Presynaptic modulation by VIP, secretin and isoproterenol of somatostatin release from enriched enteric synaptosomes: role of cAMP

The release of somatostatin-like immunoreactivity was studied in isolated synaptosomes. A significant release of somatostatin-like immunoreactivity was observed in the presence of vasoactive intestinal polypeptide (VIP) (10(-6) M: 53.0 +/- 12.4 pg/mg, basal: 14.3 +/- 1.7 pg/mg, n = 5, P < 0.05), secretin (10(-6) M: 56.1 +/- 3.8 pg/mg, basal: 25.8 +/- 1.6 pg/mg, n = 6, P < 0.01) and isoproterenol (10(-5) M: 54.0 +/- 13.4 pg/mg, basal: 20.0 +/- 3.4 pg/mg, n = 8, P < 0.05). Forskolin, an unspecified activator of the adenylate cyclase, caused a significant release of somatostatin-like immunoreactivity (10(-6) M: 57.3 +/- 13.2 pg/mg, basal: 30.0 +/- 5.8 pg/mg, n = 13, P < 0.01) which was further augmented in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX 10(-4) M) (77.0 +/- 17.8 pg/mg, n = 13, P < 0.01). 3-Isobutyl-l-methylxanthine and N6, 2'-O-dibutyryladenosine-3',5'-cyclic monophosphate mimicked at effect of forskolin and VIP. The release of somatostatin was paralleled by an increase of cAMP immunoreactivity in the presence of VIP (10(-6) M: 37.1 +/- 9.4 pmol/mg, basal: 19.8 +/- 4.2 pmol/mg, n = 10, P < 0.05), isoproterenol (10(-5) M: 42.4 +/- 9.8 pmol/mg basal: 16.7 +/- 2.4 pmol/mg, n = 12, P < 0.01) and forskolin (10(-6) M: 47.1 +/- 12.4 pmol/mg, basal: 19.8 +/- 4.2 pmol/mg, n = 10, P < 0.01). The effect of nitric oxide (NO) which acts as an inhibitory neurotransmitter in the enteric nervous system was studied. NO is known to activate guanylate cyclase to induce transmitter release. The NO-generating compound sodium nitroprusside and bromoguanosine-3',5'-cyclic monophosphate (8-Br-cGMP) had no effect on the release of somatostatin-like immunoreactivity. These data demonstrate the stimulatory effect of VIP, secretin and isoproterenol on release of somatostatin-like immunoreactivity from enteric synaptosomes, which is presumably mediated by cAMP-dependent mechanisms. cGMP-dependent mechanisms seem to be of minor relevance.     

Voltage gated calcium channels in molluscs: classification, Ca2+ dependent inactivation, modulation and functional roles

Molluscan neurons and muscle cells express transient (T-type like) and sustained LVA calcium channels, as well as transient and sustained HVA channels. In addition weakly voltage sensitive calcium channels are observed. In a number of cases toxin or dihydropyridine sensitivity justifies classification of the HVA currents in L, N or P-type categories. In many cases, however, pharmacological characterization is still preliminary. Characterization of novel toxins from molluscivorous Conus snails may facilitate classification of molluscan calcium channels. Molluscan preparations have been very useful to study calcium dependent inactivation of calcium channels. Proposed mechanisms explain calcium dependent inactivation through direct interaction of Ca2+ with the channel, through dephosphorylation by calcium dependent phosphatases or through calcium dependent disruption of connections with the cytoskeleton. Transmitter modulation operating through various second messenger mediated pathways is well documented. In general, phosphorylation through PKA, cGMP dependent PK or PKC facilitates the calcium channels, while putative direct G-protein action inhibits the channels. Ca2+ and cGMP may inhibit the channels through activation of phosphodiesterases or phosphatases. Detailed evidence has been provided on the role of sustained LVA channels in pacemaking and the generation of firing patterns, and on the role of HVA channels in the dynamic changes in action potentials during spiking, the regulation of the release of transmitters and hormones, and the regulation of growth cone behavior and neurite outgrowth. The accessibility of molluscan preparations (e.g. the squid giant synapse for excitation release studies, Helisoma B5 neuron for neurite and synapse formation) and the large body of knowledge on electrophysiological properties and functional connections of identified molluscan neurons (e.g. sensory neurons, R15, egg laying hormone producing cells, etc.) creates valuable opportunities to increase the insight into the functional roles of calcium channels.     

The relationship between PGE2 level in mothers' milk and physiological diarrhea of the baby and the treatment

Physiological diarrhea of baby during the period of breastfeeding often occurs. To investigate the relationship between mother's milk and the physiological diarrhea of baby, we measured the PGE2 levels in milk of 320 lactating women within 4 months of postpartum with radioimmunoassay and the mean value of PGE2 level was 216.8 +/- 145.2 ng/L. The PGE2 levels in mother's milk in the group with diarrhea were 286.5 +/- 142.2 ng/L, that of control group 130.4 +/- 76.3 ng/L. The difference was obviously significant (P < 0.001). The physiological diarrhea of baby was positively related to the PGE2 level in mother's milk (r = 0.75, P < 0.01) i.e., the high PGE2 level in mother's milk may be an important cause of diseases. The observation on 102 cases of baby with severe physiological diarrhea showed a higher level of PGE2 in the mother's milk. 52 cases of lactating women in the treated group were given indomethacin, and after treatment the PGE2 level in mother's milk decreased obviously, and the diarrhea of baby disappeared. The effective rate was 96.15%. No side effects were found in both mother and baby.     

Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group

BACKGROUND: The efficacy of prophylaxis against stress ulcers in preventing gastrointestinal bleeding in critically ill patients has led to its widespread use. The side effects and cost of prophylaxis, however, necessitate targeting preventive therapy to those patients most likely to benefit. METHODS: We conducted a prospective multicenter cohort study in which we evaluated potential risk factors for stress ulceration in patients admitted to intensive care units and documented the occurrence of clinically important gastrointestinal bleeding (defined as overt bleeding in association with hemodynamic compromise or the need for blood transfusion). RESULTS: Of 2252 patients, 33 (1.5 percent; 95 percent confidence interval, 1.0 to 2.1 percent) had clinically important bleeding. Two strong independent risk factors for bleeding were identified: respiratory failure (odds ratio, 15.6) and coagulopathy (odds ratio, 4.3). Of 847 patients who had one or both of these risk factors, 31 (3.7 percent; 95 percent confidence interval, 2.5 to 5.2 percent) had clinically important bleeding. Of 1405 patients without these risk factors, 2 (0.1 percent; 95 percent confidence interval, 0.02 to 0.5 percent) had clinically important bleeding. The mortality rate was 48.5 percent in the group with bleeding and 9.1 percent in the group without bleeding (P < 0.001). CONCLUSIONS: Few critically ill patients have clinically important gastrointestinal bleeding, and therefore prophylaxis against stress ulcers can be safely withheld from critically ill patients unless they have coagulopathy or require mechanical ventilation.     

Endothelin-1 and cell proliferation in lung organ cultures. Implications for lung allografts

Endothelin-1 (ET-1) is found in bronchoalveolar lavage fluid in patients following lung transplantation. ET-1 causes contraction of isolated pulmonary vessels and bronchi and stimulates proliferation of smooth muscle cells in culture. Therefore, ET-1 could contribute to the smooth muscle hyperplasia and stromal proliferation seen in chronic rejection of lung allografts. Experiments were designed to determine whether (1) ET-1 stimulates proliferation of pulmonary tissue, (2) proliferation is increased in rejecting allotransplanted lungs, (3) endothelin-A receptors mediate the proliferative response, and (4) ET-1 is produced by activated infiltrating immunocompetent cells. Lung organ cultures were prepared from unoperated dogs and dogs with rejecting single lung allografts. Incubation of organ cultures from unoperated dogs with ET-1 (10(-9) to 10(-7) M)) increased positive staining for proliferation cell nuclear antigen (PCNA) in lung parenchyma. PCNA staining was not decreased by the endothelin-A antagonist BQ123 (10(-6) M). In addition, immunostaining for endothelin-B receptors was present in sections of unoperated but not rejecting lungs. PCNA staining in lung cultures from rejecting allotransplanted dogs was significantly greater than that from unoperated dogs. Positive immunohistochemical staining for ET-1 was found in mononuclear cells infiltrating rejecting transplanted lungs. In conclusion, exogenous ET-1 is mitogenic in lung organ cultures through receptors other than endothelin-A. Proliferation in rejecting transplanted lungs is increased compared with unoperated lungs. Mononuclear cells may be a source of endothelin-1 in the rejecting lung. ET-1, therefore could, in synergism with other cytokines, contribute to acute and chronic pathological changes seen in pulmonary rejection.     

Lack of association between the polyadenylation polymorphism in the NAT1 (acetyltransferase 1) gene and colorectal adenomas

Smoking and a high intake of red meat are risk factors for colorectal tumors. These effects could be due to aromatic amine carcinogens. Individual susceptibility to aromatic amines has been related to acetylation phenotype, which plays a role in the bioactivation of arylamines. Polymorphisms in both N-acetyltransferase genes, NAT1 and NAT2, have been associated with an increased risk of colorectal tumors. We studied the NAT1*10 fast acetylator allele (1088 T-->A mutation) and distal adenomas in a sigmoidoscopy-based case-control study (441 cases, 484 controls). We found neither an increased adenoma prevalence in subjects homozygous or heterozygous for the NAT1*10 fast acetylator allele (odds ratio 1.04; 95% confidence interval 0.79-1.36), nor a gene-gene interaction between NA1 and NAT2 (P(interaction) = 0.59). Further NAT1 alleles must be considered for more conclusive results regarding the relevance of NAT1 activity to colorectal tumorigenesis.     

The diagnosis and clinical manifestations of activated protein C resistance: a case report and review of the literature

A survey of musculoskeletal problems among visual display unit (VDU) users was carried out in a bank using a self-administered questionnaire. The prevalence of complaints in various body parts were: neck--31.4%, back 30.6%, shoulder--16.5%, hand and wrist--14.9% and arm--6.6%. Frequent users of VDU had significantly more musculoskeletal problems in the neck and shoulder regions than infrequent users. Individual musculoskeltal complaints were associated with various risk factors including personal attributes, working posture, repetitive movements and work station design. Back, neck and shoulder problems were more related to unfavourable working postures, white arm, hand and wrist problems were more affected by repetitive movements. Some risk factors for musculoskeletal problems were specifically related to the nature or design of VDU work. Modification of the workstation design and improvement in work organization should be able to reduce the prevalence of these disorders.     

Combined effects of antenatal corticosteroids and surfactant supplementation on the outcome of very low birth weight infants

Antenatal corticosteroids in preterm pregnancy may result in the reduction of the incidence of respiratory distress syndrome (RDS) and neonatal mortality. It is well known that postnatal use of surfactant in very low birth weight (VLBW) infants with RDS results in decreased neonatal morbidity and mortality. To evaluate the additive beneficial effects of combined antenatal corticosteroids and postnatal use of rescue surfactant on the outcome of VLBW infants, we retrospectively reviewed 286 maternal/infant charts of preterm infants with gestational ages 23 to 32 weeks and birth weights 501 to 1500 gm who were born at our institution from 1991 through 1994. Of the 87 (30%) infants who were treated with corticosteroids before birth, 41 (47%) had RDS, and of the 199 (70%) infants who were not treated with corticosteroids before birth, 162 (81%) had RDS (p < 0.001). The infants who had RDS and who were treated with corticosteroids before birth had a decreased incidence of pulmonary air leaks and a decreased need for diuretic therapy. In addition, they had a significant reduction in O2 requirement and ventilator settings as reflected by FIO2, mean airway pressure, ventilator rate, O2 index, and A-aDO2 before they received the first dose of rescue surfactant (p < 0.05 to p < 0.01) in contrast to other VLBW infants who had RDS and who were not treated with corticosteroids before birth. We conclude that antenatal corticosteroid therapy in threatened premature labor combined with the use of postnatal rescue surfactant is associated with a decreased incidence of RDS and may be beneficial for reducing the severity of RDS and improving the eventual outcome of VLBW infants.