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PubMed2004

Variants and mimics of Guillain Barré Syndrome.

BACKGROUND: The clinical and pathologic spectrum of Guillain Barre Syndrome (GBS) has expanded to include both demyelinating and axon loss forms. GBS may also have atypical presentations. For these reasons, clinicians are more likely to overlook unrelated disorders that mimic GBS. REVIEW SUMMARY: In this article, the classic presentation and variants of GBS are briefly reviewed. Disorders that mimic GBS are reviewed in detail, including those caused by neurotoxins, heavy metals, chemical toxins, drugs, vasculitis, hereditary disorders, infections, critical illness, and myelopathy. Illustrative case studies accompany a number of the descriptions. CONCLUSIONS: Failure to recognize the mimics of GBS can lead to erroneous diagnosis, inappropriate treatment, and significant morbidity. Appropriate diagnosis requires a combination of careful history and examination, and accurate interpretation of diagnostic testing.

Animals↗

PubMed2000

Influence of non-MHC genes on lymphocyte response to Mycobacterium tuberculosis antigens & tuberculin reactive status in pulmonary tuberculosis.

BACKGROUND & OBJECTIVES: Major histocompatibility complex (MHC) genes are known to influence the immune functions. In the present study, the influence of non-MHC genes such as mannose binding protein (MBP), vitamin D receptor (VDR) and interleukin-1 receptor antagonist (IL-1RA) gene polymorphisms on lymphocyte response to Mycobacterium tuberculosis culture filtrate antigen (10 micrograms/ml) was studied in 44 patients with active pulmonary TB and the family contacts (35) and in 32 normal healthy subjects. The influence of these gene polymorphisms on tuberculin (1TU of PPD of M. tuberculosis) reactivity status in 146 pulmonary TB patients was also studied. METHODS: The MBP and VDR genes were amplified using polymerase chain reaction (PCR) and genotyping was carried out using sequence specific oligonucleotide probes by dot blot and IL-1RA by agarose gel electrophoresis. RESULTS: A significantly decreased lymphocyte response to M. tuberculosis antigen was seen in pulmonary TB patients positive for functional mutant homozygotes of MBP (OO) compared to heterozygote carriers (AO; P < 0.02) and wild homozygotes (AA; P < 0.01). The variant mutant genotype (tt) of VDR gene was associated with an increased lymphocyte response in control subjects compared to active TB patients with tt genotype (P < 0.05). Heterozygote carriers of MBP (AO) were associated with a significantly (P < 0.001) decreased tuberculin reactivity compared to wild homozygotes (AA). The VDR genotype Tt (heterozygote carrier) was associated with an increased tuberculin reactivity in female TB patients as compared to male patients (P < 0.001). INTERPRETATION & CONCLUSIONS: The present study suggested that MBP and VDR genes influence the cell mediated immune response in pulmonary TB patients. Non-MHC genes along with HLA-Class II genes/gene products may be playing an immunoregulatory role in the mechanism of susceptibility/resistance to tuberculosis.

Adult↗

PubMed1975

[Electrocardiographic features and vectorial analysis of cardiac potentials in electric shock-induced ventricular fibrillation (author's transl)].

The authors examined the electrocardiographic features of ventricular fibrillation and other ventricular paroxysms induced by electric shock in the guinea pig. The analysis of the electrocardiographic patterns, as well as the vectorial study of the cardiac potentials during repeated episodes of ventricular "anarchy" induced in more than forty animals, showed the following data: 1. following electric shock, ventricular paroxysms appear, featuring paroxysmal tachycardia, typical or impure flutter, tachycardia--either "torsade de pointe" or "spindle" type, and typical ventricular fibrillation. Such different electrocardiographic patterns represent evolutive stages of electric activity disorganization, leading to a complete ventricular "anarchy". Such steps may reverse when reorganization of the electric activity and spontaneous defibrillation occur; 2. an attempt can be made at present to classify ventricualr paroxysms, thus eleminating semeiotic and semantic errors, still present in the literature, and providing a standardization of both nomenclature and electrocardiographic interpretation; 3. during fibrillation, the mean ventricular rate decays, featuring an exponential curve. This phenomenon accounts for a metabolic depletion of the myocardium: the higher the number of fibrillation episodes previously induced and subsided (either spontaneously or not) in the same animal, the faster the course of the phenomenon; 4. the vectorial analysis of the fibrillation potentials and, particularly, the graphic construction of "depolarization" and "repolarization" vectorcardiograms, in the differenttypes or variants of ventricular paroxysms, show that the basic mechanisms leading to ventricular electric activity disgregation are the multiple re-entry and the irregular spreading of the activation front; 5. on the basis of the acquired data, the authors believe that the "circus movement" theory (Wiggers) is still the most suitable for explaining the onset and the evolution of ventricualr fibrillation.

Animals↗

PubMed2005

Mutations in the transketolase-like gene TKTL1: clinical implications for neurodegenerative diseases, diabetes and cancer.

Transketolase proteins or transketolase enzyme activities have been related to neurodegenerative diseases, diabetes, and cancer. Transketolase enzyme variants and reduced transketolase enzyme activities are present in patients with the neurodegenerative disease Wernicke-Korsakoff syndrome. In Alzheimer's disease patients transketolase protein variants with different isoelectric points or a proteolytic cleavage leading to small transketolase protein isoforms have been identified. In diabetes mellitus patients reduced transketolase enzyme activities have been detected and the lipid-soluble thiamine derivative benfotiamine activates transketolase enzyme reactions, thereby blocking three major pathways of hyperglycemic damage and preventing diabetic retinopathy. In cancer inhibition of transketolase enzyme reactions suppresses tumor growth and metastasis. All the observed phenomena have been interpreted solely on the basis of a single transketolase gene (TKT) encoding a single transketolase enzyme. No mutations have been identified so far in TKT transketolase explaining the altered transketolase proteins or transketolase enzyme activities found in neurodegenerative diseases, diabetes and cancer. We demonstrate the presence of a second transketolase enzyme (TKTL1) in humans. During the evolution of the vertebrate genome, mutations in this transketolase gene (TKTL1) have led to tissue-specific transcripts different in size, which encode an enzymatically active transketolase protein as well as different smaller protein isoforms. The mutations within the TKTL1 gene caused a mutant transketolase enzyme with an altered substrate specificity and reaction modus. Here we characterize the TKTL1 gene and its encoded TKTL1 protein(s) and discuss the medical and clinical implications of this mutated transketolase. We furthermore postulate a novel metabolic concept for the understanding, prevention and therapy of neurodegenerative diseases, diabetes and cancer.

Diabetes Mellitus↗

PubMed1987

[Sensory delirium of attitude in adolescence (problems of phenomenology and its dynamics)].

On the basis of a clinical follow-up of juvenile schizophrenia first manifested in delirious states with a picture of sensitive delirium of attitude (65 patients) the author has determined the stages of its development in youth and characteristics of the psychopathological structure of delirious disturbances which are poorly systematized and are still to be researched; the condition is characterized by a combination of elements of sensitive and interpretative delirium. The author has established a close correlation between the contents of delirium in these cases and the pubertal age, a peculiar nature of delirious constructions similar to super-worship formations, as well as a distinctive involvement of affective disturbances and catathymic psychic disorders in their formation. It has been shown that the pubertal age is pathogenetically significant with regard to the manifestations, course, and dynamics of the given variant of sensitive delirium of attitude.

Adolescent↗

PubMedDate not supplied

Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy.

Metazoan organisms may discriminate between self and non-self not only by the presence of foreign antigens but also by the absence of normal self markers. Mammalian adaptive immune responses use the first strategy, with the additional requirement that foreign antigens are recognized in the context of self-major histocompatibility complex (MHC) products at the cell surface. Aberrant cells which fail to express MHC products adequately can therefore avoid detection. A more primitive but complementary defence system, eliminating such cells on the basis of absent self-markers, is suggested by a re-interpretation of phenomena associated with metastasis and natural resistance. We now show that murine lymphoma cells selected for loss of H-2 expression are less malignant after low-dose inoculation in syngeneic hosts than are wild-type cells, and that the rejection of such cells is non-adaptive. On the basis of our data, we suggest that natural killer cells are effector cells in a defence system geared to detect the deleted or reduced expression of self-MHC.

Animals↗

PubMed1984

The antigenicity of myoglobin-related peptides synthesised on polyacrylamide and polystyrene resin supports.

Polyacrylamide resins [Atherton et al., Bioorg. Chem. 8, 351-370 (1979)] have been found suitable for solid-phase radioimmunoassay of peptides synthesised on the same supports; they are sufficiently stable during side-chain deprotection and swell sufficiently in aq. media to admit antibody molecules to the sites of peptide attachment. A re-examination of five synthetic peptide sequences corresponding to (15-21), (56-62), (94-99), (113-119) and (145-151) of beef myoglobin analogous to those delineated by Atassi [Immunochemistry 12, 423-438 (1975)] for sperm whale myoglobin shows that they all bind anti-beef myoglobin antibodies raised in rabbits, with binding capacities in the order V = III greater than IV greater than I = II. The resin-bound peptide (72-88) binds such antibodies even more extensively, as do certain sequential variants of peptide V. Other peptides, bound to polyacrylamide or polystyrene resins but unrelated to any of the five sequences and varying in size and amino acid composition and sequence were also tested with various antisera. It was concluded that the antibody binding properties of the 30 or so small peptides (two-seven residues) are dominated by their cationic and/or hydrophobic properties. In small peptides, therefore, antibody binding can be safely interpreted only in terms of general structural properties but not in terms of biological specificity. The latter property becomes assessable only with peptides representing larger areas of antigenic protein surfaces.

Acrylic Resins↗

PubMed2005

Antiepileptic action induced by a combination of vigabatrin and tiagabine.

Vigabatrin, an inhibitor of GABA breakdown by GABA transaminase and of GABA transporter isoform 1 (GAT1), and tiagabine, a highly specific inhibitor of GAT1, have successfully been applied in the treatment of epilepsy. We investigated the effects of individual and combined application of these drugs on GAT1 expressed in Xenopus oocytes, and examined the effects on epileptiform discharges in the CA3 area of brain slices of genetically epileptic El and control ddY mice, and on the occurrence of seizures in El mice. Simultaneous application of vigabatrin and tiagabine inhibited epileptiform discharges induced by high-K+ solution in the brain slices in an antagonistic fashion. The degree of inhibition by tiagabine after pre-treatment with vigabatrin was additive in ddY mice and synergistic in El mice. In Mg2+-free solution, co-treatment by the two drugs produced additive inhibition in slices from both mouse strains, but pre-treatment with vigabatrin produced synergistic inhibition in slices only from ddY mice. In the slices from El mice, a combination of drugs resulted in additive effects in both co- and pre-treatment by the drugs. Although these drugs are also effective in vivo at suppressing seizure occurrence in El mice, the combined application does not show synergistic effects, but rather is antagonistic under the experimental conditions in this particular variant of epilepsy. The synergistic inhibition of epileptiform discharges in brain slices may, in part, have originated from the complex interaction with GAT1. In experiments on the GAT1 expressed in oocytes it could be demonstrated that synergistic inhibition occurs only at low concentration (0.1 nM) of vigabatrin. This illustrates that the oocytes may form a powerful test system for drug screening and investigation of complex drug interactions. These results present a novel interpretation of synergistic inhibition of certain epileptic discharges using vigabatrin and another drug, and that for successful synergistic treatment of epilepsies carefully designed timed dosage regimens are essential.

Action Potentials↗

PubMed2000

Incorporating patient preferences into randomized trials.

When designing trials, an important ethical and practical concern is ensuring that proper consideration is given to patient preferences. A number of design variants on the traditional randomized trial can take account of such preferences in different ways. The partially randomized patient preference (PRPP) design is often advocated for taking these preferences into account. In studies of this type, all eligible patients are followed up, but the primary comparison is still between effects observed in patients randomly allocated to treatment arms. This design and other variants on conventional trials each have different scientific, ethical, and practical implications. We consider these diverse aspects of several modifications to the conventional method for obtaining consent and then, in more detail, the relative merits of the PRPP design. We conclude that none of these adjustments is ideal. Those designing trials should therefore always think carefully about the consent process, for its implications on participation and on how the results will be interpreted.

Epidemiologic Research Design↗

PubMed1996

V3 seroreactivity and sequence variation: tracking the emergence of V3 genotypic variation in HIV-1-infected patients.

OBJECTIVE: To investigate the relationship between V3-specific immune responses and viral quasispecies evolution in 10 HIV-1-seropositive patients enrolled in a phase I trial of recombinant gp160. METHODS: Serologic responses to the HIVLAI V3 loop and autologous V3 loop DNA sequences were sequentially determined over a 3-4-year interval. RESULTS: Six patients either seroconverted or had a > or = 42-fold boost in titer to the V3 reagent associated with an average of 3.2 amino-acid changes in their autologous V3 loops. Four patients with < or = 11-fold change in titer to the V3 loop showed an average of 0.75 amino-acid changes. Attempts to measure autologous V3 loop responses in four patients using a peptide enzyme-linked immunosorbent assay technique did not show a distinct binding preference for autologous versus heterologous V3 loop peptides. Thus, we interpret seroreactivity to the heterologous HIVLAI V3 loop to reflect the broadness of the V3 immune response rather than a direct measure of epitope-specific immune pressure. CONCLUSIONS: These data suggest that the broadness of serologic responses to viral epitopes are reflected in the rate of evolution of their cognate coding sequences and support the view that the immune response to HIV-1 results in the continuous selection of new viral variants during the course of disease.

AIDS Vaccines↗

PubMed1985

Melanoma precursor lesions and borderline melanomas.

The histopathological interpretation of melanoma precursor and borderline lesions remains difficult. The natural history of naevi is reviewed and, in the light of this, current views on the histological sub-types of melanoma, precursor lesions and benign lesions which may mimic melanoma are presented. As the criteria for these lesions are now becoming defined they should be applicable by most histopathologists, even those who may see only occasional cases. Childhood and minimal deviation variants, however, are likely to remain problems even for the expert. Fortunately such lesions are uncommon.

Adolescent↗

PubMed2006

Determining the cause of patchwork HBA1 and HBA2 genes: recurrent gene conversion or crossing over fixation events.

BACKGROUND AND OBJECTIVES: Recombinations are common between the two homologous alpha-globin genes. We report on the identification and characterization of two patchwork alpha-globin genes. DESIGN AND METHODS: Multiplex polymerase chain reaction assays were performed to rule out the presence of alpha-globin gene deletions and triplications. The HBA1 (alpha1-globin) and HBA2 (alpha2-globin) genes were individually amplified and sequenced. RESULTS: Two variants of the HBA1 and HBA2 genes were identified. One variant allele, alpha121, consists primarily of the HBA1 gene sequence except for a small segment of IVSII in which an octanucleotide segment has been replaced by an HBA2 -specific nucleotide. Conversely, the alpha212 variant consists primarily of the HBA2 gene sequence except for a segment of IVSII in which HBA2 -specific nucleotides at two sites have been replaced by HBA1-specific sequences. Both variant alleles are found in individuals of different ethnicity, geographical origin, and haplotype backgrounds. The simplest model for the origins of these patchwork alleles is a single crossover between a normal allele and an existing recombinant allele such as the -alpha(3.7) single gene deletion or the alphaalphaalpha(anti3.7) triplicated allele, but we cannot exclude a reciprocal double crossover or a non-reciprocal gene conversion between misaligned HBA1 and HBA2 genes. INTERPRETATION AND CONCLUSIONS: The a-globin patchwork alleles have arisen independently on several occasions, most likely through a single crossover between a normal and a recombinant allele. Further studies are necessary to evaluate the possible effect of these changes on alpha-globin gene expression.

Adolescent↗

PubMed1981

The problem of subclinical localised paroxysmal rhythmic discharges (psychomotor variant discharges). Report of two cases.

Two cases are reported of patients whose EEGs showed localised rhythmic seizure activity in the midtemporal regions of one or both hemispheres, unaccompanied by any clinical symptoms: the patients' histories differed: one was of classic migraine and the other complex partial epilepsy. The frequency and morphology of the paroxysmal anomalies was identical in the waking state and in sleep. The nosographic classification of the phenomenon is discussed with reference to Gibbs' reports regarding the "psychomotor variant type of seizure discharge", to the work of Lipman and Hughes on "rhythmic mid-temporal discharge" and to that of Westmoreland and Klass on the "subclinical rhythmic EEG discharge of adults". But in contrast to the last phenomenon there were no signs pointing to a diffuse cerebrovascular disease. Reports of such a pattern are rare in the European literature and nonexistent in the Italian literature, facts which make an ordinary interpretation of the phenomenon difficult.

Aged↗

PubMed2004

Lack of association between 5HT2A receptor gene haplotype, bipolar disorder and its clinical subtypes in a West European sample.

Bipolar affective disorder (BPAD) is a complex psychiatric disorder with a major genetic contribution. Abnormalities in serotonergic function have been implicated in its aetiology. The 5HT2A receptor (5HT2AR) gene is a strong candidate gene for involvement in BPAD, but previous association studies have reported conflicting results. These data are difficult to interpret because most negative results were obtained with small samples. The aim of this study was to test the association between the 5HT2AR gene and BPAD in a large West European sample. We studied the -1438G/A and the His452Tyr polymorphisms, for haplotype analysis to increase both informativity and the likelihood of detecting an association between BPAD and the 5HT2AR gene. We analysed the genotype, allele and haplotype distributions of two 5HT2AR gene variants in a population of 356 BPAD patients, which we compared with 208 healthy controls. We also carried out exploratory analysis in clinical subgroups of patients defined according to personal history of mood disorders, suicidal behaviour, comorbid psychiatric disorders and family history of affective disorders. We found no difference between BPAD patients and controls for allele, genotype and haplotype distributions. Exploratory analysis in subgroups of BPAD patients showed only a marginal difference in haplotype distribution between controls and BPAD patients with antidepressant-induced mania (P = 0.018). This difference was not significant after correction for multiple testing. Our study suggests that the 5HT2AR gene is unlikely to be involved in genetic susceptibility to BPAD but should be further investigated in a pharmacogenetic study.

Adult↗

PubMed1998

Genetics, calcium intake and osteoporosis.

Genetic factors explain a high proportion of the age-specific differences in bone density, size and turnover. The potential for interaction between hormonal, diet and lifestyle factors is likely to be important. Common allelic variation in the VDR is an example of normal gene variants altering Ca homoeostasis, with effects on body and bone size as well as bone density. The VDR findings suggesting interactions between genetic and nutritional factors are an important target for future research. These studies are complicated by the potential for effects of gene-gene interactions and of undefined environmental factors. These problems notwithstanding, considerations of environmental and nutritional contributions, such as Ca intake and vitamin D status, will be critical in interpreting these genetic pathways and in 'personalizing' nutritional recommendations.

Aging↗

PubMed2001

A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models.

Over the past decade, nearly 1,000 variants have been identified in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in classic and atypical cystic fibrosis (CF) patients worldwide, and an enormous wealth of information concerning the structure and function of the protein has also been accumulated. These data, if evaluated together in a sequence comparison of all currently available CFTR homologs, are likely to refine the global structure-function relationship of the protein, which will, in turn, facilitate interpretation of the identified mutations in the gene. Based on such a combined analysis, we had recently defined a "functional R domain" of the CFTR protein. First, presenting two full-length cDNA sequences (termed sCFTR-I and sCFTR-II) from the Atlantic salmon (Salmo salar) and an additional partial coding sequence from the eastern gray kangaroo (Macropus giganteus), this study went further to refine the boundaries of the two nucleotide-binding domains (NBDs) and the COOH-terminal tail (C-tail), wherein NBD1 was defined as going from P439 to G646, NBD2 as going from A1225 to E1417, and the C-tail as going from E1418 to L1480. This approach also provided further insights into the differential roles of the two halves of CFTR and highlighted several well-conserved motifs that may be involved in inter- or intramolecular interactions. Moreover, a serious concern that a certain fraction of missense mutations identified in the CFTR gene may not have functional consequences was raised. Finally, phylogenetic analysis of all the full-length CFTR amino acid sequences and an extended set of exon 13--coding nucleotide sequences reinforced the idea that the rabbit may represent a better CF model than the mouse and strengthened the assertion that a long-branch attraction artifact separates the murine rodents from the rabbit and the guinea pig, the other Glires.

Amino Acid Motifs↗

PubMed2000

A system for specific, high-throughput genotyping by allele-specific primer extension on microarrays.

This study describes a practical system that allows high-throughput genotyping of single nucleotide polymorphisms (SNPs) and detection of mutations by allele-specific extension on primer arrays. The method relies on the sequence-specific extension of two immobilized allele-specific primers that differ at their 3'-nucleotide defining the alleles, by a reverse transcriptase (RT) enzyme at optimized reaction conditions. We show the potential of this simple one-step procedure performed on spotted primer arrays of low redundancy by generating over 8000 genotypes for 40 mutations or SNPs. The genotypes formed three easily identifiable clusters and all known genotypes were assigned correctly. Higher degrees of multiplexing will be possible with this system as the power of discrimination between genotypes remained unaltered in the presence of over 100 amplicons in a single reaction. The enzyme-assisted reaction provides highly specific allele distinction, evidenced by its ability to detect minority sequence variants present in 5% of a sample at multiple sites. The assay format based on miniaturized reaction chambers at standard 384-well spacing on microscope slides carrying arrays with two primers per SNP for 80 samples results in low consumption of reagents and makes parallel analysis of a large number of samples convenient. In the assay one or two fluorescent nucleotide analogs are used as labels, and thus the genotyping results can be interpreted with presently available array scanners and software. The general accessibility, simple set-up, and the robust procedure of the array-based genotyping system described here will offer an easy way to increase the throughput of SNP typing in any molecular biology laboratory.

Alleles↗

PubMed1997

Review: molecular epidemiology of hepatitis C virus.

Molecular techniques have been used to investigate the epidemiology of hepatitis C virus (HCV) at several different levels. At a global level, the time of divergence of the diverse HCV genotypes isolated from different geographical regions has been estimated from the rate of divergence observed among a cohort of individuals infected from a common source. Estimates of more than 300 years for virus subtypes and more than 500-2000 years for virus types are consistent with their current geographical distributions. Analysis of virus sequences has also provided evidence for a common source of infection in several large-scale outbreaks of HCV infection, although where there is evidence that the implicated source contains more than one variant it may be difficult to distinguish individuals infected by different sources. Finally, sequence analysis has been used to investigate the vertical or horizontal transmission of HCV between pairs of individuals. The hypervariable region of the E2 gene is the most informative region to study if samples are available soon after the transmission event, but evidence for more distant events can still be obtained from analysis of genes such as NS5b and E1. Interpretation of some studies is complicated by the conservation of the gene region studied, or by the failure to make comparisons with sequences from epidemiologically unrelated viruses.

Disease Outbreaks↗