Key Residues Defining the Μ-Opioid Receptor Binding Pocket: A Site-Directed Mutagenesis Study

Structural elements of the rat Μ-opioid receptor important in ligand receptor binding and selectivity were examined using a site-directed mutagenesis approach. Five single amino acid mutations were made, three that altered conserved residues in the Μ, Δ, and Κ receptors (Asn 150 to Ala, His 297 to Ala, and Tyr 326 to Phe) and two designed to test for Μ/Δ selectivity (Ile 198 to Val and Val 202 to Ile). Mutation of His 297 in transmembrane domain 6 (TM6) resulted in no detectable binding with [ 3 H]DAMGO ( 3 H-labeled d-Ala 2 , N -Me-Phe 4 ,Gly-ol 5 -enkephalin), [ 3 H]bremazocine, or [ 3 H]ethylketocyclazocine. Mutation of Asn 150 in TM3 produces a three- to 20-fold increase in affinity for the opioid agonists morphine, DAMGO, fentanyl, Β-endorphin 1–31 , JOM-13, deltorphin II, dynorphin 1–13 , and U50,488, with no change in the binding of antagonists such as naloxone, naltrexone, naltrindole, and nor-binaltorphamine. In contrast, the Tyr 326 mutation in TM7 resulted in a decreased affinity for a wide spectrum of Μ, Δ, and Κ agonists and antagonists. Altering Val 202 to Ile in TM4 produced no change on ligand affinity, but Ile 198 to Val resulted in a four- to fivefold decreased affinity for the Μ agonists morphine and DAMGO, with no change in the binding affinities of Κ and Δ ligands.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65474/1/j.1471-4159.1997.68010344.x.pd

Highlights of the 1990 Leesburg, Virginia, International Workshop on Retrospective Exposure Assessment for Occupational Epidemiology Studies.

The International Workshop on Retrospective Exposure Assessment for Occupational Epidemiology Studies was held on 27-31 March 1990 at Leesburg, Virginia, in the United States. The presentations and discussions focused on the selection of an approach for assessing exposures, methods of exposure assessment used in industry-based and community-based studies, the evaluation of exposure estimates through measurements of validity and precision, and areas of future research

Rodent-associated Bartonella Febrile Illness, Southwestern United States

Patients showed seroconversion to rodent-associated Bartonella antigens, but not to Bartonella pathogenic for humans

The decision of African American students to complete high school: An application of the theory of planned behavior.

A longitudinal study explored high school completion among African Americans. Male and female high school students aged 14 to 17 (N 166) completed a theory of planned behavior (I. Ajzen, 1991) questionnaire early in their 2nd year. Intentions to complete the year were accurately predicted from attitudes, subjective norms, and perceived behavioral control (R .71; p .01). Attitudes were related to beliefs about short- and long-term consequences; subjective norms reflected perceived expectations of family, teachers, and friends; and control considerations included requisite academic abilities, conflict with peers and teachers, and distracting life conditions. Intentions and, to a lesser extent, perceived behavioral control, predicted graduation almost 3 years later (R .50; p .01). The findings indicate opportunities for early interventions. Obtaining a high school diploma has become an increasingly important prerequisite for economic and social mobility in the United States. High school dropouts are roughly three times more likely to be chronically poor than are high school graduates (U.S. Census Bureau, 1996). Young people without a high school edu-cation are ill equipped for the modern workforce. They are les

Adam Smith’s Green Thumb and Malthus’ Three Horsemen: Cautionary tales from classical political economy

This essay identifies a contradiction between the flourishing interest in the environmental economics of the classical period and a lack of critical parsing of the works of its leading representatives. Its focus is the work of Adam Smith and Thomas Malthus. It offers a critical analysis of their contribution to environmental thought and surveys the work of their contemporary devotees. It scrutinizes Smith's contribution to what Karl Polanyi termed the "economistic fallacy," as well as his defenses of class hierarchy, the "growth imperative" and consumerism. It subjects to critical appraisal Malthus's enthusiasm for private property and the market system, and his opposition to market regulation. While Malthus's principal attraction to ecological economists lies in his having allegedly broadened the scope of economics, and in his narrative of scarcity, this article shows that he, in fact, narrowed the scope of the discipline and conceptualized scarcity in a reified and pseudo-scientific way

A critical review of the research literature on Six Sigma, Lean and StuderGroup's Hardwiring Excellence in the United States: the need to demonstrate and communicate the effectiveness of transformation strategies in healthcare

<p>Abstract</p> <p>Background</p> <p>U.S. healthcare organizations are confronted with numerous and varied transformational strategies promising improvements along all dimensions of quality and performance. This article examines the peer-reviewed literature from the U.S. for evidence of effectiveness among three current popular transformational strategies: Six Sigma, Lean/Toyota Production System, and Studer's Hardwiring Excellence.</p> <p>Methods</p> <p>The English language health, healthcare management, and organizational science literature (up to December 2007) indexed in Medline, Web of Science, ABI/Inform, Cochrane Library, CINAHL, and ERIC was reviewed for studies on the aforementioned transformation strategies in healthcare settings. Articles were included if they: appeared in a peer-reviewed journal; described a specific intervention; were not classified as a pilot study; provided quantitative data; and were not review articles. Nine references on Six Sigma, nine on Lean/Toyota Production System, and one on StuderGroup meet the study's eligibility criteria.</p> <p>Results</p> <p>The reviewed studies universally concluded the implementations of these transformation strategies were successful in improving a variety of healthcare related processes and outcomes. Additionally, the existing literature reflects a wide application of these transformation strategies in terms of both settings and problems. However, despite these positive features, the vast majority had methodological limitations that might undermine the validity of the results. Common features included: weak study designs, inappropriate analyses, and failures to rule out alternative hypotheses. Furthermore, frequently absent was any attention to changes in organizational culture or substantial evidence of lasting effects from these efforts.</p> <p>Conclusion</p> <p>Despite the current popularity of these strategies, few studies meet the inclusion criteria for this review. Furthermore, each could have been improved substantially in order to ensure the validity of the conclusions, demonstrate sustainability, investigate changes in organizational culture, or even how one strategy interfaced with other concurrent and subsequent transformation efforts. While informative results can be gleaned from less rigorous studies, improved design and analysis can more effectively guide healthcare leaders who are motivated to transform their organizations and convince others of the need to employ such strategies. Demanding more exacting evaluation of projects consultants, or partnerships with health management researchers in academic settings, can support such efforts.</p

A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment

BACKGROUND: The prognostic significance of germline mutations in BRCA1 and BRCA2 in women with breast cancer remains unclear. A combined analysis was performed to address this uncertainty. METHODS: Two retrospective cohorts of Ashkenazi Jewish women undergoing breast-conserving treatment for invasive cancer between 1980 and 1995 (n = 584) were established. Archived tissue blocks were used as the source of DNA for Ashkenazi Jewish BRCA1/BRCA2 founder mutation analysis. Paraffin-embedded tissue and follow-up information was available for 505 women. RESULTS: Genotyping was successful in 496 women, of whom 56 (11.3%) were found to carry a BRCA1/BRCA2 founder mutation. After a median follow-up period of 116 months, breast cancer specific survival was worse in women with BRCA1 mutations than in those without (62% at 10 years versus 86%; P < 0.0001), but not in women with the BRCA2 mutation (84% versus 86% at 10 years; P = 0.76). Germline BRCA1 mutations were an independent predictor of breast cancer mortality in multivariate analysis (hazard ratio 2.4, 95% confidence interval 1.2–4.8; P = 0.01). BRCA1 status predicted breast cancer mortality only among women who did not receive chemotherapy (hazard ratio 4.8, 95% confidence interval 2.0–11.7; P = 0.001). The risk for metachronous ipsilateral cancer was not greater in women with germline BRCA1/BRCA2 founder mutations than in those without mutations (P = 0.68). CONCLUSION: BRCA1 mutations, but not BRCA2 mutations, are associated with reduced survival in Ashkenazi women undergoing breast-conserving treatment for invasive breast cancer, but the poor prognosis associated with germline BRCA1 mutations is mitigated by adjuvant chemotherapy. The risk for metachronous ipsilateral disease does not appear to be increased for either BRCA1 or BRCA2 mutation carriers, at least up to 10 years of follow up

Safety of procuring research tissue during a clinically indicated kidney biopsy from patients with lupus: data from the Accelerating Medicines Partnership RA/SLE Network

Objectives In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis.Methods 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines.Results 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved.Conclusions Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required