A re-evaluation of the use of glyceryl trinitrate to assess the degree of adrenergic beta receptor blockade

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The effects of persistent articholinesterase action at the neuromuscular junction

The effects of organophosphorus compounds which form a rapidly-ageing complex with acetylcholinesterase (AChE) (e.g. pinacolyl S-(2- trimethylaminoethyl)methylphosphonothioate (BOS)) and hence exert a persistent anticholinesterase (anti-ChE) action have been compared with other compounds with a shorter time course of inhibition (e.g. ecothiopate iodide (ECO)). Although the inhibition of AChE produced by BOS lasted longer than that seen with ECO, the time course of the myopathy appeared very similar. BOS also possessed a number of properties which have been seen with other anti-ChEs. BOS and ECO produced significant increases in neuromuscular "jitter" 5 days after injection, not only in the diaphragm but also in the soleus and extensor digitorum longus muscles. Increases in "jitter" produced by ECO could be prevented by pyridostigmine prophylaxis or rapid treatment with pyridine-2- aldoxime methiodide. Some protection from the BOS-induced increases in "jitter" could be gained by repeated treatment with pyridine-2-aldoxime methiodide, an effect which could not be accounted for simply by enzyme reactivation. From experiments performed in Rej 129 mice it was determined that increases in "jitter", although demonstrated in some dystrophic muscles, could not be used as an early diagnostic tool. Because sequalae of inhibition were present some time after intoxication, by which time AChE appeared biochemically normal, experiments were performed to investigate inactivation of physiologically important AChE. The time course of extracellular MEPPs was utilised as an indicator of physiologically important AChE and compared with the AChE activity measured by the technique of Ellman et al. (1961). It was concluded that the degree of persistence of anti-ChE action was unimportant for the induction of myopathy with a time course of 3-24 hours, but had some importance in events of longer duration.

The neurotoxic effects of enzyme inhibitors at the neuromuscular junction

Current knowledge of the long-term, low dose effects of carbamate (CB) anti-cholinesterases on skeletal muscle or on the metabolism and regulation of the molecular forms of acetylcholinesterase (AChE) is limited. This is largely due to the reversible nature of these inhibitors and the subtle effects they induce which has generally made their study difficult and preliminary investigations were conducted to determine suitable study methods. A sequential extraction technique was used to rapidly analyse AChE molecular form activity at the mouse neuromuscular junction and also in peripheral parts of muscle fibres. AChE in the synaptic cleft involved in the termination of cholinergic transmission was successfully assessed by the assay method and by an alternative method using a correlation equation which represented the relationship between synaptic AChE and the prolongation of extra-cellular miniature endplate potentials. It was found that inhibition after in vivo Carbamate (CB) dosing could not be maintained during tissue analysis because CB-inhibited enzyme complexes decarbamoylated vary rapidly and could not be prevented even when maintained on ice. The methods employed did not therefore give a measure of inhibition but presented a profile of metabolic responses to continual, low dose CB treatment. Repetitive and continual infusion with low doses of the CBs: pyridostigmine and physostigmine induced a variety of effects on mouse skeletal muscle. Both compounds induced a mild myopathy in the mouse diaphragm during continual infusion which was characterised by endplate deformation without necrosis; such deformation persisted on termination of treatment but had recovered slightly 14 days later. Endplate and non-endplate AChE molecular forms displayed selective responses to CB treatment. During treatment endplate AChE was reduced whereas non-endplate AChE was largely unaffected, and after treatment, endplate AChE recovered, whereas non-endplate AChE was up-regulated. The mechanisms by which these responses become manifest are unclear but may be due to CB-induced effects on nerve-mediated muscle activity, neurotrophic factors or morphological and physiological changes which arise at the neuromuscular junction. It was concluded that, as well as inhibiting AChE, CBs also influence the metabolism and regulation of the enzyme and induce persistent endplate deformation; possible detrimental effects of long-term, low-dose determination requires further investigation.

Blockade of interleukin 6 signaling improves the survival rate of transplanted bone marrow stromal cells and increases locomotor function in mice with spinal cord injury

Bone marrow stromal cells (BMSCs) have the potential to improve functional recovery in patients with spinal cord injury (SCI); however, they are limited by low survival rates after transplantation in the injured tissue. Our objective was to clarify the effects of a temporal blockade of interleukin 6 (IL-6)/IL-6 receptor (IL-6R) engagement using an anti-mouse IL-6R monoclonal antibody (MR16-1) on the survival rate of BMSCs after their transplantation in a mouse model of contusion SCI. MR16-1 cotreatment improved the survival rate of transplanted BMSCs, allowing some BMSCs to differentiate into neurons and astrocytes, and improved locomotor function recovery compared with BMSC transplantation or MR16-1 treatment alone. The death of transplanted BMSCs could be mainly related to apoptosis rather than necrosis. Transplantation of BMSC with cotreatment of MR16-1 was associated with a decrease of some proinflammatory cytokines, an increase of neurotrophic factors, decreased apoptosis rates of transplanted BMSCs, and enhanced expression of survival factors Akt and extracellular signal-regulated protein kinases 1/2. We conclude that MR16-1 treatment combined with BMSC transplants helped rescue neuronal cells and axons after contusion SCI better than BMSCs alone by modulating the inflammatory/immune responses and decreasing apoptosis. © 2013 by the American Association of Neuropathologists, Inc.

Tunnelling density of states at Coulomb-blockade peaks

We calculate the tunnelling density of states (TDoS) for a quantum dot in the Coulomb-blockade regime, using a functional integral representation with allowing correctly for the charge quantisation. We show that in addition to the well-known gap in the TDoS in the Coulomb-blockade valleys, there is a suppression of the TDoS at the peaks. We show that such a suppression is necessary in order to get the correct result for the peak of the differential conductance through an almost close quantum dot.

Plasma vascular endothelial growth factor, angiopoietin-2, and soluble angiopoietin receptor tie-2 in diabetic retinopathy:effects of laser photocoagulation and angiotensin receptor blockade

Background: Proliferative diabetic retinopathy (PDR) may be a response to abnormal angiogenic growth factors such as vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), and the soluble angiopoietin receptor tie-2. The authors hypothesised the following: (a) there are differences in plasma levels of these growth factors in different grades of diabetic retinopathy; and (b) that the effects of intervention with panretinal laser photocoagulation (PRP) for PDR, and angiotensin receptor blockade (using eprosartan) for patients with other grades of diabetic retinopathy will be to reduce levels of the growth factors. Methods: Cross sectional and interventional study (using PRP and eprosartan) in diabetic patients. VEGF, Ang-2, and tie-2 were measured by ELISA. Results: VEGF (p<0.001) and Ang-2 levels (p<0.001) were significantly higher in 93 diabetic patients compared to 20 healthy controls, with the highest levels in grade 2 and grade 3 diabetic retinopathy (p<0.05). Tie-2 was lower in diabetics compared to controls (p = 0.008), with no significant differences between the diabetic subgroups. Overall, VEGF significantly correlated with Ang-2 (p<0.001) and tie-2 (p = 0.004) but the correlation between Ang-2 and tie-2 levels was not significant (p = 0.065). Among diabetic patients only, VEGF levels were significantly correlated with Ang-2 (p<0.001) and tie-2 (p<0.001); the correlation between Ang-2 and tie-2 levels was also significant (p<0.001). There were no statistically significant effects of laser photocoagulation on plasma VEGF, Ang-2, and tie-2 in the 19 patients with PDR, or any effects of eprosartan in the 28 patients with non-proliferative diabetic retinopathy. Conclusion: Increased plasma levels of VEGF and Ang-2, as well as lower soluble tie-2, were found in diabetic patients. The highest VEGF and Ang-2 levels were seen among patients with pre-proliferative and proliferative retinopathy, but there was no relation of tie-2 to the severity of retinopathy. As the majority of previous research into Ang-2 and tie-2 has been in relation to angiogenesis and malignancy, the present study would suggest that Ang-2 and tie-2 may be used as potential indices of angiogenesis in diabetes mellitus (in addition to VEGF) and may help elucidate the role of the angiopoietin/tie-2 system in this condition.

Diabetic retinopathy and blockade of the renin–angiotensin system:new data from the DIRECT study programme

The pathogenesis and medical management of diabetic retinopathy is reviewed. The importance of good control of blood glucose and blood pressure remain key elements in the prevention and treatment of diabetic retinopathy, and a number of specific metabolic pathways have been identified that may be useful additional targets for therapeutic intervention. Trial data, however, aimed specifically to answer the questions of optimum medical management are limited, so the DIRECT study of renin-angiotensin blockade using oral candesartan 32 mg daily is a welcome addition to our knowledge. This arose from the promising improvement of retinopathy outcomes in the EUCLID study of lisinopril in type I diabetes. In DIRECT, 5 years of candesartan treatment in type I diabetes reduced the incidence of retinopathy by two or more steps (EDTRS) in severity by 18% (P = 0.0508) and, in a post hoc analysis, reduced the incidence of retinopathy by three-step progression by 35% (P = 0.034). In type I diabetes patients there was no effect on progression of established retinopathy. In contrast, in type II diabetes, 5 years of candesartan treatment resulted in 34% regression of retinopathy (P ≤0.009). Importantly, an overall significant change towards less-severe retinopathy was noted in both type I and II diabetes (P0.03). Although there is still no absolute proof that these effects were specific to RAS blockade, or just an effect of lower blood pressure, it is reasonable to conclude that candesartan has earned a place in the medical management of diabetic retinopathy, to prevent the problem in type I diabetes and to treat the early stages in type II diabetes. © 2010 Macmillan Publishers Limited All rights reserved.

Neuromuscular response to whole body vibration treatment during static and dynamic squat exercises

The impact of whole body vibrations (vibration stimulus mechanically transferred to the body) on muscular activity and neuromuscular response has been widely studied but without standard protocol and by using different kinds of exercises and parameters. In this study, we investigated how whole body vibration treatments affect electromyographic signal of rectus femoris during static and dynamic squat exercises. The aim was the identification of squat exercise characteristics useful to maximize neuromuscular activation and hence progress in training efficacy. Fourteen healthy volunteers performed both static and dynamic squat exercises without and with vibration treatments. Surface electromyographic signals of rectus femoris were recorded during the whole exercise and processed to reduce artifacts and to extract root mean square values. Paired t-test results demonstrated an increase of the root mean square values (p<0.05) in both static and dynamic squat exercises with vibrations respectively of 63% and 108%. For each exercise, subjects gave a rating of the perceived exertion according to the Borg's scale but there were no significant changes in the perceived exertion rate between exercises with and without vibration. Finally, results from analysis of electromyographic signals identified the static squat with WBV treatment as the exercise with higher neuromuscular system response. © 2012 IEEE.

Blockade of interleukin-6 effects on cytokine profiles and macrophage activation after spinal cord injury in mice

The objective of this study was to clarify the effects of a temporal blockade of IL-6/IL-6 receptor (IL-6R) engagement, using an anti-mouse IL-6R monoclonal antibody (MR16-1), on macrophage activation and the inflammatory response in the acute phase after spinal cord injury (SCI) in mice. MR16-1 antibodies versus isotype control antibodies or saline alone was administered immediately after thoracic SCI in mice. MR16-1-treated group samples showed increased neuronal regeneration and locomotor recovery compared with controls. Immunoblot analysis of the MR16-1-treated samples identified downregulation of Th1 and upregulation of Th2 cytokines. MR16-1 treatment promoted arginase-1-positive, CD206-positive M2 macrophages, with preferential localization of these cells at the injury site and enhanced positivity for Mac-2 and Mac-3, suggestive of increased phagocytic behavior. The results suggest that temporal blockade of IL-6 signaling after SCI abrogates damaging inflammatory activity and promotes functional recovery by promoting the formation of alternatively activated M2 macrophages.

Acute Effects of Neuromuscular-Training with Handheld-Vibration on Elbow Joint Position Sense

Context: Clinicians use exercises in rehabilitation to enhance sensorimotor-function, however evidence supporting their use is scarce. Objective: To evaluate acute effects of handheld-vibration on joint position sense (JPS). Design: A repeated-measure, randomized, counter-balanced 3-condition design. Setting: Sports Medicine and Science Research Laboratory. Patients or Other Participants: 31 healthy college-aged volunteers (16-males, 15-females; age=23+3y, mass=76+14kg, height=173+8cm). Interventions: We measured elbow JPS and monitored training using the Flock-of-Birds system (Ascension Technology, Burlington, VT) and MotionMonitor software (Innsport, Chicago, IL), accurate to 0.5°. For each condition (15,5,0Hz vibration), subjects completed three 15-s bouts holding a 2.55kg Mini-VibraFlex dumbbell (Orthometric, New York, NY), and used software-generated audio/visual biofeedback to locate the target. Participants performed separate pre- and post-test JPS measures for each condition. For JPS testing, subjects held a non-vibrating dumbbell, identified the target (90°flexion) using biofeedback, and relaxed 3-5s. We removed feedback and subjects recreated the target and pressed a trigger. We used SPSS 14.0 (SPSS Inc., Chicago, IL) to perform separate ANOVAs (p<0.05) for each protocol and calculated effect sizes using standard-mean differences. Main Outcome Measures: Dependent variables were absolute and variable error between target and reproduced angles, pre-post vibration training. Results: 0Hz (F1,61=1.310,p=0.3) and 5Hz (F1,61=2.625,p=0.1) vibration did not affect accuracy. 15Hz vibration enhanced accuracy (6.5±0.6 to 5.0±0.5°) (F1,61=8.681,p=0.005,ES=0.3). 0Hz did not affect variability (F1,61=0.007,p=0.9). 5Hz vibration decreased variability (3.0±1.8 to 2.3±1.3°) (F1,61=7.250,p=0.009), as did 15Hz (2.8±1.8 to 1.8±1.2°) (F1,61=24.027, p<0.001). Conclusions: Our results support using handheld-vibration to improve sensorimotor-function. Future research should include injured subjects, functional multi-joint/multi-planar measures, and long-term effects of similar training.

The Allelic Abundance of Afghanistan, a Pool for West and South Eurasian Genes and a Blockade against Eastern Admixture

In this study, I divided samples from individuals within Afghanistan based upon geography (i.e., north versus south). I determined allelic frequencies and other statistical parameters for 15 STR loci (i.e., D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, Dl3S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818, and FGA). I conducted pairwise comparisons with 19 neighboring Eurasian populations to assign Gstatistics and p-values. Categorizing the populations into five groups (i.e., Central Asia, East Asia, South Asia, the Middle East, and the Caucasus/Anatolia), I derived values for intra-population, inter-population, and total variance. Admixture analyses determined the highest allelic contributions to be from the Caucasus/ Anatolia, while negligible contributions were made by Central Asia and East Asia. A Correspondence Analysis revealed clustering of both northern and southern Afghanistan with Georgia, Turkey, northern Iran, and southern Iran of the Caucasus/ Anatolia and the Middle East. A Neighbor-Joining phylogenetic tree was constructed to generate bootstrap values over 1, 000 reiterations.

Neuromuscular Changes in Older Adults during the Lateral Step Task

Older adults may have trouble when performing activities of daily living due to decrease in physical strength and degradation of neuromotor and musculoskeletal function. Motor activation patterns during Lateral Step Down and Step Up from 4-inch and 8-inch step heights was assessed in younger (n=8, 24.4 years) and older adults (n=8, 58.9 years) using joint angle kinematics and electromyography of lower extremity muscles. Ground reaction forces were used to ascertain the loading, stabilization and unloading phases of the tasks. Older adults had an altered muscle activation sequence and significantly longer muscle bursts during loading for the tibialis anterior, gastrocnemius, vastus medialis, bicep femoris, gluteus medius and gluteus maximus muscles of the stationary leg. They also demonstrated a significantly larger swing time (579.1 ms vs. 444.8 ms) during the step down task for the moving leg. The novel data suggests presence of age-related differences in motor coordination during lateral stepping.