Long-term results of paclitaxel in FIGO stage III ovarian carcinoma

The combination of platinum and paclitaxel is the standard treatment of advanced ovarian carcinoma; however, recent studies have questioned the actual role of the combination as compared to either of the two agents alone. We report an open-label, two-center, phase II study of upfront paclitaxel for patients with histological diagnosis of stage III ovarian carcinoma. Treatment consisted of paclitaxel at 175 mg/m2 administered in a 3-h infusion every 21 days. Response was evaluated after the third course by either laparoscopy or exploratory laparotomy. Patients with stable or progressive disease discontinued treatment, whereas responding patients continued treatment until a maximum of six courses. Response, toxicity, time to progression (TTP) and survival were evaluated. From November 1993 to December 1995, 30 patients were accrued. All patients underwent primary cytoreduction; 17 (57%) and 13 (43%) patients had residual tumors <2 and >2 cm, respectively. Of 27 patients evaluable, objective responses were seen in 18 (66.4%) (95% CI 49.5-83.2)--12 complete (45%) and six partial (22%). Four patients had stable disease (15%) and five (18%) patients progressed. A total of 149 courses were administered to 30 patients, median 4 (range 1-6). Grade 3/4 neutropenia was seen in 13% of courses, peripheral neuropathy, myalgia and arthralgia were frequent, but transitory and relieved with analgesics. At a median follow-up time of 44.5 months (0-99) the TTP and median survival were 16.6 and 43.1 months, respectively. We conclude that single-agent paclitaxel is an effective and well-tolerated first-line treatment for advanced ovarian carcinoma.     

Utilization of care during pregnancy in rural Guatemala: does obstetrical need matter?

This study examines factors associated with the use of biomedical care during pregnancy in Guatemala, focusing on the extent to which complications in an ongoing or previous pregnancy affect a woman's decisions to seek care. The findings, based on multilevel models, suggest that obstetrical need, as well as demographic, social, and cultural factors, are important predictors of pregnancy care. In contrast, measures of availability and access to health services have modest effects. The results also suggest the importance of unobserved variables–such as quality of care–in explaining women's decisions about pregnancy care. These results imply that improving proximity to biomedical services is unlikely to have a dramatic impact on utilization in the absence of additional changes that improve the quality of care or reduce barriers to access. Moreover, current efforts aimed at incorporating midwives into the formal health-care system may need to extend their focus beyond the modification of midwife practices to consider the provision of culturally appropriate, high-quality services by traditional and biomedical providers alike.     

Lung resistance-related protein as a predictor of clinical outcome in advanced testicular germ-cell tumours

This study was undertaken to investigate the expression and predictive value for outcome of multidrug resistance-associated (MDR) proteins P-glycoprotein (Pgp), MRP1, BCRP, and LRP, in advanced testicular germ-cell tumours (TGCT). Paraffin-embedded sections from 56 previously untreated patients with metastatic TGCT were immunostained for Pgp, MRP1, BCRP, and LRP. All patients received platinum-based chemotherapy after orchidectomy. Immunostaining was related to clinicopathological parameters, response to chemotherapy, and outcome. Strong and intermediate expressions of the different MDR-related proteins were: 27 and 41% (Pgp), 54 and 37% (MRP1), 86 and 7% (BCRP), and 14 and 29% (LRP). P-glycoprotein and MRP1 associated, respectively, to low AFP (P=0.026) and high LDH levels (P=0.014), whereas LRP expression associated with high beta-hCG levels (P=0.003) and stage IV tumours (P=0.029). No correlation was found between Pgp, MRP1, and BCRP expression and response to chemotherapy and survival. In contrast, patients with LRP-positive tumours (strong or intermediate expression) had shorter progression-free (P=0.0006) and overall survival (P=0.0116) than LRP-negative patients, even after individual log-rank adjustments by statistically associated variables. Our data suggest that a positive LRP immunostaining at the time of diagnosis in metastatic TGCT is associated with an adverse clinical outcome.     

Concentration of adipogenic and proinflammatory cytokines in the bone marrow supernatant fluid of osteoporotic women

Osteoporosis is characterized by low bone mass, microarchitectural deterioration of bone tissue leading to increased bone fragility, and a resulting susceptibility to fractures. Distinctive environmental bone marrow conditions appear to support the development and maintenance of the unbalance between bone resorption and bone formation; these complex bone marrow circumstances would be reflected in the fluid surrounding bone marrow cells. The content of regulatory molecules in the extracellular fluid from the human bone marrow is practically unknown. Since the content of cytokines such as adiponectin, leptin, osteoprogeterin (OPG), soluble receptor activator of nuclear factor κB ligand (s‐RANKL), tumor necrosis factor α, and interleukin 6 (IL‐6) may elicit conditions promoting or sustaining osteoporosis, in this work we compared the concentrations of the above‐mentioned cytokines and also the level of the soluble receptors for both IL‐6 and leptin in the extracellular fluid from the bone marrow of nonosteoporotic and osteoporotic human donors. A supernatant fluid (bone marrow supernatant fluid [BMSF]) was obtained after spinning the aspirated bone marrow samples; donors were classified as nonosteoporotic or osteoporotic after dual‐energy X‐ray absorptiometry (DXA) measuring. Specific commercially available kits were used for all measurements. The cytokines' concentration in BMSF showed differently among nonosteoporotic and osteoporotic women; this last group was characterized by higher content of proinflammatory and adipogenic cytokines. Also, osteoporotic BMSF differentiated by decreased leptin bioavailability, suggesting that insufficient leptin action may distinguish the osteoporotic bone marrow. © 2010 American Society for Bone and Mineral Research     

Nitric Oxide-Mediated Toxicity in Paraquat-Exposed SH-SY5Y Cells: A Protective Role of 7-Nitroindazole

The precise mechanism underlying the role of nitric oxide (NO) or nitric oxide synthases (NOSs) in paraquat-mediated toxicity is yet to be fully elucidated. The importance of the NADPH-diaphorase activity of NOSs in paraquat toxicity, in addition to the production of NO, has previously been reported as a mechanism of toxicity. However, other studies have highlighted the toxicity of NO alone and, conversely a protective role of NO in paraquat-mediated toxicity has also been described. The goal of this study was to clarify the involvement of NO and NOS in paraquat-mediated toxicity in an SH-SY5Y cell system, and to evaluate the putative role of 7-nitroindazole as a protective agent in human neural cells. Our results indicate that the three previously described isoforms of NOS are expressed in SH-SY5Y cells, with the data showing that these synthases act as paraquat diaphorases. While this process could occur at the expense of NO production, NO alone does play a toxic role, with its production leading to the formation of the toxicant peroxynitrite. Although the efficacies of the different inhibitors tested cannot be directly compared because the various NOS forms were probably inhibited to differing extents, the results support the idea that endogenous and inducible NO is a neurotoxic mediator of the effects of paraquat. The NADPH-diaphorase activity of NOS and NO production are therefore factors implicated in the toxicity mediated by the herbicide paraquat.     

Tratamiento radioterápico exclusivo en el carcinoma del pabellón auricular. Análisis de una serie de 104 casos

We assessed the role of the radiation therapy as the exclusive treatment of the epithelial tumours of the pinna, evaluating the control disease, the rate of late complications and the cosmetic results. One hundred and four patients with epidermoid carcinoma of the pinna and radical treatment with radiotherapy were analyzed retrospectively. 53 (51%) were squamous cell carcinoma and 51 (49%) basocelular carcinoma. Classification according to tumours size was as follows: ≤1 cm, 22 (21.2%); 1–2 cm, 47 (45.2%); 2–3 cm, 19 (18.3%), and >3 cm, 11 (10.6%). Eighty eight patients (84.6%) were treated with⁶⁰Co, 15 (14.4%) with ortovoltage and one patient with 9 MeV electron. The median follow up is 55 month (14–257). The local control, complication like condritis, condronecrosis and audition damage, and the cosmetic result were the factors analyzed. The 5 and 10 years actuarial local control rate is 89.8% and 87.6%, respectively. In an univariate analysis including variables like size, localization, histologic type, differentiation grade, energy type, irradiation technique, doses and response to treatment, the bad prognostic factors regarding to local control, were found to be the size (>3 cm) (p=0.013), localization (posterior sulcus) (p=0.012) and response to treatment (not complete) (p=0.046). In a multivariate analysis only the size showed this tendency (p=0.05). After the intent of rescue in the 11 patients that failed locally, the final local control rate was 95.19% (99/104). Four patients with squamous cell carcinoma had nodal regional recurrence, which didn't occur in the patients with basocelular carcinoma. Eight (7.7%) patients presented some degree of condritis, which was resolved medically in all the cases except one patient that evolved to condronecrosis. The cosmetic results in the 76 patients evaluated was excellent in 53 (69.7%) and acceptable in 12 (22.6%). Radiotherapy is recommended for treatment of the epithelial tumour of the pinna, mainly in tumors less than 3 cm, getting local control rate similar to surgery but avoiding its cosmetic and functional sequelae.     

Quercetin and naringenin reduce abnormal development of mouse embryos produced by hydroxyurea

Objectives There is limited evidence about the impact of quercetin and naringenin on embryonic development. The purpose of this work was to evaluate in vitro their direct teratogenic potential as well as their protective activity against teratogenesis mediated by oxidative damage on mouse embryos. Methods Quercetin and naringenin toxicity on whole mouse cultured embryos, as well as their ability to protect embryos against hydroxyurea‐induced insult were evaluated. Key findings Quercetin 100 µm and naringenin 300 µm produced significant reduction of developmental and growth parameters, in comparison with those of the control group. Embryos exposed to the concurrent administration of quercetin or naringenin with hydroxyurea (2 µm , 2 h) were significantly protected from growth and developmental retardation, and abnormalities induced by hydroxyurea. Interestingly, embryos exposed to hydroxyurea and dimethyl sulfoxide 0.1%, the vehicle employed to dissolve flavonoids, also showed significant damage amelioration. Conclusions These results indicate that quercetin and naringenin have not only a minor toxic effect on development, but also a protective effect against hydroxyurea‐induced embryonic damage.     

Radioimmune imaging of bone marrow in patients with suspected bone metastases from primary breast cancer

Radioimmune imaging of bone marrow was performed by technetium-99m- (99mTc) labeled antigranulocyte monoclonal antibody BW 250/183 (AGMoAb) scans in 32 patients with suspected bone metastases from primary breast cancer. AGMoAb scans showed bone marrow defects in 25/32 (78%) patients; bone invasion was subsequently confirmed in 23 (72%) patients. Conventional bone scans performed within the same week detected bone metastases in 17/32 (53%) patients (p less than 0.001). AGMoAb scans detected more sites indicating metastatic disease than bone scans in 12 of these 17 patients (71%). All patients with bone metastases in the axial skeleton had bone marrow defects at least at the sites of bone metastases. Of 15 patients with normal, or indicative of, benign disease bone scans, 8 patients (53%) presented with bone marrow defects in the AGMoAb scans. Bone invasion was confirmed in six of them. AGMoAb bone marrow scans provide a method for the early detection of bone metastatic invasion in patients with breast cancer and suspected bone metastases.     

Quantitative morphometry of electrophysiologically identified CA3b interneurons reveals robust local geometry and distinct cell classes

The morphological and electrophysiological diversity of inhibitory cells in hippocampal area CA3 may underlie specific computational roles and is not yet fully elucidated. In particular, interneurons with somata in strata radiatum (R) and lacunosum‐moleculare (L‐M) receive converging stimulation from the dentate gyrus and entorhinal cortex as well as within CA3. Although these cells express different forms of synaptic plasticity, their axonal trees and connectivity are still largely unknown. We investigated the branching and spatial patterns, plus the membrane and synaptic properties, of rat CA3b R and L‐M interneurons digitally reconstructed after intracellular labeling. We found considerable variability within but no difference between the two layers, and no correlation between morphological and biophysical properties. Nevertheless, two cell types were identified based on the number of dendritic bifurcations, with significantly different anatomical and electrophysiological features. Axons generally branched an order of magnitude more than dendrites. However, interneurons on both sides of the R/L‐M boundary revealed surprisingly modular axodendritic arborizations with consistently uniform local branch geometry. Both axons and dendrites followed a lamellar organization, and axons displayed a spatial preference toward the fissure. Moreover, only a small fraction of the axonal arbor extended to the outer portion of the invaded volume, and tended to return toward the proximal region. In contrast, dendritic trees demonstrated more limited but isotropic volume occupancy. These results suggest a role of predominantly local feedforward and lateral inhibitory control for both R and L‐M interneurons. Such a role may be essential to balance the extensive recurrent excitation of area CA3 underlying hippocampal autoassociative memory function. J. Comp. Neurol. 515:677–695, 2009. © 2009 Wiley‐Liss, Inc.     

Potentiation of des-Arg9-kallidin-induced vasoconstrictor responses by metallopeptidase inhibition in isolated human umbilical artery

Several metallopeptidases have been reported to be involved in bradykinin (BK) B(1) receptor agonist metabolism. Our goal was to evaluate in vitro roles of metallopeptidases [e.g., neutral endopeptidase (NEP), aminopeptidase M (APM), and angiotensin-converting enzyme (ACE)] as functional inactivators of the selective BKB(1) receptor agonist Lys-des-Arg(9)-BK (DAKD) in isolated human umbilical artery (HUA) rings. Concentration-response curves (CRCs) to DAKD were performed after a 5-h incubation period. Treatment with 10 microM phosphoramidon (NEP inhibitor) or 10 microM amastatin (APM inhibitor) potentiated DAKD-elicited responses, whereas 1 microM captopril (ACE inhibitor) had no significant effects. However, when the three enzymes were simultaneously inhibited, a significant potentiation over responses obtained under concurrent NEP and aminopeptidase M inhibition was observed. In contrast, responses induced by the peptidase resistant BKB(1) receptor agonist Sar-D-Phe(8)-des-Arg(9)-BK were not modified by triple peptidase inhibition. In addition, endothelial denudation failed to alter DAKD-induced responses in HUA. Finally, in the presence of NEP, ACE, and APM inhibition, Lys-des-Arg(9)-[Leu(8)]-BK, the potent BKB(1) receptor antagonist, produced a parallel, concentration-dependent, rightward shift of DAKD CRCs. The obtained pK(B) (8.57) and the Schild slope not different from unity are in agreement with an interaction at a single homogeneous BKB(1) receptor population. In summary, this work constitutes the first pharmacological evidence that metallopeptidases NEP, APM, and ACE represent a relevant inactivation mechanism of the endogenous BKB(1) receptor agonist DAKD in isolated HUA.