Fetal blood-brain barrier P-glycoprotein contributes to brain protection during human development

During brain development and blood-brain barrier (BBB) differentiation the expression of P-glycoprotein (P-gp) may complement the protective function of the placental barrier against xenobiotic substances. To establish an immunohistochemical procedure for P-gp detection, different anti-P-gp monoclonal antibodies were first tested on a fibrosarcoma cell line and colonic carcinoma tissue. The protocol was then tested on adult human brains as a BBB-P-gp tissue-specific control and for double labeling with anti-P-gp and the astroglia marker glial fibrillary acidic protein (GFAP). The protocol was then used to analyze the expression and localization of P-gp in human fetuses during cerebral cortex formation. At the earliest examined stage, 12 weeks of gestation (wg), P-gp was detectable as diffuse cytoplasmic labeling of the endothelial cells lining the primary cortex microvessels. At 18 wg, a punctate P-gp staining pattern was detected on cortex and subcortical vessels and on their side branches. At 22 wg, P-gp staining was linear and concentrated on endothelial cell membranes. In all examined ages, GFAP-positive radial glial cells and astrocytes did not stain for P-gp, even at their perivascular processes, whereas faint P-gp labeling was seen on vimentin-reactive radial glia at the earliest examined fetal age. At midgestation, P-gp colocalized with caveolin-pY14 on the abluminal endothelial cell membrane. These results demonstrate that P-gp is expressed early during human cerebral cortical microvessel development, and suggest that at midgestation there may be efflux activity that is regulated by interactions with the caveolar endothelial cell compartment.     

High level of messenger RNA for BRMS1 in primary breast carcinomas is associated with poor prognosis

BRMS1 is regarded as a metastasis suppressor gene for its ability to reduce metastatic potential of human and murine breast cancer cells as well as human melanoma cells. However, BRMS1 association to human tumor progression is not clearly understood. In the present study we analyzed BRMS1 mRNA expression in tumor progression and its potential prognostic value for breast carcinoma. BRMS1 mRNA expression level was quantified by real-time PCR in 47 tumoral, in 14 peritumoral and in 15 metastatic microdissected cellular populations from 47 breast cancer patients with 10-year follow up. We found BRMS1 expression to be higher in carcinoma cells than in matching normal epithelial cell populations in 10 out of 14 cases (p = 0.0005), while lymph-nodal carcinoma cells showed lower BRMS1 expression in 9 out of 15 cases (p = 0.001). Using both in vivo (human mammary breast carcinomas) and in vitro systems (breast cancer cell lines) we were able to demonstrate that BRMS1 overexpression was not a bias effect induced by cell proliferation rate. BRMS1 expression levels did not correlate with standard breast cancer prognostic factors but BRMS1 higher expression was associated with patient shorter disease-free and overall survival. Our findings are apparently inconsistent with the concept of BRMS1 as a metastasis suppressor gene. One possible explanation is that epithelial cells increase their BRMS1 expression as a compensatory response to tumor formation or metastasis progression, which is elevated in proportion to tumor aggressiveness, whereas those cells of the primary tumor that cannot upregulate BRMS1 escape to form metastasis.     

Novel types of polysaccharidic assemblies

New types of polysaccharidic assemblies based on chitosan and uncharged or charged derivatives of scleroglucan are presented. Macroscopic assemblies having a spherical skinlike shape were prepared by controlled mixing of two polyelectrolyte solutions. Hydrogels based exclusively on the above natural derivatized polysaccharides crosslinked via simple chemical processes, avoiding the use of extraneous reticulating agents and organic solvents, are also described. These biocompatible materials may, eventually, be used in drug release formulations or for the incapsulation of bioactive macromolecules. The interesting possibility exists to study the micelle formation of amphiphiles within the spherical skins.     

A phase II trial of paclitaxel (Taxol®) as first line treatment in advanced breast cancer

Summary Paclitaxel (Taxol®) is a natural product with a broad spectrum of activity against various solid tumors. This report includes nineteen patients with advanced breast cancer who have not previously received chemotherapy for metastatic disease. Fifteen patients had received adjuvant chemotherapy, eight of which were doxorubicin based. Patients were treated with 135 mg/m² over 24 hours by continuous infusion given every 21 days. There were 2 complete and 4 partial responses for an objective response rate of 32% (95% C.I.: 14%, 57%) and eight patients or 42% with stable disease. Three of eight patients (38%) who had received adjuvant doxorubicin did respond to paclitaxel. Responses occurred in lung, liver, and soft tissue. The primary toxicity was hematologic with 13 hospitalizations for febrile neutropenia in 180 cycles (7%). Paclitaxel has moderate activity in a small number of patients with metastatic breast cancer at the dose of 135 mg/m² over 24 hours in this study.     

Dietary Exposure to Tebuconazole Affects Testicular and Epididymal Histomorphometry in Frugivorous Bats

This study evaluated the effects of a commercially recommended concentration (1 mL/L) of a fungicide tebuconazole (TBZ) on testicular and epididymal histomorphometry of Artibeus lituratus, following 7 and 30-day oral exposure. TBZ30 bats showed a reduction in the percentage of tubules and seminiferous epithelium, as well as a decrease in tubule and epithelium somatic indexes, and tubular diameter. Inversely, these animals showed increased percentage of intertubular compartment, Leydig cells and blood vessels. The volume of Leydig cells and their number per gram of testis also increased in TBZ30 bats. Alterations in epididymal morphometry were observed in all regions of the organ, with increase of ductal diameter in both exposure times. These results indicate that exposure to low concentration of TBZ resulted in testicular and epididymal morphometric changes in fruit bats, mainly at 30-day exposure, suggesting that functional alterations might be occurring in these organs and impacting reproductive capacity.     

Incidence of type 1 and type 2 diabetes in adults aged 30-49 years: the population-based registry in the province of Turin, Italy

OBJECTIVE: Incidence of type 1 diabetes is considered to be low in adults, but no study has been performed in Mediterranean countries. RESEARCH DESIGN AND METHODS: We extended the study base of the registry of the province of Turin, Italy, to subjects aged 30-49 years in the period 1999-2001 to estimate the incidences of type 1 and type 2 diabetes. Diagnosis of type 1 diabetes was based on permanent insulin treatment or a fasting C-peptide level < or =0.20 nmol/l or islet cell (ICA) or GAD (GADA) antibody positivities. RESULTS: We identified 1,135 case subjects with high completeness of ascertainment (99%), giving an incidence rate of 58.0 per 100,000 person-years (95% CI 54.7-61.5). The incidence of type 1 diabetes was 7.3 per 100,000 person-years (6.2-8.6), comparable with the rates in subjects aged 0-14 and 15-29 years (10.3 [9.5-11.2] and 6.8 [6.3-7.4]). Male subjects had a higher risk than female subjects for both type 1 (rate ratio [RR] 1.70 [95% CI 1.21-2.38]) and type 2 (2.10 [1.84-2.40]) diabetes. ICA and/or GADA positivities were found in 16% of the cohort. In logistic regression, variables independently associated with autoimmune diabetes were age 30-39 years (odds ratio [OR] 2.39 [95% CI 1.40-4.07]), fasting C-peptide <0.60 nmol/l (3.09 [1.74-5.5]), and BMI <26 kg/m2 (2.17 [1.22-3.85]). CONCLUSIONS: Risk of type 1 diabetes between age 30 and 49 years is similar to that found in the same area between age 15 and 29 years. Further studies are required to allow geographical comparisons of risks of both childhood and adulthood autoimmune diabetes, the latter being probably higher than previously believed.     

Treatment and control of arterial hypertension in a rural community in Ecuador

Cardiovascular diseases are widespread in developing countries, but little is known about cardiovascular risk profiles in rural communities. To assess the importance of arterial hypertension in a rural district of Ecuador, we screened 4284 of the 8876 adults who lived in the area. 1542 (36%) individuals had hypertension, only four (0.3%) of whom were well controlled by treatment. We monitored all deaths for 2.5 years, and noted that cardiovascular diseases were the primary cause of death in the adult population. Furthermore, of the individuals who died of a cardiovascular disease, four out of five had a history of hypertension. Our findings indicate that in this rural area of Ecuador the high prevalence of uncontrolled hypertension is a major cause of total mortality.