Detrusor overactivity in becker muscular dystrophy

A 20‐year‐old man with normal motor milestones as an infant but subsequent progressive difficulty in walking in childhood, was genetically confirmed to have Becker muscular dystrophy (BMD) at age 13. He was independent in ambulation and activities of daily living. He was referred to the Department of Uro‐neurology for a 5‐year history of urinary urgency and incontinence. He would visit the toilet 10 times in the daytime and experience urinary urgency daily, often associated with incontinence. He did not report difficulties initiating voiding, stress incontinence, pain, or hematuria. There was no history of urinary tract infections. Muscle Nerve 47:464‐465, 2013     

5-HT2A deletion protects against Clozapine-induced hyperglycemia

Clozapine is an antipsychotic known for its superior efficacy in treating drug-resistant Schizophrenia. However, Clozapine induces various side effects such as hyperglycemia, agranulocytosis, weight gain etc. The mechanisms of these Clozapine-induced side effects have remained largely elusive though an important role is ascribed to 5-HT_2A (Serotonin receptor subtype-2A). In this pilot study, we report for the first time that the 5-HT_2A ‘global’ knockout mice (Htr2a^?/?) are resistant to the Clozapine-induced hyperglycemia. Importantly though, the Htr2a^?/? mice exhibit near normal basal glucose metabolism in the glucose tolerance tests. Collectively, the Htr2a^?/? mice provide an important tool to study the Clozapine-induced hyperglycemia.     

Immediate Effect of Grade IV Inferior Hip Joint Mobilization on Hip Abductor Torque: A Pilot Study

Joint mobilization and manipulation stimulate mechanoreceptors, which may influence the joint and surrounding muscles. The purpose of this pilot study was to determine the effect of grade IV inferior hip joint mobilization on hip abductor torque. Thirty healthy subjects were randomly assigned to a control group (grade I inferior hip joint mobilization) or an experimental group (grade IV inferior hip joint mobilization). Subjects performed a pre- and post-intervention test of five isometric repetitions on the Cybex Normö dynamometer; the average torque was determined for both pre- and post-intervention measurements. These data were analyzed using the independent samples t-test with the significance level set at P<0.05. The results showed a statistically significant difference between the two groups for an increase in hip abductor torque in the experimental group (P=0.03). The experimental group demonstrated a 17.35% increase in average torque whereas the control group demonstrated a 3.68% decrease in average torque. These findings are consistent with other studies demonstrating that the use of grade IV non-thrust mobilization improves strength immediately post-intervention in healthy individuals. The results of this pilot study provide physical therapists with further support for the utilization of manual therapy in conjunction with therapeutic exercise to enhance muscle strength.Key Words: Arthrokinetic Reflex, Hip Abductors, Hip Joint, Isometric Torque, Manual Therapy, Non-Thrust Mobilization, Muscle StrengthThe hip joint is a ball-and-socket joint composed of the acetabulum and femur^{1, 2}. The hip has strong muscular support, with the gluteus medius functioning as an important stabilizer with a main function of hip abduction. The anterior portion of this muscle also assists in the secondary function of internal rotation^{1, 3}, and the posterior portion of the gluteus medius assists in external rotation of the hip⁴. The gluteus medius functions to stabilize the hip at mid-stance of gait in the coronal plane; it provides lateral pelvic stabilization at terminal stance^{5 – 7}. Compromise in hip abductor muscle function can lead to a Trendelenburg gait pattern, described as a contralateral pelvic drop during stance phase. This may be compensated for by an upper body shift toward the involved side to maintain the center of gravity over the affected hip^{1, 8}; the contralateral quadratus lumborum then compensates by pulling the pelvis superiorly⁹ or the lumbar spine may compensate with ipsilateral lateral trunk flexion¹⁰.The hip abductors transfer forces from the lower extremity to the spine, explaining their frequent involvement in patients with spinal complaints^{9, 11 – 13}. Beckman and Buchanan¹⁴ demonstrated differences in the firing and strength of the hip abductor muscles in the presence of distal lower extremity involvement. Studies have shown that chronic ankle instability was associated with delayed firing of the hip abductor muscles^{9, 14, 15}. Further studies have correlated weakness with isokinetic testing of hip abductor and adductor muscles with ankle and foot injuries^{16, 17}. Friel et al¹⁸ demonstrated a correlation between chronic ankle sprains and ipsilateral hip abductor weakness. Powers¹⁹ described the influence of altered lower extremity kinematics on the patellofemoral joint by identifying two possible mechanisms leading to patellofemoral pain: femoral rotation and knee valgus. Increased femoral internal rotation—as might be caused by gluteus medius weakness—results in an increased Q-angle. Powers et al²⁰ demonstrated that this femoral rotation was the primary contributor to patellar tilts and displacements. Using pressure-sensitive film, these authors reported that 30° of femoral internal rotation significantly increased patellofemoral stress (force per unit) when the knee was flexed beyond 30°. Hip abductor weakness can also lead to valgus at the knee during dynamic tasks. Knee valgus also leads to an increase in the Q-angle, displacing the patella laterally with respect to the patellar groove of the distal femur. Excessive pronation is the end result of tibial abduction, as it compensates for femoral adduction.Joints influence motor unit activation and, therefore, muscle function. The capability of a joint to alter muscle function is mediated by the articular receptors; the articular receptors can inhibit or facilitate muscle tone²¹. In this paper, the term arthrokinetic reflex is used to refer to the tonic and phasic reflex neuromuscular activity, both facilitating and inhibiting, emanating primarily from the Type I and II articular mechanoreceptors^{21, 22}.The Guide to Physical Therapist Practice ²³ has defined mobilization and manipulation as synonymous terms describing a manual therapy technique comprising a continuum of skilled passive movements to the joints and/or related soft tissues that are applied at varying speeds and amplitudes, including a small-amplitude/high-velocity therapeutic movement. During mobilization/manipulation, the capsuloligamentous tissues of a joint are mechanically stretched²¹. One primary goal of mobilization is to improve extensibility of restricted capsuloligamentous tissue; secondarily, articular mechanoreceptor activation level is affected. Joint mobilization has been demonstrated to improve physiologic and accessory motions to hypomobile structures²⁴. This in turn causes an alteration in the articular mechanoreceptor resulting by way of arthrokinetic reflex activity in enhanced muscle strength^{21, 22}. These arthrokinetic reflex actions have been hypothesized to occur through the down-regulation of inhibitory input on motor unit activity^{21, 22}. Joint mobilization not only has an impact on the motor unit activity in muscles functioning over the joint, but it also has been shown to affect more remote muscles as well, including muscles on the contralateral side of the body²². Herzog et al²⁴ demonstrated that distracting cervical facet joints stimulated the articular mechanoreceptors exerting significant coordinated reflexogenic influences on the activity of the neck and limb musculature. Cibulka²⁵ performed mobilization to a dysfunctional sacroiliac joint and restored the normal length-tension relationship of the hamstrings, thereby increasing the main torque produced. Liebler et al²⁶ demonstrated a significant increase in lower trapezius strength with the utilization of grade IV spinal mobilization: The Cybex Norm® dynamometer recorded a 6% increase in lower trapezius strength in the experimental group as compared to a 0.2% increase in the control group. Cleland et al²⁷ similarly demonstrated improved lower trapezius strength in response to manipulative treatment of the lower thoracic spine (T6-12) using grade V thrust techniques; they reported a statistically significant increase (P<0.01) in peak strength of 14.5% for the experimental group versus 3.9% for the control group. Yerys et al²⁸ demonstrated a significant effect of grade IV mobilization on gluteus maximus strength; the experimental group demonstrated a 14% increase in strength as compared to a 4% increase in the control group. As in the present study, both Liebler et al²⁶ and Yerys et al²⁸ applied a grade IV non-thrust mobilization to the subjects in the experimental group and a grade I to those in the control group.The above studies highlight the role of the joint capsule and its reflexogenic influence on muscles. Failure to recognize the importance of these arthrokinetic reflex circuits may explain the difficulty in neuromuscular re-education and strengthening of muscle groups. This in turn leads to failure of an exercise regime to achieve the desired results with regard to improved muscle function²⁹. Many rehabilitation programs focus on strengthening exercises using resistance regimens; however, few focus on the actual quality and control of movement. Manual techniques may effectively be used in cases of muscle imbalances, which are a form of dysfunction. Bookhout²⁹ suggested that greater success in rehabilitation might be achieved through the use of manual techniques, either before or in conjunction with resistive exercises.Mobilizing a restricted joint may increase muscular strength by removing the reflexogenic inhibition emanating from the joint mechanoreceptors^{21, 22, 24, 26, 29}. For example, a mechanical hip joint disorder associated with ipsilateral adductor muscle contracture, inferior capsuloligamentous hypomobility, and gluteus medius weakness, especially of the posterior fibers³⁰, will theoretically impose inhibitory neural input on the gluteus medius while simultaneously imposing reflex facilitation on the adductor muscles each time that the hip abducts against its restrictive barrier of motion^{21, 22}. This may lead to further functional destabilization of the hip joint. Above we discussed the important role of the gluteus medius muscle not only at the hip but also in the entire lower extremity and in the spine. Considering this important role of the gluteus medius muscle and the information on arthrokinetic reflex circuits discussed above, the research hypothesis in this pilot study is that grade IV inferior hip joint mobilization performed at the end of abduction will result in an immediate increase in hip abductor torque when compared to a grade I inferior hip joint mobilization.     

The resting and house frequenting behavior of Mansonia annulifera, Ma. uniformis and Ma. indiana, the vectors of Malayan filariasis in Kerala State, India.

Mansonia annulifera, was recorded to be an endophilic species, preferring to rest indoors, while Ma. uniformis was exophilic, having a predilection for outdoor resting habitats, eg bushes and shrubs. Ma. indiana did not show a clear preference to either of these biotopes. In indoor resting collections, the unfed proportion of Ma. uniformis was significantly higher during post-dusk compared to day hours (p < 0.05), indicating that this exophilic species enters houses during dusk hours for feeding. The full fed proportion was higher during day hours compared to dusk/night hours. The semigravid proportion showed a significant reduction during post-dusk hours (p < 0.05). These findings suggest that after having a blood-meal this species rest indoors and leave the houses for outdoor resting sites during the dusk hours on the subsequent night.     

Monocyte-derived macrophages from men and women with Type 2 diabetes mellitus differ in fatty acid composition compared with non-diabetic controls

We examined whether macrophages from men and women with Type 2 diabetes mellitus (T2DM) exhibited differences in expression of key genes involved in fatty acid metabolism and in fatty acid composition compared with macrophages from non-diabetic controls. Peripheral blood monocytes from subjects with T2DM (n=9) and non-diabetic controls (n=10) were differentiated into macrophages in 10% autologous serum and normal (5mM) or high (22mM) glucose. Levels of PPARalpha, PPARgamma, LXRalpha, SCD and ABCA1 mRNAs were similar in macrophages from subjects with T2DM and controls. At 5mM glucose, macrophage stearic acid (C18:0) was 12.6+/-1.0% of total fatty acids for T2DM compared with 18.1+/-2.0% for controls (p=0.03). Macrophage linoleic acid (C18:2) was 15.5+/-0.8% for T2DM and 9.3+/-2.0% for controls (p=0.005). The ratio of macrophage stearic acid (C18:0)/oleic acid (C18:1) was 0.29 [0.25,0.48] for T2DM versus 0.54 [0.36,0.82] for controls (p=0.04). Compared with non-diabetic controls, macrophages from men and women with T2DM had significantly different fatty acid profiles consistent with increased stearoyl-CoA desaturase (SCD) activity and increased C18:2 accumulation. This pattern of altered macrophage fatty acid composition may be relevant to diabetic atherogenesis.     

Amlodipine alters hemorheological parameters: Increased efficacy at the cost of edema?

Background

Despite several decades of use of calcium channel blockers, the side effect of edema persists as a class effect, and its mechanism is unresolved. Amlodipine has effects on hemorheology (HR), and its hemodilutory property may partly contribute to its antihypertensive action. This aspect is not well studied, and the literature is sparse in this regard.

Comparison of 5 methods of QT interval measurements on electrocardiograms from a thorough QT/QTc study: effect on assay sensitivity and categorical outliers

Introduction

We studied moxifloxacin-induced QT prolongation and proportion of categorical QTc outliers when 5 methods of QT measurement were used to analyze electrocardiograms (ECGs) from a thorough QT study.

Methods

QT interval was measured by the threshold, tangent, superimposed median beat, automated global median beat, and longest QT methods in a central ECG laboratory in 2730 digital ECGs from 39 subjects during placebo and moxifloxacin treatment.

Results

All 5 methods were able to demonstrate statistically significant moxifloxacin-induced QTcF prolongation. However, lower bound of 95% 1-sided confidence interval of QTcF prolongation did not exceed 5 milliseconds with the longest QT method. More QTcF outliers were observed with the longest QT and tangent methods, whereas the other 3 methods were comparable. QTcF values greater than 500 milliseconds were observed only with moxifloxacin by the tangent method, and with moxifloxacin and placebo by the longest QT method.

Conclusion

The method of QT measurement must be considered when interpreting individual thorough QT/QTc studies.     

Circulating levels of MCP-1 and eotaxin are not associated with presence of atherosclerosis or previous myocardial infarction

The chemokines are a family of signalling proteins that participate in regulation of the immune system and have been implicated in the pathogenesis of vascular diseases. Deleting the gene encoding the chemokine MCP-1 in mouse models of atherosclerosis reduces lipid lesion formation and circulating chemokines are upregulated in man immediately following myocardial infarction (MI) or coronary angioplasty. We have therefore investigated whether circulating levels of two chemokines (MCP-1 and eotaxin) differ between subjects with and without atherosclerosis. We have used three different methods of measuring the presence and extent of atherosclerosis in human subjects: duplex ultrasonography of the carotid arteries and clinical diagnosis of coronary heart disease on individuals from the general population and coronary angiography on patients with suspected heart disease. There was no difference in the levels of circulating MCP-1 or eotaxin, measured by ELISA, between subjects with and without atherosclerosis. Furthermore, any increase in circulating MCP-1 following acute MI must be short-lived, since chemokine levels were not different in subjects who had had an MI previously compared to those who had not. We conclude that although there may be a transient increase in circulating chemokine levels following coronary angioplasty, there is no difference in the levels of circulating MCP-1 or eotaxin in subjects with and without atherosclerosis.     

Current status of filariasis in Chavakad taluk, Trichur district, Kerala

A sample survey using parasitological, clinical and entomological indicators was carried out in all the 18 administrative units of Chavakad taluk, Trichur district, Kerala, India to assess the current filariasis situation. Cluster sampling procedure was followed to screen individuals. Both Wuchereria bancrofti and Brugia malayi species were found to be prevalent in this taluk. Microfilaria (mf) carriers with W. bancrofti were detected in eight areas while B. malayi was recorded only from one area. The two species were found to co-exist in another area. The highest infection rate registered for W. bancrofti was 1.51 while it was 0.3 for B. malayi. Infection due to W. bancrofti constituted 87.88% of the total 33 microfilaria cases. Prevalence of B. malayi was very low. Cases with clinical manifestation of filariasis were recorded in all the four areas surveyed. The present trend in the prevalence of infection (mf) and disease showed a decline in both the species when compared to earlier surveys of 1960s. At least 11 areas are still endemic for filariasis in this taluk. Although prevalence of mf was recorded for the first time in one of the areas viz., Elavalli, the rate was only 0.16%. Entomological surveys revealed the presence of 14 mosquito species, of which Culex quinquefasciatus contributed 84.85% and Mansonia 0.77%. While C. quinquefasciatus was recorded in all the 18 areas, Mansonia spp were found only in 8 areas. Only C. quinquefasciatus was found to harbour different developmental stages of W. bancrofti, with overall infection and infectivity rates of 1.94 and 0.97 respectively. The possible reason for the decline in vector density and infection in man are postulated.     

Induced pluripotent stem cell model recapitulates pathologic hallmarks of Gaucher disease

Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid β-glucocerebrosidase gene. To model GD, we generated human induced pluripotent stem cells (hiPSC), by reprogramming skin fibroblasts from patients with type 1 (N370S/N370S), type 2 (L444P/RecNciI), and type 3 (L444P/L444P) GD. Pluripotency was demonstrated by the ability of GD hiPSC to differentiate to all three germ layers and to form teratomas in vivo. GD hiPSC differentiated efficiently to the cell types most affected in GD, i.e., macrophages and neuronal cells. GD hiPSC-macrophages expressed macrophage-specific markers, were phagocytic, and were capable of releasing inflammatory mediators in response to LPS. Moreover, GD hiPSC-macrophages recapitulated the phenotypic hallmarks of the disease. They exhibited low glucocerebrosidase (GC) enzymatic activity and accumulated sphingolipids, and their lysosomal functions were severely compromised. GD hiPSC-macrophages had a defect in their ability to clear phagocytosed RBC, a phenotype of tissue-infiltrating GD macrophages. The kinetics of RBC clearance by types 1, 2, and 3 GD hiPSC-macrophages correlated with the severity of the mutations. Incubation with recombinant GC completely reversed the delay in RBC clearance from all three types of GD hiPSC-macrophages, indicating that their functional defects were indeed caused by GC deficiency. However, treatment of induced macrophages with the chaperone isofagomine restored phagocytosed RBC clearance only partially, regardless of genotype. These findings are consistent with the known clinical efficacies of recombinant GC and isofagomine. We conclude that cell types derived from GD hiPSC can effectively recapitulate pathologic hallmarks of the disease.