Effect of nifedipine on glucose tolerance, serum insulin, and serum fructosamine in diabetic and nondiabetic patients

The hypothesis that nifedipine may cause an insidious but reversible change in glucose tolerance, similar to that associated with thiazide therapy, was studied in six nondiabetic and six noninsulin-dependent diabetic patients with hypertension. After medium-term nifedipine therapy (mean duration, 11.5 months) was stopped for one month and then resumed for a month, values for fasting blood glucose, fasting serum insulin, serum fructosamine, glucose tolerance, and insulin release in response to oral glucose were unchanged in both groups. These findings suggest that nifedipine in conventional doses does not have important effects on glucose handling in either diabetic or nondiabetic patients.     

Evaluation of the echinocandin antifungal MK-0991 (L-743,872): efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis.

The in vivo activity of the Merck antifungal echinocandin drug candidate MK-0991 (L-743,872) was evaluated in mouse models of disseminated candidiasis, aspergillosis, and cryptococcosis. The echinocandins are potent inhibitors of 1,3-beta-D-glucan synthase. Two models of disseminated candidiasis were used. In a Candida albicans mouse survival model with both DBA/2N and CD-1 mice, estimates of the 50% effective doses (ED50s) of MK-0991 were 0.04 and 0.10 mg/kg of body weight/dose at 21 days after challenge, respectively. In a C. albicans target organ assay (TOA) with DBA/2N mice, MK-0991 at levels of > or =0.09 mg/kg/dose significantly reduced the numbers of C. albicans CFU/g of kidneys compared to the numbers in the kidneys of control mice from 1 to 28 days after challenge. Even when given as a single intraperitoneal dose either 30 min or 24 h after challenge, MK-0991 was effective and significantly reduced the numbers of C. albicans CFU/g of kidney compared to those in the controls. MK-0991 was >300-fold less active when it was administered orally than when it was administered parenterally. MK-0991 was efficacious in mouse TOAs against other C. albicans strains and Candida species including Candida tropicalis, Candida (Torulopsis) glabrata, Candida lusitaniae, Candida parapsilosis, and Candida krusei. MK-0991 was ineffective against disseminated Cryptococcus neoformans infections. In the model of disseminated aspergillosis in mice, MK-0991 at doses of > or =0.02 mg/kg/dose significantly prolonged the survival of DBA/2N mice, with estimates of the ED50 and ED90 of MK-0991 being 0.03 and 0.12 mg/kg/dose, respectively, at 28 days after challenge. MK-0991 is a potent, parenterally administered therapeutic agent against disseminated candidiasis and aspergillosis that warrants further investigation in human clinical trials.     

Absolute bioavailability and pharmacokinetics of linezolid in hospitalized patients given enteral feedings

Linezolid is a new antimicrobial agent effective against drug-resistant gram-positive pathogens which are common causes of infections in hospitalized patients. Many such patients rely on the intravenous or enteral route for nutrition and drug administration. Therefore, the bioavailability of linezolid administered enterally in the presence of enteral feedings in hospitalized patients was examined. Eighteen subjects were assessed in a randomized single-dose crossover study; 12 received continuous enteral feedings, while 6 did not (controls). Both groups received linezolid 600 mg intravenously and orally (control) or enterally, with the alternate route of administration separated by a 24-h washout period. Pharmacokinetic parameters derived from noncompartmental and compartmental analysis incorporating linear and nonlinear elimination pathways were compared between groups: F, Ka, Vs, K23, K32, Vmax, Km, and K20 (bioavailability, absorption rate constant, volume of central compartment normalized to body weight, intercompartmental rate constants, maximum velocity, Michaelis-Menten constant, and elimination rate constant, respectively). Pharmacokinetic (PK) data were available from 17 patients. The linezolid oral suspension was rapidly and completely absorbed by either the oral or enteral route of administration. Bioavailability was unaltered in the presence of enteral feedings. PK estimates remain similar regardless of the model applied. At the therapeutic dose used, only slight nonlinearity in elimination was observed. A linezolid oral suspension may be administered via the enteral route to hospitalized patients without compromise in its excellent bioavailability and rapid rate of absorption. Compartmental pharmacokinetic analysis offers a more flexible study application, since bioavailability (F) can be estimated directly with intermixed intravenous/oral doses without a need for a washout period.     

New model of oropharyngeal and gastrointestinal colonization by Candida albicans in CD4+ T-cell-deficient mice for evaluation of antifungal agents.

A new model for the evaluation of antifungal compounds against oropharyngeal and gastrointestinal mucosal colonization by Candida albicans was developed. To simulate the immune deficiency observed in AIDS patients, mice were depleted of CD4+ T lymphocytes by the injection of either GK1.5 hybridoma cells or purified anti-CD4+ T lymphocytes by the injection of either GK1.5 hybridoma cells or purified anti-CD4+ monoclonal antibody derived from GK1.5 hybridoma cells in tissue culture. Fluorescence-activated cell sorter analysis of splenic lymphocytes confirmed the elimination of the CD4+ T-cell population. Gentamicin, a broad-spectrum, nonabsorbable aminoglycoside antibiotic, was given via the drinking water to reduce the normal gastrointestinal microflora, allowing less competition for colonization of the gastrointestinal tract by the C. albicans isolates. Mice were challenged by gavage and swabbing their oral mucosae with a pure culture of C. albicans. Gentamicin was withdrawn 3 days postchallenge, and antifungal compounds were administered via the drinking water ad libitum at concentrations ranging from 25 to 400 micrograms/ml. L-693989, a water-soluble phosphorylated cyclic lipopeptide prodrug of pneumocandin Bo, and L-733560, a semisynthetic derivative of pneumocandin Bo, are inhibitors of 1,3-beta-D-glucan synthesis that exhibit potent in vivo anti-Candida spp. and anti-Pneumocystis carinii activities. The efficacies of L-693989, L-733560, fluconazole, ketoconazole, and nystatin were evaluated in this new oropharyngeal and gastrointestinal model of mucosal colonization. L-693989, L-733560, fluconazole, and ketoconazole showed superior efficacies in reducing the numbers of C. albicans CFU per gram of feces and the numbers of oral CFU relative to those in sham-treated controls in this model, while nystatin was moderately effective in reducing oral and fecal colonization by C. albicans in this model.     

“黄芪-莪术”药对通过PTEN与p-AKT对人乳腺癌细胞增殖的影响

目的：探讨“黄芪-莪术”药对通过PTEN与p-AKT对人乳腺癌细胞（MDA-MB-231）增殖的作用机制。方法：将MDA-MB-231细胞进行“黄芪-莪术”药对（药对组）、顺铂（顺铂组）、“黄芪-莪术”药对联合顺铂（药对+顺铂组）治疗,并设置空白对照组。MTT法检测细胞增殖,RT-qPCR检测PTEN与p-AKT的mRNA表达水平,Western Blotting检测p-AKT蛋白表达水平。结果：与空白对照组比较,药对组PTEN mRNA表达水平上升,OD值与p-AKT蛋白表达水平下降（P<0.05）,p-AKT mRNA蛋白表达水平变化差异无统计学意义（P>0.05）;顺铂组OD值与PTEN mRNA表达水平下降（P<0.05）,p-AKT mRNA与蛋白表达水平变化差异无统计学意义（P>0.05）;而药对+顺铂组在药对治疗的基础上能进一步抑制MDA-MB-231细胞增殖,促进PTEN mRNA的表达,抑制p-AKT mRNA与蛋白表达水平。结论：“黄芪-莪术”药对抑制MDA-MB-231细胞增殖的机制可能通过上调PTEN基因而直接抑制AKT蛋白水平。     

D-dimer testing is useful to exclude deep vein thrombosis in elderly outpatients

Summary.  Background:  Deep vein thrombosis (DVT) can be safely and reliably excluded in patients with a low clinical probability and a negative D-dimer result but the accuracy and utility of such a strategy is unclear in elderly patients. Objectives:  We sough to compare the performance of the Wells pretest probability (PTP) model and D-dimer testing between patients of different age groups and to examine the utility of the two PTP model classification schemes (low/moderate/high vs. unlikely/likely) in excluding DVT in elderly outpatients. Patients/Methods:  Pooled analysis of databases from three prospective diagnostic studies evaluating consecutive outpatients with suspected DVT. Results:  A total of 2696 patients were evaluated. DVT was diagnosed in 400 (15%) patients overall and in 50 out of 325 (15.5%) patients ≥ 60 years old. The PTP distribution and the prevalence of DVT in each PTP category were similar among the different age groups. The negative predictive values of a low or unlikely PTP score in combination with a negative D-dimer result were 99% for all groups. A negative D-dimer in combination with a low or unlikely PTP excluded 21.7% and 31% of patients ≥ 80 years old, respectively. Conclusions:  The combination of a low or unlikely PTP with a negative D-dimer result can effectively and safely exclude DVT in a significant proportion of elderly outpatients. However, this clinical prediction rule needs to be prospectively validated with different D-dimer assays in this specific population.     

Heritability of low back pain and the role of disc degeneration

Twin studies suggest that both disc degeneration and back pain have a genetic component. We were interested in estimating the heritability of low back pain in men and examining whether genetic influences on back pain are mediated through genetic influences on disc degeneration. Thus, we conducted a classic twin study with multivariate quantitative genetic models to estimate the degree to which genetic (or environmental) effects on back pain were correlated with genetic (or environmental) effects on disc degeneration. Subjects included 147 monozygotic and 153 dizygotic male twin pairs (N=600 subjects) from the population-based Finnish Twin Cohort. All subjects underwent lumbar magnetic resonance imaging and completed an extensive interview, including back pain history and exposure to suspected risk factors. Disc height narrowing was the degenerative finding most associated with pain history, and was used to index disc degeneration in the models. Statistically significant genetic correlations were found for disc height narrowing and different definitions of back pain, such as duration of the worst back pain episode (r(g)=0.46) and hospitalization for back problems (r(g)=0.49), as well as disability in the previous year from back pain (r(g)=0.33). The heritability estimates for these back pain variables ranged from 30% to 46%. There also were statistically significant, but weaker, environmental correlations for disc height narrowing with back symptoms over the prior year. A substantial minority of the genetic influences on pain was due to the same genetic influences affecting disc degeneration. This suggests that disc degeneration is one pathway through which genes influence back pain.     

Ignoring theory and misinterpreting evidence: the false belief in fear appeals

Use of fear appeals assumes that when people are emotionally confronted with the negative effects of their behaviour they will change that behaviour. That reasoning is simple and intuitive, but only true under specific, rare circumstances. Risk perception theories predict that if people will experience a threat, they want to counter that threat. However, how they do so is determined by their coping efficacy level: if efficacy is high, they may change their behaviour in the suggested direction; if efficacy is low, they react defensively. Research on fear appeals should be methodologically sound, comparing a threatening to a non-threatening intervention under high and low efficacy levels, random assignment and measuring behaviour as outcome. We critically review extant empirical evidence and conclude that it does not support positive effects of fear appeals. Nonetheless, their use persists and is even promoted by health psychology researchers, causing scientific insights to be ignored or misinterpreted.