Incidence, clinical significance and prognosis of ventricular fibrillation in the early phase of myocardial infarction

Of 1265 patients admitted to the CCU with the diagnosis of acuteMI, 96 (7.6%) developed ventricular fibrillation within 72 hoursfollowing admission. Of these 96, 35 (36.5%) had secondary VFassociated with left ventricular failure; they had a high in-hospitalmortality of 57.1%. The remaining 61 (63.5%) had primary VF,i.e. VF occurring in the absence of significant LV failure.Fourteen of these (23%) died in hospital: 9 due to PVF (3 duringthe first episode, 6 during a recurrence). This mortality figurewas significantly higher (P<0.001) than the mortality of10% seen among patients who did not experience VF. Primary VFshowed a recurrence rate of 20%. Compared with the 1061 patientswho left the hospital without primary VF, the 61 subjects withthis rhythm disorder were older, had larger infarcts and morefrequent complications, such as pericarditis, conduction abnormalities,frequent ventricular premature contractions and signs of rightventricular failure. These findings, in contrast with a widelyheld view, suggest that primary VFmay carry a guarded prognosis.     

Sensitivity and specificity of four assays to detect human T− lymphotropic virus type I or type I/II antibodies

BACKGROUND: Assays that detect human T-lymphotropic virus type I and type II antibody (HTLV-I/II) are widely used in the routine screening of blood donors. STUDY DESIGN AND METHODS: Four commercially available anti-HTLV-I (Fujirebio and Organon Teknika) or -HTLV-I/II assays (Murex and Ortho) were evaluated in various serum panels: A) HTLV-I-positive specimens (n = 41), confirmed by Western blot and polymerase chain reaction; B) a commercially available anti-HTLV-I/II panel; C) serial dilutions of sera from HTLV-I-positive individuals (n = 30), confirmed by immunofluorescence assay and Western blot: D) serial dilutions of HTLV-II-positive blood donors (n = 20), confirmed by Western blot and polymerase chain reaction, and E) sera from first-time blood donors (n = 1055). RESULTS: All four assays elicited reactions in all 82 HTLV-I- positive samples in Panels A, B, and C. Of 32 HTLV-II-positive specimens in Panels B and D, 31 (96.9%) reacted in the Organon Teknika assay and all 32 reacted in the remaining tests. Probit analysis of test results in Panels C and D indicated that the Fujirebio test was the most sensitive assay, followed by Organon Teknika, Ortho, and Murex. The specificities of Fujirebio, Murex, Organon Teknika, and Ortho tests in 1055 first-time blood donors were 99.9, 100, 99.6, and 99.9 percent, respectively. CONCLUSION: All four studied assays for detecting HTLV-I or HTLV-I/II antibodies are appropriate as screening tests.     

The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry

Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot explain the clustering of type 1 diabetes in families, and a role for other genes is inferred. In the present report we describe linkage and association of type 1 diabetes to the CTLA-4 gene (cytotoxic T lymphocyte associated-4) on chromosome 2q33 (designated IDDM12). CTLA-4 is a strong candidate gene for T cell- mediated autoimmune disease because it encodes a T cell receptor that mediates T cell apoptosis and is a vital negative regulator of T cell activation. In addition, we provide supporting evidence that CTLA-4 is associated with susceptibility to Graves' disease, another organ- specific autoimmune disease.      

46, XY gonadal dysgenesis: new SRY point mutation in two siblings with paternal germ line mosaicism

Stoppa‐Vaucher S, Ayabe T, Paquette J, Patey N, Francoeur D, Vuissoz J‐M, Deladoëy J, Samuels ME, Ogata T, Deal CL. 46, XY gonadal dysgenesis: new SRY point mutation in two siblings with paternal germ line mosaicism. Familial recurrence risks are poorly understood in cases of de novo mutations. In the event of parental germ line mosaicism, recurrence risks can be higher than generally appreciated, with implications for genetic counseling and clinical practice. In the course of treating a female with pubertal delay and hypergonadotropic hypogonadism, we identified a new missense mutation in the SRY gene, leading to somatic feminization of this karyotypically normal XY individual. We tested a younger sister despite a normal onset of puberty, who also possessed an XY karyotype and the same SRY mutation. Imaging studies in the sister revealed an ovarian tumor, which was removed. DNA from the father's blood possessed the wild type SRY sequence, and paternity testing was consistent with the given family structure. A brother was 46, XY with a wild type SRY sequence strongly suggesting paternal Y‐chromosome germline mosaicism for the mutation. In disorders of sexual development (DSDs), early diagnosis is critical for optimal psychological development of the affected patients. In this case, preventive karyotypic screening allowed early diagnosis of a gonadal tumor in the sibling prior to the age of normal puberty. Our results suggest that cytological or molecular diagnosis should be applied for siblings of an affected DSD individual.     

Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP)

Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with homologies to endopeptidases, on the X-chromosome), are responsible for X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has raised important questions regarding PEX function at the molecular level. The aim of this study was to analyse 99 HYP families for PEX gene mutations, and to correlate predicted changes in the protein structure with Zn2+ metallopeptidase gene function. Primers flanking 22 characterised exons were used to amplify DNA by PCR, and SSCP was then used to screen for mutations. Deletions, insertions, nonsense mutations, stop codons and splice mutations occurred in 83% of families screened for in all 22 exons, and 51% of a separate set of families screened in 17 PEX gene exons. Missense mutations in four regions of the gene were informative regarding function, with one mutation in the Zn2+-binding site predicted to alter substrate enzyme interaction and catalysis. Computer analysis of the remaining mutations predicted changes in secondary structure, N-glycosylation, protein phosphorylation and catalytic site molecular structure. The wide range of mutations that align with regions required for protease activity in NEP suggests that PEX also functions as a protease, and may act by processing factor(s) involved in bone mineral metabolism.      

Measuring maternal mortality: An overview of opportunities and options for developing countries

Background  

There is currently an unprecedented expressed need and demand for estimates of maternal mortality in developing countries. This has been stimulated in part by the creation of a Millennium Development Goal that will be judged partly on the basis of reductions in maternal mortality by 2015.     

Identification of the key amino acids of gliai cell line-derived neurotrophic factor family receptor alpha 1 involved in its biological function

Glial cell line-derived neurotrophic factor （GDNF） plays a critical role in neurodevelopment and survival of midbrain dopaminergic and spinal motor neurons in vitro and in vivo. The biological actions of GDNF are mediated by a two-receptor complex consisting of a glycosylphosphatidylinositol-linked cell surface molecule, the GDNF family receptor alpha 1 （GFR alpha 1）, and receptor protein tyrosine kinase Ret. Although structural analysis of GDNF has been extensively examined, less is known about the structural basis of GFR alpha 1 function. In this study, based on evolutionary trace method and relative solvent accessibility prediction of residues, a set of trace residues that are solvent-accessible was selected for site-directed mutagenesis. A series of GFR alpha 1 mutations was made, and PC12 cell lines stably expressing different GFR alpha 1 mutants were generated. According to the survival and differentiation responses of these stable PC12 cells upon GDNF stimulation and the GDNF- GFR alpha 1-Ret interaction assay, residues 152NN153, Arg259, and 316SNS318 in the GFR alpha 1 central region were found to be critical for GFR alpha 1 binding to GDNF and eliciting downstream signal transduction. The single mutation R259A in the GFR alpha 1 molecule simultaneously lost its binding ability to GDNF and Ret. However N152A/N153A or S316A/N317A/ S318A mutation in the GFR alpha 1 molecule still retained the ability to bind with Ret. These findings suggest that distinct structural elements in GFR alpha 1 may be involved in binding to GDNF and Ret.     

Reversible findings of restricted diffusion in 5‐flourouracil neurotoxicity

A 35‐year‐old woman presented with neurotoxicity correlated to an i.v. regimen of 5‐fluorouracil as episodes of acute confusional state and abnormalities of symmetrically restricted diffusion in the periventricular white matter and corpus callosum. On discontinuing the medication, the areas of severely restricted diffusion had entirely resolved, with minimal residual T2 signal abnormality. In this case, immediate discontinuation of the chemotherapeutic agent apparently reversed the patient's symptoms and findings on MRI. The scant information available in the published literature regarding this phenomenon is reviewed with regard to 5‐fluorouracil.