Activation of TRPA1 by membrane permeable local anesthetics

<p>Abstract</p> <p>Background</p> <p>Low concentrations of local anesthetics (LAs) suppress cellular excitability by inhibiting voltage-gated Na⁺channels. In contrast, LAs at high concentrations can be excitatory and neurotoxic. We recently demonstrated that LA-evoked activation of sensory neurons is mediated by the capsaicin receptor TRPV1, and, to a lesser extent by the irritant receptor TRPA1. LA-induced activation and sensitization of TRPV1 involves a domain that is similar, but not identical to the vanilloid-binding domain. Additionally, activation of TRPV1 by LAs involves PLC and PI(4,5)P₂-signalling. In the present study we aimed to characterize essential structural determinants for LA-evoked activation of TRPA1.</p> <p>Results</p> <p>Recombinant rodent and human TRPA1 were expressed in HEK293t cells and investigated by means of whole-cell patch clamp recordings. The LA lidocaine activates TRPA1 in a concentration-dependent manner. The membrane impermeable lidocaine-derivative QX-314 is inactive when applied extracellularly. Lidocaine-activated TRPA1-currents are blocked by the TRPA1-antagonist HC-030031. Lidocaine is also an inhibitor of TRPA1, an effect that is more obvious in rodent than in human TRPA1. This species-specific difference is linked to the pore region (transmembrane domain 5 and 6) as described for activation of TRPA1 by menthol. Unlike menthol-sensitivity however, lidocaine-sensitivity is not similarly determined by serine- and threonine-residues within TM5. Instead, intracellular cysteine residues known to be covalently bound by reactive TRPA1-agonists seem to mediate activation of TRPA1 by LAs.</p> <p>Conclusions</p> <p>The structural determinants involved in activation of TRPA1 by LAs are disparate from those involved in activation by menthol or those involved in activation of TRPV1 by LAs.</p

Health-state utilities in a prisoner population : a cross-sectional survey

Background: Health-state utilities for prisoners have not been described. Methods: We used data from a 1996 cross-sectional survey of Australian prisoners (n = 734). Respondent-level SF-36 data was transformed into utility scores by both the SF-6D and Nichol's method. Socio-demographic and clinical predictors of SF-6D utility were assessed in univariate analyses and a multivariate general linear model. Results: The overall mean SF-6D utility was 0.725 (SD 0.119). When subdivided by various medical conditions, prisoner SF-6D utilities ranged from 0.620 for angina to 0.764 for those with none/mild depressive symptoms. Utilities derived by the Nichol's method were higher than SF-6D scores, often by more than 0.1. In multivariate analysis, significant independent predictors of worse utility included female gender, increasing age, increasing number of comorbidities and more severe depressive symptoms. Conclusion: The utilities presented may prove useful for future economic and decision models evaluating prison-based health programs

Mapping the disease-specific LupusQoL to the SF-6D

Purpose To derive a mapping algorithm to predict SF-6D utility scores from the non-preference-based LupusQoL and test the performance of the developed algorithm on a separate independent validation data set. Method LupusQoL and SF-6D data were collected from 320 patients with systemic lupus erythematosus (SLE) attending routine rheumatology outpatient appointments at seven centres in the UK. Ordinary least squares (OLS) regression was used to estimate models of increasing complexity in order to predict individuals’ SF-6D utility scores from their responses to the LupusQoL questionnaire. Model performance was judged on predictive ability through the size and pattern of prediction errors generated. The performance of the selected model was externally validated on an independent data set containing 113 female SLE patients who had again completed both the LupusQoL and SF-36 questionnaires. Results Four of the eight LupusQoL domains (physical health, pain, emotional health, and fatigue) were selected as dependent variables in the final model. Overall model fit was good, with R2 0.7219, MAE 0.0557, and RMSE 0.0706 when applied to the estimation data set, and R2 0.7431, MAE 0.0528, and RMSE 0.0663 when applied to the validation sample. Conclusion This study provides a method by which health state utility values can be estimated from patient responses to the non-preference-based LupusQoL, generalisable beyond the data set upon which it was estimated. Despite concerns over the use of OLS to develop mapping algorithms, we find this method to be suitable in this case due to the normality of the SF-6D data

Measuring the effect of intimate partner violence on health-related quality of life: a qualitative focus group study

Abstract Background Health related quality of life (HRQOL) can be measured by a wide range of instruments, many of which have been designed for specific conditions or uses. Preference-based measures assess the value individuals place on health, and are included in economic evaluations of treatments and interventions (such as cost effectiveness analysis). As economic evaluation becomes more common, it is important to assess the applicability of preference-based health related quality of life (HRQOL) measures to public health issues. This study investigated the usefulness of such instruments in the context of intimate partner violence (IPV), a public health concern that that can seriously affect quality of life. Methods The study consisted of focus groups with abused women to determine the aspects of life affected by IPV, and an analysis of existing HRQOL measures. Eight focus groups (n = 40) were conducted in which participants discussed the domains of health affected by IPV. Results were content analyzed and compared with the domains of health included in four commonly-used, preference-based HRQOL measures. Results The average focus group participant was 43 years old, unemployed, African American, with 3 children. Domains of health reported to be affected by IPV included physical functioning, emotional and psychological functioning, social functioning and children\u27s functioning. Psychological health was the most severely affected domain. The Short Form 36, the Health Utilities Index, the EuroQol 5D, and the Quality of Well-being Scale were found to vary in the degree to which they include domains of health important in IPV. Psychological health is included to a limited extent, and the spill-over effect of a condition on other family members, including children, is not included at all. Conclusion Emotional and psychological health plays an important role in the overall HRQOL of abused women but is relatively underemphasized in preference-based HRQOL measures. This may lead to an underestimation of the impact of partner violence on HRQOL when using these measures and in economic evaluations that rely thereon. Holistic measurement approaches or expanded measures that capture the far-reaching effects of IPV on HRQOL may be needed to accurately measure the effect of this condition on women\u27s health

Consolidated health economic evaluation reporting standards (CHEERS) statement

&lt;p&gt;Economic evaluations of health interventions pose a particular challenge for reporting. There is also a need to consolidate and update existing guidelines and promote their use in a user friendly manner. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement is an attempt to consolidate and update previous health economic evaluation guidelines efforts into one current, useful reporting guidance. The primary audiences for the CHEERS statement are researchers reporting economic evaluations and the editors and peer reviewers assessing them for publication.&lt;/p&gt; &lt;p&gt;The need for new reporting guidance was identified by a survey of medical editors. A list of possible items based on a systematic review was created. A two round, modified Delphi panel consisting of representatives from academia, clinical practice, industry, government, and the editorial community was conducted. Out of 44 candidate items, 24 items and accompanying recommendations were developed. The recommendations are contained in a user friendly, 24 item checklist. A copy of the statement, accompanying checklist, and this report can be found on the ISPOR Health Economic Evaluations Publication Guidelines Task Force website (www.ispor.org/TaskForces/EconomicPubGuidelines.asp).&lt;/p&gt; &lt;p&gt;We hope CHEERS will lead to better reporting, and ultimately, better health decisions. To facilitate dissemination and uptake, the CHEERS statement is being co-published across 10 health economics and medical journals. We encourage other journals and groups, to endorse CHEERS. The author team plans to review the checklist for an update in five years.&lt;/p&gt

Effects of esomeprazole treatment for gastroesophageal reflux disease on quality of life in 12- to 17-year-old adolescents: an international health outcomes study

<p>Abstract</p> <p>Background</p> <p>Although gastroesophageal reflux disease (GERD) is common in adolescents, the burden of GERD on health-related quality of life (HRQOL) in adolescents has not been previously evaluated. Therefore, the objective of the study was to examine the effect of GERD on HRQOL in adolescents.</p> <p>Methods</p> <p>This international, 31-site, 8-week safety study randomized adolescents, aged 12 to 17 years inclusive, with GERD to receive esomeprazole 20 or 40 mg once daily. The Quality of Life in Reflux and Dyspepsia questionnaire (QOLRAD), previously validated in adults, consists of 25 questions grouped into 5 domains: emotional distress, sleep disturbance, food/drink problems, physical/social functioning, and vitality. The QOLRAD was administered at the baseline and week-8 (final) visits.</p> <p>Results</p> <p>Of the 149 patients randomized, 134 completed the QOLRAD at baseline and final visits and were eligible for analysis of their HRQOL data. Baseline QOLRAD scores indicated GERD had a negative effect on the HRQOL of these adolescents, especially in the domains of vitality and emotional distress, and problems with food/drink. At the final visit, mean scores for all 5 QOLRAD domains improved significantly (<it>P </it>< .0001); change of scores (ie, delta) for all domains met or exceeded the adult QOLRAD minimal clinically significant difference standard of 0.5 units.</p> <p>Conclusion</p> <p>GERD had a negative effect on QOL in adolescents. After esomeprazole treatment, statistically and clinically significant improvements occurred in all domains of the QOLRAD for these adolescents.</p> <p>Trial Registration</p> <p>D9614C00098; ClinicalTrials.gov Identifier NCT00241501</p

Learning while evaluating: the use of an electronic evaluation portfolio in a geriatric medicine clerkship

BACKGROUND: Electronic evaluation portfolios may play a role in learning and evaluation in clinical settings and may complement other traditional evaluation methods (bedside evaluations, written exams and tutor-led evaluations). METHODS: 133 third-year medical students used the McGill Electronic Evaluation Portfolio (MEEP) during their one-month clerkship rotation in Geriatric Medicine between September 2002 and September 2003. Students were divided into two groups, one who received an introductory hands-on session about the electronic evaluation portfolio and one who did not. Students' marks in their portfolios were compared between both groups. Additionally, students self-evaluated their performance and received feedback using the electronic portfolio during their mandatory clerkship rotation. Students were surveyed immediately after the rotation and at the end of the clerkship year. Tutors' opinions about this method were surveyed once. Finally, the number of evaluations/month was quantified. In all surveys, Likert scales were used and were analyzed using Chi-square tests and t-tests to assess significant differences in the responses from surveyed subjects. RESULTS: The introductory session had a significant effect on students' portfolio marks as well as on their comfort using the system. Both tutors and students reported positive notions about the method. Remarkably, an average (± SD) of 520 (± 70) evaluations/month was recorded with 30 (± 5) evaluations per student/month. CONCLUSION: The MEEP showed a significant and positive effect on both students' self-evaluations and tutors' evaluations involving an important amount of self-reflection and feedback which may complement the more traditional evaluation methods

Effect of C-2 substitution on the stability of non-traditional cephalosporins in mouse plasma

This work is licensed under a Creative Commons Attribution 4.0 International License.A systematic study of the stability of a set of cephalosporins in mouse plasma reveals that cephalosporins lacking an acidic moiety at C-2 may be vulnerable to β-lactam cleavage in mouse plasma

Abstinence-Only Education and Teen Pregnancy Rates: Why We Need Comprehensive Sex Education in the U.S

The United States ranks first among developed nations in rates of both teenage pregnancy and sexually transmitted diseases. In an effort to reduce these rates, the U.S. government has funded abstinence-only sex education programs for more than a decade. However, a public controversy remains over whether this investment has been successful and whether these programs should be continued. Using the most recent national data (2005) from all U.S. states with information on sex education laws or policies (N = 48), we show that increasing emphasis on abstinence education is positively correlated with teenage pregnancy and birth rates. This trend remains significant after accounting for socioeconomic status, teen educational attainment, ethnic composition of the teen population, and availability of Medicaid waivers for family planning services in each state. These data show clearly that abstinence-only education as a state policy is ineffective in preventing teenage pregnancy and may actually be contributing to the high teenage pregnancy rates in the U.S. In alignment with the new evidence-based Teen Pregnancy Prevention Initiative and the Precaution Adoption Process Model advocated by the National Institutes of Health, we propose the integration of comprehensive sex and STD education into the biology curriculum in middle and high school science classes and a parallel social studies curriculum that addresses risk-aversion behaviors and planning for the future

Health, Health-Related Quality of Life, and Quality of Life: What is the Difference?

The terms health, health-related quality of life (HRQoL), and quality of life (QoL) are used interchangeably. Given that these are three key terms in the literature, their appropriate and clear use is important. This paper reviews the history and definitions of the terms and considers how they have been used. It is argued that the definitions of HRQoL in the literature are problematic because some definitions fail to distinguish between HRQoL and health or between HRQoL and QoL. Many so-called HRQoL questionnaires actually measure self-perceived health status and the use of the phrase QoL is unjustified. It is concluded that the concept of HRQoL as used now is confusing. A potential solution is to define HRQoL as the way health is empirically estimated to affect QoL or use the term to only signify the utility associated with a health state