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PubMed2005

Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease).

INTRODUCTION: Membranoproliferative glomerulonephritis type II or dense deposit disease (MPGN II/DDD) causes chronic renal dysfunction that progresses to end stage renal disease in about half of patients within 10 years of diagnosis. Deficiency of and mutations in the complement factor H (CFH) gene are associated with the development of MPGN II/DDD, suggesting that dysregulation of the alternative pathway of the complement cascade is important in disease pathophysiology. SUBJECTS: Patients with MPGN II/DDD were studied to determine whether specific allele variants of CFH and CFHR5 segregate preferentially with the MPGN II/DDD disease phenotype. The control group was compromised of 131 people in whom age related macular degeneration had been excluded. RESULTS: Allele frequencies of four single nucleotide polymorphisms in CFH and three in CFHR5 were significantly different between MPGN II/DDD patients and controls. CONCLUSION: We have identified specific allele variants of CFH and CFHR5 associated with the MPGN II/DDD disease phenotype. While our data can be interpreted to further implicate complement in the pathogenesis of MPGN II/DDD, these associations could also be unrelated to disease pathophysiology. Functional studies are required to resolve this question.

Biopsy↗

PubMed2006

Electrocardiogram differentiation of benign early repolarization versus acute myocardial infarction by emergency physicians and cardiologists.

OBJECTIVES: ST-segment elevation (STE) related to benign early repolarization (BER), a common normal variant, can be difficult to distinguish from acute myocardial infarction (AMI). The authors compared the electrocardiogram (ECG) interpretations of these two entities by emergency physicians (EPs) and cardiologists. METHODS: Twenty-five cases (13 BER, 12 AMI) of patients presenting to the emergency department with chest pain were identified. Criteria for BER required four of the following: 1) widespread STE (precordial greater than limb leads), 2) J-point elevation, 3) concavity of initial up-sloping portion of ST segment, 4) notching or irregular contour of J point, and 5) prominent, concordant T waves. Additional BER criteria were 1) stable ECG pattern, 2) negative cardiac injury markers, and 3) normal cardiac stress test or angiography. AMI criteria were 1) regional STE, 2) positive cardiac injury markers, and 3) identification of culprit coronary artery by angiography in less than eight hours of presentation. The 25 ECGs were distributed to 12 EPs and 12 cardiologists (four in academic medicine, four in community practice, and four in community academics [health maintenance organization] in each physician group). The physicians were informed of the patients' age, gender, and race, and they then interpreted the ECGs as BER or AMI. Undercalls (AMI misdiagnosed as BER) and overcalls (BER misdiagnosed as AMI) were calculated for each physician group. RESULTS: Cardiologists correctly interpreted 90% of ECGs, and EPs correctly interpreted 81% of ECGs. The proportion of undercalls (missed AMI/total AMI) was 2.8% for cardiologists (95% confidence interval [CI] = 0.09% to 5.5%) compared with 9.7% for EPs (95% CI = 4.8% to 14.6%) (p = 0.02). The proportion of overcalls (missed BER/total BER) was 17.3% for cardiologists (95% CI = 11.4% to 23.3%) versus 27.6% for EPs (95% CI = 20.6% to 34.6%) (p = 0.03). The mean number of years in practice was 19.8 for cardiologists (95% CI = 19 to 20.5) and 11 years for EPs (95% CI = 10.5 to 12.0) (p < 0.001). CONCLUSIONS: Although correct interpretation was high in both groups, cardiologists, who had significantly more years of practice, had fewer misinterpretations than EPs in distinguishing BER from AMI electrocardiographically.

Atrial Function↗

PubMed1997

Expression of variant forms of insulin receptor substrate-1 identified in patients with noninsulin-dependent diabetes mellitus.

Several polymorphisms have been identified in the amino acid sequence of human insulin receptor substrate-1 (IRS-1). Some of the variant sequences have been reported to be increased in prevalence among patients with noninsulin-dependent diabetes mellitus (NIDDM). This observation led to the hypothesis that these amino acid substitutions may impair the function of IRS-1, thereby causing the insulin resistance seen in patients with NIDDM. To address this question, we have designed studies to evaluate the effects of three variant sequences identified in our laboratory: Gly819-->Arg, Gly972-->Arg, and Arg1221-->Cys. We constructed four IRS-1 expression vectors for transfection in COS-7 cells: wild-type, single mutant (Gly819-->Arg), double mutant (Gly819-->Arg; Gly972-->Arg), and triple mutant (Gly819-->Arg; Gly972-->Arg; Arg1221-->Cys) IRS-1. The mutations did not alter the level of expression or the extent of insulin receptor-mediated tyrosine phosphorylation of recombinant IRS-1. Moreover, the mutations did not lead to a detectable impairment in the association of recombinant IRS-1 with important downstream effectors, including the p85 subunit of phosphatidylinositol 3-kinase and growth factor receptor-binding protein-2. We conclude that these amino acid substitutions do not appear to cause a major defect in the function of IRS-1, as judged by our assays. However, this type of assay probably lacks the sensitivity to detect subtle functional defects. In light of the suggestive associations observed in epidemiological studies, it is premature to totally discard the hypothesis that variant sequences of IRS-1 may contribute to the pathogenesis of NIDDM. Nevertheless, our studies cannot be interpreted as lending support to that hypothesis.

Adaptor Proteins, Signal Transducing↗

PubMed1978

Anomalies in the extrahepatic biliary tract of the rabbit.

A systematic autopsy study found that 29 of 112 animals had anomalies of the bile ducts. Another rabbit had a septate gallbladder. Awareness of these variants is important during hepatic bile collection, studies involving surgical transplantation or manipulation of the extrahepatic ducts, interpretation of results in experimental cholelithiasis and extrahepatic obstructive jaundice.

Animals↗

PubMed1983

Laboratory evaluation of thyroid function in Australian aborigines.

The presence of what we believe is a unique variant of thyroxine-binding globulin in a high proportion of Australian Aborigines causes difficulty in the interpretation of thyroid function tests in such subjects. We present reference ranges for the common tests of thyroid function and a suitable combination of tests for the laboratory investigation of thyroid function in Aborigines. We suggest that the thyroid status of Aborigines previously diagnosed as hypothyroid should be reviewed.

Australia↗

PubMedDate not supplied

[Typing of STR locus in biological objects with pronounced degeneration: analysis of DNA in exhumed remains of victims of war actions].

The authors describe some specific features of enzymatic amplification typing of DNA preparations obtained from degraded tissues of remains of humans, which were brought from regions of war actions in the Chechen Republic. Special attention is paid to the specific artefact of polymerase chain reaction, for the first time detected by the authors in examinations of the above-mentioned objects. This so-called "ladder" effect manifesting by simultaneous nonspecific amplification of many variants of allele fragments of the STR locus on the individual DNA matrix, which can be erroneously interpreted as an evidence of mixed DNA preparation, is apparently characteristic of individual objects with pronounced degradation of biological material. Such phenomena were observed in typing of STR locuses in biological tissues subjected to biological, thermal, and physicohemical degradation. The phenomenon was studied in detail.

Bone and Bones↗

PubMed2004

Ultrastructural analysis of granulocyte inclusions in genetically confirmed MYH9-related disorders.

BACKGROUND AND OBJECTIVES: MYH9-related disorders are autosomal dominant hereditary macrothrombocytopenias caused by mutations in the MYH9 gene. This gene encodes the non-muscular myosin heavy chain type II A (MHCIIA). Among these disorders, May-Hegglin anomaly (MHA), Sebastian syndrome (SS), and Fechtner syndrome (FS) are associated with different types of ribosome inclusions in granulocytes. FS also exhibits Alport-like manifestations: nephropathy, neurosensory deafness, and cataracts. The aim of our study was to assess the granulocyte inclusion ultrastructure in genetically confirmed MYH9-related disorders. DESIGN AND METHODS: Ten individuals were studied. All fulfilled the clinical and laboratory findings to be diagnosed as having an MYH9-related disorder. The ultrastructure of 50 granulocyte sections for each patient was examined, and the percentages of the different types of inclusion were established. Mutations of the MYH9 gene were also analyzed. RESULTS: The patients were classified as having MHA if the inclusions contained parallel longitudinal filaments. If not, they were classified as having SS or FS. FS patients also showed Alport-like manifestations. In all syndromes we observed a wide variability of the inclusion ultrastructure. Moreover, a small number of inclusions typical of other syndromes was observed. A new cross-striated inclusion variant was identified in SS. A significant number of pure ribosome aggregates were identified in all syndromes. INTERPRETATION AND CONCLUSIONS: Like other MYH9-related traits, the variation and partial overlap in the inclusion ultrastructure could be attributed to specific changes in the polymerization, assembly, or stability of the MHCIIA. These changes might be associated with MYH9 gene mutations as well as with its heterogeneous expression.

Adult↗

PubMed1999

Frequency of class I HLA-restricted anti-HIV CD8+ T cells in individuals receiving highly active antiretroviral therapy (HAART).

Peptide/MHC tetrameric complexes were used to enumerate the frequency of HLA class I-restricted epitope-specific CD8+ T cells in 18 HLA-A*0201 HIV type 1-infected asymptomatic patients. HLA-A*0201 molecules were complexed to HIV Gag p17 (amino acids 77-85) and reverse transcriptase (amino acids 464-472) peptides, biotinylated, and bound to streptavidin-phycoerythrin to form tetramers. We show in this study that 17 of 18 HIV-1-infected asymptomatic patients have circulating frequencies of 1/50-1/1000 CD8+ T cells that recognize both Gag and Pol CTL epitopes or either epitope alone. The functional nature of these cells is open to interpretation, as we show that despite relatively high frequencies of fresh epitope-specific CD8+ T cells, variant epitope sequences in viral plasma progeny were rare. In addition, the majority of tetramer-positive cells did not display discernible fresh CTL activity; only after restimulation with specific peptide in culture was there an expansion of epitope-specific CD8+ cells, correlating with high CTL activity. These data suggest that fresh tetramer-stained cells probably represent memory precursors; we demonstrate, with the application of highly active antiretroviral therapy, that the interruption of chronic antigenic stimulation causes significant reductions in the frequency of these cells in five of six patients. In conclusion, this study provides evidence that persistently replicating viral populations are probably required to maintain high frequencies of HIV-1 epitope-specific CD8+ T cells in asymptomatic chronically infected individuals

Amino Acid Sequence↗

PubMed1994

Probing the structure of hirudin from Hirudinaria manillensis by limited proteolysis. Isolation, characterization and thrombin-inhibitory properties of N-terminal fragments.

Hirudin is the most potent and specific inhibitor of the blood-clotting enzyme thrombin so far known. Several hirudin variants were isolated mostly from Hirudo medicinalis and shown to be polypeptide chains of approximately 7 kDa with three internal disulfide bridges. In this study, limited proteolysis has been used to probe aspects of the structure and dynamics of a hirudin variant HM2 isolated from Hirudinaria manillensis. Proteolysis of the polypeptide chain of 64-amino-acid residues of hirudin HM2 by protease from Staphylococcus aureus V8, trypsin, thermolysin and subtilisin occurs at region 41-49 of the chain. The N-terminal fragments 1-41 and 1-47 were isolated to homogeneity and shown to maintain inhibitory action on thrombin, though much lower than the intact protein. The results were interpreted on the basis of a proposed three-dimensional structure of hirudin HM2 deduced by protein modelling the known structure of hirudin variant HV1 from Hirudo medicinalis (75% sequence similarity between HM2 and HV1). Both proteolysis experiments and protein modelling provide evidence for the existence in hirudin HM2 of a N-terminal well-structured domain (core) and a C-terminal flexible polypeptide segment. Determination of the accessible surface area of the three-dimensional model of hirudin HM2 showed that the sites of preferential cleavages are at the surface of the polypeptide molecule.

Amino Acid Sequence↗

PubMed1997

[CT angiography of cerebral venous circulation: anatomical visualization and diagnostic pitfalls in interpretation].

PURPOSE: To show the frequency of visualisation of the dural sinuses and cerebral veins with CT-angiography (CTA) with special reference to anatomical variants. METHODS: 34 CTA (1 mm slice thickness, 120 ml nonionic KM, 2 ml/s flow, 40 s prescanning delay) were performed in 30 patients to examine the cerebral venous system. In an anatomic study of cadavers (n = 10) without known disease of the cerebral veins the great sinuses were opened and examined. RESULTS: The superior sagittal, the transverse, the sigmoid and the straight sinus could be evaluated in all cases (100%). The cortical and deep cerebral veins as well as the small sinuses were visualised in 12-97% of the examinations. A sinovenous thrombosis was diagnosed in 4 of the 30 patients. Asymmetric superior sagittal sinus bifurcation (12/30), a hypoplastic sinus transversus (2/30) and a persistent sinus occipitalis (4/30) were found as anatomical variants. In 10 of the 30 patients we discovered 17 dural sinus filling defects produced by large arachnoid granulations. Similar findings could be demonstrated in the pathologico-anatomic examination series. CONCLUSION: CT angiography is suitable for detailed evaluation of the cerebral veins. Anatomic variants, arachnoid granulations, as well as fibrous bands and septa, which may lead to misinterpretation in conventional CT, can be clearly demonstrated. The sensitivity and specificity of CT in diagnosis of sinovenous thrombosis were increased thereby.

Adolescent↗

PubMed1980

[Diagnostic significance of the "streaming phenomenon" in interpreting splenoportograms in the portal hypertension syndrome].

The "phenomenon of streaming" has been found by the author in splenoportography in 9,4% of patients. The variants of the phenomenon are described. The phemenon seen as a conoid shade superimposed on the shade of the portal vein trunk can suggest possible stenosis of the mouth of the splenic vein. Under these conditions it is inexpedient to fulfill distal splenorenal anastomosis.

Diagnosis, Differential↗

PubMed2000

Structural differences in unbleached and mildly-bleached synthetic tyrosine-derived melanins identified by scanning probe microscopies.

Using scanning tunneling microscopy (STM), we have imaged two types of mildly-bleached, synthetic tyrosine-derived melanins for comparison with the unbleached melanin from which they were prepared. These mildly-bleached melanins were generated by mild oxidation of the unbleached melanin, using either basic hydrogen peroxide or air/light. The unbleached melanin, and two mildly-bleached melanins, were independently deposited from very dilute tetrahydrofuran (THF) solutions onto highly oriented pyrolytic graphite (HOPG) substrate for STM imaging. Lateral dimensions (23 A, average of two directions) of structures from each of the three samples showed no differences. However, structures from both mildly-bleached melanins showed similar dramatic decreases (from approximately 15 A to approximately 5 A) in their STM-measured apparent heights, compared with structures from the unbleached melanin sample. These STM observations are compatible with structural models for unbleached and mildly-bleached melanins, incorporating a three-dimensional structure for unbleached melanin composed of multi-layered, pi-pi-stacked, carboxylic and amino variants of polyaromatic polymeric sheets. The STM-observed decrease in apparent heights after mild oxidation, which we associate with a change in stack height, has been confirmed by experiments using tapping mode atomic force microscopy (TM-AFM) for the unbleached and mildly-hydrogen-peroXide-bleached melanins (from approximately 14 A to approximately 6 A). In these TM-AFM experiments, the melanins were deposited directly onto magnesium cation-treated glass substrates in contact with methanolic solutions of each of the melanins. We interpret our mild-bleaching results as an oxidative conversion of the multi-layered, stacked sheets of mainly carboxylic and amino variants of polyquinhydrone-like moieties, to largely de-stacked, mildly-bleached melanin sheets. These oxidized and, hence, electron-deficient sheets should not readily form multi-layered, pi-pi interacting stacks, but instead appear to be either single-layer polyquinone sheets or, at most, double-layer polyquinhydrone sheets. The effects of such de-stacking on in vivo melanin photoprotection, and structural similarities between melanin derived from natural sources and the synthetic melanin samples used in this work are discussed.

Absorption↗

PubMed1996

Bis-methionine ligation to heme iron in mutants of cytochrome b562. 2. Characterization by NMR of heme-ligand interactions.

Previous work has shown that, in variants of cytochrome b562 containing the H102M mutation, methionine residues provide both axial ligands to the heme iron. NMR spectroscopic studies of such bis-methionine-coordinated cytochrome have not previously been feasible, since the only other cytochrome with such a ligand arrangement, bacterioferritin, is too large to be studied by current NMR methods. The present work provides the first NMR characterization of 6-coordinate, bis-methionine-ligated heme centers in both ferrous and ferric oxidation states. We have used one and two dimensional, homonuclear NMR spectroscopy to assign the proton resonances of the heme group and ligand side chains in the reduced, cytochrome b562 variants, H102M and covR98C/H102M. The latter protein has heme covalently attached to the protein, and our results prove that the covalent linkage is a c-type thioether bond formed between the cysteine at residue 98 and the heme 2-vinyl group. Spectra of the ferrous H102M variant are consistent with the presence of two species differing in the orientation of the heme in the protein. We have interpreted results from NOESY experiments on the ferrous covR98C/H102M protein in terms of the conformation of the two methionine side chains, and we present a model for the structure of the heme ligand arrangement. The Met7 side chain adopts an extended conformation almost identical to that observed in the wild type protein with R stereochemistry at the chiral sulfur ligand. The Met102 side chain has a different, buckled side chain conformation and has S stereochemistry at the chiral center. Our NMR derived model is consistent with the spectroscopic data presented in the previous paper. Studies on the ferric forms of these proteins confirm that the double variant at low pH has a "stable" bis-methionine ligation arrangement, but that it is a thermal mixture of species with differing spin states. No hyperfine coupled proton resonances can be identified in spectra of the high-spin forms of either of these proteins.

Cytochrome b Group↗

PubMed1979

Significance of the electrophoretic modifications of defective pyruvate kinase variants. Study of six new observations.

Six new defective pyruvate kinase variants have been characterized in patients suffering from chronic hemolysis. Partially purified enzyme variants exhibited various anomalies from immunological, kinetic, stability and electrophoretic points of view. The significance of the electrophoretic anomalies has been interpreted in view of the normal post-synthetic maturation of the precursor enzyme L'4 into L2L'2 and L4, and the ability of trypsin to induce in vitro the transition L'4 leads to L4 has been tested. One defective enzyme existed in a single L'4 form and could not be transformed by trypsin into L4. In three cases slow-moving L'4 and L2L'2 forms were transformed by trypsin into an abnormal slow-moving L4 form. In the last two observations the L'4 and L2L'2 forms exhibited normal mobility and were normally transformed by trypsin into L4. The relevance of these data to the functional anomalies of the defective variants and to the nature of the primary genetic anomaly giving rise to the congenital defects in erythrocyte pyruvate kinase is discussed.

Anemia, Hemolytic, Congenital↗

PubMed2001

Predictive and interpretive simulation of green fluorescent protein expression in reporter bacteria.

We have formulated a numerical model that simulates the accumulation of green fluorescent protein (GFP) in bacterial cells from a generic promoter-gfp fusion. The model takes into account the activity of the promoter, the time it takes GFP to mature into its fluorescent form, the susceptibility of GFP to proteolytic degradation, and the growth rate of the bacteria. From the model, we derived a simple formula with which promoter activity can be inferred easily and quantitatively from actual measurements of GFP fluorescence in growing bacterial cultures. To test the usefulness of the formula, we determined the activity of the LacI-repressible promoter P(A1/O4/O3) in response to increasing concentrations of the inducer IPTG (isopropyl-beta-D-thiogalactopyranoside) and were able to predict cooperativity between the LacI repressors on each of the two operator sites within P(A1/O4/O3). Aided by the model, we also quantified the proteolytic degradation of GFP[AAV], GFP[ASV], and GFP[LVA], which are popular variants of GFP with reduced stability in bacteria. Best described by Michaelis-Menten kinetics, the rate at which these variants were degraded was a function of the activity of the promoter that drives their synthesis: a weak promoter yielded proportionally less GFP fluorescence than a strong one. The degree of disproportionality is species dependent: the effect was more pronounced in Erwinia herbicola than in Escherichia coli. This phenomenon has important implications for the interpretation of fluorescence from bacterial reporters based on these GFP variants. The model furthermore predicted a significant effect of growth rate on the GFP content of individual bacteria, which if not accounted for might lead to misinterpretation of GFP data. In practice, our model will be helpful for prior testing of different combinations of promoter-gfp fusions that best fit the application of a particular bacterial reporter strain, and also for the interpretation of actual GFP fluorescence data that are obtained with that reporter.

Bacteria↗

PubMed2025

OctopuSV and TentacleSV: a one-stop toolkit for multi-sample, cross-platform structural variant comparison and analysis.

MOTIVATION: Structural variants (SVs) influence gene regulation, disease progression, and diagnostics, yet integrating SV calls across platforms remains difficult due to inconsistent annotations, limited merging flexibility, and fragmented workflows. Ambiguous breakend (BND) annotations, which comprise many variant calls, are often discarded or misclassified, hindering variant characterization. Existing tools lack advanced merging operations essential for precise identification of disease-specific or somatic variants across samples or patient groups. Additionally, current SV analysis pipelines require extensive manual intervention and complex parameter tuning, compromising reproducibility and scalability. Addressing these gaps is crucial for improving the accuracy, interpretability, and clinical utility of SV analyses. RESULTS: We developed OctopuSV and TentacleSV to address these long-standing challenges in SV analysis. OctopuSV features a specialized BND correction module that converts ambiguous BND annotations into canonical SV types, recovering important variants that are often overlooked by existing tools. Additionally, it provides advanced set operations (difference, complement, custom-defined) that enable sophisticated variant filtering without programming expertise, critical for identifying tumor-specific SVs or variants unique to specific sample groups. TentacleSV completes our solution by automating the entire SV analysis process from raw sequencing data to high-confidence callsets, ensuring consistency and reproducibility across projects. Benchmarking across short-read and long-read platforms showed superior F1 score, complete SV type consistency compared to existing tools. Our framework enables experimental biologists and clinical researchers to perform sophisticated analyses ranging from cancer subtype-specific SV identification to multi-sample comparative studies without requiring specialized programming skills. AVAILABILITY AND IMPLEMENTATION: All codes are available at https://github.com/ylab-hi/OctopuSV; https://github.com/ylab-hi/TentacleSV.

Software↗

PubMedDate not supplied

Measuring inequalities in health in the presence of multiple-category morbidity indicators.

This paper considers the problems which arise in seeking to measure socioeconomic inequalities in health when the health indicator is a categorical variable, such as self-assessed health. It shows that the standard approach--which involves dichotomizing the categorical variable--is unreliable. The degree of measured inequality is found to depend on the cut-off point chosen and the choice of cut-off point to affect the conclusions one can reach about trends in or differences in health inequality. The paper goes on to propose an alternative approach which involves constructing a latent health variable and then measuring inequalities in this latent variable by means of a variant of the health concentration curve.

Data Interpretation, Statistical↗

PubMed1980

Structural polypeptides of canine distemper virus.

The structural polypeptides of two strains of canine distemper virus and the Lec strain of measles virus were analysed by SDS-polyacrylamide-slab-gel electrophoresis. One strain of canine distemper virus derived from a live vaccine (Convac, Dumex), contained six major structural polypeptides with mol.wt. of 85, 78, 59, 43, 41 and 34 x 10(3). The 85K polypeptide was glycosylated. It was interpreted to be equivalent ot the 79K glycoprotein of the measles hemagglutinin. The second strain, a rapidly growing variant of the Onderstepoort strain of canine distemper virus characterized by extensive syncytium forming cytopathic effects in tissue culture, contained the 5, 43, 41 and 34K polypeptides, but the 85 and 78K polypeptides were not present in detectable amounts. The 43K polypeptide was identified as cellular actin by limited proteolysis. By use of monospecific rabbit hyperimmune sera against each of the major structural polypeptides of measles virus, the 59, 41 and 34K structural polypeptides could be identified as nucleocapsid protein (NP), fusion (F) polypeptide, and the membrane (M) polypeptide, respectively. In neutralization tests with rabbit hyperimmune sera against each of the two strains, this Onderstepoort strain, which contained reduced amounts of the hemagglutinin glycoprotein, gave higher neutralization titers than the vaccine strain.

Actins↗