Divergent effects of putative anxiolytics on stress-induced fos expression in the mesoprefrontal system of the rat

Previously, we reported that R(+)HA-966, a weak partial agonist for the glycine/NMDA receptor, and guanfacine, a noradrenergic alpha2 agonist, have anxiolytic-like actions on the biochemical activation of the mesoprefrontal dopamine neurons and fear-induced behaviors. Here, we examined these two putative anxiolytic agents, both with primary actions independent of GABAergic systems, for their ability to alter stress-induced Fos-like immunoreactivity in the mesoprefrontal cortex and in tyrosine hydroxylase-stained, presumed dopaminergic, neurons in the ventral tegmental area. The benzodiazepine agonist, lorazepam, and partial agonist, bretazenil, were also tested in this footshock paradigm [10 x 0.5 sec, 0.8 mA paired with a 5-sec tone]. In saline-treated rats, footshock resulted in an increase in Fos-li in the prelimbic and infralimbic cortices and tyrosine hydroxylase-labeled cells in the ventral tegmental area. Treatment with lorazepam or bretazenil prevented the stress-induced activation in Fos-li nuclei in all regions of the medial prefrontal cortex and in dopaminergic neurons in the ventral tegmental area. In contrast, the actions of the novel anxiolytic-like agents on stress-induced Fos-li were different than those observed with benzodiazepine agonists. Both putative anxiolytics, R(+)HA-966 and guanfacine, did not reduce, but significantly enhanced the stress-induced Fos-li in the prelimbic region of the medial prefrontal cortex. Additionally, treatment with R(+)HA-966 completely blocked, while guanfacine attenuated, the stress-induced increase in the number of Fos-li, TH-li cells in the ventral tegmental area. These results indicate that the putative anxiolytics, R(+)HA-966 and guanfacine, have actions on the stress-sensitive mesoprefrontal system which appear distinct from those of traditional anxiolytics.     

Application of the TIMI risk score for ST-elevation MI in the National Registry of Myocardial Infarction 3

CONTEXT: The Thrombolysis in Myocardial Infarction (TIMI) risk score for ST-elevation myocardial infarction (STEMI) is a simple integer score for bedside risk assessment of patients with STEMI. Developed and validated in multiple clinical trials of fibrinolysis, the risk score has not been validated in a community-based population. OBJECTIVE: To validate the TIMI risk score in a population of STEMI patients reflective of contemporary practice. DESIGN, SETTING, AND PARTICIPANTS: The risk score was evaluated among 84 029 patients with STEMI from the National Registry of Myocardial Infarction 3 (NRMI 3), which collected data on consecutive patients with myocardial infarction (MI) from 1529 US hospitals between April 1998 and June 2000. MAIN OUTCOME MEASURES: Ability of the TIMI risk score to correctly predict risk of death in terms of model discrimination (c statistic) and calibration (agreement of predicted and observed death rates). RESULTS: Patients in NRMI 3 tended to be older, to be more often female, and to have a history of coronary disease more often than those in the derivation set. Forty-eight percent received reperfusion therapy. The TIMI risk score revealed a significant graded increase in mortality with rising score (range, 1.1%-30.0%; P<.001 for trend). The risk score showed strong prognostic capacity overall (c = 0.74 vs 0.78 in derivation set) and among patients receiving acute reperfusion therapy (c = 0.79). Predictive behavior of the risk score was similar between fibrinolytic-treated patients (n = 23 960; c = 0.79) and primary percutaneous coronary intervention patients (n = 15 348; c = 0.80). In contrast, among patients not receiving reperfusion therapy, the risk score underestimated death rates and offered lower discriminatory capacity (c = 0.65). CONCLUSIONS: Sufficiently simple to be practical at the bedside and effective for risk assessment across a spectrum of patients, the TIMI risk score may be useful in triage and treatment of patients with STEMI who are treated with reperfusion therapy.     

Basis of the gabamimetic profile of ethanol

This article summarizes the proceedings of a symposium held at the 2005 Research Society on Alcoholism meeting. The initial presentation by Dr. Wallner provided evidence that selected GABA(A) receptors containing the delta subunit display sensitivity to low intoxicating ethanol concentrations and this sensitivity is further increased by a mutation in the cerebellar alpha6 subunit, found in alcohol-hypersensitive rats. Dr. Mameli reported that ethanol affects gamma-aminobutyric acid (GABA) function by affecting neural circuits that influence GABA release. Dr. Parsons presented data from electrophysiological and microdialysis investigations that ethanol is capable of releasing GABA from presynaptic terminals. Dr. Morrow demonstrated that systemic ethanol increases neuroactive steroids in brain, the absence of which alters various functional responses to ethanol. Dr. Criswell presented evidence that the ability of ethanol to increase GABA was apparent in some, but not all, brain regions indicative of regional specificity. Further, Dr. Criswell demonstrated that neurosteroids alone and when synthesized locally by ethanol act postsynaptically to enhance the effect of GABA released by ethanol in a region specific manner. Collectively, this series of reports support the GABAmimetic profile of acutely administered ethanol being dependent on several specific mechanisms distinct from a direct effect on the major synaptic isoforms of GABA(A) receptors.     

TIMI risk index and the benefit of enoxaparin in patients with ST-elevation myocardial infarction

Purpose

The purpose of the study was to evaluate the cause of death, risk of nonfatal complications, and relative outcomes with an enoxaparin versus unfractionated heparin strategy in ST-elevation myocardial infarction stratified using the Thrombolysis in Myocardial Infarction (TIMI) Risk Index (TRI).

Methods

We evaluated 30-day outcomes in 19,941 patients with ST-elevation myocardial infarction treated with fibrinolysis and unfractionated heparin or enoxaparin. Patients were categorized on the basis of prespecified ranges of the TRI [heart rate × (age/10)²/systolic blood pressure].

Results

There was a strongly graded increase in 30-day mortality with increasing TRI (1.2%-20.7%, P <.0001). The proportion of deaths due to mechanical causes (congestive heart failure, shock, and myocardial rupture) increased progressively with the TRI. There also was a significant positively graded association between the TRI and nonfatal heart failure or shock (0.4%-4.4%, P <.0001). In contrast, death resulting from recurrent ischemic events predominated in the lowest TRI group. The relative reduction in death/myocardial infarction with the enoxaparin strategy appeared inversely graded with the TRI. There was a 38% reduction in the lowest risk group (relative risk 0.62, 95% confidence interval 0.45-0.86) and a decrease in the relative benefit of enoxaparin with increasing risk index.

Conclusions

The TRI was a strong predictor of all-cause mortality in a broad population, with a positive association with the risk of death due to mechanical complications and an inverse association with deaths due to recurrent ischemia. The enoxaparin strategy was superior to unfractionated heparin in a majority of patients with ST-elevation myocardial infarction, except for the group at the highest risk for severe mechanical complications, in whom the 2 anticoagulant strategies showed similar results.     

A health comparison of Alabama nurses versus US, UK, and Canadian normative populations

This article is one of a two part series examining the people and environment associated with patient handling. The approach used was that of an occupational injury investigation of a job class, which incorporates defining in the task, environment, tools, and worker health status. Hence, the objective of this portion of the research was to develop a method and use it to compare the physical and mental health of Alabama nurses with known normative populations to determine a baseline of overall health. For this purpose, the validated SF-36© survey was used to collect data on Alabama nurses who had been registered in the state for at least one year. The potential participant pool included 1000 nurses randomly selected from more than 49,000 registered. Physical mailers with a pre-paid return envelope and a follow-up reminder post-card were used. A return rate of 10% was expected based on nursing literature. One hundred and one surveys were returned with 87 being complete. Results confirmed that nursing in the US is a female dominated profession with the survey matching both the Alabama and US national average of 92%. Comparisons of the sample data to general populations yielded significant differences in 3 of the 8 outcome measures: social functioning; physical functioning; bodily pain. In each of these measures, Alabama nurses had a reduced health status compared to at least one comparative population. Additionally, data related to body mass index (BMI) for Alabama nurses were stratified by gender and age. Results indicated 28% had a “healthy” BMI with 37% and 35% of the nurses being “overweight” or “obese”, respectively. Consequently, results suggest Alabama nurses have a reduced health status compared to normative populations and show similar but not identical BMI trends to the general populations for the state of Alabama and the US, which warrants concerns about potential declines in health status among caregivers.

Significance to healthcare

Nurses constitute the largest proportion of the healthcare industry’s workforce. Understanding the perceptions of health status of this employee group is essential to gain further information about possible influences of health on nurses’ ability to continue to perform their jobs.     

Incidence and determinants of moderate COPD (GOLD II) in male smokers aged 40–65 years: 5-year follow up

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major health problem with an estimated prevalence of 10-15% among smokers. The incidence of moderate COPD, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), is largely unknown. AIM: To determine the cumulative incidence of moderate COPD (forced expiratory volume in 1 second/forced vital capacity ratio [FEV1/FVC] <0.7 and FEV1 <80% predicted) and its association with patient characteristics in a cohort of male smokers. DESIGN: Prospective cohort study. SETTING: The city of IJsselstein, a small town in the Netherlands. METHOD: Smokers aged 40-65 years who were registered with local GPs, participated in a study to identify undetected COPD. Baseline measurements were taken in 1998 of 399 smokers with normal spirometry (n = 292) or mild COPD (FEV1/FVC <0.7 and FEV1 >or=80% predicted, n = 107) and follow-up measurements were conducted in 2003. RESULTS: After a mean follow-up of 5.2 years, 33 participants developed moderate COPD (GOLD II). This showed an estimated cumulative incidence of 8.3% (95% CI = 5.8 to 11.4) and a mean annual incidence of 1.6%. No participant developed severe airflow obstruction. The risk of developing moderate COPD in smokers with baseline mild COPD (GOLD I) was five times higher than in those with baseline normal spirometry (one in five versus one in 25). CONCLUSIONS: In a cohort of middle-aged male smokers, the estimated cumulative incidence of moderate COPD (GOLD II) over 5 years was relatively high (8.3%). Age, childhood smoking, cough, and one or more GP contacts for lower respiratory tract problems were independently associated with incident moderate COPD.     

Combat experience and the acquired capability for suicide

Rising suicide rates are an increasing concern among military personnel. The interpersonal‐psychological theory of suicide proposes that three necessary factors are needed to die by suicide: feelings that one does not belong with other people, feelings that one is a burden on others or society, and an acquired capability to overcome the fear and pain associated with suicide. The current study tests the theory's proposal that acquired capability may be particularly influenced by military experience, because combat exposure may cause habituation to fear of painful experiences such as suicide. Utilizing clinical and nonclinical samples of military personnel deployed to Iraq, results of the current study indicate that a greater range of combat experiences predicts acquired capability above and beyond depression and post‐traumatic stress disorder symptoms, previous suicidality, and other common risk factors for suicide. Combat experiences did not, however, predict perceived burdensomeness or thwarted belongingness. The authors discuss how combat experiences might serve as a mechanism for elevating suicide risk and implications for clinical interventions and suicide prevention efforts. © 2010 Wiley Periodicals, Inc. J Clin Psychol: 66:1–13, 2010.     

A validated cultural competence curriculum for US pediatric clerkships

Objective

A 2006 national survey of pediatric clerkship directors revealed that only 25% taught cultural competence, but 81% expressed interest in a validated cultural competence curriculum. The authors designed and evaluated a multi-modality cultural competence curriculum for pediatric clerkships including a validated cultural knowledge test.

Methods

Curriculum content included two interactive workshops, multimedia web cases, and a Cultural and Linguistic Competence Pocket Guide. Evaluation included a student satisfaction survey, a Nominal Technique Focus Group, and a validated knowledge test. The knowledge test comprised 6 case studies with 49 multiple choice items covering the curricular content.

Results

Of 149/160 (93%) students who completed satisfaction surveys using a 5-point Likert scale, >82% strongly agreed or agreed that the curricular intervention was a meaningful experience (93%), increased their understanding of the culture of medicine (91%), increased their knowledge of racial and ethnic disparities (89%) and core cultural issues (91%), and improved their skills in working with interpreters (90%) and cross-cultural communication (82%). Top strengths identified by a focus group (34 students) included learning about interpreters, examples of cultural practices, and raised cultural awareness. Pre- and post-knowledge test scores improved by 17% (p < .0001). After six administrations, the test achieved the target reliability of .7.

Conclusions

The authors successfully designed and validated a practical cultural competence curriculum for pediatric clerkships that meets the need demonstrated in the 2006 national survey.

Practice implications

This curriculum will enable pediatric clerkship directors to equip more graduates to provide culturally sensitive pediatric care to an increasingly diverse US population.     

Clinical correlates of index values in the focus HerpeSelect ELISA for antibodies to herpes simplex virus type 2 (HSV-2).

BACKGROUND: Clinical correlates of HerpeSelect ELISA index values are poorly understood. OBJECTIVES: This study was designed to determine the effects of time of infection, test variability, and antibody avidity on index values. STUDY DESIGN: Sera (N=313) from 81 patients with new HSV-2 infections and 236 sera from 32 patients with long-standing (median 11.3 years) HSV-2 were tested by HerpeSelect HSV-2 ELISA. High positive, low positive and negative controls were run on 42 test plates to establish test variability. RESULTS: Index values tended to rise after infection, peaking a median of 9-10 weeks post-infection (range 8-323 days). Of 32 patients with established HSV-2 infections, 7 (22%) had at least one low index value (>1.1 to < or =3.5), and one had a transient seroreversion event. Test variability of index values was substantially lower than inter- or intra-patient variability. Median antibody avidity was higher in sera with high versus low index values in established infections, but unrelated to index value in patients with early infections. CONCLUSIONS: Index values or index value changes are not absolute indicators of early versus established HSV-2 infection or solely a function of test variability. Low antibody avidity may contribute to low index values once infection is established.     

Chest radiography in general practice: indications, diagnostic yield and consequences for patient management

BACKGROUND: Chest radiography (CXR) is frequently performed in Western societies. There is insufficient knowledge of its diagnostic value in terms of changes in patient management decisions in primary care. AIM: To assess the influence of CXR on patient management in general practice. DESIGN OF STUDY: Prospective cohort study. SETTING: Seventy-eight GPs and three general hospitals in the Netherlands. METHOD: Patients (n = 792) aged > or =18 years referred by their GPs for CXR were included. The main outcome was change in patient management assessed by means of questionnaires filled in by GPs before and after CXR. RESULTS: Mean age of the patients was 57.3+/-16.2 years and 53% were male. Clinically relevant abnormalities were found in 24% of the CXRs. Patient management changed in 60% of the patients following CXR. Main changes included: fewer referrals to a medical specialist (from 26 to 12%); reduction in initiation or change in therapy (from 24 to 15%); and more frequent reassurance (from 25 to 46%). However, this reassurance was not perceived as such in a quarter of these patients. A change in patient management occurred significantly more frequently in patients with complaints of cough (67%), those who exhibited abnormalities during physical examination (69%), or those with a suspected diagnosis of pneumonia (68%). CONCLUSION: Patient management by the GP changed in 60% of patients following CXR. CXR substantially reduced the number of referrals and initiation or change in therapy, and more patients were reassured by their GP. Thus, CXR is an important diagnostic tool for GPs and seems a cost-effective diagnostic test.