Molecular pathogenesis of uterine smooth muscle tumors from transcriptional profiling

Uterine smooth muscle tumors range from the very common benign leiomyoma to the uncommon, but frequently lethal, leiomyosarcoma. Morphological and clinical differences between these tumors are presumed to result from differences in gene expression. To test this hypothesis, RNAs from four normal uterine myometria, seven uterine leiomyomas, and nine uterine leiomyosarcomas were profiled using microarrays of oligonucleotides representing about 7,000 unique probe sets. RNAs whose levels distinguished any of the three sample types were selected by analysis of variance (ANOVA). The 153 (2.2% of the total) probe sets representing 146 unique genes with the highest test statistic selected for further analysis met minimum ratio and range thresholds between groups. Cluster analysis distinguished benign and malignant samples at the first node, and myometrium and leiomyoma were resolved in a secondary node. Downregulation of specific genes in uterine leiomyosarcoma was the most common pattern of differential gene expression selected by the three-way ANOVA. Four extrauterine leiomyosarcomas had profiles most similar to that of the uterine leiomyosarcomas. Functional analysis of the 146 genes did not reveal any strong biological theme. These genes were distributed throughout the genome, but there was slight overrepresentation of genes on 1p and 2q. These genes define a tumor signature for uterine smooth muscle neoplasia, and they suggest that the molecular pathways in leiomyoma and leiomyosarcoma are distinct.     

Giving a voice to patient experiences through the insights of pragmatism

As a philosophical position, pragmatism can be critiqued to distinguish truth only with methods that bring about desired results, predominantly with scientific enquiry. The article hopes to dismiss this oversimplification and propose that within mental health nursing, enquiry enlightened by pragmatism can be anchored to methods helping to tackle genuine human problems. Whilst pragmatists suggest one reality exists, fluctuating experiences and shifting beliefs about the world can inhabit within; hence, pragmatists propose reality has the potential to change. Moreover, pragmatism includes being cognisant of what works to whom reality concerns, making reality context-driven, with a view to understand how actions shape experiences so what is generated has usefulness. Hence, it somewhat follows pragmatism can inform mental health nursing, after all, nursing is a discipline of action, and awareness is needed in how actions produce experiences that patients find helpful. Given the principles of recovery are preferably adopted in mental health care, the paper will explore how pragmatism can help nurses move towards that goal; specifically, with patients voicing their experiences. This is because like pragmatism, recovery subscribes to hope that reality can progress, and through meaningful experiences and beliefs, patients have expertise about personal difficulties alongside how life may flourish, despite mental illness.     

The Psychology of Kink: A Cross-Sectional Survey Study Investigating the Roles of Sensation Seeking and Coping Style in BDSM-Related Interests

Archives of Sexual Behavior - Despite the gaining popularity in mainstream media of the phenomenon that is BDSM, empirical research on the motives and underlying psychological mechanisms driving...     

An expert system to teach troubleshooting of common problems associated with the automated anesthesia recordkeeper

Automated anesthesia recordkeepers have been used to monitor patients during surgery in up to 90% of cases at The Ohio State University. The record-keeping devices are complex and can be difficult to troubleshoot. The 1st-CLASS Fusion Program, an expert system shell-program, has been programmed to allow the resident or nurse anesthetist to solve the two most common types of problems associated with the recordkeeper: printer problems and patient monitor problems. Use of this program allows the resident or nurse anesthetist to troubleshoot the recordkeeper quickly and accurately and promotes in the user a sense of competence and control over the technology.     

Phase I clinical and pharmacological study of chloroquinoxaline sulfonamide.

Chloroquinoxaline sulfonamide (CQS) is a halogenated heterocyclic sulfanilamide identified by the in vitro human tumor colony-forming assay as an active agent in a variety of human solid tumors. In this phase I study, 182 courses of CQS were administered intravenously every 28 days to 88 patients at doses ranging from 18 to 4870 mg/m2. Hypoglycemia associated with hyperinsulinemia was the dose-limiting adverse effect at 4870 mg/m2. Supraventricular tachyarrhythmias were observed at doses > 4000 mg/m2. Less common reactions included infusion site phlebitis, nausea, anemia, alopecia, perioral numbness, and diarrhea. Cumulative toxicity was not observed. Minor objective antitumor responses were noted in 7 patients; 6 of the 7 responses occurred in patients with non-small cell lung cancer. Results of pharmacokinetic studies were consistent with the preclinical observations that CQS is highly bound to plasma protein. Plasma elimination followed a two-compartment model; the mean t 1/2 alpha was 2.7 +/- 0.3 h and the t 1/2 beta was 52 +/- 6 h (+/- SE). The total body clearance and the volume of distribution at steady state of CQS both increased with the dose (distribution at steady state, 3.7-10.5 liter/m2; total body clearance, 53-264 ml/h/m2 for doses of 18-4060 mg/m2) and may reflect saturation of the protein binding and "free" drug clearance. Although inactive against common animal tumors in preclinical screening systems both in vitro and in vivo, CQS has demonstrated definite activity in the human tumor stem cell colony-forming assays, as well as modest anticancer activity in this phase I study in patients with advanced solid tumors. The pharmacokinetic results and the limiting effect of transient hypoglycemia suggest that considerably higher cumulative doses of CQS could be administered using a more frequent dosing schedule.     

10-propargyl-10-deazaaminopterin: an antifolate with activity in patients with previously treated non-small cell lung cancer.

PURPOSE: 10-propargyl-10-deazaaminopterin (PDX) has superior antitumor efficacy in mouse xenograft models, likely attributable to increased uptake by the RFC-1 folate transporter and greater intracellular polyglutamylation. In a previous Phase I trial, stomatitis was the dose-limiting (and only clinically significant) toxicity of PDX. The recommended Phase II dose was 150 mg/m(2) i.v. every 2 weeks. Responses observed in patients with non-small cell lung cancer (NSCLC) in the Phase I trial prompted this Phase II trial. EXPERIMENTAL DESIGN: Patients had stage IIIB or IV NSCLC and either no previous chemotherapy or progression after initial response or stable disease to one previous chemotherapy regimen. Initially, PDX was administered at a dose of 150 mg/m(2) every 2 weeks. However, to decrease the frequency of stomatitis, the last 10 patients were treated at a dose of 135 mg/m(2). We planned to correlate PDX effects with folate and homocysteine levels and the expression of genes associated with folate transport and polyglutamylation. RESULTS: Thirty-nine patients were enrolled, 38 of whom were evaluable for response. Four patients had confirmed, major objective responses (10% based on intent to treat, 95% confidence interval 3-25) lasting 4, 9, 12, and 15 months. Twelve patients (31%) had stable disease. The median survival was 13.5 months. The predicted 1- and 2-year survival rates were 56 and 36%, respectively. Two patients (5%) suffered grade 4 stomatitis, and 6 (15%) had grade 3. No clinically significant myelosuppression occurred. No correlation between homocysteine or serum folate levels and severity of stomatitis was observed. Area under the curve (calculated using a limited sampling model) correlated with mucositis grade. A trend was noted between folate transporter expression and treatment effect. CONCLUSIONS: The broad applicability of this new antifolate with limited toxicity and proven efficacy in NSCLC encourage further development of this compound. Several trials are now underway combining PDX with other chemotherapeutic agents and testing its efficacy in other cancers.