Jianghua He

Aerobic exercise improves cognition and motor function poststroke.

Background. Cognitive deficits impede stroke recovery. Aerobic exercise (AEX) improves cognitive executive function (EF) processes in healthy individuals, although the learning benefits after stroke are unknown. Objective. To understand AEX-induced improvements in EF, motor learning, and mobility poststroke. Methods. Following cardiorespiratory testing, 38 chronic stroke survivors were randomized to 2 different groups that exercised 3 times a week (45-minute sessions) for 8 weeks. The AEX group (n = 19; 9 women; 10 men; 64.10 ± 12.30 years) performed progressive resistive stationary bicycle training at 70% maximal heart rate, whereas the Stretching Exercise (SE) group (n = 19; 12 women; 7 men; 58.96 ± 14.68 years) performed stretches at home. Between-group comparisons were performed on the change in performance at “Post” and “Retention” (8 weeks later) for neuropsychological and motor function measures. Results. VO2max significantly improved at Post with AEX (P = .04). AEX also improved motor learning in the less-affected hand, with large effect sizes (Cohen’s d calculation). Specifically, AEX significantly improved information processing speed on the serial reaction time task (SRTT; ie, “procedural motor learning”) compared with the SE group at Post (P = .024), but not at Retention. Also, at Post (P = .038), AEX significantly improved predictive force accuracy for a precision grip task requiring attention and conditional motor learning of visual cues. Ambulation and sit-to-stand transfers were significantly faster in the AEX group at Post (P = .038), with balance control significantly improved at Retention (P = .041). EF measurements were not significantly different for the AEX group. Conclusion. AEX improved mobility and selected cognitive domains related to motor learning, which enhances sensorimotor control after stroke.

Safety and efficacy of once-daily nasal irrigation for the treatment of pediatric chronic rhinosinusitis.

To compare efficacy and outcome of daily saline irrigation versus saline/gentamicin for treating chronic rhinosinusitis (CRS).

Targeting protein homeostasis in sporadic inclusion body myositis

Augmenting the heat shock response with arimoclomol ameliorates pathology in cellular and animal models of inclusion body myositis. Targeting protein dyshomeostasis in myopathy Sporadic inclusion body myositis (sIBM) is a debilitating adult myopathy that is difficult to treat. Although both inflammation and protein dyshomeostasis have been implicated in sIBM pathogenesis, treatments have only targeted the inflammatory component, and all have failed in clinical trials. In a new study, Ahmed et al. tested the effects of targeting protein dyshomeostasis using arimoclomol, a co-inducer of the heat shock response. In rat myoblast cell culture, arimoclomol reduced key pathological features of IBM. In mutant valosin-containing protein (VCP) mice, which develop an inclusion body myopathy, treatment with arimoclomol ameliorated disease pathology and improved muscle function. The authors then treated a small number of sIBM patients with arimoclomol and showed that it was safe and well tolerated. Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients more than 50 years of age. Previous therapeutic trials have targeted the inflammatory features of sIBM but all have failed. Because protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing protein (VCP) mice, which develop an inclusion body myopathy, treatment with arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated arimoclomol in an investigator-led, randomized, double-blind, placebo-controlled, proof-of-concept trial in sIBM patients and showed that arimoclomol was safe and well tolerated. Although arimoclomol improved some IBM-like pathology in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in the proof-of-concept patient trial.

Parent Reactions to a School-Based Body Mass Index Screening Program

BACKGROUND This study assessed parent reactions to school-based body mass index (BMI) screening. METHODS After a K-8 BMI screening program, parents were sent a letter detailing their childs BMI results. Approximately 50 parents were randomly selected for interview from each of 4 child weight-classification groups (overweight, at risk of overweight, normal weight, underweight) to assess parent recall of the letter, reactions to BMI screening, and actions taken in response to the childs BMI results. RESULTS Most parents found the BMI screening letter easy to read and had poor recall of numerical information (eg, the childs BMI percentile) but good recall of the childs weight classification (eg, normal weight or overweight). Most parents, and ethnic-minority parents in particular, supported school-based BMI screening. Parents of children whose weight was outside of the normal range were more likely to recall receiving the letter and talking to the child and the childs doctor about it. Parents who recalled their child as being overweight were more likely to report changing the childs diet and activity level. Most parents, and ethnic-minority parents in particular, wanted their child to participate in an after-school exercise program. An overweight condition in parents, but not children, was associated with an interest in family-based cooking and exercise classes. CONCLUSIONS Most parents, and ethnic-minority parents in particular, viewed school-based BMI screening and after-school exercise programs favorably. Parents reported taking action in response to a BMI result outside of the normal range. Parents who were overweight themselves were particularly interested in family cooking and exercise classes.

Visuomotor Training Improves Stroke-Related Ipsilesional Upper Extremity Impairments

Background. Unilateral middle cerebral artery infarction has been reported to impair bilateral hand grasp. Methods. Individuals (5 males and 5 females; age 33-86 years) with chronic unilateral middle cerebral artery stroke (4 right lesions and 6 left lesions) repeatedly lifted a 260-g object. Participants were then trained to lift the object using visuomotor feedback via an oscilloscope that displayed their actual grip force (GF) and a target GF, which roughly matched the physical properties of the object. Results.The subjects failed to accurately modulate the predictive GF when relying on somatosensory information from the previous lifts. Instead, for all the lifts, they programmed excessive GF equivalent to the force used for the first lift. The predictive GF was lowered for lifts following the removal of the visual feedback. The mean difference in predictive GF between the lifts before and after visual training was significant (4.35 ± 0.027 N; P ≤ .001; 95% confidence interval [CI] = 3.80-4.88). After removal of visual feedback, there was also a significant mean difference in the applied predictive GF between the “early” and “late” lifts (0.78 ± 0.029 N; P ≤ .006; 95% CI = 0.22-1.35), demonstrating continued increase in predictive GF accuracy. Conclusion. Predictive or feedforward fingertip force generation is impaired in the ipsilesional hand when lifting a novel object with precision grip. Reacquisition of the motor forces for the grasp of objects is possible after stroke. Potentially, retraining grasp control for the ipsilesional hand may translate to improved function and motor learning within the contralesional hand.

A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis

Objective: To determine the steroid-sparing effect of methotrexate (MTX) in patients with symptomatic generalized myasthenia gravis (MG). Methods: We performed a 12-month multicenter, randomized, double-blind, placebo-controlled trial of MTX 20 mg orally every week vs placebo in 50 acetylcholine receptor antibody–positive patients with MG between April 2009 and August 2014. The primary outcome measure was the prednisone area under the dose-time curve (AUDTC) from months 4 to 12. Secondary outcome measures included 12-month changes of the Quantitative Myasthenia Gravis Score, the Myasthenia Gravis Composite Score, Manual Muscle Testing, the Myasthenia Gravis Quality of Life, and the Myasthenia Gravis Activities of Daily Living. Results: Fifty-eight patients were screened and 50 enrolled. MTX did not reduce the month 4–12 prednisone AUDTC when compared to placebo (difference MTX − placebo: −488.0 mg, 95% confidence interval −2,443.4 to 1,467.3, p = 0.26); however, the average daily prednisone dose decreased in both groups. MTX did not improve secondary measures of MG compared to placebo over 12 months. Eight participants withdrew during the course of the study (1 MTX, 7 placebo). There were no serious MTX-related adverse events. The most common adverse event was nonspecific pain (19%). Conclusions: We found no steroid-sparing benefit of MTX in MG over 12 months of treatment, despite being well-tolerated. This study demonstrates the challenges of conducting clinical trials in MG, including difficulties with recruitment, participants improving on prednisone alone, and the need for a better understanding of outcome measure variability for future clinical trials. Classification of evidence: This study provides Class I evidence that for patients with generalized MG MTX does not significantly reduce the prednisone AUDTC over 12 months of therapy.

Examining the Dynamic Association of BMI and Mortality in the Framingham Heart Study

Based on the 40-year follow-up of the Framingham Heart Study (FHS), we used logistic regression models to demonstrate that different designs of an observational study may lead to different results about the association between BMI and all-cause mortality. We also used dynamic survival models to capture the time-varying relationships between BMI and mortality in FHS. The results consistently show that the association between BMI and mortality is dynamic, especially for men. Our analysis suggests that the dynamic property may explain part of the heterogeneity observed in the literature about the association of BMI and mortality.

LB0002 Safety and Tolerability of Arimoclomol in Patients with Sporadic Inclusion Body Myositis: A Randomised, Double-Blind, Placebo-Controlled, Phase IIa Proof-of-Concept Trial

Background Sporadic inclusion body myositis (IBM) is the commonest idiopathic inflammatory myopathy occurring in patients over the age of 50 years. IBM muscle displays inflammatory and degenerative features. Previous trials have only involved agents directed purely at the inflammatory component of IBM pathology and all were ineffective. Modulating the cytoprotective “heat shock response” (HSR) represents a therapeutic strategy through which the detrimental aspects of both inflammation and degeneration could be dampened. Arimoclomol is an orally administered pharmacological agent that can up-regulate the HSR by amplifying heat shock protein (HSP) expression. Objectives To evaluate the safety and tolerability of arimoclomol in IBM and to gather exploratory efficacy data of arimoclomol in IBM. Methods In this double-blind, placebo-controlled, two-centre (London, UK and Kansas, USA), phase IIa study, 24 patients with IBM were randomised to arimoclomol 100mg TID or placebo (2:1 ratio) over 4 months (as mandated by the FDA), followed by an 8 month follow up period. The primary outcome was adverse event reporting (safety and tolerability). Measures of physical function (IBM functional rating scale (IBMFRS)), muscle strength (manual muscle testing (MMT) and maximum isometric contraction testing (MVICT)) and fat-free mass percentage (measured by dual-energy X-ray absorptiometry (DEXA)) were included as secondary outcome measures. HSP70 levels in muscle biopsy tissue (adjusted to myosin content) before and after the treatment phase were also measured. Mann-Whitney U test was used to compare changes in the arimoclomol and placebo groups at 4 months (IBMFRS, MMT, MVICT, DEXA and HSP70), 8 months (IBMFRS, MMT and MVICT) and 12 months (IBMFRS, MMT, MVICT and DEXA). Results We enrolled 17 men and 7women with a mean age of 66.8±7.5 years and mean disease duration of 8.4±4.3 years. All patients fulfilled the Griggs criteria for definite (42%) or probable (58%) IBM. One serious adverse event was observed in the arimoclomol group (hypertension requiring prolonged hospitalization on the day of the first biopsy). One arimoclomol recipient developed transient hyponatremia. Ophthalmologic examination did not reveal any significant ocular morbidity. Overall, the safety and tolerability profiles were similar between groups. At 8 months, we detected a trend of slower decline in the IBMFRS (-0.68±1.58 vs -2.50±3.31, p=0.055), average MMT (-0.12±0.22 vs -0.26±0.27, p=0.147) and MVICT of right hand grip (1.26±2.63 vs -0.54±1.86, p=0.064) of the arimoclomol group but no differences were seen for changes in the other MVICT scores (left hand grip, left and right quadriceps, and total sum score), DEXA fat free mass percentage and HSP70 levels in the muscle tissue. Conclusions Arimoclomol was safe and well tolerated and demonstrated a preliminary signal for potential therapeutic benefit in patients with IBM. These data support further research of arimoclomol in IBM. Acknowledgements This investigator-initiated trial was funded by Arthritis Research UK, Kansas University Neurology Ziegler Grant and Kansas University General Clinical Research Centre CReFF Grant. Disclosure of Interest None Declared

Phase II trial of methotrexate in myasthenia gravis

Prednisone is a frequently used treatment for myasthenia gravis (MG) but it has numerous side effects. Methotrexate is a selective inhibitor of dihydrofolate reductase and lymphocyte proliferation and is an effective immuosuppressive medication for autoimmune diseases. Given the negative results of the mycophenolate mofetil study, search for an effective immunosuppressant drug therapy is ongoing. The objective is to determine if oral methotrexate is safe and effective for MG patients who take prednisone. We have initiated a randomized, double‐blind, placebo‐controlled multicenter trial of methotrexate versus placebo in patients taking at least 10 mg/day of prednisone at enrollment. The methotrexate dose is increased to 20 mg and the prednisone dose is adjusted per protocol during the study. Clinical and laboratory evaluations are performed monthly for 12 months, with the primary efficacy measure being the nine‐month prednisone area under the curve (AUC) from months 3 to 12. Secondary outcome measures include MG outcomes, quality of life measures, and a polyglutamation biomarker assay. A total of 18 U.S. sites and 2 Canadian sites are participating, with 48 screened cases, 42 enrolled, with 19 still active in the study.

Modeling the Dynamic Association of BMI and Mortality in the Framingham Heart Study

PURPOSE To examine and model the dynamic association of BMI and mortality in the Framingham Heart Study (FHS). METHODS BMI is transformed to facilitate modeling curvature associations. Logistic models are used to demonstrate whether different conclusions may be obtained for the same group of individuals under different settings created from FHS. Time-dependent covariates Cox models are used to model the association of BMI and mortality when the proportional hazards assumptions for Cox models are violated. RESULTS Both the measurement time of BMI and the length of follow-up affect the conclusions obtained from logistic models, especially for men. Time-dependent covariates Cox models show that the association between BMI and mortality for men depends on the follow-up time, while that for women depends on the age of BMI measurement. CONCLUSION The association of BMI and mortality in FHS is a dynamic system that traditional analyses methods may lead to different conclusions for different study designs. This finding is consistent with the results of several other studies done from different perspectives, suggesting that the dynamic features demonstrated in FHS may apply to other populations. Advanced methods such as time-dependent covariates Cox models may be helpful for future analysis.