell envelope protein composition. A comparison of the envelope proteins of eight species of non-pathogenic Neisseria showed that each had a characteristic composition. A classification of the organisms based on the relatedness of the protein patterns seen on SDS-polyacrylamide gels was in close agreement with classifications based on more usual methods.

Anti-Bacterial Agents↗

What do we really know about antibiotic pharmacodynamics?

Antibiotic pharmacodynamics is an evolving science that focuses on the relationship between drug concentration and pharmacologic effect, which is an antibiotic-induced bacterial death that also can manifest as an adverse drug reaction. The pharmacologic action of antibiotics usually can be described as concentration dependent or independent, although such classifications are highly reliant on the specific antibiotic and bacterial pathogen being studied. Quantitative pharmacodynamic parameters, such as ratio of the area under the concentration-time curve during a 24-hour dosing period to minimum inhibitory concentration (AUC0-24:MIC), ratio of maximum serum antibiotic concentration to MIC (Cmax:MIC), and duration of time that antibiotic concentrations exceed MIC (T>MIC), have been proposed as likely predictors of clinical and microbiologic success or failure for different pairings of antibiotic and bacteria. Thus far, most pharmacodynamic data reported have focused on fluoroquinolones, but work has been conducted on vancomycin, beta-lactams, macrolides, aminoglycosides, and other antibiotics. Despite the development of a number of different pharmacodynamic modeling systems, remarkable agreement exists between in vitro, animal, and limited human data. Although still somewhat premature and requiring additional clinical validation, antibiotic pharmacodynamics will likely advance on four fronts: the science should prove to be extremely useful and represent a cost-effective and efficient method to help develop new antibiotics; formulary committees will likely use pharmacodynamic parameters to assist in differentiating antibiotics of the same chemical class in making antibiotic formulary selections; pharmacodynamic principles will likely be used to design optimal antibiotic strategies for patients with severe infections; and limited data to date suggest that the application of pharmacodynamic concepts may limit or prevent the development of antibiotic resistance. The study of antibiotic pharmacodynamics appears to hold great promise and will likely become a routine part of our daily clinical practices.

Animals↗

Idiopathic hypercalciuria: effects of calcium load test on magnesiuria.

Twenty-three children with idiopathic hypercalciuria and 7 control children were studied. Patients were classified into three groups according to the response to an oral calcium load. Five children displayed absorptive hypercalciuria (UCa/Cr 0.14 +/- 0.04 mg/mg with poor calcium diet and 0.33 +/- 0.16 after loading, p less than 0.01); 10 were classified renal hypercalciuria (UCa/Cr during the fasting state of 0.28 +/- 0.09 and 0.31 +/- 0.11 after loading) and 8 were classified as alimentary hypercalciuria (UCa/Cr 0.14 +/- 0.07 during the fasting state and 0.15 +/- 0.04 after loading). The urinary cAMP showed no significant differences in any of the three groups compared to the control. Magnesiuria did not show significant differences between the two forms of hypercalciuria and the control; a significant increase was observed after the loading and a positive correlation between magnesiuria and calciuria in the absorptive form. Our study supports the validity of the test for the classification of the different forms of hypercalciuria in children. The urinary cAMP is not a valid approach for classification. The difference observed in the magnesiuria suggests a different pathogenic mechanism between the two types of idiopathic hypercalciuria.

Administration, Oral↗

[Interpretation of the cell concentration of cow's milk for the diagnosis of mammary infection].

The potential utilisation of monthly cell counts per cow to determine their infection status was studied for 30 months on 62 cows from an experimental herd, and by simulation, on different herd models with defined epidemiological characteristics. During this period, the cows of the experimental herd were regularly submitted to bacteriological tests for intramammary infections and individual cell counts. The cows which were not chronically infected by a major pathogen were characterised by cell counts of less than 300 000 cells/ml throughout lactation. The chronically infected cows were characterised by at least two peaks over 300 000 with at least one beyond 800 000, but cell counts could be, at other time intervals, below 300 000 cells/ml. Provided that at least two monthly cell counts were available for each cow, it was possible to discriminate strongly the cows not chronically infected and the cows chronically infected by a major pathogen which are reservoirs of infection. The percentage of correct classifications varied between 74 and 87% in relation with the chosen threshold and the infection status of the herd in which this threshold was used. With the same threshold, there were higher percentages of false negative diagnosis in a herd model where staphylococcal like long-term infections were prevalent and of false positive when there was a high incidence of clinical short-term infections. Monthly cell counts per cow did not correctly reveal short-term clinical infections which are particularly prevalent in herds affected mainly by environmental mastitis. The precision and practical importance of this individual diagnosis was discussed for different herd models.

Animals↗

Biosafety considerations in handling medically important fungi.

Over 500,000 workers in the USA alone are employed in laboratories that range from small physician offices to large clinical laboratories handling microbes for comprehensive research and/or diagnostic work. These workers are exposed to a variety of potential occupational health risks such as exposure to infectious clinical materials, environmental specimens, cultures, complex and inflammable chemicals, radiation, and electrical and mechanical hazards. As members of the International Society for Human and Animal Mycology, we have no policy statement on biosafety standards for handling medically important fungi. The intent of the symposium is to cover some of the important aspects of biosafety; (1) standards in handling dimorphic fungal pathogens; (2) the principles and criteria of biosafety levels and classification of known medically important fungi, aerobic actinomycetes, environmental fungi according to their biosafety levels; (3) medically important fungal waste and its safe disposal; and (4) biosafety and regulatory considerations in handling and mailing medically important fungi in a culture collection.

Animals↗