Guanylin and related peptides.

Guanylin and uroguanylin are short peptides homologous to heat-stable enterotoxins of Escherichia coli and other enteric bacteria. Guanylin and uroguanylin are synthetized from the respective prepropeptides mainly in gastrointestinal mucosa and are secreted both into intestinal lumen and into the blood. Luminally secreted peptides stimulate chloride and bicarbonate secretion in the intestine through the mechanism involving guanylate cyclase C receptor, cyclic GMP, protein kinase G and cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Bacterial enterotoxins, which have greater potency than endogenous peptides, induce excessive fluid secretion into intestinal lumen leading to secretory diarhea. Uroguanylin is expressed mainly in enterochromaffin cells of duodenum and proximal small intestine whereas guanylin is abundant in goblet cells of colonic epithelium. Uroguanylin and guanylin increase urinary sodium and potassium excretion both as circulating hormones and as paracrine mediators produced within the kidney. Uroguanylin functions as "intestinal natriuretic hormone" which is secreted in response to oral sodium loading and maintains sodium balance during postprandial period. Plasma and urinary concentrations of guanylin and uroguanylin increase in renal failure and heart failure. Guanylin peptides possess antiproliferative activity in intestinal cells culture and their expression decreases in colonic carcinoma indicating that their deficiency may contribute to the pathogenesis of this disease.     

Unrecognised HIV related deaths.

OBJECTIVES--To establish whether follow up of deaths from selected HIV related causes could increase the number of cases of HIV infection reported to the Public Health Laboratory Service Communicable Disease Surveillance Centre (CDSC), and to estimate the proportion of deaths among HIV positive men that occurred in men who were not known to be HIV positive at the time of death by the person who signed the death certificate. DESIGN--Follow up of draft death entries received by the Office of Population Censuses and Surveys on which one of 11 medical or external causes likely to be related to HIV was stated; letters were sent to the people who signed the certificates. The respondents were invited to report men known to have been HIV positive who were not already on the CDSC register. SETTING--England and Wales. SUBJECTS--Men aged 15-54 who died in February 1989 to July 1989 with one of the 11 selected HIV related diseases as cause of death on their death certificates. MAIN OUTCOME MEASURES--Number of men reported to the CDSC as a result of this follow up; estimate of excess deaths due to an HIV related cause; estimate of the proportion of excess deaths that occurred in those who were not known to be HIV positive at the time of death. RESULTS--Replies were received for 473 deaths (86%). Forty were for men known to have been HIV positive, 31 of whom had been reported to CDSC by the time they died; six were subsequently reported. The respondent did not know that the decreased was HIV positive for 20 (35%) of the 57 excess deaths in men for whom one of the medical causes was stated and 41 (93%) of the 44 excess deaths in men for whom one of the external causes was stated. CONCLUSION--Follow up of death registrations is not an efficient way of increasing the number of cases of HIV infection reported to CDSC. Between 35% and 60% of HIV positive people for whom certain causes are stated may be dying without HIV positivity having been diagnosed. There may be implications for those caring for people with these conditions and those who carry out postmortem examinations.     

Sleep related vehicle accidents.

OBJECTIVES--To assess the incidence, time of day, and driver morbidity associated with vehicle accidents where the most likely cause was the driver falling asleep at the wheel. DESIGN--Two surveys were undertaken, in southwest England and the midlands, by using police databases or on the spot interviews. SUBJECTS--Drivers involved in 679 sleep related vehicle accidents. RESULTS--Of all vehicle accidents to which the police were summoned, sleep related vehicle accidents comprised 16% on major roads in southwest England, and over 20% on midland motorways. During the 24 hour period there were three major peaks: at around 0200, 0600, and 1600. About half these drivers were men under 30 years; few such accidents involved women. CONCLUSIONS--Sleep related vehicle accidents are largely dependent on the time of day and account for a considerable proportion of vehicle accidents, especially those on motorways and other monotonous roads. As there are no norms for the United Kingdom on road use by age and sex for time of day with which to compare these data, we cannot determine what the hourly exposure v risk factors are for these subgroups. The findings are in close agreement with those from other countries.     

Position effect and related phenomena.

Position-effect variegation in Drosophila, the mosaic expression of genes juxtaposed to heterochromatin, remains an enigmatic long-range phenomenon. While the chromatin-conformation model has been challenged, compelling contrary evidence is lacking. Nevertheless, progress has been made in the genetic and molecular analysis of genes involved in the process of heterochromatin formation and in the characterization of genetic elements normally located in pericentric heterochromatin. In addition, telomeric position effect in yeast provides a new model system for the study of the quasi-stable inheritance of an inactivated state.     

Selenotyrosine and related phenylalanine derivatives.

A new series of Se-substituted phenylalanine derivatives has been synthesized having the para position of the phenyl ring substituted by selenocyanate (-SeCN), seleninic acid (-SeO(2)H), or selenol (-SeH) functional groups. The starting material for synthesis was 4'-aminophenylalanine, which is readily available in DL- or L- forms. Selenium was incorporated into the ring by reacting the unprotected amino acid with nitrous acid, followed by reaction of the diazotized aromatic amine with potassium selenocyanate at pH 4-5 to give phenylalanine selenocyanate. The selenocyanate derivative was converted to the selenol directly by reduction with sodium borohydride, or oxidized to the seleninic acid, which was then reduced to the selenol. Alkylation of the selenol ('selenotyrosine') gave the selenoether derivatives of phenylalanine [(Phe-SeR), R=methyl or allyl], and air oxidation of the selenol gave the diselenide. Mild oxidation of the selenoether 4'-(MeSe)Phe with peroxide gave the selenoxide derivative, 4'-[Se(O)Me]. Because of their stability and useful redox properties, aromatic selenoamino acids can be used as synthetic analogues to increase chemical functionality in proteins or peptides, and have potential pharmaceutical or nutritional applications. The possibility that aromatic selenoamino acids could be formed metabolically through reactions of reactive selenium intermediates with aromatic amino acid residues is discussed.