Osteopenia in a teenage boy presenting with previously undiagnosed guanidinoacetate methyltransferase (GAMT) deficiency and response to creatine supplementation

A 16 y.o. fully ambulant boy born to consanguineous Indian parents, presented for assessment of a fragility femoral neck fracture sustained against a background of autism and moderately severe intellectual disability. He had a past history of infantile eczema, and epilepsy treated with anticonvulsants from 2 to 10 years of age, with no further seizures following cessation of anticonvulsants. He had a thin body habitus (see Table 1) with long fingers and a high arched palate. He had no speech and negligible social interaction, but physical examination was otherwise unremarkable. Positive investigations revealed an undetectable serum creatinine and a urinary metabolic screen which showed an elevated GUA:Phe of 160 (< 36) and a decreased creatinine of 0.3 mmol/l (1.2–29.5) consistent with the diagnosis of guanidinoacetate methyltransferase(GAMT) deficiency. He was commenced on oral creatine 5 g three times daily. Despite improvement in physical activity, height and bone density, there was no discernable improvement in his intellectual functioning. Proton and phosphorous brain and leg magnetic resonance spectroscopy(MRS) was performed at baseline and showed an increased inorganic phosphorus peak and decreased phosphocreatine synthesis in brain and decreased creatine concentration in muscle. Following creatine treatment total brain creatine(1H-MRS) and phosphocreatine/ATP ratio (31P-MRS) content increased to 30% and 60% of control values, respectively. Brain GUA returned to normal levels.

Benign Epilepsy with Centro-temporal Spikes: Spike Triggered fMRI Shows Somato-sensory Cortex Activity

Summary:  Objective: We performed spike triggered functional MRI (fMRI) in a 12 year old girl with Benign Epilepsy with Centro-temporal Spikes (BECTS) and left-sided spikes. Our aim was to demonstrate the cerebral origin of her interictal spikes. Methods: EEG was recorded within the 3 Tesla MRI. Whole brain fMRI images were acquired, beginning 2–3 seconds after spikes. Baseline fMRI images were acquired when there were no spikes for 20 seconds. Image sets were compared with the Student's t-test. Results: Ten spike and 20 baseline brain volumes were analysed. Focal activiation was seen in the inferior left sensorimotor cortex near the face area. The anterior cingulate was more active during baseline than spikes. Conclusions: Left sided epileptiform activity in this patient with BECTS is associated with fMRI activation in the left face region of the somatosensory cortex, which would be consistent with the facial sensorimotor involvement in BECT seizures. The presence of BOLD signal change in other regions raises the possibility that the scalp recorded field of this patient with BECTs may reflect electrical change in more than one brain region.

Myoinositol Abnormalities in Temporal Lobe Epilepsy

Purpose: This study used magnetic resonance spectroscopy (MRS) to examine metabolite abnormalities in the temporal and frontal lobe of patients with temporal lobe epilepsy (TLE) of differing severity. Methods: We investigated myoinositol in TLE by using short-echo MRS in 34 TLE patients [26 late onset (LO-TLE), eight hippocampal sclerosis (HS-TLE)], and 16 controls. Single-voxel short-echo (35 ms) MR spectra of temporal and frontal lobes were acquired at 1.5 T and analyzed by using LCModel. Results: The temporal lobe ipsilateral to seizure origin in HS-TLE, but not LO-TLE, had reduced N-acetylaspartate (NA) and elevated myoinositol (MI; HS-TLE NA, 7.8 ± 1.9 mM, control NA, 9.2 ± 1.3 mM; p < 0.05; HS-TLE MI, 6.1 ± 1.6 mM, control mI 4.9 ± 0.8 mM, p< 0.05). Frontal lobe MI was low in both patient groups (LO-TLE, 4.3 ± 0.8 mM; p < 0.05; HS-TLE, 3.6 ±.05 mM; p < 0.001; controls, 4.8 ± 0.5 mM). Ipsilateral frontal lobes had lower MI (3.8 ± 0.7 mM; p < 0.01) than contralateral frontal lobes (4.3 ± 0.8 mM; p < 0.05). Conclusions: MI changes may distinguish between the seizure focus, where MI is increased, and areas of seizure spread where MI is decreased.

Delta opioid-receptor function in the dorsal striatum plays a role in high levels of ethanol consumption in rats

Binge-like patterns of excessive drinking during young adulthood increase the propensity for alcohol use disorders (AUDs) later in adult life; however, the mechanisms that drive this are not completely understood. Previous studies showed that the δ-opioid peptide receptor (DOP-R) is dynamically regulated by exposure to ethanol and that the DOP-R plays a role in ethanol-mediated behaviors. The aim of this study was to determine the role of the DOP-R in high ethanol consumption from young adulthood through to late adulthood by measuring DOP-R-mediated [(35)S]GTPγS binding in brain membranes and DOP-R-mediated analgesia using a rat model of high ethanol consumption in Long Evans rats. We show that DOP-R activity in the dorsal striatum and DOP-R-mediated analgesia changes during development, being highest during early adulthood and reduced in late adulthood. Intermittent access to ethanol but not continuous ethanol or water from young adulthood leads to an increase in DOP-R activity in the dorsal striatum and DOP-R-mediated analgesia into late adulthood. Multiple microinfusions of naltrindole into the dorsal striatum or multiple systemic administration of naltrindole reduces ethanol consumption, and following termination of treatment, DOP-R activity in the dorsal striatum is attenuated. These findings suggest that DOP-R activity in the dorsal striatum plays a role in high levels of ethanol consumption and suggest that targeting the DOP-R is an alternative strategy for the treatment of AUDs.

The relationship between Bayesian motor unit number estimation and histological measurements of motor neurons in wild-type and SOD1 G93A mice

Objective: To assess the relationship between Bayesian MUNE and histological motor neuron counts in wild-type mice and in an animal model of ALS. Methods: We performed Bayesian MUNE paired with histological counts of motor neurons in the lumbar spinal cord of wild-type mice and transgenic SOD1 G93A mice that show progressive weakness over time. We evaluated the number of acetylcholine endplates that were innervated by a presynaptic nerve. Results: In wild-type mice, the motor unit number in the gastrocnemius muscle estimated by Bayesian MUNE was approximately half the number of motor neurons in the region of the spinal cord that contains the cell bodies of the motor neurons supplying the hindlimb crural flexor muscles. In SOD1 G93A mice, motor neuron numbers declined over time. This was associated with motor endplate denervation at the end-stage of disease. Conclusion: The number of motor neurons in the spinal cord of wild-type mice is proportional to the number of motor units estimated by Bayesian MUNE. In SOD1 G93A mice, there is a lower number of estimated motor units compared to the number of spinal cord motor neurons at the end-stage of disease, and this is associated with disruption of the neuromuscular junction. Significance: Our finding that the Bayesian MUNE method gives estimates of motor unit numbers that are proportional to the numbers of motor neurons in the spinal cord supports the clinical use of Bayesian MUNE in monitoring motor unit loss in ALS patients. © 2012 International Federation of Clinical Neurophysiology.

Wide-field assessment of the human corneal subbasal nerve plexus in diabetic neuropathy using a novel mapping technique

To develop a rapid optimized technique of wide-field imaging of the human corneal subbasal nerve plexus. A dynamic fixation target was developed and, coupled with semiautomated tiling software, a rapid method of capturing and montaging multiple corneal confocal microscopy images was created. To illustrate the utility of this technique, wide-field maps of the subbasal nerve plexus were produced in 2 participants with diabetes, 1 with and 1 without neuropathy. The technique produced montages of the central 3 mm of the subbasal corneal nerve plexus. The maps seem to show a general reduction in the number of nerve fibers and branches in the diabetic participant with neuropathy compared with the individual without neuropathy. This novel technique will allow more routine and widespread use of subbasal nerve plexus mapping in clinical and research situations. The significant reduction in the time to image the corneal subbasal nerve plexus should expedite studies of larger groups of diabetic patients and those with other conditions affecting nerve fibers. The inferior whorl and the surrounding areas may show the greatest loss of nerve fibers in individuals with diabetic neuropathy, but this should be further investigated in a larger cohort.

A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation

Gait freezing is an episodic arrest of locomotion due to an inability to take normal steps. Pedunculopontine nucleus stimulation is an emerging therapy proposed to improve gait freezing, even where refractory to medication. However, the efficacy and precise effects of pedunculopontine nucleus stimulation on Parkinsonian gait disturbance are not established. The clinical application of this new therapy is controversial and it is unknown if bilateral stimulation is more effective than unilateral. Here, in a double-blinded study using objective spatiotemporal gait analysis, we assessed the impact of unilateral and bilateral pedunculopontine nucleus stimulation on triggered episodes of gait freezing and on background deficits of unconstrained gait in Parkinson’s disease. Under experimental conditions, while OFF medication, Parkinsonian patients with severe gait freezing implanted with pedunculopontine nucleus stimulators below the pontomesencephalic junction were assessed during three conditions; off stimulation, unilateral stimulation and bilateral stimulation. Results were compared to Parkinsonian patients without gait freezing matched for disease severity and healthy controls. Pedunculopontine nucleus stimulation improved objective measures of gait freezing, with bilateral stimulation more effective than unilateral. During unconstrained walking, Parkinsonian patients who experience gait freezing had reduced step length and increased step length variability compared to patients without gait freezing; however, these deficits were unchanged by pedunculopontine nucleus stimulation. Chronic pedunculopontine nucleus stimulation improved Freezing of Gait Questionnaire scores, reflecting a reduction of the freezing encountered in patients’ usual environments and medication states. This study provides objective, double-blinded evidence that in a specific subgroup of Parkinsonian patients, stimulation of a caudal pedunculopontine nucleus region selectively improves gait freezing but not background deficits in step length. Bilateral stimulation was more effective than unilateral.

Understanding the relationships between the calf muscle pump, ankle range of motion and healing for adults with venous leg ulcers: a review of the literature

Exercise offers the potential to improve circulation, wound healing outcomes, and functional and emotional wellbeing for adults experiencing venous leg ulceration. Individuals with chronic leg ulcers typically have multiple comorbidities such as arthritis, asthma, chronic obstructive airways disease, cardiac disease or neuromuscular disorders, which would also benefit from regular exercise. The aim of this review is to highlight the relationships between the calf muscle pump and venous return and range of ankle motion for adults with venous leg ulcers. The effect of exercise will also be considered in relation to the healing rates for adults experiencing venous leg ulceration. The findings suggest there is evidence that exercises which engage the calf muscle pump improve venous return. Ankle range of motion, which is crucial for complete activation of the calf muscle pump, can also be improved with simple, home-based exercise programs. However, observational studies still report that venous leg ulcer patients are less physically active than age-matched controls. Therefore, the behavioural reasons for not exercising must be considered. Only two studies, both underpowered, have assessed the effect of exercise on the healing rates of venous leg ulcers. In conclusion, exercise is feasible with this patient population. However, future studies with larger sample sizes are needed to provide stronger evidence to support the therapeutic benefit of exercise as an adjunct therapy in wound care.

Characterisation of multi wall carbon nanotube–polymer composites for strain sensing applications

Carbon nanotubes (CNTs) have excellent electrical, mechanical and electromechanical properties. When CNTs are incorporated into polymers, electrically conductive composites with high electrical conductivity at very low CNT content (often below 1% wt CNT) result. Due to the change in electrical properties under mechanical load, carbon nanotube/polymer composites have attracted significant research interest especially due to their potential for application in in-situ monitoring of stress distribution and active control of strain sensing in composite structures or as strain sensors. To sucessfully develop novel devices for such applications, some of the major challenges that need to be overcome include; in-depth understanding of structure-electrical conductivity relationships, response of the composites under changing environmental conditions and piezoresistivity of different types of carbon nanotube/polymer sensing devices. In this thesis, direct current (DC) and alternating current (AC) conductivity of CNT-epoxy composites was investigated. Details of microstructure obtained by scanning electron microscopy were used to link observed electrical properties with structure using equivalent circuit modeling. The role of polymer coatings on macro and micro level electrical conductivity was investigated using atomic force microscopy. Thermal analysis and Raman spectroscopy were used to evaluate the heat flow and deformation of carbon nanotubes embedded in the epoxy, respectively, and related to temperature induced resistivity changes. A comparative assessment of piezoresistivity was conducted using randomly mixed carbon nanotube/epoxy composites, and new concept epoxy- and polyurethane-coated carbon nanotube films. The results indicate that equivalent circuit modelling is a reliable technique for estimating values of the resistance and capacitive components in linear, low aspect ratio-epoxy composites. Using this approach, the dominant role of tunneling resistance in determining the electrical conductivity was confirmed, a result further verified using conductive-atomic force microscopy analysis. Randomly mixed CNT-epoxy composites were found to be highly sensitive to mechanical strain and temperature variation compared to polymer-coated CNT films. In the vicinity of the glass transition temperature, the CNT-epoxy composites exhibited pronounced resistivity peaks. Thermal and Raman spectroscopy analyses indicated that this phenomenon can be attributed to physical aging of the epoxy matrix phase and structural rearrangement of the conductive network induced by matrix expansion. The resistivity of polymercoated CNT composites was mainly dominated by the intrinsic resistivity of CNTs and the CNT junctions, and their linear, weakly temperature sensitive response can be described by a modified Luttinger liquid model. Piezoresistivity of the polymer coated sensors was dominated by break up of the conducting carbon nanotube network and the consequent degradation of nanotube-nanotube contacts while that of the randomly mixed CNT-epoxy composites was determined by tunnelling resistance between neighbouring CNTs. This thesis has demonstrated that it is possible to use microstructure information to develop equivalent circuit models that are capable of representing the electrical conductivity of CNT/epoxy composites accurately. New designs of carbon nanotube based sensing devices, utilising carbon nanotube films as the key functional element, can be used to overcome the high temperature sensitivity of randomly mixed CNT/polymer composites without compromising on desired high strain sensitivity. This concept can be extended to develop large area intelligent CNT based coatings and targeted weak-point specific strain sensors for use in structural health monitoring.

Rate of torque and electromyographic development during anticipated eccentric contraction is lower in previously strained hamstrings

Background: Hamstring strain injuries are prevalent in sport and re-injury rates have been high for many years. Whilst much focus has centred on the impact of previous hamstring strain injury on maximal eccentric strength, high rates of torque development is also of interest, given the important role of the hamstrings during the terminal swing phase of running. The impact of prior strain injury on myoelectrical activity of the hamstrings during tasks requiring high rates of torque development has received little attention. Purpose: To determine if recreational athletes with a history of unilateral hamstring strain injury, who have returned to training and competition, will exhibit lower levels of myoelectrical activity during eccentric contraction, rate of torque development and impulse 30, 50 and 100ms after the onset of myoelectrical activity or torque development in the previously injured limb compared to the uninjured limb. Study design: Case-control study Methods: Twenty-six recreational athletes were recruited. Of these, 13 athletes had a history of unilateral hamstring strain injury (all confined to biceps femoris long head) and 13 had no history of hamstring strain injury. Following familiarisation, all athletes undertook isokinetic dynamometry testing and surface electromyography assessment of the biceps femoris long head and medial hamstrings during eccentric contractions at -60 and -1800.s-1. Results: In the injured limb of the injured group, compared to the contralateral uninjured limb rate of torque development and impulse was lower during -600.s-1 eccentric contractions at 50 (RTD, injured limb = 312.27 ± 191.78Nm.s-1 vs. uninjured limb = 518.54 ± 172.81Nm.s-1, p=0.008; IMP, injured limb = 0.73 ± 0.30 Nm.s vs. uninjured limb = 0.97 ± 0.23 Nm.s, p=0.005) and 100ms (RTD, injured limb = 280.03 ± 131.42Nm.s-1 vs. uninjured limb = 460.54.54 ± 152.94Nm.s-1,p=0.001; IMP, injured limb = 2.15 ± 0.89 Nm.s vs. uninjured limb = 3.07 ± 0.63 Nm.s, p<0.001) after the onset of contraction. Biceps femoris long head muscle activation was lower at 100ms at both contraction speeds (-600.s-1, normalised iEMG activity (x1000), injured limb = 26.25 ± 10.11 vs. uninjured limb 33.57 ± 8.29, p=0.009; -1800.s-1, normalised iEMG activity (x1000), injured limb = 31.16 ± 10.01 vs. uninjured limb 39.64 ± 8.36, p=0.009). Medial hamstring activation did not differ between limbs in the injured group. Comparisons in the uninjured group showed no significant between limbs difference for any variables. Conclusion: Previously injured hamstrings displayed lower rate of torque development and impulse during slow maximal eccentric contraction compared to the contralateral uninjured limb. Lower myoelectrical activity was confined to the biceps femoris long head. Regardless of whether these deficits are the cause of or the result of injury, these findings could have important implications for hamstring strain injury and re-injury. Particularly, given the importance of high levels of muscle activity to bring about specific muscular adaptations, lower levels of myoelectrical activity may limit the adaptive response to rehabilitation interventions and suggest greater attention be given to neural function of the knee flexors following hamstring strain injury.

Impact of previous hamstring strain injury on rate of torque and EMG development during eccentric contraction.

Background: Hamstring strain injuries (HSIs) are prevalent in sport and re-injury rates have been high for many years. Whilst much focus has centred on the impact of previous hamstring strain injury on maximal eccentric strength, high rates of torque development is also of interest, given the important role of the hamstrings during the terminal swing phase of gait. The impact of prior strain injury on neuromuscular function of the hamstrings during tasks requiring high rates of torque development has received little attention. The purpose of this study is to determine if recreational athletes with a history of unilateral hamstring strain injury, who have returned to training and competition, will exhibit lower levels of eccentric muscle activation, rate of torque development and impulse 30, 50 and 100ms after the onset of electromyographical or torque development in the previously injured limb compared to the uninjured limb. Methods: Twenty-six recreational athletes were recruited. Of these, 13 athletes had a history of unilateral hamstring strain injury (all confined to biceps femoris long head) and 13 had no history of hamstring strain injury. Following familiarisation, all athletes undertook isokinetic dynamometry testing and surface electromyography assessment of the biceps femoris long head and medial hamstrings during eccentric contractions at -60 and -1800.s-1. Results: In the injured limb of the injured group, compared to the contralateral uninjured limb rate of torque development and impulse was lower during -600.s-1 eccentric contractions at 50 (RTD, p=0.008; IMP, p=0.005) and 100ms (RTD, p=0.001; IMP p<0.001) after the onset of contraction. There was also a non-significant trend for rate of torque development during -1800.s-1 to be lower 100ms after onset of contraction (p=0.064). Biceps femoris long head muscle activation was lower at 100ms at both contraction speeds (-600.s-1, p=0.009; -1800.s-1, p=0.009). Medial hamstring activation did not differ between limbs in the injured group. Comparisons in the uninjured group showed no significant between limbs difference for any variables. Conclusion: Previously injured hamstrings displayed lower rate of torque development and impulse during eccentric contraction. Lower muscle activation was confined to the biceps femoris long head. Regardless of whether these deficits are the cause of or the result of injury, these findings have important implications for hamstring strain injury and re-injury and suggest greater attention be given to neural function of the knee flexors.

Drugs and the somatic nervous system

Drugs and the somatic nervous system 8.1 The somatic nervous system 8.2 Anticholinesterases 8.3 Neuromuscular blockers 8.4 Botox

The cell surface glycoprotein CUB domain-containing protein 1 (CDCP1) contributes to epidermal growth factor receptor-mediated cell migration

Epidermal growth factor (EGF) activation of the EGF receptor (EGFR) is an important mediator of cell migration, and aberrant signaling via this system promotes a number of malignancies including ovarian cancer. We have identified the cell surface glycoprotein CDCP1 as a key regulator of EGF/EGFR-induced cell migration. We show that signaling via EGF/EGFR induces migration of ovarian cancer Caov3 and OVCA420 cells with concomitant up-regulation of CDCP1 mRNA and protein. Consistent with a role in cell migration CDCP1 relocates from cell-cell junctions to punctate structures on filopodia after activation of EGFR. Significantly, disruption of CDCP1 either by silencing or the use of a function blocking antibody efficiently reduces EGF/EGFR-induced cell migration of Caov3 and OVCA420 cells. We also show that up-regulation of CDCP1 is inhibited by pharmacological agents blocking ERK but not Src signaling, indicating that the RAS/RAF/MEK/ERK pathway is required downstream of EGF/EGFR to induce increased expression of CDCP1. Our immunohistochemical analysis of benign, primary, and metastatic serous epithelial ovarian tumors demonstrates that CDCP1 is expressed during progression of this cancer. These data highlight a novel role for CDCP1 in EGF/EGFR-induced cell migration and indicate that targeting of CDCP1 may be a rational approach to inhibit progression of cancers driven by EGFR signaling including those resistant to anti-EGFR drugs because of activating mutations in the RAS/RAF/MEK/ERK pathway.