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PubMed1968

Malate dehydrogenase: evidence for tetrameric structure in Mus musculus.

Two electrophoretically distinct variants of supernatant nicotinamideadenine dinucleotide phosphate-dependent malate dehydrogenase exist in mice (Mus musculus). They are controlled by codominant alleles segregating at an autosomal locus. The two forms exist in a polymorphic condition in wild populations of Mus musculus and are fixed in a homozygous condition in inbred lines. These genetic electrophoretic variants are used here to study the subunit structure of this enzyme. Evidence indicating a tetrameric structure for mouse nicotinamideadenine dinucleotide phosphate-dependent malate dehydrogenase is presented. This interpretation is based on the occurrence in heterozygote tissue extracts of five electrophoretically distinct enzymes. This is the predicted phenotype for tetramers composed of two types of subunits which associate randomly in heterozygotes forming three hybrid enzymes having mobilities intermediate between the parental forms.

Alleles↗

PubMed1991

Anchoring and degradation of glycolipid-anchored membrane proteins by L929 versus by LM-TK- mouse fibroblasts: implications for anchor biosynthesis.

Although many cells anchor surface proteins via moieties that are sensitive to phosphatidylinositol-specific phospholipase C (PI-PLC), the anchor moieties of surface proteins of mouse L929 cells resist PI-PLC. By constructing stable hybrids between L929 and lymphoma cells that express glycolipid-anchored proteins in a PI-PLC-sensitive form, we show that PI-PLC resistance behaves as a recessive trait. Since putative mannolipid precursors of the lipid anchors bear alkali-labile substituents which make them resist PI-PLC, these observations are most simply interpreted by postulating that L929 lacks a critical anchor deacylase. Unlike the L929 cell line, two of its descendants, the LM cell line and its thymidine kinase-negative variant (LM-TK-), do not express glycolipid-anchored proteins on their surface. Moreover, unlike L929 cells, LM-TK- cells rapidly inactivate at least one lipid-anchored enzyme in a compartment sensitive to acidotropic amines and leupeptin. By fusion of LM-TK- cells to mouse Thy-1- lymphoma mutants and monitoring of surface expression of lipid-anchored proteins, we assign LM-TK- to lymphoma mutant complementation group H. This genetic assignment is matched by analysis of mannolipids of L929, LM-TK-, wild-type, and class H lymphoma mutant cells: striking similarities are seen between the two wild-type cells by contrast to the mutants. Since the differences pertain to lipids which have properties consistent with their being anchor precursors, we suggest that LM-TK- has a lesion in the synthesis of anchor precursor mannolipids.

Alkaline Phosphatase↗

PubMed1998

Melatonin for sleep EEG.

Melatonin 3 mg and secobarbital 100 mg assigned randomly were given to 40 psychiatric patients for sleep induction during EEG recording. Nine patients who did sleep naturally comprised a comparison group. EEGs were read blind; most were interpreted as mildly abnormal or within normal limits. No statistically significant differences between the three groups were observed in response to photic stimulation, hyperventilation or in frequency of paroxysmal variants. The electroencephalographer was able to identify the melatonin patients significantly more accurately than those who received secobarbital on the basis of lack of EEG manifestations of fast frequencies typical of barbiturate effects. Self-assessments of drowsiness, anxiety and performance on a perceptual-motor task were similar in the melatonin and secobarbital patients. However, the secobarbital group showed more impairment on a locomotion test than those who received melatonin or slept spontaneously. The results suggest that melatonin is a plausible alternative for EEG sleep sedation, especially for ambulatory patients.

Adult↗

PubMed2004

Unusual uptake of radioiodine in the chest in a patient with thyroid carcinoma.

A wide spectrum of potentially misleading artefacts can arise in 131I whole body scans from various anatomical variants and physiological processes as well as several unrelated non-thyroidal disease processes. A proper understanding of the causes of false positive 131I scans is essential for accurate interpretation of the images and to obviate diagnostic errors which may lead to administration of unnecessary therapy doses. The authors, in this article, present a case which had 131I uptake in the mediastinum persisting after surgical excision of mediastinal nodes, which was subsequently found to be due to accumulation of radioiodine in a hugely dilated oesophagus in secondary to achalasia. A comprehensive and rational classification of the various false positive 131I scintigraphic patterns based on the knowledge of the existing literature is reviewed.

Artifacts↗

PubMed2004

Unexpected diversity in the fine specificity of monoclonal antibodies that use the same V region gene to glucuronoxylomannan of Cryptococcus neoformans.

Most mAbs to the capsular polysaccharide glucuronoxylomannan (GXM) of Cryptococcus neoformans are generated from the same VH and VL gene families. Prior Ab studies have assessed protective efficacy, Id structure and binding to capsular polysaccharides, and peptide mimetics. These data have been interpreted as indicating that most mAbs to GXM have the same specificity. A new approach to Ab specificity analysis was investigated that uses genetic manipulation to generate C. neoformans variants with structurally different capsules. C. neoformans mutants expressing GXM with defective O-acetylation were isolated and complemented by the C. neoformans gene CAS1, which is necessary for the O-acetylation of GXM. The mAbs exhibited differences in their binding to the GXM from these mutant strains, indicating previously unsuspected differences in specificity. Analysis of three closely related IgMs revealed that one (mAb 12A1) bound to an epitope that did not require O-acetylation, another (mAb 21D2) was inhibited by O-acetylation, and the third (mAb 13F1) recognized an O-acetylation-dependent conformational epitope. Furthermore, an IgG Ab (mAb 18B7) in clinical development retained binding to de-O-acetylated polysaccharide; however, greater binding was observed to O-acetylated GXM. Our findings suggest that microbial genetic techniques can provide a new approach for epitope mapping of polysaccharide-binding Abs and suggest that this method may applicable for studying the antigenic complexity of polysaccharide Ags in other capsulated microorganisms.

Antibodies, Fungal↗

PubMed1981

Positive contrast cisternography: analysis of 1) false negative studies, 2) false positive diagnoses of acoustic neuroma.

In performing and interpreting positive contrast cisternograms, one must be aware that both false negative and false positive studies are possible. The former may be avoided by an appreciation of normal anatomical variants of the cisterns and by adequate projections. The false positive study in which a lesion other than an acoustic neuroma is found, is mainly a problem where there is non-filling of the internal auditory canal without a significant angle mass. The differential diagnosis of such lesions is discussed.

Adult↗

PubMedDate not supplied

[Possible interpretation errors in studying the pelvis in children. Description of 2 clinical cases].

The Authors describe two clinical cases in which the report of an abnormal conformation of the pubic bones required a careful differential diagnosis between a pathological condition and physiological variants of the normal ossification. Considering the different ways of this process of ossification, the pediatrician and the radiologist can avoid a wrong diagnosis with considerable consequences for the little patient.

Child↗

PubMed2005

Changes induced by levodopa and subthalamic nucleus stimulation on parkinsonian speech.

Levodopa (L-dopa) and subthalamic nucleus (STN) stimulation treatments have been associated with both improvement and exacerbation of dysarthria in Parkinson's disease (PD). We report four cases illustrating variant responses of dysarthria to dopaminergic and STN stimulation therapies. Patients' motor disability and dysarthria were perceptually rated by the Unified Parkinson's Disease Rating Scale (UPDRS) in four conditions according to medication and STN stimulation. Dedicated software packages allowed acquisition and analysis of acoustic recordings. Case 1, who had a severe off period aphonia, experienced improvement of speech induced by both levodopa and STN stimulation. In Case 2, both treatments worsened speech due to the appearance of dyskinesias. Case 3 had a dysarthria exacerbation induced by STN stimulation with parameters above optimal levels, interpreted as current diffusion from the STN to corticobulbar fibers. In Case 4, dysarthria exacerbation occurred with stimulation at an electrode contact located caudally to the target, also arguing for current diffusion as a potential mechanism of speech worsening. The presented cases demonstrated variant effects in relation to L-dopa and STN stimulation on speech. It seems that motor speech subcomponents can be improved like other limb motor aspect, but that complex coordination of all speech anatomical substrates is not responsive to STN stimulation. These hypotheses may be helpful for better understanding and management of STN stimulation effects on motor speech and skeleton-motor subsystems.

Adult↗

PubMed1999

A new translocation, t(2;4;12)(p21;q12;p13), in CD7-positive acute myeloid leukemia: a variant form of t(4;12).

We describe a 41-year-old man with CD7-positive acute myeloid leukemia (AML-M0) with trilineage-myelodysplasia. Chromosome analysis of the bone marrow cells showed 46.XY.t(2;4;12) (p21;q12;p13). Cytological and clinical features of our case were quite similar to those of AML with t(4;12)(q11-12;p13). The karyotypic interpretation was confirmed by fluorescence in situ hybridization (FISH) by using the whole-chromosome painting probes specific for chromosomes 2, 4, and 12. FISH analysis with the use of the YAC 936e2 probe, which covers the TEL gene, did not show the split signal, suggesting that a gene other than TEL was involved in the leukemogenesis of the present case. Our case with AML with t(2;4;12)(p21;q12;p13) appears to be the first case of a variant type of AML with t(4;12) (q11-12;p13).

Acute Disease↗

PubMed1991

[The manifestations of the epidemic process in shigellosis and their theoretical interpretation].

This work, based on the retrospective analysis of shigellosis morbidity among organized groups of adults, as well as the whole population of the city, demonstrates the manifestations of the epidemic process. Water supply was common in the city, while water consumption was autonomous. The organized groups of adults did not use the products of the local milk-processing factory. The following facts were established. The dynamics of morbidity in Flexner's dysentery showed the change of dominating variants of the infective agent, which reflected the action of internal mechanisms of the development of the epidemic process. The role of Sonne dysentery in the total structure of shigellosis morbidity did not correlate with the consumption of milk and milk products. The theory of the self-regulation of the parasitic system and the theory of correspondence served as the basis for the theoretical interpretation of the manifestations of the epidemic process of Shigella infections. To ascertain the real correspondence of individual Shigella species to concrete transmission factors, further investigation are necessary.

Adult↗

PubMed2001

[HIV-1 resistance against antiretroviral agents].

BACKGROUND: Failure of antiretroviral drugs to completely suppress HIV-1 replication inevitably leads to selection of drug-resistant variants. Emergence of drug resistance plays a major role in limiting the long-term success of antiretroviral therapy. MATERIAL AND METHODS: From August 1998 until April 2001, a total of 183 samples from 152 patients were analysed for HIV-1 drug resistance using genotypic analysis. RESULTS: Mutations associated with resistance were found in virus from 112 patients who received antiretroviral therapy. Mutations were frequently identified in the reverse transcriptase gene and to a lesser extent in the protease gene. Mutations associated with reduced drug susceptibility or polymorphisms were identified in 22 treatment naive patients. In addition, resistance mutations were observed in three out of eight patients with a recent infection. INTERPRETATION: Genotypic resistance testing is a valuable tool for rational decision-making when the current therapy is failing. In addition, patients with a recent HIV-1 infection should be tested for the surveillance of transmission of drug-resistant genotypic variants.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Linkage and associated studies of schizophrenia.

Genetic epidemiology has provided consistent evidence over many years that schizophrenia has a genetic component, and that this genetic component is complex, polygenic, and involves epistatic interaction between loci. Molecular genetics studies have, however, so far failed to identify any DNA variant that can be demonstrated to contribute to either liability to schizophrenia or to any identifiable part of the underlying pathology. Replication studies of positive findings have been difficult to interpret for a variety of reasons. First, few have reproduced the initial findings, which may be due either to random variation between two samples in the genetic inputs involved, or to a lack of power to replicate an effect at a given alpha level. Where positive data have been found in replication studies, the positioning of the locus has been unreliable, leading no closer to positional cloning of genes involved. However, an assessment of all the linkage studies performed over the past ten years does suggest a number of regions where positive results are found numerous times. These include regions on chromosomes 1, 2, 4, 5, 6, 7, 8, 9, 10, 13, 15, 18, 22 and the X. All of these data are critically reviewed and their locations compared. Reasons for the difficulty in obtaining consistent results and possible strategies for overcoming them are discussed. Am. J. Med. Genet. (Semin. Med. Genet.) 97:23-44, 2000.

Chromosome Mapping↗

PubMed1999

Role of histidine-50, glutamic acid-96, and histidine-137 in the ribonucleolytic mechanism of the ribotoxin alpha-sarcin.

alpha-Sarcin is a ribotoxin secreted by the mold Aspergillus giganteus that degrades the ribosomal RNA by acting as a cyclizing ribonuclease. Three residues potentially involved in the mechanism of catalysis--histidine-50, glutamic acid-96, and histidine-137--were changed to glutamine. Three different single mutation variants (H50Q, E96Q, H137Q) as well as a double variant (H50/137Q) and a triple variant (H50/137Q/E96Q) were prepared and isolated to homogeneity. These variants were spectroscopically (circular dichroism, fluorescence emission, and proton nuclear magnetic resonance) characterized. According to these results, the three-dimensional structure of these variants of alpha-sarcin was preserved; only very minor local changes were detected. All the variants were inactive when assayed against either intact ribosomes or poly(A). The effect of pH on the ribonucleolytic activity of alpha-sarcin was evaluated against the ApA dinucleotide. This assay revealed that only the H50Q variant still retained its ability to cleave a phosphodiester bond, but it did so to a lesser extent than did wild-type alpha-sarcin. The results obtained are interpreted in terms of His137 and Glu96 as essential residues for the catalytic activity of alpha-sarcin (His137 as the general acid and Glu96 as the general base) and His50 stabilizing the transition state of the reaction catalyzed by alpha-sarcin.

Aspergillus↗

PubMed2001

Prevalence and distribution of human herpesvirus 6 variants A and B in adult human brain.

The presence of human herpesvirus 6 (HHV-6) in brain tissues of 40 consecutive post-mortem cases was examined. For each case, autopsy samples were collected from the cerebellum, frontal, temporal, parietal and occipital lobes of both sides of the brain. HHV-6 DNA was detected by nested polymerase chain reaction and characterised into variants A and B. Overall, 97/400 (24.3%) samples were positive for HHV-6 DNA with 16 being variant A and 81 being variant B, but none of the samples harboured both variants. When analysed by patient, 34/40 (85%) had HHV-6 DNA detected in the brain. The viral DNA positivity did not show significant variation with gender and age. Four patients harboured variant A, 23 harboured variant B, and seven had both variants at different positions. The results indicate that both HHV-6A and HHV-6B are neurotropic and human brain may be another site for latency. HHV-6B was detected in brain tissues of a majority (75%) of the studied population and with a widespread distribution within the brain. Although the observed prevalence of HHV-6A in brain is lower (27.5%), in view of its lower seroprevalence, the neuroinvasive potential of variant A may be comparable to that of variant B. Although both variants are potential pathogens for the nervous system, the fact that they can exist, probably for most of the time, as commensals in human brain needs to be considered when interpreting their roles in neuropathology.

Adult↗

PubMed1993

The pathologist's appraisal of neck dissections.

A critical assessment is presented on the description and interpretation of histopathological findings in neck dissections undertaken in patients with squamous carcinomas originating in the head and neck. The topics covered include the localization and measurement of nodal metastases, variant histopathological appearances, micrometastases and extranodal spread.

Carcinoma, Squamous Cell↗

PubMed1995

Excessive anteriorisation of the superior vena cava associated with an azygos lobe.

A wide variety of congenital vascular anomalies of the superior mediastinum exist. Being clinically silent, most of these anomalies are detected incidentally on plain radiographs or CT scans where they could be mistaken for mediastinal masses. Familiarity with these anomalies is very important for correct interpretation and avoidance of confusion. We present a case of a mediastinal mass detected accidentally on plain radiography which on further radiological investigation was found to be an unreported normal variant of the superior vena cava (SVC). CT scans of the thorax and superior vena cavograms showed excessive anteriorisation of the SVC in the presence of an azygos lobe. After reviewing the literature and the embryology of the SVC and azygos lobe, we postulate that the variation in the location of the SVC was possibly due to the presence of the azygos lobe.

Adolescent↗

PubMed1989

Glaucomalike disks without increased intraocular pressure or visual field loss.

We studied 48 patients who had glaucomalike disks with increased cupping and pallor, superior or inferior extension of cupping and pallor and asymmetry of cupping and pallor between eyes without increased intraocular pressure or visual field loss, and open angles. We compared these patients with a randomly selected group of 48 patients with primary open-angle glaucoma. The mean age of the patients with glaucomalike disks (45.1 +/- 16.1 years) was significantly younger than the group with open-angle glaucoma (63.8 +/- 11.3 years). Of the patients with glaucomalike disks, 11 (23%) had a family history of glaucoma, 75% of 22 eyes with optic disk fluorescein angiograms had abnormal readings, and 59% of 43 eyes with retinal nerve fiber layer defects had abnormal readings. Photogrammetric measurements of the left disk cups were compared in 22 of the patients with glaucomalike disks to 16 matched patients with primary open-angle glaucoma. The only statistically significant difference was that the patients in the glaucoma group showed a larger cup area (surface opening) of the inferior quadrant. Our findings suggest that some glaucomalike disks may be one variant of primary open-angle glaucoma.

Adult↗

PubMedDate not supplied

Homocysteine and stroke: evidence on a causal link from mendelian randomisation.

BACKGROUND: Individuals homozygous for the T allele of the MTHFR C677T polymorphism have higher plasma homocysteine concentrations (the phenotype) than those with the CC genotype, which, if pathogenetic, should put them at increased risk of stroke. Since this polymorphism is distributed randomly during gamete formation, its association with stroke should not be biased or confounded. We investigated consistency between the expected odds ratio for stroke among TT homozygotes, extrapolated from genotype-phenotype and phenotype-disease studies, and the observed odds ratio from a meta-analysis of genotype-disease association studies. METHODS: We searched MEDLINE and EMBASE up to June, 2003, for all relevant studies on the association between homocysteine concentration and the MTHFR polymorphism, and until December, 2003, for those on the association between the polymorphism and the risk of stroke. Pooled odds ratios and 95% CI were calculated by random-effects and fixed-effects models. Consistency between expected and observed odds ratios was assessed by interaction test. FINDINGS: 111 studies met the selection criteria. Among 15635 people without cardiovascular disease, the weighted mean difference in homocysteine concentration between TT and CC homozygotes was 1.93 micromol/L (95% CI 1.38 to 2.47). The expected odds ratio for stroke corresponding to this difference based on previous observational studies was 1.20 (1.10 to 1.31). In our genetic meta-analysis (n=13928) the odds ratio for stroke was 1.26 (1.14 to 1.40) for TT versus CC homozygotes, similar to the expected odds ratio (p=0.29). Consistency between the odds ratios was preserved in analyses by age-group, ethnic background, and geographical location. INTERPRETATION: The observed increase in risk of stroke among individuals homozygous for the MTHFR T allele is close to that predicted from the differences in homocysteine concentration conferred by this variant. This concordance is consistent with a causal relation between homocysteine concentration and stroke.

Causality↗