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.

Early inflammatory and myogenic responses to resistance exercise in the elderly

Introduction and Methods: This study compared changes in myokine and myogenic genes following resistance exercise (3 sets of 12 repetitions of maximal unilateral knee extension) in 20 elderly men (67.8 ± 1.0 years) and 15 elderly women (67.2 ± 1.5 years). Results: Monocyte chemotactic protein (MCP)-1, macrophage inhibitory protein (MIP)-1β, interleukin (IL)-6 and MyoD mRNA increased significantly (P < 0.05), whereas myogenin and myostatin mRNA decreased significantly after exercise in both groups. Macrophage-1 (Mac-1) and MCP-3 mRNA did not change significantly after exercise in either group. MIP-1β, Mac-1 and myostatin mRNA were significantly higher before and after exercise in men compared with women. In contrast, MCP-3 and myogenin mRNA were significantly higher before and after exercise in the women compared with the men. Conclusions: In elderly individuals, gender influences the mRNA expression of certain myokines and growth factors, both at rest and after resistance exercise. These differences may influence muscle regeneration following muscle injury

Utility of corneal confocal microscopy for assessing mild diabetic neuropathy: baseline findings of the LANDMark study

Background:  For those in the field of managing diabetic complications, the accurate diagnosis and monitoring of diabetic peripheral neuropathy (DPN) continues to be a challenge. Assessment of sub-basal corneal nerve morphology has recently shown promise as a novel ophthalmic marker for the detection of DPN. Methods:  Two hundred and thirty-one individuals with diabetes with predominantly mild or no neuropathy and 61 controls underwent evaluation of diabetic neuropathy symptom score, neuropathy disability score, testing with 10 g monofilament, quantitative sensory testing (warm, cold, vibration detection) and nerve conduction studies. Corneal nerve fibre length, branch density and tortuosity were measured using corneal confocal microscopy. Differences in corneal nerve morphology between individuals with and without DPN and controls were investigated using analysis of variance and correlations were determined between corneal morphology and established tests of, and risk factors for, DPN. Results:  Corneal nerve fibre length was significantly reduced in diabetic individuals with mild DPN compared with both controls (p < 0.001) and diabetic individuals without DPN (p = 0.012). Corneal nerve branch density was significantly reduced in individuals with mild DPN compared with controls (p = 0.032). Corneal nerve fibre tortuosity did not show significant differences. Corneal nerve fibre length and corneal nerve branch density showed modest correlations to most measures of neuropathy, with the strongest correlations to nerve conduction study parameters (r = 0.15 to 0.25). Corneal nerve fibre tortuosity showed only a weak correlation to the vibration detection threshold. Corneal nerve fibre length was inversely correlated to glycated haemoglobin (r = -0.24) and duration of diabetes (r = -0.20). Conclusion:  Assessment of corneal nerve morphology is a non-invasive, rapid test capable of showing differences between individuals with and without DPN. Corneal nerve fibre length shows the strongest associations with other diagnostic tests of neuropathy and with established risk factors for neuropathy.

Corneal sensitivity is related to established measures of diabetic peripheral neuropathy

Purpose:  The objective was to investigate the association between corneal sensitivity and established measures of diabetic peripheral neuropathy (DPN). Methods:  Corneal sensitivity was measured in 93 individuals with diabetes, 146 diabetic individuals without neuropathy and 61 control individuals without diabetes or neuropathy using a non-contact corneal aesthesiometer at the baseline visit of a five-year longitudinal natural history study of DPN. The correlation between corneal sensitivity and established measures of neuropathy was estimated and multi-dimensional scaling was used to represent similarities and dissimilarities between variables. Results:  The corneal sensitivity threshold was significantly correlated with a majority of established measures of DPN. Correlation coefficients ranged from -0.32 to 0.26. Using multi-dimensional scaling, non-contact corneal aesthesiometry was closer to the neuropathy disability score, diabetic neuropathy symptom score and Neuropad and most dissimilar to electrophysiological parameters and quantitative sensory testing. Conclusion:  Corneal sensitivity, although not strongly related, is associated with other functional measures of DPN and might provide a useful adjunct in identifying functional loss of small nerve fibre integrity.

The post-illumination pupil response of melanopsin expressing intrinsically photosensitive retinal ganglion cells in diabetes

Purpose: This study investigates the clinical utility of the melanopsin expressing intrinsically photosensitive retinal ganglion cell (ipRGC) controlled post-illumination pupil response (PIPR) as a novel technique for documenting inner retinal function in patients with Type II diabetes without diabetic retinopathy. Methods: The post-illumination pupil response (PIPR) was measured in seven patients with Type II diabetes, normal retinal nerve fiber thickness and no diabetic retinopathy. A 488 nm and 610 nm, 7.15º diameter stimulus was presented in Maxwellian view to the right eye and the left consensual pupil light reflex was recorded. Results: The group data for the blue PIPR (488 nm) identified a trend of reduced ipRGC function in patients with diabetes with no retinopathy. The transient pupil constriction was lower on average in the diabetic group. The relationship between duration of diabetes and the blue PIPR amplitude was linear, suggesting that ipRGC function decreases with increasing diabetes duration. Conclusion: This is the first report to show that the ipRGC controlled post-illumination pupil response may have clinical applications as a non-invasive technique for determining progression of inner neuroretinal changes in patients with diabetes before they are ophthalmoscopically or anatomically evident. The lower transient pupil constriction amplitude indicates that outer retinal photoreceptor inputs to the pupil light reflex may also be affected in diabetes.

More men than women make mucosal IgA antibodies to human papillomavirus type 16 (HPV-16) and HPV-18: A study of oral HPV and oral HPV antibodies in a normal healthy population

Background: We have previously shown the high prevalence of oral anti-human papillomavirus type 16 (HPV-16) antibodies in women with HPV-associated cervical neoplasia. It was postulated that the HPV antibodies were initiated after HPV antigenic stimulation at the cervix via the common mucosal immune system. The present study aimed to further evaluate the effectiveness of oral fluid testing for detecting the mucosal humoral response to HPV infection and to advance our limited understanding of the immune response to HPV. Methods: The prevalence of oral HPV infection and oral antibodies to HPV types 16, 18 and 11 was determined in a normal, healthy population of children, adolescents and adults, both male and female, attending a dental clinic. HPV types in buccal cells were determined by DNA sequencing. Oral fluid was collected from the gingival crevice of the mouth by the OraSure method. HPV-16, HPV-18 and HPV-11 antibodies in oral fluid were detected by virus-like particle-based enzyme-linked immunosorbent assay. As a reference group 44 women with cervical neoplasia were included in the study. Results: Oral HPV infection was h ighest in children (9/114, 7.9%), followed by adolescents (4/78, 5.1%), and lowest in normal adults (4/116, 3.5%). The predominant HPV type found was HPV-13 (7/22, 31.8%) followed by HPV-32 (5/22, 22.7%). The prevalence of oral antibodies to HPV-16, HPV-18 and HPV-11 was low in children and increased substantially in adolescents and normal adults. Oral HPV-16 IgA was significantly more prevalent in women with cervical neoplasia (30/44, 68.2%) than the women from the dental clinic (18/69, 26.1% P = 0.0001). Significantly more adult men than women displayed oral HPV-16 IgA (30/47 compared with 18/69, OR 5.0, 95% CI 2.09-12.1, P < 0.001) and HPV-18 IgA (17/47 compared with 13/69, OR 2.4, 95% CI 0.97-6.2, P = 0.04). Conclusion: The increased prevalence of oral HPV antibodies in adolescent individuals compared with children was attributed to the onset of sexual activity. The increased prevalence of oral anti-HPV IgA in men compared with women was noteworthy considering reportedly fewer men than women make serum antibodies, and warrants further investigation. © 2006 Marais et al; licensee BioMed Central Ltd.

Neural differentiation of mouse embryonic stem cells on conductive nanofiber scaffolds

Nerve tissue engineering requires suitable precursor cells as well as the necessary biochemical and physical cues to guide neurite extension and tissue development. An ideal scaffold for neural regeneration would be both fibrous and electrically conductive. We have contrasted the growth and neural differentiation of mouse embryonic stem cells on three different aligned nanofiber scaffolds composed of poly L: -lactic acid supplemented with either single- or multi-walled carbon-nanotubes. The addition of the nanotubes conferred conductivity to the nanofibers and promoted mESC neural differentiation as evidenced by an increased mature neuronal markers expression. We propose that the conductive scaffold could be a useful tool for the generation of neural tissue mimics in vitro and potentially as a scaffold for the repair of neural defects in vivo.

Vestibular rehabilitation following the removal of an acoustic neuroma : a systematic review of randomized trials

An acoustic neuroma (also known as a vestibular schwannoma) is an intracranial tumour of the vestibular nerve that is commonly treated by surgical resection. Following resection of an acoustic neuroma, patients may experience a range of symptoms that include deficits in gaze stability, mobility and balance. Vestibular rehabilitation may be useful in reducing the severity and minimizing the impact of these symptoms.

Who's afraid of China? The challenge of Chinese soft power [Review]

What role does China play in Western imagination and how does it affect Western selfconceptions? The rise of China as an alternative model to Western liberalism has created a fear that developing countries will stray from Western standards of democracy, transparency and human rights. However, such fears often say as much about those who hold them as they do about China itself. In this short and easily readable book Barr holds a mirror to Sino–Western relations in order to better understand how the West’s own past, hopes and fears shape the way it thinks about and engages with China. Focusing on three key areas—models of development, soft power and ethnocentrism—he argues that the rise of China ‘hits a nerve in the Western psyche . . . because its actions reflect the West’s own ambivalence to modernity and uncertainty over the proper role and limits of state power’ (p. 21). To make his point, Barr focuses on China’s soft power and the connections between China’s domestic politics and its attempts to shape its image internationally...

Steps toward the validation of the Trendelenburg Test : the effect of experimentally reduced hip abductor muscle function on frontal plane mechanics

Objective: To investigate the validity of the Trendelenburg test (TT) using an ultrasound-guided nerve block (UNB) of the superior gluteal nerve and determine whether the reduction in hip abductor muscle (HABD) strength would result in the theorized mechanical compensatory strategies measured during the TT. Design: Quasi-experimental. Setting: Hospital. Participants: Convenience sample of 9 healthy men. Only participants with no current or previous injury to the lumbar spine, pelvis, or lower extremities, and no previous surgeries were included. Interventions: Ultrasound-guided nerve block. Main Outcome Measures: Hip abductor muscle strength (percent body weight [%BW]), contralateral pelvic drop (cPD), change in contralateral pelvic drop (Delta cPD), ipsilateral hip adduction, and ipsilateral trunk sway (TRUNK) measured in degrees. Results: The median age and weight of the participants were 31 years (interquartile range [IQR], 22-32 years) and 73 kg (IQR, 67-81 kg), respectively. An average 52% reduction of HABD strength (z = 2.36, P = 0.02) resulted after the UNB. No differences were found in cPD or Delta cPD (z = 0.01, P = 0.99, z = 20.67, P = 0.49, respectively). Individual changes in biomechanics showed no consistency between participants and nonsystematic changes across the group. One participant demonstrated the mechanical compensations described by Trendelenburg. Conclusions: The TT should not be used as a screening measure for HABD strength in populations demonstrating strength greater than 30% BW but should be reserved for use with populations with marked HABD weakness. Clinical Relevance: This study presents data regarding a critical level of HABD strength required to support the pelvis during the TT.

Steps towards the validation of the Trendelenburg test : The effect of experimentally reduced hip abductor muscle function on frontal plane mechanics

Introduction: The Trendelenburg Test (TT) is used to assess the functional strength of the hip abductor muscles (HABD), their ability to control frontal plane motion of the pelvis, and the ability of the lumbopelvic complex to transfer load into single leg stance. Rationale: Although a standard method to perform the test has been described for use within clinical populations, no study has directly investigated Trendelenburg’s hypotheses. Purpose: To investigate the validity of the TT using an ultrasound guided nerve block (UNB) of the superior gluteal nerve and determine whether the reduction in HABD strength would result in the theorized mechanical compensatory strategies measured during the TT. Methods: Quasi-experimental design using a convenience sample of nine healthy males. Only subjects with no current or previous injury to the lumbar spine, pelvis, or lower extremities, and no previous surgeries were included. Force dynamometry was used to evaluation HABD strength (%BW). 2D mechanics were used to evaluate contralateral pelvic drop (cMPD), change in contralateral pelvic drop (∆cMPD), ipsilateral hip adduction (iHADD) and ipsilateral trunk sway (TRUNK) measured in degrees (°). All measures were collected prior to and following a UNB on the superior gluteal nerve performed by an interventional radiologist. Results: Subjects’ age was median 31yrs (IQR:22-32yrs); and weight was median 73kg (IQR:67-81kg). An average 52% reduction of HABD strength (z=2.36,p=0.02) resulted following the UNB. No differences were found in cMPD or ∆cMPD (z=0.01,p= 0.99, z=-0.67,p=0.49). Individual changes in biomechanics show no consistency between subjects and non-systematic changes across the group. One subject demonstrated the mechanical compensations described by Trendelenburg. Discussion: The TT should not be used as screening measure for HABD strength in populations demonstrating strength greater than 30%BW but reserved for use with populations with marked HABD weakness. Importance: This study presents data regarding a critical level of HABD strength required to support the pelvis during the TT.

Investigation of lymphotoxin α genetic variants in migraine

Migraine is a common neurological disease with a genetic basis affecting approximately 12% of the population. Pain during a migraine attack is associated with activation of the trigeminal nerve system, which carries pain signals from the meninges and the blood vessels infusing the meninges to the trigeminal nucleus in the brain stem. The release of inflammatory mediators following cortical spreading depression (CSD) may further promote and sustain the activation and sensitization of meningeal nociceptors, inducing the persistent throbbing headache characterised in migraine. Lymphotoxin α (LTA) is a cytokine secreted by lymphocytes and is a member of the tumour necrosis factor (TNF) family. Genetic variation with the TNF and LTA genes may contribute to threshold brain excitability, propagation of neuronal hyperexcitability and thus initiation and maintenance of a migraine attack. Three LTA variants rs2009658, rs2844482 and rs2229094 were identified in a recent pGWAS study conducted in the Norfolk Island population as being potentially implicated in migraine with nominally significant p values of p = 0.0093, p = 0.0088 and p = 0.033 respectively. To determine whether these SNPs played a role in migraine in a general outbred population these SNPs were gentoyped in a large case control Australian Caucasian population and tested for association with migraine. All three SNPs showed no association in our cohort (p > 0.05). Validation of GWAS data in independent case-controls cohorts is essential to establish risk validity within specific population groups. The importance of cytokines in modulating neural inflammation and pain threshold in addition to other studies showing associations between TNF-α and SNPs in the LTA gene with migraine, suggests that LTA could be an important factor contributing to migraine. Although the present study did not support a role for the tested LTA variants in migraine, investigation of other variants within the LTA gene is still warranted.

A new method to detect loss of heterozygosity using cohort heterozygosity comparisons

Background Loss of heterozygosity (LOH) is an important marker for one of the 'two-hits' required for tumor suppressor gene inactivation. Traditional methods for mapping LOH regions require the comparison of both tumor and patient-matched normal DNA samples. However, for many archival samples, patient-matched normal DNA is not available leading to the under-utilization of this important resource in LOH studies. Here we describe a new method for LOH analysis that relies on the genome-wide comparison of heterozygosity of single nucleotide polymorphisms (SNPs) between cohorts of cases and un-matched healthy control samples. Regions of LOH are defined by consistent decreases in heterozygosity across a genetic region in the case cohort compared to the control cohort. Methods DNA was collected from 20 Follicular Lymphoma (FL) tumor samples, 20 Diffuse Large B-cell Lymphoma (DLBCL) tumor samples, neoplastic B-cells of 10 B-cell Chronic Lymphocytic Leukemia (B-CLL) patients and Buccal cell samples matched to 4 of these B-CLL patients. The cohort heterozygosity comparison method was developed and validated using LOH derived in a small cohort of B-CLL by traditional comparisons of tumor and normal DNA samples, and compared to the only alternative method for LOH analysis without patient matched controls. LOH candidate regions were then generated for enlarged cohorts of B-CLL, FL and DLBCL samples using our cohort heterozygosity comparison method in order to evaluate potential LOH candidate regions in these non-Hodgkin's lymphoma tumor subtypes. Results Using a small cohort of B-CLL samples with patient-matched normal DNA we have validated the utility of this method and shown that it displays more accuracy and sensitivity in detecting LOH candidate regions compared to the only alternative method, the Hidden Markov Model (HMM) method. Subsequently, using B-CLL, FL and DLBCL tumor samples we have utilised cohort heterozygosity comparisons to localise LOH candidate regions in these subtypes of non-Hodgkin's lymphoma. Detected LOH regions included both previously described regions of LOH as well as novel genomic candidate regions. Conclusions We have proven the efficacy of the use of cohort heterozygosity comparisons for genome-wide mapping of LOH and shown it to be in many ways superior to the HMM method. Additionally, the use of this method to analyse SNP microarray data from 3 common forms of non-Hodgkin's lymphoma yielded interesting tumor suppressor gene candidates, including the ETV3 gene that was highlighted in both B-CLL and FL.

No association between MTHFR A1298C and MTRR A66G polymorphisms, and MS in an Australian cohort

Multiple sclerosis (MS) is a complex neurological disease that affects the central nervous system (CNS) resulting in debilitating neuropathology. Pathogenesis is primarily defined by CNS inflammation and demyelination of nerve axons. Methionine synthase reductase (MTRR) is an enzyme that catalyzes the remethylation of homocysteine (Hcy) to methionine via cobalamin and folate dependant reactions. Cobalamin acts as an intermediate methyl carrier between methylenetetrahydrofolate reductase (MTHFR) and Hcy. MTRR plays a critical role in maintaining cobalamin in an active form and is consequently an important determinant of total plasma Hcy (pHcy) concentrations. Elevated intracellular pHcy levels have been suggested to play a role in CNS dysfunction, neurodegenerative, and cerebrovascular diseases. Our investigation entailed the genotyping of a cohort of 140 cases and matched controls for MTRR and MTHFR, by restriction length polymorphism (RFLP) techniques. Two polymorphisms: MTRR A66G and MTHFR A1298C were investigated in an Australian age and gender matched case-control study. No significant allelic frequency difference was observed between cases and controls at the α = 0.05 level (MTRR χ2 = 0.005, P = 0.95, MTHFR χ2 = 1.15, P = 0.28). Our preliminary findings suggest no association between the MTRR A66G and MTHFR A1298C polymorphisms and MS

Quantitative and qualitative changes in gene expression patterns characterize the activity of plaques in multiple sclerosis

Multiple sclerosis (MS) is a complex autoimmune disorder of the CNS with both genetic and environmental contributing factors. Clinical symptoms are broadly characterized by initial onset, and progressive debilitating neurological impairment. In this study, RNA from MS chronic active and MS acute lesions was extracted, and compared with patient matched normal white matter by fluorescent cDNA microarray hybridization analysis. This resulted in the identification of 139 genes that were differentially regulated in MS plaque tissue compared to normal tissue. Of these, 69 genes showed a common pattern of expression in the chronic active and acute plaque tissues investigated (Pvalue<0.0001, ρ=0.73, by Spearman's ρ analysis); while 70 transcripts were uniquely differentially expressed (≥1.5-fold) in either acute or chronic active tissues. These results included known markers of MS such as the myelin basic protein (MBP) and glutathione S-transferase (GST) M1, nerve growth factors, such as nerve injury-induced protein 1 (NINJ1), X-ray and excision DNA repair factors (XRCC9 and ERCC5) and X-linked genes such as the ribosomal protein, RPS4X. Primers were then designed for seven array-selected genes, including transferrin (TF), superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPX1), GSTP1, crystallin, alpha-B (CRYAB), phosphomannomutase 1 (PMM1) and tubulin β-5 (TBB5), and real time quantitative (Q)-PCR analysis was performed. The results of comparative Q-PCR analysis correlated significantly with those obtained by array analysis (r=0.75, Pvalue<0.01, by Pearson's bivariate correlation). Both chronic active and acute plaques shared the majority of factors identified suggesting that quantitative, rather than gross qualitative differences in gene expression pattern may define the progression from acute to chronic active plaques in MS.