Multidrug resistance modulator interactions with neutral and anionic liposomes: membrane binding affinity and membrane perturbing activity

A variety of cationic lipophilic compounds (modulators) have been found to reverse the multidrug resistance of cancer cells. In order to determine the membrane perturbing efficacy and the binding affinity of such drugs in neutral and anionic liposomes, the leakage of Sulfan blue induced by five modulators bearing different electric charges was quantified using liposomes with and without phosphatidic acid (xEPA=0 and 0.1), at four lipid concentrations. The binding isotherms were drawn up using the indirect method based on the dependency of the leakage rate on the modulator and the lipid concentrations. Upon inclusion of negatively charged lipids in the liposomes: (i) the binding of cationic drugs was favoured, except in a case where modulator aggregation occurred in the lipid phase; (ii) the drugs with a net electric charge greater than 1.1 displayed a greater enhancement in their potency to produce membrane perturbation; and (iii) the EPA effect on membrane permeation was due mainly to that on membrane perturbation (>or=50%) and, to a lesser extent, to that on the binding affinity (相似文献   

Renin-secreting tumour: about a new diagnosed case during pregnancy

A 29 year-old female patient developed severe arterial hypertension in the beginning of her second pregnancy. Investigations performed at 16 weeks of amenorrhea showed hypokaliemia in relation to severe hyperreninism: plasma active renin was 25 fold normal value, 94% as prorenin (prorenin representing 94% of total renin). Radiological investigations including ultrasonography and MRI disclosed an homogenous and avascular tumor in the right kidney. Its ablation confirmed renin tumor, and allowed recovery from HTA and continuation of pregnancy. This is the 75th reported case in the literature, enabling to make a new statement about diagnostic and therapeutic procedures, which are modified during pregnancy by contra-indication to X-rays and renin-angiotensin-aldosteron axis inhibitors.     

Antibiotic prophylaxis in oral health care: administration strategies of general dental practitioners

OBJECTIVE: To examine the strategies that general dental practitioners (GDPs) use to administer antibiotic prophylaxis and to study the agreement between the administration strategies of GDPs and local recommendations. METHODS: Postal questionnaires in combination with telephone interviews were used. Two hundred GDPs in two Swedish counties, Sk?ne and Orebro, were asked to participate. The response rate was 51% (n = 101). The GDPs were presented with eight simulated cases of patients with different medical conditions for which antibiotic prophylaxis might be considered necessary when performing dental procedures (scaling, tooth removal, root canal treatment). The administration strategies of the GDPs were compared with local recommendations. RESULTS: In general, the variation in the administration strategies of the GDPs was large. For two medical conditions, type 1 diabetes that was not well controlled and hip prosthesis, significantly more GDPs in Sk?ne than in Orebro administered antibiotic prophylaxis for tooth removal. Agreement between the administration strategies of the GDPs and local recommendations was low. Differences between the two counties were non-significant. Furthermore, within Orebro, GDPs who did not have formal access to local recommendations did not differ in their administration strategies from those who did. The choice of substance was seldom in agreement with the substance recommended, while the majority followed the recommended duration of treatment. CONCLUSION: Although recommendations existed, their impact appeared to be limited. This is significant, since the implementation of recommendations is crucial in making clinical practice more effective and in promoting the health of patients.     

The Second International Conference on Sentinel Node Biopsy in Mucosal Head and Neck Cancer

Background The Second International Conference on Sentinel Node Biopsy in Mucosal Head and Neck Cancer was hosted by the Department of Otorhinolaryngology, Head and Neck Surgery of the University Hospital in Zurich, Switzerland, from September 12 to 13, 2003. The aims of this conference were to present the results of validation studies and to achieve a consensus on methodological requirements. Methods More than 80 delegates from 20 countries attended the conference. The presented validation studies were summarized and compared with the literature. Consensus was achieved concerning requirements for lymphatic mapping and histopathologic work-up. Results Twenty centers presented results on 379 patients with cN0 disease. Sentinel nodes were identified in 366 (97%) of 379. Of these 366, 103 (29%) were positive for occult metastasis, and 263 (71%) were negative. Of those 263 patients, 11 patients (4%) showed nodal disease not revealed by the sentinel lymph node biopsy (SNB). The negative predictive value of a negative sentinel node for the remaining neck was 96%. The consensus conference resulted in the use of a radiotracer, lymphoscintigraphy, and a handheld gamma probe for lymphatic mapping as minimal requirements. The use of conventional hematoxylin and eosin staining and immunohistochemistry for cytokeratin is mandatory. Step-sectioning of the entire node at intervals of 150 μm is recommended. Conclusions The conference attracted delegates from all over the world, thus underscoring the high interest in the topic. With regard to the presented data and the data from the literature, SNB for early oral and oropharyngeal cancer is sufficiently validated. The consensus conference resulted in the definition of minimal methodological requirements for accurate SNB.     

Micronutrient deficiencies and gender: social and economic costs

Vitamin and mineral deficiencies adversely affect a third of the world's people. Consequently, a series of global goals and a serious amount of donor and national resources have been directed at such micronutrient deficiencies. Drawing on the extensive experience of the authors in a variety of institutional settings, the article used a computer search of the published scientific literature of the topic, supplemented by reports and published and unpublished work from the various agencies. In examining the effect of sex on the economic and social costs of micronutrient deficiencies, the paper found that: (1) micronutrient deficiencies affect global health outcomes; (2) micronutrient deficiencies incur substantial economic costs; (3) health and nutrition outcomes are affected by sex; (4) micronutrient deficiencies are affected by sex, but this is often culturally specific; and finally, (5) the social and economic costs of micronutrient deficiencies, with particular reference to women and female adolescents and children, are likely to be considerable but are not well quantified. Given the potential impact on reducing infant and child mortality, reducing maternal mortality, and enhancing neuro-intellectual development and growth, the right of women and children to adequate food and nutrition should more explicitly reflect their special requirements in terms of micronutrients. The positive impact of alleviating micronutrient malnutrition on physical activity, education and productivity, and hence on national economies suggests that there is also an urgent need for increased effort to demonstrate the cost of these deficiencies, as well as the benefits of addressing them, especially compared with other health and nutrition interventions.     

A phase II trial of dexamethasone, vitamin D, and carboplatin in patients with hormone-refractory prostate cancer

BACKGROUND: A Phase II prospective trial was performed to study the efficacy of combination therapy with dexamethasone, calcitriol (1,25-dihydroxyvitamin D3), and carboplatin in patients with hormone-refractory prostate cancer (HRPC). Preclinical data from prostate cancer cell lines suggested a synergistic effect of these therapies. METHODS: All patients had pathologically confirmed prostate cancer with at least 2 consecutive increases in prostate-specific antigen (PSA). Treatment started with 1 mg of oral dexamethasone given daily with 0.5 mcg of daily calcitriol added at the start of Week 5. Carboplatin (area under the concentration time curve = 2) was started at the beginning of Week 7. Initially, carboplatin was given weekly; however, the protocol was changed later to give carboplatin for the first 4 weeks of a 6-week cycle. Of 40 patients who consented to participate, 6 patients were ineligible or declined to start therapy, leaving 34 treated patients. The median follow-up was 80.7 weeks (range, 11.5-260 weeks). RESULTS: A formal PSA response was seen in 13 of 34 treated patients (38.2%; 95% confidence interval [95% CI], 22.2-56.4%). The median overall survival was 97.7 weeks (95% CI, 61-114 weeks). Significant adverse events that were observed during the trial period included 2 deaths (myocardial infarction and cardiogenic shock), 4 patients with Grade 3 neutropenia (according to the National Cancer Institute Common Toxicity Criteria, version 2.0), 2 patients with thrombosis, 2 patients with inflammatory bowel symptoms, and 2 patients with new-onset diabetes mellitus. CONCLUSIONS: The novel combination of dexamethasone, calcitriol, and carboplatin for patients with HRPC produced a PSA response in 13 of 34 patients and had an acceptable side-effect profile.     

Effects of chili consumption on postprandial glucose, insulin, and energy metabolism

BACKGROUND: Animal and some human studies have indicated that the consumption of chili-containing meals increases energy expenditure and fat oxidation, which may help to reduce obesity and related disorders. Because habitual diets affect the activity and responsiveness of receptors involved in regulating and transporting nutrients, the effects of regular consumption of chili on metabolic responses to meals require investigation. OBJECTIVE: The objective was to investigate the metabolic effects of a chili-containing meal after the consumption of a bland diet and a chili-blend (30 g/d; 55% cayenne chili) supplemented diet. DESIGN: Thirty-six subjects with a mean (+/-SD) age of 46 +/- 12 y and a body mass index (in kg/m2) of 26.3 +/- 4.6 participated in a randomized, crossover, intervention study with 2 dietary periods (chili and bland) of 4 wk each. The postprandial effects of a bland meal after a bland diet (BAB), a chili meal after a bland diet (CAB), and a chili meal after a chili-containing diet (CAC) were evaluated. Serum insulin, C-peptide, and glucose concentrations and energy expenditure (EE) were measured at fasting and up to 120 min postprandially. RESULTS: Significant heterogeneity was observed between the meals for the maximum increase in insulin and the incremental area under the curve (iAUC) for insulin (P = 0.0002); the highest concentrations were with the BAB meal and the lowest with the CAC meal. When separated at the median BMI (26.3), the subjects with a BMI > or = 26.3 also showed heterogeneity in C-peptide, iAUC C-peptide, and net AUC EE (P < 0.02 for all); the highest values occurred after the BAB meal and the lowest after the CAC meal. Conversely, the C-peptide/insulin quotient (an indicator of hepatic insulin clearance) was highest after the CAC meal (P = 0.002). CONCLUSION: Regular consumption of chili may attenuate postprandial hyperinsulinemia.     

Genetic variants of the ADPRT, XRCC1 and APE1 genes and risk of cutaneous melanoma

Sunlight causes various kinds of DNA damage, including oxidative lesions that are removed effectively by the base excision repair (BER) pathway, in which ADPRT, XRCC1 and APE1 play a key role. However, genetic variation in these genes may alter their functions. We hypothesized that ADPRT, XRCC1 and APE1 polymorphisms are associated with risk of cutaneous melanoma (CM). In a hospital-based case-control study of 602 CM patients and 603 cancer-free control subjects frequency matched on age, sex and ethnicity, we genotyped for three non-synonymous single nucleotide polymorphisms (SNPs) (i.e. the ADPRT Val762Ala, XRCC1 Arg399Gln and APE1Asp148Glu) and assessed their associations with risk of CM. We found no significant difference in the allele frequencies between cases and controls for any of these three SNPs. However, we found that, compared with the APE1 Asp/Asp genotype, a significantly decreased risk of CM was associated with the APE1 Asp/Glu [adjusted odds ratio (OR), 0.60; 95% confidence interval (CI), 0.41-0.86], Glu/Glu (OR, 0.58; 95% CI, 0.38-0.88) and combined APE1 Asp/Glu+Glu/Glu (OR, 0.59; 95% CI, 0.42-0.83) genotypes, but not for other XRCC1 variant genotypes. Moreover, there was evidence for a possible gene-gene interaction between XRCC1 and APE1 variants in the association with risk of CM (P=0.030). We conclude that the APE1 Glu variant may have an effect or interact with XRCC1 in the etiology of CM or in linkage disequilibrium with other untyped protective alleles. Larger studies with more SNPs in the BER genes are needed to verify these findings.