Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy

Human Molecular     

Basal B-cell receptor signaling in B lymphocytes: mechanisms of regulation and role in positive selection, differentiation, and peripheral survival

Summary:  B-cell development is a highly ordered multistep process dependent upon signals generated by the pre-B and B-cell antigen receptor (BCR). BCR signals drive maturation of the B cell by integrating a number of parallel and sequential biological processes that result in generation of fully immunocompetent B cells. Among these biological processes are positive selection through several developmental checkpoints, negative selection of potentially self-reactive B cells, and activation of the mature B cell. In addition, recent studies have shown that developing and mature B cells rely on the constant activity of the BCR for their continued survival. Ligand (antigen)-dependent and -independent mechanisms of BCR signaling have been proposed, but their specific contributions to B-cell maturation and differentiation in the bone marrow and periphery are not completely clear. We discuss here a model, whereby ligand-independent basal BCR activity would be sufficient to trigger B-cell development through to the mature stage. However, long-term survival and formation of specific mature B-cell populations may be dependent on ligand–receptor interactions.     

Chemotherapy of advanced breast cancer: outcome and prognostic factors.

The outcome for 758 consecutive patients who had received one or more chemotherapy regimens for recurrent or metastatic breast cancer is presented. The response rate following first line treatment was 34%. Median duration of response was 7.8 months, median time to progression was 3.7 months and median survival was 7.9 months. The only factor predicting for response, of factors recorded at presentation and at initiation of chemotherapy, was the use of anthracycline based regimens, though this may reflect the patient selection policy. Initial disease free interval, presence of liver metastases and use of anthracyclines were significantly related to time to progression. Several factors related to survival following first chemotherapy, but anthracycline usage showed only a very weak correlation. One third of patients (249/758) received two or more chemotherapy regimens. The response rate (16%) and median time to progression (2.3 months) were significantly worse than for first line treatment. The outcome after third line chemotherapy was very similar to that observed following second line treatment. Achievement of an objective response with first line chemotherapy predicted for second response, but with insufficient power to be of use in selecting patients for subsequent chemotherapy. Time to progression following first line chemotherapy did not influence that after second line treatment.     

Employment, medical absenteeism, and disability perception in Parkinson's disease: A pilot double-blind, randomized, placebo-controlled study of entacapone adjunctive therapy.

The objective of this study was to test the impact of entacapone (ENT) addition to levodopa with a decarboxylase inhibitor (LD) in full-time-employed patients with Parkinson's disease (PD), focusing on retirement rates, medical absenteeism, self-perception of disability, as well as motor assessments of parkinsonism, motor fluctuations, and dyskinesias. Thirty full-time-employed PD patients (disease onset before age 60 years) and on optimized monotherapy with LD exhibiting minor motor fluctuations or dyskinesias were entered into a 2-year randomized double-blind placebo-controlled study of ENT adjunctive therapy. The outcome measures were the number of full-time-employed patients at study end, cumulative days of medical absenteeism, patient-completed disability assessments, diary records, and the Unified Parkinson's Disease Rating Scale-based measures of motor fluctuations and dyskinesias. LD + ENT treatment was associated with a lower retirement rate (2 [17%] of 12 vs. 6 [50%] of 12; P = 0.12), lower absenteeism rate (21.5 vs. 43.5 days; P < 0.0001), improved self-perception of disability progression over 2 years (change score 1.0 vs. 4.5; P < 0.0001), and lower scores for both motor fluctuations and dyskinesia assessments compared to LD monotherapy. In this pilot study, LD with ENT adjunctive therapy positively influenced employment rate over 2 years; this effect was associated with reduced motor complications and patient perceptions of stabilized disability.     

Cyclooxygenase 2 expression in serous tumors of the ovary.

This study was designed to investigate the expression of cyclooxygenase (COX)-2 in ovarian serous tumors (benign, borderline tumors, and carcinomas) and primary peritoneal serous carcinomas. Cases diagnosed between 1995 and 2001 were reviewed; 47 benign tumors, 6 borderline tumors, and 39 carcinomas were examined, as well as 12 normal ovaries that served as controls. Blocks were stained with anti COX-2 polyclonal antibody and staining was graded qualitatively. The staining intensity was assessed as weak (score of 1), moderate (score of 2), or strong (score of 3). Normal ovarian and tubal epithelium, inclusion cysts, benign serous tumors, and borderline tumors had a uniform score 3 staining pattern. Serous ovarian carcinomas had variable staining scores, tending to correlate with the level of tumor differentiation. Well-differentiated carcinomas had more intense COX-2 staining than poorly differentiated carcinomas, which had only weak COX-2 staining. The degree of COX-2 staining was not significantly related to overall survival. In conclusion, COX-2 expression is present in serous tumors, including benign tumors, borderline tumors, and carcinomas. Similar to the findings in other neoplasms, COX-2 expression is strongest in well-differentiated tumors and is much less evident in those that are poorly differentiated. The clinical utility of these findings is related to the potential role of nonsteroidal anti-inflammatory drugs, which are COX-2 inhibitors, in treating and/or preventing some forms of ovarian carcinoma.     

Propofol versus traditional sedative agents for gastrointestinal endoscopy: a meta-analysis.

BACKGROUND & AIMS: Even though propofol has better recovery profile than traditional agents, its use is limited because of the perception of increased complication rates. Because an adequately powered trial comparing risk of propofol with traditional agents is lacking, we performed a meta-analysis of the current literature. METHODS: We searched Medline (1966-October 2004), EMBASE (1980-October 2004), and Cochrane controlled trials registry. The following 4 cardiopulmonary complications were assessed: hypoxia, hypotension, arrhythmias, and apnea. Procedures were divided into 3 groups: esophagogastroduodenoscopy group, colonoscopy group, and endoscopic retrograde cholangiopancreatography/endoscopic ultrasonography group. Pooled odds ratios for complications were calculated for all the procedures combined and then separately for the 3 groups. Random effects models were used for 2-proportion comparisons. RESULTS: Of the 90 citations identified, 12 original studies qualified for this meta-analysis and included 1161 patients. Of these, 634 received propofol, and 527 received midazolam, meperidine, and/or fentanyl. Most of the included studies were randomized trials of moderate quality and nonsignificant heterogeneity (Cochran Q = 4.81, P = .90). Compared with traditional sedative agents, the pooled odds ratio with the use of propofol for developing hypoxia or hypotension for all the procedures combined was 0.74 (95% confidence interval [CI], 0.44-1.24); for EGD, 0.85 (95% CI, 0.33-2.17); for colonoscopy, 0.4 (95% CI, 0.2-0.79); and for ERCP/EUS, 1.07 (95% CI, 0.38-3.01). CONCLUSIONS: Propofol sedation during colonoscopy appears to have lower odds of cardiopulmonary complications compared with traditional agents, but for other procedures, the risk of complications is similar.