Prevention of Mrp2 activity impairment in ethinylestradiol-induced cholestasis by ursodeoxycholate in the rat.

Ethinylestradiol (EE) induces cholestasis by affecting bile salt-dependent and -independent fractions of the bile flow. The decrease in bile salt-independent flow is thought to be due, in part, to a reduction in the expression of the canalicular transporter Mrp2. The impact of modulation of Mrp2 function by sodium ursodeoxycholate (UDC) in EE cholestasis is unknown. We evaluated the protective effect of UDC on EE-induced impairment of Mrp2 activity in vivo and in isolated hepatocytes, by using the substrate dinitrophenyl S-glutathione (DNP-SG). EE was administered to male Wistar rats at a dose of 5 mg/kg s.c. for 5 days. UDC was coadministered with EE at a dose of 25 mg/kg b.wt. i.p. for the same period. EE alone reduced DNP-SG biliary excretion by 55% when compared with controls. Coadministration with UDC partially restored the alteration. Secretion rate of DNP-SG was decreased by 30% in isolated hepatocytes from EE-treated rats, but, contrary to in vivo results, UDC coadministration did not restore DNP-SG transport, likely as a consequence of bile salt washout resulting from the isolation procedure. As a confirmation, tauroursodeoxycholate hepatocyte preloading significantly increased Mrp2 activity. Western blotting analysis of Mrp2 indicated that EE administration significantly reduced its level in total and plasma membranes and that UDC coadministration failed to revert this alteration. In conclusion, UDC improvement in Mrp2 transport activity in vivo likely derived from a direct enhancement of Mrp2 function rather than from a restoration of its expression levels. This provides a novel mechanism explaining the beneficial effects of UDC in EE-induced cholestasis.     

Evaluation of a spinal needle locking device for use with the combined spinal epidural technique

Success of the 'needle-through-needle' technique for combined spinal epidural analgesia requires the immobilisation of the spinal needle during intrathecal injection. A device that achieves this was evaluated in 200 labouring women, randomly allocated to receive a combined spinal epidural using the CSEcure(R) (SIMS Portex, UK) locking needle or a conventional, non-locking technique. Data collection included the incidence of dural click as the spinal needle penetrated the dura mater, presence of cerebrospinal fluid in the spinal needle hub and the number of technical failures with the spinal component. Successful dural punctures with the spinal needle were similar for locking and non-locking needles (99.0 vs. 98.0%; p = 0.55), despite a small but significant reduction in dural click with the locking needle compared with the non-locking technique (97. 0 vs. 84.7%; p < 0.01). Although not statistically significant, there was a higher number of technical failures, mainly due to spinal needle movement, in the non-locking group (9.1 vs. 3.1%; p = 0.08). The locking needle device may be a useful alternative to conventional methods for combined spinal epidural analgesia.     

Social, familial, and behavioral risk factors for obesity in adolescents]

OBJECTIVE: To examine the impact of different social, familial, and behavioral factors on the risk of developing obesity in adolescents. METHODS: We performed a case-control study nested in a population-based cohort that was followed from birth in 1982. Cases were adolescents with obesity, as defined by the World Health Organization. Controls came from a randomly chosen sample of members of the cohort, examined in 1997 and 1998. Information concerning risk factors was obtained from cohort records that were collected at different ages. Multivariate analysis was carried out using logistic regression. RESULTS: Risk factors varied according to sex. Among boys, a family income at birth above one minimum wage was associated with a six-fold increase in obesity, and the presence of trait anxiety in adolescence with a four-fold increase. In both sexes, a one-unit increase in pre-pregnancy maternal body mass index was associated with a 10% increase in obesity. Smoking, fat consumption, time spent watching television or performing physical activity, and concurrent maternal weight were not associated with obesity. CONCLUSIONS: Our results show that it is important to stratify data from obesity studies according to sex. In addition, early-life factors were more strongly associated with obesity than factors present during adolescence. However, the possibility of reporting bias cannot be ruled out, especially in terms of the information provided on diet and physical exercise. Whenever possible, the study of concurrent risk factors for obesity in adolescence should take into account the confounding effect of early-life factors.     

Concomitant boost radiation and concurrent cisplatin for advanced head and neck carcinomas. Preliminary results of a phase II, single-institutional trial

INTRODUCTION: This study aims to asses the effectiveness and toxicity of boost radiotherapy concomitant and concurrent cisplatin for patients with locally advanced head and neck cancer (LAHNC). MATERIAL AND METHODS: There were 30 patients included in a prospective, phase II single-institution trial and of whom, 29 were at AJCC stage IV and 1 at stage III. Treatment consisted of radiotherapy acceleration fractionation with concomitant boost, 72 Gy, and 2 cycles of concomitant cisplatin (20 mg/m2/day continuous infusion; days 1-5 and 29-33). Amifostine, (i.v. 200 mg/m2) was administered to 26 prior to the first fraction of radiotherapy. Endpoints of the study were quality-of-life (QL), overall survival, and local control of disease. RESULTS: Complete response (CR) was achieved in 23 patients (77%), 2 patients had partial response (PR) (7%), 4 had no response (13%), and 1 was not evaluated for response. The 2-year overall survival and loco-regional control were 60% and 56%, respectively. Main toxicity was grade 3 or 4 mucositis in 93% of the patients. QL scores (questionnaire QLQC30; version 3.0) and the HN cancer module QLQ-HN35) showed a worsening in areas related to the treatment e.g. dry mouth, problems stretching the mouth, and sticky saliva. CONCLUSIONS: this combination modality is active, but toxic, in the treatment for LAHNC. Concomitant boost radiotherapy is probably, not the best radiotherapy schema for combining with chemotherapy in LAHNC.     

Análisis coste-efectividad de samario-153 (Quadramet®) en el tratamiento del dolor en pacientes con cáncer de próstata y metástasis óseas

Objective. To evaluate the cost-effectiveness of samarium [¹⁵³Sm-EDTMP] (Quadramet®) compared to conventional therapy in the treatment of pain in patients with prostate cancer and bone metastases. Method. A decision tree model for the treatment of bone pain due to metastases was adapted to the Spanish context. The model represents the standard treatment patterns in Spain for the study population. The time-course of the model is 4 months and it computes an estimate for the cost of pain control per patient. The effectiveness data for the model derive from a randomised trial. The current treatment patterns have been established according to the consensus opinions of a group of medical experts. Results. The cost of pain control per patient is ? 12,515.39 for conventional therapy and ? 5,595.52 for samarium-153 (Quadramet®) therapy. The incremental cost-effectiveness analysis shows that samarium-153 (Quadramet®) is a dominant therapy. It presents lower costs and higher efficacy than the conventional strategy. The sensitivity analyses showed these results to be robust. Conclusion. Samarium-153 (Quadramet®) is costeffective in treating pain in patients with prostate cancer and bone metastases.     

Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma.

PURPOSE: Evaluate efficacy and toxicity of bortezomib in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. PATIENTS AND METHODS: Patients were stratified, based on preclinical data, into arm A (mantle-cell lymphoma) or arm B (other B-cell lymphomas) without limitation in number of prior therapies. Bortezomib was administered as an intravenous push (1.5 mg/m2) on days 1, 4, 8, and 11 every 21 days for a maximum of six cycles. RESULTS: Sixty patients with a median number of prior therapies of 3.5 (range, one to 12 therapies) were enrolled; 33 patients were in arm A and 27 were in arm B, including 12 diffuse large B-cell lymphomas, five follicular lymphomas (FL), three transformed FLs, four small lymphocytic lymphomas (SLL), two Waldenstrom's macroglobulinemias (WM), and one marginal zone lymphoma. In arm A, 12 of 29 assessable patients responded (six complete responses [CR] and six partial responses [PR]) for an overall response rate (ORR) of 41% (95% CI, 24% to 61%), and a median time to progression not reached yet, with a median follow-up of 9.3 months (range, 1.7 to 24 months). In arm B, four of 21 assessable patients responded (one SLL patient had a CR, one FL patient had a CR unconfirmed, one diffuse large B-cell lymphoma patient had a PR, and one WM patient had a PR) for an ORR of 19% (95% CI, 5% to 42%). Grade 3 toxicity included thrombocytopenia (47%), gastrointestinal (20%), fatigue (13%), neutropenia (10%), and peripheral neuropathy (5%). Grade 4 toxicity occurred in nine patients (15%), and three deaths from progression of disease occurred within 30 days of withdrawal from study. CONCLUSION: Bortezomib showed promising activity in relapsed mantle-cell lymphoma and encouraging results in other B-cell lymphomas. Future studies will explore bortezomib in combination with other cytotoxic or biologic agents.     

Epididymal metastases as the first sign of a colon cancer recurrence

Metastastic tumours involving the epididymis are rare and most often found in patients with disseminated disease. It is even more unusual when the metastasis of the epididymis is the first sign of tumour recurrence. We report a case of an asymptomatic recurrent colon carcinoma presenting as metastasis in the epididymis. Although metastatic cancer presenting as an intra-scrotal mass is extremely rare, it should be considered as a possibility in patients who present with a mass involving the testicle or epididymis.     

Genetic and enzymatic characterization of sphingomyelinase D isoforms from the North American fiddleback spiders Loxosceles boneti and Loxosceles reclusa.

In this study we report the isolation and characterization of several sphingomyelinase D isoforms from the venoms of the North American spiders Loxosceles boneti and Loxosceles reclusa, from Mexico and the United States, respectively. We have measured their enzymatic activity, their capacity to induce necrotic lesions in rabbits, cloned the cDNAs coding for the mature forms of two of the isoforms from L. boneti and two of L. reclusa based on N-terminal sequence information of the purified proteins, and performed a comprehensive comparison of the sequence data generated by us with that reported for other sphingomyelinase genes to date.     

Total esterase activity in human saliva: Validation of an automated assay,characterization and behaviour after physical stress

Although saliva has esterase activity, this activity has not been characterized or studied in individuals subjected to physical stress. The aim of this report was to develop and validate an automated spectrophotometric assay for total esterase activity measurement in human saliva, as well as to study the contribution of different enzymes on this activity and its behaviour under physical stress in healthy subjects. The assay used 4-nitrophenyl acetate as substrate and was precise, accurate and provided low limits of detection and quantification. Inhibition with diisopropylfluorophosphate showed that cholinesterase, carboxylesterase and cholesterol esterase contributions not represented more than 20% of total esterase. Addition of standards of lipase and albumin to saliva samples showed that both proteins significantly contributed to esterase activity only when equal or higher than 11.6?IU/L and 250?μg/mL, respectively. Western blot analyses showed absence of paraoxonase-1 and high amount of carbonic anhydrase-VI. The high affinity of purified carbonic anhydrase-VI for the substrate supported a major contribution of this enzyme. Total esterase activity and alpha-amylase was measured in saliva samples from 12 healthy male students before and after participation in an indoor football match. The activity significantly increased after match and positively correlated with salivary alpha-amylase. This method could be used as a biomarker of physical stress in humans, with carbonic anhydrase-VI being the esterase that contributed more to the activity of the assay.