dna damage in muscular dystrophy, polymyositis and als
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Publication
Journal: Journal of Substance Abuse Treatment
December/18/2008
Abstract
This article addresses common questions that clinicians face when treating pregnant women with opioid dependence. Guidance, based on both research evidence and the collective clinical experience of the authors, which include investigators in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) project, is provided to aid clinical decision making. The MOTHER project is a double-blind, double-dummy, flexible-dosing, parallel-group clinical trial examining the comparative safety and efficacy of methadone and buprenorphine for the treatment of opioid dependence in pregnant women and their neonates. The article begins with a discussion of appropriate assessment during pregnancy and then addresses clinical management stages including maintenance medication selection, induction, and stabilization; opioid agonist medication management before, during, and after delivery; pain management; breast-feeding; and transfer to aftercare. Lastly, other important clinical issues including managing co-occurring psychiatric disorders and medication interactions are discussed.
Publication
Journal: Neurology
January/28/2004
Abstract
OBJECTIVE
To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS.
METHODS
A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival.
RESULTS
Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis).
CONCLUSIONS
At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.
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Publication
Journal: Analytical Chemistry
April/4/2007
Abstract
Stable isotope-enriched molecules are used as internal standards and as tracers of in vivo substrate metabolism. The accurate conversion of measured ratios in the mass spectrometer to mole ratios is complicated because a polyatomic molecule containing enriched atoms will result in a combinatorial distribution of isotopomers depending on the enrichment and number of "labeled" atoms. This effect could potentially cause a large error in the mole ratio measurement depending on which isotope peak or peaks were used to determine the ratio. We report a computational method that predicts isotope distributions over a range of enrichments and compares the predicted distributions to experimental peptide isotope distributions obtained by Fourier transform ion cyclotron resonance mass spectrometry. Our approach is accurate with measured enrichments within 1.5% of expected isotope distributions. The method is also precise with 4.9, 2.0, and 0.8% relative standard deviations for peptides containing 59, 79, and 99 atom % excess (15)N, respectively. The approach is automated making isotope enrichment calculations possible for thousands of peptides in a single muLC-FTICR-MS experiment.
Publication
Journal: Journal of Physiology
January/27/2011
Abstract
Skeletal muscle function is impaired in heart failure patients due, in part, to loss of myofibrillar protein content, in particular myosin. In the present study, we utilized small-amplitude sinusoidal analysis for the first time in single human skeletal muscle fibres to measure muscle mechanics, including cross-bridge kinetics, to determine if heart failure further impairs contractile performance by altering myofibrillar protein function. Patients with chronic heart failure (n = 9) and controls (n = 6) were recruited of similar age and physical activity to diminish the potentially confounding effects of ageing and muscle disuse. Patients showed decreased cross-bridge kinetics in myosin heavy chain (MHC) I and IIA fibres, partially due to increased myosin attachment time (t(on)). The increased t(on) compensated for myosin protein loss previously found in heart failure patients by increasing the fraction of the total cycle time myosin is bound to actin, resulting in a similar number of strongly bound cross-bridges in patients and controls. Accordingly, isometric tension did not differ between patients and controls in MHC I or IIA fibres. Patients also had decreased calcium sensitivity in MHC IIA fibres and alterations in the viscoelastic properties of the lattice structure of MHC I and IIA fibres. Collectively, these results show that heart failure alters skeletal muscle contraction at the level of the myosin-actin cross-bridge, leading to changes in muscle mechanics which could contribute to impaired muscle function. Additionally, we uncovered a unique kinetic property of MHC I fibres, a potential indication of two distinct populations of cross-bridges, which may have important physiological consequences.
Publication
Journal: Journal of Nutrition
July/26/2005
Abstract
Since the in vitro study of Buse and Reid in 1975 showing a stimulatory effect of leucine upon rat muscle protein synthesis and reduction in proteolysis, a similar effect has been sought in humans. In 1978, Sherwin demonstrated in humans an improvement in N balance with infusion of leucine in obese subjects fasting to lose weight. A variety of subsequent studies have been performed in humans where leucine alone or the BCAAs have been administered in varying amounts and durations, and the effect upon protein metabolism has been measured. Measurements of changes in muscle amino acid metabolism were made by arteriovenous difference measurements and by biopsies. An anabolic effect of leucine and the branched-chain amino acids (BCAAs) on reduction of muscle protein breakdown was found in these studies, with no measured effect upon muscle protein synthesis. Later studies using stable isotope tracers to define both whole-body protein turnover and leg or arm protein metabolism have similarly concluded that leucine administration specifically induces a reduction in protein breakdown without increasing protein synthesis. This anabolic effect, produced through a reduction of protein breakdown in vivo in humans by leucine is contrary to in vitro studies of rat muscle where stimulation of protein synthesis, has been demonstrated by leucine. Likewise an increase in protein synthesis has also been demonstrated by insulin in rat muscle that is not seen in humans. Of the various studies administering BCAAs or leucine to humans for varying periods of time and amount, the results have been consistent. In addition, no untoward effects have been reported in any of these studies from infusion of the BCAAs at upward 3 times basal flux or 6 times normal dietary intake during the fed portion of the day.
Publication
Journal: Addiction
April/27/2011
Abstract
OBJECTIVE
This study examined whether smoking cessation using voucher-based contingency management (CM) improves birth outcomes.
METHODS
Data were combined from three controlled trials.
METHODS
Each of the trials was conducted in the same research clinic devoted to smoking and pregnancy.
METHODS
Participants (n=166) were pregnant women who participated in trials examining the efficacy of voucher-based CM for smoking cessation. Women were assigned to either a contingent condition, wherein they earned vouchers exchangeable for retail items by abstaining from smoking, or to a non-contingent condition where they received vouchers independent of smoking status.
METHODS
Birth outcomes were determined by review of hospital delivery records.
RESULTS
Antepartum abstinence was greater in the contingent than non-contingent condition, with late-pregnancy abstinence being 34.1% versus 7.4% (P<0.001). Mean birth weight of infants born to mothers treated in the contingent condition was greater than infants born to mothers treated in the non-contingent condition (3295.6 ± 63.8 g versus 3093.6 ± 67.0 g, P = 0.03) and the percentage of low birth weight (<2500 g) deliveries was less (5.9% versus 18.5%, P = 0.02). No significant treatment effects were observed across three other outcomes investigated, although each was in the direction of improved outcomes in the contingent versus the non-contingent condition: mean gestational age (39.1 ± 0.2 weeks versus 38.5 ± 0.3 weeks, P = 0.06), percentage of preterm deliveries (5.9 versus 13.6, P = 0.09), and percentage of admissions to the neonatal intensive care unit (4.7% versus 13.8%, P = 0.06).
CONCLUSIONS
These results provide evidence that smoking-cessation treatment with voucher-based CM may improve important birth outcomes.
Publication
Journal: Psychopharmacology
September/25/2003
Abstract
BACKGROUND
Psychomotor stimulants often increase cigarette smoking, although the mechanisms responsible for that effect remain unclear.
OBJECTIVE
The present study was conducted to extend our investigation of the effects of psychomotor stimulant use on the reinforcing effects of cigarette smoking.
METHODS
A progressive-ratio (PR) schedule was used to examine the acute effects of orally administered D-amphetamine (placebo, 5, 10, 15 mg/70 kg) on the reinforcing effects of smoking (2 puffs/ratio) and money (1.00 US dollar/ratio) in 18 adult smokers.
RESULTS
Among the overall sample of 18 smokers, D-amphetamine produced only a modest, non-significant increase in the amount of responding maintained by smoking (PR break point), but effects varied systematically between subjects. D-Amphetamine increased the smoking break point among ten subjects (responders), while leaving unchanged or decreasing the break point in the remaining eight individuals (non-responders). Responders also were more sensitive than non-responders to d-amphetamine's effects on visual-analog ratings of "high", "good effects", "drowsy", and "slurred speech", but not on other subject ratings (i.e., "bad effects", "jittery", "confused") or on any physiological measures (i.e., heart rate, blood pressure, skin temperature). D-Amphetamine did not significantly alter PR break point maintained by money.
CONCLUSIONS
These results provide further evidence that D-amphetamine can increase the reinforcing effects of cigarette smoking, at least among a subset of smokers.
Publication
Journal: Metabolism: Clinical and Experimental
January/7/2008
Abstract
Considerable controversy exists regarding the use of chromium (Cr) supplementation to modulate carbohydrate metabolism in subjects with diabetes. Recently, we reported that Cr supplementation, provided as 1000 microg/d as Cr picolinate, enhanced insulin sensitivity in subjects with type 2 diabetes mellitus. Our data agreed with some, but not all, studies that evaluated a similar dose and formulation in type 2 diabetes mellitus and suggested that subject selection and characteristics may be important considerations when assessing the clinical response. Thus, the goal of this study was to assess which metabolic or clinical characteristics, when obtained at baseline, best determine a clinical response to Cr when assessing changes in insulin sensitivity. Seventy-three subjects with type 2 diabetes mellitus were assessed in a double-blinded, randomized, placebo-controlled study. Subjects were assessed at baseline for glycemic control with glycated hemoglobin measures, oral glucose tolerance tests, and body weight and body fat measures (dual-energy x-ray absorptiometry). After baseline, insulin sensitivity in vivo was assessed with the use of hyperinsulinemic-euglycemic clamps. After the baseline clamp, subjects were randomized to receive Cr supplementation (1000 microg Cr/d provided as Cr picolinate) or placebo daily for 6 months. All study parameters were repeated after 6 months. The relationship of the baseline characteristics of the study subjects to the change in insulin sensitivity was determined. Sixty-three percent of the subjects with type 2 diabetes mellitus responded to the Cr treatment as compared with 30% with placebo. The only subject variable significantly associated with the clinical response to Cr was the baseline insulin sensitivity, as assessed with the hyperinsulinemic-euglycemic clamp (partial R(2) = .4038) (P = .0004). Subject phenotype appears to be very important when assessing the clinical response to Cr because baseline insulin sensitivity was found to account for nearly 40% of the variance in the clinical response to Cr.
Publication
Journal: Obesity
April/7/2008
Abstract
OBJECTIVE
Because estrogen and testosterone affect transcription factors regulating mitochondrial function, we assessed the effects of gender on the metabolic response to dietary palmitic acid (PA) vs. oleic acid (OA) in subjects participating in a previously described trial.
METHODS
Adults (N = 43) were studied after following a baseline diet (PA = 8.4% kcal, OA = 13.1% kcal) and after undergoing one of two experimental diets: high PA (HI PA) (PA = 16.8%, OA = 16.4% kcal) (N = 21; 11 men) or high OA (HI OA) (PA = 1.7%, and OA = 31.4%) (N = 22; 11 men).
RESULTS
Relative to baseline, the rate of fatty acid (FA) oxidation (% resting energy expenditure(REE)) (mean +/- s.e.m.) increased in women on HI OA while decreasing on HI PA in the fed (+11.8 +/- 5.6% vs. -6.3 +/- 4.2%, P = 0.02) and fasting states (+13.4 +/- 4.2% vs. -12.7 +/- 6.9%, P = 0.047), but changes in men were not statistically significant. Daily energy expenditure changed only in men, increasing on HI OA and decreasing on HI PA (+66 +/- 61 kcal/day or 1.2 +/- 1.0 kcal/kg fat-free mass (FFM)/day vs. -266 +/- 78 kcal/day or -4.2 +/- 1.3 kcal/kg FFM/day, P = 0.004 and P = 0.007, respectively).
CONCLUSIONS
Increased dietary PA/OA caused decreased FA oxidation in women, in the fed and fasted states and decreased daily energy expenditure (DEE) in men.
Publication
Journal: American Journal of Clinical Nutrition
August/7/1996
Abstract
A possible cause of accelerated atherothrombosis in the syndrome of insulin resistance appears to be an elevated blood concentration of plasminogen activator inhibitor type-1 (PAI-1). Insulin resistance occurs with aging, attributable partly to increased adiposity. Scarce information exists regarding the effects of weight loss in elderly, obese individuals on PAI-1 concentrations. Consequently, weight loss (9 +/- 1 kg) was induced by energy intake restriction in 19 elderly, obese individuals, and its effect on fibrinolytic system peptides was measured. Initially elevated PAI-1 concentrations decreased by 50%, with a simultaneous decrease in the concentration of tissue-type plasminogen activator (t-PA)/PAI-1 complexes but no significant change in t-PA suggested a decrease in inhibition of the fibrinolytic system. The concentration of plasmin/antiplasmin complexes (PAP complex) increased by approximately 20%, indicating augmented fibrinolytic system activity. The decline in PAI-1 correlated with that of the decrease in body weight (r = 0.5, P < 0.05) and fat mass losses (r = 0.46, P < 0.05). The increase in PAP complexes correlated with weight and fat mass losses (r = 0.4 and r = 0.46, respectively; P < 0.05 for both). No correlation was seen between fibrinolytic system variables and baseline concentrations of substrates or insulin, but the change in PAI-1 correlated with the change in plasma triacylglycerols (r = 0.58, P < 0.05). Results indicate that energy restriction sufficient to induce moderate weight loss leads to diminution of elevated plasma PAI-1 and relief of inhibition of the fibrinolytic system in elderly, obese subjects. To the extent that these changes are associated with a decrease in the progression of vasculopathy, weight loss in elderly, obese individuals may be a useful means to reduce cardiovascular morbidity and mortality.
Publication
Journal: Journal of Nutrition
August/5/2007
Abstract
The initial use of a tracer of phenylalanine was by Moss and Schoenheimer in rats in 1940 to determine that phenylalanine was hydroxylated to tyrosine, defining for the first time the primacy of this pathway. Phenylalanine and tyrosine kinetics were not measured in humans until the 1970-80s. The first application was to determine the degree of blockage of phenylalanine hydroxylation in patients with hyperphenylalanemia and phenylketonuria, but this approach was expanded to determination of phenylalanine hydroxylation in normal subjects. Far more uses have been demonstrated for measuring rates of phenylalanine disposal and tyrosine production in relatively normal subjects than in patients with in-born errors of metabolism. Key to use of tracers to determine phenylalanine and tyrosine metabolic rates has been the development of appropriate tracer models. Most applications have used relatively simple models ignoring the intracellular hydroxylation rate component. Because the liver is the primary site of hydroxylation in the body, the intracellular enrichment at the site of hydroxylation can be assessed from the tracer enrichments at isotopic steady state in rapid-turnover plasma proteins, such as Apo-B, made and secreted by the liver. Although there are potential problems with use of deuterated tracers of phenylalanine, suitable tracers are available and have been demonstrated for general measurement of phenylalanine and tyrosine kinetics in humans.
Publication
Journal: American Journal of Clinical Nutrition
June/5/1985
Authors
Publication
Journal: Journal of Nutrition
July/7/2004
Abstract
As the average human lifespan increases, so does the recognition that advancing age is associated with changes in nutrient intake and requirements as a consequence of biological, social, and pathological factors. Studies show that whereas protein requirements may not differ significantly between younger and older adults, the adaptive mechanisms and responses to nutritional or pathological stressors may differ and alter the balance between requirement and toxicity of specific amino acids (AAs). As an individual gets older, cardiovascular disease and cancer become the leading causes of morbidity and mortality. Advancing age is also associated with changes in appetite, food intake, and physical activity, all of which can influence protein and AA metabolism. The sulfur amino acids (SAAs) methionine and cysteine recently attracted attention because of their pivotal roles in methyl group metabolism and maintenance of the cellular redox state. Methionine, an indispensable AA, is important for methylation reactions and as a precursor for cysteine, which is the rate-limiting AA for glutathione (GSH) synthesis. On one hand, high intake levels or blood concentrations of methionine are associated with adverse consequences such as hyperhomocysteinemia and endothelial dysfunction, which are risk factors for cardiovascular disease. On the other hand, methionine deficiency is reported to lower the threshold of chemical-induced toxicity and play a role in carcinogenesis. Therefore, it is evident that understanding the biological significance of the interrelationship between SAAs, GSH, and methyl group metabolism is key to determining optimal dietary intakes of SAAs in older individuals.
Publication
Journal: Addiction
October/21/2013
Abstract
OBJECTIVE
To characterize infections and compare obstetric outcomes in opioid-dependent pregnant women who participated in a randomized clinical trial comparing agonist medications, methadone and buprenorphine.
METHODS
Incidence of infections was identified as part of the screening medical assessment. As part of a planned secondary analysis, analysis of variance and polytomous logistic regressions were conducted on obstetric outcome variables using treatment randomization condition (maternal maintenance with either methadone or buprenorphine) as the predictor variable, controlling for differences between study sites.
METHODS
Six United States sites and one European site that provided comprehensive treatment to opioid-dependent pregnant women.
METHODS
Pregnant opioid-dependent women (n = 131) who delivered while participating in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study.
METHODS
Obstetric, infectious and other maternal medical complications captured by medical records, physical examination, blood tests and self-report. Neonatal medical complications captured by medical records.
RESULTS
Hepatitis C was the most common infection (32.3%), followed by hepatitis B (7.6%) and chlamydia (6.1%) among participants at study enrollment. Maternal methadone versus buprenorphine maintenance was associated with a higher incidence of preterm labor (P = 0.04) and a significantly higher percentage of signs of respiratory distress in neonates at delivery (P = 0.05). Other medical and obstetric complications were infrequent in the total sample, as well as in both methadone and buprenorphine conditions.
CONCLUSIONS
Buprenorphine appears to have an acceptable safety profile for use during pregnancy.
Publication
Journal: Obesity
October/25/2007
Abstract
OBJECTIVE
Using tracers, we showed, over 9 hours, that palmitic acid (PA) is oxidized at a lower rate than oleic acid (OA). Our subsequent clinical trial showed that enriching the diet for 28 days with PA, relative to OA, lowered fatty acid (FA) oxidation. However, because this conclusion was based on indirect calorimetry for 7 hours after a test meal, transient differences in the kinetics of oxidation of OA and PA could explain these results. Thus, we hypothesized that increasing PA vs. OA would decrease FA oxidation during the first day of feeding the diets.
METHODS
A double-masked trial was conducted in 20 adults, who, after a baseline diet, were randomized to one of two experimental formula diets: high (HI) OA (PA=1.7% kcal, OA=31.4% kcal; N=11) or HI PA (PA=16.8% kcal, OA=16.4% kcal; N=9). Respiratory quotient (RQ) was measured over the first 14 hours of feeding the experimental diets (7:00 am to 9:00 pm). To determine whether these subjects were representative of the subjects in the previous trial, we assessed RQ 28 days after beginning either diet.
RESULTS
During the first 14 hours of feeding the diets, time (p=0.026) but not diet group had an effect on the difference between the RQ post-feeding and the fasting pre-value. However, RQ in the fed state was significantly higher in the HI PA group after 28 days of feeding.
CONCLUSIONS
Chronically increasing dietary PA for 28 days, but not acute meal feeding, lowers total FA oxidation.
Publication
Journal: Antimicrobial Agents and Chemotherapy
October/3/2001
Abstract
To establish whether a feline model can predict nucleoside analogue behavior in human semen, zidovudine (ZDV) and lamivudine (3TC) pharmacokinetic parameters (PKs) were determined in the blood and seminal plasma of healthy cats. Our results show considerable similarity in ZDV and 3TC PKs between cats and humans. As in humans, ZDV and 3TC tend to accumulate in feline seminal plasma. Area under the blood plasma concentration-time curve was predictive of seminal plasma excretion. The felid model offers a unique in vivo experimental alternative for investigating the pharmacokinetics of nucleoside analogues in the male genital tract.