Effect of Roux-en-Y gastric bypass on testosterone and prostate-specific antigen.

BACKGROUND: Obese men have lower serum levels of testosterone, dehydroepiandrosterone (DHEA) and prostate-specific antigen (PSA), but an increased risk of dying from prostate cancer. The aim of this study was to examine the effect of surgically induced weight loss on serum testosterone, DHEA and PSA levels in obese men. METHODS: Consecutive men undergoing Roux-en-Y gastric bypass (RYGB) participated in a prospective, longitudinal study. Main outcomes were changes were body mass index (BMI), percentage excess weight loss, serum levels of testosterone, DHEA and PSA, PSA mass and plasma volume, measured before operation and 3, 6 and 12 months later. RESULTS: In 64 patients, mean BMI fell from 48.2 kg/m(2) before operation to 39.2, 35.6 and 32.4 kg/m(2) at 3, 6 and 12 months after RYGB. Testosterone levels rose significantly from 259 ng/dl to 386, 452 and 520 ng/dl respectively. Serum PSA levels increased significantly from 0.51 ng/ml to 0.67 ng/ml at 12 months. There were no significant changes in DHEA or PSA mass. CONCLUSION: RYGB normalizes the serum testosterone level. PSA levels increase with weight loss and may be inversely correlated with changes in plasma volume, indicating that PSA levels may be artificially low in obese men owing to haemodilution.

Orais and STIMs: physiological mechanisms and disease.

The stromal interaction molecules STIM1 and STIM2 are Ca(2+) sensors, mostly located in the endoplasmic reticulum, that detect changes in the intraluminal Ca(2+) concentration and communicate this information to plasma membrane store-operated channels, including members of the Orai family, thus mediating store-operated Ca(2+) entry (SOCE). Orai and STIM proteins are almost ubiquitously expressed in human cells, where SOCE has been reported to play a relevant functional role. The phenotype of patients bearing mutations in STIM and Orai proteins, together with models of STIM or Orai deficiency in mice, as well as other organisms such as Drosophila melanogaster, have provided compelling evidence on the relevant role of these proteins in cellular physiology and pathology. Orai1-deficient patients suffer from severe immunodeficiency, congenital myopathy, chronic pulmonary disease, anhydrotic ectodermal dysplasia and defective dental enamel calcification. STIM1-deficient patients showed similar abnormalities, as well as autoimmune disorders. This review summarizes the current evidence that identifies and explains diseases induced by disturbances in SOCE due to deficiencies or mutations in Orai and STIM proteins.

Inhibitory effect of Ca(2+) on ATP-mediated stimulation of NPR-A-coupled guanylyl cyclase in renal glomeruli from spontaneously hypertensive and normotensive rats.

Atrial natriuretic peptide (ANP) regulates blood pressure mainly through the occupation of the guanylyl cyclase-coupled receptor NPR-A, which requires ATP interaction for maximal activation. This study investigates the effect of extracellular Ca(2+) on ATP-mediated regulation of NPR-A-coupled guanylyl cyclase activity in glomerular membranes from Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). ATP induced a significant increase in basal and ANP(1-28)-stimulated guanylyl cyclase activity that was greater in SHR than in WKY. Extracellular Ca(2+) inhibited ATP-stimulated guanylyl cyclase activity in a concentration-dependent manner, but did not modify basal and ANP(1-28)-stimulated guanylyl cyclase activity. In the presence of ATP, NPR-A showed higher affinity for ANP(1-28) and lower Bmax. Ca(2+) did not modify NPR-A-ANP(1-28) binding properties. The different effects of extracellular Ca(2+) on ANP(1-28)- or ATP-mediated guanylyl cyclase activation suggest that these events are differentially regulated. Addition of extracellular Ca(2+) induced similar effects in hypertensive and normotensive rats, suggesting that it is not responsible for the elevated cGMP production observed in SHR.

Different effect of ATP on ANP receptor guanylyl cyclase in spontaneously hypertensive and normotensive rats.

AIM: Natriuretic peptide receptor A (NPR-A) is the main physiological receptor for atrial natriuretic peptide (ANP). Maximal activation of NPR-A guanylyl cyclase (GC) requires ANP binding and ATP interaction with a putative cytoplasmic site. This study investigates the regulatory effect of ATP on GC-coupled NPR-A activity in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). METHODS: Cyclic GMP production and competitive inhibition of [(125)I]ANP(1-28) binding were performed in solubilized glomerular and papillary renal membranes. RESULTS: Here, we report that incubation of renal glomerular and papillary membranes with ATP induced a concentration-dependent increase in basal and ANP(1-28)-stimulated GC activity that was significantly greater in SHR than in age-matched WKY. ATPgammaS was more effective than ATP and induced a greater stimulation of cGMP production in SHR than in WKY. In contrast, in solubilized membranes ATP exerted an inhibitory role on basal and ANP(1-28)-induced GC activity, suggesting that an accessory protein is required for ATP-induced GC activation. ATP increases NPR-A affinity for ANP(1-28) and decreased B(max) in crude and solubilized membranes. Kinetic analysis of GC-coupled NPR-A revealed that ATP reduced the Km and increased the V(max), an effect that was greater in SHR. CONCLUSION: Our observations indicate that ATP exerts a greater net effect on NPR-A in SHR than in WKY, which might explain the greater rate of cGMP production observed in SHR compared to WKY.

Characteristics of the renal C-type natriuretic peptide receptor in hypertrophied and developing rat kidney.

This study investigates the effect of hypertrophy, using one kidney and one kidney/one clip rats, and development, comparing 3- and 12-week-old rats, on the expression of the 28-amino acid atrial natriuretic peptide (ANP(1-28)) binding sites in rat kidney. Here we report an increased B(max) value of glomerular binding sites for ANP(1-28) and C-type natriuretic peptide 1-22 (CNP(1-22)) in hypertrophied and developing kidney, without modifying their affinity, an effect that was prevented in the presence of the synthetic des[Gln(18), Ser(19), Gly(20), Leu(21), Gly(22)]ANP(4-23)-amide (C-ANF), suggesting that natriuretic peptide receptor (NPR)-C binding sites might be enhanced. The enhanced B(max) was only detected in the high affinity binding site for CNP(1-22), which has been identified as the 67 kDa NPR-C-like protein. A similar effect was observed in renal glomeruli from 3-week-old rats compared with 12-week-old rats. Our results indicate that ANP(1-28), CNP(1-22) and C-ANF inhibited cAMP synthesis stimulated by the physiological agonists histamine and 5-hydroxytryptamine or directly by forskolin. The inhibitory effect was found to be significantly greater in 1-kidney and 1-kidney/1-clip rats than in controls, and in 3-week-old rats compared with 12-week-old rats. Our observations suggest that this effect must be attributed to the 67 kDa NPR-C-like protein due to the enhanced B(max) values and the reported inhibitory role for this receptor on adenylyl cyclase activity. The enhanced inhibitory role of natriuretic peptides on cAMP synthesis in hypertrophied and developing kidney may influence glomerular function in the rat kidney and suggests a role for the 67 kDa NPR-C-like protein in growth.

The Saskatchewan dissemination story.

The Saskatchewan Heart Health Program (SHHP) Dissemination Phase "Building Health Promotion Capacity" is a five-year program funded by Health Canada, Saskatchewan Health and the Heart and Stroke Foundation of Saskatchewan. This phase began in July 1998 and builds on two previous SHHP phases: the provincial heart health survey (Saskatchewan Health, 1990), and the community demonstration projects (SHHP, 1998a, b, c, d). The evolution of the SHHP has occurred in a dynamic provincial context. Saskatchewan is a Canadian prairie province of one million people with most living in the southern and central parts of the province. The population is ageing and urbanizing, and the economy is shifting away from agricultural production toward a diversified service sector. In 1993, health reform created 30 Districts in southern and central Saskatchewan; the formation of three northern Districts followed five years later. All but two Districts are rural-based. Population served ranges from 2,261 to 237,274; total area ranges from 4,019 to 133,900 square kilometers.

Genetic relationships between clinical isolates of Streptococcus pneumoniae, Streptococcus oralis, and Streptococcus mitis: characterization of "Atypical" pneumococci and organisms allied to S. mitis harboring S. pneumoniae virulence factor-encoding genes.

The oral streptococcal group (mitis phylogenetic group) currently consists of nine recognized species, although the group has been traditionally difficult to classify, with frequent changes in nomenclature over the years. The pneumococcus (Streptococcus pneumoniae), an important human pathogen, is traditionally distinguished from the most closely related oral streptococcal species Streptococcus mitis and Streptococcus oralis on the basis of three differentiating characteristics: optochin susceptibility, bile solubility, and agglutination with antipneumococcal polysaccharide capsule antibodies. However, there are many reports in the literature of pneumococci lacking one or more of these defining characteristics. Sometimes called "atypical" pneumococci, these isolates can be the source of considerable confusion in the clinical laboratory. Little is known to date about the genetic relationships of such organisms with classical S. pneumoniae isolates. Here we describe these relationships based on sequence analysis of housekeeping genes in comparison with previously characterized isolates of S. pneumoniae, S. mitis, and S. oralis. While most pneumococci were found to represent a closely related group these studies identified a subgroup of atypical pneumococcal isolates (bile insoluble and/or "acapsular") distinct from, though most closely related to, the "typical" pneumococcal isolates. However, a large proportion of isolates, found to be atypical on the basis of capsule reaction alone, did group with typical pneumococci, suggesting that they have either lost capsule production or represent as-yet-unrecognized capsular types. In contrast to typical S. pneumoniae, isolates phenotypically identified as S. mitis and S. oralis, which included isolates previously characterized in taxonomic studies, were genetically diverse. While most of the S. oralis isolates did fall into a well-separated group, S. mitis isolates did not cluster into a well-separated group. During the course of these studies we also identified a number of potentially important pathogenic isolates, which were frequently associated with respiratory disease, that phenotypically and genetically are most closely related to S. mitis but which harbor genes encoding the virulence determinants pneumolysin and autolysin classically associated with S. pneumoniae.

Reaching out: a community initiative for disadvantaged pregnant women.

A major challenge for public health services is to reach disadvantaged pregnant women with a relevant program that assists them to reduce modifiable risk factors. A community development approach was used to initiate an outreach program aimed at urban natives and other high-risk pregnant women. Community involvement in program planning, the use of native and non-native community health workers, the provision of social support and the tangible health benefits of the program contributed to its success in attracting women for service.

A silica gel plate-based qualitative assay for acetylcholinesterase activity: a mass method to screen for potential inhibitors.

A procedure for the qualitative assessment of inhibitory activity towards acetylcholinesterase for a given compound is described. Solutions of the compounds of interest are spotted on silica gel TLC plates in a matrix pattern. The silica gel plate is sprayed with a solution of acetylthiocholine iodide and 5,5-dithiobis(2-nitrobenzoic acid) followed by a solution of acetylcholinesterase. The enzyme reaction produces a yellow background color with inhibitor compounds exposed as white zones where color has failed to develop. The results for a test set of compounds were compared to those obtained using the standard Ellman assay procedure and found to agree for virtually all of these compounds. The conditions of silica gel plate thickness, reagent concentration, and enzyme source under which this procedure is suitable were investigated. This represents an extremely rapid method to screen large numbers of compounds to uncover new inhibitors of acetylcholinesterase and potentially other enzymes as well.

Mouse targets undergo double-strand DNA fragmentation when exposed to syngeneic or xenogeneic LAK cells whereas human targets undergo single-strand breaks.

A number of recent studies have shown that mouse target cells (TC) of hematopoietic origin, when exposed to cytotoxic lymphocytes, undergo double-stranded DNA fragmentation. The cause and relevance of the fragmentation remain controversial. In this study we generated a number of mouse (M-LAK) and human LAK (H-LAK) cells and exposed them to a variety of mouse and human TC. YAC and SP/2, 2 mouse TC underwent rapid and extensive fragmentation when lysed by either human or mouse LAK whereas K562 and Daudi, 2 human TC, under the same conditions did not. All 4 TC, however, were killed quite efficiently. Next we labeled TC with 125I-deoxyuridine, exposed them to LAK cells for up to 18 h and loaded the LAK:TC mixtures over an alkaline linear sucrose gradient. After lysing the cells with a lysis buffer containing Triton X-100 we showed that K562 that had been in contact with LAK cells for more than 1 h exhibited single-strand nicks. However, whereas double-strand fragmentation preceded chromium release (lytic activity), the appearance of single-strand nicks did not. Finally, protein synthesis was not required for either type of fragmentation. In summary, we have demonstrated that: (1) the ability to undergo DNA fragmentation is a property of the TC rather than the effector cells that mediated their death, and (2) K562 and Daudi, 2 human TC, undergo single-strand nicks when lysed by LAK cells whereas SP/2 and YAC, 2 mouse TC undergo double-strand fragmentation when exposed to the same syngeneic or xenogeneic effector cells.

Interaction of cromolyn sodium in aqueous solution with magnesium ions.

The interaction of the antiasthmatic drug cromolyn sodium with Mg2+ ions in solution was studied. Selective ion electrode and torsion viscometer measurements were used to establish the degree of interaction. At the concentrations studied, the cromolyn ion had no more affinity for Mg2+ than SO42-. However, thixotropic gels were formed between 4 X 10(-2) M cromolyn sodium and 4 X 10(-4) Mg2+. At lower concentrations of Mg2+, viscosity still increased significantly. However, when the cromolyn concentration was lowered, the increase in viscosity was much less marked.