Benefits and risks of simvastatin in patients with familial hypercholesterolaemia.

Familial hypercholesterolaemia is a frequent, inherited, monogenic disorder, associated with accelerated development of atherosclerotic disease leading to coronary artery disease. Life expectancy of patients with familial hypercholesterolaemia is reduced by 15-30 years unless they are adequately treated with lipid-lowering therapy. Given the chronic nature of this disease, the selection of a therapeutic approach should be strongly based on its long-term safety and tolerability. The introduction of HMG-CoA reductase inhibitors has revolutionised the treatment of familial hypercholesterolaemia.Simvastatin 40-80 mg/day effectively reduces serum low density lipoprotein (LDL)-cholesterol levels. Furthermore, simvastatin reduces triglycerides and mildly raises high density lipoprotein-cholesterol levels. In addition to the hypolipidaemic effect, other potentially important effects, such as improvement of endothelial function and reduction of LDL oxidation and vascular inflammation, have been associated with HMG-CoA reductase inhibitor therapy. Simvastatin has also been shown to abolish the progression, and even facilitate the regression, of existing human atherosclerotic lesions.The good safety and tolerability profile of simvastatin is clearly highlighted by the low rate of therapy discontinuation observed in several population-based clinical trials. The most common adverse events leading to the discontinuation of therapy are gastrointestinal upset and headache. Asymptomatic elevations in liver transaminase levels and myopathy are uncommon.The overwhelming clinical evidence regarding the long-term use of HMG-CoA reductase inhibitor therapy in patients with familial hypercholesterolaemia together with the long-term safety data (particularly relating to simvastatin) provide support for the use of this drug as a first-line agent when pharmacological treatment is indicated. Early intervention with simvastatin treatment can be successfully implemented with favourable economic benefits.     

A single VH family and long CDR3s are the targets for hypermutation in bovine immunoglobulin heavy chains

Summary: Bovine immunoglobulins are made from genes belonging to a small family of closely related Vh, genes. In this respect cattle resemble all species of domesticated mammals, which also use one VH family The family, named BoVH1, is homologous to the mouse Q52 family, and there are no more than 20 genes of this family in the bovine genome. Another feature of bovine heavy chains is the use of long CDR3s, which have an average of 21 codons. It seems that there are several families of long, closely related D genes rich in glycine and tyrosine responsible for this length. Sequences described as targets for mutations in other species can be found in CDR1, CDR2, and the putative D genes. The mutation mechanism starts at some point between late fetal stage and birth and seems to be antigen Independent. Diversity seems to be generated by hypermutation, although other mechanistns cannot be discomited at this time. Contrary to humans and mice, which have several Vh gene families comprising more than 100 genes, cattle use only a few genes and long CDR3s followed by somatic mutation to generate the necessary diversity to recognize the universe of antigens they will encounter during their life.     

Application of ECCLS guidelines to the analysis of Toxoplasma IgG and Rubella IgG using laboratory kits based on the Meia method.

The Meia method is an enzymo-immunoassay involving fluorometric detection, which is used in the Abbott IMx automatic analyzer. The purpose of this report was to analyse the Meia Toxoplasma gondii IgG antibody and Rubella IgG antibody assays, following ECCLS guidelines for the analysis of laboratory kits. The results showed that between-run imprecision for Rubella IgG was close to 15%; for Toxoplasma IgG the percentage was 13%. The mean recovery for Rubella IgG was 104% and 94% for Toxoplasma IgG. The carry-over for Rubella IgG was 0.64% and 0.26% for Toxoplasma IgG which, in both cases, was less than the analytical variability. Both Meia and Elisa showed a linear relationship in the analytical range of the method. Comparing Meia with the Elisa method, constant and proportional differences were found for IgG Rubella and proportional differences for IgG Toxoplasma. The Meia method has many positive analytical features to recommend and it can easily be used in a multidisciplinary laboratory, needing only a small number of serum samples.     

Pathophysiology of HPA axis abnormalities in patients with major depression: an update

Four hypotheses have been proposed to explain why nonsuppression on the dexamethasone suppression test occurs in patients with major depression. These include 1) increased metabolism of dexamethasone, 2) decreased sensitivity of pituitary glucocorticoid receptors to dexamethasone, 3) hyperresponsivity of the adrenal gland to ACTH stimulation, and 4) increased central drive of the pituitary from hypothalamic/limbic structures that overrides the action of the dexamethasone. A critical review of the literature suggests that the last hypothesis is most closely supported by the data. Despite this conclusion, factors other than depression may be involved in hypothalamic-pituitary-adrenal axis dysfunction.     

Adenosine 5′-triphosphate,uridine 5′-triphosphate,bradykinin, and lysophosphatidic acid induce different patterns of calcium responses by human articular chondrocytes

Small calcium-mobilizing inflammatory mediators have been implicated in joint pathology. Here we demonstrate that bradykinin, adenosine 5′-triphosphate, uridine 5′-triphosphate, and lysophosphatidic acid raise the intracellular calcium concentration ([Ca²⁺]_i) in human articular chondrocytes. Heterologous cross-desensitization experiments showed that the uridine 5′-triphosphate response was abolished by prior treatment with adenosine 5′-triphosphate and conversely, that the adenosine 5′-triphosphate response was abolished by prior treatment with uridine 5′-triphosphate: this indicated competition for the same receptor site, whereas bradykinin and lysophosphatidic acid did not compete with other ligands. Pretreatment with thapsigargin abolished ligand-mediated Ca²⁺ responses but not vice versa: this confirmed that Ca²⁺ release occurred from intracellular stores. Single-cell analysis of Fura-2 acetoxymethyl ester loaded chondrocytes showed mediator-dependent patterns of oscillatory Ca²⁺ changes in a subset of cells when challenged with submaximal concentrations of bradykinin, adenosine 5′-triphosphate, or uridine 5′-triphosphate in the presence of extracellular Ca²⁺. However, no oscillatory responses were seen after a challenge with lysophosphatidic acid. Therefore, although a number of different Ca²⁺-mobilizing ligands activate chondrocytes, the differences that occur in the temporal patterning of Ca²⁺ responses may result in unique mediator-dependent changes in cellular activity.     

Group protocol to mitigate disaster stress and enhance social support in adolescents exposed to Hurricane Hugo.

Literature reports that cognitive understanding and social support can mitigate stress in both adults and adolescents. As a subcomponent of the Carolina Adolescent Health Project (CAHP), this research evaluated the efficacy of a Cognitive Social Support (CSS) group protocol designed to mitigate the disaster stress of adolescents who had been exposed seriously to Hurricane Hugo. A purposive sample of 259 students participated in and evaluated the CSS. This article reports the specific structure, content, process, rationale, and cost of the CSS. Evaluations indicated that 82% of the students evaluated the small-group component of the CSS as "very good" or "excellent," while 70% rated the large-group component as "very good" or "excellent."     

Partial purification of parathyrin from the corpuscles of Stannius (PCS) of the eel (Anguilla anguilla, L.)

It has been previously shown that the eel corpuscles of Stannius (CS) synthesize and secrete a substance (PCS) which is functionally and immunologically related to the mammalian parathyrin family. Purification of PCS, including anion-exchange chromatography, ODS C-18 reverse-phase HPLC, and affinity chromatography, showed that a biologically active peak, eluted in 32% acetonitrile, contains a 32- to 34-kDa protein which is 600-fold more potent than the crude extract is a test involving the hypocalcemic response in the CS-deprived eel. Specific immunoprecipitation of protein encoded by mRNA extracted from eel CS indicates that a 45-kDa precursor is involved in PCS synthesis. The hypothetical significance of a "large" parathyrin-like molecule in fish is suggested in relation to what is known about mammalian parathyrin gene expression.