Strength of synaptic transmission at neuromuscular junctions of crustaceans and insects in relation to calcium entry

Crustacean and insect neuromuscular junctions typically include numerous small synapses, each of which usually contains one or more active zones, which possess voltage-sensitive calcium channels and are specialized for release of synaptic vesicles. Strength of transmission (the number of quantal units released per synapse by a nerve impulse) varies greatly among different endings of individual neurons, and from one neuron to another. Ultrastructural features of synapses account for some of the physiological differences at endings of individual neurons. The nerve terminals that release more neurotransmitter per impulse have a higher incidence of synapses with more than one active zone, and this is correlated with more calcium build-up during stimulation. However, comparison of synaptic structure in neurons with different physiological phenotypes indicates no major differences in structure that could account for their different levels of neurotransmitter release per impulse, and release per synapse differs among neurons despite similar calcium build-up in their terminals during stimulation. The evidence indicates differences in calcium sensitivity of the release process among neurons as an aspect of physiological specialization.     

Simplified method for the measurement of segmental colonic transit time

Segmental colonic transit has been measured in 101 patients. Two MBq of 111Indium absorbed on resin pellets and encapsulated in an enteric coated capsule was given at 7 00 am. Hourly images during the first day, and three images during each subsequent day were acquired for up to three days. Using all scan and patient data the scans were categorised in one of the five patterns of colonic transit: normal, rapid, right delay, left delay, or generalised delay. The geometric centres and per cent activity at each time point was compared between the five groups of colonic transit patients to find the best time for imaging and so to distinguish the five groups. During the first day, early images did not help in diagnosis of patterns of transit, however, in the later images (six hours onwards after the ingestion of the activity) the rapid transit groups could be identified. Images at 27 and 51 hours were both required to distinguish all five groups of patients from each other. Only in the 'normal' transit patients was there some excretion of the activity during the course of the second day, otherwise there was no difference in the images taken in the course of a day (second or third day). A simplified protocol requires a minimum of three images to distinguish all five patterns of colonic transit. The activity should be ingested in the morning (7 00 am) and the first image taken at the end of the working day (8-10 hours after ingestion), the second image on the morning of the second day, and the third image during the course of the third day. This simple protocol would provide all the clinically relevant information necessary for correct classification of the colonic transit.     

The liberal ophthalmologists of the northern France and management of children with vision deficiencies

PURPOSE: The purpose of this analysis was to appreciate the management of visually handicaped children outside specialized structures. We also assessed relays between primary physicians, hospitals and specialized structures. METHOD: A 12-question survey was sent to 144 liberal ophthalmologists of the North of France. The questionnary included 12 questions. We compared the results to litterature. RESULTS: The response-rate was 59.6%. This study indicated that the observed children by the liberal ophtalmologists had more simple diseases than in specialized structures. In hospitals, it seemed that the ophtalmologists diagnosed more severe diseases. These practitioners diagnosed some of these diseases. However some of diagnosis were to late. This study showed that specialized structures were not enough known by the practitioners who detected this handicap and that the families prefered the taking in charge near their home. CONCLUSION: We demonstrated the necessary organisation of precocious and systematic detection, and the necessary information to all practitioners on specialized structures.     

Paget's disease of the breast in a man without underlying breast carcinoma

A case of histologically confirmed Paget's disease of the breast in a 72 year old man, without underlying breast carcinoma, is reported. This report raises questions about the pathogenesis of this condition and suggests that Paget's disease is an independent, intraepidermal carcinoma rather than a direct extension of intraductal carcinoma of the breast to the nipple and areola.     

How the Listeria monocytogenes ActA protein converts actin polymerization into a motile force

The ActA protein is an essential determinant of pathogenicity that is responsible for the actin-based motility of Listeria monocytogenes in mammalian cells and cell-free extracts. ActA appears to control at least four functions that collectively lead to actin-based motility: (1) initiation of actin polymerization, (2) polarization of ActA function, (3) transformation of actin polymerization into a motile force and (4) acceleration of movement mediated by the host protein profilin.     

The crystal structure of HIV-1 Nef protein bound to the Fyn kinase SH3 domain suggests a role for this complex in altered T cell receptor signaling

BACKGROUND: Human immunodeficiency virus (HIV) Nef protein accelerates virulent progression of acquired immunodeficiency syndrome (AIDS) by its interaction with specific cellular proteins involved in signal transduction and host cell activation. Nef has been shown to bind specifically to a subset of the Src family of kinases. The structures of free Nef and Nef bound to Src homology region 3 (SH3) domain are important for the elucidation of how the affinity and specificity for the Src kinase family SH3 domains are achieved, and also for the development of potential drugs and vaccines against AIDS. RESULTS: We have determined the crystal structures of the conserved core of HIV-1 Nef protein alone and in complex with the wild-type SH3 domain of the p59fyn protein tyrosine kinase (Fyn), at 3.0 A resolution. Comparison of the bound and unbound Nef structures revealed that a proline-rich motif (Pro-x-x-Pro), which is implicated in SH3 binding, is partially disordered in the absence of the binding partner; this motif only fully adopts a left-handed polyproline type II helix conformation upon complex formation with the Fyn SH3 domain. In addition, the structures show how an arginine residue (Arg77) of Nef interacts with Asp 100 of the so-called RT loop within the Fyn SH3 domain, and triggers a hydrogen-bond rearrangement which allows the loop to adapt to complement the Nef surface. The Arg96 residue of the Fyn SH3 domain is specifically accommodated in the same hydrophobic pocket of Nef as the isoleucine residue of a previously described Fyn SH3 (Arg96-->lle) mutant that binds to Nef with higher affinity than the wild type. CONCLUSIONS: The three-dimensional structures support evidence that the Nef-Fyn complex forms in vivo and may have a crucial role in the T cell perturbating action of Nef by altering T cell receptor signaling. The structures of bound and unbound Nef reveal that the multivalency of SH3 binding may be achieved by a ligand induced flexibility in the RT loop. The structures suggest possible targets for the design of inhibitors which specifically block Nef-SH3 interactions.     

Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q

The epilepsies are a group of disorders characterised by recurrent seizures caused by episodes of abnormal neuronal hyperexcitability involving the brain. Up to 60 million people are affected worldwide and genetic factors may contribute to the aetiology in up to 40% of patients. The most common human genetic epilepsies display a complex pattern of inheritance. These are categorised as idiopathic in the absence of detectable structural or metabolic abnormalities. Juvenile myoclonic epilepsy (JME) is a distinctive and common variety of familial idiopathic generalised epilepsy (IGE) with a prevalence of 0.5-1.0 per 1000 and a ratio of sibling risk to population prevalence (lambda(s)) of 42. The molecular genetic basis of these familial idiopathic epilepsies is entirely unknown, but a mutation in the gene CHRNA4, encoding the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), was recently identified in a rare Mendelian variety of idiopathic epilepsy. Chromosomal regions harbouring genes for nAChR subunits were therefore tested for linkage to the JME trait in 34 pedigrees. Significant evidence for linkage with heterogeneity was found to polymorphic loci encompassing the region in which the gene encoding the alpha7 subunit of nAChR (CHRNA7) maps on chromosome 15q14 (HLOD = 4.4 at alpha = 0.65; Z(all) = 2.94, P = 0.0005). This major locus contributes to genetic susceptibility to JME in a majority of the families studied.     

Goodpasture syndrome involving overlap with Wegener's granulomatosis and anti-glomerular basement membrane disease

A 68-year-old Caucasian woman presented to the hospital with nodular pulmonary infiltrates and acute renal failure. Wegener's granulomatosis was initially considered to be most likely because of the presence of increased serum levels of c-anti-neutrophil cytoplasmic antibodies (c-ANCA). A consultation through the Internet after a renal biopsy demonstrated crescentic, necrotizing glomerulonephritis and linear deposits of immunoglobulin G (IgG) and complement C3, typical of anti-glomerular basement membrane (GBM) disease. Hemodialysis was instituted; however, the patient suddenly developed a massive cerebral hemorrhage and died before full therapy could take effect. Postmortem analysis of the patient's sera revealed high titers of IgG against the alpha 3 NC1 domain of type IV collagen. Serologic evidence of both p-ANCA and anti-GBM antibodies are becoming more frequently recognized in the setting of rapidly progressive glomerulonephritis. The patient reported here had the unusual combination of c-ANCA antibodies with anti-GBM disease, and this association raises complex questions regarding the pathogenesis of this type of renal injury.