Baseline fat fraction is a strong predictor of disease progression in Becker muscular dystrophy

In Becker muscular dystrophy (BMD), muscle weakness progresses relatively slowly, with a highly variable rate among patients. This complicates clinical trials, as clinically relevant changes are difficult to capture within the typical duration of a trial. Therefore, predictors for disease progression are needed. We assessed if temporal increase of fat fraction (FF) in BMD follows a sigmoidal trajectory and whether fat fraction at baseline (FFbase) could therefore predict FF increase after 2 years (ΔFF). Thereafter, for two different MR-based parameters, we tested the additional predictive value to FFbase. We used 3-T Dixon data from the upper and lower leg, and multiecho spin-echo MRI and 7-T ³¹P MRS datasets from the lower leg, acquired in 24 BMD patients (age: 41.4 [SD 12.8] years). We assessed the pattern of increase in FF using mixed-effects modelling. Subsequently, we tested if indicators of muscle damage like standard deviation in water T₂ (stdT₂) and the phosphodiester (PDE) over ATP ratio at baseline had additional value to FFbase for predicting ∆FF. The association between FFbase and ΔFF was described by the derivative of a sigmoid function and resulted in a peak ΔFF around 0.45 FFbase (fourth-order polynomial term: t = 3.7, p < .001). StdT₂ and PDE/ATP were not significantly associated with ∆FF if FFbase was included in the model. The relationship between FFbase and ∆FF suggests a sigmoidal trajectory of the increase in FF over time in BMD, similar to that described for Duchenne muscular dystrophy. Our results can be used to identify muscles (or patients) that are in the fast progressing stage of the disease, thereby facilitating the conduct of clinical trials.     

Seat height in handrim wheelchair propulsion

To study the effect of seat height on the cardiorespiratory system and kinematics in handrim wheelchair ambulation, nine non-wheelchair users participated in a wheelchair exercise experiment on a motor-driven treadmill. The subjects conducted five progressive exercise tests. After an initial try-out test, four tests were performed at different standardized seat heights of 100, 120, 140, and 160 degrees elbow extension (subject sitting erect, hands on the rim in top-dead-center = 12.00 hrs; full extension = 180 degrees). Each test consisted of four 3-minute exercise blocks at speeds of respectively 0.55, 0.83, 1.11, and 1.39 m.s-1 (2-5 km.hr-1). Analysis of variance revealed significant effects of seat height (P less than 0.05) on gross mechanical efficiency (ME), oxygen cost, push range, and push duration, and on the ranges of motion in the different arm segments and trunk. Mean ME appeared higher at the lower seat heights of 100 and 120 degrees elbow extension. This is reflected in an enhanced oxygen consumption at seat heights of 140 and 160 degrees elbow extension. Simultaneously, the push range showed a 15 to 20 degree decrease with increasing seat height, which is reflected in a decreased push duration. In the push phase, decreases in retroflexion and abduction/adduction of the upper arm were seen. The trunk shifted further forward, and the motion range in the elbow joint shifted to extension with increasing seat height. No shifts in minimum and maximum angular velocities were seen with increasing seat height. The results showed an interrelationship between wheelchair seat height and both cardiorespiratory and kinematic parameters. With respect to the cardiorespiratory system, the optimization of the wheelchair geometry, based on functional characteristics of the user, appears beneficial.     

Mechanical properties of achilles tendon in rats induced to experimental diabetes

The aim of this study was to quantify the effect of chemically induced diabetes mellitus (DM) on the mechanical properties of the Achilles tendon of rats and correlate it with metabolic and biomechanical findings. Adult rats were selected randomly and assigned to two groups, the diabetic group consisted of animals receiving a dose of streptozotocin to induce type I diabetes and the control group. The animals were placed in metabolic cages for analysis of metabolism. Ten weeks after diabetes induction, the Achilles tendon of both groups were collected and submitted to a traction test in a conventional testing machine. The measurements of mechanical properties indicated that the elastic modulus (MPa) was significantly higher in the control group (p < 0.01). In Maximum tension (MPa), the groups did not have differences (p > 0.01). Energy/tendon area (N mm/mm²), specific strain (%) and maximum specific strain (mm) were higher in tendon tests of the diabetic group (p < 0.01). We observed that the mechanical properties of tendons have correlations with metabolic properties of the diabetic animals. These results showed that induced DM in rats have an important negative effect on the mechanical properties of the Achilles tendon.     

A systematic review of serologic tests in the diagnosis of necrotizing enterocolitis

Background

Although many serologic markers have been suggested for diagnosis of necrotizing enterocolitis, there is little consensus on which of these is potentially clinically useful. Our aims were (i) to systematically review circulating markers that are potentially useful in the diagnosis of NEC and (ii) to compare the relative performance of each serologic marker of NEC by pooling estimates of marker accuracies and presenting their combined diagnostic accuracies.

Methods

We undertook a systematic review of the literature to identify studies that reported serologic markers at the time of diagnosis of necrotizing enterocolitis. Where possible, we constructed 2-by-2 tables of diagnostic accuracy from each article, if 2 or more studies investigated the same test, their results were meta-analyzed by pooling estimates of sensitivity, specificity, likelihood ratio for positive index test (LR+), likelihood ratio for negative index test (LR−), diagnostic odds ratio, and their corresponding 95% confidence intervals.

Results

Twenty-five articles provided information on serology at the time of diagnosis of necrotizing enterocolitis. Of these, it was possible to construct diagnostic accuracy tables from 16 articles and to combine data from studies that used C-reactive protein, intestinal fatty acid binding protein, and platelet-activating factor. Of these C-reactive protein was a sensitive but nonspecific marker for necrotizing enterocolitis, whereas platelet-activating factor and intestinal fatty acid binding protein were both sensitive and specific.

Conclusions

Most serologic markers of necrotizing enterocolitis have been used in too few studies to evaluate their use. Of those tests that have been tested repeatedly, platelet-activating factor and intestinal fatty acid binding protein are potentially useful, although their use must be further tested in larger prospective studies.     

Lactase persistence-related genetic variant: population substructure and health outcomes

Lactase persistence is an autosomal-dominant trait that is common in European-derived populations. A basic tendency for lactase persistence to increase from the southeast to the northwest across European populations has been noted, but such trends within countries have not been extensively studied. We genotyped the C/T(-13910) variant (rs4988235) that constitutes the putatively causal allele for lactase persistence (T allele representing persistence) in a general population sample of 3344 women aged 60-79 years from 23 towns across Britain. We found an overall frequency of 0.253 for the C (lactase non-persistence) allele, but with considerable gradients of decreasing frequency from the south to the north and from the east to the west of Britain for this allele. Daily sunlight was positively related to C (non-persistence) allele prevalence. However, sunlight exposure and latitude are strongly correlated, and it was not possible to identify which is the primary factor statistically underlying the distribution of lactase persistence. The C/T(-13910) variant (rs4988235) was not related to drinking milk or bone health (although drinking milk itself was protective of bone health), and was essentially unrelated to a wide range of other lifestyle, health and demographic characteristics. One exception was general health being rated as being poor or fair, for which there was an odds ratio of 1.38 (1.04, 1.84) for women homozygous for the C allele; on adjustment for latitude and longitude of place of birth, this attenuated to 1.19 (0.87, 1.64). The lactase persistence variant could contribute to the examination of data for the existence of, and then statistical control for, population substructure in genetic association studies.     

Anxiolytic-like effect of 5-HT(2) ligands and benzodiazepines co-administration: comparison of two animal models of anxiety (the four-plate test and the elevated plus maze)

Animal models of anxiety remain a useful tool for evaluating the anxiolytic-like effect of new treatments. Even though many tests are similarly based on exploration tasks, using more than one animal model is all the more recommended since there are qualitative differences between such tests. Furthermore, although many tests are excellent tool for detecting benzodiazepines/GABA compounds, inconsistent results have been reported for 5-HT ligands. Here, two animal models have been chosen, the elevated plus maze (EPM) based on the natural aversion of rodents for open spaces and the four-plates test (FPT) a models involving the animal's conditioned response to stressful events. In a recent study, we have demonstrated that the 5-HT(2A/2C) agonist DOI and the 5-HT(2B) agonist BW 723C86 were shown to produce an anxiolytic-like effect in both tests. This study aimed to evaluate a putative interaction between benzodiazepine and 5-HT(2) ligands in the FPT and the EPM. Indeed, close distribution of GABA(A) and 5-HT(2) receptors was found in brain structures leading to functional interrelation. In the FPT, sub-active doses of alprazolam and diazepam were strongly potentiated by DOI. BW 723C86, also potentiated the anxiolytic-like effect of the two benzodiazepines with a weaker effect. In the same way, DOI and benzodiazepines administration induced an increase in the anxiolytic-like parameters in the EPM with a strongest effect observed with alprazolam. Regardless of anxiety models used in this study, 5-HT(2A) ligands exerted facilitatory influence upon GABAergic system. Therefore, the FPT and the EPM might implicate the same kind of anxiety.     

Absolute annual incidences of first events of venous thromboembolism and arterial vascular events in individuals with elevated FVIII:c. A prospective family cohort study

Elevated levels of factor VIII:c (elevated FVIII:c) are associated with an increased risk for venous thromboembolism (VTE) and arterial vascular events, and are at least in part determined genetically. We prospectively followed 192 asymptomatic individuals with elevated FVIII:c (>150%) and 340 with normal levels for an average duration of 31 months (range 7 to 56 months) to investigate the risk of VTE and arterial vascular events. Participants were first degree relatives of consecutive patients with elevated FVIII:c and VTE or arterial vascular events before the age of 50 years. The incidences of VTE were 1.25% (0.46-2.73) per year in the subjects with elevated FVIII:c, versus 0.23% (0.03-0.82) in those with normal levels (OR 5.5 [1.1-27.3]). The annual incidences of arterial vascular events were 1.04% (0.34-2.42) and 0.23% (0.03-0.82) in relatives with and without elevated levels of FVIII:c, respectively (OR: 4.5 [0.9-23.5]). After adjustment for age, smoking, known diabetes mellitus, hyperlipidemia, and hypertension, the odds ratio for any event was 3.7 (1.1-13.1). In conclusion, asymptomatic individuals with elevated FVIII:c levels and a positive family history of VTE or arterial vascular events before the age of 50 appear to have a high annual incidence of first VTE and arterial vascular events. Elevated FVIII:c may be a common risk factor for both clinical entities.     

A double-blind switch study of paroxetine and venlafaxine in obsessive-compulsive disorder

BACKGROUND: The treatment guidelines for obsessive-compulsive disorder (OCD) propose to switch serotonin reuptake inhibitors (SRIs) in case of refractoriness. However, no controlled research has been published yet that prospectively examined the effects of changing SRIs. This article describes the first double-blind switch study of 2 SRIs in patients with OCD. METHOD: 150 patients with primary OCD, according to DSM-IV criteria, were randomly assigned in a 12-week, double-blind trial to receive dosages titrated upward to 300 mg/day of venlafaxine (N = 75) or 60 mg/day of paroxetine (N = 75). Primary efficacy was assessed by the change from baseline on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and nonresponse was defined as less than 25% reduction on the Y-BOCS. After a 4-week tapering phase, 43 nonresponders were switched to 12 additional weeks of the alternate antidepressant, of which 16 patients received venlafaxine and 27 received paroxetine. RESULTS: Eighteen of 43 patients benefited from a switch to the alternate SRI with a mean +/- SD decrease of at least 25% on the Y-BOCS. At the end of 12 weeks, responder rates were 56% for paroxetine (15/27) and 19% for venlafaxine (3/16). An intent-to-treat, last-observation-carried-forward analysis demonstrated a mean decrease on the Y-BOCS of 1.8 +/- 3.5 in the venlafaxine group and 6.5 +/- 7.1 in the paroxetine group. After 2 consecutive SRI trials, 109 of 150 patients (73%) achieved a Y-BOCS decrease of at least 25%. CONCLUSION: The results of the current study show that 42% of the nonresponders benefited from a crossover to the other SRI, and that paroxetine was more efficacious than venlafaxine in the treatment of nonresponders to a previous SRI trial. Switching SRIs in case of refractoriness may be considered a useful strategy for patients with OCD.     

Relationship Among Shoulder Proprioception, Kinematics, and Pain After Stroke

Niessen MH, Veeger DH, Meskers CG, Koppe PA, Konijnenbelt MH, Janssen TW. Relationship among shoulder proprioception, kinematics, and pain after stroke.

Objective

To identify a possible relationship among chronic poststroke shoulder pain (PSSP), scapular resting pose, and shoulder proprioception.

Design

Case-control study.

Setting

Rehabilitation center.

Participants

A total of 21 inpatients with stroke and 10 healthy control subjects.

Interventions

Not applicable.

Main Outcome Measures

Orientations of both the contralateral and ipsilateral (ie, paretic and nonparetic) shoulders during rest in degrees, angular displacement (degrees) for threshold to detection of passive motion (TDPM) tests, and absolute error (degrees) for passive reproduction of joint position (PRJP) tests.

Results

The contralateral shoulder of patients with PSSP showed more scapular lateral rotation and larger TDPM and PRJP scores than both patients without PSSP and control subjects. Additionally, the contralateral shoulder of patients with deteriorated proprioception showed more scapular lateral rotation than control subjects, whereas their ipsilateral shoulder showed more scapular lateral rotation than both control subjects and patients with good proprioception.

Conclusions

A clear relation among affected shoulder kinematics, affected proprioception, and PSSP was found. In determining the risk of developing PSSP, attention should be paid to a patients shoulder proprioception and kinematics. If both are altered after stroke, this could worsen the initial pathology or cause secondary pathologies and thus initiate a vicious circle of repetitive soft tissue damage leading to chronic PSSP. Additionally, more attention should be paid to the ipsilateral (ie, nonparetic) shoulder because it could be used in determining the risk of developing PSSP in the contralateral (ie, paretic) shoulder.