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PubMed1994

Protection against lethal lymphocytic choriomeningitis virus (LCMV) infection by immunization of mice with an influenza virus containing an LCMV epitope recognized by cytotoxic T lymphocytes.

The reverse genetics system has made it possible to modify the influenza virus genome. By this method, we were able to assess influenza virus as a vaccine vector for protecting BALB/c mice against otherwise lethal lymphocytic choriomeningitis virus (LCMV) infection. A single dose of influenza virus [A/WSN/33 (H1N1)] bearing a cytotoxic T-lymphocyte-specific epitope of the LCMV nucleoprotein (residues 116 to 127) in the neuraminidase stalk protected mice against LCMV challenge for at least 4 months. The immunity was mediated by cytotoxic T lymphocytes and was haplotype specific, indicating that the observed protective response was solely a consequence of prior priming with the H-2d LCMV nucleoprotein epitope expressed in the recombinant influenza virus. We also found that as many as 58 amino acids could be inserted into the neuraminidase stalk without loss of viral function. These findings demonstrate the potential of influenza virus as a vaccine vector, with the neuraminidase stalk as a repository for foreign epitopes.

Amino Acid Sequence↗
PubMed1996

PCR engineering of viral quasispecies: a new method to preserve and manipulate genetic diversity of RNA virus populations.

A PCR-based method for the controlled manipulation of individual genomic sites of poliovirus with concomitant preservation of the sequence heterogeneity of the rest of the genome is proposed. The new approach can be used for the creation of stable DNA repositories of populations of extremely heterogenous RNA viruses and may have implications for live vaccine technology.

Genetic Variation↗
PubMed1997

Comprehensive quantification of herpes simplex virus latency at the single-cell level.

To date, characterization of latently infected tissue with respect to the number of cells in the tissue harboring the viral genome and the number of viral genomes contained within individual latently infected cells has not been possible. This level of cellular quantification is a critical step in determining (i) viral or host cell factors which function in the establishment and maintenance of latency, (ii) the relationship between latency burden and reactivation, and (iii) the effectiveness of vaccines or antivirals in reducing or preventing the establishment of latent infections. Presented here is a novel approach for the quantitative analysis of nucleic acids within the individual cells comprising complex solid tissues. One unique feature is that the analysis reflects the nucleic acids within the individual cells as they were in the context of the intact tissue-hence the name CXA, for contextual analysis. Trigeminal ganglia latently infected with herpes simplex virus (HSV) were analyzed by CXA of viral DNA. Both the type and the number of cells harboring the viral genome as well as the number of viral genomes within the individual latently infected cells were determined. Here it is demonstrated that (i) the long-term repository of HSV-1 DNA in the ganglion is the neuron, (ii) the viral-genome copy number within individual latently infected neurons is variable, ranging over 3 orders of magnitude from <10 to >1,000, (iii) there is a direct correlation between increasing viral input titer and the number of neurons in which latency is established in the ganglion, (iv) increasing viral input titer results in more neurons with greater numbers of viral-genome copies, (v) treatment with acyclovir (ACV) during acute infection reduces the number of latently infected ganglionic neurons 20-fold, and (vi) ACV treatment results in uniformly low (<10)-copy-number latency. This report represents the first comprehensive quantification of HSV latency at the level of single cells. Beyond viral latency, CXA has the potential to advance many studies in which rare cellular events occur in the background of a complex solid tissue mass, including microbial pathogenesis, tumorigenesis, and analysis of gene transfer.

Animals↗
PubMed2002

Changes in human immunodeficiency virus type 1 Gag at positions L449 and P453 are linked to I50V protease mutants in vivo and cause reduction of sensitivity to amprenavir and improved viral fitness in vitro.

Human immunodeficiency virus type 1 (HIV-1) Gag protease cleavage sites (CS) undergo sequence changes during the development of resistance to several protease inhibitors (PIs). We have analyzed the association of sequence variation at the p7/p1 and p1/p6 CS in conjunction with amprenavir (APV)-specific protease mutations following PI combination therapy with APV. Querying a central resistance data repository resulted in the detection of significant associations (P < 0.001) between the presence of APV protease signature mutations and Gag L449F (p1/p6 LP1'F) and P453L (p1/p6 PP5'L) CS changes. In population-based sequence analyses the I50V mutant was invariably linked to either L449F or P453L. Clonal analysis revealed that both CS mutations were never present in the same genome. Sequential plasma samples from one patient revealed a transition from I50V M46L P453L viruses at early time points to I50V M46I L449F viruses in later samples. Various combinations of the protease and Gag mutations were introduced into the HXB2 laboratory strain of HIV-1. In both single- and multiple-cycle assay systems and in the context of I50V, the L449F and P453L changes consistently increased the 50% inhibitory concentration of APV, while the CS changes alone had no measurable effect on inhibitor sensitivity. The decreased in vitro fitness of the I50V mutant was only partially improved by addition of either CS change (I50V M46I L449F mutant replicative capacity approximately 16% of that of wild-type virus). Western blot analysis of Pr55 Gag precursor cleavage products from infected-cell cultures indicated accumulation of uncleaved Gag p1-p6 in all I50V viruses without coexisting CS changes. Purified I50V protease catalyzed cleavage of decapeptides incorporating the L449F or P453L change 10-fold and 22-fold more efficiently than cleavage of the wild-type substrate, respectively. HIV-1 protease CS changes are selected during PI therapy and can have effects on both viral fitness and phenotypic resistance to PIs.

Binding Sites↗
PubMed2026

Novelty, diversity, and genetic dark matter in enterococci of invertebrates.

Enterococci appear to have originated in the guts of early terrestrializing arthropods and invertebrates over 425 million years ago-hosts that are now highly diverse and widespread in nature today. Yet most knowledge of the genus comes from human infection-associated lineages with genomes swollen by the recent accretion of foreign DNA conveyed by mobile elements. Because invertebrates dominate terrestrial animal diversity and biomass, they would be predicted to constitute a major but little-explored reservoir of enterococcal diversity. We therefore systematically examined Enterococcus association and species diversification in invertebrate hosts of the comparatively natural, isolated, but well-characterized environment of the Azorean island of Terceira. Over 100 invertebrate specimens were examined for associated enterococci, which were taxonomically classified by whole-genome sequencing. Supporting the existence of a large pool of uncharacterized enterococci and Enterococcus-adapted genes, 40% (eight of 20) of the Enterococcus species identified were either undescribed, including four candidate new species described here, or very recently discovered. In contrast, control isolates from vertebrates were exclusively of known species typical of sampling elsewhere, discounting geographic isolation as a main driver of the novelty observed. Further, because of the abundance of E. casseliflavus and E. flavescens in this collection, we obtained the resolution necessary to quantify the divergence and decipher the drivers of speciation in the controversial division between these naturally vancomycin-resistant species. These findings provide robust support for the existence of a large pool of new species and unexplored adaptive traits in invertebrate-associated enterococci-diverse environmental survival traits optimized for expression in an enterococcal background, and well positioned for transmission into human-associated enterococcal strains.IMPORTANCEEnterococci are auxotrophic gut-associated bacteria that co-evolved with their terrestrial hosts over many eons. In the last 75 years-the "antibiotic era"-E. faecalis and E. faecium gained genes for antibiotic resistance and enhanced virulence, emerging as leading causes of multidrug-resistant infection. Little is known about the source of those genes or the pathway by which they entered human-associated strains. A recent global survey suggested a potentially large repository of uncharacterized genetic diversity in the enterococci of invertebrates. We directly tested this prospect by examining enterococci of invertebrate hosts in a largely natural and pastoral environment. Our findings provide clear evidence that invertebrates naturally harbor vast unexplored enterococcal diversity. Moreover, associations are likely driven by intrinsic host selection factors rather than geographic isolation. This expands our knowledge of Enterococcus biodiversity, including the identification of four novel species, identifying a vast reservoir of enterococcal genes available to species that colonize and infect humans.

Animals↗
PubMed2004

Abnormal cardiac development in the absence of heart glycogen.

Glycogen serves as a repository of glucose in many mammalian tissues. Mice lacking this glucose reserve in muscle, heart, and several other tissues were generated by disruption of the GYS1 gene, which encodes an isoform of glycogen synthase. Crossing mice heterozygous for the GYS1 disruption resulted in a significant underrepresentation of GYS1-null mice in the offspring. Timed matings established that Mendelian inheritance was followed for up to 18.5 days postcoitum (dpc) and that approximately 90% of GYS1-null animals died soon after birth due to impaired cardiac function. Defects in cardiac development began between 11.5 and 14.5 dpc. At 18.5 dpc, the hearts were significantly smaller, with reduced ventricular chamber size and enlarged atria. Consistent with impaired cardiac function, edema, pooling of blood, and hemorrhagic liver were seen. Glycogen synthase and glycogen were undetectable in cardiac muscle and skeletal muscle from the surviving null mice, and the hearts showed normal morphology and function. Congenital heart disease is one of the most common birth defects in humans, at up to 1 in 50 live births. The results provide the first direct evidence that the ability to synthesize glycogen in cardiac muscle is critical for normal heart development and hence that its impairment could be a significant contributor to congenital heart defects.

Animals↗
PubMed2025

PMkbase (version 1.0): an interactive web-based tool for tracking bacterial metabolic traits using phenotype microarrays made interoperable with sequence information and visualizing/processing PM data.

Bacteria showcase remarkable metabolic diversity and traits, even among strains of the same species. In recent years, a large number of bacterial genomes have been sequenced, leading to the elucidation and documentation of genomic differences and commonalities across and within species. Genome-scale metabolic reconstructions, which are often defined and curated using data from phenotype microarrays, elucidate the differences in metabolic traits resulting from genomic diversity. These microarrays measure cellular respiration on a variety of carbon, nitrogen, phosphorus, and sulfur sources and various stressors and inhibitors over a period of time to determine the metabolic activity of a given strain. Despite their popularity in measuring bacterial metabolic activity and traits, no public databases that allow researchers to warehouse, access, and analyze this information currently exist. Additionally, there are no publicly available tools that allow researchers to view the variance of these metabolic traits across bacterial strains. To address this need, we present Phenotype Microarray Knowledgebase (PMkbase [version 1.0], https://pmkbase.com/), an interactive database that acts as a repository of phenotype microarray (PM) data with integrated sequence information. Binarized activity calls, along with associated kinetic parameters, are made for all metabolic substrates and inhibitors. Users can upload their own data for analysis and visualization and to perform quality checks on their experiments. PMkbase will address an unmet need to track and view bacterial metabolic traits and provide researchers with valuable information to develop metabolic models, enrich pangenomic analyses, and design new experiments.IMPORTANCEBacterial species can be differentiated by their metabolic profiles or the type of nutrients they consume. Interestingly, strains within the same species also display differences in nutrient consumption. Phenotype microarrays are a high-throughput, widely used technology to measure which substrates can be metabolized by various microbial strains and the extent to which inhibitors can affect it. Despite their widespread use, public databases to parse and access this data type at scale do not exist. PMkbase, which contains 9,024 data points for nitrogen substrate utilization, 41,664 data points for carbon substrate utilization, 8,448 data points for phosphorus/sulfur substrate utilization, and 27,264 data points on various antibiotics across three species (Escherichia coli, Pseudomonas putida, and Staphylococcus aureus), has been developed to allow researchers to freely access PM data, along with enriching the data with sequence information.

Bacteria↗
PubMed1995

Lack of influence of non-inherited maternal HLA-DR alleles on susceptibility to rheumatoid arthritis.

OBJECTIVE: To reproduce findings from previous reports that non-inherited maternal HLA class II antigens might contribute to rheumatoid arthritis (RA) susceptibility in the offspring. METHODS: Families were recruited from the Arthritis and Rheumatism Council's National Repository of RA families and HLA-DRB1 alleles were examined in these individuals and their first degree relatives using DNA typing methods. RESULTS: There was no evidence of an increase in either non-inherited maternal HLA-DR4 or the HLA-DRB1 shared epitope as a whole compared with the frequency expected using the non-inherited paternal antigens as controls. CONCLUSIONS: The numbers of probands who were shared epitope negative were small, but we are unable to confirm in these families the findings that non-inherited maternal HLA contributes an additional susceptibility factor to rheumatoid arthritis.

Alleles↗
PubMed1996

Further evidence for genetic anticipation in familial rheumatoid arthritis.

OBJECTIVE: To determine whether preliminary evidence supporting features of genetic anticipation in familial rheumatoid arthritis (RA) could be replicated in independent and larger samples. METHOD: Data were obtained from records of 59 multicase families from the Arthritis and Rheumatism Council (ARC) National Repository in Manchester, 65 multicase families from Cleveland, Ohio, USA, and 253 consecutive patients with RA attending clinics in Nottingham. RESULTS: Mean ages of disease onset in the parents affected with RA were consistently greater than those in the probands. In the ARC data, the mean age difference in disease onset between the affected mother and proband pairs was 16.0 years (95% confidence interval (CI) 7.2 to 24.8 years, n = 11); in the Cleveland data it was 7.8 years (95% CI 0.9 to 14.7 years, n = 24), and in the Nottingham data it was 10.4 years (95% CI 2.8 to 18.0 years, n = 28). Similar results were found in the limited number of father-proband pairs. Unlike the findings of earlier work, there was no correlation between proband age at disease onset and age of the parent at conception of the proband. CONCLUSION: In independent and larger familial RA data sets, features of genetic anticipation were replicated. Our findings support the case for further research at a molecular level into genetic anticipation in those families with two successive generations affected by RA.

Adult↗
PubMed2003

Contribution of patient related differences to multidrug resistance in rheumatoid arthritis.

BACKGROUND: There is a wide variation in responses to standard disease modifying antirheumatic drug (DMARD) treatment in rheumatoid arthritis (RA). Whether multidrug resistance, failure to respond to several DMARDs, is a specific entity over and above that expected by chance alone is unclear. OBJECTIVE: To identify patients with RA who demonstrate a multidrug resistant phenotype and to determine what proportion of the variance in drug responses is due to patient related factors. METHODS: Patients with RA (1987 American College of Rheumatology criteria) were identified from clinics at Manchester Royal Infirmary and through the Arthritis Research Campaign National RA Repository. The clinic records were reviewed and multidrug resistance was defined as stopping three or more DMARDs owing to lack of efficacy after an adequate trial of the drug. Logistic regression measured by a random effects model was used to determine the relative contribution of the drug and subject related differences to the multidrug resistance. RESULTS: 265 patients (210 (79.3%) female) were studied. The mean (SD) age and disease duration were 52.2 (12.9) and 10.7 (8.8) years, respectively. Patients had a median (range) of 2 (1-8) DMARD courses. Failure of at least one DMARD due to inefficacy occurred in 105 (40%) and 13 (5%) were multidrug resistant. Overall, 35% of the variance in drug responses was due to between-subject differences (p=0.02). Rheumatoid factor (RF) status contributed significantly to this (OR=2.15, 95% confidence interval (95% CI) 1.00 to 4.62) but explained only 3% of the total variance in drug inefficacy. CONCLUSION: Multidrug resistance occurs in an uncommon (5%) but important subgroup of patients with RA. The between-subject variance is not fully explained by demographics and RF status. Understanding the biological mechanisms that contribute to multidrug resistance may suggest new therapeutic approaches and targets in RA.

Adult↗
PubMed2001

Latent TGFbeta binding protein-1 and fibrillin-1 in human capsular opacification and in cultured lens epithelial cells.

BACKGROUND/AIM: It was previously reported that collagenous extracellular matrix (ECM) in human capsular opacification contained isoforms of transforming growth factor beta (TGFbeta). In the present study, the authors performed immunohistochemistry to examine whether ECM in human capsular opacification and in cultures of bovine lens epithelial cells (LECs) contained latent TGFbeta binding protein-1 (LTBP-1), TGFbeta1 latency associated peptide (beta1-LAP), and fibrillin-1, a suspected ligand of LTBP-1 as well as a component of the extracellular microfibrillar apparatus. The aim of the study was to further clarify the mechanism of TGFbeta1 deposition in ECM of capsular opacification. METHODS: Human capsular opacification specimens and uninjured lens capsules, as well as cultured bovine LECs, were processed for immunohistochemistry using antibodies against LTBP-1, beta1-LAP, fibrillin-1, and collagen type I. RESULTS: LTBP-1, beta1-LAP, and fibrillin-1 all were localised to the ECM in human capsular opacification. Uninjured lens epithelium stained for beta1-LAP, but not for LTBP-1 and fibrillin-1. ECM deposited in confluent LEC cultures stained for LTBP-1, beta1-LAP, and fibrillin-1, while cultures with only sparse cellularity were unstained for LTBP-1 or fibrillin-1. CONCLUSIONS: LECs upregulate LTBP-1 and fibrillin-1 during postoperative healing. LTBP-1, beta1-LAP, and fibrillin-1 colocalised to the ECM in capsular opacification and in confluent LEC cultures. TGFbeta1 is considered to deposit in ECM in the large latent form. ECM secreted by LEC may function as a scavenger or repository of TGFbeta.

Activin Receptors, Type I↗
PubMed2025

Pharmacoproteomics in the development of personalised medicine in Age-related Macular Degeneration (PHARPRO-AMD) study protocol.

INTRODUCTION: Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among people over 55 years of age globally, being neovascular AMD (nAMD) its most aggressive form. Its treatment consists of the use of drugs that block vascular endothelial growth factor (anti-VEGF). Proteomics may allow the identification of differentially expressed proteins between responders and non-responders to each anti-VEGF drug. Thus, the objective of Pharmacoproteomics in the development of personalised medicine in Age-related Macular Degeneration (PHARPRO-AMD) is to find new proteomic biomarkers, predictive of response to antiangiogenic treatment in patients with nAMD. METHODS AND ANALYSIS: PHARPRO-AMD is a nationwide, multicentre, prospective, observational study. Treatment-na&#xef;ve patients with nAMD starting anti-VEGF therapy will be enrolled and followed up for 2 years. During this period, clinical variables will be gathered to classify treatment response. In addition, blood, tear and vitreous and aqueous humour samples will be collected and will undergo a ZenoSWATH proteomic analysis. Relevant biomarkers identified and response classification will be used to perform a multivariate logistic regression and construct receiver operating characteristic curves. RESULTS: The study is expected to identify a panel of proteomic biomarkers predictive of anti-VEGF treatment response. Integrating data from invasive and non-invasive biological samples may enhance clinical applicability. Once validated, these biomarkers could support the design of future clinical trials on biomarker-guided therapies, helping to optimise treatment regimens and improve visual outcomes. CONCLUSIONS: The PHARPRO-AMD study aims to provide proof-of-concept for biomarker-guided anti-VEGF therapy in nAMD, potentially improving vision outcomes. A notable limitation is the exclusion of patients with visual acuity above 73 Early Treatment of Diabetic Retinopathy Study letters, a criterion chosen to reduce potential ceiling effects and improve response assessment accuracy. ETHICS AND DISSEMINATION: Approved by the Galician Network of Ethics Committees, with nationwide validity. Anonymised data will be deposited in open-access repositories and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Spanish Clinical Studies Registry (REec) (0033-2024-OBS).

Humans↗
PubMed2005

Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease.

BACKGROUND AND AIMS: Several antibodies have been reported in the sera of patients with Crohn's disease (CD) and ulcerative colitis (UC). The most commonly described are anti-Saccharomyces cerevisiae mannan antibodies (ASCA) in CD and perinuclear antineutrophil cytoplasm antibodies (pANCA) in UC. Familial clustering of these antibodies has been described, suggesting they might be genetic markers. Our aim was to investigate the presence of these antibodies before the emergence of overt clinical manifestations. METHODS: Since 1980, the Israeli Defense Force (IDF) Medical Corps Serum Repository has stored serum samples obtained systematically from 5% of all recruits on enlistment, and from the same population on discharge from compulsory military service. We evaluated serum samples obtained from 32 subjects with CD and eight with UC before they were clinically diagnosed, along with samples from matched controls. RESULTS: ASCA were present in 10/32 (31.3%) CD patients before clinical diagnosis compared with 0/95 (0%) controls (p<0.001). None of the eight patients with serum samples available before diagnosis of UC were ASCA positive. ASCA was positive in 54.5% of patients after diagnosis of CD. The mean interval between ASCA detection and diagnosis was 38 months. In 90% of patients, antibodies were detected in the first available serum sample; therefore, measurements of the average time from the presence of ASCA to diagnosis may be even longer. pANCA were present in 2/8 (25%) patients with available sera before the diagnosis of UC. None of their 24 matched controls were positive (p = 0.014). CONCLUSIONS: ASCA and pANCA may predict development of inflammatory bowel disease years before the disease is clinically diagnosed.

Adult↗
PubMedDate not supplied

Benefits of an object-oriented database representation for controlled medical terminologies.

OBJECTIVE: Controlled medical terminologies (CMTs) have been recognized as important tools in a variety of medical informatics applications, ranging from patient-record systems to decision-support systems. Controlled medical terminologies are typically organized in semantic network structures consisting of tens to hundreds of thousands of concepts. This overwhelming size and complexity can be a serious barrier to their maintenance and widespread utilization. The authors propose the use of object-oriented databases to address the problems posed by the extensive scope and high complexity of most CMTs for maintenance personnel and general users alike. DESIGN: The authors present a methodology that allows an existing CMT, modeled as a semantic network, to be represented as an equivalent object-oriented database. Such a representation is called an object-oriented health care terminology repository (OOHTR). RESULTS: The major benefit of an OOHTR is its schema, which provides an important layer of structural abstraction. Using the high-level view of a CMT afforded by the schema, one can gain insight into the CMT's overarching organization and begin to better comprehend it. The authors' methodology is applied to the Medical Entities Dictionary (MED), a large CMT developed at Columbia-Presbyterian Medical Center. Examples of how the OOHTR schema facilitated updating, correcting, and improving the design of the MED are presented. CONCLUSION: The OOHTR schema can serve as an important abstraction mechanism for enhancing comprehension of a large CMT, and thus promotes its usability.

Classification↗
PubMedDate not supplied

Temporal expressiveness in querying a time-stamp--based clinical database.

Most health care databases include time-stamped instant data as the only temporal representation of patient information. Many previous efforts have attempted to provide frameworks in which medical databases could be queried in relation to time. These, however, have required either a sophisticated database representation of time, including time intervals, or a time-stamp-based database coupled with a nonstandard temporal query language. In this work, the authors demonstrate how their previously described data retrieval application, DXtractor, can be used as a database querying application with expressive power close to that of temporal databases and temporal query languages, using only standard SQL and existing time-stamp-based repositories. DXtractor provides the ability to compose temporal queries through an interface that is understood by nonprogramming medical personnel. Not all temporal constructs are easily implemented using this framework; nonetheless, DXtractor's temporal capabilities provide a significant improvement in the temporal expressivity accessible to clinicians using standard time-stamped clinical databases.

Database Management Systems↗
PubMedDate not supplied

A UMLS-based knowledge acquisition tool for rule-based clinical decision support system development.

Decision support systems in the medical field have to be easily modified by medical experts themselves. The authors have designed a knowledge acquisition tool to facilitate the creation and maintenance of a knowledge base by the domain expert and its sharing and reuse by other institutions. The Unified Medical Language System (UMLS) contains the domain entities and constitutes the relations repository from which the expert builds, through a specific browser, the explicit domain ontology. The expert is then guided in creating the knowledge base according to the pre-established domain ontology and condition-action rule templates that are well adapted to several clinical decision-making processes. Corresponding medical logic modules are eventually generated. The application of this knowledge acquisition tool to the construction of a decision support system in blood transfusion demonstrates the value of such a pragmatic methodology for the design of rule-based clinical systems that rely on the highly progressive knowledge embedded in hospital information systems.

Artificial Intelligence↗
PubMedDate not supplied

Clinical decision support systems for the practice of evidence-based medicine.

BACKGROUND: The use of clinical decision support systems to facilitate the practice of evidence-based medicine promises to substantially improve health care quality. OBJECTIVE: To describe, on the basis of the proceedings of the Evidence and Decision Support track at the 2000 AMIA Spring Symposium, the research and policy challenges for capturing research and practice-based evidence in machine-interpretable repositories, and to present recommendations for accelerating the development and adoption of clinical decision support systems for evidence-based medicine. RESULTS: The recommendations fall into five broad areas--capture literature-based and practice-based evidence in machine--interpretable knowledge bases; develop maintainable technical and methodological foundations for computer-based decision support; evaluate the clinical effects and costs of clinical decision support systems and the ways clinical decision support systems affect and are affected by professional and organizational practices; identify and disseminate best practices for work flow-sensitive implementations of clinical decision support systems; and establish public policies that provide incentives for implementing clinical decision support systems to improve health care quality. CONCLUSIONS: Although the promise of clinical decision support system-facilitated evidence-based medicine is strong, substantial work remains to be done to realize the potential benefits.

Decision Support Systems, Clinical↗
PubMed2004

The loss of calretinin expression indicates aganglionosis in Hirschsprung's disease.

BACKGROUND: Hirschsprung's disease (HD) is a congenital disorder characterised by the absence of ganglion cells in the large bowel, leading to functional obstruction and colonic dilatation proximal to the affected segment. A subclass of nerve cell bodies in both submucosa and myenteric ganglia of the human gastrointestinal tract were found to show immunopositivity for calretinin, a calcium binding protein, which plays an important role in the organisation and functioning of the central nervous system. AIM: To investigate calretinin immunostaining in ganglionic and aganglionic HD colon specimens, and compare it with staining for S100, neurone specific enolase, and c-kit. METHODS: Ten large bowel, full thickness specimens from patients with classic rectosigmoid HD were selected from the pathology repository. In total, 54 paraffin wax blocks-24 from the ganglionic zone, 17 from the aganglionic zone, and 13 from the transitional zone-were processed. RESULTS: Calretinin was not expressed in aganglionic segments of HD and associated nerve fibres, whereas in ganglionic HD segments and in normal colon both ganglion cells and nerve fibres were immunopositive. In addition, c-kit showed an altered distribution in the interstitial cells of Cajal. The transitional zone showed a broad spectrum of histomorphological and immunohistochemical patterns of both calretinin and c-kit expression. CONCLUSION: The absence of calretinin expression may serve as a diagnostic aid in identifying aganglionic segments in HD.

Adult↗