No effect of carbohydrate feeding on 16 km cycling time trial performance

The aim of this study is to investigate the effects of CHO ingestion during high intensity exercise performance lasting approximately 25 min. Twelve endurance trained male cyclists (age 19-41 years; body mass 73.2 +/- 4.2 kg; VO(2)max 66.4 +/- 6.2 ml kg(-1) min(-1)) completed a simulated 16 km time trial (457 +/- 37 kJ) time trial in the lab on three occasions. Once they received a 6% carbohydrate electrolyte solution (CHO) and twice they received the same electrolyte containing placebo drink (PLA). Carbohydrate or placebo drinks were ingested 5 min before the start (4 ml kg(-1)) and at 25, 50, and 75% of completion of the time trial (1.4 ml kg(-1)). The CHO drink was a 6% sucrose-glucose-electrolyte solution. No differences were observed in the time to complete the time trials with either treatment. Time in min:s were 25:30 +/- 1:34 and 25:27 +/- 1:46 for the two placebo trials and 25:38 +/- 1:59 in the CHO trial. Power output during the time trials was also remarkably similar: 300 +/- 37 W, 301 +/- 39 W and 299 +/- 40 W, respectively. Pacing strategies and heart rate were identical in all three trials. From the two placebo trials, a coefficient of variation for this performance task was calculated to be 1.1%. Data from this study provides evidence that carbohydrate ingestion during short high intensity exercise (approximately 30 min, 85-90% VO(2)max) does not improve performance. Furthermore, this study found a very low coefficient of variation (1.1%) for a simulated 16 km time trial.     

Effect of a putative ERα antagonist, MPP, on food intake in cycling and ovariectomized rats

Estrogens exert many of their behavioral effects by binding to nuclear estrogen receptor (ER) proteins, ERα and ERβ. Recent studies involving ER knockout mice and selective ER agonists suggest that estradiol's anorexigenic effect is mediated via activation of ERα. To investigate this hypothesis, we examined whether the presumptive ERα antagonist, MPP, could block estradiol's anorexigenic effect. In the first series of experiments, the effects of MPP on food intake and uterine weight were monitored in ovariectomized (OVX) rats treated with either a physiological dose of estradiol benzoate (EB) or a selective ERα agonist (PPT). In the final experiment, food intake was monitored following acute administration of MPP in ovarian-intact (cycling) female rats. Contrary to our hypothesis, MPP failed to attenuate either EB's or PPT's ability to decrease food intake and increase uterine weight in OVX rats. However, in ovarian-intact rats, a similar regimen of MPP treatment attenuated the phasic decrease in food intake that is associated with estrus. We conclude that MPP may be a useful tool to investigate the behavioral actions of endogenous estradiol, but may have limited utility in studying the behavioral effects of exogenous estradiol in OVX rats.     

Supporting patients to self-monitor their oral anticoagulation therapy: recommendations based on a qualitative study of patients’ experiences

BackgroundClinical trials suggest that oral anticoagulation therapy (OAT) self-monitoring is safe and effective, however little is known about the patient experience of this process. There is a lack of understanding about how best to train and support patients embarking on OAT self-monitoring.AimTo collect in-depth information about patients’ experiences of OAT self-monitoring outside of clinical trial conditions and to produce a set of recommendations on how best to support such patients.MethodIn total, 26 of the 267 (9.7%) who participated in the Cohort study of Anticoagulation Self-Monitoring (CASM) and were still self-monitoring after 12 months’ follow-up were interviewed. Topics discussed included experiences of OAT self-monitoring, healthcare support, training, and decision making. Framework analysis was used.ResultsFollowing initial problems using the monitoring device, interviewees described a mostly positive experience. Although less effort was expended attending monitoring appointments with health professionals, effort was required to conduct self-monitoring tests and to interpret and act on the results. Desire to self-manage was variable, especially when dosing advice systems worked promptly and reliably. Interviewees overcame patchy healthcare system knowledge and support of self-monitoring by educating themselves. Family and friends provided support with learning to use the monitor and managing OAT dosage adjustments.ConclusionBetter, more-consistent training and health-service support would have alleviated a number of problems encountered by these patients who were self-monitoring. This training and support will become even more important if self-monitoring becomes more accessible to the general population of people on OAT.     

A VBM study demonstrating ‘apparent’ effects of a single dose of medication on T1-weighted MRIs

Voxel-based morphometry (VBM) studies have interpreted longitudinal medication- or behaviorally induced changes observed on T1-weighted magnetic resonance images (MRIs) as changes in neuronal structure. Although neurogenesis or atrophy certainly occurs, the use of T1-weighted scans to identify change in brain structure in vivo in humans has vulnerability: the T1 relaxation time for arterial blood and gray matter are not clearly distinguishable and therefore, apparent reported structural findings might be at least partially related to changes in blood flow or other physiological signals. To examine the hypothesis that apparent structural modifications may reflect changes introduced by additional mechanisms irrespective of potential neuronal growth/atrophy, we acquired a high-resolution T1-weighted structural scan and a 5-min perfusion fMRI scan (a measurement of blood flow), before and after administration of an acute pharmacological manipulation. In a within-subject design, 15 subjects were either un-medicated or were administered a 20 mg dose of baclofen (an FDA-approved anti-spastic) approximately 110 min before acquiring a T1-weighted scan and a pseudo continuous arterial spin labeled perfusion fMRI scan. Using diffeomorphic anatomical registration through exponentiated lie algebra within SPM7, we observed macroscopic, and therefore implausible, baclofen-induced decreases in VBM ‘gray matter’ signal in the dorsal rostral anterior cingulate (family wise error corrected at p < 0.04, T = 6.54, extent: 1,460 voxels) that overlapped with changes in blood flow. Given that gray matter reductions are unlikely following a single dose of medication these findings suggest that changes in blood flow are masquerading as reductions in gray matter on the T1-weighted scan irrespective of the temporal interval between baseline measures and longitudinal manipulations. These results underscore the crucial and immediate need to develop in vivo neuroimaging biomarkers for humans that can uniquely capture changes in neuronal structure dissociable from those related to blood flow or other physiological signals.     

Predictors of incident atrial fibrillation and influence of medications: a retrospective case�Ccontrol study

Background

Atrial fibrillation (AF) is a common condition, associated with raisedmortality and risk of majormorbidity, and is predicted to increase due to an aging population.

Aim

To update earlier research of AF predictors using UK data.

Design and setting

Case–control analysis of adults aged 18 years and older with a diagnosis of AF in practices registered with the General Practice Research Database (GPRD) in the UK.

Method

Using the GPRD, a case.control analysis was performed using logistic regression to compare 55 412 incident AF cases to 216 400 controls, for medical history and prior use of drugs. The association between time since start of diagnosis or drug use and AF risk was summarised using Spline regression.

Results

The following were confirmed as risk factors for AF: heart failure (risk ratio [RR] 2.91 [95% CI = 2.59 to 3.27]); ischaemic heart disease (IHD) (RR 2.00 [95% CI = 1.78 to 2.24]); hypertension (RR 2.60 [95% CI = 2.32 to 2.92]); hyperthyroidism (RR 1.56 [95% CI = 1.39 to 1.75]); being a heavy drinker (RR 1.43 [95% CI = 1.27 to 1.60]); cerebrovascular accident (RR 1.48 [95% CI = 1.32 to 1.66]); and obesity (bodymass index ≥30 kg/m² RR 1.29 [95% CI = 1.15 to 1.45]). Current use of oral glucocorticoids (RR 1.62 [95% CI = 1.44 to 1.82]) and of beta-2 agonists (RR 1.30 [95% CI = 1.16 to 1.46]) were identified as significant risk factors, and statins (RR 0.82 [95% CI = 0.73 to 0.92]) as a significant protective factor. No effect was found for current use of bisphosphonates (RR 0.95 [95% CI = 0.85 to 1.07]), renin.angiotensin.aldosterone system (RAAS) agents (RR 1.04 [95% CI = 0.93 to 1.17]), or xanthine derivatives (RR 1.09 [95% CI = 0.97 to 1.22]). Spline regression analysis found the effect of heart failure, IHD, use of oral glucocorticoids, and use of statins on the likelihood of developing AF was sustained over a number of years.

Conclusion

These findings update the risk factors that are associated with AF, and confirmthe protective properties of statins and the risks of beta-2 agonists in developing AF, but not the supposed protective qualities of glucocorticoids and RAAS agents.     

Effect of timed incentives on subject participation in a study of long-term breast cancer survivors: are there ethnic differences?

The recruitment and retention of African Americans into cancer control studies presents a formidable task to the scientific and policy communities as well as patient and advocacy communities. The purpose of this investigation was to assess the role of a timed incentive schedule on response rates in a study of African American and white breast cancer survivors. A mailed quality-of-life survey battery was sent to 583 breast cancer survivors (50% African American, 50% white). Half of the participants received payment in advance, whereas the other half was promised payment. The overall response rate was 54% (n = 278). The timing of incentives did not affect participation rates in either ethnic group. About 51% of the respondents were from the payment-in-advance condition and 49% were from the paid-on-completion condition. Therefore, we conclude that payment on completion may be the more cost-effective approach in studies with higher socioeconomic status patients, such as this sample of breast cancer survivors.     

Predictors of the quality of cardiovascular prevention �C a multilevel cross-sectional study

Aim

To attempt to develop a model of predictors for quality of the process of cardiovascular prevention in patients at high risk of cardiovascular disease (CVD).

Methods

We formed a random sample of patients from a stratified sample of 36 family practice registers of patients at high risk of CVD without diabetes and without established CVD. Data were gathered by chart audit and questionnaires about patient and practice characteristics. We defined the process of care as a dependent variable by principle component analysis and tested the relationship of the process with several independent variables (family physicians’, patients’, and practice characteristics). To study the effects of independent variables (predictors) on the process of care we carried out multilevel regression analysis with the patients constituting the lower level and nested within the family physician/practice (the second level).

Results

Multilevel regression analysis included 645 patients from 36 practices (74.1% from the final sample). Patients’ characteristics that predicted the higher-quality process of CVD prevention were younger age (t = -4.94, 95% confidence interval [CI] -0.018 to -0.008) and lower socioeconomic status (t = -2.18, 95%CI -0.195 to -0.010). Practice characteristics that predicted the higher-quality process of CVD prevention were smaller practice size (t = 2.83, 95% CI 0.063 to 1.166), a good information system for CVD prevention (t = 3.15, 95% CI 0.030 to 0.282), and the organization of education on CVD prevention (t = 3.19, 95%CI 0.043 to 0.380).

Conclusion

This study shows that the quality of cardiovascular prevention could be measured as a composite outcome and future studies should further develop this approach and test the impact of several practice/patient characteristics on the quality of CVD prevention with the international data.Prevention of cardiovascular diseases (CVD) is an important task for family physicians. While patients with a low risk of CVD profit mostly from public health activities, high risk patients also need preventive activities provided by their family physicians (1,2). In the countries with a national program of CVD prevention (Slovenia is one of them), these activities and procedures can be highly standardized (3) and, therefore, should be easily measurable. The Slovenian national preventive program for CVD was launched in 2001 and requires preventive check-ups for the defined age groups of patients (women from 45 to 70 years and men from 35 to 65 years). Eighty percent of the target group in every practice needs to go through the program in 5 years, and a register of high risk patients is created in each practice and collected on the national level. The preventive activities consist of two parts: the first part includes a health check-up with determination of risk factors (information on life-style, clinical exam, laboratory tests of lipids and fasting blood glucose) and the second part includes the referral of patients at high risk to preventive workshops, for example for healthy weight reduction, smoking cessation, etc.Although there is some evidence on several isolated aspects of CVD prevention in Slovenia (4-6), a comprehensive and systematic approach for measuring its quality and actual outcomes is still not available. Therefore, we aimed to develop an integral statistically evaluated presentation of the process of cardiovascular prevention and determine the variables that influence it. Post-hoc analyses were performed on patients at a high risk for coronary diseases using Slovenian data from the international EPA-Cardio study, a cross-sectional study conducted in 9 European countries that had developed quality indicators for cardiovascular prevention on the international level (7) and evaluated the quality of cardiovascular prevention for high-risk patients (8).     

β LACTA test performance for detection of extended-spectrum β-lactamase-producing Gram-negative bacilli directly on bronchial aspirates samples: a validation study

ObjectivesIncidence of extended-spectrum β-lactamase-producing Gram-negative bacilli (ESBL-PE-GNB)-related infections is worryingly increasing worldwide. ESBL-PE-GNB detection directly on bronchial aspirate samples (BAS) performed for suspected pneumonia may help save empirical carbapenems. Our objectives were to optimize β-LACTA™ test (BLT) realization and evaluate BLT performance for ESBL-PE-GNB detection directly on BAS.MethodsWe studied BLT technical optimization using BAS of different matrix types spiked with increasing concentrations of CTX-M-15-producing Klebsiella pneumoniae; in vitro validation of BLT diagnostic performance on 17 ESBL enzymes, belonging to CTX-M, SHV, TEM, OXA, GES, VEB and PER groups; and clinical validation of BLT performance on 126 BAS prospectively collected from seven intensive care units.ResultsAfter optimization, BLT detected with 100% sensitivity the presence of CTX-M-15-producing K. pneumoniae spiked in sterile BAS for inoculums upon two or more GNB per field upon microscopic Gram staining examination (MGSE). The BLT accurately detected the 17 ESBLs tested at 10⁶ CFU/mL and all ESBLs except Pseudomonas aeruginosa–related OXA-14 at 10⁴ CFU/mL. Among the 126 BAS of the validation cohort, 21 (17%) gave positive BLT (ten in BAS positive and 11 in BAS negative on MGSE). All BLT-positive BAS grew with ESBL-PE-GNB, including five hyper-L2-producing Stenotrophomonas maltophilia strains. BLT detected ESBL-PE-GNB directly on clinical BAS positive for GNB on MGSE and/or growing with ≥10⁴ CFU/mL with 100% sensitivity, specificity, and positive and negative predictive values.ConclusionsBLT is an accurate tool for ESBL-PE-GNB detection directly on BAS. Further studies are needed to evaluate the impact of BLT-guided early antimicrobial de-escalation strategies.     

Effect of post-exercise protein–leucine feeding on neutrophil function, immunomodulatory plasma metabolites and cortisol during a 6-day block of intense cycling

Whey protein and leucine ingestion following exercise increases muscle protein synthesis and could influence neutrophil function during recovery from prolonged intense exercise. We examined the effects of whey protein and leucine ingestion post-exercise on neutrophil function and immunomodulators during a period of intense cycling. In a randomized double-blind crossover, 12 male cyclists ingested protein/leucine/carbohydrate/fat (LEUPRO 20/7.5/89/22 g h^?1, respectively) or isocaloric carbohydrate/fat control (CON 119/22 g h^?1) beverages for 1–3 h post-exercise during 6 days of high-intensity training. Blood was taken pre- and post-exercise on days 1, 2, 4 and 6 for phorbol myristate acetate (PMA)-stimulated neutrophil superoxide (O₂ ^?) production, immune cell counts, amino acid and lipid metabolism via metabolomics, hormones (cortisol, testosterone) and cytokines (interleukin-6, interleukin-10). During recovery on day 1, LEUPRO ingestion increased mean concentrations of plasma amino acids (glycine, arginine, glutamine, leucine) and myristic acid metabolites (acylcarnitines C14, myristoylcarnitine; and C14:1-OH, hydroxymyristoleylcarnitine) with neutrophil priming capacity, and reduced neutrophil O₂ production (15–17 mmol O₂ ^? cell^?1 ± 90 % confidence limits 20 mmol O₂ ^? cell^?1). On day 2, LEUPRO increased pre-exercise plasma volume (6.6 ± 3.8 %) but haematological effects were trivial. LEUPRO supplementation did not substantially alter neutrophil elastase, testosterone, or cytokine concentrations. By day 6, however, LEUPRO reduced pre-exercise cortisol 21 % (±15 %) and acylcarnitine C16 (palmitoylcarnitine) during exercise, and increased post-exercise neutrophil O₂ ^? (33 ± 20 mmol O₂ ^? cell^?1), relative to control. Altered plasma amino acid and acylcarnitine concentrations with protein–leucine feeding might partly explain the acute post-exercise reduction in neutrophil function and increased exercise-stimulated neutrophil oxidative burst on day 6, which could impact neutrophil-dependent processes during recovery from intense training.     

The impact of sleep duration and subject intelligence on declarative and motor memory performance: how much is enough?

Recent findings clearly demonstrate that daytime naps impart substantial memory benefits compared with equivalent periods of wakefulness. Using a declarative paired associates task and a procedural motor sequence task, this study examined the effect of two lengthier durations of nocturnal sleep [either a half night (3.5 h) or a full night (7.5 h) of sleep] on over-sleep changes in memory performance. We also assessed whether subject intelligence is associated with heightened task acquisition and, more importantly, whether greater intelligence translates to greater over-sleep declarative and procedural memory enhancement. Across both tasks, we demonstrate that postsleep performance gains are nearly equivalent, regardless of whether subjects obtain a half night or a full night of sleep. Remarkably, the over-sleep memory changes observed on both tasks are very similar to findings from studies examining performance following a daytime nap. Consistent with previous research, we also observed a strong positive correlation between amount of Stage 2 sleep and motor skill performance in the full-night sleep group. This finding contrasts with a highly significant correlation between spectral power in the spindle frequency band (12–15 Hz) and motor skill enhancement only in the half-night group, suggesting that sigma power and amount of Stage 2 sleep are both important for optimal motor memory processing. While subject intelligence correlated positively with acquisition and retest performance on both tasks, it did not correlate with over-sleep changes in performance on either task, suggesting that intelligence may not be a powerful modulator of sleep's effect on memory performance.     

The effects of progressive dehydration on strength and power: is there a dose response?

This study examined the effect of exercise- and heat-induced dehydration on strength, jump capacity and neuromuscular function. Twelve recreationally active males completed six resistance exercise bouts (baseline and after each 5 exposure sessions) in an increasing state of hypohydration obtained by repeated heat exposure and exercise sessions (5 periods of 20 min jogging at up to ~80% age predicted heart rate maximum at 48.5 ± 0.48°C, relative humidity 50 ± 4%). Relative to starting values, body mass decreased 1.0 ± 0.5, 1.9 ± 0.7, 2.6 ± 0.8, 3.3 ± 0.9 and 3.9 ± 1.0% after exposure 1, 2, 3, 4 and 5, respectively. However, plasma volume remained constant. No significant differences existed amongst trials in vertical jump height, electromyography data or isokinetic leg extension at a rate of 120° s⁻¹. Isometric leg extensions were significantly reduced (P < 0.05) after the first (1% body mass loss) and subsequent exposures in comparison to baseline. Isokinetic leg extensions at a rate of 30° s⁻¹ were significantly reduced after the third (2.6% body mass loss) and subsequent exposures compared with baseline. No dose response was identified in any of the tested variables yet a threshold was observed in isometric and isokinetic strength at 30° s⁻¹. In conclusion, dehydration caused by jogging in the heat had no effect on vertical jumping or isokinetic leg extensions at a rate of 120° s⁻¹. Alternatively, exercise-induced dehydration was detrimental to isometric and isokinetic leg extensions at a rate of 30° s⁻¹, suggesting the force–velocity relationship in hypohydration merits further research.     

The effect of short-course gentamicin therapy on kidney function in patients with bacteraemia—a retrospective cohort study

The nephrotoxic potential of aminoglycosides is primarily correlated to the duration of therapy. However, there are discrepancies between previous studies regarding the effect of short course treatment. The aim of this study was to compare renal function, renal recovery and mortality in a large cohort of patients with bacteraemia, who were empirically treated with regimens with and without a short course (≤?3 days) of once daily dosing of gentamicin. This was a retrospective propensity score-matched cohort study based on all patients with bacteraemia in a Danish hospital in the period 2010–2013. We included 702 patients who received gentamicin, and 702 who did not receive gentamicin. To determine the impact of gentamicin on renal function, we used a modified version of the Kidney Disease: Improving Global Outcomes (KDIGO) criteria for acute kidney injury (AKI), and the resulting data were analyzed by logistic regression. We used Cox regression analysis to compare the adjusted mortality rates between the two groups. According to the KDIGO criteria, we found no significant difference in the occurrence of AKI between the two groups (odds ratio (OR) 0.90 (95% CI 0.68–1.20)). We found that recovery of renal function was similar in the two groups, OR 1.00 (95% CI 0.63–1.60). The hazard ratio for 90-day all-cause mortality was 1.02 (95% CI 0.84–1.25). Short-course empirical gentamicin treatment of patients with bacteraemia was not associated with an increased incidence of AKI nor all-cause mortality in this study, and we observed similar reversibility of renal function.     

Anti-IL-13Rα2 therapy promotes recovery in a murine model of inflammatory bowel disease

There continues to be a major need for more effective inflammatory bowel disease (IBD) therapies. IL-13Rα2 is a decoy receptor that binds the cytokine IL-13 with high affinity and diminishes its STAT6-mediated effector functions. Previously, we found that IL-13Rα2 was necessary for IBD in mice deficient in the anti-inflammatory cytokine IL-10. Here, we tested for the first time a therapeutic antibody specifically targeting IL-13Rα2. We also used the antibody and Il13ra2^−/− mice to dissect the role of IL-13Rα2 in IBD pathogenesis and recovery. Il13ra2^−/− mice were modestly protected from induction of dextran sodium sulfate (DSS)-induced colitis. Following a 7-day recovery period, Il13ra2^−/− mice or wild-type mice administered the IL-13Rα2-neutralizing antibody had significantly improved colon health compared to control mice. Neutralizing IL-13Rα2 to increase IL-13 bioavailability promoted resolution of IBD even if neutralization occurred only during recovery. To link our observations in mice to a large human cohort, we conducted a phenome-wide association study of a more active variant of IL-13 (R130Q) that has reduced affinity for IL-13Rα2. Human subjects carrying R130Q reported a lower risk for Crohn's disease. Our findings endorse moving anti-IL-13Rα2 into preclinical drug development with the goal of accelerating recovery and maintaining remission in Crohn's disease patients.     

The effects of high dose interferon-β1a on plasma microparticles: Correlation with MRI parameters

Background

Autoimmunity to brain may play a pathogenic role in autism. In autoimmune disorders, the formation of antigen-antibody complexes triggers an inflammatory response by inducing the infiltration of neutrophils. Local administration of recombinant progranulin, which is an anti-inflammatory neurotrophic factor, potently inhibit neutrophilic inflammation in vivo, demonstrating that progranulin represents a crucial inflammation-suppressing mediator. We are the first to measure plasma progranulin levels in autism.

Methods

Plasma levels of progranulin were measured, by ELISA, in 40 autistic patients, aged between 3 and 12 years, and 40 healthy-matched children.

Results

Autistic children had significantly lower plasma progranulin levels, P = 0.001. Reduced plasma progranulin levels were found in 65% (26/40) of autistic children. On the other hand, there was a non significant difference between plasma progranulin levels of children with mild to moderate autism and patients with severe autism, P = 0.11.

Conclusions

Plasma progranulin levels were reduced in a subgroup of patients with autism. Progranulin insufficiency in some patients with autism may result in many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation that may have a role in autism. However, these data should be treated with caution until further investigations are performed, with a larger subject population, to determine whether the decrease of plasma progranulin levels is a mere consequence of autism or has a pathogenic role in the disease. The role of progranulin therapy should also be studied in autism.