Glucose activates both K(ATP) channel-dependent and K(ATP) channel-independent signaling pathways in human islets

We investigated the effects of platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) on intracellular Ca2+ concentration ([Ca2+]i) and cell length in isolated and field-stimulated rat cardiomyocytes. [Ca2+]i and cell length of field-stimulated cells were determined simultaneously by confocal laser scan microscopy by using the fluorescent Ca2+ dye Fluo-3. PAF (10(-12)-10(-8) M) inhibited systolic [Ca2+]i increase in a time- and concentration-dependent manner. Maximal effects were observed after an incubation time of 6-8 min, resulting in a 17% (10(-12) M), 41% (10(-10) M), and 52% (10(-8) M PAF) inhibition of systolic [Ca2+]i increase. A time- and concentration-dependent decrease in simultaneously measured cell shortening also was demonstrated. Cell shortening was inhibited by 10% (10(-12) M), 32% (10(-10) M), and 50% (10(-8) M) after an incubation time of 8 min. The effects of PAF could be antagonized by the PAF-receptor antagonist WEB 2170. These data demonstrate that PAF receptor-dependently induces a negative inotropic effect, which is correlated with a decrease in systolic [Ca2+]i and is most likely not due to a decrease in myofilament sensitivity.     

Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group

BACKGROUND: The congenital long-QT syndrome, caused by mutations in cardiac potassium-channel genes (KVLQT1 at the LQT1 locus and HERG at the LQT2 locus) and the sodium-channel gene (SCN5A at the LQT3 locus), has distinct repolarization patterns on electrocardiography, but it is not known whether the genotype influences the clinical course of the disease. METHODS: We determined the genotypes of 541 of 1378 members of 38 families enrolled in the International Long-QT Syndrome Registry: 112 had mutations at the LQT1 locus, 72 had mutations at the LQT2 locus, and 62 had mutations at the LQT3 locus. We determined the cumulative probability and lethality of cardiac events (syncope, aborted cardiac arrest, or sudden death) occurring from birth through the age of 40 years according to genotype in the 246 gene carriers and in all 1378 members of the families studied. RESULTS: The frequency of cardiac events was higher among subjects with mutations at the LQT1 locus (63 percent) or the LQT2 locus (46 percent) than among subjects with mutations at the LQT3 locus (18 percent) (P<0.001 for the comparison of all three groups). In a multivariate Cox analysis, the genotype and the QT interval corrected for heart rate were significant independent predictors of a first cardiac event. The cumulative mortality through the age of 40 among members of the three groups of families studied was similar; however, the likelihood of dying during a cardiac event was significantly higher (P<0.001) among families with mutations at the LQT3 locus (20 percent) than among those with mutations at the LQT1 locus (4 percent) or the LQT2 locus (4 percent). CONCLUSIONS: The genotype of the long-QT syndrome influences the clinical course. The risk of cardiac events is significantly higher among subjects with mutations at the LQT1 or LQT2 locus than among those with mutations at the LQT3 locus. Although cumulative mortality is similar regardless of the genotype, the percentage of cardiac events that are lethal is significantly higher in families with mutations at the LQT3 locus.     

Citalopram enhances the activity of chloroquine in resistant plasmodium in vitro and in vivo

Citalopram, is an extremely potent inhibitor of neuronal serotonin reuptake. It is structurally unrelated to other antidepressants, but it contains the chemical features associated with reversal of drug resistance and exhibits minimal cardiotoxic side effects and fewer of the anticholinergic and adrenolytic side effects associated with other psychotropic agents. Sensitivity tests to citalopram alone and in combination with chloroquine were performed against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum and Plasmodium chabaudi. Citalopram alone showed intrinsic activity against the chloroquine-resistant strains of P. falciparum (IC50 = 1.51 +/- .6 microM) but only limited activity against the chloroquine-sensitive strain (IC50 = 33.27 +/- 5.87 microM) and no activity in vivo. The interaction of chloroquine and citalopram in vitro resulted in a synergistic response in the chloroquine-resistant strain but there was no interaction between the drugs in the chloroquine-sensitive strain--a pattern found with other reversal agents. Citalopram enhanced chloroquine susceptibility in both strains of P. chabaudi, however, the potentiating effect was seen at lower doses in the chloroquine-resistant strain. The results of this study suggest that citalopram may have potential as a chemosensitizer in Plasmodium infections on the basis of the low toxicity of citalopram at concentrations potentiating chloroquine activity both in vitro and in vivo.     

"What the ''caine was tellin'' me to do." Crack users'' risk of HIV: an exploratory study of female inmates

Statistics show that use of harmful substances (alcohol, cigarettes, marijuana, cocaine) among women of childbearing age is widespread and serious. Numerous theoretical models and empirical studies have attempted to explain the complex factors that lead individuals to use drugs. The Social Stress Model of Substance Abuse [1] is one model developed to explain parameters that influence drug use. According to the model, the likelihood of an individual engaging in drug use is seen as a function of the stress level and the extent to which it is offset by stress modifiers such as social networks, social competencies, and resources. The variables of the denominator are viewed as interacting with each other to buffer the impact of stress [1]. This article focuses on one of the constructs in this model: that of competence. It presents a summary of theoretical and conceptual formulations for the construct of competence, a review of empirical evidence for the association of competence with drug use, and describes the preliminary development of a multi-scale instrument designed to assess drug protective competence among low-income Hispanic childbearing women. Based upon theoretical and empirical studies, eight domains of drug protective competence were identified and conceptually defined. Using subscales from existing instruments with psychometric evidence for their validity and reliability, a multi-scale instrument was developed to assess drug protective competence. Hypothesis testing was used to assess construct validity. Four drug protective competence domains (social influence, sociability, self-worth, and control/responsibility) were found to be statistically associated with drug use behaviors. Although not statistically significant, expected trends were observed between drug use and the other four domains of drug protective competence (intimacy, nurturance, goal directedness, and spiritual directedness). Study limitations and suggestions for further psychometric testing of the instrument are described.     

Should the presence of coiled blood flow in the left heart ventricle and aorta be taken into consideration when constructing artificial heart valves?]

This study presented the outcome of 92 EOC patients treated by platinum or platinum analogue with cyclophosphamide from January 1, 1993 to December 31, 1995. There were 77 evaluable patients. The follow-up ranged from 4-42 months (median 14 months). The over all 3-year survival was 64 per cent and the median progression-free interval was 16 months for the whole group. There was no significant difference in survival between patients who received cisplatin and those who received carboplatin (P = 0.093). Patients who underwent optimal debulking surgery had significantly longer progression-free interval (P = 0.001) than those who had sub-optimal surgery. Fifty four per cent of patients with clear cell carcinoma died of the disease. Patients who received cisplatin had a drop out rate while on therapy more often (24% vs 5.3%) than that of carboplatin. Toxicities from chemotherapy were moderate but manageable.     

Measurement of genetic variation within and between Japanese quail lines using DNA fingerprinting

The objective of the present experiment was to study genetic variation within and among well-defined Japanese quail lines by DNA fingerprinting. The Japanese quail lines included a randombred control line (R1) and lines developed from R1 by divergent selection over 30 generations for 4-wk BW (HW, LW) and total plasma phosphorus (TPP) (HP, LP), a measure of yolk precursor in the blood. In addition, two sublines (HW-HP, HW-LP) of HW, developed in the ninth generation, were included in the analysis. Males of the sublines were selected for increased 4-wk BW whereas females were selected for increased (HW-HP) or decreased (HW-LP) TPP. Sixteen individual DNA samples per line were digested with HaeIII restriction enzyme and hybridized with Jeffreys' 33.6 probe. The DNA fingerprints were analyzed with computer programs designed to measure band sharing (BS). Within lines, BS ranged from 0.384 to 0.525. The BS within the R1 line was less than that of all selected lines, except for the HP and LP lines, indicating that, in general, selection had increased genetic homogeneity within the selected lines. Between lines, BS was less than within lines and the R1 line had the highest average level of BS (0.278) with the other lines. The BS between lines for the selected lines ranged from 0.230 to 0.308 with an average of 0.265. In the comparison of the R1 line with the selected lines, it appeared that selection for increased TPP or decreased BW may have influenced BS levels. The relationships of the HW line with its sublines (HW-HP and HW-LP) were not accurately predicted by the DNA fingerprinting technique used. All lines were separated, as indicated by the genetic distance between lines.     

Mature T cell reactivity altered by peptide agonist that induces positive selection

Recent studies have investigated how defined peptides influence T cell development. Using a T cell receptor-transgenic beta2-microglobulin-deficient model, we have examined T cell maturation in fetal thymic organ cultures in the presence of various peptides containing single-alanine substitutions of the strong peptide agonist, p33. Cocultivation with the peptide A4Y, which contains an altered T cell contact residue, resulted in efficient positive selection. Several in vitro assays demonstrated that A4Y was a moderate agonist relative to p33. Although A4Y promoted positive selection over a wide concentration range, high doses of this peptide could not induce clonal deletion. Thymocytes maturing in the presence of A4Y were no longer able to respond to A4Y, but could proliferate against p33. These studies demonstrate that (a) peptides that induce efficient positive selection at high concentrations are not exclusively antagonists; (b) some agonists do not promote clonal deletion; (c) positive selection requires a unique T cell receptor-peptide-major histocompatibility complex interaction; and (d) interactions with selecting peptides during T cell ontogeny may define the functional reactivity of mature T cells.     

Improvement of sini decoction on hemorheology following percutaneous transluminal coronary angioplasty

OBJECTIVE: To study the hemorheological effects of Sini decoction on patients following percutaneous transluminal coronary angioplasty (PTCA). METHODS: Forty-six patients were randomly divided into Sini decoction and control groups. The hemorheologic variables were determined before and after Sini decoction treatment. RESULTS: No hemorheologic changes were observed in the patients (n = 23) only with PTCA, but the patients (n = 23) with Sini decoction were found to be significantly decreased in whole blood viscosity and red cell aggregation and dredging the blood of microcirculation as post-PTCA compared to pre-PTCA. CONCLUSION: Sini decoction could improve the patient's hemorheology.     

Mutations in the carboxyl terminus of the agouti protein decrease agouti inhibition of ligand binding to the melanocortin receptors

Several mutations that cause ectopic expression of the agouti gene result in obesity, hyperinsulinemia, and yellow coat color. A candidate pathway for agouti induced obesity and hyperinsulinemia is through altered signaling by melanocortin receptors, as agouti normally regulates coat coloration through antagonism of melanocortin receptor 1. Furthermore, melanocortin peptides mediate functions including steroidogenesis, lipolysis, and thermoregulation. We report apparent inhibition dissociation constants for mouse and human agouti protein inhibition of ligand binding to the melanocortin receptors, to determine which of these receptors might be involved in agouti induced diabetes. The similarity in the apparent K(I) values for agouti inhibition of ligand binding to the brain melanocortin receptors 3 and 4 (mouse: K(I) app = 190 +/- 74 and 54 +/- 18 nM; human: K(I) app = 140 +/- 56 and 70 +/- 18 nM, respectively) suggests that the MC3-R is a potential candidate for a receptor mediating the effects of agouti protein overexpression. Agouti residues important for melanocortin receptor inhibition were identified through the analysis of deletion constructs and site-specific variants. Val83 is important for inhibition of binding to MC1-R (K(I) app for Val83Ala agouti increased 13-fold relative to wild-type protein). Arg85, Pro86, and Pro89 are important for selective inhibition of binding between MC1-R and MC3-R and MC4-R as their apparent K(I) values are essentially unchanged at MC1-R, while they have increased 6-10-fold relative to wild-type protein at MC3-R and MC4-R.