Skeletal muscle-specific overexpression of SIRT1 does not enhance whole-body energy expenditure or insulin sensitivity in young mice.

AIMS/HYPOTHESIS: The NAD(+)-dependent protein deacetylase sirtuin (SIRT)1 is thought to be a key regulator of skeletal muscle metabolism. However, its precise role in the regulation of insulin sensitivity is unclear. Accordingly, we sought to determine the effect of skeletal muscle-specific overexpression of SIRT1 on skeletal muscle insulin sensitivity and whole-body energy metabolism. METHODS: At 10 weeks of age, mice with muscle-specific overexpression of SIRT1 and their wild-type littermates were fed a standard diet with free access to chow or an energy-restricted (60% of standard) diet for 20 days. Energy expenditure and body composition were measured by indirect calorimetry and magnetic resonance imaging, respectively. Skeletal muscle insulin-stimulated glucose uptake was measured ex vivo in soleus and extensor digitorum longus muscles using a 2-deoxyglucose uptake technique with a physiological insulin concentration of 360 pmol/l (60 µU/ml). RESULTS: Sirt1 mRNA and SIRT1 protein levels were increased by approximately 100- and 150-fold, respectively, in skeletal muscle of mice with SIRT1 overexpression compared with wild-type mice. Despite this large-scale overexpression of SIRT1, body composition, whole-body energy expenditure, substrate oxidation and voluntary activity were comparable between genotypes. Similarly, skeletal muscle basal and insulin-stimulated glucose uptake were unaltered with SIRT1 overexpression. Finally, while 20 days of energy restriction enhanced insulin-stimulated glucose uptake in skeletal muscles of wild-type mice, no additional effect of SIRT1 overexpression was observed. CONCLUSIONS/INTERPRETATION: These results demonstrate that upregulation of SIRT1 activity in skeletal muscle does not affect whole-body energy expenditure or enhance skeletal muscle insulin sensitivity in young mice on a standard diet with free access to chow or in young mice on energy-restricted diets.

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome.

OBJECTIVES: To determine mRNA expression differences in genes involved in signalling and modulating sensory fatigue, and muscle pain in patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FM) at baseline, and following moderate exercise. DESIGN: Forty-eight patients with CFS only, or CFS with comorbid FM, 18 patients with FM that did not meet criteria for CFS, and 49 healthy controls underwent moderate exercise (25 min at 70% maximum age-predicted heart rate). Visual-analogue measures of fatigue and pain were taken before, during and after exercise. Blood samples were taken before and 0.5, 8, 24 and 48 h after exercise. Leucocytes were immediately isolated from blood, number coded for blind processing and analyses and flash frozen. Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic and immune functions was compared between groups at baseline and following exercise. Changes in amounts of mRNA were correlated with behavioural measures and functional clinical assessments. RESULTS: No gene expression changes occurred following exercise in controls. In 71% of patients with CFS, moderate exercise increased most sensory and adrenergic receptor's and one cytokine gene's transcription for 48 h. These postexercise increases correlated with behavioural measures of fatigue and pain. In contrast, for the other 29% of patients with CFS, adrenergic α-2A receptor's transcription was decreased at all time-points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup. FM-only patients showed no postexercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than controls. CONCLUSIONS: At least two subgroups of patients with CFS can be identified by gene expression changes following exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine. The smaller subgroup contained most of the patients with CFS with orthostatic intolerance, showed no postexercise increases in any gene and was defined by decreases in mRNA for α-2A. FM-only patients can be identified by baseline increases in three genes. Postexercise increases for four genes meet published criteria as an objective biomarker for CFS and could be useful in guiding treatment selection for different subgroups.

Cigarettes and Straws: Late Positive Potential Modulation in Mental Illness and Nicotine Addiction.

Tobacco use remains a major preventable cause of death worldwide, accumulating billions of dollars in healthcare spending annually in the U.S. alone. Evidence has found that among those addicted, individuals suffering with psychiatric illnesses are disproportionally abusing. To assess this disparity, our study observed event related potential (ERP) responses recorded with electroencephalogram (EEG) in chronic smokers with (MI; n=6) and without mental illness (NMI; n=6). We found that the MI group alone presented heightened late positive potential (LPP) responses while processing cigarette (addictive) stimuli compared to neutral images (t-value = 3.11 at Cz, 3.92 at Pz). Our study illustrates the significance of the LPP as a promising biomarker to assess tobacco addiction in individuals facing mental illness.

Non-Invasive, Cost-Effective, Early Diagnosis of Mild Cognitive Impairment in an Outpatient Setting: Pilot Study.

Mild cognitive impairment (MCI) and Alzheimer's Disease (AD) affect millions worldwide, yet no curative treatments for these neuro-degenerative disorders have been developed to date. The current study aims to propose a noninvasive, cost-effective, early diagnostic protocol for individuals suffering with MCI in an outpatient setting. Elderly participants (n=11) were screened for MCI utilizing the Montreal Cognitive Assessment (MoCA) questionnaire preceding a visual stimuli task. Participants were presented with facial stimuli to elicit event related potentials (ERP) while their cortical activity was recorded utilizing electroencephalogram (EEG). Combining regional neurophysiological biomarkers into a multidimensional feature space allowed for differentiation between healthy and MCI participants based on their respective MoCA scores. This study illustrates the feasibility of recording reliable EEG in an outpatient setting while presenting a novel method for diagnosing MCI in elderly (age >60) populations.

Study on the dehydrating effect of the red cell Na+/K+-pump in nystatin-treated cells with varying Na+ and water contents.

Using the antibiotic Nystatin, we have developed a systematic method for the preparation of red blood cells with independently selected levels of intracellular Na+ concentrations and water content. Such cells provided an experimental model to study the effect of Na+/K+ pump stimulation on red cell water content. Even in initially dehydrated cells, stimulation of the Na+/K+ pump by elevated intracellular Na+ caused subsequent further loss of cell water. Cell water loss was reflected in decreased monovalent cation content per unit mass of hemoglobin and by a shift in the density distribution of the cell populations to higher densities on discontinuous Stractan gradients. We conclude that the 3 Na+out : 2 K+in stoichiometry of the Na+/K+ pump results in a net desalting effect with increased pump activity. Under the conditions of these experiments, the cell appears to have no effective mechanism to compensate for a net loss of ions and water.

Grand rounds revisited: results of a survey of U.S. Departments of Medicine.

Medical grand rounds is a time-honored weekly conference at United States teaching hospitals. We surveyed 122 departments of medicine to test the hypothesis that grand rounds may have changed with the changing training environment. Our goal was to gain a new perspective on the way physicians learn clinical medicine and maintain their fund of information. A questionnaire was designed to assess several aspects of grand rounds, including format, objectives, popularity, and changes over time. The questionnaire was directed to department heads of 122 U.S. medical schools. Seventy-five percent of respondents were department chairs; the remainder were chief residents and other faculty. Survey response rate was 96%. According to respondents, the major objective of grand rounds was to provide "updates in diagnosis and treatment." Case presentations were regularly included in about one third of departments; patients were rarely present for examination or interview. The popularity of grand rounds was thought to have decreased. These data support the impression that medical grand rounds is still considered important in most academic medical centers. Suggestions are made for increasing the clinical relevance of the conference. New techniques for presenting clinical material are reviewed, and an argument is made for returning to a basic strategy of "solving the patient's problem."

Improvement in severe onchocercal skin disease after a single dose of ivermectin.

PURPOSE: Skin disease is the most common clinically important manifestation of onchocerciasis. Ivermectin, a newly available drug, is well tolerated and effective in Onchocerca volvulus infection. However, little information is available regarding its effect on onchocercal skin disease. The purpose of this study was to examine, in patients with well-characterized onchodermatitis, the effect of a single dose of ivermectin. SUBJECTS AND METHODS: Twenty-one persons with severe onchodermatitis were followed over a 6-month period. In order to evaluate the effect of ivermectin on their skin lesions, photographic transparencies were made before treatment and at 3 and 6 months after treatment. These were then evaluated in a blinded fashion. RESULTS: Following a single dose of 150 micrograms/kg, there was a significant improvement in dermatitis in the first 3 months after treatment. All 14 persons with the worst skin disease showed improvement. The drug had no demonstrable effect on depigmented lesions over the period of observation. Treatment was well tolerated. CONCLUSION: Single-dose ivermectin shows promise as the first acceptable treatment for severe onchocercal dermatitis.

Treatment of onchocerciasis. The ocular effects of ivermectin and diethylcarbamazine.

The ocular changes that occur with diethylcarbamazine treatment of onchocerciasis seriously restrict its usefulness. Ivermectin, a newly developed antifilarial drug, was compared with diethylcarbamazine for treatment of onchocerciasis in a double-masked, placebo-controlled trial. Thirty men with moderate to severe infection and ocular involvement were randomly assigned to receive ivermectin as a single oral dose (200 micrograms/kg), diethylcarbamazine (administered for eight days), or placebo. Detailed ocular examinations were performed serially over a 12-month period. Diethylcarbamazine treatment caused a marked increase in living and dead microfilariae in the cornea, punctate opacities, and limbitis during the first week of therapy. Ivermectin had no such effect. However, ivermectin therapy resulted in a long-term reduction in intraocular microfilariae comparable to that seen with diethylcarbamazine. Ivermectin appears to have few ocular complications and be a better-tolerated and more effective microfilaricidal agent than diethylcarbamazine for the treatment of onchocerciasis.

Motor-evoked potentials in response to fatiguing grip exercise in multiple sclerosis patients.

OBJECTIVE: This study examined central and peripheral effects of fatiguing exercise (3 min maximal grip) in healthy controls (n=10) and multiple sclerosis (MS) subjects with weakness, MS-W (n=16) and normal motor function, MS-NM (n=16) in the studied extremity. METHOD: Transcranial magnetic stimulation (TMS) was used to assess resting and facilitated motor-evoked potentials (MEPs) of abductor pollicus brevis (APB) and flexor carpi radialis (FCR) muscles before and after fatiguing exercise. Exercise-induced depletion and recovery of phosphocreatine (PCr) were measured using (31)P magnetic resonance spectroscopy ((31)PMRS) in FCR. RESULTS AND CONCLUSION: MS subjects demonstrated significantly lower peak force and a faster decline in force than controls. Contralateral muscle activation (hand grip) before the fatigue protocol resulted in significantly increased MEP amplitudes in all groups. Contralateral hand grip following fatiguing exercise resulted in significantly higher MEP amplitudes in controls and MS-NM subjects, but not MS-W subjects. Fatiguing exercise resulted in prolonged central motor conduction time (CMCT) in MS subjects, but not controls. No group differences in PCr depletion or resynthesis were observed. All groups demonstrated significant post-exercise depression (PED) of MEP amplitude that persisted beyond the time course of PCr recovery, indicating fatigue was central in origin. MS subjects were less able than controls to increase cortical excitability using contralateral muscle activation following fatiguing exercise, possibly indicating impaired conduction in the corpus callosum.

Physiological aspects and injury in elite Alpine skiers.

Alpine skiing requires aerobic and anaerobic power, muscular strength, and a variety of complex motor abilities including quickness, agility, balance and coordination. There is evidence of variability in physical characteristics between skiers of different events. Generally, successful alpine competitors are taller and heavier than in the past. Greater size, specifically lean mass, may be related to technique changes because of the advent of breakaway poles. Aerobic power, although important, does not discriminate competitors of varying ability categories. Aerobic power is more likely to be a result of conditioning for alpine skiing rather than a profound requirement of the sport. Anaerobic power is important for skiing and both laboratory and field power tests correlate well with performance. Tests that measure explosive and sustained anaerobic power such as the Wingate, vertical jump, 60-second repeated jump, and Margaria-Kalamen stair run are valuable in assessing skiers. On-snow lactate and oxygen consumption measurements further substantiate the need for high anaerobic power. Alpine skiers have very high leg strength compared with other athletes. Isokinetic testing has been used to evaluate dynamic leg strength in skiers, but little is known about high speed dynamic or eccentric strength capabilities. A new mechanism of knee injury that is associated with tibial acceleration has been identified in competitive alpine skiers. A release binding that is sensitive to physiological factors in addition to release forces should be developed. Strength profiling of skiers may also be valuable in evaluating injury risk.

Recommendations for physical activity in patients with multiple sclerosis.

For many years, patients with multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system, have been advised to avoid exercise. MS is believed to be autoimmune in origin, mediated by activated T cells which penetrate the blood-brain barrier and attack myelin. The pathophysiology, with respect to function is an impairment of saltatory conduction, specifically, slowing of conduction speed and/or conduction block. Symptoms can temporarily worsen on exposure to heat or during physical exercise. Exercise programmes must be designed to activate working muscles but avoid overload that results in conduction block. Fatigue, often severe, affects about 85% of MS patients and, along with motor and sensory symptoms, results in decreased mobility and reduced quality of life. Physical activity and recreation are reduced in patients with MS. Before developing recommendations, physical activity patterns and the physical effects of MS should be assessed in individual patients. Patients may then be functionally classified. Physical activity can also be classified in a pyramid structure, with the most basic functions forming the base and the most integrated functions on top. The muscular fitness pyramid progresses through passive range of motion, active resistive, specific strengthening and integrated strength exercises Overall physical activity may be increased according to functional level by performing activities of daily living, incorporating inefficiencies into daily living, pursuing more active recreation and eventually developing a structured exercise programme. The importance of the proper exercise environment, balance and coordination issues and factors related to adherence are discussed.

Ocular manifestations of onchocerciasis in a rain forest area of west Africa.

The epidemiology and natural history of onchocerciasis and its ocular complications in rain forest areas are poorly understood. The present study was conducted on a rubber plantation in a hyperendemic area in the rain forest of Liberia, West Africa, where 800 persons were examined. The prevalence of infection was 84% overall 29% had intraocular microfilariae, and 2.4% were blind in one or both eyes. Onchocerciasis was the cause of all binocular blindness and one-third of all visual impairment. Over half of the visual impairment caused by onchocerciasis was due to posterior segment diseases. Chorioretinal changes were present in 75% of people, and included intraretinal pigment clumping in 52% and retinal pigment epithelium atrophy in 32%. Atrophy of the retinal pigment epithelium was associated with increasing age and severity of infection. Intraretinal pigment was strongly associated with anterior uveitis. There was a strong correlation between uveitis and the inflammatory chorioretinal sequelae: retinitis, intraretinal pigment, subretinal fibrosis, and optic neuropathy. These findings indicate that considerable visual impairment associated with rain forest onchocerciasis is common and is due largely to chorioretinal disease.

Effect of single-dose ivermectin therapy on human Onchocerca volvulus infection with onchocercal ocular involvement.

Ivermectin has shown promise as a potentially safe and effective microfilaricidal drug for the treatment of onchocerciasis. Several limited studies have shown it to have fewer side effects, especially ocular complications, than the currently available drug, diethylcarbamazine. The detailed ocular findings in 200 moderately to heavily infected Liberians who were enrolled in a safety and dose-finding study are presented. They received either 0, 100, 150, or 200 micrograms/kg of ivermectin and were followed up for 12 months. In clinical studies so far carried out ivermectin in a dose of 100, 150, or 200 micrograms/kg has not been associated with any major adverse reactions nor were there any sight-threatening effects even in the presence of severe ocular disease. Each of these doses significantly reduced the ocular microfilaria load for at least 12 months when compared with either the placebo (p less than 0.05) or pretreatment values (p less than 0.001). However, the 100 and 150 micrograms/kg doses caused fewer minor side effects than the higher dose. These results confirm that ivermectin in a single oral dose may be a safe and effective microfilaricidal drug for the treatment of onchocerciasis and that it appears to be free of major ocular side effects.

An investigation of age-related factors in the age-job-satisfaction relationship.

Most researchers have found a positive linear relation between age and job satisfaction. We attempted to account for this relationship by measuring variables that had been proposed to be causal factors. Subjects were 496 city and county managers working in Florida. Potential explanatory variables were (a) job congruence (the difference between what managers prefer and what they perceive they have in a job), (b) internal-external locus of control, and (c) related demographics-age, salary, organizational tenure, position tenure, and organizational level. Multiple regression analyses found that job congruence and work locus of control accounted for almost all of the variance in the age-satisfaction relationship. This study supports the job change hypothesis, which proposes tha older workers get more of what they want out of work.

Non-specific abdominal pain: the resource implications.

Non-specific abdominal pain (NSAP) is responsible for a significant proportion of emergency surgical admissions with resultant resource implications. The extent of the problem was assessed in a consecutive group of 100 patients, aged between 15 and 35 years, admitted with lower abdominal pain to one general surgical firm. No less than 67 of these patients (67%) were diagnosed as having NSAP (13.29% of all general surgical admissions), most (75%) being female and having a mean hospital stay of 4.1 days. Only 11 patients (11%) had appendicitis and the remaining 22 had miscellaneous gynaecological, urological or gastrointestinal problems. Detailed analysis of the resources used revealed that the mean cost to the NHS of each case of NSAP was 807 pounds, the bulk of which was attributable to the hospital stay. Wider assessment of the problem (by means of postal questionnaire) suggests that the cost to the NHS in Wales is in the region of 6 million pounds per year and may be over 100 million pounds per year in the UK as a whole.

Leukocyte Gene Expression in Patients with Medication Refractory Depression before and after Treatment with ECT or Isoflurane Anesthesia: A Pilot Study.

Objective. To evaluate leukocyte gene expression for 9 selected genes (mRNAs) as biological markers in patients with medication refractory depression before and after treatment with ECT or isoflurane anesthesia (ISO). Methods. In a substudy of a nonrandomized open-label trial comparing effects of ECT to ISO therapy, blood samples were obtained before and after treatment from 22 patients with refractory depression, and leukocyte mRNA was assessed by quantitative PCR. Patients' mRNAs were also compared to 17 healthy controls. Results. Relative to controls, patients before treatment showed significantly higher IL10 and DBI and lower ADRA2A and ASIC3 mRNA (P < 0.025). Both ECT and ISO induced significant decreases after treatment in 4 genes: IL10, NR3C1, DRD4, and Sult1A1. After treatment, patients' DBI, ASIC3, and ADRA2A mRNA remained dysregulated. Conclusion. Significant differences from controls and/or significant changes after ECT or ISO treatment were observed for 7 of the 9 mRNAs studied. Decreased expression of 4 genes after effective treatment with either ECT or ISO suggests possible overlap of underlying mechanisms. Three genes showing dysregulation before and after treatment may be trait-like biomarkers of medication refractory depression. Gene expression for these patients has the potential to facilitate diagnosis, clarify pathophysiology, and identify potential biomarkers for treatment effects.

Brain activation in multiple sclerosis: a BOLD fMRI study of the effects of fatiguing hand exercise.

BACKGROUND: Multiple sclerosis (MS) patients experience fatigue as a chronic symptom that decreases quality of life. Commonly, fatigue in MS patients is manifested as decreased motor function during or after physical activity and is associated with changes in brain metabolism. OBJECTIVE: To determine brain activation patterns in MS patients and healthy controls during a simple motor task before and after fatiguing hand-grip exercise. METHODS: Functional magnetic resonance imaging (fMRI) scans were conducted on 10 MS patients and 13 healthy controls during 4-finger flexion and extension in rested and fatigued states. RESULTS: Before the fatigue protocol, MS patients had greater activation in the contralateral primary motor cortex, insula, and cingulate gyrus than controls. Following fatiguing exercise, controls showed increased activation of precentral gyrus and insula while patients did not show any activation increases and actually decreased activity to the insula. CONCLUSION: Results indicate that before fatiguing exercise, MS patients marshaled more brain activation compared to controls, which may represent functionally adaptive changes in response to demyelination. This increased activation may suggest that patients require more effort to perform even simple motor tasks, possibly because peripheral or central signals for fatigue are chronically enhanced. When fatigued further by muscle contraction, brain activation cannot be further increased.

Physiological comparison of international, national and regional alpine skiers.

The purpose of this study was to evaluate the predictive power of physiological tests in categorizing competitive alpine skiers. Sixty-one subjects (30 female and 31 male) were classified into three levels: international, national, and regional on the basis of past competition results. Hydrostatic weighing, maximal cycling, Wingate, 60-s repeated jump, and vertical jump tests were used to assess body composition, aerobic and anaerobic power, respectively. MANOVA revealed a significant group by gender interaction (Hotellings T, p less than .001), and main effects of gender and group (p less than .001). Discriminant analyses performed separately for male and female groups determined which variables were responsible for differences and resulted in selection of the following variables for classification of the men: average work from the repeated jump, absolute power for the vertical jump, and Wingate endurance. For the women, average work from the repeated jump, absolute and relative vertical jump power, absolute maximum Wingate power, and relative repeated jump power were most important. Fat-free mass was a powerful predictor for both sexes because of its strong relationship (r greater than 0.85) with power results. Aerobic power was not useful in group classification. In conclusion, physiological tests of anaerobic power and fat-free mass were the best predictors of group membership.

Sequence organization of cloned intracisternal A particle genes.

Seven recombinant DNA clones containing mouse intracisternal A particle genes were isolated and analyzed by restriction enzyme digestion, Southern blot analysis and heteroduplex mapping. The sequence organization of the individual genes was found to differ, with one end of the gene region being most variable, while a central segment of 1.8 kb was missing from two of the clones. A third region, common to all the clones and containing the 3' end of the gene, is present in about 1800 copies per haploid genome, but the central portion is found in only 650 copies. The same reiteration frequency is found in both myeloma tumor and mouse liver DNA. The most abundant intracisternal A particle RNA in two different myeloma lines was found to be 3.5 kb, and RNA/DNA hybrids show that the RNA is homologous to all but a small internal segment of one of the clones.

The physiological effects of beverage ingestion during cross country ski training in elite collegiate skiers.

The purpose of this study was to investigate the effects of beverage ingestion on fluid balance during 1.5 hr of low intensity cross country skiing. In Part I, 6 skiers drank water ad libitum during ski training. In Part II, 10 skiers were matched by body weight (BW) and assigned to ingest 2.5 ml.kg-1 BW of water or a carbohydrate/electrolyte (CE) beverage every 2.5 km. Skiing speed averaged 11.5 km.hr-1 for 90 min around a 5 km groomed track. Following 20 min of seated rest, blood samples were collected immediately before and approximately 30 min after skiing. Part I data indicated that subjects ingested 576 +/- 189 ml of fluid and produced 266 +/- 205 ml of urine; BW, plasma and urine osmolality, and plasma protein decreased significantly. In Part II, the CE group produced less urine (135u75 vs. 450 +/- 262 ml) and had smaller decreases in plasma osmolality (-1.0 +/- 1.0 vs. -7.0 +/- 2.4 mOsm.kg H2O) and protein (-0.11 +/- 08 vs. -0.42 +/- 0.24 gL-1) than the water group. No differences were observed for BW loss, % change in PV, FWC, or change in urine osmolality. It was concluded that ad lib water ingestion was inadequate to minimize fluid balance disruption. Plain water ingestion also led to significant dilution of the plasma and increased urine output. However, the ingestion of CE led to attenuation of fluid balance disruption, presumably due to the maintenance of osmotic balance in the plasma.