Ethanol modulates BKCa channels by acting as an adjuvant of calcium

Ethanol modulation of calcium- and voltage-gated potassium (slo1) channels alters neuronal excitability, cerebrovascular tone, brain function, and behavior, yet the mechanism of this modulation remains unknown. Using patch-clamp electrophysiology on recombinant BK(Ca) channels cloned from mouse brain and expressed in Xenopus laevis oocytes, we demonstrate that ethanol, even at concentrations maximally effective to modulate BK(Ca) channel function (100 mM), fails to gate the channel in absence of activating calcium. Moreover, ethanol does not modify intrinsic, voltage- or physiological magnesium-driven gating. The alcohol works as an adjuvant of calcium by selectively facilitating calcium-driven gating. This facilitation, however, renders differential ethanol effects on channel activity: potentiation at low (<10 microM) and inhibition at high (>10 microM) calcium, this dual pattern remaining largely unmodified by coexpression of brain slo1 channels with the neuronally abundant BK(Ca) channel beta(4) subunit. Calcium recognition by either of the slo1 high-affinity sensors (calcium bowl and RCK1 Asp362/Asp367) is required for ethanol to amplify channel activation by calcium. The Asp362/Asp367 site, however, is necessary and sufficient to sustain ethanol inhibition. This inhibition also results from ethanol facilitation of calcium action; in this case, ethanol favors channel dwelling in a calcium-driven, low-activity mode. The agonist-adjuvant mechanism that we advance from the calcium-ethanol interaction on slo1 might be applicable to data of ethanol action on a wide variety of ligand-gated channels.     

Gender, alcohol consumption, and renal cell carcinoma

The nature of the association between alcohol consumption and renal cell carcinoma (RCC) is not well understood, but there are indications of effect modification by gender. The authors report data from a population-based case-control study conducted in Iowa from 1986 to 1989. RCC cases (261 men and 145 women) were identified through the Iowa Cancer Registry, while controls (1,598 men and 831 women) were randomly selected from the general population, frequency matched on age and gender. Subjects provided detailed information on a mailed questionnaire regarding demographic, anthropometric, lifestyle, dietary, and medical history risk factors. In age-adjusted analysis, there was a decrease in risk for women who reported consuming more than three servings (median among drinkers) of alcohol per week (odds ratio = 0.5, 95% confidence interval: 0.2, 0.9) compared with never drinkers. No evidence of an association among men was noted (odds ratio = 1.1, 95% confidence interval: 0.8, 1.5). Multivariate adjustment for anthropometric, lifestyle, smoking, and dietary factors did not alter the findings. Analysis by type of alcohol suggested that the inverse association was strongest for beer consumption, but estimates were imprecise. These findings suggest an inverse association of alcohol consumption and RCC development among women but not among men.     

Child maltreatment,alcohol use and drinking consequences among male and female college students: An examination of drinking motives as mediators

Although the relationship between child maltreatment and alcohol use and drinking problems is well established, the mechanisms involved in this relationship remain largely unknown and research has focused primarily on women. Using the Modified Drinking Motives Questionnaire-Revised (M-DMQ-R; Grant, Stewart, O'Connor, Blackwell & Conrod, 2007), drinking motives were examined as mediators in the relationship between childhood maltreatment and alcohol consumption and consequences among male and female college student drinkers (N = 218, 60.6% women). Participants completed questionnaires assessing child maltreatment, drinking motives, alcohol consumption and alcohol consequences. Enhancement motives in particular mediated the relationship between childhood abuse and alcohol consequences for men, whereas coping-depression motives mediated this relationship for women. Implications of these findings for alcohol interventions and future research are discussed, along with limitations of the present study.     

Managing children with acute non‐traumatic limp: the utility of clinical findings,laboratory inflammatory markers and X‐rays

Objectives: To examine the utility of clinical findings, laboratory markers and X‐ray radiographs (X‐ray) in the assessment of children presenting with an acute non‐traumatic limp. Methods: A retrospective review of all children who received hip X‐rays over a 2 year period in the Children's Emergency Department, Starship Children's Hospital, Auckland, New Zealand. Children were identified from the radiology database and clinical notes reviewed. Children aged 0–12 years old were included if the limp was acute (less than 2 weeks of duration) with no history of trauma. X‐rays were reported by a consultant paediatric radiologist. Univariate and multivariate analysis was performed to determine predictors of osteomyelitis and septic arthritis. Receiver operator curves were used to assess the optimum cut‐off points for C reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white cell count (WCC). Results: A total of 350 patients were enrolled. There were 21 (6%) abnormal X‐rays . Fever, non‐weight bearing, raised white cell count, raised erythrocyte sedimentation rate and raised CRP were all associated with increased risk of septic hip or osteomyelitis. The optimum inflammatory marker cut‐off was a CRP of 12 with a sensitivity of 87% and specificity of 91%. Conclusion: In acute non‐traumatic limp, X‐rays of the hips diagnose slipped upper femoral epiphysis, as such they should be routinely used from the age of 9 years upwards. Below this age they are of little value. Inflammatory markers have utility in risk‐stratifying children and selecting a group in whom to proceed with definitive tests to exclude osteomyelitis or septic hip. Children with a short history and minimal symptoms can be managed with appropriate follow up and no investigations.     

Personalized Medicine for Diabetes: Environmental Influences on Development of Type 2 Diabetes and Obesity: Challenges in Personalizing Prevention and Management

Recent epidemic increases in the U.S. prevalence of obesity and diabetes are a consequence of widespread environmental changes affecting energy balance and its regulation. These environmental changes range from exposure to endocrine disrupting pollutants to shortened sleep duration to physical inactivity to excess caloric intake. Overall, we need a better understanding of the factors affecting individual susceptibility and resistance to adverse exposures and behaviors and of determinants of individual response to treatment. Obesity and diabetes prevention will require responding to two primary behavioral risk factors: excess energy intake and insufficient energy expenditure. Adverse food environments (external, nonphysiological influences on eating behaviors) contribute to excess caloric intake but can be countered through behavioral and economic approaches. Adverse built environments, which can be modified to foster more physical activity, are promising venues for community-level intervention. Techniques to help people to modulate energy intake and increase energy expenditure must address their personal situations: health literacy, psychological factors, and social relationships. Behaviorally oriented translational research can help in developing useful interventions and environmental modifications that are tailored to individual needs.     

Airway interventions in children with Pierre Robin Sequence

OBJECTIVE: To describe the interventions required for successful airway management in children with Pierre Robin Sequence (PRS). STUDY DESIGN: Case series. SUBJECTS AND METHODS: The records of both a cleft and craniofacial clinic and a pediatric otolaryngology clinic were searched, and all children with PRS were identified. Data concerning feeding interventions, airway interventions, and comorbid conditions were extracted. RESULTS: Seventy-four cases of PRS were identified. Thirty-eight of the 74 children required airway intervention other than prone positioning. Fourteen of these 38 were managed nonsurgically with nasopharyngeal airway and/or short-term endotracheal intubation, whereas the remaining 24 required surgical intervention. Eighteen of the 24 underwent distraction osteogenesis of the mandible, one underwent tracheostomy, and five underwent tracheostomy followed by eventual distraction. CONCLUSION: In our series, over 50 percent of children with PRS required an airway intervention. These were both nonsurgical and surgical. As otolaryngologists, we must be prepared for the challenges children with PRS may present and the interventions that may be necessary to successfully manage these difficult airways.     

Student USMLE Step 1 Preparation and Performance

Objectives: Many medical students take commercial preparation courses to prepare for the USMLE Step 1. This investigation examined the relationships among Step 1 performance, preparation method, and academic achievement in medical school. Method: A survey was conducted on 148 junior students at a medical school in July 2000 regarding their preparation methods for Step 1. Additional data was collected on student Step 1 scores, attendance record on preparation courses, and course grades in medical school. Results: One hundred students (68%) responded to the survey including 32 preparation course participants. Course participants had significantly lower Step 1 scores and second-year GPAs than those of the non-participants (p < 0.05). However, the effect of preparation method was not significant by using ANCOVA when the second-year GPA was used as a covariate (p = 0.71). Conclusion: Performance on Step 1 is related to academic performance in medical school and not the type of preparation methods.     

Why and how to improve physical activity promotion: Lessons from behavioral science and related fields

This commentary highlights the importance of regular physical activity to the nation’s health and discusses some of the major challenges and opportunities currently facing the field.     

Role of Plasma Vasopressin in Impaired Water Excretion of Glucocorticoid Deficiency

In the present study, the effect of selective glucocorticoid deficiency on renal water excretion was investigated in conscious, trained, adrenalectomized dogs. The animals were studied before and after a water load while on replacement therapy of desoxycorticosterone acetate, 5 mg/day, and dexamethasone, 0.8 mg/day (group I), and while off dexamethasone for 5-9 days (group II). Before the water load the weight, inulin space, cardiac output, blood pressure, glomerular filtration rate, renal blood flow, plasma osmolality, and plasma antidiuretic hormone measured by radioimmunoassay were similar in both groups I and II. However, after a 40 ml/kg water load a marked impairment in renal water excretion in the glucocorticoid deficient dogs became apparent. Maximal free water clearance was −0.046±0.16 vs. 6.51±0.72 ml/min (P < 0.001) and minimal urinary osmolality was 425±56 vs. 82±3.5 mosmol/kg H₂O (P < 0.001) in group II as compared to group I. Plasma antidiuretic hormone was maximally suppressed during the water load in group I to 0.34±0.08 pg/ml but remained elevated at 9.18±1.79 pg/ml (P < 0.005) in group II. This nonsuppressibility of plasma antidiuretic hormone during water loading in group II was associated with a significant tachycardia of 145±6 vs. 87±6 beats/min (P < 0.001) in group I and a significantly lower stroke volume of 27±0 vs. 59±0.5 ml/beat (P < 0.001). In conclusion, our results implicate a persistent secretion of antidiuretic hormone as an important factor in the impaired water excretion of glucocorticoid deficiency. A deleterious effect of glucocorticoid deficiency on cardiac function was observed and this hemodynamic alteration could be involved in initiating a nonosmolar, baroreceptor-mediated release of vasopressin.