metabolic rate and protein, carbohydrate and lipid metabolism in obesity
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Publication
Journal: New England Journal of Medicine
March/21/2002
Abstract
BACKGROUND
Childhood obesity, epidemic in the United States, has been accompanied by an increase in the prevalence of type 2 diabetes among children and adolescents. We determined the prevalence of impaired glucose tolerance in a multiethnic cohort of 167 obese children and adolescents.
METHODS
All subjects underwent a two-hour oral glucose-tolerance test (1.75 g [DOSAGE ERROR CORRECTED] of glucose per kilogram of body weight), and glucose, insulin, and C-peptide levels were measured. Fasting levels of proinsulin were obtained, and the ratio of proinsulin to insulin was calculated. Insulin resistance was estimated by homeostatic model assessment, and beta-cell function was estimated by calculating the ratio between the changes in the insulin level and the glucose level during the first 30 minutes after the ingestion of glucose.
RESULTS
Impaired glucose tolerance was detected in 25 percent of the 55 obese children (4 to 10 years of age) and 21 percent of the 112 obese adolescents (11 to 18 years of age); silent type 2 diabetes was identified in 4 percent of the obese adolescents. Insulin and C-peptide levels were markedly elevated after the glucose-tolerance test in subjects with impaired glucose tolerance but not in adolescents with diabetes, who had a reduced ratio of the 30-minute change in the insulin level to the 30-minute change in the glucose level. After the body-mass index had been controlled for, insulin resistance was greater in the affected cohort and was the best predictor of impaired glucose tolerance.
CONCLUSIONS
Impaired glucose tolerance is highly prevalent among children and adolescents with severe obesity, irrespective of ethnic group. Impaired oral glucose tolerance was associated with insulin resistance while beta-cell function was still relatively preserved. Overt type 2 diabetes was linked to beta-cell failure.
Publication
Journal: Archives of general psychiatry
March/28/2006
Abstract
BACKGROUND
Cocaine dependence is associated with high rates of relapse. Stress and drug cue exposure are known to increase cocaine craving and stress arousal, but the association between these responses and cocaine relapse has not been previously studied.
OBJECTIVE
To examine whether stress-induced and drug cue-induced cocaine craving and hypothalamic-pituitary-adrenal axis responses evoked in the laboratory are associated with subsequent cocaine relapse.
METHODS
Prospective study design assessing cocaine relapse and drug use during a 90-day follow-up period after discharge from inpatient treatment and research. Data were analyzed by Cox proportional hazards regression and multiple regression.
METHODS
Inpatient treatment and research unit in a community mental health center.
METHODS
Forty-nine treatment-seeking cocaine-dependent individuals.
METHODS
Time to cocaine relapse, number of days of cocaine use, and amount of cocaine used per occasion in the follow-up phase.
RESULTS
Greater stress-induced, but not drug cue-induced, cocaine craving was associated with a shorter time to cocaine relapse. Stress-induced corticotropin and cortisol responses predicted higher amounts of cocaine use per occasion in the 90-day follow-up.
CONCLUSIONS
These results demonstrate that stress-related increases in cocaine craving and hypothalamic-pituitary-adrenal axis responses are each associated with specific cocaine relapse outcomes. The findings support the use of stress-induced drug craving and associated hypothalamic-pituitary-adrenal axis responses to evaluate cocaine relapse propensity. Furthermore, treatments that address stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses could be of benefit in improving relapse outcomes in cocaine dependence.
Publication
Journal: Biological Psychiatry
November/21/2002
Abstract
BACKGROUND
Sex differences in stress responses may be one mechanism underlying gender differences in depression. We hypothesized that men and women would show different adrenocortical responses to different stressors. In particular, we predicted that women would show greater responses to social rejection stressors, whereas men would demonstrate greater responses to achievement stressors.
METHODS
Following a rest session in which they habituated to the laboratory, 50 healthy volunteers (24 men and 26 women, mean age 19.1, SD = 1.13) were randomly assigned to achievement or rejection stress conditions. The achievement condition involved a mathematical and a verbal challenge; the rejection condition involved two social interaction challenges. Self-reported affect and salivary cortisol were measured throughout each stress session (baseline, stress, and poststress periods).
RESULTS
There were no sex differences in mood ratings following the stressors; however, cortisol responses showed the predicted gender by condition by time interaction. Men showed significantly greater cortisol responses to the achievement challenges, but women showed greater cortisol responses to the social rejection challenges.
CONCLUSIONS
Women appear more physiologically reactive to social rejection challenges, but men react more to achievement challenges. Women's greater reactivity to rejection stress may contribute to the increased rates of affective disorders in women.
Publication
Journal: Diabetes
June/18/2007
Abstract
Insulin resistance is the best predictor for the development of diabetes in offspring of type 2 diabetic patients, but the mechanism responsible for it remains unknown. Recent studies have demonstrated increased intramyocellular lipid, decreased mitochondrial ATP synthesis, and decreased mitochondrial density in the muscle of lean, insulin-resistant offspring of type 2 diabetic patients. These data suggest an important role for mitochondrial dysfunction in the pathogenesis of type 2 diabetes. To further explore this hypothesis, we assessed rates of substrate oxidation in the muscle of these same individuals using (13)C magnetic resonance spectroscopy (MRS). Young, lean, insulin-resistant offspring of type 2 diabetic patients and insulin-sensitive control subjects underwent (13)C MRS studies to noninvasively assess rates of substrate oxidation in muscle by monitoring the incorporation of (13)C label into C(4) glutamate during a [2-(13)C]acetate infusion. Using this approach, we found that rates of muscle mitochondrial substrate oxidation were decreased by 30% in lean, insulin-resistant offspring (59.8 +/- 5.1 nmol x g(-1) x min(-1), P = 0.02) compared with insulin-sensitive control subjects (96.1 +/- 16.3 nmol x g(-1) x min(-1)). These data support the hypothesis that insulin resistance in skeletal muscle of insulin-resistant offspring is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in the activity of mitochondrial oxidative phosphorylation.
Publication
Journal: American Journal of Psychiatry
September/8/2005
Abstract
The high rate of co-occurrence of substance use disorders and other psychiatric disorders is well established. The population of people with co-occurring disorders is heterogeneous, and the prevalence of comorbidity differs by diagnostic group. One of the overarching issues in the area of comorbidity is the nature of the connection between psychiatric disorders and substance use disorders. The rapid development of technical advances in the neurosciences has led to a better understanding of the molecular biology, neurotransmitter systems, and neural circuitry involved in mental illness and substance use disorders. The authors discuss the neurobiological interface between substance use disorders and other psychiatric disorders with an emphasis on emerging data concerning four psychiatric disorders that commonly co-occur with substance use disorders: depression/mood disorders, posttraumatic stress disorder, attention deficit hyperactivity disorder, and schizophrenia. Better understanding of the connection between substance use disorders and psychiatric disorders could have a profound effect on prevention and treatment.
Publication
Journal: PLoS Medicine
August/17/2006
Abstract
BACKGROUND
Insulin resistance is the best predictor for the development of type 2 diabetes. Recent studies have shown that young, lean, insulin-resistant (IR) offspring of parents with type 2 diabetes have reduced basal rates of muscle mitochondrial phosphorylation activity associated with increased intramyocellular lipid (IMCL) content, which in turn blocks insulin signaling and insulin action in muscle. In order to further characterize mitochondrial activity in these individuals, we examined insulin-stimulated rates of adenosine triphosphate (ATP) synthesis and phosphate transport in skeletal muscle in a similar cohort of participants.
RESULTS
Rates of insulin-stimulated muscle mitochondrial ATP synthase flux and insulin-stimulated increases in concentrations of intramyocellular inorganic phosphate (Pi) were assessed by 31P magnetic resonance spectroscopy (MRS) in healthy, lean, IR offspring of parents with type 2 diabetes and healthy, lean control participants with normal insulin sensitivity. IMCL content in the soleus muscle of all participants was assessed by 1H MRS. During a hyperinsulinemic-euglycemic clamp, rates of insulin-stimulated glucose uptake were decreased by approximately 50% in the IR offspring compared to the control participants (p = 0.007 versus controls) and were associated with an approximately 2-fold increase in IMCL content (p < 0.006 versus controls). In the control participants rates of ATP synthesis increased by approximately 90% during the hyperinsulinemic-euglycemic clamp. In contrast, insulin-stimulated rates of muscle mitochondrial ATP synthesis increased by only 5% in the IR offspring (p = 0.001 versus controls) and was associated with a severe reduction of insulin-stimulated increases in the intramyocellular Pi concentrations (IR offspring: 4.7% +/- 1.9% versus controls: 19.3% +/- 5.7%; p = 0.03). Insulin-induced increases in intramyocellular Pi concentrations correlated well with insulin-stimulated increases in rates of ATP synthesis (r = 0.67; p = 0.008).
CONCLUSIONS
These data demonstrate that insulin-stimulated rates of mitochondrial ATP synthesis are reduced in IR offspring of parents with type 2 diabetes. Furthermore, these IR offspring also have impaired insulin-stimulated phosphate transport in muscle, which may contribute to their defects in insulin-stimulated rates of mitochondrial ATP synthesis.
Publication
Journal: New England Journal of Medicine
June/11/1987
Abstract
We infused small doses of insulin (0.3 mU per kilogram of body weight per minute; range, 0.9 to 1.7 U per hour) for three hours into 8 subjects who did not have diabetes, 11 patients with well-controlled diabetes (hemoglobin A1, 7.6 +/- 0.7 percent), and 10 patients with poorly controlled diabetes (hemoglobin A1, 11.5 +/- 1.7 percent) to simulate the mild peripheral hyperinsulinemia observed during insulin treatment. Normoglycemia was established in the patients during the night before study. During the insulin infusion, the plasma glucose level stabilized at 60 to 70 mg per deciliter (3.3 to 3.9 mmol per liter) in the subjects without diabetes and the patients with poorly controlled diabetes, because of a rebound increase in hepatic glucose production. In contrast, hypoglycemia developed in the patients with well-controlled diabetes (42 +/- 2 mg of glucose per deciliter, or 2.3 +/- 0.1 mmol per liter, P less than 0.01) as glucose production remained suppressed. The hypoglycemia in the patients with well-controlled diabetes was associated with a lowering of the plasma threshold of glucose that triggered a release of epinephrine (less than 45 mg of glucose per deciliter, or 2.5 mmol per liter, vs. greater than 55 mg per deciliter, or 3.1 mmol per liter, in the other groups, P less than 0.01) as well as an enhanced sensitivity to the suppressive effects of insulin on hepatic glucose production. Nearly identical disturbances in glucose counterregulation and decreased perception of hypoglycemia developed when four of the subjects with poorly controlled diabetes were restudied after intensive treatment. We conclude that strict control of diabetes induces physiologic alterations (delayed release of epinephrine and persistent suppression of glucose production) that impair glucose counterregulation to doses of insulin in the therapeutic range. These defects may contribute to the increased incidence of severe hypoglycemia reported during intensive insulin therapy.
Publication
Journal: Psychoneuroendocrinology
December/7/2005
Abstract
BACKGROUND
Stress is known to increase drug craving, associated physiological arousal and risk of relapse in drug dependent individuals. However, it is unclear whether these responses are altered by recent frequency of drug use. The current study examined whether frequency of cocaine and alcohol abuse alters drug craving and associated arousal with laboratory exposure to stress and to drug related cues.
METHODS
Fifty-four recently abstinent treatment-seeking cocaine abusers who were part of a study on stress and drug craving were categorized into high- and low-frequency users on the basis of their recent cocaine use. The high use cocaine group also consumed significantly more alcohol than the low use cocaine group. Participants were exposed to a brief 5-min guided imagery procedure that involved imagining a recent personal stressful situation, a personal drug-related situation and a neutral-relaxing situation, one imagery session on separate days presented in random order. Subjective (craving and anxiety), cardiovascular (heart rate, systolic blood pressure (SBP) and diastolic blood pressure (DBP)) and biochemical (adrenocorticotropic hormone (ACTH), cortisol, prolactin) measures were assessed.
RESULTS
High-frequency abusers demonstrated a significantly greater drug craving, anxiety and associated cardiovascular and hypothalamic-pituitary-adrenal (HPA) response to both stress and drug-cue exposure as compared to low-frequency abusers.
CONCLUSIONS
Increased frequency of recent cocaine and alcohol use is associated with an enhanced stress and cue-induced drug craving and arousal response that appears to be similar to the effects of cocaine, and one that may increase the vulnerability to drug-seeking behavior and relapse in drug dependent individuals.
Publication
Journal: Journal of Clinical Investigation
September/26/2001
Abstract
The mechanism underlying the regulation of basal metabolic rate by thyroid hormone remains unclear. Although it has been suggested that thyroid hormone might uncouple substrate oxidation from ATP synthesis, there are no data from studies on humans to support this hypothesis. To examine this possibility, we used a novel combined (13)C/(31)P nuclear magnetic resonance (NMR) approach to assess mitochondrial energy coupling in skeletal muscle of seven healthy adults before and after three days of triiodothyronine (T(3)) treatment. Rates of ATP synthesis and tricarboxylic acid (TCA) cycle fluxes were measured by (31)P and (13)C NMR spectroscopy, respectively, and mitochondrial energy coupling was assessed as the ratio. Muscle TCA cycle flux increased by approximately 70% following T(3) treatment. In contrast, the rate of ATP synthesis remained unchanged. Given the disproportionate increase in TCA cycle flux compared with ATP synthesis, these data suggest that T(3) promotes increased thermogenesis in part by promoting mitochondrial energy uncoupling in skeletal muscle.
Publication
Journal: Biological Psychiatry
May/8/2006
Abstract
BACKGROUND
Neuroimaging data suggest that deficits in ventral prefrontal cortex (VPFC) function in bipolar disorder (BD) progress during adolescence and young adulthood. However, the developmental trajectory of VPFC morphological abnormalities in BD is unknown. This study investigated potential age-dependent volume abnormalities in VPFC in BD.
METHODS
Thirty-seven individuals diagnosed with BD I (14 adolescents, 10 young adults and 13 older adults) and 56 healthy comparison subjects (HC) participated in imaging. Gray and white matter volumes of VPFC were measured using high-resolution structural magnetic resonance imaging (MRI). We used a mixed model, repeated measures analysis to examine VPFC volumes across age groups while co-varying for total brain volume. Potential effects of illness features including rapid-cycling and medication were explored.
RESULTS
VPFC volumes declined with age (p < .001). The diagnosis-by-age group interaction was significant (p = .01). Relative to HC subjects, VPFC gray and white matter volumes were significantly smaller in BD patients only in young adulthood (p = .04). In participants with BD, VPFC volumes were significantly smaller in participants with rapid-cycling than participants without rapid-cycling (p = .02). Conversely, current use of medication was associated with larger VPFC gray matter volumes (p = .005), independent of age.
CONCLUSIONS
These preliminary findings suggest the presence of a more rapid initial decline in VPFC volumes with age in adolescents and young adults with BD than HC. These findings also suggest that the rapid-cycling subtype of BD is associated with larger VPFC volume deficits than the non-rapid-cycling subtype, and that pharmacotherapy may have trophic or protective effects on VPFC volumes in BD patients.
Publication
Journal: Neurology
November/20/2000
Abstract
BACKGROUND
There is an increasingly recognized association between pulmonary arteriovenous malformations (PAVM) and cerebral ischemia, frequently attributed to paradoxical embolization. PAVM occur in 20 to 30% of the hereditary hemorrhagic telangiectasia (HHT) population.
OBJECTIVE
To evaluate the risk determinants for cerebral ischemia and neurologic manifestations in patients with PAVM.
METHODS
A retrospective cross-sectional study was performed on consecutive patients admitted between 1988 and 1992 for treatment of PAVM. The number of PAVM, feeding artery (FA) diameters, and aneurysmal sizes were determined by pulmonary angiography. Patients were categorized as having single or multiple PAVM with an FA diameter of>> or = 3 mm. History, examination, and cerebral imaging studies were used to determine the prevalence of neurologic manifestations. Patients were defined as having cerebral paradoxical embolization if there was radiologic evidence of cortical infarction.
RESULTS
There were 75 cases: 26 single PAVM and 49 multiple PAVM. Cortical infarction was present in 14% of patients with single PAVM. Patients with multiple PAVM had a greater prevalence of any infarction (OR 3.2; 95% CI, 1.2 to 9.44, p = 0.030), cortical infarctions (OR 2.3; 95% CI, 0.58 to 9.2, p = 0.230), subcortical infarctions (OR 2.1; 95% CI, 0.58 to 7.95, p = 0.249), abscesses (OR 2.3; 95% CI, 0.46 to 11.94; p = 0.295), and seizures (OR 6.4, 95% CI 0.77 to 53.2, p = 0.054). Patients with multiple PAVM had markedly greater odds of having any clinical or radiologic evidence of cerebral ischemic involvement (OR 4.5; 95% CI, 1.47 to 14; p = 0.008).
CONCLUSIONS
There is a strong association between single PAVM and various neurologic manifestations. The prevalence is greater for patients with multiple PAVM, suggesting increased predisposition for paradoxical embolization with a greater number of malformations.
Publication
Journal: Diabetologia
March/18/2002
Abstract
OBJECTIVE
To study the effects of a specific glucagon receptor antagonist (Bay 27-9955), on plasma glucose concentrations and rates of glucose production in response to hyperglucagonaemia in humans.
METHODS
The study was conducted as a two-dose [Low Dose Bay 27-9955 70 mg, (n = 6), High Dose Bay 27-9955 200 mg, (n = 8)], double blind, placebo controlled, crossover study. Basal glucose production was measured after an overnight fast with [6,6-2H]. At 0 min Bay 27-9955 or placebo was administered and at 120 min an infusion of somatostatin [0.1 microg x (kg x min)(-1)], insulin [24 pmol x (m2 x min)(-1)] and glucagon [3 ng x (kg x min)(-1)] was initiated.
RESULTS
Basal plasma glucose concentrations were about 5 mmol/l and basal rates of glucose production were about 13 micromol x (kg x min)(-1). During the hyperglucagonaemic period, plasma glucagon concentrations doubled to 100 pg/ml, plasma glucose concentration increased by 75 % to a peak of about 10 mmol/l and glucose production doubled to about 23 micromol x (kg x min)(-1) (p < 0.0001 vs basal). In the High Dose Group these effects of glucagon were markedly blunted, plasma glucose concentrations were 7.6 +/- 1.1 mmol/l (p = 0.012 vs placebo) and rates of glucose production increased minimally to 15.3 +/- 1.9 micromol x (kg-min)(-1) (p < 0.0003 vs placebo]. In the Low Dose Group, there was a proportional decrease in the effects of Bay 27-9955 on these parameters.
CONCLUSIONS
Bay 27-9955 is an effective and safe glucagon antagonist in humans. Given the potentially important role of glucagon in increasing glucose production and gluconeogenesis in patients with Type II (non-insulin-dependent) diabetes mellitus this agent could represent an innovative class of therapeutic agents for the disease.
Publication
Journal: American Journal of Pathology
February/4/1985
Abstract
In 17 patients with Lyme disease, synovial specimens, obtained by synovectomy or needle biopsy, showed nonspecific villous hypertrophy, synovial cell hyperplasia, prominent microvasculature, lymphoplasmacellular infiltration, and sometimes lymphoid follicles. The larger surgically obtained specimens also showed striking deposition of fibrin in synovial stroma and a form of endarteritis obliterans. In 2 patients, spirochetes were seen in and around blood vessels by the Dieterle silver stain. Compared with 55 cases of other synovial disease, obliterative microvascular lesions were seen only in Lyme synovia, but marked stromal deposition of fibrin seemed nonspecific. These findings imply that the Lyme spirochete may survive for years in affected synovium and may be directly responsible for the microvascular injury.
Publication
Journal: Journal of Clinical Endocrinology and Metabolism
February/9/2005
Abstract
Although high-protein diets induce hypercalciuria in humans, the source of the additional urinary calcium remains unclear. One hypothesis is that the high endogenous acid load of a high-protein diet is partially buffered by bone, leading to increased skeletal resorption and hypercalciuria. We used dual stable calcium isotopes to quantify the effect of a high-protein diet on calcium kinetics in women. The study consisted of 2 wk of a lead-in, well-balanced diet followed by 10 d of an experimental diet containing either moderate (1.0 g/kg) or high (2.1 g/kg) protein. Thirteen healthy women received both levels of protein in random order. Intestinal calcium absorption increased during the high-protein diet in comparison with the moderate (26.2 +/- 1.9% vs. 18.5 +/- 1.6%, P < 0.0001, mean +/- sem) as did urinary calcium (5.23 +/- 0.37 vs. 3.57 +/- 0.35 mmol/d, P < 0.0001, mean +/- sem). The high-protein diet caused a significant reduction in the fraction of urinary calcium of bone origin and a nonsignificant trend toward a reduction in the rate of bone turnover. There were no protein-induced effects on net bone balance. These data directly demonstrate that, at least in the short term, high-protein diets are not detrimental to bone.
Publication
Journal: Drug and Alcohol Dependence
October/4/2006
Abstract
Sleep disturbance has been implicated in cocaine use; however, the nature of the disturbance and its potential effects on cognition and learning are largely unknown. Twelve chronic cocaine users completed a 23-day inpatient study that included randomized, placebo-controlled, cocaine self-administration sessions. Six subjects received cocaine on each of days 4-6 and placebo on days 18-20, the other six received cocaine on each of days 18-20 and placebo on days 4-6. Sleep was measured by polysomnography, the Nightcap sleep monitor, and self-reported measures. Simple and vigilance reaction times were measured daily; a motor-sequence test of procedural learning was administered four times. Electrophysiological measures of sleep showed a different pattern than self-reported sleep across cocaine administration and abstinence: total sleep time and sleep latency were at their worst by 14-17 days of abstinence while self-reported sleep was at its best. Vigilance correlated positively with electrophysiologically measured sleep and negatively with self-reported measures. Similarly, sleep-dependent procedural learning correlated with total sleep time and was impaired at 17 days abstinence relative to 2- and 3-days abstinence. Slow-wave activity was lowest at days 4-9 of abstinence and highest during use and days 10-17 of abstinence. With sustained abstinence, chronic cocaine users exhibit decreased sleep, impaired vigilance and sleep-dependent procedural learning, and spectral activity suggestive of chronic insomnia. However, they report subjectively improving sleep, indicating they are unaware of this "occult" insomnia. These results suggest the possibility of homeostatic sleep drive dysregulation in chronic cocaine users.
Publication
Journal: Pediatric Diabetes
October/18/2007
Abstract
OBJECTIVE
We sought to examine prospectively patterns of clinical and psychosocial outcomes during the transition from adolescence to young adulthood in a cohort initiating intensive therapy after the Diabetes Control and Complications Trial.
METHODS
We conducted a prospective, descriptive analysis of data from a randomized intervention study with 117 adolescents (45 males and 72 females, mean age at entry = 14.4 +/- 2.0 yr, mean diabetes duration at entry = 5.7 +/- 3.7 yr) recruited from a large pediatric diabetes clinic. Data were collected for each subject over periods of up to 5 yr at 6-month intervals using measures of depressive symptoms, quality of life, and metabolic control, with chart review for prevalence of diabetes complications.
RESULTS
Metabolic control worsens during adolescence but returns to early adolescent levels in young adulthood. The negative impact of diabetes on quality of life, disease-related worries, and life satisfaction did not change significantly with age. These results did not vary with treatment group or gender. Participants who showed high levels of depressive symptoms as adolescents were somewhat more likely to be depressed when older. Despite relatively long duration of diabetes, relatively few complications were observed in young adulthood.
CONCLUSIONS
These data suggest that youth who begin intensive treatment as adolescents generally have good metabolic and psychosocial outcomes as young adults. However, those who have high levels of depressive symptoms in adolescence tend to continue to have such symptoms in early adulthood.
Publication
Journal: American Journal of Medicine
March/4/1985
Abstract
The diagnostic value of clinical, culture, and serologic findings was studied prospectively in 41 patients with early Lyme disease. Fifteen patients had erythema chronicum migrans alone, and 26 had clinical evidence of disseminated infection, most commonly affecting the brain or meninges, other skin sites, lymph nodes, or joints. Of 40 blood cultures, only one, from a patient with disseminated infection, yielded spirochetes. One of 10 patients tested with localized infection had an elevated IgM response to the Lyme spirochete (200 units or greater) during acute disease. Two to three weeks after beginning antibiotic therapy, four of the 10 patients had elevated specific IgM or IgG responses (200 units or greater). Of the 22 patients tested with disseminated disease, 10 initially had elevated levels of specific IgM or IgG, and 12 had such responses by convalescence. Because of the low yield of cultures and the delay in the specific antibody response, recognition of the clinical picture remains very important in diagnosing early Lyme disease.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
November/30/2008
Abstract
Endurance exercise training is accompanied by physiological changes that improve muscle function and performance. Several studies have demonstrated that markers of mitochondrial capacity are elevated, however, these studies tend to be performed ex vivo under conditions that yield maximal enzyme activities or in vivo but monitoring the response to exercise. Therefore, it is unclear whether basal mitochondrial metabolism is affected by exercise training. To explore whether resting muscle metabolism was altered in trained individuals in vivo, two independent parameters of metabolic function-tricarboxylic acid (TCA) cycle flux (V(TCA)), and ATP synthesis (V(ATP))-were assessed noninvasively by using magnetic resonance spectroscopy in a cohort of young endurance trained subjects (n = 7) and a group of matched sedentary subjects (n = 8). V(TCA) was 54% higher in the muscle of endurance trained compared with sedentary subjects (91.7 +/- 7.6 vs. 59.6 +/- 4.9 nmol/g/min, P < 0.01); however, V(ATP) was not different between the trained and sedentary subjects (5.98 +/- 0.43 vs. 6.35 +/- 0.70 mumol/g/min, P = 0.67). The ratio V(ATP)/V(TCA) (an estimate of mitochondrial coupling) was also significantly reduced in trained subjects (P < 0.04). These data demonstrate that basal mitochondrial substrate oxidation is increased in the muscle of endurance trained individuals yet energy production is unaltered, leading to an uncoupling of oxidative phosphorylation at rest. Increased mitochondrial uncoupling may represent another mechanism by which exercise training enhances muscle insulin sensitivity via increased fatty acid oxidation in the resting state.
Publication
Journal: Psychopharmacology
May/18/2008
Abstract
BACKGROUND
Nicotine replacement is commonly used to treat tobacco use in heavy-drinking smokers. However, few studies have examined the effect of nicotine replacement on subjective and physiological responses to alcohol and alcohol drinking behavior.
OBJECTIVE
The primary aim of this within-subject, double-blind study was to examine whether transdermal nicotine replacement (0 mg vs 21 mg/day) altered response to a low-dose priming drink and subsequent ad libitum drinking behavior.
METHODS
Subjects (n=19) were non-treatment-seeking, non-dependent heavy drinkers who were daily smokers. Six hours after transdermal patch application, subjective and physiological responses to a priming drink [designed to raise blood alcohol levels (BALs) to 0.03 g/dl] were assessed. This was followed by a 2-h self-administration period where subjects could choose to consume up to eight additional drinks (each designed to raise BALs by 0.015 g/dl) or to receive monetary reinforcement for drinks not consumed.
RESULTS
We found that 6 h after patch application, tobacco craving associated with withdrawal relief was decreased, and systolic blood pressure and heart rate were increased in the active patch condition compared to the placebo patch condition. Subjective intoxication in response to the priming drink was attenuated in the active nicotine patch condition compared to 6 h of nicotine deprivation (i.e., placebo patch). During the self-administration period, subjects had longer latencies to start drinking and consequently appeared to consume fewer drinks when administered the active patch compared to the placebo patch.
CONCLUSIONS
In heavy drinkers, transdermal nicotine replacement compared to mild nicotine deprivation attenuated subjective and physiological alcohol responses and delayed the initiation of drinking.
Publication
Journal: American Journal of Human Genetics
April/17/2002
Abstract
A genome scan of the hoarding phenotype (a component of obsessive-compulsive disorder) was conducted on 77 sib pairs collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG). All sib pairs were concordant for a diagnosis of Gilles de la Tourette syndrome (GTS). However, the analyses reported here were conducted for hoarding as both a dichotomous trait and a quantitative trait. Not all sib pairs in the sample were concordant for hoarding. Standard linkage analyses were performed using GENEHUNTER and Haseman-Elston methods. In addition, novel analyses with a recursive-partitioning technique were employed. Significant allele sharing was observed for both the dichotomous and the quantitative hoarding phenotypes for markers at 4q34-35 (P=.0007), by use of GENEHUNTER, and at 5q35.2-35.3 (P=.000002) and 17q25 (P=.00002), by use of the revisited Haseman-Elston method. The 4q site is in proximity to D4S1625, which was identified by the TSAICG as a region linked to the GTS phenotype. The recursive-partitioning technique examined multiple markers simultaneously. Results suggest joint effects of specific loci on 5q and 4q, with an overall P value of.000003. Although P values were not adjusted for multiple comparison, nearly all were much smaller than the customary significance level of.0001 for genomewide scans.
Publication
Journal: Psychopharmacology
March/12/2007
Abstract
BACKGROUND
In both animals and humans, nicotine produces behavioral effects that vary across individuals. Studies examining the role of genetic variability in modulating individual response to nicotine in humans have increased, with recent work showing that genetic variation at the dopamine D2 receptor (DRD2) predicts response to pharmacotherapy for tobacco dependence.
OBJECTIVE
To determine whether a polymorphism of the DRD2 gene, C957T, that alters DRD2 binding availability in humans modifies the effects of nicotine on verbal working memory performance and on processing efficiency of brain regions that support verbal working memory.
METHODS
Working memory and brain function were assessed in 36 adult subjects (15,957T allele carriers and 21,957C homozygotes), each of whom was studied twice, once after placement of a placebo patch and once after placement of a nicotine patch. Brain function was assessed using functional magnetic resonance imaging while the subjects performed a verbal working memory task.
RESULTS
During performance of a task with high verbal working memory load, nicotine administration worsened performance accuracy and reduced the processing efficiency of brain regions that support phonological rehearsal during verbal working memory in carriers of the 957T allele.
CONCLUSIONS
These findings are consistent with the notion that genetic variation in DRD2 contributes to individual variation in a range of behavioral and brain responses to nicotine in humans.
Publication
Journal: Annals of Internal Medicine
August/6/1985
Abstract
Counterregulatory hormone responses to hypoglycemia were examined in six healthy controls and in six patients with type I diabetes before and after 4 to 8 months of insulin pump treatment. The insulin clamp technique was used to provide an identical hypoglycemic stimulus (about 50 mg/dL) in each study group. Before pump treatment, the release of counterregulatory hormones (except glucagon) during the hypoglycemic period was not significantly different in diabetics from that in normal controls. However, when values before and after pump treatment in diabetics were compared, there were significant reductions in epinephrine (304 +/- 70 and 127 +/- 43 pg/mL; p less than 0.01), growth hormone (45 +/- 12 and 18 +/- 5 ng/mL; p less than 0.05), and cortisol (20 +/- 3 and 10 +/- 2 micrograms/dL; p less than 0.01) levels during hypoglycemia. Defective glucagon release during hypoglycemia in the diabetics was not corrected by pump treatment. Intensive insulin treatment of patients with type I diabetes causes a generalized reduction in counterregulatory hormone release after a moderate fall in blood glucose levels. This reduction may impair glucose counterregulation and diminish perception of hypoglycemia, thereby increasing the risk of hypoglycemic episodes.
Publication
Journal: Journal of Clinical Endocrinology and Metabolism
April/11/2001
Abstract
Alterations in nutritional status, such as obesity, markedly influence insulin, leptin, GH secretion, and free fatty acid (FFA) levels. We measured every hour for 24 h circulating leptin, insulin, GH, and FFA levels in lean and obese adolescents to determine: 1) the impact of adolescent obesity on the diurnal changes in leptin concentrations; and 2) the temporal relationships between the diurnal patterns of circulating leptin levels and insulin, GH, and FFA levels. During puberty, we found that the 24-h profile of circulating plasma leptin levels follows a bimodal pattern with minimal concentrations occurring early in the afternoon and a nocturnal elevation starting after midnight and culminating early morning. The time course of the diurnal variation in leptin levels in the obese adolescents was not different from that in lean controls. Of note, however, in obese girls leptin 24-h excursion and leptin night to day ratio were lower than those found in lean girls. In obese adolescents, mean GH levels varied significantly less during the day and night than lean controls. During the day, there were distinct preprandial increases and postprandial decreases in FFA levels, whereas after midnight FFA levels rose in both lean and obese adolescents. A significant positive correlation was found between mean plasma insulin levels between 0800 h and 2000 h and peak in leptin in lean and obese girls and boys (r = 0.63, P: < 0.001). Peak leptin was inversely correlated with the area under the nocturnal GH levels in all groups (r = -0.31, P: < 0.0003), whereas it was positively correlated with the nocturnal peak in FFA levels (r = 0.45, P: < 0.004). In summary, we report in obese adolescent girls a blunted relative diurnal excursion in leptin levels. This abnormal rhythmicity may, in part, explain their leptin resistance state. The nocturnal rise in leptin was paralleled by a nocturnal rise in GH and FFA levels. Additional studies are needed to test the potential link between the adipose-derived peptide and GH axis in humans.
Publication
Journal: Psychological Medicine
November/17/2008
Abstract
BACKGROUND
Determining how patients distinguish auditory verbal hallucinations (AVHs) from their everyday thoughts may shed light on neurocognitive processes leading to these symptoms.
METHODS
Fifty patients reporting active AVHs ('voices') with a diagnosis of schizophrenia or schizo-affective disorder were surveyed using a structured questionnaire. Data were collected to determine: (a) the degree to which patients distinguished voices from their own thoughts; (b) the degree to which their thoughts had verbal form; and (c) the experiential basis for identifying experiences as voices versus their own verbal thoughts. Six characteristics of acoustic/verbal images were considered: (1) non-self speaking voice, (2) loudness, (3) clarity, (4) verbal content, (5) repetition of verbal content, and (6) sense of control.
RESULTS
Four subjects were eliminated from the analysis because they reported absent verbal thought or a total inability to differentiate their own verbal thoughts from voices. For the remaining 46 patients, verbal content and sense of control were rated as most salient in distinguishing voices from everyday thoughts. With regard to sensory/perceptual features, identification of speaking voice as non-self was more important in differentiating voices from thought than either loudness or clarity of sound images.
CONCLUSIONS
Most patients with schizophrenia and persistent AVHs clearly distinguish these experiences from their everyday thoughts. An adequate mechanistic model of AVHs should account for distinctive content, recognizable non-self speaking voices, and diminished sense of control relative to ordinary thought. Loudness and clarity of sound images appear to be of secondary importance in demarcating these hallucination experiences.
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