AMPK and PGC-α following maximal and supramaximal exercise in men and women: a randomized cross-over study.

We tested the hypothesis that AMPK activation and peroxisome proliferator gamma coactivator 1 alpha (PGC-1α) expression are not augmented as exercise intensity (power output) increases from maximal to supramaximal intensities and conducted an exploratory analysis comparing AMPK activation and PGC-1α expression in males and females. Seventeen (n = 9 males; n = 8 females) recreationally active, healthy, young individuals volunteered to participate in the current study. Participants completed work matched interval exercise at 100% (Max) and 133% (Supra) of peak work rate (WRpeak). Intervals were 1 min in duration and participants were prescribed 6 and 8 intervals of Max and Supra, respectively, to equate external work across protocols. PGC-1α mRNA expression and activation of AMPK (p-ACC) were examined in muscle biopsy samples. Interval WR (watts; W), intensity (%WRpeak) and average HR (bpm), blood lactate (mmol/L) and rating of perceived exertion were all higher (all p < 0.05) in Supra. Fatigue was greater (p < 0.05) in Supra. PGC-1α mRNA expression significantly increased after exercise in Max (p < 0.01) and Supra (p < 0.01), but was not significantly different (p = 0.71) between intensities. A main effect of time (Pre - 0 h) (p < 0.01) was observed for p-ACC; however, no effect of intensity (p = 0.08) or interaction (p = 0.97) was observed. No significant effects of time (p = 0.05) intensity (p = 0.42), or interaction (p = 0.97) were observed for p-AMPK (Thr172). Exploratory sex analysis demonstrated a main effect of sex for p-ACC (greater p-ACC in males; p < 0.05) but not for p-AMPK or PGC-1α expression. Our results confirm that AMPK-PGC-1α signalling is not augmented following supramaximal exercise and provide novel data demonstrating a decrease in AMPK activation (p-ACC) in females compared to men. Trial registration: https://doi.org/10.17605/OSF.IO/U7PX9.

A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia.

The emerging understanding of gut microbiota as 'metabolic machinery' influencing many aspects of physiology has gained substantial attention in the field of psychiatry. This is largely due to the many overlapping pathophysiological mechanisms associated with both the potential functionality of the gut microbiota and the biological mechanisms thought to be underpinning mental disorders. In this systematic review, we synthesised the current literature investigating differences in gut microbiota composition in people with the major psychiatric disorders, major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ), compared to 'healthy' controls. We also explored gut microbiota composition across disorders in an attempt to elucidate potential commonalities in the microbial signatures associated with these mental disorders. Following the PRISMA guidelines, databases were searched from inception through to December 2021. We identified 44 studies (including a total of 2510 psychiatric cases and 2407 controls) that met inclusion criteria, of which 24 investigated gut microbiota composition in MDD, seven investigated gut microbiota composition in BD, and 15 investigated gut microbiota composition in SZ. Our syntheses provide no strong evidence for a difference in the number or distribution (α-diversity) of bacteria in those with a mental disorder compared to controls. However, studies were relatively consistent in reporting differences in overall community composition (ß-diversity) in people with and without mental disorders. Our syntheses also identified specific bacterial taxa commonly associated with mental disorders, including lower levels of bacterial genera that produce short-chain fatty acids (e.g. butyrate), higher levels of lactic acid-producing bacteria, and higher levels of bacteria associated with glutamate and GABA metabolism. We also observed substantial heterogeneity across studies with regards to methodologies and reporting. Further prospective and experimental research using new tools and robust guidelines hold promise for improving our understanding of the role of the gut microbiota in mental and brain health and the development of interventions based on modification of gut microbiota.

Serum levels of sclerostin, Dickkopf-1, and secreted frizzled-related protein-4 are not changed in individuals with high bone mass causing mutations in LRP5.

SUMMARY: We compared circulating levels of Wnt inhibitors among patients with high bone mass mutations in LRP5, unaffected kindred, and unrelated normal controls. Inhibitors were unchanged in affected and unaffected kindred. We saw no meaningful differences between controls and affected individuals. LRP5 signaling may not influence circulating levels of these inhibitors. INTRODUCTION: It is thought that gain-of-function mutations in LRP5 result in high bone mass syndromes because these allelic variants confer resistance to the actions of endogenous inhibitors of Wnt signaling. We therefore attempted to determine if circulating levels of Wnt inhibitors are altered in patients with gain-of-function mutations in LRP5. METHODS: This is a cross-sectional study in a university research center. Serum was collected from consented volunteers known to have either the G171V or N198S gain-of-function mutations in LRP5, kindred members affected with either mutation, unrelated kindred, and unrelated normal age-matched controls. BMD was provided or measured on site. RESULTS: There were no significant differences found in the serum levels of sclerostin (SOST), Dickkopf-1 (Dkk-1), or secreted frizzled-related protein-4 (SFRP-4) in affected vs. unaffected individuals from different kindreds or when compared to age-matched unrelated normal individuals. Mean serum SOST values in affected and unaffected kindred members and unrelated normal controls were 52.7 ± 6.1, 36.5 ± 9.6, and 54.8 ± 5.4, respectively. For Dkk-1, the values were 25.9 ± 3.4, 25.7 ± 3.0, and 17.3 ± 2.3 and for SFRP-4, 38.1 ± 2.3, 39.8 ± 3.6, and 28.5 ± 1.7. Serum levels of RANKL and osteoprotegerin (OPG) were not different in the three groups. CONCLUSIONS: Circulating levels of endogenous Wnt inhibitors do not change in patients with gain-of-function mutations in LRP5 including Dkk1, which is suppressed by Wnt signaling. It may be that circulating levels of Wnt inhibitors do not reflect changes in target tissues. It is also possible that other mechanisms besides or in addition to resistance in Wnt inhibitors explains the skeletal effects of these mutations.

Risk associated with transportation and lairage on hide contamination with Salmonella enterica in finished beef cattle at slaughter.

Transportation of cattle to the slaughter plant could influence hide contamination with Salmonella enterica. Fecal and hide samples were obtained from 40 lots of cattle at the feedlot and again at the slaughter plant. Potential risk factors for hide contamination were evaluated. A multilevel Poisson regression model was used to determine whether transportation and lairage were associated with hide contamination by Salmonella. Cattle with hide samples positive for Salmonella at the feedlot had twice the risk of having positive slaughter hide samples compared with cattle without positive feedlot hide samples (relative risk [RR], 1.9). Cattle transported in trailers from which samples positive for Salmonella were collected had twice the risk of having positive slaughter hide samples compared with cattle transported in culture-negative trailers (RR, 2.3). Cattle transported for long distances had twice the risk of having positive hide samples at slaughter compared with cattle transported shorter distances (RR, 2.3). Cattle held in lairage pens contaminated with feces had twice the risk of having positive slaughter hide samples compared with cattle held in clean pens (RR, 1.8). Cattle held off feed longer than 18 h before loading had twice the risk of having positive slaughter hide samples compared with cattle held off feed for shorter times (RR, 1.7). Cattle that were agitated during loading had twice the risk of having positive slaughter hide samples compared with cattle that were calm (RR, 2.2). These findings suggest that variables associated with transportation and lairage can impact the presence of Salmonella on the hides of cattle at slaughter.

Evaluation of changes in Listeria monocytogenes populations on frankfurters at different stages from manufacturing to consumption.

This study evaluated the fate of inoculated Listeria monocytogenes on frankfurters stored under conditions simulating those that may be encountered between manufacturing and consumption. Frankfurters with or without 1.5% potassium lactate and 0.1% sodium diacetate (PL/SD) were inoculated (1.8 +/- 0.1 log CFU/cm(2)) with a 10-strain composite of L. monocytogenes, vacuum-packaged, and stored under conditions simulating predistribution storage (24 h, 4 degrees C), temperature abuse during transportation (7 h, 7 degrees C followed by 7 h, 12 degrees C), and storage before purchase (60 d, 4 degrees C; SBP). At 0, 20, 40, and 60 d of SBP, samples were exposed to conditions simulating delivery from stores to homes or food establishments (3 h, 23 degrees C), and then opened or held vacuum-packaged at 4 or 7 degrees C for 14 d (SHF). Pathogen counts remained relatively constant on frankfurters with PL/SD regardless of product age and storage conditions; however, they increased on product without antimicrobials. In vacuum-packaged samples, during SHF at 4 degrees C, the pathogen grew faster (P < 0.05) on older product (20 d of SBP) compared to product that was fresh (0 d of SBP); a similar trend was observed in opened packages. At 7 degrees C, the fastest growth (0.35 +/- 0.02 log CFU/cm(2)/d) was observed on fresh product in opened packages; in vacuum-packages, growth rates on fresh and aged products were similar. By day 40 of SBP the pathogen reached high numbers and increased slowly or remained unchanged during SHF. This information may be valuable in L. monocytogenes risk assessments and in development of guidelines for storage of frankfurters between package opening and product consumption.

Impact of transportation and lairage on hide contamination with Escherichia coli O157 in finished beef cattle.

Transportation of cattle from the feedlot to the slaughter plant could influence hide contamination of Escherichia coli O157. A study was initiated to investigate the influence of transportation and lairage on shedding and hide contamination of E. coli O157. Fecal and hide samples were obtained from 40 pens of harvest-ready beef cattle at the feedlot prior to transport and again at the slaughter plant immediately after slaughter. Potential risk factors for hide contamination at the feedlot, during transport, and at slaughter were evaluated. A multilevel Poisson regression model was used to evaluate if transportation and lairage were associated with hide contamination by E. coli O157 in finished beef cattle. Lots of cattle held in E. coli O157-positive lairage pens had eight times greater risk of having positive slaughter hide samples compared with cattle held in culture-negative pens (relative risk, 8.0; 95% confidence interval, 1.6 to 38.8). Lots of cattle that were held in lairage pens contaminated with feces had three times greater risk for positive slaughter hide samples compared with cattle held in clean pens (relative risk, 3.1; 95% confidence interval, 1.2 to 7.9). Lots of cattle that were transported for long distances (> 160.9 km) had twice the risk of having positive hide samples at slaughter compared with cattle transported a shorter distance (relative risk, 2.4; 95% confidence interval, 1.1 to 5.1). These findings suggest that transportation and lairage should be considered in E. coli O157 control strategies.

Molecular characterization of Escherichia coli O157:H7 hide contamination routes: feedlot to harvest.

This study was conducted to identify the origin of Escherichia coli O157:H7 contamination on steer hides at the time of harvest. Samples were collected from the feedlot, transport trailers, and packing plant holding pens and from the colons and hides of feedlot steers. A total of 50 hide samples were positive for E. coli O157:H7 in two geographical locations: the Midwest (25 positive hides) and Southwest (25 positive hides). Hide samples were screened, and the presence of E. coli O157: H7 was confirmed. E. coli O157:H7 isolates were fingerprinted by pulsed-field gel electrophoresis and subjected to multiplex PCR procedures for amplification of E. coli O157:H7 genes stx1, stx2, eaeA, fliC, rfbEO157, and hlyA. Feedlot water trough, pen floor, feed bunk, loading chute, truck trailer side wall and floor, packing plant holding pen floor and side rail, and packing plant cattle drinking water samples were positive for E. coli O157:H7. Pulsed-field gel electrophoresis banding patterns were analyzed after classifying isolates according to the marker genes present and according to packing plant. In this study, hide samples positive for E. coli O157:H7 were traced to other E. coli O157:H7-positive hide, colon, feedlot pen floor fecal, packing plant holding pen drinking water, and transport trailer side wall samples. Links were found between packing plant side rails, feedlot loading chutes, and feedlot pens and between truck trailer, different feedlots, and colons of multiple cattle. This study is the first in which genotypic matches have been made between E. coli O157:H7 isolates obtained from transport trailer side walls and those from cattle hide samples within the packing plant.

Analysis of chromosomal instability in human colorectal adenomas with two mutational hits at APC.

In vitro data show that the adenomatous polyposis coli (APC) protein associates with the mitotic spindle and that mouse embryonic stem cells with biallelic Apc mutations are karyotypically unstable. These findings led to suggestions that APC acts in chromosomal segregation and that APC inactivation leads to chromosomal instability (CIN). An alternative hypothesis based on allelic loss studies in colorectal adenomas proposes that CIN precedes and contributes to genetic changes at APC. We determined whether colorectal adenomas with two mutations at APC show features consistent with these models by studying 55 lesions (average size 5 mm; range 1-13 mm) from patients with familial adenomatous polyposis. A variety of methods was used depending on available material, including flow cytometry, comparative genomic hybridization, and loss of heterozygosity (LOH) analysis. Selected adenomas were assessed for proliferative activity by Ki-67 immunocytochemistry. Seventeen of 20 (85%) tumors were diploid, two were near-diploid, and one was hypotetraploid. Just one (near-diploid) tumor showed increased proliferative activity. LOH was found occasionally on chromosome 15q (2 of 49 tumors), but not on chromosome 18q (0 of 48). In 20 adenomas, LOH at APC was associated with loss at 5q but not 5p markers, with the former encompassing a minimum of 20 Mb. However, three of these lesions analyzed by comparative genomic hybridization displayed normal profiles, suggesting, together with other data, that the mechanism of LOH at APC is probably somatic recombination. Our results therefore do not support the hypothesis that CIN precedes APC mutations in tumorigenesis. Regarding the model in which APC mutations lead directly to CIN, if APC mutations do have this effect in vivo, it must be subtle. Alternatively, CIN associated with APC mutations might be essentially an in vitro phenomenon.

Parameters of high bone-turnover predict bone loss in renal transplant patients: a longitudinal study.

BACKGROUND: Osteoporosis is a serious complication of kidney transplantation. Various factors have been postulated to contribute to posttransplant bone loss, among them treatment with corticosteroids, the use of cyclosporine and cyclosporine-like agents, and persistent hyperparathyroidism. In a previous cross-sectional study of long-term renal transplant recipients, we observed that osteoporosis or osteopenia was present in 88% of patients. Because biochemical markers of bone formation (serum osteocalcin) and bone resorption (urine pyridinoline, PYD, and deoxypyridinoline, DPD) were elevated in the majority of study subjects, we hypothesized that elevated rates of bone-turnover contribute to posttransplant bone loss in long-term renal transplant patients. This study was performed to examine this hypothesis. METHODS: The study population was composed of 62 patients who were more than 1-year postrenal transplantation and who had preserved renal function. They were followed prospectively for 1 year. Biochemical markers of bone-turnover were measured at study entry, and patients were classified as having high bone-turnover based on elevated urinary levels of at least one marker of bone resorption (i.e., PYD or DPD) and/or serum osteocalcin (group 1). If none of these were present, they were classified as having normal bone-turnover (group 2). Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DEXA) at time of entry into the study and again after 1 year of follow-up. The changes in BMD at the lumbar spine, hip, and wrist over the period of the study were compared between the high and normal bone-turnover groups. RESULTS: Forty-three patients (69%) were classified as having high bone-turnover (Group 1), and 19 patients (31%) were classified as having normal bone-turnover (Group 2). There was a statistically significant difference in change in BMD between the two groups at the lumbar spine (-1.11+/-0.42%, high bone-turnover, vs. 0.64+/-0.54%, normal bone-turnover; P=0.02) and the hip (-0.69+/-0.38%, high bone-turnover, vs. 1.36+/-0.66%, normal bone-turnover; P=0.006). Whereas group 2 had stable bone mass, group 1 exhibited bone loss at these skeletal sites. CONCLUSIONS: Our results indicate that bone loss is greater in renal transplant recipients with elevated biochemical markers of bone-turnover, suggesting that these markers may be useful in identifying patients at risk for continued bone loss. These data support the hypothesis that continued bone loss in long-term renal transplant recipients is associated with high bone-turnover. If accelerated bone resorption does play a role in posttransplant bone loss, this would provide a strong rationale for use of antiresorptive therapy for the prevention and treatment of this complication.

Reinforcing and subject-rated effects of methylphenidate and d-amphetamine in non-drug-abusing humans.

The reinforcing effects of methylphenidate (20-40 mg), d-amphetamine (10-20 mg), and placebo were assessed in eight healthy, non-sleep-deprived, non-drug-abusing outpatient volunteers. A modified progressive-ratio schedule was used to assess drug reinforcement in which a sampling session always preceded a self-administration session. During sampling sessions, volunteers received a drug dose to acquaint them with the drug effects. Drug doses were administered in eight identical capsules (i.e., each capsule contained 12.5% of the total dose). During self-administration sessions, which generally were conducted the next day, volunteers were given eight opportunities to work on a computer and could earn all, or some, of the capsules that were administered the previous day. To earn the first capsule, volunteers had to click a computer mouse 50 times. The number of clicks required to earn each additional capsule doubled (i.e., 100, 200, 400, 800, 1,600, 3,200, and 6,400 clicks). The dependent measure on this task was the break point (i.e., the last ratio completed). To characterize more fully the behavioral effects of methylphenidate and d-amphetamine, a battery of subject-rated drug-effect questionnaires, performance tasks, and physiologic measures was also used. Both doses of d-amphetamine increased the break point significantly above placebo levels, whereas only the high dose of methylphenidate did so. Break-point values for the doses of methylphenidate and d-amphetamine that maintained the greatest responding did not differ significantly. Methylphenidate and d-amphetamine produced some stimulantlike subject-rated drug effects (e.g., increased ratings of "drug liking"). These data suggest that methylphenidate, like d-amphetamine, can function as a reinforcer under a modified progressive-ratio schedule and, by inference, has at least some abuse potential in healthy, non-sleep-deprived, non-drug-abusing volunteers.

The development of a locus of control measure predictive of injured athletes' adherence to treatment.

The Sports Rehabilitation Locus of Control (SRLC) scale was developed to facilitate study of the behaviour of athletes recovering from injury. The SRLC was built specifically to assess locus of control in injured athletes by adapting selected items from the Multidimensional Health Locus of Control (MHLC) questionnaire developed by Wallston, Wallston, & DeVellis (1978), and in accordance with their rationale for the construction of domain-specific LOC scales. The resultant locus of control measures (internal, powerful others, and chance) were administered (along with the MHLC) to a sample of 145 sports-injured athletes. Good internal consistency (alphas ranged from .72 to .79) and test-retest reliability (correlations ranged from .75 to .85) was shown by the SRLC scales, and the pattern of inter-scale correlations supported the three-factor conceptualisation of locus of control on which the SRLC was based. In the subsequent initial validation study, the relationship between SRLC scale scores and adherence to treatment was tested with a sample of injured athletes. Encouragingly, internality was positively associated p<.05 with treatment adherence.

Hyperbolic temporal discounting in social drinkers and problem drinkers.

Two studies compared participants, distinguished by their typical alcohol consumption, on the degree to which they discounted the value of delayed, hypothetical amounts of money. Heavy social drinkers in Study 1 and problem drinkers in Study 2 both showed greater temporal discounting than light social drinkers; this difference was stronger in Study 2. Both studies found that a hyperbolic function described temporal discounting more accurately than an exponential function. These results are consistent with extending behavioral theories of intertemporal choice to characterize the determinants of alcohol consumption. The discounting differences also are consistent with more general behavioral economic and economic theories of addiction, although the hyperbolic functional form is inconsistent with the exponential discounting function in economic theory. The drinker groups also differed on impulsiveness and time orientation questionnaires, with light drinkers being less impulsive and more future oriented; however, these measures were not strongly correlated with the measure of temporal discounting.

Ambulatory electrocardiography for the detection of pacemaker lead failure.

The suboptimal performance of some polyurethane bipolar pacing leads has highlighted concern about the optimal method of monitoring pacemaker lead performance. Since the manifestations of premature lead failure may be initially intermittent, we hypothesized that ambulatory electrocardiography (AECG) would be a more sensitive tool for the detection of pacing lead failure compared to increased pacemaker clinic surveillance. Since the Medtronic safety alerts on the 4012, 4082, and 4004 leads, we have followed 261 patients by serial AECG and 165 patients by increased pacemaker clinic surveillance. Lead failures were identified in 75 patients: 68 in the AECG group (31%) and 7 in the clinic group (4%, P < 0.001). Repeat AECG confirmed the lead failure in 38 (97%) of 39 patients in which it could be done. Pacing lead failure documented by AECG could be confirmed by a subsequent clinic assessment in only 15 (25%) of 60 patients evaluated (P < 0.001). The actuarial survival of the 4012 lead was significantly lower in the AECG group compared to the clinic group (56% vs 87% survival at 8 years, P < 0.002). Similar trends were observed for the 4082 and 4004 leads. AECG is a more sensitive method of surveillance for pacemaker lead function compared to pacemaker clinic assessment. AECG should be incorporated into the routine follow-up of pacemaker patients.

Effects of an inhibitor of cathepsin L on bone resorption in thyroparathyroidectomized and ovariectomized rats.

The process of bone resorption by osteoclasts involves the dissolution of mineral salts and enzymatic degradation of the mainly collagenous extracellular matrix. Cysteine proteinases, which can efficiently degrade collagen at acidic pH, have been suggested to play an important role in the bone resorptive process. The cysteine proteinase cathepsin L is secreted by osteoclasts, and inhibitors of this enzyme can prevent bone resorption in vitro. The activity of acetyl-leu-leu-norleucinol (ALLN), a selective inhibitor of cathepsin L, was investigated in two models of bone resorption in vivo. In the first study, the ability of ALLN to inhibit bone resorption was investigated in Ro-13-6298 (arotinoid)-treated thyroparathyroidectomized (TPTX) rats. ALLN [100 mg/kg, intraperitoneally (i.p.)] inhibited hypercalcemia by 62.8% acutely (p < 0.001), compared to 94.9% (p < 0.001) inhibition by salmon calcitonin (sCT) (10 IU/kg, subcutaneously). In rats treated for 3 days with ALLN, arotinoid-induced reduction in cortical bone mineral density measured by peripheral quantitative computed tomography (pQCT) was inhibited by 86.4% (p < 0.05) in rats treated with ALLN 100 mg/kg, i.p., and by 82% in rats treated with 50 mg/kg, i.p. (p < 0.05). In a second study, the efficacy of ALLN was tested in a longitudinal study in ovariectomized (ovx) rats. Bone loss, measured by pQCT, was unaffected by treatment with ALLN. The bisphosphonate alendronate, however, inhibited bone loss in this model. These data demonstrate the ability of a cathepsin L inhibitor to inhibit bone resorption in arotinoid-treated TPTX rats, a process which may be dependent on the activity of cathepsin L-like cysteine proteinases. In contrast to its effects in TPTX rats, ALLN had no inhibitory activity on bone resorption in ovx rats. It is possible that in chronic bone resorption in ovx rats, the activity of other enzymes such as cathepsins OC-2 or K allows the process of resorption to continue even when cathepsin L is inhibited by ALLN. Further studies are required to determine why the activity of ALLN varies between different animal models. These data indicate that there may be variations in the effects of drugs in different animal models of bone resorption which should be considered when investigating novel antiresorptive therapies.

Integrating chiropractic in managed care.

Alternatives to traditional health care are emerging as an important element in the mix of services offered by managed care plans. Integrating these nontraditional services, such as chiropractic, presents special challenges for plan managers. ChiroNet, an Oregon-based chiropractic specialty PPO network, has formed partnerships with a variety of managed care plans bringing managed chiropractic services to the PPO, EPO, and HMO environments. Practical experience with benefit design, access protocols, utilization management, quality assurance, provider credentialing, and administrative integration has been developed over the period of the network's cooperation with its managed care partners. Successful integration of these nontraditional provider groups depends on alignment of goals and incentives among all players in the system, including providers, their network, the patients, and the managed care plan.

Calculating costs of drug therapy: a review of a decade of literature (1977-1987).

Cost analysis and cost benefit analysis are useful tools in the objective comparison of drug therapy regimens. The authors report on their systematic evaluation of all available English language papers cited in the MEDLINE database from 1977 to February 1988 that were referenced under the medical subject headings, "costs and cost analysis" or "cost benefit analysis." The 94 papers that met the criteria for inclusion are described in a tabular summary of the approaches of calculating costs and methods of comparing relative costs of therapy for a variety of agents and disease entities. Additional references offering analyses of specific aspects of drug therapy which may provide practitioners with additional direction in analyzing costs of therapy, as well as a number of editorials and reviews offering useful insights and discussions regarding cost analysis, are also included.