Field and Laboratory Alcohol Detection With 2 Types of Transdermal Devices

Background: Two types of transdermal electrochemical sensors that detect alcohol at the skin surface were evaluated. One, the AMS SCRAM? device, is locked onto the ankle and is based on a fuel cell sensor; the other, a Giner WrisTAS? device, worn on the wrist, is based on a proton exchange membrane. SCRAM is used by several court systems in the United States to monitor alcohol offenders, WrisTAS, a research prototype, is not commercially available. Methods: The 2 devices were worn concurrently by 22 paid research subjects (15 men, 7 women), for a combined total of 96 weeks. Subjects participated in both laboratory‐dosed drinking to a target of 0.08 g/dl blood alcohol concentration (BAC), and normal drinking on their own; all subjects were trained to use and carry a portable fuel‐cell breath tester for BAC determinations. Overall 271 drinking episodes with BAC ≥ 0.02 g/dl formed the signal for detection—60 from laboratory dosing, and 211 from self‐dosed drinking, with BAC ranging from 0.02 to 0.230 g/dl (mean 0.077 g/dl). Results: False negatives were defined as a transdermal alcohol concentration response equivalent <0.02 g/dl when BAC ≥ 0.02 g/dl. The overall true‐positive hit rate detected by WrisTAS was 24%. The low detection rate was due to erratic output and not recording during nearly 67% of all episodes; reportedly a chipset, not a sensor problem. SCRAM correctly detected 57% across all BAC events, with another 22% (total 79%) detected, but as <0.02 g/dl. When subjects dosed themselves to BAC ≥ 0.08 g/dl, SCRAM correctly detected 88% of these events. SCRAM devices lost accuracy over time likely due to water accumulation in the sensor housing. Neither unit had false‐positive problems when true BAC was <0.02 g/dl. Conclusions: Each device had peculiarities that reduced performance, but both types are able to detect alcohol at the skin surface. With product improvements, transdermal sensing may become a valuable way to monitor the alcohol consumption of those who should be abstaining.     

Acute Effect of Alcohol on Estradiol, Estrone, Progesterone, Prolactin, Cortisol, and Luteinizing Hormone in Premenopausal Women

BACKGROUND: Heavy alcohol consumption is associated with menstrual irregularities, including anovulation, luteal-phase dysfunction, recurrent amenorrhea, and early menopause. In addition, moderate to heavy alcohol intake has been found to increase the risk of spontaneous abortions and breast cancer. These adverse effects could at least in part originate from alcohol-mediated changes in hormone levels. METHODS: The acute effect of alcohol on the hormone balance in women using oral contraceptives (OC+) and also in nonusers (OC-), was evaluated in 30 OC- and 31 OC+ subjects, representing the whole period of the menstrual cycle. It was also evaluated in 40 OC- and 47 OC+ subjects during the midcycle phase and in 10 OC+ subjects with unknown cycle phase. RESULTS: We found that among subjects who used oral contraceptives, estradiol levels increased and progesterone levels decreased after intake of alcohol (0.5 g/kg). No dose effect (0.34-1.02 g/kg) on progesterone was observed in a substudy on 10 OC+ subjects. With regard to estrone levels, no effect was observed, although a significant increase was found in the estradiol-to-estrone ratio. Among subjects not using oral contraceptives, progesterone levels decreased after intake of alcohol (0.5 g/kg). No effect was found in estradiol, estrone, or the estradiol-to-estrone ratio during midcycle in this study group. A transient elevating effect of alcohol (0.5 g/kg) on prolactin levels was observed in both study groups. We found that alcohol (0.5 g/kg) had no significant effect on luteinizing hormone (LH) levels among subjects not using oral contraceptives, and observed a decline among subjects using oral contraceptives at midcycle. CONCLUSIONS: We suggest that the estradiol and progesterone effects are related to decreased steroid catabolism, resulting from the alcohol-mediated increase in the hepatic NADH-to-NAD ratio. The transient effect on prolactin levels may reflect acute changes in opioid and dopamine levels in the hypothalamus. The present findings regarding female sex steroids may be of relevance in the association between moderate to heavy alcohol consumption and the development of breast cancer.     

Effects of a moderate evening alcohol dose. II: performance

BACKGROUND: This second of a pair of papers investigates the effects of a moderate dose of alcohol and staying up late on driving simulation performance and simple visual reaction time (RT) at a known circadian phase in well-rested young adults. METHODS: Twenty-nine adults (9 males), ages 21 to 25 years, spent 1 week on an at-home stabilization schedule of 8.5 to 9 hours, followed by 3 nonconsecutive nights in-lab: adaptation, placebo, and alcohol. Performance task practice occurred on 3 occasions before the study. Alcohol (vodka; 0.54 g/kg men; 0.49 g/kg women mixed with tonic) was consumed over 30 minutes ending 1 hour before normal bedtime; the same quantity of beverage was given on placebo. Driving simulation (with drive-only and dual-task drive and subtract components) and psychomotor vigilance task (PVT) testing occurred before and after alcohol/placebo ingestion. Breath alcohol concentration (BrAC) readings were taken before all test sessions. Saliva samples were taken approximately every 30 minutes to determine circadian phase. RESULTS: Driving simulation and PVT variables significantly deteriorated with increasing time awake. Driving simulator lane variability was worse with alcohol compared with placebo at 15.5 hours awake. No PVT variable showed an effect of alcohol. CONCLUSIONS: Driving simulation performance deteriorated with extended waking and with alcohol; driving was most impaired at the peak alcohol level. The PVT, less complex than the driving simulation, did not show effects of alcohol, a finding consistent with previous literature that disruptive effects of low alcohol concentrations increase with task complexity. Overall, simulated driving performance is significantly impaired late at night when even a moderate dose of alcohol is consumed.     

Influence of acute alcohol ingestion on the hormonal responses to modest hypoglycaemia in patients with Type 1 diabetes.

AIMS: To determine whether mild alcohol intoxication (45-50 mg/dl) influences counterregulatory hormone responses to moderate hypoglycaemia (2.8 mmol/l)in patients with Type 1 diabetes. METHODS: Seventeen subjects (14 male, age range 21-46 years) with Type 1 diabetes underwent four hyperinsulinaemic glucose clamps: euglycaemia with placebo; euglycaemia with alcohol (0.4 g/kg); hypoglycaemia (2.8 mmol/l for 65 min)with placebo; and hypoglycaemia (2.8 mmol/l for 65 min) with alcohol (0.4 g/kg).Arterialized venous blood samples were taken for measurement of insulin and counterregulatory hormones. RESULTS: During hypoglycaemia, peak growth hormone concentrations were significantly lower after alcohol compared with placebo (14.3 +/- 2.9 vs.25.9 +/- 3.4 microg/l,P< 0.001) associated with reduced insulin sensitivity in both hypoglycaemia and euglycaemia studies. CONCLUSIONS: We found an attenuated growth hormone response to hypoglycaemia associated with mild alcohol intoxication. Although this may potentially contribute to impaired recovery of glucose after hypoglycaemia in patients with Type 1 diabetes, it appears to be offset by a reduction in insulin action.     

Reversal of steroid-induced insulin resistance by a nicotinic-acid derivative in man.

A recent report suggested that the glucose-free fatty acid (FFA) cycle may contribute to steroid-induced insulin resistance in rats, and that glucose tolerance could be restored to normal when FFA levels were lowered with nicotinic acid. To test this hypothesis in man, we measured insulin sensitivity (by euglycemic insulin clamp in combination with indirect calorimetry and infusion of tritiated glucose) before and after short-term administration of a nicotinic-acid derivative (Acipimox) in 10 steroid-treated, kidney transplant patients with insulin resistance. Thirty-five healthy subjects served as controls. Six of them received Acipimox. Total body glucose metabolism was reduced in steroid-treated patients compared with control subjects (41.7 +/- 3.3 v 50.0 +/- 2.2 mumol/kg lean body mass [LBM].min, P less than .05). The reduction in insulin-stimulated glucose uptake was mainly due to an impairment in nonoxidative glucose metabolism (primarily glucose storage as glycogen) (18.3 +/- 2.8 v 27.2 +/- 2.2 mumol/kg LBM.min, P less than .01). Acipimox lowered basal FFA concentrations (from 672 +/- 63 to 114 +/- 11 mumol/L, P less than .05) and the rate of lipid oxidation measured in the basal state (1.5 +/- 0.2 to 0.6 +/- 0.1 mumol/kg LBM.min, P less than .01) and during the clamp (0.7 +/- 0.2 to 0.03 +/- 0.2 mumol/kg LBM.min, P less than .05). In addition, Acipimox administration normalized total glucose disposal (to 54.4 +/- 4.4 mumol/kg LBM.min), mainly due to enhanced nonoxidative glucose metabolism (to 28.9 +/- 3.9 mumol/kg LBM.min) in steroid-treated patients (both P less than .05 v before Acipimox).(ABSTRACT TRUNCATED AT 250 WORDS)     

Variability of Ethanol Absorption and Breath Concentrations During a Large-Scale Alcohol Administration Study

Ethanol disposition was evaluated in 77 female and 97 male college seniors during an alcohol challenge study. All were regular drinkers who exceeded legal intoxication levels at least twice a month by history. A standard ethanol dose (females, 0.43 g/kg; males, 0.51 g/kg) was administered over 10 min, after a 4-hr fast, and breath alcohol concentrations (BrACs) were measured for 2 hr. Intersubject variability in BrACs was greatest early in the study, during ethanol absorption; the coefficient of variation decreased from 39% at 14 min to 14% at 125 min after the start of drinking. The time to peak BrAC varied from 10 to 91 min after the start of drinking (mean 39.6 min). Mean BrACs were significantly lower in females than males; mean peak BrACs were 0.054 g/210 liters in females and 0.058 g/210 liters in males ( p = 0.031). The β and r-values for both genders were higher than those typically used in ethanol dose calculation formulas. Data are discussed to direct future research. The constants used in Widmark's formula need to be revised differentially for males and females in this population to reach specific target BrACs. Furthermore, substantial variability in absorption rates must be accounted for when assessing rising versus falling limb BrAC phenomena.     

Subjective and objective responses to ethanol in moderate/heavy and light social drinkers

BACKGROUND: Individuals who drink heavily are at an increased risk for adverse consequences of drinking and progression of their drinking habits to abuse or dependence. Therefore, it is important to delineate factors associated with their heavy drinking. METHODS: We examined individual differences in subjective and objective responses to ethanol associated with level of consumption by reanalyzing data from the nine heaviest and nine lightest social drinkers from each of two independently collected subject samples: Holdstock and de Wit (1998) and King et al. (1997). The light drinkers in both samples consumed five or less alcoholic drinks per week, whereas the moderate/heavy drinkers consumed eight or more drinks per week with frequent binge episodes. Acute subjective and objective responses to ethanol (0.6 or 0.8 g/kg) or placebo were compared in the two groups at baseline and during rising and falling blood alcohol concentrations. RESULTS: Moderate/heavy drinkers reported greater stimulant-like and fewer sedative-like and aversive subjective effects after ethanol than did lighter drinkers. These differences occurred in the absence of any group differences in breath alcohol levels, performance effects, or neuroendocrine changes or in overall reports of feeling any drug effects. CONCLUSIONS: These data indicate that habitual moderate/heavy ethanol use was associated with greater stimulant-like effects after an acute dose of alcohol. This finding is consistent with the idea (Newlin and Thomson, 1990, 1999) that individuals who experience greater stimulant-like effects during the ascending limb and lesser sedative-like effects on the descending limb of the blood alcohol concentration curve may be at greater risk for developing ethanol use disorders. Although we cannot determine the causality of this association, sensitivity to the stimulant effects of ethanol may play an important role in the continuation of heavy ethanol use and the increased risk of negative consequences from this use.     

Evaluation of the reproducibility of the GHRH plus GHRP-6 test of growth hormone reserve in adults

BACKGROUND: The diagnosis of GH deficiency (GHD) is controversial, relying on GH secretion elicited by the provocative tests of GH reserve. However, the performance of most of the tests in use have not been evaluated rigorously. The repeatability of a test is a prerequisite before evaluating its diagnostic capability. OBJECTIVE: The combined administration of GH-releasing hormone (GHRH) and GH-releasing hexapeptide (GHRP-6) is an efficacious test of GH reserve in adults, and the target of this work was to evaluate its reproducibility. METHODS: Seventeen healthy subjects were challenged with GHRH plus GHRP-6 (1 micro g/kg i.v.). All subjects underwent four tests on different days separated by at least 2 months. GH peaks were evaluated by several mathematical analyses of reproducibility. RESULTS: As a group, the subjects showed high reproducibility after the four tests, with GH peaks of 46.0 +/- 5.1; 48.4 +/- 6.4; 50.1 +/- 5.4 and 52.9 +/- 5.8 micro g/l, respectively (1 micro g/l = 3 mU/l). Individually analysed, the reproducibility was good, and the regression analysis showed a correlation between tests 1 and 2 of R = 0.729, P < 0.0009, between tests 1 and 3 of R = 0.710, P < 0.001, and between tests 1 and 4 of R = 0.683, P < 0.002. Under mathematical analysis, the multiple correlation coefficient analysis, analysis of variance (anova) with repeated measurements, repeatability index, the simplest coefficient of variation and the intraclass correlation coefficient (ICC) all unambiguously showed that the GHRH + GHRP-6 test was reproducible. Furthermore, the repeated tests did not alter the biochemical diagnosis of the subjects, with absence of false-positive values. CONCLUSIONS: The GHRH + GHRP-6 test of GH reserve is reproducible in adult subjects.     

Alcohol Expectancies and Behavioral and Emotional Responses to Placebo Versus Alcohol Administration

Forty normal drinking males were recruited for a study of "responses to alcohol." Following the completion of an alcohol use questionnaire that included measures of expectancies of alcohol effects, subjects were randomly assigned to either receive the actual 0.6 g/kg dose of ethanol to bring their peak blood alcohol concentration (BAC) to near 0.075 g/dl or to receive a placebo dose. Neither the subject nor the tester was aware of the condition to which the subject has been assigned. Prior to dosing and at repeated 1/2-hr intervals following dosing, subjects were tested on a battery of motor coordination, perceptual speed, reaction time, and mood measures. Significant alcohol effects were found for several measures, but the only significant interaction of individual differences in expectancies of alcohol effects with alcohol dosing occurred for self-perceived intoxication. Subjects who expected more disinhibition after alcohol dosing and who were administered alcohol reported more intoxication than those expecting less disinhibition, while no expectancy effect was found for subjects administered the placebo.     

Alcohol, Cocaine, and Brain Stimulation-Reward in C57Bl6/J and DBA2/J Mice

Background: Pleasure and reward are critical features of alcohol drinking that are difficult to measure in animal studies. Intracranial self‐stimulation (ICSS) is a behavioral method for studying the effects of drugs directly on the neural circuitry that underlies brain reward. These experiments had 2 objectives: first, to establish the effects of alcohol on ICSS responding in the C57Bl6/J (C57) and DBA2/J (DBA) mouse strains; and second, to compare these effects to those of the psychostimulant cocaine. Methods: Male C57 and DBA mice were implanted with unipolar stimulating electrodes in the lateral hypothalamus and conditioned to spin a wheel for reinforcement by the delivery of rewarding electrical stimulation (i.e., brain stimulation‐reward or BSR). Using the curve‐shift method, the BSR threshold (θ₀) was determined immediately before and after oral gavage with alcohol (0.3, 0.6, 1.0, 1.7 g/kg) or water. Blood alcohol concentration (BAC) was measured to determine the influence of alcohol metabolism on BSR threshold. Separately, mice were administered cocaine (1.0, 3.0, 10.0, 30.0 mg/kg) or saline intraperitoneally. Results: In C57 mice, the 0.6 g/kg dose of alcohol lowered BSR thresholds by about 20%, during the rising (up to 40 mg/dl), but not falling, phase of BAC. When given to the DBA mice, alcohol lowered BSR thresholds over the entire dose range; the largest reduction was by about 50%. Cocaine lowered BSR thresholds in both strains. However, cocaine was more potent in DBA mice than in C57 mice as revealed by a leftward shift in the cocaine dose–response curve. For both alcohol and cocaine, effects on BSR threshold were dissociable from effects on operant response rates. Conclusions: In C57 and DBA mice, reductions in BSR threshold reflect the ability of alcohol to potentiate the neural mechanisms of brain reward. The DBA mice are more sensitive to the reward‐potentiating effects of both alcohol and cocaine, suggesting that there are mouse strain differences in the neural mechanisms of brain reward that can be measured with the ICSS technique.     

Significant Increase of Blood Alcohol by Cimetidine after Repetitive Drinking of Small Alcohol Doses

To assess effects of repetitive alcohol drinking and pre-existing first-pass metabolism on the cimetidine induced increase in blood alcohol concentrations, 20 healthy men (aged 20 to 40) of varied ethnicity and consuming less than 60 g alcohol per week underwent baseline quantitation of first-pass metabolism of alcohol. This was followed by oral administration of 0.6 g/kg ethanol given postprandially in 3 to 4 drinks spread over 135 min, before and after cimetidine (400 mg twice a day for 7 days). Blood alcohol concentrations were determined by breath analysis. First-pass metabolism was quantified by applying Michaelis-Menten kinetics to blood alcohol curves after intravenous or oral administration of equal alcohol doses. At baseline, 15 subjects had a substantial first-pass metabolism (over one sixth of the dose); their alcohol levels increased with repeated doses with a mean peak of 27 ± 3 mg/dl before and 39 ± 5 after cimetidine ( P < 0.01), an effect much greater and longer than after a single alcohol dose. Three subjects exceeded 50 mg/dl, the legal limit for driving in several countries. By contrast, in the five subjects with minimal first-pass metabolism, cimetidine did not increase alcohol levels. Thus, under conditions mimicking social drinking, cimetidine increased blood alcohol to concentrations known to impair psychomotor skills and they persisted at those levels over prolonged periods of time. In a minority of subjects, no such interaction was found, but their first-pass metabolism at baseline was absent or minimal and thus no inhibition by the drug was to be expected.     

Effects of Moderate Alcohol Consumption on the Central Nervous System*

The concept of moderate consumption of ethanol (beverage alcohol) has evolved over time from considering this level of intake to be nonintoxicating and noninjurious, to encompassing levels defined as “statistically” normal in particular populations, and the public health-driven concepts that define moderate drinking as the level corresponding to the lowest overall rate of morbidity or mortality in a population. The various approaches to defining moderate consumption of ethanol provide for a range of intakes that can result in blood ethanol concentrations ranging from 5 to 6 mg/dl, to levels of over 90 mg/dl (i.e., 20 mM). This review summarizes available information regarding the effects of moderate consumption of ethanol on the adult and the developing nervous systems. The metabolism of ethanol in the human is reviewed to allow for proper appreciation of the important variables that interact to influence the level of exposure of the brain to ethanol once ethanol is orally consumed. At the neurochemical level, the moderate consumption of ethanol selectively affects the function of GABA, glutamatergic, serotonergic, dopaminergic, cholinergic, and opioid neuronal systems. Ethanol can affect these systems directly, and/or the interactions between and among these systems become important in the expression of ethanol's actions. The behavioral consequences of ethanol's actions on brain neurochemistry, and the neurochemical effects themselves, are very much dose- and time-related, and the collage of ethanol's actions can change significantly even on the rising and falling phases of the blood ethanol curve. The behavioral effects of moderate ethanol intake can encompass events that the human or other animal can perceive as reinforcing through either positive (e.g., pleasurable, activating) or negative (e.g., anxiolysis, stress reduction) reinforcement mechanisms. Genetic factors and gender play an important role in the metabolism and behavioral actions of ethanol, and doses of ethanol producing pleasurable feelings, activation, and reduction of anxiety in some humans/animals can have aversive, sedative, or no effect in others. Research on the cognitive effects of acute and chronic moderate intake of ethanol is reviewed, and although a number of studies have noted a measurable diminution in neuropsychologic parameters in habitual consumers of moderate amounts of ethanol, others have not found such changes. Recent studies have also noted some positive effects of moderate ethanol consumption on cognitive performance in the aging human. The moderate consumption of ethanol by pregnant women can have significant consequences on the developing nervous system of the fetus. Consumption of ethanol during pregnancy at levels considered to be in the moderate range can generate fetal alcohol effects (behavioral, cognitive anomalies) in the offspring. A number of factors–including gestational period, the periodicity of the mother's drinking, genetic factors, etc.–play important roles in determining the effect of ethanol on the developing central nervous system. A series of recommendations for future research endeavors, at all levels, is included with this review as part of the assessment of the effects of moderate ethanol consumption on the central nervous system     

Low- and standard-dose corticotropin and insulin hypoglycemia testing in the assessment of hypothalamic-pituitary-adrenal function after pituitary surgery

The optimal means of assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis after pituitary surgery remains controversial. We compared low-dose (1 micro g iv) and standard-dose (250 micro g im) corticotropin tests performed 1 and 4-6 wk after pituitary surgery with an insulin hypoglycemia test performed at 4-6 wk. Forty-one patients (21 male and 20 female; median age, 52 yr; range, 23-73 yr) who had undergone pituitary surgery were studied (Cushing's disease excluded). Twenty-two of the 41 patients had normal cortisol responses to all tests both at 1 and 4-6 wk after surgery. Eight patients had subnormal cortisol responses to all tests. Of the 11 patients with discrepant results, seven had subnormal responses only after the low-dose corticotropin test; the remaining four patients had borderline responses to one or more tests. At 4-6 wk after surgery, subjects with a 30-min serum cortisol after standard-dose corticotropin of less than 350 nmol/liter (12.7 micro g/dl) consistently had a subnormal response to hypoglycemia, and those with a serum cortisol greater than 650 nmol/liter (23.6 micro g/dl) had a normal response to hypoglycemia. Definitive testing of the HPA axis using the standard-dose corticotropin test can be carried out provided it is performed at least 4 wk after pituitary surgery. A 30-min cortisol level greater than 650 nmol/liter (23.6 micro g/dl) indicates adequacy of the HPA axis, and a level of less than 350 nmol/liter (12.7 micro g/dl) indicates ACTH deficiency. No further testing is then required. An intermediate level of 350-650 nmol/liter (12.7-23.6 micro g/dl) warrants further assessment using the insulin hypoglycemia test.     

Dose-dependent deficits in dual interstimulus interval classical eyeblink conditioning tasks following neonatal binge alcohol exposure in rats

Background: Neonatal alcohol consumption in rats is widely used to model cerebellar injury arising from 3rd‐trimester human fetal alcohol exposure. Binge alcohol exposure of 5 g/kg/day or more over postnatal days (PD) 4 to 9 in rats damages the cerebellum and consequently impairs classical eyeblink conditioning (EBC). The present study sought to identify deficits in EBC using doses lower than those that have been reported previously following alcohol exposure limited to PD4‐9. Complex conditioned response (CR) timing tasks utilizing 2 interstimulus intervals (ISIs) were used to test the hypothesis that 3 g/kg/day of alcohol would produce early onset and early peaked CRs, whereas 4 and 5 g/kg/day would impair CR acquisition. Methods: Five neonatal treatment groups were used: (1) undisturbed controls, (2) sham intubation controls, (3) 3 g/kg/day of alcohol, (4) 4 g/kg/day of alcohol, or (5) 5 g/kg/day of alcohol. Intubations occurred over PD4‐9. In adulthood, rats were trained using ISI discrimination (Experiment 1) or temporal uncertainty (Experiment 2) EBC tasks. In ISI discrimination, 2 distinct conditioned stimuli (CSs; tone and light) are reinforced with a periocular shock unconditioned stimulus (US) at 2 different CS–US intervals. Temporal uncertainty is identical in design with the exception that the same CS is presented at both CS–US intervals. Results: Alcohol‐exposed subjects were impaired in CR acquisition in a task‐ and dose‐dependent fashion. CR deficits were most salient in the peak amplitude measure and occurred in both tasks following alcohol exposure at 4 and 5 g/kg/day. Alcohol at a dosage of 3 g/kg/day impaired CR acquisition only in ISI discrimination. All alcohol doses failed to produce short latency CRs in either task. Alcohol‐exposed subjects displayed later‐onset and later‐peaked CRs to the long‐ISI CS in ISI discrimination relative to controls. Conclusions: ISI discrimination training may be ideal to identify CR deficits resulting from neonatal exposure to moderate alcohol doses. Applications of this EBC task to humans may enable reliable early identification and diagnosis of individuals with fetal alcohol spectrum disorders.     

Adults with partial growth hormone deficiency have an adverse body composition

The current biochemical definition of severe GH deficiency (stimulated peak GH < 3 micro g/liter) provides good separation of GH-deficient (GHD) adults from normal subjects, although it may not account for all patients with impaired GH secretion. The vast majority of normal subjects display a peak GH level in excess of 7 micro g/liter in response to the insulin tolerance test. Using a peak GH response of 7 micro g/liter as an arbitrary upper limit, we investigated the effects of partial GH deficiency (GH insufficiency, GHI; peak GH response of 3-7 micro g/liter) on the body composition of hypopituitary adults. GHD adults (n = 30, peak GH < 3 micro g/liter) were of shorter stature than the controls. Body mass index was not significantly increased, but waist/hip ratio (0.885 vs. 0.818, P = 0.001) and skinfold thickness (78.2 vs. 59.6 mm, P = 0.003) were greater than control subjects. Bioimpedance analysis revealed these patients to have reduced lean body mass (LBM) (44.4 vs. 51.2 kg, P = 0.023) and increased fat mass (FM) (25.7 vs. 18.4 kg, P = 0.039). Dual-energy x-ray absorptiometry (DXA) analysis of body composition confirmed reduced LBM (43.6 vs. 50.6 kg, P = 0.010) and increased FM (26.0 vs. 19.2 kg, P = 0.015). The excess FM was observed to be primarily truncal in distribution. Similarly, GHI adults were of shorter stature but with increased waist/hip ratio (0.871 vs. 0.818, P = 0.006) and skinfold thickness (80.8 vs. 59.6 mm, P = 0.003), compared with controls. Bioimpedance analysis revealed a reduction in LBM (44.9 vs. 51.2 kg, P = 0.020). DXA studies confirmed the reduced LBM (45.0 vs. 50.6 kg, P = 0.041) and additionally noted an increase in percent FM (32.9 vs. 27.4%, P = 0.019). All measures of body composition in the GHI patients were intermediate between those of the controls and GHD patients. Serum leptin levels were significantly elevated in both the GHD (41.5 vs. 20.7 ng/ml, P = 0.009) and GHI (36.7 vs. 20.7 ng/ml, P = 0.022) adults, compared with healthy controls. The excess FM observed using DXA in the GHD and GHI adults equated to 6.5 kg (8%) and 3.5 kg (5.5%), respectively, relative to healthy controls. In summary, we have shown that adults with GHI have abnormalities of body composition characteristic of GHD. The degree of abnormality of body composition lies between that of healthy subjects and GHD adults and correlates with the IGF-I level. Any future trials of GH replacement in patients with GHI must await further studies to establish the exact impact of this relative deficiency on the broad spectrum of biological end points influenced by GH status.     

Single nucleotide polymorphisms of the melanocortin-3 receptor gene are associated with substrate oxidation and first-phase insulin secretion in offspring of type 2 diabetic subjects

CONTEXT: The melanocortin-3 receptor (MC3R) is a part of the melanocortin system that regulates appetite and energy metabolism. The Thr/Thr 6 and Val/Val81 [corrected] polymorphisms of the MC3R gene have been previously associated with high insulin levels and obesity in children. OBJECTIVE: The objective was to determine whether single nucleotide polymorphisms (SNPs) of MC3R are associated with glucose, lipid, and energy metabolism. DESIGN, SETTING, AND PARTICIPANTS: We screened the Lys/Thr6 and Ile/Val81 mutations and six noncoding SNPs of MC3R in a cross-sectional study of 216 middle-aged nondiabetic Finnish subjects who were offspring of type 2 diabetic patients. MAIN OUTCOME MEASURES: Insulin secretion was evaluated by an iv glucose tolerance test, and insulin sensitivity and energy metabolism by the hyperinsulinemic euglycemic clamp and indirect calorimetry. RESULTS: Carriers of the Lys 6 and Ile 81 [corrected] alleles had significantly lower rates of lipid oxidation [0.85 +/- 0.38 vs. 1.00 +/- 0.43 mg/kg of lean body mass (LBM)/min; P = 0.022, adjusted for sex, body mass index, age, and family relationship] and higher rates of glucose oxidation in the fasting state (11.28 +/- 4.64 vs. 9.71 +/- 4.53 micromol/kg of LBM/min; P = 0.031) than subjects with the Thr/Thr 6 and Val/Val 81 [corrected] genotypes. They had lower rates of lipid oxidation during the hyperinsulinemic clamp (0.32 +/- 0.41 vs. 0.44 +/- 0.34 mg/kg of LBM/min; P = 0.021) and higher insulin levels in an iv glucose tolerance test (insulin under the curve during the first 10 min, 3220 +/- 1765 vs. 2454 +/- 1538 pmol/liter.min; P = 0.025) compared to subjects with the common genotypes. CONCLUSIONS: Our results suggest that SNPs of MC3R may regulate substrate oxidation and first-phase insulin secretion.     

Impulsivity, Sensation Seeking, and Behavioral and Emotional Responses to Alcohol

Three hundred forty-two male and female subjects from the Colorado Alcohol Research on Twins and Adoptees returned a mailed questionnaire that included the Eysenck Impulsivity-Venturesomeness-Empathy scales. These subjects had previously been tested in a procedure in which they were given a 0.8 g/kg dose of ethanol to bring their peak blood alcohol concentration (BAC) to near 0.10 g/dl, given topping doses to maintain this BAC over a 3-hr period, and repeatedly tested on a battery of diverse physiological, psychomotor, perceptual speed, and mood measures. Impulsivity was significantly correlated with higher levels of self-reported alcohol use and the occurrence of alcohol use problems in males, while both impulsivity and venturesomeness (sensation seeking) were significantly correlated with lessened motor impairment following alcohol use in males. These personality measures, however, were not significantly correlated with mood measures following initial alcohol dosing. Impulsivity and venturesomeness were uncorrelated with alcohol use and responses to alcohol in females, but as with males, impulsivity was related to the occurrence of alcohol use problems in females.     

The treatment of anaemia in the myelodysplastic syndromes with recombinant human erythropoietin

Recombinant human erythropoietin was administered subcutaneously to 10 patients with myelodysplasia (MDS) who had haemoglobin concentrations less than 10 g/dl, in an attempt to relieve their anaemia. Doses of 60 units/kg/d rising to 90 units/kg/d were given over a maximum period of 16 weeks. Two out of 10 patients showed a steady rise in haemoglobin concentration during treatment. One patient with refractory anaemia had a sustained rise from 9.9 g/dl to 11.3 g/dl, and one patient with refractory anaemia with excess blasts (RAEB) had a rise from 9.5 g/dl to 11.4 g/dl but then relapsed with the development of an iron deficient state. Serum concentrations of immunoreactive EPO varied considerably between patients, but both responders had relatively low baseline levels. Both responders were also new diagnoses and had received no red cell transfusions. The criteria for response to recombinant human erythropoietin therapy, as well as the indications for therapy remain to be clarified.     

The effect of anemia and white matter hyperintensities (WMH) on cognitive impairment in patients with amnestic mild cognitive impairment (MCI)

Anemia and subcortical ischemic change might be associated with increased risks for cognitive impairment among the elderly. This study examined the associations among anemia, WMH and cognitive function in patients with amnestic MCI. We recruited 278 subjects with amnestic MCI from the Clinical Research Center for Dementia of South Korea (CREDOS), a hospital-based cohort study. A standardized neuropsychological battery, containing tests of language, visuospatial function, verbal memory and executive function, was used for all patients. Anemia was defined as a hemoglobin concentration below 12 g/dl for women and below 13 g/dl for men. The severity of WMH was also examined using brain magnetic resonance imaging (MRI). After multivariable adjustments, anemia and WMH were associated with poorer performance on cognitive function tests (anemia: Stroop test, F=4.17, p=0.042; WMH: Stroop test, F=6.45, p=0.002; Rey-complex figure test-copy, F=4.08, p=0.018). Moreover, a significant interaction between anemia and the severity of WMH was observed in performance on the Go/no go test (F=4.50, p=0.012) and the Stroop test (F=3.36, p=0.037). In post hoc analysis, anemic patients with severe WMH had significantly worse scores on measure of executive function (Go/no go test, p=0.011; Stroop test, p=0.001). Anemia and WMH had interactive effects on executive function impairment among the elderly with amnestic MCI.     

Acute and Chronic Alcohol Tolerance in Humans: Effects of Dose and Consecutive Days of Exposure

Male social drinkers received doses of either 0.75 or 1.0 g/kg body weight of alcohol over 5 consecutive days. The beverage was divided into three equal drinks, and subjects performed an eye-hand coordination motor task after each drink. The breath alcohol concentration (BAC) was assessed at each performance measurement period. Performance was also assessed when the BAC level on the descending limb of the BAC curve was similar to each of the three BAC measurements on the ascending curve. Each group developed chronic tolerance (comparing the daily postalcohol performance with the daily prealcohol performance) by the 4th day of exposure. The development of a degree of acute tolerance (assessed by comparing the performance on the ascending and descending limbs of the BAC curve) was not observed consistently in the 1.0 g/kg dose group, but was seen in more than half of the subjects in the 0.75 g/kg dose group by the 4th and 5th day of exposure.