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PubMed2002

[Chlamydial diseases of domestic animals--zoonotic potential of the agents and diagnostic issues].

The role of chlamydiae as agents of a number of important animal and human diseases is still the subject of intensive research. Recently, a proposal for taxonomic reclassification of this group of obligate intracellular bacteria was published, which was based on a large amount of new data on genetic relatedness. According to this proposal, the family Chlamydiaceae now comprises two genera (Chlamydia and Chlamydophila) with 9 largely host-related species. The previously accepted classification scheme had distinguished 4 species within the genus Chlamydia. The most important animal chlamydiosis with zoonotic character is psittacosis, a systemic disease in psittacine birds of acute, protracted, chronic or subclinical manifestation. The analogous infection in domestic and wild fowl is known as ornithosis. Avian strains of C. psittaci (new classification: Chlamydophila psittaci) can also infect humans, the symptoms being mainly unspecific and influenza-like, but severe pneumonia, endocarditis and encephalitis are also known. The main group of persons facing an elevated risk of infection includes those having frequent contact with domestic and companion birds at work or in their spare time. In Germany, the annual average of notified cases is approximately 100. Cases of transmission to humans were repeatedly reported in connection with enzootic abortion in sheep (causative agent: C. psittaci or Chlamydophila abortus, respectively). Various chlamydial species occur as pathogens and commensals as well in cattle, pigs, horses, and cats. The assessment of the actual epidemiological importance is, however, often difficult because of their almost ubiquitous spread. Likewise, those strains of C. pneumoniae (new classification: Chlamydophila pneumoniae) found in several animal species can not yet be assessed for pathogenic properties. The possibilities for diagnostic detection of chlamydiae have considerably improved following the introduction of molecular methods, particularly the polymerase chain reaction (PCR), which permits direct identification from clinical specimens and differentiation of species.

Animals↗

PubMed2006

Neuropathology of Alzheimer disease: pathognomonic but not pathogenic.

Neuropathological changes in subjects with dementia are, by definition, end-stage phenomena. While such changes allow case characterization and lend themselves to disease classification and modeling, the lesions themselves are not etiological. This truth would appear to be self-evident, yet the medical and scientific literature suggests otherwise. Indeed it is now customary to view amyloid plaques in Alzheimer disease as primary etiological, neurotoxic lesions and, hence, removing them (e.g., by immunotherapy) is believed to lead to clinical improvement. The foundation for this line of thinking lies in the existence of rare kindreds with mutations in amyloid-beta, or mutations believed to be involved in the processing of amyloid-beta, and then the extrapolation of the inherited condition to sporadic disease. We believe that this overall construct ignores early events that are more critical to onset and progression of sporadic disease. Likewise, we have studied subjects with sporadic Alzheimer disease, as well as early onset familial Alzheimer disease and Down's syndrome, over a spectrum of ages, and have found that markers of oxidative stress precede amyloid deposits in all three conditions. Amyloid and neurofibrillary pathology in the Alzheimer brain show a decrease in oxidative stress relative to vulnerable but morphologically intact neurons, suggesting that neurodegenerative lesions are compensatory phenomena, and thus manifestations of cellular adaptation. The pathology of neurodegenerative diseases should be viewed as the end-stage consequence, as opposed to cause, of the disease processes, so that early disease processes that are amenable to intervention can be properly recognized and treated.

Alzheimer Disease↗

PubMed2002

Heterogeneity within the gram-positive anaerobic cocci demonstrated by analysis of 16S-23S intergenic ribosomal RNA polymorphisms.

Peptostreptococci are gram-positive, strictly anaerobic bacteria which, although regarded as members of the commensal human microflora, are also frequently isolated from sites of clinical infection. The study of this diverse group of opportunist pathogens has been hindered by an inadequate taxonomy and the lack of a valid identification scheme. Recent re-classification of the Peptostreptococcus family into five distinct genus groups has helped to clarify the situation. However, this has been on the basis of 16S rRNA sequence determinations, which are both time-consuming and expensive. The aim of the present study was to evaluate the use of PCR-amplified ribosomal DNA spacer polymorphisms for the rapid differentiation of the currently recognised taxa within the group of anaerobic gram-positive cocci. A collection comprising 19 reference strains with representatives of each of the 15 species, two close relatives and two of the well-characterised groups, together with 38 test strains was studied. All strains were identified to species group level by phenotypic means. Amplification of the 16S-23S intergenic spacer region (ISR) with universal primers produced distinct banding patterns for all the 19 reference strains and the patterns could be differentiated easily visually. However, of the 38 test strains, less than half could be speciated from ISR analysis alone. Only five groups produced correlating banding patterns for all members tested (Peptoniphilus lacrimalis, P. ivorii, Anaerococcus octavius, Peptostreptococcus anaerobius and Micromonas micros). For other species, either the type strain differed significantly from other species members (e.g., A. hydrogenalis) or there appeared to be considerable intra-species variation (e.g., A. vaginalis). Partial 16S rRNA gene sequences for the 'trisimilis' and 'betaGAL' groups showed that both are most closely related to the Anaerococcus group. This work highlights the heterogeneous nature of a number of Peptostreptococcus species and hence the need for still further revision of the taxonomy of this important group of pathogens.

Anaerobiosis↗

PubMed1990

Epigenesis theory: a mathematical model relating causal concepts of pathogenesis in individuals to disease patterns in populations.

A mathematical modeling approach called epigenesis theory is presented which relates three aspects of pathogenesis to the population distribution of disease. The three aspects of pathogenesis involve how two or more measured variables interact. They are 1) whether the measured variables are related to the same causal action, 2) whether there is only one pathogenic process leading to disease, and 3) whether the measured variables contribute to the same pathogenic process. Epigenesis theory defines the following multivariable relations between two disease causes: 1) "Complementary" causes contribute different causal actions to the sole pathogenic process leading to disease. They have multiplicative relations. 2) "Separate process" causes contribute different causal actions to different pathogenic processes. They have the relations of simple independent action which are slightly less than additive. 3) "Intermediate" causes contribute different causal actions to the same pathogenic process in the presence of additional pathogenic processes where at most one of them may also participate. They have relations somewhere between multiplicative and simple independent actions. 4) "Cooperative-competitive" causes share the same causal action and act within the same pathogenic process. Their relations can change from greater than multiplicative to less than simple independent action at increasing dichotomization points of the measured variables. Epigenesis theory unifies the sufficient-component causes model and the simple independent action model and exceeds either model in the range of observations it can explain. It is most useful given directly causal measured variables and specific disease outcomes, but it will assist in etiologic investigations of nonspecific outcomes in which new disease classifications are proposed. While it is less useful given surveillance-type variables such as age or sex or outcomes resulting from numerous pathogenic processes such as death, it gains utility as more causal variables are entered into an analysis and as more cut points of continuous complementary, independent, or intermediate variables are distinguished.

Adult↗

PubMed2004

West Nile virus: an overview of its spread in Europe and the Mediterranean basin in contrast to its spread in the Americas.

West Nile (WN) virus is a mosquito-transmitted flavivirus. It is widely distributed in Africa, the Middle East, Asia, and southern Europe and was recently introduced to North America. Birds are involved in the cycle of transmission as amplifying hosts. Humans and horses are considered accidental dead-end hosts. WN fever was initially considered a minor arbovirosis, usually inducing a nonsymptomatic or a mild flu-like illness in humans, but some cases of encephalitis associated with fatalities were reported in Israel in the 1950s. After two silent decades, several human and equine outbreaks of fatal encephalitis occurred from 1996 to 2000 in Romania, Morocco, Tunisia, Italy, Russia, Israel, and France. In Romania, a few cases of WN encephalitis in humans are noticed every year, and in France, recent WN infections have been detected in monitored sentinel birds in 2001 and 2002. Phylogenetic studies have shown two main lineages of WN strains. Strains from lineage I are present in Africa, India, and Australia and are responsible for the outbreaks in Europe and in the Mediterranean basin, and strains from lineage II have been reported only in sub-Saharan Africa. In 1998, a virulent WN strain from lineage I was identified in dying migrating storks and domestic geese showing clinical symptoms of encephalitis and paralysis in Israel. A nearly identical WN strain suddenly emerged in New York in 1999, killing thousands of native birds and causing fatal cases in humans. The virus is now well established in the New World, and it disseminates rapidly. New modes of transmission through blood donations, organ transplants, and the intrauterine route have been reported. In Europe, an enhanced surveillance of WN infection in humans, horses, birds, and vectors may reveal the presence of the virus in different locations. Nevertheless, outbreaks of WN virus remain unpredictable. Further coordinated studies are needed for a better understanding of the ecology and the pathogenicity of the WN virus.

Americas↗

PubMed1988

Ocular herpes simplex infection: pathogenesis and current therapy.

Ocular herpes simplex disease has a variable pattern of manifestations and recurrences as a result of the site and extent of the infection, the host immunologic events, the trophic damage within ocular tissues, and the toxic effects of antiviral medications. Laboratory research has established a clinical model and a working hypothesis about the complex pathophysiologic features of the disease and the interaction of the virus with its host tissue. Recent studies have further defined the viral genome and its role in virulence and pathogenicity. Antiviral therapy is effective in some but not all aspects of the ocular infection. A proposed clinical classification of ocular herpes simplex is based on the manifestations associated with viral disease and those associated with the host response and the subsequent structural damage. A plan for medical and surgical management of ocular herpes simplex, based on current knowledge of the disease process, relates to the integrity of the epithelium and the presence of active viral disease.

Humans↗

PubMed1985

Management of complications of portal hypertension.

The management of portal hypertension focuses on control of its complications, the most important of which is bleeding esophageal varices. Other complications, such as ascites, bleeding intestinal stomas, and hypersplenism, rarely require surgical intervention. Other than medical management, the three basic procedures now available for the treatment of bleeding esophageal varices include decompression of varices with a portosystemic shunt, nonshunting operations that attack directly the esophageal variceal-bearing area, and liver transplantation as the procedure of choice in selected patients. Patients who present with episodes of acute bleeding are usually treated initially with medical therapy including acute sclerotherapy or balloon tamponade techniques when necessary. If the patient fails to respond or if episodes of bleeding recur, further therapy is required. Although selection of therapy remains controversial, it is based on multiple factors. These include the basic pathogenic mechanism of portal hypertension in the individual patient, status of the patient as defined by Child's classification, elective or urgent nature of the operation, hemodynamic stability of the patient at the time of the procedure, site of the block in the portal system, and caliber and anatomic relationship of the vessels available for anastomosis in the portal system. Additional factors include the presence and severity of ascites or encephalopathy, age of the patient, site of bleeding (esophageal or gastric), severity of associated hypersplenism, and techniques and expertise available at a given institution. Shunting procedures achieve the best long-term control of bleeding, but they can precipitate the development of encephalopathy. Nonshunting procedures do not induce encephalopathy, but they are usually associated with a high rate of rebleeding. Also, with the possible exception of sclerotherapy, they are still associated with a high operative mortality rate in alcoholic patients classified as Child's C. Although sclerotherapy controls acute variceal bleeding more successfully than conventional methods, it is not readily applicable in patients with bleeding gastric varices. Also, it has not yet clearly been proved to be an effective method of permanent control of gastroesophageal bleeding and has not been demonstrated to increase survival. The new methods of extensive esophagogastric devascularization (for example, porta-azygos disconnection using the Sugiura procedure) are attractive because of the low late recurrence rate for bleeding without the induction of encephalopathy.(ABSTRACT TRUNCATED AT 400 WORDS)

Collateral Circulation↗

PubMed2026

Integrating Next-Generation Sequencing into von Willebrand Disease Diagnostics: Insights from the PCM-EVW-ES Multicenter Project.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, caused by quantitative or qualitative defects in von Willebrand factor (VWF). Diagnosis is challenging and requires integrating bleeding history, VWF antigen and activity measurements, FVIII assays, and specialized phenotyping. Genetic testing is increasingly recognized as a key component. Here, we review current concepts in VWD diagnostics and highlight the Spanish Clinical and Molecular Profile of von Willebrand Disease (PCM-EVW-ES) project as a model for genomics-enabled precision medicine. PCM-EVW-ES is a multicenter initiative involving 48 hospitals, centralized phenotypic testing, and next-generation sequencing of the VWF coding region, enabling definitive classification in 730 individuals with VWD to date. Harmonized recruitment criteria and standardized workflows improve subtype assignment, uncover complex genotypes, refine genotype-phenotype correlations, and facilitate the identification of asymptomatic carriers. The PCM-EVW-ES variant spectrum highlights recurrent disease-causing variants in Spain and underscores the value of coordinated national registries for variant curation. Building on these data, we propose a diagnostic algorithm in which bleeding assessment and first-line VWF/FVIII assays, combined with, early VWF molecular testing increases diagnostic accuracy and guides targeted second-line investigations to confirm and refine VWD subtype classification. We also outline persisting challenges, including the interpretation of variants of uncertain significance and patients without identifiable pathogenic VWF variants, and future directions integrating third-generation sequencing, expanded gene panels, functional studies, and artificial-intelligence-driven multiomic approaches. Together, these advances illustrate how robust multicenter studies can bridge the gap between complex diagnostics and clinical practice in VWD.

Humans↗

PubMed2002

Antibiotic policies and control of resistance.

PURPOSE OF THE REVIEW: The current worldwide pandemic of antibiotic resistance shows no signs of abating. It is clear that it is driven mainly by heavy and often inappropriate antibiotic use. Although control measures are widely practised, it is important that we assess their efficacy critically in order to concentrate expensive control efforts where they will be most effective. The past year has seen much activity in this area, with evidence-based assessments of the literature according to strict guidelines, as well as progress in basic science studies of mechanisms of resistance, and their causes and relations to pathogenicity and adaptability. RECENT FINDINGS: The present review summarizes current developments in the causes of antibiotic resistance, the classification of antibiotic stewardship and control measures, the evidence base for their efficacy, current problems in hospital practice, the adaptability of bacteria, the content of antibiotic policies and anticipated activities. SUMMARY: The conclusions from the published literature are that much of it that pertains to changing prescribing practices does not stand up to modern evidence-based analysis concepts. Nevertheless, we can learn from experience in changing other areas of medical practice. We must be pragmatic and must not expect to change the world, but rather take it step by step, recognizing barriers and measuring outcomes and quality indicators. Studies into the molecular basis of resistance confirm the superb genetic adaptability of micro-organisms. They will always be several steps ahead of us. Nevertheless, we are learning how to modify our prescribing habits to minimize resistance, not only by using antibiotics less frequently but also by altering dosing schedules in various ways.

Anti-Bacterial Agents↗

PubMed1994

Nucleotide sequence of the original Brazilian isolate of coleus yellow viroid from Solenostemon scutellarioides and infectivity of its complementary DNA.

The complete nucleotide (nt) sequence of the original coleus yellow viroid (CYVd) from Solenostemon scutellarioides, 'Golden Bedder', has been determined. The covalently closed single-stranded CYVd RNA molecule consists of 248 nt residues which assumes a rod-like secondary structure when folded in the model of lowest free energy. The sequence was determined by direct sequencing of RNA and from three overlapping cDNA clones. Comparison of the CYVd sequence with that of Coleus blumei viroid 1 (CbVd 1) from Germany demonstrated that they are closely related. The differences observed in the genome organization of CYVd relative to CbVd 1 were at three sites: position 25 (one U deletion), position 26 (a U was replaced by an A) and position 241 (one A insertion). The first two mutations were detected in one A-rich segment of eight nt (between positions 25 and 34). Northern blot hybridization of partially purified nucleic acids from the leaf tissue of S. scutellarioides 'Frilled Fantasy', inoculated with double-stranded cDNA, demonstrated that this fragment was infectious. These data enable CYVd to be assigned to the viroid class of plant pathogens, based on its biological properties and molecular structure. This work also gives additional support to the present classification system, in which the viroids isolated from S. scutellarioides form a distinct subgroup.

Base Sequence↗

PubMed2005

Large-scale identification of expressed sequence tags involved in rice and rice blast fungus interaction.

To better understand the molecular basis of the defense response against the rice blast fungus (Magnaporthe grisea), a large-scale expressed sequence tag (EST) sequencing approach was used to identify genes involved in the early infection stages in rice (Oryza sativa). Six cDNA libraries were constructed using infected leaf tissues harvested from 6 conditions: resistant, partially resistant, and susceptible reactions at both 6 and 24 h after inoculation. Two additional libraries were constructed using uninoculated leaves and leaves from the lesion mimic mutant spl11. A total of 68,920 ESTs were generated from 8 libraries. Clustering and assembly analyses resulted in 13,570 unique sequences from 10,934 contigs and 2,636 singletons. Gene function classification showed that 42% of the ESTs were predicted to have putative gene function. Comparison of the pathogen-challenged libraries with the uninoculated control library revealed an increase in the percentage of genes in the functional categories of defense and signal transduction mechanisms and cell cycle control, cell division, and chromosome partitioning. In addition, hierarchical clustering analysis grouped the eight libraries based on their disease reactions. A total of 7,748 new and unique ESTs were identified from our collection compared with the KOME full-length cDNA collection. Interestingly, we found that rice ESTs are more closely related to sorghum (Sorghum bicolor) ESTs than to barley (Hordeum vulgare), wheat (Triticum aestivum), and maize (Zea mays) ESTs. The large cataloged collection of rice ESTs in this study provides a solid foundation for further characterization of the rice defense response and is a useful public genomic resource for rice functional genomics studies.

Disease Susceptibility↗

PubMed1975

Motility-indole-lysine medium for presumptive identification of enteric pathogens of Enterobacteriaceae.

Detection of lysine decarboxylase activity is a useful supplement to reactions on triple sugar-iron (TSI) and urea agars in the initial examination of suspected pathogenic isolates from fecal cultures. Owing to the added value of motility and indole production in the differentiation of enteric pathogens, we prepared and evaluated a motility-indole-lysine (MIL) medium. The following 890 organisms were tested: 264 Shigella, 2 Edwardsiella, 182 Salmonella enteritidis, 235 S. typhi, 3 Arizona, 32 Yersinia enterocolitica, and 172 other members of the family Enterobacteriaceae. With few exceptions the MIL medium gave the same results as the standard motility, indole, and lysine decarboxylase (Moeller) test media. All discrepancies were with the indole reaction, which was weak in 2 of 67 strains of Escherichia coli and falsely negative in 6 of 32 strains of Y. enterocolitica. When both TSI agar and lysine-iron agar (LIA) slants are used in the evaluation isolates from fecal cultures, detection of H2S is duplicated. Both LIA and MIL medium detect lysine decarboxylase and deaminase activity equally well. Because of its ability to detect motility and indole production, the MIL medium is more useful than LIA when used with TSI agar. The combination of TSI agar, MIL medium, and urea agar enables reliable initial recognition of enteric pathogens of the Enterobacteriaceae.

Carboxy-Lyases↗

PubMed2002

Polymerase chain reaction in diagnosis of Borrelia burgdorferi infections and studies on taxonomic classification.

Lyme borreliosis caused by the spirochete Borrelia burgdorferi is now the most common vectorborne disease in North America, Europe and Asia. It is a multisystemic infection which may cause skin, neurological, cardiac or rheumatologic disorders. The aims of the present thesis were: (i) to develop a PCR assay for direct detection of B. burgdorferi DNA and to evaluate the diagnostic utility of PCR in clinical specimens from patients with Lyme borreliosis and (ii) to study the taxonomic classification of B. burgdorferi isolates and its implications for epidemiology and clinical presentation. Laboratory diagnosis of Lyme borreliosis by direct demonstration of B. burgdorferi in clinical specimens would compared to current serology allow (i) optimal specificity, (ii) increased sensitivity during the first weeks of infection, when the antibody response is not yet detectable and (iii) discrimination between ongoing and past infection. Due to the extreme paucity of spirochetes in clinical specimens neither in vitro culture nor antigen detection had yielded a sufficient diagnostic sensitivity. Thus the recently introduced highly sensitive PCR methodology could be a solution and was thus studied. Assays for PCR amplification and subsequent identification of B. burgdorferi specific sequences were established and used. For all assays the analytical sensitivity was a few genome copies using purified DNA as template. The efficacy of PCR was initially evaluated using tissue samples from experimentally infected gerbils in order to start with biological samples a priori known to contain B. burgdorferi. B. burgdorferi DNA was detectable in 88% of the specimens. Thus the diagnostic sensitivity of PCR was comparable to and even higher than in vitro culture. PCR was significantly more sensitive than a histological B. burgdorferi specific immunophosphatase-staining method. The utility of the PCR was then tested for identification of B. burgdorferi DNA in skin biopsies from 31 patients with erythema migrans. The sensitivity of PCR was 71%, which was superior to culture and serology. Based on own and otherwise published results there is clear evidence for PCR being the most sensitive and specific test for detection of B. burgdorferi in skin biopsies from patients with both early and late dermatoborreliosis. However, since the clinical diagnosis of dermatoborreliosis in most instances is easy, an invasive procedure as a skin biopsy, will only be justified in patients with an atypical clinical presentation. The most frequent and serious manifestation of disseminated Lyme borreliosis is neuroborreliosis. PCR was applied to 190 patients with untreated and confirmed neuroborreliosis. B. burgdorferi DNA was detectable in 17-21% of CSF samples from patients with neuroborreliosis. In patients with very early neuroborreliosis (< 2 weeks), still being negative for specific intrathecal antibody synthesis, a positive PCR was more frequent than in patients with longer disease duration. PCR can be used as a diagnostic aid in these patients. However, in general the measurement of specific intrathecal antibody production in patients with neuroborreliosis was superior to PCR. In urine samples from patients with Lyme borreliosis the diagnostic sensitivity varied, generally showing a low reproducibility. Urine is thus not regarded as a suitable sample source for B. burgdorferi PCR. The reason may be the variable presence of Taq polymerase inhibitors. Based on a semi-quantitative detection system for amplicons, reflecting the input amount of specific DNA and thus the density of spirochetes in the clinical samples high amounts of DNA were found in skin biopsies whereas especially in urine the amount of DNA was low. When the present study was initiated there was no accepted classification of B. burgdorferi. A heterogeneity among B. burgdorferi strains might have important implications for understanding the epidemiology and different clinical presentations (dermatoborreliosis versus neuroborreliosis) and courses (self-limiting versus chronic disease). Furthermore, strain differences were of importance for selection of suitable antigens for diagnostic assays and for vaccine development. Since then, B. burgdorferi isolates have been studied by phenotypic and genotypic traits and have been shown to be highly heterogeneous. Our first approach was to genotype a panel of human B. burgdorferi isolates by restriction fragment length polymorphism (RFLP) of three genes. Thereafter, sequencing and dideoxy fingerprinting of ospA was applied. By RFLP the strains could be differentiated into two to five groups. The RFLP classification was compared with four different phenotypic and genotypic methods including the rRNA typing. Results obtained with the different methods correlated highly and confirmed the meanwhile accepted taxonomic classification by Baranton et al., According to this the term B. burgdorferi sensu lato comprises three different human pathogenic genospecies B. burgdorferi sensu stricto, B. garinii and B. afzelii. All three genospecies have been isolated among Danish patients with Lyme borreliosis and are thus prevalent in Denmark. Since isolation of B. burgdorferi from patients with Lyme borreliosis is laborious and often unsuccessful molecular typing methods based on PCR are recommended obviating the need for isolation by prior culture. Of special interest was to study a possible association of neuroborreliosis to certain B. burgdorferi genospecies, indicating species depended organotropism. By RFLP all six CSF isolates tested belonged to B. garinii and that 6 out of 7 isolates from patients with acrodermatitis chronica atrophicans belonged to B. afzelii. Due to the low culture yield of B. burgdorferi from CSF, the association of B. garinii and neuroborreliosis was further studied by sequence analysis and dideoxyfingerprinting analysis of ospA PCR amplicons obtained from CSF samples from patients with neuroborreliosis. Phylogenetic analysis showed that in 11 out of 13 patients B. garinii DNA was found in CSF. These data strongly supports the hypothesis that B. garinii is the principal agent of Lyme neuroborreliosis in Europe. Similarly it was shown that B. afzelii is associated with acrodermatitis chronica atrophicans and thus dermatoborreliosis. Due to a strain dependent different selection pressure in culture only PCR based methods can be used to answer whether mixed infection in patients specimens occur. Our data indicate that mixed infections in humans if ever are rare.

Bacterial Typing Techniques↗

PubMed2025

Recent Advances in nccRCC Classification and Therapeutic Approaches.

Non-clear cell renal cell carcinoma (nccRCC) constitutes a biologically diverse category of renal malignancies. The 2022 WHO classification framework has significantly evolved to incorporate molecularly defined entities alongside traditional histologic subtypes, reflecting the growing recognition of distinct pathogenic drivers. Current therapeutic paradigms for advanced disease remain suboptimal, with treatment strategies often extrapolated from clear cell renal cell carcinoma (ccRCC). In this review, we highlight transformative multi-omics approaches to address nccRCC's profound heterogeneity, which enables molecular stratification beyond conventional pathology, identifying novel subtypes characterized by unique immune microenvironment features, metabolic profiles, and genomic instability patterns. This molecular reclassification provides a foundational framework for precision oncology, facilitating patient selection for targeted therapies and immunomodulatory strategies. Advancements in multi-omics subtyping represent a pivotal shift toward biologically guided clinical management and underscore the imperative for biomarker-driven therapeutic development in nccRCC.

Humans↗

PubMed2026

Bayesian Integration of Tumor Mutational Signatures and Somatic Features Refines Pathogenicity Assessment of Germline Mismatch Repair Variants.

Variants of uncertain significance (VUS) in mismatch repair (MMR) genes represent a persistent bottleneck in germline interpretation for Lynch syndrome, creating a critical opportunity to leverage tumor biology to refine pathogenicity assessment. Although tumor features such as microsatellite instability (MSI) and immunohistochemistry (IHC) are routinely evaluated, they are typically interpreted separately from germline classification, and their quantitative contribution within ACMG/AMP frameworks remains poorly defined. We therefore analyzed paired germline and tumor sequencing data from 1110 tumors across 1073 patients with colorectal or endometrial cancer to determine whether mismatch repair-deficient (MMR-d) mutational signatures can be quantitatively integrated into Bayesian germline variant interpretation. Using COSMIC single-base substitution signatures, tumors were classified as MMR-d or MMR proficient, and an empirically derived likelihood ratio (LR) quantified the association between MMR-d signatures and pathogenic germline MMR variants. The presence of an MMR-d signature increased the likelihood of an underlying pathogenic germline MMR variant approximately eightfold (LR ≈ 8; log10 LR ≈ 0.90), whereas its absence provided moderate-to-strong benign evidence (LR ≈ 0.156; log10 LR ≈ -0.81). Applying this integrative framework to 45 germline MMR VUS, joint modeling of tumor mutational signatures with additional somatic and variant-level evidence resulted in clinically significant reclassification of 38 (84.4%) variants, including three reclassified as pathogenic or likely pathogenic and 35 as likely benign. A total of 16 downgraded variants were independently downgraded by Invitae. These findings demonstrate that tumor mutational signatures can be formally incorporated into Bayesian germline interpretation, transforming tumor data into quantitative pathogenicity evidence and offering a principled strategy to reduce VUS burden in hereditary cancer genetics.

Humans↗

PubMed2003

Subtyping of pathogenic Escherichia coli strains using flagellar (H)-antigens: serotyping versus fliC polymorphisms.

Serotyping of O- and H-antigens is regarded as the gold standard in classification of E. coli for taxonomic and epidemiological purposes similar to the Kaufmann-White scheme for Salmonella enterica. Molecular methods to replace or to support the serotyping have been applied recently. Using the molecular polymorphism of the flagella (H-antigen) gene fliC, more than 220 E. coli strains derived from the E. coli reference collection for O- and H-antigens (The International Escherichia and Klebsiella Centre (WHO)) and from clinical origins have been characterised and a reproducible and clear cut classification with very good correlation to serotyping was found. Only some of the H-antigens have revealed multiple fliC classes and vice versa only rarely some of the fliC classes belong to various H-antigen groups. Since also H-antigen-negative and H-antigen non-typeable strains subjected to fliC classification could be typed properly, it is recommended here to use this rapid approach to classify E. coli under routine conditions rather than using classical serotyping. However, scrotyping--in particular using hyperimmune rabbit sera--will remain the gold standard and the task of Reference Centres only, e.g. for defining novel H-antigen types.

Antigens, Bacterial↗

PubMed1994

Taxonomical classification of 20 newly isolated Listeria bacteriophages by electron microscopy and protein analysis.

A set of 20 newly isolated temperate bacteriophages for phage typing of the pathogen Listeria monocytogenes has been investigated by means of electron microscopy and electrophoretic analysis of phage structural proteins. All phages had isometric capsids (60-64 nm diameter), and long contractile or non-contractile tails of 170-320 nm length. They could be classified into 2 morphotypes (A1 and B1) and were assigned to 3 listeriaphage species (4211, 2671, and 2389). Individual protein profiles were generated by SDS-PAGE of viral polypeptides, as well as isoelectric focusing of solubilized phage proteins in immobilized pH gradient gels. The major structural proteins ranged in size from approximately 15 to 38 kD, and showed isoelectric points from pI 4.3 to 6.2. Protein compositions permitted the differentiation of individual phages as well as the recognition and grouping of similar viruses.

Bacteriophage Typing↗

PubMed2003

Rightward cerebral asymmetry in subtypes of schizophrenia according to Leonhard's classification and to DSM-IV: a structural MRI study.

Although well documented, brain structural abnormalities in schizophrenia are non-specific, and morphometric parameters show significant overlap between patients and healthy controls. Such inconsistencies in neuroimaging findings could represent different levels of severity along a single pathogenic process or distinct clinical and etiopathological psychoses within a schizophrenic spectrum. The aim of the present study was the investigation of distinct brain abnormalities in different subtypes of schizophrenia. Forty patients were classified according to DSM-IV and Leonhard's classifications. Psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS) and the Negative Symptom Rating Scale (NSRS). Patients were compared to 20 healthy volunteers on volumetric measures of cerebral structures (hemisphere, hippocampus and planum temporale) and ventricular-brain ratio (VBR) obtained by magnetic resonance imaging. Patients showed rightward asymmetry of cerebral hemispheres and increased VBR. Rightward asymmetry correlated with severity of negative symptoms and prevailed in the systematic forms of Leonhard, suggesting a distinct pattern of left hemisphere abnormality in this subgroup of psychoses. Increased VBR values showed a single normal distribution in the subgroups, indicating that ventricular enlargement is not restricted to a subgroup but is present to a certain degree in all cases.

Adult↗