High prevalence of foot diseases in Europe: results of the Achilles Project

OBJECTIVE: To provide an insight into the prevalence of foot disease in Europe, and to include an assessment of the prevalence of predisposing factors and their correlation with foot disease. DESIGN: Large population-based survey conducted in 16 European countries. SETTING: The project consisted of two parts (study I and study II), in which all patients presenting to general practitioners and dermatologists over a defined time period were invited to participate. Patients. In study I, 70,497 patients presenting to dermatologists or general practitioners were recruited, and in study II 19,588 patients presenting to dermatologists were recruited. MAIN OUTCOME MEASURE: The feet of all participants were examined for signs of foot disease. The assessors also recorded relevant details such as the age and sex of patients, and the presence of predisposing factors for foot disease. In addition, patients in study II were offered a free mycological examination of the toenails and skin on the feet. RESULTS: In study I, 57.0% of patients had at least one foot disease. In study II, 61.3% had at least one foot disease. The proportions of patients with fungal foot disease and non-fungal foot disease in study I were 34.9% and 38.4%, respectively, and in study II were 40.6% and 41.7%, respectively. Orthopedic conditions and metatarsal corns were the most frequently reported non-fungal foot diseases, and onychomycosis and tinea pedis were the most frequently observed fungal infections. CONCLUSIONS: This large-scale survey suggests that the prevalence of fungal and non-fungal foot disease is higher than previously estimated.     

In vitro antiplasmodial evaluation of medicinal plants from Zimbabwe

In this study the in vitro antiplasmodial activities of extracts from Cussonia spicata (Araliaceae), Artemisia afra, Vernonia colorata, V. natalensis (Asteraceae), Parinari curatellifolia (Chrysobalanaceae), Clutia hirsuta, Flueggea virosa, (Euphorbiaceae), Adenia gummifera (Passifloraceae) and Hymenodictyon floribundum, (Rubiaceae) were evaluated. The lipophilic extracts from the aerial parts of Artemisia afra and Vernonia colorata proved to be the most active against the chloroquine-sensitive strain PoW and against the chloroquine-resistant clone Dd2 of Plasmodium falciparum. Bioassay-guided fractionation of the extract of A. afra yielded seven flavonoids, from which acacetin, genkwanin and 7-methoxyacacetin showed in vitro activity; the IC(50) values ranged from 4.3 microgram/mL to 12.6 microgram/mL. In addition, several sesquiterpene lactones could be obtained from the most active fractions. Whereas eudesmaafraglaucolide proved to be inactive, the guaianolides 1-desoxy-1alpha-peroxy-rupicolin A-8-O-acetate, 1alpha,4alpha-dihydroxybishopsolicepolide and rupicolin A-8-O-acetate revealed in vitro antiplasmodial activity. Evaluation of V. colorata gained four sesquiterpenes 11beta,13-dihydrovernodalin, vernodalol, 11beta,13-dihydrovernolide and 11beta,13,17,18-tetrahydrovernolide, from which the first two constituents exhibited the strongest antiplasmodial activity (IC(50) values: 1.1-4.8 microgram/mL).     

Functional regions of the presynaptic cytomatrix protein bassoon: significance for synaptic targeting and cytomatrix anchoring

Exocytosis of neurotransmitter from synaptic vesicles is restricted to specialized sites of the presynaptic plasma membrane called active zones. A complex cytomatrix of proteins exclusively assembled at active zones, the CAZ, is thought to form a molecular scaffold that organizes neurotransmitter release sites. Here, we have analyzed synaptic targeting and cytomatrix association of Bassoon, a major scaffolding protein of the CAZ. By combining immunocytochemistry and transfection of cultured hippocampal neurons, we show that the central portion of Bassoon is crucially involved in synaptic targeting and CAZ association. An N-terminal region harbors a distinct capacity for N-myristoylation-dependent targeting to synaptic vesicle clusters, but is not incorporated into the CAZ. Our data provide the first experimental evidence for the existence of distinct functional regions in Bassoon and suggest that a centrally located CAZ targeting function may be complemented by an N-terminal capacity for targeting to membrane-bounded synaptic organelles.     

Kainate-induced epileptic seizures induce a recruitment of caldendrin to the postsynaptic density in rat brain

Caldendrin defines a novel family of neuronal calcium-sensor proteins, the C-terminal moiety of which displays high similarity to calmodulin. We now report that the protein is recruited to the postsynaptic density (PSD) of cortical and hippocampal neurons in response to kainate-induced epileptic seizures, an animal model of human temporal lobe epilepsy. The translocation of caldendrin to the PSD did not occur in kainate-treated rats that did not develop seizures. The enhanced PSD levels of caldendrin are not due to increased protein synthesis and most likely reflect a recruitment from the soluble caldendrin protein pool. These findings suggest that the transduction of dendritic Ca2+-signals via caldendrin is altered by epileptic seizures and that caldendrin might be involved in the pathophysiology of temporal lobe epilepsy.     

Stimulation of plasminogen activation by recombinant cellular prion protein is conserved in the NH2-terminal fragment PrP23-110

The cellular prion protein (PrP(c)), tissue-type plasminogen activator (t-PA) and plasminogen are expressed in synaptic membranes in vivo. In the central nervous system the fibrinolytic system is associated with excitotoxin-mediated neurotoxicity and Alzheimer's disease. Recently binding of the disease associated isoform of the prion protein (PrP(Sc)) to plasminogen and stimulation of t-PA activity have been reported. In this study the interaction of PrP(c) and plasminogen was investigated using chromogenic assays in vitro. We found that plasmin is able to cleave recombinant PrP(c) at lysine residue 110 generating an NH(2)-terminal truncated molecule that has previously been described as a major product of PrP(c) metabolism. We further characterized the proteolytic fragments with respect to their ability to stimulate plasminogen activation in vitro. Our results show that the NH(2)-terminal part of PrP(c) spanning amino acids 23-110 (PrP23-110) together with low molecular weight heparin stimulates t-PA mediated plasminogen activation in vitro. The apparent rate constant was increased 57 fold in the presence of 800 nM PrP23-110. Furthermore, we compared the stimulation of t-PA activity by PrP(c) and beta-amyloid peptide (1-42). While the activity of the beta-amyloid was independent of low molecular weight heparin, PrP23-110 was approximately 4- and 37 fold more active than beta-amyloid in the absence or presence of low molecular weight heparin. In summary, plasmin cleaves PrP(c) in vitro and the liberated NH(2)-terminal fragment accelerates plasminogen activation. Cleavage of PrP c has previously been reported. Thus cleavage of PrP(c) enhancing plasminogen activation at the cell surface could constitute a regulatory mechanism of pericellular proteolysis.     

An outbreak of viral gastroenteritis in a mother-and-child health clinic

An outbreak of diarrhoeal disease in a modern mother-and-child health clinic prompted the health authorities to initiate a retrospective cohort study in order to assess the scope of the outbreak and to identify possible risk factors. The management of the clinic had been rather concerned because four similar outbreaks had occurred during the last two years. A total of 151 guests, i.e. mothers with their children, who had arrived some days before the peak of the outbreak for a three-week-stay and another 15 guests who had arrived earlier and had extended their stay were enrolled in the study which mainly focused on the possible role of treatment measures as risk factors. In addition, a total of 49 staff members were requested to provide information about symptoms, working area and attendance at work. Relevant data were available from 164 of 166 guests and 47 of 49 staff members (response rates 98.8% and 96.0%, respectively). The attack rate among guests was 44.0% (adults 27.0%, children 54.0%) and among staff 23.4%. The mean age of affected children (3.5 years) was significantly lower than that of those not affected (6.3 years). The main symptoms were diarrhoea and vomiting. The sudden start of the outbreak suggested a single source of infection which, however, remained unknown. Person-to-person transmission was supposed to be the cause of the following spread. No association between distinct treatment measures and the disease was proven by the cohort study. Norwalk-like viruses as well as astroviruses were detected by polymerase chain reaction in specimens taken from seven patients. No other enteropathogenic agents were found. Regarding the special conditions in a mother-and-child health clinic where social contacts among guests are much more frequent and intensive than among patients in a "normal" hospital, measures to prevent the spread of gastrointestinal infections should concentrate on early recognition and isolation of symptomatic individuals. Guests and staff members should be instructed to keep to the rules of personal hygiene, especially handwashing. If disinfection is required, it should be virucidal.     

Inhibition of adenovirus DNA polymerase by modified nucleoside triphosphate analogs correlate with their antiviral effects on cellular level

Adenovirus (Ad) infection results in significant morbidity and mortality in both immunocompetent and immunosuppressed hosts. There is currently no licensed chemotherapy effective in dealing with this virus infection. In this study the anti-adenoviral activity of a group of modified nucleoside analogs was investigated. The most efficient 3-fluorosubstituted nucleoside triphosphate inhibitors of Ad DNA polymerase were 3′-fluorothymidine triphosphate (IC₅₀ 0.63 μM), 2′,3′-dideoxy-3′-fluoroguanosine triphosphate (IC₅₀ 0.71 μM) and 2′,3′-dideoxy-3′-fluorouridine triphosphate (IC₅₀ 2.96 μM). The most efficient 2′,3′-dideoxynucleoside triphosphates were 2′,3′-dideoxycytidine triphosphate (ddCTP; IC₅₀ 1.0 μM), 2′,3′-dideoxyadenosine triphosphate (IC₅₀ 1.6 μM) and 2′,3′-dideoxythymidine triphosphate (IC₅₀ 1.82 μM). Kinetic studies indicate competitive inhibition of adenovirus DNA polymerase by ddCTP. These data confirm results previously obtained at the cellular level using a focus reduction assay involving Ad2-infected FL cells. Whereas the D-enantiomers 3′-fluorothymidine and 2′,3′-dideoxycytidine are potent inhibitors of adenoviral replication, the corresponding L-enantiomers exhibited no inhibitory activity. Received: 5 April 2000     

Clozapine-associated elevation of plasma cholinesterase

Objective The goal of this study was to identify adverse effects of the atypical neuroleptic clozapine on liver function and lipid metabolism. Methods Data which included serum levels of clozapine and its hepatic metabolite N-desmethyl clozapine were collected from medical records of patients treated with clozapine and controls. Results We identified a clozapine-associated marked elevation of plasma cholinesterase (ChE) with unchanged levels of AST, ALT or g-GT. ChE was correlated to the serum level of clozapine and even closer to N-desmethyl clozapine. For the total patient group we observed significant correlations of ChE with the body-mass index and body weight. However, clozapine-treated patients and controls did not differ with regard to body-mass index, triglycerides, and cholesterol. Conclusion We report for the first time a clozapine-associated and dose-dependent elevation of plasma ChE, which may be related to clozapine-associated effects on hepatic lipid metabolism or ChE enzyme induction. Received: 14 Mai 2001 / Accepted: 24 September 2001     

Ventricular fibrillation refractory to automatic internal cardiac defibrillator in Fabry's disease. Review of cardiovascular manifestations

Fabry's disease is a disorder of glycosphingolipid metabolism leading to alpha-galactosidase deficiency with systemic sequelae. Clinical cardiac manifestations include dysrhythmias, structural abnormalities apparent on echocardiography, and histologic changes secondary to glycosphingolipid deposition. The introduction of automated internal cardiac defibrillators (AICD) has been shown to decrease the incidence of circulatory collapse in individuals with known terminal arrhythmias. We present a patient with Fabry's disease, who underwent coronary angiography without finding of obstructive disease. He returned after aborted sudden cardiac death necessitating the placement of an AICD. He again presented after an episode of ventricular fibrillation refractory to internal defibrillation necessitating advanced life support, and subsequently expired. We review the electrocardiographic, cardiovascular structural, and histologic manifestations of Fabry's disease.