Improved orthostatic tolerance in familial amyloidotic polyneuropathy with unnatural noradrenaline precursor L-threo-3,4-dihydroxyphenylserine

Disabling orthostatic hypotension, due to insufficiency of the autonomic nervous system, is a common complication of type I familial amyloidotic polyneuropathy (FAP). We investigated whether oral treatment with L-threo-3,4-dihydroxyphenylserine (L-threo-Dops), a noradrenaline precursor, might be of therapeutical benefit. In twenty untreated FAP patients, aged 33 to 44 years, who, because of severe orthostatic hypotension, were bedridden or constrained to a sitting life, supine and erect blood pressure (BP), plasma noradrenaline and tilting time, defined as the interval (s) between the beginning of a 60 degrees head-up tilt and the occurrence of orthostatic symptoms (dizziness, blurred vision or near syncope) were determined before and at repeated intervals during oral treatment with L-threo-Dops, 100 mg bid, for 6 months. Before treatment supine mean BP was 80 (76-85) mmHg (mean and 95% CI), supine plasma noradrenaline was low, 59 (41-77) pg/ml and tilting time ranged from 38 to 118 s. In response to tilt, mean BP immediately fell by 36 (31-41) mmHg, whereas plasma noradrenaline increased by only 11 (0-21) pg/ml (p = 0.05). After 3 to 5 days of treatment with L-threo-Dops all patients experienced marked improvement of their orthostatic tolerance as reflected by their ability to walk freely around. This effect sustained throughout the six months of treatment. Plasma noradrenaline increased moderately by 37 (11-63) pg/ml (p = 0.02) and supine mean BP increased by 8.6 (5.8-12.4) mmHg (p < 0.001) during chronic treatment. Supine or nocturnal hypertension did not develop, the fall in mean BP in response to tilt diminished by 12.5 (6.5-17.3) mmHg (p < 0.001) and tilting time became longer than 600 s in all patients. Because of its efficacy, its sustained duration of action and the lack of side effects, L-threo-Dops is advocated to improve orthostatic tolerance in patients with autonomic insufficiency due to FAP.     

Urban small area variation in adolescents' health behaviour

Our previous study indicated that region plays a relatively small role in adolescents' health behaviour. Here, the regional patterning of health behaviour is studied further by shifting the focus to small areas. First, we test whether small area socioeconomic, demographic and housing characteristics correlate with health behaviour. The analysis then turns to the relationship between these characteristics and their individual level correlates. We wish to ascertain if behaviour is related to small area characteristics similarly for both genders and for adolescents' socioeconomic characteristics. The Adolescent Health and Lifestyle Survey data from 1989-1995 (16- and 18-year-olds, n = 1048, response rate 71%) were linked with data describing 33 subareas of Helsinki, the capital of Finland. Smoking, alcohol use, abstention from dietary fat and physical activity were used as lifestyle indicators. Gender apparently influences the extent to which the area plays a role. Logistic regression demonstrated that prolonged unemployment predicted low prevalence of abstention from dietary fat (traditional dietary patterns) among girls and heavy drinking among boys. High total rate of unemployment predicted lower physical activity among girls. Also owner-occupied housing correlated positively with girls' physical activity. Although the individual level socioeconomic characteristics were not as strongly related to health behaviour as the small area factors, a low level of education predicted smoking and alcohol use and, among girls, decreased physical activity. We conclude that small area characteristics, especially the level of unemployment of the area, may be even more strongly related to health behaviour than individual socioeconomic characteristics.     

Attenuation of alcohol consumption by a novel nontoxic ibogaine analogue (18-methoxycoronaridine) in alcohol-preferring rats

We previously reported that single administration of ibogaine, an indol alkaloid with antiaddictive properties, dose dependently reduced alcohol intake in three strains of alcohol-preferring rats. The present study examined the effect of different doses of a newly developed nontoxic ibogaine analogue, 18-methoxycoronaridine (18-MC), on alcohol intake. Selectively bred alcohol-preferring rats received a single intraperitoneal injection of vehicle or 5, 20 and 40 mg/kg of 18-MC at 9:30 AM, and their consumption of alcohol, water and food was measured for 24 h. Our results demonstrate that a single injection of 18-MC significantly and dose dependently attenuated alcohol consumption and preference and commensurately increased water intake. Only the highest dose of 18-MC significantly decreased food intake. Although the true mechanism of action of 18-MC in suppressing alcohol intake is not yet fully understood, it may, like ibogaine, exert its attenuating effects on alcohol consumption by modulating neurotransmitters believed to be involved in the regulation of alcohol intake.     

Neandertal capitate-metacarpal articular morphology

The cost effectiveness of several modes of family planning service delivery based on the cost per couple-year of protection (CYP), including commodity costs, is assessed for 1991-92 using programme and project data from fourteen developing countries (five in Africa, four in Asia, three in Latin America and two in the Middle East). More than 100 million CYP were provided through these family planning services during the 12 months studied. Sterilisation services provided both the highest volume (over 60% of total) and the lowest cost per CYP ($1.85). Social marketing programmes (CSM), delivering almost 9 million CYPs, had the next lowest cost per CYP on average ($2.14). Clinic-based services excluding sterilisation had an average cost of $6.10. The highest costs were for community-based distribution projects (0.7 million CYPs), which averaged $9.93, and clinic-based services with a community-based distribution component (almost 6 million CYPs), at a cost of $14.00 per CYP. Based on a weighted average, costs were lowest in the Middle East ($3.37 per CYP for all modes of delivery combined) and highest in Africa ($11.20).     

Alloimmune neonatal neutropenia in Australian aboriginals: an unrecognized disorder?

Alloimmune neonatal neutropenia (ANN) is reported for the first time in two Australian aboriginals. Both infants displayed the typical clinical features of ANN with profound neutropenia which persisted for 7 weeks and only minor infectious episodes. However, management strategies differed for the two infants because in one case (complicated by uncertain paternity) serological confirmation of ANN was not obtained until after recovery of the infant's neutrophil count. The maternal antibodies could not be assigned to known neutrophil antigen specificities and a new antigen may be involved. The antibodies were reactive with > 99% of neutrophils in a Caucasian population. Aboriginals comprise 1% of the total population of Australia and 1-2% of the obstetric population at our institution. Thus, ANN may be an unrecognized disorder in this ethnic group and a possible cause of neonatal infection and mortality.     

Thomas G. Orr Memorial Lectureship. The general, general surgeon

BACKGROUND: The obvious advantages of rapid arterial anastomoses have prompted the continuing search for more rapid anastomotic techniques to complement the standard sutured anastomosis. Nonpenetrating, arcuate-legged titanium vascular closure staple (VCS) clips were initially developed for microvascular anastomoses. The purpose of this study was to compare VCS clips with sutured arterial end-to-end anastomosis in larger vessels. METHODS: In 6 pigs, transacted iliac arteries were reanastomosed with VCS clips on one side and continuous 6-0 polypropylene suture on the other. RESULTS: The reconstruction time was 8.4+/-5.2 minutes for clip closure and 12.0+/-6.6 minutes for suture closure (P = 0.033). All vessels were patent half an hour after completing the anastomoses with no signs of early thrombosis. CONCLUSIONS: Arterial end-to-end anastomosis can be performed more rapidly with VCS clips than continuous sutures, and are potentially useful in situations where the clamp time of the vessel is critical.     

Hemolytic uremic syndromes in childhood

The hemolytic uremic syndrome (HUS) comprises hemolytic anemia, acute renal failure, and thrombocytopenia. It is the most frequent cause of acute renal failure in childhood. Ninety percent of the patients have a diarrheal prodrome, and are referred to as having typical HUS. Approximately 10% exhibit the so-called atypical HUS. Typical HUS is caused by shigatoxin-producing Escherichia coli. The toxin, bound to the globotriosyl ceramide cell receptor and internalized, interferes with protein synthesis, predominantly of endothelial cells. The main target is the kidney, but nearly every organ system can be involved. The most common extrarenal involvement is damage to the central nervous system. The central event is probably an insult to the endothelial cell with consecutive loss of antithrombogenic properties. The von Willebrand factor, activation of platelets via platelet-activating factor, other growth factors (e.g., interleukins 1, 6, 8), nitric oxide, lipopolysaccharides, activated polymorphonucleated neutrophils, and the metabolites of the arachidonic acid cascade (e.g., prostaglandin I2) are believed to be involved in the pathogenic cascade. Controlled therapeutic trials with heparin, dipyridamole, aspirin, and urokinase have not been associated with improved outcome. Antibiotics have not yielded any benefit. Plasma infusions and plasma exchange appear to be efficacious, and are justified in cases of atypical HUS and thrombotic thrombocytopenic purpura. Binding of the toxin to the intestinal lumen, and thereby inhibition of enteral reabsorption, is under investigation.     

Lower extremity arterial occlusions in young patients with Crohn''s colitis and premature atherosclerosis: report of six cases

AlphaKAP is a protein produced from a gene within the gene of the a isoform of calmodulin-dependent protein kinase II (CaM-kinase IIa). It consists of the association domain of CaM-kinase IIa and a highly hydrophobic amino-terminal stretch consisting of 25 amino acids which is absent from CaM-kinase IIalpha. We previously demonstrated that alphaKAP is an integral membrane protein by subcellular fractionation analysis [Sugai, R., Takeuchi, M., Okuno, S., and Fujisawa, H. (1996) J. Biochem. 120, 773-779], but the exact subcellular localization of alphaKAP was not well understood. Here we demonstrate that alphaKAP is localized on the nuclear membrane of COS-7 cells transiently expressing alphaKAP. The nuclear membrane and perinuclear small vesicles were immunostained with an antibody against a synthetic peptide corresponding to the carboxyl-terminal 15 amino acids of alphaKAP. In contrast to the intact alphaKAP, the mutant alphaKAP, from which the hydrophobic amino-terminal segment had been deleted, accumulated within nuclei. Thus, alphaKAP may function as an anchoring protein for CaM-kinase II and/or other proteins in the perinuclear membrane.     

Modes of association of Trypanosoma cruzi with the intestinal tract of the vector Triatoma infestans

Cyclophilins (Cyps) catalyze the cis/trans isomerization of peptidyl-prolyl bonds, a rate-limiting step in protein folding. In some cases, cyclophilins have also been shown to form stable complexes with specific proteins in vivo and may thus also act as chaperone-like molecules. We have characterized the 20kD protein of the spliceosomal 25S [U4/U6.U5] tri-snRNP complex from HeLa cells and show that it is a novel human cyclophilin (denoted SnuCyp-20). Purified [U4/U6.U5] tri-snRNPs, but not U1, U2, or U5 snRNPs, exhibit peptidyl-prolyl cis/trans isomerase activity in vitro, which is cyclosporin A-sensitive, suggesting that SnuCyp-20 is an active isomerase. Consistent with its specific association with tri-snRNPs in vitro, immunofluorescence microscopy studies showed that SnuCyp-20 is predominantly located in the nucleus, where it colocalizes in situ with typical snRNP-containing structures referred to as nuclear speckles. As a first step toward the identification of possible targets of SnuCyp-20, we have investigated the interaction of SnuCyp-20 with other proteins of the tri-snRNP. Fractionation of RNA-free protein complexes dissociated from isolated tri-snRNPs by treatment with high salt revealed that SnuCyp-20 is part of a biochemically stable heteromer containing additionally the U4/U6-specific 60kD and 90kD proteins. By coimmunoprecipitation experiments performed with in vitro-translated proteins, we could further demonstrate a direct interaction between SnuCyp-20 and the 60kD protein, but failed to detect a protein complex containing the 90kD protein. The formation of a stable SnuCyp-20/60kD/90kD heteromer may thus require additional factors not present in our in vitro reconstitution system. We discuss possible roles of SnuCyp-20 in the assembly of [U4/U6.U5] tri-snRNPs and/or in conformational changes occurring during the splicing process.