Chronic developmental exposure to phenytoin has long-term behavioral consequences

Anti-epileptic compounds have been linked to several developmental disorders. Specifically, fetal exposure to phenytoin is linked to fetal hydantoin syndrome in humans. We have developed a rat model of fetal hydantoin syndrome in an effort to explore the relationship between drug exposure, development, and learning and memory. Previous studies of this animal model have used various embryological periods of exposure; however, the human syndrome is reported in the offspring of mothers that maintain drug regimens throughout gestation and nursing. To that end, the present study investigated associative learning in rats exposed to therapeutic levels of phenytoin throughout prenatal development and the postnatal pre-weaning period. We used an instrumental appetitive-to-aversive transfer paradigm, which has hippocampal-dependent components, and an avoidance-conditioning paradigm to test simple associative learning and higher-order learning and memory. Compared to controls, we report increased rates of acquisition and performance by the phenytoin group in both the appetitive and the avoidance learning paradigm, and a substantial impairment in avoidance learning following the transfer from appetitive to aversive conditioning. The positive deficit observed with simple associative learning and the negative transfer effect associated with higher order learning suggests that chronic exposure to phenytoin throughout gestation disrupts hippocampal development, which subsequently leads to impaired function in adulthood.     

Core temperature variation is associated with heart rate variability independent of cardiac index: a study of 278 trauma patients

Purpose

The purpose of this study is to determine if temperature extremes are associated with reduced heart rate variability (HRV) and “cardiac uncoupling.”

Materials and Methods

This was a retrospective, observational cohort study performed on 278 trauma intensive care unit admissions that had continuous HR, cardiac index (CI), and core temperature data from “thermodilution” Swan-Ganz catheter. Dense (captured second-by-second) physiologic data were divided into 5-minute intervals (N = 136 133; 11 344 hours of data). Mean CI, mean temperature, and integer HR SD were computed for each interval. Critically low HRV was defined as HR SD from 0.3 to 0.6 beats per minute. Temperature extremes were defined as less than 36°C or greater than 39°C.

Results

Low HRV and CI vary with temperature. Temperature extremes are associated with increased risk for critically low HRV (odds ratio, >1.8). Cardiac index increases with temperature until hyperthermia (>40°C). At temperature extremes, changes in CI were not explained solely by changes in HR.

Conclusions

The conclusions of this study are (1) temperature extremes are associated with low HRV, potentially reflecting cardiac autonomic dysfunction; (2) CI increases with temperature; and (3) HRV provides additional physiologic information unobtainable via current invasive cardiac monitoring and current vital signs.     

Thalamic POm projections to the dorsolateral striatum of rats: potential pathway for mediating stimulus-response associations for sensorimotor habits

The dorsolateral part of the striatum (DLS) represents the initial stage for processing sensorimotor information in the basal ganglia. Although the DLS receives much of its input from the primary somatosensory (SI) cortex, peripheral somesthetic stimulation activates the DLS at latencies that are shorter than the response latencies recorded in the SI cortex. To identify the subcortical regions that transmit somesthetic information directly to the DLS, we deposited small quantities of retrograde tracers at DLS sites that displayed consistent time-locked responses to controlled whisker stimulation. The neurons that were retrogradely labeled by these injections were located mainly in the sensorimotor cortex and, to a lesser degree, in the amygdala and thalamus. Quantitative analysis of neuronal labeling in the thalamus indicated that the strongest thalamic input to the whisker-sensitive part of the DLS originates from the medial posterior nucleus (POm), a somesthetic-related region that receives inputs from the spinal trigeminal nucleus. Anterograde tracer injections in POm confirmed that this thalamic region projects to the DLS neuropil. In subsequent experiments, simultaneous recordings from POm and the DLS during whisker stimulation showed that POm consistently responds before the DLS. These results suggest that POm could transmit somesthetic information to the DLS, and this modality-specific thalamostriatal pathway may cooperate with the thalamostriatal projections that originate from the intralaminar nuclei.     

FIRST-DOSE RESPONSE TO ANGIOTENSIN-CONVERTING ENZYME INHIBITION IN CONGESTIVE CARDIAC FAILURE: A MALAYSIAN EXPERIENCE

Despite their proven value in reducing morbidity and mortality in different grades of heart failure, angiotensin converting enzyme (ACE) inhibitors continue to be underused. One reason for this is clinicians' apprehension of first-dose hypotension. We conducted a double-blind, randomised, placebo-controlled parallel group study to investigate the effect of various ACE inhibitors on first-dose hypotension. Eighty unselected patients were randomised into five treatment groups: placebo, captopril 6.25 mg, enalapril 2.5 mg, perindopril 2 mg and lisinopril 2.5 mg. Blood pressure was measured at baseline, half hourly for two hours and hourly for three hours after drug treatment. The maximum drops in mean arterial pressure (in mmHg ± SD) were placebo 5.89 ± 2.65, perindopril 5.29 ± 2.49, enalapril 13.28 ± 3.31, lisinopril 15.04 ± 5.74 and captopril 16.76 ± 5.74 (all p< 0.05 vs placebo except for perindopril). Perindopril, unlike the other ACE inhibitors studied, did not produce first-dose hypotension following its initiation in patients with congestive heart failure.     

Hemoglobin Nigeria (alpha-81 Ser replaced by Cys):a new variant associated with alpha-thalassemia

Hematologic evaluation of a Nigerian obstetrical patient disclosed the presence of sickle-cell trait as well as evidence of a hemoglobin alpha- chain abnormality. Hemoglobins containing the variant alpha-chain were isolated by DEAE-cellulose column chromatography, and analysis of the purified alpha-chain demonstrated a ser replaced by cys substitution at alpha-81. The abnormal alpha-chain represented approximately 45% of the total, and hemoglobins containing this alpha-chain appeared to have normal stability and functional properties. In addition to the abnormal hemoglobins that were identified in this patient, she also was found to have persistent microcytosis in the absence of iron deficiency, and the percentage of HbS in her erythrocytes was less than that usually present in individuals with sickle cell trait. These findings, together with a reduced alpha/beta globin synthesis ratio from her peripheral blood reticulocytes, indicated that the presence of alpha-thalassemia trait. Hematologic findings from members of the patients's family suggest that an alpha-thalassemia gene may be linked to that of the structurally abnormal alpha-chain.     

Menthol Brand Switching Among Adolescents and Young Adults in the National Youth Smoking Cessation Survey

This study examines patterns of menthol and nonmenthol cigarette use from 2003 to 2005 in a cohort of smokers, aged 16 to 24 years in the National Youth Smoking Cessation Survey. At follow-up, 15.0% of baseline menthol smokers had switched to nonmentholated cigarettes; by contrast, 6.9% of baseline nonmenthol smokers had switched to mentholated cigarettes. Differences in switching patterns were evident by gender, race/ethnicity, parental education, and smoking frequency. These data support previous evidence that young smokers start with mentholated cigarettes and progress to nonmentholated cigarettes.Following enactment of the Family Smoking Prevention and Tobacco Control Act in June 2009,1 fruit, candy, and clove characterizing flavorings in cigarettes were banned to reduce youth smoking initiation. Menthol is the only characterizing flavor that was not banned outright by the act. Nationally representative surveys have shown an age gradient in menthol use, with the youngest smokers (aged 12–17 years) most likely to smoke mentholated cigarettes.2^,3 Studies of adolescents report that middle school smokers and recent initiates are more likely to use mentholated cigarettes than high school smokers and those smoking longer than 1 year, respectively.4 With other studies,5–7 these results argue that menthol facilitates smoking initiation and that mentholated cigarettes serve as starter tobacco products for youths.4Although these nationally representative studies document an age gradient in menthol use, they do not address smoking patterns in the same individuals over time and whether there is a disproportionate shift from early use of mentholated cigarettes to nonmentholated cigarette use later on. The current study assesses patterns in menthol and nonmenthol cigarette use over time in young smokers, aged 16 to 24 years.     

A primer on medical education in the United States through the lens of a current resident physician

Physician training and standards for medical licensure differ widely across the globe. The medical education process in the United States (US) typically involves a minimum of 11 years of formal training and multiple standardized examinations between graduating from secondary school and becoming an attending physician with full medical licensure. Students in the US traditionally enter a 4-year medical school after completing an undergraduate bachelor’s degree, in contrast to most other countries where medical training begins after graduation from high school. Medical school seniors planning to practice medicine in the US must complete postgraduate clinical training, referred to as residency, within the specialty of their choosing. The duration of residency varies depending on specialty, typically lasting between 3 and 7 years. For subspecialty fields, additional clinical training is often required in the form of a fellowship. Many experts have called for changes in the medical education system to shorten medical training in the US, and reforms are ongoing in some institutions. However, physician education in the US generally remains a progression from undergraduate premedical coursework to 4 years of medical school, followed by residency training with an optional subspecialty fellowship.