Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Epidemiological data show that reproductive and hormonal factors are involved in the etiology of endometrial cancer, but there is little data on the association with endogenous sex hormone levels. We analyzed the association between prediagnostic serum concentrations of sex steroids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition using a nested case-control design of 247 incident endometrial cancer cases and 481 controls, matched on center, menopausal status, age, variables relating to blood collection, and, for premenopausal women, phase of menstrual cycle. Using conditional regression analysis, endometrial cancer risk among postmenopausal women was positively associated with increasing levels of total testosterone, free testosterone, estrone, total estradiol, and free estradiol. The odds ratios (ORs) for the highest versus lowest tertile were 2.66 (95% confidence interval (CI) 1.50-4.72; P=0.002 for a continuous linear trend) for estrone, 2.07 (95% CI 1.20-3.60; P=0.001) for estradiol, and 1.66 (95% CI 0.98-2.82; P=0.001) for free estradiol. For total and free testosterone, ORs for the highest versus lowest tertile were 1.44 (95% CI 0.88-2.36; P=0.05) and 2.05 (95% CI 1.23-3.42; P=0.005) respectively. Androstenedione and dehydroepiandrosterone sulfate were not associated with risk. Sex hormone-binding globulin was significantly inversely associated with risk (OR for the highest versus lowest tertile was 0.57, 95% CI 0.34-0.95; P=0.004). In premenopausal women, serum sex hormone concentrations were not clearly associated with endometrial cancer risk, but numbers were too small to draw firm conclusions. In conclusion, relatively high blood concentrations of estrogens and free testosterone are associated with an increased endometrial cancer risk in postmenopausal women.     

Tratamiento del dolor anal por patología anorrectal aguda en urgencias: ¿baños de asiento con agua fría o caliente? resultados de un ensayo clínico aleatorizado

IntroductionThe popular belief advocates the use of sitz (sitting) baths with cold water for the treatment of acute anal pain, but clinical practice guides recommend the use of hot water for its known effect on the at-rest anal pressure.AimThe objective of the study was to examine the analgesic effect on the quality of life, manometer data and clinical progress, of the two temperatures in sitz baths in patients with anal pain.Material and methodsA randomised clinical trial on patients with acute anal pain due to haemorrhoids or anal fissures, divided into Group 1: Sitz baths with water at a temperature of less than 15 °C, and Group 2: Baths with a water temperature above 30 °C. The analgesia was the same in both groups. An analysis was made of the pain at 7 days (visual analogue scale), quality of life (SF-36), anal at-rest pressure and disease progress.ResultsOf the 27 eligible patients, 24 were randomised (Group 1: n=12 y Group 2: n=12). There were no statistical differences in pain, but it remained stable in Group 1, but gradually decreased in the patients of Group 2, the difference being in the pain scores on the first day compared to the seventh in Group 2 (p=0.244). The rest of the variables were similar.ConclusionThere were no statistically significant differences in pain control from day 1 to day 7 in the Group with sitz baths with hot water.(ISRCTN Number: 50105150).     

Immunoglobulin therapy to control lung damage in patients with common variable immunodeficiency

BACKGROUND: Lung damage progression is the most frequent condition in patients with common variable immunodeficiency (CVID). Appropriate immunoglobulin dose adjustments and follow-up guidelines to evaluate this have not been well established. Objective: To assess the evolution of lung damage once stable residual serum levels of IgG over 600 mg/dl had been achieved. METHODS: A prospective study was conducted in 24 adult patients consecutively diagnosed with CVID, with no previous intravenous immunoglobulin (IVIG) treatment. IVIG dose, total serum IgG level, bacterial infection rate, pulmonary function tests (PFTs) and high resolution computed tomography (HRCT) of the thorax were monitored over 2 years. Moreover, outcome data were determined by measurement of chronic pulmonary disease (CPD). RESULTS: IVIG dose variability (205-372 mg/kg/21 days) to obtain the required serum IgG levels was determined. Patients with CPD needed higher doses than those without CPD (p=0.045). A significant reduction in severe and mild infections/patient-year was observed during treatment. Overall, there were no changes in PFTs and HRCT scores in patients without CPD, but both improved in patients with CPD. An increase of over 15% in overall HRCT score was detected in two patients without evidence of impairment in either clinical status or PFT values. CONCLUSIONS: Residual levels of total IgG over 600 mg/dl may help prevent progression of lung damage in patients with CVID. Levels of IgG, clinical manifestations and PFTs seem sufficient for routine follow-up. HRCT examination of the thorax, at least biennially, may help to identify patients in whom lung injury is progressing even though they may remain symptom-free and with stable PFTs.     

Euphopubescenol and euphopubescene, two new jatrophane polyesters, and lathyrane-type diterpenes from Euphorbia pubescens

The structures of euphopubescenol and euphopubescene, two new macrocyclic jatrophane diterpene polyesters, isolated from the whole dried plant of Euphorbia pubescens, were established as 5alpha,8alpha,15beta-triacetoxy-3alpha-benzoyloxy -4alpha-hydroxy -9,14-dioxo-13beta H-jatropha-6(17),11 E-diene ( 1) and 3beta,7beta,8beta,9alpha,14alpha,15beta-hexaacetoxy-2beta H-jatropha-5 E,11 E-diene ( 2) by 1D- and 2D-NMR (COSY, HMQC, HMBC and NOESY), IR, EI-MS and EI-FTICR-MS. Two known lathyrane derivatives, jolkinol A ( 3) and jolkinol A ( 4), whose (13)C-NMR spectra were assigned, were also isolated. Compounds 1 - 3 have been evaluated for their ability to inhibit the in vitro growth of three human tumour cell lines representing different tumour types, MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and SF-268 (CNS cancer). They inhibited both MCF-7 and NCI-H460 cell lines, with GI50 values ranging between 40.9 microM and 95.3 microM, but were found to be ineffective as growth inhibitors of the SF-268 cell line.     

Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial

Background

Imatinib, given concurrently or alternating with chemotherapy, has improved the response and survival of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) but relapses are still frequent. The aim of this study was to evaluate the feasibility and results of giving imatinib concurrently with intensive chemotherapy, stem cell transplantation and post-transplant imatinib maintenance therapy in patients with newly diagnosed Ph⁺ ALL.

Design and Methods

This was a phase II study of patients with newly diagnosed Ph⁺ ALL given standard chemotherapy, together with imatinib (400 mg/day) until stem cell transplantation, followed by imatinib maintenance therapy for all patients regardless of the molecular status of the disease.

Results

Of the 30 patients included, 27 (90%) achieved complete remission, one was resistant to treatment and two died during induction therapy. The percentages of major and complete molecular responses were 86% and 21% after induction, and 81% and 65% after consolidation, respectively. Similar results were observed assessing minimal residual disease by flow cytometry. Of the 27 patients who achieved complete remission, 21 underwent stem cell transplantation (16 allogeneic, 5 autologous). Imatinib (400 mg/day) could be administered after transplantation for a median of 3.9 months in 12 patients, although it was interrupted in 10 patients (in 2 cases because of side effects of the drug). Nine patients relapsed, four before and five after stem cell transplantation and eight patients died of transplant-related causes. With a median follow-up of 4.1 years, the probabilities (95% CI) of disease-free and overall survival were 30% (15% to 45%) and 30% (16% to 45%), respectively.

Conclusions

These results confirm that imatinib is an effective first-line treatment for adult Ph⁺ ALL when given concurrently with chemotherapy, making stem cell transplantation feasible in a high proportion of patients. However, post-transplantation imatinib administration was limited, mainly because of transplantation-derived complications rather than drug-specific toxicity.     

Inhibition of efflux pumps in methicillin-resistant Staphylococcus aureus and Enterococcus faecalis resistant strains by triterpenoids from Momordica balsamina

Six cucurbitane-type triterpenoids (1-6) isolated from the aerial parts of Momordica balsamina were evaluated for their ability to inhibit the activity of bacterial efflux pumps of methicillin-resistant Staphylococcus aureus (MRSA) COL(OXA), Enterococcus faecalis ATCC 29212, Salmonella enterica subsp. I serovar Typhimurium 5408 and S. Typhimurium 5408CIP strains. The latter strain overproduces the AcrB transporter of the AcrAB-TolC efflux pump six-fold compared with its parent. Compounds 4-6 were also tested for similar activity against Escherichia coli AG100 wild-type strain and E. coli AG100TET8 that overproduces the AcrAB-TolC efflux pump. Evaluation of efflux activity was performed using a semi-automated method that measures accumulation of the universal efflux pump substrate ethidium bromide (EtBr). Some of the compounds significantly inhibited efflux of EtBr by MRSA COL(OXA) and E. faecalis ATCC 29212. A correlation between activity and the topological polar surface area of the compounds was found for MRSA COL(OXA).     

Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis

Neural stem cells (NSCs) are slowly dividing astrocytes that are intimately associated with capillary endothelial cells in the subventricular zone (SVZ) of the brain. Functionally, members of the vascular endothelial growth factor (VEGF) family can stimulate neurogenesis as well as angiogenesis, but it has been unclear whether they act directly via VEGF receptors (VEGFRs) expressed by neural cells, or indirectly via the release of growth factors from angiogenic capillaries. Here, we show that VEGFR-3, a receptor required for lymphangiogenesis, is expressed by NSCs and is directly required for neurogenesis. Vegfr3:YFP reporter mice show VEGFR-3 expression in multipotent NSCs, which are capable of self-renewal and are activated by the VEGFR-3 ligand VEGF-C in vitro. Overexpression of VEGF-C stimulates VEGFR-3-expressing NSCs and neurogenesis in the SVZ without affecting angiogenesis. Conversely, conditional deletion of Vegfr3 in neural cells, inducible deletion in subventricular astrocytes, and blocking of VEGFR-3 signaling with antibodies reduce SVZ neurogenesis. Therefore, VEGF-C/VEGFR-3 signaling acts directly on NSCs and regulates adult neurogenesis, opening potential approaches for treatment of neurodegenerative diseases.     

Recurrent ATP1A2 mutations in Portuguese families with familial hemiplegic migraine

Familial hemiplegic migraine is a rare autosomal dominant subtype of migraine with aura. Three genes have been identified, all involved in ion transport. There is considerable clinical variation associated with FHM mutations. Genotype–phenotype correlation studies are needed, but are challenging mainly because the number of carriers of individual mutations is low. One exception is the recurrent T666M mutation in the FHM1 CACNA1A gene that was identified in almost one-third of FHM families and showed variable associated clinical features and severity, both within and among FHM families. Similar studies in the FHM2 ATP1A2 gene have not been performed because of the low number of carriers with individual mutations. Here we report on the recurrence of ATP1A2 mutations M731T and T376M that affect sodium–potassium pump functioning in two Portuguese FHM families. Considerably increasing the number of mutation carriers with these mutations indicated a clear genotype–phenotype correlation: both mutations are associated with pure FHM. In addition, we show that recurrent mutations for ATP1A2 are more frequent than previously thought, which has implications for genotype–phenotype correlations and genetic testing.     

Euphoportlandols A and B, tetracylic diterpene polyesters from Euphorbia portlandica and their anti-MDR effects in cancer cells

Two new tetracyclic diterpene polyesters, euphoportlandols A (1) and B (2), have been isolated along with 12 known tetracyclic triterpenes from an acetone extract of Euphorbia portlandica. Their structures were established as 5alpha,11alpha,14alpha,17-tetraacetoxy-3beta-benzoyloxy-6beta,15beta-dihydroxy-9-oxoseget-8(12)-ene (1) and 5alpha,11alpha,14alpha,17-tetraacetoxy-3beta-benzoyloxy-6beta,15beta-dihydroxy-9-oxosegetane (2), respectively, by spectroscopic data interpretation. Compounds 1 and 2 were evaluated for their ability to inhibit multidrug resistance in cancer cells. Both compounds were found to be inhibitors of P-glycoprotein activity.