Use of antifungal Saponin SC-2 of Solanum chrysotrichum for the treatment of vulvovaginal candidiasis: in vitro studies and clinical experiences

Saponin SC-2 from Solanum chrysotrichum showed antifungal activity, demonstrated in vitro, which inhibited the growth of dermatophytes, and in vivo, to be effective in the treatment against tinea pedis and pityriasis capitis. Fungistatic and fungicidal activity of saponin SC-2 on Candida albicans and other Candida species, fluconazole and ketoconazole resistaent strains was demostrated. SC-2-associated ultrastructural alterations in several Candida species were observed. An exploratoryclinical, randomized, double-blind, and controlled ketoconazole study of ketoconazole was conducted with the aim of assessing the effectiveness and tolerability of an herbal medicinal product containing SC-2, on women with Vulvovaginal candidiasis (VVC). The results exhibited a percentage of therapeutic clinical effectiveness similar to that of ketoconazole (X2, p .0.30), but obtained a smaller percentage of mycological effectiveness, and 100% tolerability. In conclusion, saponin SC-2 possesses fungicidale and fungistatic activity on Candida albicans and other multi resistant Candida species, causes morphological changes and fungal death, and it is an alternative therapy for the treatment of VVC.Key words: Solanum chrysotrichum, saponins, antifungal activity, vulvovaginal candidiasis, alternative therapy

Social Cohesion, Structural Holes, and a Tale of Two Measures

EMBARGOED - author can archive pre-print or post-print on any open access repository after 12 months from publication. Publication date is May 2013 so embargoed until May 2014.This is an author’s accepted manuscript (deposited at arXiv arXiv:1211.0719v2 [physics.soc-ph] ), which was subsequently published in Journal of Statistical Physics May 2013, Volume 151, Issue 3-4, pp 745-764. The final publication is available at link.springer.com http://link.springer.com/article/10.1007/s10955-013-0722-

First-Trimester Follistatin-Like-3 Levels in Pregnancies Complicated by Subsequent Gestational Diabetes Mellitus

Objective: To determine whether maternal levels of follistatin-like-3 (FSTL3), an inhibitor of activin and myostatin involved in glucose homeostasis, are altered in the first trimester of pregnancies complicated by subsequent gestational diabetes mellitus (GDM). Research Design and Methods: This was a nested case-control study of subjects enrolled in a prospective cohort of pregnant women with and without GDM ($\geq$2 abnormal values on a 100-g glucose tolerance test at ~28 weeks of gestation). We measured FSTL3 levels in serum collected during the first trimester of pregnancy. Logistic regression analyses were used to determine the risk of GDM. Results: Women who developed GDM (n = 37) had lower first-trimester serum levels of FSTL3 compared with women who did not (n = 127) (median 10,789 [interquartile range 7,013-18,939] vs. 30,670 [18,370-55,484] pg/ml, P < 0.001). When subjects were divided into tertiles based on FSTL3 levels, women with the lowest levels demonstrated a marked increase in risk for developing GDM in univariate (odds ratio 11.2 [95% CI 3.6-35.3]) and multivariate (14.0 [4.1-47.9]) analyses. There was a significant negative correlation between first-trimester FSTL3 levels and ~28-week nonfasting glucose levels (r = -0.30, P < 0.001). Conclusions: First-trimester FSTL3 levels are associated with glucose intolerance and GDM later in pregnancy

Poorly differentiated neuroendocrine larynx carcinoma: Clinical features and mirnas signature—a new goal for early diagnosis and therapy?

Laryngeal neuroendocrine carcinomas (LNECs) are rare and highly heterogeneous malignancies presenting a wide range of pathological and clinical manifestations. Herein, we retrospectively characterize ten patients diagnosticated with LNEC, five of which were defined as well‐moderately differentiated neuroendocrine carcinomas, and five that were defined as poorly differentiated neuroendocrine carcinomas, according to the latest WHO classification. Clinical features were analyzed and compared between the two subgroups together with a microRNA study which evidenced a peculiar signature likely related to poorly differentiated larynx neuroendocrine carcinomas. These findings may offer new useful insights for clinicians to improve diagnosis efficiency, therapy response, and patients’ outcome for this aggressive neoplasm

Phase II study of sequential hormonal therapy with anastrozole/exemestane in advanced and metastatic breast cancer

Hormonal therapy is the preferred systemic treatment for recurrent or metastatic, post-menopausal hormone-receptor-positive breast cancer. Previous studies have shown that there is no cross-resistance between exemestane and reversible aromatase inhibitors. Exposure to hormonal therapy does not hamper later response to chemotherapy. Patients with locally advanced or metastatic, hormonal receptor positive or unknown, breast cancer were treated with oral anastrozole, until disease progression, followed by oral exemestane until new evidence of disease progression. The primary end point of the study was clinical benefit, defined as the sum of complete responses (CR), partial responses (PR) and > 24 weeks stable disease (SD). In all, 100 patients were enrolled in the study. Anastrozole produced eight CR and 19 PR for an overall response rate of 27% (95% CI: 18.6-36.8%). An additional 46 patients had long-term (> 24 weeks) SD for an overall clinical benefit of 73% (95% CI: 63.2-81.4). Median time to progression (TTP) was 11 months (95% CI: 10-12). A total of 50 patients were evaluated for the second-line treatment: exemestane produced one CR and three PR; 25 patients had SD which lasted ≥ 6 months in 18 patients. Median TTP was 5 months. Toxicity of treatment was low. Our study confirms that treatment with sequential hormonal agents can extend the period of time during which endocrine therapy can be used, thereby deferring the decision to use chemotherapy. © 2005 Cancer Research UK

Cefuroxime Pharmacokinetics in Pediatric Cardiovascular Surgery Patients Undergoing Cardiopulmonary Bypass

Objectives The objective of this study was to determine the pharmacokinetics of cefuroxime in children undergoing cardiopulmonary bypass (CPB) for cardiovascular surgery. Design A prospective study. Setting A tertiary pediatric teaching hospital. Participants Infants and children undergoing CPB were enrolled in the study. Intervention An initial dose (mean, 24.2 ± 1.6 mg/kg) of cefuroxime was administered before surgical incision, and a second dose (mean, 14.4 ± 7.9 mg/kg) was administered in the CPB prime solution. Serial blood samples were obtained before, during, and after the CPB process. Samples were shipped on dry ice to the analytic laboratory and concentrations determined by a validated high-performance liquid chromatography method. A 2-compartment pharmacokinetic model was fitted to the data using maximum a priori–Bayesian estimation, with weight as a covariate. Monte Carlo simulations of a single-dose (25 mg/kg pre-CPB) approach and a 2-dose (25 mg/kg pre- and 12.5-mg/kg prime solution dose) approach were performed. Measurements and Main Results Fifteen subjects (9 males/6 females) were enrolled in the study, with median (range) age and weight of 11 (3-34) months and 9.5 (4.5-15.4) kg, respectively. The median (range) duration of CPB was 136 (71-243) minutes. Median and range cefuroxime pharmacokinetic parameters were as follows: maximum concentration (Cmax) dose, 1: 328 (150-512) μg/mL; systemic clearance, 0.050 (0.041-0.058) L/h/kg; steady-state volume of distribution, 0.213 (0.081-0.423) L/kg; volume of distribution in the central compartment, 0.081 (0.046-0.162) L/kg; and elimination half-life, 3.76 (1.03-6.81) hours. The median 8-hour post–dose-simulated cefuroxime concentrations were 26.5 and 16.0 mg/L for the 2-dose and single-dose regimens, respectively. Conclusion Manufacturers recommend that pediatric doses of cefuroxime (25-50 mg/kg) can be used in infants and children undergoing CPB to maintain adequate serum concentrations for surgical-site infection prophylaxis. A second intraoperative dose, administered through the CPB circuit, provides no additional prophylactic advantage

Paclitaxel, vinorelbine and 5-fluorouracil in breast cancer patients pretreated with adjuvant anthracyclines

We investigated the activity and toxicity of a combination of vinorelbine (VNB), paclitaxel (PTX) and 5-fluorouracil (5-FU) continuous infusion administered as first-line chemotherapy in metastatic breast cancer patients pretreated with adjuvant anthracyclines. A total of 61 patients received a regimen consisting of VNB 25 mg m−2 on days 1 and 15, PTX 60 mg m−2 on days 1, 8 and 15 and continuous infusion of 5-FU at 200 mg m−2 every day. Cycles were repeated every 28 days. Disease response was evaluated by both RECIST and World Health Organization (WHO) criteria. Objective responses were recorded in 39 of 61 patients (64.0%) assessed by WHO and in 36 of 50 patients (72.0%) assessable by RECIST criteria. Complete remission occurred in 15 (24.6%) and 14 patients (28.0%), respectively. The median time to progression and overall survival of entire population was 10.6 and 27.3 months, respectively, and median duration of complete response was 14.8 months. The dose-limiting toxicity was myelosuppression (leucopenia grade 3/4 in 52.5% of patients). Grade 3/4 nonhaematologic toxicities included mucositis/diarrhoea in 13.1%, skin in 3.3% and cardiac in 1.6% of patients. Grade 2/3 neurotoxicity was observed in five patients (7.2%). The VNB, PTX and 5-FU continuous infusion combination regimen was active and manageable. Complete responses were frequent and durable

Agrin Binds BMP2, BMP4 and TGFβ1

The C-terminal 95 kDa fragment of some isoforms of vertebrate agrins is sufficient to induce clustering of acetylcholine receptors but despite two decades of intense agrin research very little is known about the function of the other isoforms and the function of the larger, N-terminal part of agrins that is common to all isoforms. Since the N-terminal part of agrins contains several follistatin-domains, a domain type that is frequently implicated in binding TGFβs, we have explored the interaction of the N-terminal part of rat agrin (Agrin-Nterm) with members of the TGFβ family using surface plasmon resonance spectroscopy and reporter assays. Here we show that agrin binds BMP2, BMP4 and TGFβ1 with relatively high affinity, the KD values of the interactions calculated from SPR experiments fall in the 10−8 M–10−7 M range. In reporter assays Agrin-Nterm inhibited the activities of BMP2 and BMP4, half maximal inhibition being achieved at ∼5×10−7 M. Paradoxically, in the case of TGFβ1 Agrin N-term caused a slight increase in activity in reporter assays. Our finding that agrin binds members of the TGFβ family may have important implications for the role of these growth factors in the regulation of synaptogenesis as well as for the role of agrin isoforms that are unable to induce clustering of acetylcholine receptors. We suggest that binding of these TGFβ family members to agrin may have a dual function: agrin may serve as a reservoir for these growth factors and may also inhibit their growth promoting activity. Based on analysis of the evolutionary history of agrin we suggest that agrin's growth factor binding function is more ancient than its involvement in acetylcholine receptor clustering