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BACKGROUND: Despite its ubiquity, hangover has received remarkably little systematic attention in alcohol research. This may be due in part to the lack of a standard measure of hangover symptoms that cleanly taps the physiologic and subjective effects commonly experienced the morning after drinking. In the present study, we developed and evaluated a new scale, the Hangover Symptoms Scale (HSS), to potentially fill this void. METHODS: Participants were 1230 currently drinking college students (62% women, 91% Caucasian). They were administered a self-report inventory in which they reported the frequency of occurrence of 13 different hangover symptoms during the past 12 months. Participants also reported their history of alcohol involvement, alcohol-related problems, and family history of alcohol-related problems. RESULTS: On average, participants experienced 5 out of 13 different hangover symptoms in the past year; the three most common symptoms were feeling extremely thirsty/dehydrated, feeling more tired than usual, and headache. Higher scores on the HSS were significantly positively associated with the frequency of drinking and getting drunk and the typical quantity of alcohol consumed when drinking, a personal history of alcohol-related problems, and a family history of alcohol-related problems. After controlling for sex differences in alcohol involvement, women had higher scores on the HSS than men. CONCLUSIONS: The HSS appears to capture a reasonably valid set of adjectives describing common hangover effects. It is hoped that the availability of a brief, valid hangover assessment such as the HSS will encourage further study of hangover's frequency, correlates, and consequences. Future research is needed to explore the performance of a re-worded HSS in laboratory settings, which may help bridge the gap between laboratory and survey investigations of hangover. [ABSTRACT FROM AUTHOR]

Purpose: Relaxation correction is crucial for accurately estimating metabolite concentrations measured using in vivo MRS. However, the majority of MRS quantification routines assume that relaxation values remain constant across the lifespan, despite prior evidence of T 2 changes with aging for multiple of the major metabolites. Here, we comprehensively investigate correlations between T 2 and age in a large, multi-site cohort., Methods: We recruited approximately 10 male and 10 female participants from each decade of life: 18-29, 30-39, 40-49, 50-59, and 60+ y old (n = 101 total). We collected PRESS data at eight TEs (30, 50, 74, 101, 135, 179, 241, and 350 ms) from voxels placed in white-matter-rich centrum semiovale (CSO) and gray-matter-rich posterior cingulate cortex (PCC). We quantified metabolite amplitudes using Osprey and fit exponential decay curves to estimate T 2 ., Results: Older age was correlated with shorter T 2 for tNAA 2.0 , tCr 3.0 , tCr 3.9 , tCho, and tissue water (CSO and PCC), as well as mI and Glx (PCC only); r s  = -0.22 to -0.63, all p < 0.05, false discovery rate (FDR)-corrected. These associations largely remained statistically significant when controlling for cortical atrophy. By region, T 2 values were longer in the CSO for tNAA 2.0 , tCr 3.9 , Glx, and tissue water and longer in the PCC for tCho and mI. T 2 did not differ by region for tCr 3.0 ., Conclusion: These findings underscore the importance of considering metabolite T 2 differences with aging in MRS quantification. We suggest that future 3T work utilize the equations presented here to estimate age-specific T 2 values instead of relying on uniform default values., (© 2024 International Society for Magnetic Resonance in Medicine.)

Purpose: Relaxation correction is crucial for accurately estimating metabolite concentrations measured using in vivo magnetic resonance spectroscopy (MRS). However, the majority of MRS quantification routines assume that relaxation values remain constant across the lifespan, despite prior evidence of T 2 changes with aging for multiple of the major metabolites. Here, we comprehensively investigate correlations between T 2 and age in a large, multi-site cohort., Methods: We recruited approximately 10 male and 10 female participants from each decade of life: 18-29, 30-39, 40-49, 50-59, and 60+ years old ( n =101 total). We collected PRESS data at 8 TEs (30, 50, 74, 101, 135, 179, 241, and 350 ms) from voxels placed in white-matter-rich centrum semiovale (CSO) and gray-matter-rich posterior cingulate cortex (PCC). We quantified metabolite amplitudes using Osprey and fit exponential decay curves to estimate T 2 ., Results: Older age was correlated with shorter T 2 for tNAA, tCr 3.0 , tCr 3.9 , tCho, Glx, and tissue water in CSO and PCC; r s = -0.21 to -0.65, all p <0.05, FDR-corrected for multiple comparisons. These associations remained statistically significant when controlling for cortical atrophy. T 2 values did not differ across the adult lifespan for mI. By region, T 2 values were longer in the CSO for tNAA, tCr 3.0 , tCr 3.9 , Glx, and tissue water and longer in the PCC for tCho and mI., Conclusion: These findings underscore the importance of considering metabolite T 2 changes with aging in MRS quantification. We suggest that future 3T work utilize the equations presented here to estimate age-specific T 2 values instead of relying on uniform default values., Competing Interests: Competing Interests All authors declare that they have no competing interests.

Background: Sexual and gender minority (SGM) persons experience stark health disparities. Efforts to mitigate disparities through medical education have met some success. However, evaluations have largely focused on subjective perspectives rather than objective measures. This study aimed to quantify Boston University School of Medicine's sexual and gender minority (SGM) education through surveys of course directors (CDs) and medical students regarding where SGM topics were taught in the preclerkship medical curriculum. Responses were compared to identify concordance between faculty intention and student perceptions regarding SGM education., Methods: A cross-sectional survey was distributed to preclerkship CDs and current medical students in Spring 2019 and 2021, respectively, regarding where in the mandatory preclerkship curriculum CDs deliberately taught and where first- and second-year students recalled having learned 10 SGM topic domains., Results: 64.3% of CDs (n = 18), 47.0% of the first-year class (n = 71), and 67.3% of the second-year class (n = 101) responded to the surveys. Results indicate that, as anticipated, deliberate SGM teaching correlates with greater student recall as students recalled topics that were reported by CDs as intentionally taught at a significantly higher rate compared to those not intentionally taught (32.0% vs. 15.3%; p < 0.01). Students most commonly recalled learning SGM-related language and terminology, which is likely partly but not entirely attributed to curricular modifications and faculty development made between distribution of the faculty and student surveys, indicating the importance of all faculty being trained in appropriate SGM terminology and concepts. Discordance between faculty intention and student recall of when topics were taught reveals opportunities to enhance the intentionality and impact of SGM teaching., Conclusions: Students perceive and recall SGM content that is not listed as learning objectives, and all faculty who utilize this material in their teachings should receive foundational training and be thoughtful about how information is framed. Faculty who intentionally teach SGM topics should be explicit and direct about the conclusions they intend students to draw from their curricular content., (© 2023. The Author(s).)

Problem: Medical education aspires to mitigate bias in future professionals by providing robust curricula that include perspectives of and practices for caring for sexual and gender minority (SGM) populations; however, implementation of these ideals remains challenging. Medical school leaders motivated to improve curricula on caring for SGM populations must survey their school's current curricula to identify strengths and opportunities for improvement. In 2014, the Association of American Medical Colleges (AAMC) published 30 SGM competencies that curricula should address. Here the authors describe the development of a tool to efficiently assess whether an undergraduate medical education (UME) curriculum adequately incorporates the AAMC-recommended SGM competencies., Approach: In 2018, Boston University School of Medicine (BUSM) convened a group of faculty and students with experience and expertise regarding SGM health. The group distilled the 30 AAMC competencies into 12 SGM topic areas that should be addressed in any UME curriculum, and they developed a curriculum assessment tool to evaluate the presence and timing of these topic areas in the BUSM curriculum. This tool was distributed to all course and clerkship directors responsible for the required UME curriculum at BUSM to investigate where these topic areas are addressed (May-June 2019)., Outcomes: The curriculum assessment tool identified several strengths in the preclerkship and clerkship curricula, including faculty willingness and enthusiasm to include SGM content. The assessment tool also revealed that some SGM topic areas are underrepresented in the BUSM curriculum, particularly during clerkships., Next Steps: The curriculum assessment tool described here is a straightforward, standardized instrument to map SGM topic areas within any UME curriculum. It is designed to be comprehensible by individuals who are not familiar with SGM health. The tool minimizes barriers to medical curricular change by providing a mechanism to assess and understand how SGM health is incorporated into existing curricula., (Copyright © 2021 by the Association of American Medical Colleges.)

Purpose: For transgender (TG) women preparing to undergo neovaginoplasty, multidisciplinary care is essential, with physicians working together to ensure timely, complete, and cost-effective treatment. Methods: The protocol was developed through the clinical experience with >30 patients for preneovaginoplasty laser hair removal (LHR). Results: This report details the procedure used at an academic medical center for preneovaginoplasty genital LHR. Although treatment must often be individualized, methods as described for evaluation and treatment of presurgical hair have been successfully used in >30 patients. Conclusion: Given the limited available literature regarding this topic, it is our hope that this report will encourage other centers to offer safe and effective presurgical genital LHR to TG patients., Competing Interests: No competing financial interests exist., (Copyright 2021, Mary Ann Liebert, Inc., publishers.)

The A. aeolicus intrinsically disordered protein FlgM has four well-defined α-helices when bound to σ28, but in water FlgM undergoes a change in tertiary structure. In this work, we investigate the structure of FlgM in aqueous solutions of the ionic liquid [C4mpy][Tf2N]. We find that FlgM is induced to fold by the addition of the ionic liquid, achieving average α-helicity values similar to the bound state. Analysis of secondary structure reveals significant similarity with the bound state, but the tertiary structure is found to be more compact. Interestingly, the ionic liquid is not homogeneously dispersed in the water, but instead aggregates near the protein. Separate simulations of aqueous ionic liquid do not show ion clustering, which suggests that FlgM stabilizes ionic liquid aggregation.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that can potentially lead to serious organ complications and even death. Its global burden - in terms of incidence and prevalence, differential impact on populations, economic costs and capacity to compromise health-related quality of life - remains incompletely understood. The reported worldwide incidence and prevalence of SLE vary considerably; this variation is probably attributable to a variety of factors, including ethnic and geographic differences in the populations being studied, the definition of SLE applied, and the methods of case identification. Despite the heterogeneous nature of the disease, distinct patterns of disease presentation, severity and course can often be related to differences in ethnicity, income level, education, health insurance status, level of social support and medication compliance, as well as environmental and occupational factors. Given the potential for the disease to cause such severe and widespread organ damage, not only are the attendant direct costs high, but these costs are sometimes exceeded by indirect costs owing to loss of economic productivity. As an intangible cost, patients with SLE are, not surprisingly, likely to endure considerably reduced health-related quality of life.

Hypoxia is a consequence of cardiac disease and downregulates mitochondrial metabolism, yet the molecular mechanisms through which this occurs in the heart are incompletely characterized. Therefore, we aimed to use a contracting HL-1 cardiomyocyte model to investigate the effects of hypoxia on mitochondrial metabolism. Cells were exposed to hypoxia (2% O2) for 6, 12, 24, and 48 hours to characterize the metabolic response. Cells were subsequently treated with the hypoxia inducible factor (HIF)-activating compound, dimethyloxalylglycine (DMOG), to determine whether hypoxia-induced mitochondrial changes were HIF dependent or independent, and to assess the suitability of this cultured cardiac cell line for cardiovascular pharmacological studies. Hypoxic cells had increased glycolysis after 24 hours, with glucose transporter 1 and lactate levels increased 5-fold and 15-fold, respectively. After 24 hours of hypoxia, mitochondrial networks were more fragmented but there was no change in citrate synthase activity, indicating that mitochondrial content was unchanged. Cellular oxygen consumption was 30% lower, accompanied by decreases in the enzymatic activities of electron transport chain (ETC) complexes I and IV, and aconitase by 81%, 96%, and 72%, relative to controls. Pharmacological HIF activation with DMOG decreased cellular oxygen consumption by 43%, coincident with decreases in the activities of aconitase and complex I by 26% and 30%, indicating that these adaptations were HIF mediated. In contrast, the hypoxia-mediated decrease in complex IV activity was not replicated by DMOG treatment, suggesting HIF-independent regulation of this complex. In conclusion, 24 hours of hypoxia increased anaerobic glycolysis and decreased mitochondrial respiration, which was associated with changes in ETC and tricarboxylic acid cycle enzyme activities in contracting HL-1 cells. Pharmacological HIF activation in this cardiac cell line allowed both HIF-dependent and independent mitochondrial metabolic changes to be identified., (© The Author(s) 2014.)

A 42-year-old man diagnosed with pseudohypoparathyroidism and Albright's hereditary osteodystrophy as an infant was lost to follow-up and remained, unmonitored, on calcitriol and calcium for over 20 years. He presented after having an ST-elevation myocardial infarction. In addition to coronary artery calcifications, he was found to have diffuse subcutaneous and joint calcifications. His calcium, phosphate and parathyroid hormone (PTH) levels were normal, and given the lack of prior documentation in the diagnosis he was instructed to discontinue calcitriol and calcium until further investigations were completed. Despite stopping the medication, his serum calcium remained normal for over 1 year. It was not until 18 months later, when his soft tissue calcium stores were depleted, that he finally developed symptomatic hypocalcaemia and an elevated PTH. This case not only emphasises the importance of long-term follow-up for patients with pseudohypoparathyroidism, but also highlights the potential complications of long-term, unmonitored, calcitriol use.

Chronic hypoxia decreases cardiomyocyte respiration, yet the mitochondrial mechanisms remain largely unknown. We investigated the mitochondrial metabolic pathways and enzymes that were decreased following in vivo hypoxia, and questioned whether hypoxic adaptation was protective for the mitochondria. Wistar rats were housed in hypoxia (7 days acclimatisation and 14 days at 11% oxygen), while control rats were housed in normoxia. Chronic exposure to physiological hypoxia increased haematocrit and cardiac vascular endothelial growth factor, in the absence of weight loss and changes in cardiac mass. In both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria isolated from hypoxic hearts, state 3 respiration rates with fatty acid were decreased by 17-18%, and with pyruvate were decreased by 29-15%, respectively. State 3 respiration rates with electron transport chain (ETC) substrates were decreased only in hypoxic SSM, not in hypoxic IFM. SSM from hypoxic hearts had decreased activities of ETC complexes I, II and IV, which were associated with decreased reactive oxygen species generation and protection against mitochondrial permeability transition pore (MPTP) opening. In contrast, IFM from hypoxic hearts had decreased activity of the Krebs cycle enzyme, aconitase, which did not modify ROS production or MPTP opening. In conclusion, cardiac mitochondrial respiration was decreased following chronic hypoxia, associated with downregulation of different pathways in the two mitochondrial populations, determined by their subcellular location. Hypoxic adaptation was not deleterious for the mitochondria, in fact, SSM acquired increased protection against oxidative damage under the oxygen-limited conditions.

Aims: Vascular disease states are associated with endothelial dysfunction and increased production of reactive oxygen species derived from NADPH oxidases. However, it remains unclear whether a primary increase in superoxide production specifically in the endothelium alters the initiation or progression of atherosclerosis., Methods and Results: Mice overexpressing Nox2 specifically in the endothelium (Nox2-Tg) were crossed with ApoE(-/-) mice to produce Nox2-Tg ApoE(-/-) mice and ApoE(-/-) littermates. Endothelial overexpression of Nox2 in ApoE(-/-) mice did not alter blood pressure, but significantly increased vascular superoxide production compared with ApoE(-/-) littermates, measured using both lucigenin chemiluminescence and 2-hydroxyethidium production (ApoE(-/-), 19.9 ± 6.3 vs. Nox2-Tg ApoE(-/-), 47.0 ± 7.0 nmol 2-hydroxyethidium/aorta, P< 0.05). Increased endothelial superoxide production increased endothelial levels of vascular cell adhesion protein 1 and enhanced macrophage recruitment in early lesions in the aortic roots of 9-week-old mice, indicating increased atherosclerotic plaque initiation. However, endothelial-specific Nox2 overexpression did not alter native or angiotensin II-driven atherosclerosis in either the aortic root or the descending aorta., Conclusion: Endothelial-targeted Nox2 overexpression in ApoE(-/-) mice is sufficient to increase vascular superoxide production and increase macrophage recruitment possible via activation of endothelial cells. However, this initial increase in macrophage recruitment did not alter the progression of atherosclerosis. These results indicate that Nox-mediated reactive oxygen species signalling has important cell-specific and distinct temporal roles in the initiation and progression of atherosclerosis.

We recently showed that a week-long, high-fat diet reduced whole body exercise efficiency in sedentary men by >10% (Edwards LM, Murray AJ, Holloway CJ, Carter EE, Kemp GJ, Codreanu I, Brooker H, Tyler DJ, Robbins PA, Clarke K. FASEB J 25: 1088-1096, 2011). To test if a similar dietary regime would blunt whole body efficiency in endurance-trained men and, as a consequence, hinder aerobic exercise performance, 16 endurance-trained men were given a short-term, high-fat (70% kcal from fat) and a moderate carbohydrate (50% kcal from carbohydrate) diet, in random order. Efficiency was assessed during a standardized exercise task on a cycle ergometer, with aerobic performance assessed during a 1-h time trial and mitochondrial function later measured using (31)P-magnetic resonance spectroscopy. The subjects then underwent a 2-wk wash-out period, before the study was repeated with the diets crossed over. Muscle biopsies, for mitochondrial protein analysis, were taken at the start of the study and on the 5th day of each diet. Plasma fatty acids were 60% higher on the high-fat diet compared with moderate carbohydrate diet (P < 0.05). However, there was no change in whole body efficiency and no change in mitochondrial function. Endurance exercise performance was significantly reduced (P < 0.01), most probably due to glycogen depletion. Neither diet led to changes in citrate synthase, ATP synthase, or mitochondrial uncoupling protein 3. We conclude that prior exercise training blunts the deleterious effect of short-term, high-fat feeding on whole body efficiency.

Background: Hyperglycemia with insulin resistance is commonly seen in severely burned patients and tight glycemia control with insulin may be beneficial in this condition. The most potent insulinotropic hormone, glucagon-like peptide 1 (GLP-1), stimulates insulin secretion in a glucose-dependent manner. Because infusion of GLP-1 never reduces glucose levels to below ∼70 mg/dL, the risk of hypoglycemia by using insulin is reduced. In this study we investigated the metabolic effects of GLP-1 infusion after burn injury in an animal model., Methods: Male CD rats were divided in 3 groups: burn injury with saline, burn injury with GLP-1 treatment, and sham burn (SB). Burn injury was full thickness 40% total body surface area. The burn injury with GLP-1 treatment group received GLP-1 infusion via osmotic pump. Fasting blood glucose, plasma insulin, and plasma GLP-1 levels were measured during intraperitoneal glucose tolerance tests. Expressions of caspase 3 and bcl-2 were evaluated in pancreatic islets. In a subset of animals, protein metabolism and total energy expenditure were measured., Results: Fasting GLP-1 was reduced in burn injury with saline compared to SB or burn injury with GLP-1 treatment. Burn injury with GLP-1 treatment showed reduced fasting blood glucose, improved intraperitoneal glucose tolerance test results, with increased plasma insulin and GLP-1 responses to glucose. GLP-1 reduced protein breakdown and total energy expenditure in burn injury with GLP-1 treatment versus burn injury with saline, with improved protein balance. Increased expression of caspase 3 and decreased expression of bcl-2 in islet cells by burn injury were ameliorated by GLP-1., Conclusion: Burn injury reduced plasma GLP-1 in association with insulin resistance. GLP-1 infusion improved glucose tolerance and showed anabolic effects on protein metabolism and reduced total energy expenditure after burn injury, possibly via insulinotropic and non insulinotropic mechanisms., (Copyright © 2011 Mosby, Inc. All rights reserved.)

The Wisconsin Inventory of Smoking Dependence Motives (WISDM) assesses 13 domains of smoking motivation emphasized by diverse theoretical perspectives. Emerging findings support a distinction between four primary dependence motives (PDM) indexing core features of tobacco dependence and nine secondary dependence motives (SDM) indexing accessory features. The current study explored the validity of this distinction using data from two samples (Ns=50 and 88) of college smokers who self-monitored their reasons for smoking with electronic diaries. PDM scores were associated with diary endorsement of habitual or automatic motives for smoking individual cigarettes, which are conceptually consistent with the content of the PDM subscales. SDM did not clearly predict conceptually related self-monitored motives when tested alone. However, when these two correlated scale composites were co-entered, PDM predicted being a daily vs. nondaily smoker, being higher in nicotine dependence, and smoking individual cigarettes because of habit or automaticity. Conversely, after PDM-SDM co-entry, the unique variance in the SDM composite predicted the tendency to report smoking individual cigarettes for situational or instrumental motives (e.g., to control negative affect). The results suggest that the PDM composite may reflect core motivational features of nicotine dependence in these young smokers. The relative prominence of primary motives in advanced or dependent use may be even clearer when motives for smoking are assessed in real time rather than reported via questionnaire., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

We recently showed that a short-term high-fat diet blunted exercise performance in rats, accompanied by increased uncoupling protein levels and greater respiratory uncoupling. In this study, we investigated the effects of a similar diet on physical and cognitive performance in humans. Twenty sedentary men were assessed when consuming a standardized, nutritionally balanced diet (control) and after 7 d of consuming a diet comprising 74% kcal from fat. Efficiency was measured during a standardized exercise task, and cognition was assessed using a computerized assessment battery. Skeletal muscle mitochondrial function was measured using (31)P magnetic resonance spectroscopy. The diet increased mean ± se plasma free fatty acids by 44% (0.32±0.03 vs. 0.46±0.05 mM; P<0.05) and decreased whole-body efficiency by 3% (21±1 vs. 18±1%; P<0.05), although muscle uncoupling protein (UCP3) content and maximal mitochondrial function were unchanged. High-fat diet consumption also increased subjects' simple reaction times (P<0.01) and decreased power of attention (P<0.01). Thus, we have shown that a high-fat diet blunts whole-body efficiency and cognition in sedentary men. We suggest that this effect may be due to increased respiratory uncoupling.

Many diseases of the heart are characterised by changes in substrate utilisation, which is regulated in part by the activity of the enzyme pyruvate dehydrogenase (PDH). Consequently, there is much interest in the in vivo evaluation of PDH activity in a range of physiological and pathological states to obtain information on the metabolic mechanisms of cardiac diseases. Hyperpolarised [1-(13)C]pyruvate, detected using MRS, is a novel technique for the noninvasive evaluation of PDH flux. PDH flux has been assumed to directly reflect in vivo PDH activity, although to date this assumption remains unproven. Control animals and animals undergoing interventions known to modulate PDH activity, namely high fat feeding and dichloroacetate infusion, were used to investigate the relationship between in vivo hyperpolarised MRS measurements of PDH flux and ex vivo measurements of PDH enzyme activity (PDH(a)). Further, the plasma concentrations of pyruvate and other important metabolites were evaluated following pyruvate infusion to assess the metabolic consequences of pyruvate infusion during hyperpolarised MRS experiments. Hyperpolarised MRS measurements of PDH flux correlated significantly with ex vivo measurements of PDH(a), confirming that PDH activity influences directly the in vivo flux of hyperpolarised pyruvate through cardiac PDH. The maximum plasma concentration of pyruvate reached during hyperpolarised MRS experiments was approximately 250 µM, equivalent to physiological pyruvate concentrations reached during exercise or with dietary interventions. The concentrations of other metabolites, including lactate, glucose and β-hydroxybutyrate, did not vary during the 60 s following pyruvate infusion. Hence, during the 60-s data acquisition period, metabolism was minimally affected by pyruvate infusion., (Copyright © 2010 John Wiley & Sons, Ltd.)

Although most literature suggests a relative protection of slow twitch muscle with aging, there is limited data in senescence when muscle atrophy and functional decline markedly accelerate. To address this issue we examined age-related changes in muscle mass, contractile function, mitochondrial enzyme activities, and myosin heavy chain (MHC) expression in the slow twitch soleus (Sol) and fast twitch gastrocnemius (Gas) muscle of young adult (YA) and senescent (SEN) rats. Muscle mass declined between YA and SEN in the Sol by 35% compared to 55% in the Gas muscle. After normalizing for muscle mass, tetanic force per g of muscle declined by 58% in Sol and by 36% in Gas muscle. Time-to-peak tension was increased only in the Gas (30%), whereas time-to-half relaxation was increased by 70% in Sol and 51% in Gas. Citrate synthase and complex IV activity declined in homogenates of Sol (30-36%) and red oxidative region of Gas (46-51%), but not white glycolytic region of Gas. Strikingly, the shift away from the dominant adult MHC isoform with aging was much greater in Sol (fibers positive for MHC fast: 11+/-2% in YA versus 36+/-3% in SEN) than in Gas (fibers positive for MHC slow: 12+/-1% in YA versus 26+/-3% in SEN) muscle. Collectively, these results show that the slow twitch Sol muscle undergoes large phenotypic alterations in very old age and for several measures (tetanic tension per g, time-to-half relaxation and shift in adult MHC expression) that is of greater magnitude than fast twitch muscle, underscoring the importance of including age-related changes in slow twitch muscle in seeking potential treatments for sarcopenia., (Copyright 2010 Elsevier Inc. All rights reserved.)

A sample of college students, oversampled for smoking (N = 127, 43% smokers), monitored their daily experiences using electronic diaries over 14 days. We examined the frequency and correlates of liberally defined hangoverlike experiences (HLEs) using data from 1,595 person-days (1,325 after abstention from drinking and 270 after drinking, including 125 HLEs). More than 40% of the sample reported at least one HLE, and nearly half of all drinking episodes were followed by HLE. Endorsement of HLE was more likely as the number of drinks increased and was associated with modest elevations of hangover symptoms. Gender did not predict rates of overall HLE endorsement, but male students were less likely than female students to report an HLE after a drinking episode and showed a weaker relation between number of drinks and HLE. Smokers were more likely to report HLE, but there was no evidence that smoking status was associated with increased HLE susceptibility. Self-reported parental alcohol problems were associated with more frequent HLE and incrementally predicted HLE endorsement when number of drinks was covaried. The findings suggest that HLE is a common outcome of college drinking and attest to the feasibility of using electronic diaries to assess its episode- and person-level correlates.

Aims: The chronically infarcted rat heart has multiple defects in metabolism, yet the location of the primary metabolic abnormality arising after myocardial infarction is unknown. Therefore, we investigated cardiac mitochondrial metabolism shortly after infarction., Methods and Results: Myocardial infarctions (n = 11) and sham operations (n = 9) were performed on Wistar rats, at 2 weeks cardiac function was assessed using echocardiography, and rats were grouped into failing (ejection fraction < or =45%), moderately impaired (46-60%), and sham-operated (>60%). Respiration rates were decreased by 28% in both subsarcolemmal and interfibrillar mitochondria isolated from failing hearts, compared with sham-operated controls. However, respiration rates were not impaired in mitochondria from hearts with moderately impaired function. The mitochondrial defect in the failing hearts was located within the electron transport chain (ETC), as respiration rates were suppressed to the same extent when fatty acids, ketone bodies, or glutamate were used as substrates. Complex III protein levels were decreased by 46% and complex III activity was decreased by 26%, in mitochondria from failing hearts, but all other ETC complexes were unchanged. Decreased complex III activity was accompanied by a three-fold increase in complex III-derived H(2)O(2) production, decreased cardiolipin content, and a 60% decrease in mitochondrial cytochrome c levels from failing hearts. Respiration rates, complex III activity, cardiolipin content, and reactive oxygen species generation rates correlated with ejection fraction., Conclusion: In conclusion, a specific defect in complex III occurred acutely after myocardial infarction, which increased oxidative damage and impaired mitochondrial respiration. The extent of mitochondrial dysfunction in the failing heart was proportional to the degree of cardiac dysfunction induced by myocardial infarction.

3-Hydroxy-3-methyglutaryl-coenzyme A (HMGCoA) reductase is the enzyme that catalyzes the rate-determining step in cholesterol synthesis; it is also the target for statin drugs, which are competitive inhibitors of the enzyme. We examine potentially important enzyme-ligand interactions currently not incorporated into statin drug design: weak, induction/dispersion interactions between ligands and residue tyrosine 479 in the HMGCoA reductase active site. HMGCoA is a large molecule with a long coenzyme A "tail", and in order to study the interactions of interest, it was necessary to find the smallest possible portion of the HMGCoA molecule that would serve as a reasonable model for the entire molecule. Using this minimal model, we calculated BSSE-corrected electronic interaction energies between the residue and the ligand molecule using several DFT methods (local, hybrid, and gradient-corrected DFT methods) as well as MP2. We also performed several in silico mutations of the tyrosine 479 residue to determine the potential effects of these changes on protein-ligand interaction energies. Our work shows that this previously unexploited protein-ligand interaction between tyrosine residue 479 and HMGCoA can be important in the design of future statin drugs. Per our previous work, our results show that local DFT methods more closely match MP2 energy values for aromatic binding than do hybrid or gradient-corrected DFT methods.

The association of college attendance with alcohol use and alcohol use disorders was examined in a population-based young adult female twin sample identified from a systematic search of birth records. College-attending women consumed a larger overall volume of alcohol than did their non-college-attending peers, but they were not more likely to be diagnosed with an alcohol use disorder. Significant associations between college attendance and alcohol involvement were probed using 3 different complementary research designs: multivariate cross-sectional analyses, longitudinal analyses of the precollege and college years, and cotwin-control analyses of twin pairs discordant for attending college. Although demographic and lifestyle characteristics accounted for most or all of the association between college attendance and alcohol involvement, there was 1 aspect of drinking behavior, occasionally consuming large quantities of alcohol, that remained significantly associated with college attendance even after controlling for these characteristics or for genetic and family background factors. These results are consistent with the conclusion that some aspect of the college experience may be an important environmental risk factor for this pattern of drinking among young adults., (Copyright 2004 APA.)

Background: Adenoviruses have many advantages as vehicles for gene delivery to the central nervous system (CNS) and retrograde transport of vectors to axonally linked sites has been postulated as a method for targeting neurons in remote brain regions. To investigate optimisation of this we injected different doses of vector and have documented the neuropathological side effects., Methods: Increasing doses of a first-generation adenoviral vector, expressing the lacZ gene, were inoculated in the rat striatum and beta-galactosidase expression was examined at the primary and secondary sites. Subsequently, at the highest dose of vector, transgene expression, the inflammatory response, tyrosine hydroxylase (TH) expression and the rotational behaviour of animals were studied over time., Results: When a high dose of an adenoviral vector was delivered to the rat striatum, high levels of transgene expression were seen at 5 days in the injection site and in the substantia nigra. Smaller doses gave lower levels of expression with little expression detectable in the substantia nigra. At later time points, with the high dose, a marked reduction in transgene expression was detected and was accompanied by cytopathic damage, a strong inflammatory response and animal weight loss. This was associated with depletion in TH levels and abnormal motor behaviour in animals., Conclusions: Neuropathological damage in the dopaminergic system, caused by high doses of adenoviral vectors, has not previously been documented. To minimise damage and prolong transgene expression, it is important that the dose of vectors to be delivered is carefully optimised., (Copyright 2004 John Wiley & Sons, Ltd.)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra. This loss leads to complete dopamine depletion in the striatum and severe motor impairment. It has been demonstrated previously that a lentiviral vector system based on equine infectious anemia virus (EIAV) gives rise to highly efficient and sustained transduction of neurons in the rat brain. Therefore, a dopamine replacement strategy using EIAV has been investigated as a treatment in the 6-hydroxydopamine (6-OHDA) animal model of PD. A self-inactivating EIAV minimal lentiviral vector that expresses tyrosine hydroxylase (TH), aromatic amino acid dopa decarboxylase (AADC), and GTP cyclohydrolase 1 (CH1) in a single transcription unit has been generated. In cultured striatal neurons transduced with this vector, TH, AADC, and CH1 proteins can all be detected. After stereotactic delivery into the dopamine-denervated striatum of the 6-OHDA-lesioned rat, sustained expression of each enzyme and effective production of catecholamines were detected, resulting in significant reduction of apomorphine-induced motor asymmetry compared with control animals (p < 0.003). Expression of each enzyme in the striatum was observed for up to 5 months after injection. These data indicate that the delivery of three catecholaminergic synthetic enzymes by a single lentiviral vector can achieve functional improvement and thus open the potential for the use of this vector for gene therapy of late-stage PD patients.

In this report it is demonstrated for the first time that rabies-G envelope of the rabies virus is sufficient to confer retrograde axonal transport to a heterologous virus/vector. After delivery of rabies-G pseudotyped equine infectious anaemia virus (EIAV) based vectors encoding a marker gene to the rat striatum, neurons in regions distal from but projecting to the injection site, such as the dopaminergic neurons of the substantia nigra pars compacta, become transduced. This retrograde transport to appropriate distal neurons was also demonstrated after delivery to substantia nigra, hippocampus and spinal cord and did not occur when vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped vectors were delivered to these sites. In addition, peripheral administration of rabies-G pseudotyped vectors to the rat gastrocnemius muscle leads to gene transfer in motoneurons of lumbar spinal cord. In contrast the same vector pseudotyped with VSV-G transduced muscle cells surrounding the injection site, but did not result in expression in any cells in the spinal cord. Long-term expression was observed after gene transfer in the nervous system and a minimal immune response which, together with the possibility of non-invasive administration, greatly extends the utility of lentiviral vectors for gene therapy of human neurological disease.

1. Five glucocorticoids, when administered daily to rats for 5-7 days at a dosage of 5mg/kg, were in the following order of effectiveness with respect to their ability to decrease the weight gain of whole animals and the vastus lateralis, vastus medialis and gluteus medius muscles: corticosterone