ALS-CSF-induced structural changes in spinal motor neurons of rat pups cause deficits in motor behaviour.

Amyotrophic lateral sclerosis (ALS) is a late-onset, neurodegenerative disease associated with the loss of motor neurons in the spinal cord, brain stem and primary motor cortex. Deficit in the motor function is one of the clinical features of this disease. However, the association between adverse morphological alterations in the spinal motor neurons and motor deficit in sporadic ALS (SALS) is still debated. The present study has sought to investigate the effects of serial intrathecal injections of ALS-CSF into rat pups, at post-natal (P) days 3, 9 and 14, on the motor neuronal (MN) morphology at the cervical and lumbar levels of the spinal cord at P16 and P22. The present study used Cresyl violet and Golgi-Cox staining methods to determine the progressive changes in the morphology of spinal MNs in both cervical and lumbar extensions. The study found a loss of motor neurons in the spinal cord (36% for P16 in cervical and 41.7% in P16 lumbar and 49.57% for P22 cervical and 44.63% for P22 lumbar) and reduced choline acetyl transferase (ChAT) expression after repeated infusion of ALS-CSF. Significant increase in the soma area was also found in ALS-CSF rats (around 21% in P22 cervical and 26.4% in P22 lumbar). Soma hypertrophy was associated with increased dendritic arborization of MNs at both cervical and lumbar levels of the spinal cord. The data also showed a direct correlation between ALS-CSF induced changes in the MN number in the spinal cord and motor behavioral deficits. The loss of MNs, reduced ChAT, changes in soma and dendritic morphology with declined rotarod performance, thus, confirming the pathological phenotypes as seen in ALS patients.

Etiogenic factors present in the cerebrospinal fluid from amyotrophic lateral sclerosis patients induce predominantly pro-inflammatory responses in microglia.

BACKGROUND: Microglial cell-associated neuroinflammation is considered as a potential contributor to the pathophysiology of sporadic amyotrophic lateral sclerosis. However, the specific role of microglia in the disease pathogenesis remains to be elucidated. METHODS: We studied the activation profiles of the microglial cultures exposed to the cerebrospinal fluid from these patients which recapitulates the neurodegeneration seen in sporadic amyotrophic lateral sclerosis. This was done by investigating the morphological and functional changes including the expression levels of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), TNF-α, IL-6, IFN-γ, IL-10, inducible nitric oxide synthase (iNOS), arginase, and trophic factors. We also studied the effect of chitotriosidase, the inflammatory protein found upregulated in the cerebrospinal fluid from amyotrophic lateral sclerosis patients, on these cultures. RESULTS: We report that the cerebrospinal fluid from amyotrophic lateral sclerosis patients could induce an early and potent response in the form of microglial activation, skewed primarily towards a pro-inflammatory profile. It was seen in the form of upregulation of the pro-inflammatory cytokines and factors including IL-6, TNF-α, iNOS, COX-2, and PGE2. Concomitantly, a downregulation of beneficial trophic factors and anti-inflammatory markers including VEGF, glial cell line-derived neurotrophic factor, and IFN-γ was seen. In addition, chitotriosidase-1 appeared to act specifically via the microglial cells. CONCLUSION: Our findings demonstrate that the cerebrospinal fluid from amyotrophic lateral sclerosis patients holds enough cues to induce microglial inflammatory processes as an early event, which may contribute to the neurodegeneration seen in the sporadic amyotrophic lateral sclerosis. These findings highlight the dynamic role of microglial cells in the pathogenesis of the disease, thus suggesting the need for a multidimensional and temporally guarded therapeutic approach targeting the inflammatory pathways for its treatment.

Brain-Derived Neurotrophic Factor Facilitates Functional Recovery from ALS-Cerebral Spinal Fluid-Induced Neurodegenerative Changes in the NSC-34 Motor Neuron Cell Line.

BACKGROUND: The survival of motor neurons is dependent upon neurotrophic factors both during childhood and adolescence and during adult life. In disease conditions, such as in patients with amyotrophic lateral sclerosis (ALS), the mRNA levels of trophic factors like brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), fibroblast growth factor-2 (FGF-2), and vascular endothelial growth factor are downregulated. This was replicated in our in vivo experimental system following the injection of cerebral spinal fluid (CSF) of sporadic ALS (ALS-CSF) patients. OBJECTIVE: To evaluate the protective role of BDNF in a model of sporadic ALS patients. METHODS: The expressions of endogenous BDNF, its receptor TrkB, the enzyme choline acetyl transferase (ChAT), and phosphorylated neurofilaments were studied in NSC-34 cells. The calcium-buffering and proapoptotic effects were assessed by calbindin-D28K and caspase-3 expression, respectively. RESULTS: ALS-CSF considerably depleted the endogenous BDNF protein, while its effect on IGF-1 and FGF-2 was inconsequential; this indirectly indicates a key role for BDNF in supporting motor neuronal survival. The exogenous supplementation of BDNF reversed autocrine expression; however, it may not be completely receptor mediated, as the TrkB levels were not restored. BDNF completely revived ChAT expression. It may inhibit apoptosis by restoring Ca2+ homeostasis, since caspase-3 and calbindin-D28K expression was back to normal. The organellar ultrastructural changes were only partially reversed. CONCLUSION: Our study provides evidence that BDNF supplementation ameliorates most but not all degenerative changes. The incomplete revival at the ultrastructural level signifies the requirement of factors other than BDNF for near-total protection of motor neurons, and, to an extent, it explains why only a partial success is achieved in clinical trials with BDNF in ALS patients.

Family with Ehlers-Danlos syndrome (combined classic and vascular type) with rare presentation of progressive myopathy and unusual association of severe facial and trigeminal motor weakness.

We report the clinical, radiological, biochemical, muscle histology, and electron microscopic features of two members of a family with combined Ehlers-Danlos syndrome (EDS) [classic and vascular type] and progressive myopathy as the primary manifestation. A 35-year old lady presented with severe gluteal and thigh muscle pain and easy fatigability for 5 years. She developed weakness and wasting of pelvic and pectoral girdles and thighs for 3 years and severe neck flexor and truncal weakness for 6 months. She had a history of recurrent jaw dislocation, easy bruising with hyperpigmentation, hyperextensibility of joints, translucent skin, and papyraceous scars. She had high myopia with astigmatism. She had wasting of temporalis, masseters, sternocleidomastoids and trapezius. There was moderate weakness of temporalis, masseters, and facial muscles. Muscle power was Medical Research Council (MRC) grade 4 at shoulders and arms, and grade 3+ at pelvis and thighs. Serum homocysteine level was normal, and creatine kinase (CK) was 275 IU. Two dimensional echocardiogram (2D Echo) showed myxomatous degeneration of mitral valves. Electromyography (EMG) was suggestive of a myopathic pattern. Muscle magnetic resonance imaging (MR) revealed severe fatty infiltration of paraspinal muscles, gluteus maximus and medius, quadriceps, hamstrings, and gastrocnemius. Electron microscopy showed an occasional distorted fibril with mild increase in oxytalan fibers and variation in thickness of blood vessel basement membrane. Her 15-year old daughter had exertion-induced myalgias, right hemifacial hypoplasia, myopia, hyperextensible joints, hyperelastic skin, and neck muscle weakness. However, her CK and 2D Echo were normal. This report presents the rare combination of classic and vascular type of EDS primarily presenting as muscle weakness and associated with facial and trigeminal motor weakness.

Astroglia acquires a toxic neuroinflammatory role in response to the cerebrospinal fluid from amyotrophic lateral sclerosis patients.

BACKGROUND: Non-cell autonomous toxicity is one of the potential mechanisms implicated in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). However, the exact role of glial cells in ALS pathology is yet to be fully understood. In a cellular model recapitulating the pathology of sporadic ALS, we have studied the inflammatory response of astroglia following exposure to the cerebrospinal fluid from ALS patients (ALS-CSF). METHODS: Various inflammatory markers including pro-inflammatory and anti-inflammatory cytokines, COX-2, PGE-2, trophic factors, glutamate, nitric oxide (NO), and reactive oxygen species (ROS) were analyzed in the rat astroglial cultures exposed to ALS-CSF and compared with the disease control or normal controls. We used immunofluorescence, ELISA, and immunoblotting techniques to investigate the protein expression and real-time PCR to study the messenger RNA (mRNA) expression. Glutamate, NO, and ROS were estimated using appropriate biochemical assays. Further, the effect of conditioned medium from the astroglial cultures exposed to ALS-CSF on NSC-34 motor neuronal cell line was detected using the MTT assay. Statistical analysis was carried out using one-way ANOVA followed by Tukey's post hoc test, or Student's t test, as applicable. RESULTS: Here, we report that the ALS-CSF enhanced the production and release of inflammatory cytokines IL-6 and TNF-α, as well as COX-2 and PGE-2. Concomitantly, anti-inflammatory cytokine IL-10 and the beneficial trophic factors, namely VEGF and GDNF, were down-regulated. We also found impaired regulation of glutamate, NO, and ROS in the astroglial cultures treated with ALS-CSF. The conditioned medium from the ALS-CSF exposed astroglial cultures induced degeneration in NSC-34 cells. CONCLUSIONS: Our study demonstrates that the astroglial cells contribute to the neuroinflammation-mediated neurodegeneration in the in vitro model of sporadic ALS.

Clinical and imaging characteristics of 16 patients with autoimmune neuronal synaptic encephalitis.

OBJECTIVES: Autoimmune neuronal synaptic encephalitis (AIE) encompasses a heterogeneous group of disorders characterized by immune-mediated neuronal cell destruction. In this study, we aim to study the clinical features, imaging profile and treatment outcome of patients with AIE. METHODS: This is a chart review of 16 (M: F-3:13) patients with AIE from 2011 to 2015. RESULTS: Among the patients, 10 had anti-NMDA, 4 had anti-TPO, and 2 had anti-VGKC antibody positivity. Cognitive impairment and seizures were the predominant symptoms present in nearly all patients, followed by psychiatric disturbances (87.5%), mutism (62.5%), movement disorders (62.5%), myoclonic jerks (37.5%) and visual hallucinations (18.75%). Magnetic resonance imaging (MRI) of the brain was available in 15 patients; it was abnormal in 53.3% patients. Abnormalities were seen in all patients with anti-VGKC positivity; and, 60% of patients with anti-NMDA positivity. Imaging was normal in 26.7% of the patients (3: anti-NMDA; and, 1: anti-TPO positivity); and, diffuse cerebral atrophy was noted in rest of the 20% (3: anti-TPO positivity) patients. All patients improved gradually with immunomodulation. CONCLUSIONS: All patients with anti-VGKC, anti-NMDA and anti-TPO antibody positivity presented with a triad of behavioral changes, impaired cognition and seizures. Mutism was a predominant symptom in patients with an anti-NMDA antibody positivity, which may help in the early identification of this disorder. MRI brain showed changes restricted to limbic structures in anti-NMDA and anti-VGKC antibody positivity. An early diagnosis and treatment of autoimmune encephalitis is essential for a better outcome and for prevention of long-term sequel.

A comparative study of mPCR, MLPA, and muscle biopsy results in a cohort of children with Duchenne muscular dystrophy: a first study.

BACKGROUND: Multiplex ligation-dependant probe amplification (MLPA) is a highly sensitive and rapid alternative to multiplex polymerase chain reaction (PCR). Muscle biopsy should be reserved for mutation-negative cases. MATERIALS AND METHODS: An attempt was made to compare the sensitivity and pattern of mutations by mPCR and MLPA testing in a cohort with suspected Duchenne muscular dystrophy (DMD). Eighty-three children with DMD were enrolled for mPCR and MLPA testing. MLPA-negative cases underwent muscle immunohistochemistry (IHC) for dystrophin. RESULTS: Mean age of onset was 45.3 ± 25.2 months; and mean duration of illness was - 53.3 ± 30.8 months. About 11.9% patients had delayed mental milestones. Mean creatine kinase (CK) value was 12136.1 ± 8591.1 LU/L. mPCR detected deletions in 60/83 (72.3%). Proximal deletions were found in 8 (8.6%), distal deletions in 51 (54.8%), and, both proximal and distal deletions were found in 1. Majority of the deletions were <5 exons [34(36.6%)]; two showed large deletions of >10 exons (2.2%). Deletions in hot spot region occurred in 83.3%. MLPA in the same 83 samples detected deletions in an additional six cases and duplications in 6 (6.5%). Combined detection rate of deletion was 79.5%. Duplications were found in 7.2% of the whole sample. MLPA showed 14 (15.1%) proximal and 57 (61.3%) distal deletions, and proximal and distal deletion in 1. Large deletions (>10 exons) were seen in 6.5%, and single deletions were observed in 24 (36.4%). Most common multiple exon deletion was seen at 45-52 region in 7 samples (10.6%). Longest duplication extended from exon 60 to 66. In the 11 MLPA-negative cases, IHC confirmed dystrophinopathy in 36.36%, sarcoglycanopathy in 36.36%, and no deficiency in 27.27%. CONCLUSIONS: This is the first study from India and possibly in English literature, comparing the sensitivity and pattern of mutations by both mPCR and MLPA in the same cohort of DMD. It further validates that 36.4% of MLPA-negative cases were confirmed to have DMD by IHC. The clinical accuracy has been very high in our cohort. MLPA-negative samples should be subjected for next-generation sequencing before contemplating a biopsy.

Reach task-associated excitatory overdrive of motor cortical neurons following infusion with ALS-CSF.

Converging evidence from transgenic animal models of amyotrophic lateral sclerosis (ALS) and human studies suggest alterations in excitability of the motor neurons in ALS. Specifically, in studies on human subjects with ALS the motor cortex was reported to be hyperexcitable. The present study was designed to test the hypothesis that infusion of cerebrospinal fluid from patients with sporadic ALS (ALS-CSF) into the rat brain ventricle can induce hyperexcitability and structural changes in the motor cortex leading to motor dysfunction. A robust model of sporadic ALS was developed experimentally by infusing ALS-CSF into the rat ventricle. The effects of ALS-CSF at the single neuron level were examined by recording extracellular single unit activity from the motor cortex while rats were performing a reach to grasp task. We observed an increase in the firing rate of the neurons of the motor cortex in rats infused with ALS-CSF compared to control groups. This was associated with impairment in a specific component of reach with alterations in the morphological characteristics of the motor cortex. It is likely that the increased cortical excitability observed in the present study could be the result of changes in the intrinsic properties of motor cortical neurons, a dysfunctional inhibitory mechanism and/or an underlying structural change culminating in a behavioral deficit.

Solitary cerebral parenchymal cysticercosis: a prospective comparative study with computed tomography and magnetic resonance imaging.

AIM: To present a prospective series of 86 patients with solitary cerebral cysticerci who underwent both contrast computed tomography (CT) and contrast magnetic resonance imaging (MRI), and to correlate and compare the imaging findings using these two modalities. MATERIALS AND METHODS: Lesion characteristics, staging of the cyst and perilesional hypodensity on CT and hyperintensity on MRI were analyzed, and the lesion was described with regard to the appearance of the scolex, cyst fluid, cyst wall and the perilesional area. RESULTS: Patients were largely children and adolescents (mean age 17.4 years, range 6-52) with 52.3% males. MRI was performed, on average, 10.7 days after CT. MRI was more sensitive than plain CT scan in detecting cysticercal lesions (P = 0.003), but there was no statistically significant difference between contrast CT and MRI. None of the patients were detected with an alternative disease on serial MRI. No cyst showed significant mass effect. Non-contrast CT was less sensitive than either contrast CT or MRI in detecting the scolex (P = 0.011), but no difference was seen between the latter two modalities. Qualitative imaging characteristics of the cysticercus on MRI and CT scan are described. All cysts were round in shape, with an average diameter of <10 mm, and maximum diameter of 19 mm. CONCLUSION: In the present prospective series, contrast CT was nearly as sensitive as MRI in detecting solitary cerebral cysticerci. Thus, in highly resource-limited settings contrast CT may be sufficient for the diagnosis and management of neurocysticercosis.

Oxidative damage in muscular dystrophy correlates with the severity of the pathology: role of glutathione metabolism.

Muscular dystrophies (MDs) such as Duchenne muscular dystrophy (DMD), sarcoglycanopathy (Sgpy) and dysferlinopathy (Dysfy) are recessive genetic neuromuscular diseases that display muscle degeneration. Although these MDs have comparable endpoints of muscle pathology, the onset, severity and the course of these diseases are diverse. Different mechanisms downstream of genetic mutations might underlie the disparity in these pathologies. We surmised that oxidative damage and altered antioxidant function might contribute to these differences. The oxidant and antioxidant markers in the muscle biopsies from patients with DMD (n = 15), Sgpy (n = 15) and Dysfy (n = 15) were compared to controls (n = 10). Protein oxidation and lipid peroxidation was evident in all MDs and correlated with the severity of pathology, with DMD, the most severe dystrophic condition showing maximum damage, followed by Sgpy and Dysfy. Oxidative damage in DMD and Sgpy was attributed to the depletion of glutathione (GSH) and lowered antioxidant activities while loss of GSH peroxidase and GSH-S-transferase activities was observed in Dysfy. Lower GSH level in DMD was due to lowered activity of gamma-glutamyl cysteine ligase, the rate limiting enzyme in GSH synthesis. Similar analysis in cardiotoxin (CTX) mouse model of MD showed that the dystrophic muscle pathology correlated with GSH depletion and lipid peroxidation. Depletion of GSH prior to CTX exposure in C2C12 myoblasts exacerbated oxidative damage and myotoxicity. We deduce that the pro and anti-oxidant mechanisms could be correlated to the severity of MD and might influence the dystrophic pathology to a different extent in various MDs. On a therapeutic note, this could help in evolving novel therapies that offer myoprotection in MD.

Analysis of calpain-3 protein in muscle biopsies of different muscular dystrophies from India.

BACKGROUND & OBJECTIVES: Calpain-3, a Ca [2]+ -dependent protease has been implicated in the pathology of neuromuscular disorders (NMDs). The current study aimed to analyze calpain-3 expression in cases diagnosed as muscular dystrophy from the Indian population. METHODS: Calpain-3 Western blot analysis in muscle biopsies of immunohistochemically confirmed cases of Duchenne muscular dystrophy (DMD) (n=10), dysferlinopathy (n=30) and sarcoglycanopathy (n=8) was carried out. Calpain-3 Western blotting was also used in a blinded study to identify cases of calpain-3 deficiency in 28 NMD patients with potential muscular dystrophy. RESULTS: Calpain-3 appeared as a full length 94 kDa band with an autolytic product (~60 kDa) on Western blots with antibody NCL-CALP-12A2 (Ab-2). Eight of the 10 DMD samples showed absence of 94 kDa band but presence of 60 kDa band while one case of sarcoglycanopathy showed absence of both. Twenty one of the 30 dysferlinopathy samples showed both bands while six showed only the 60 kDa band and three showed absence of both. In the blinded study, five NMD cases with potential muscular dystrophy that showed complete absence of both bands in retrospect exhibited clinical features of limb girdle muscular dystrophy 2A (LGMD2A). INTERPRETATION & CONCLUSIONS: While the study revealed a consistent pattern of calpain-3 in DMD, one sarcoglycanopathy and three dysferlinopathy samples exhibited secondary reduction in calpain-3. It was recognized that both calpain-3 bands should be considered to confirm calpain deficiency. Further, western blot offers an economical and fast preliminary screening method for LGMD2A especially in cases of complete absence of calpain-3 prior to conclusive diagnosis by genetic testing.

Development of Guidelines for Spouses Engaged in Home-Based Care of Persons With Motor Neuron Disease From Indian Context.

Background: The caregivers of persons with motor neuron disease (MND) have several needs that are usually not voiced on any platform. Aim: To explore the lived experience of spouses of persons with MND, identify their needs and develop guidelines for better home-based care. Method: An exploratory study with 3-point in-depth interviews among 13 participants was conducted. Participants were the spouses of persons with MND under treatment at a national quaternary referral center. The interpretative phenomenological analysis identified participants' needs. These needs, with literature review synthesis, guided the drafting of guidelines, which was validated by experts. Results: The needs were emotional, social, care systems, and skills. The guidelines developed contained 2 sections (1) Information for the spouses: understanding MND, communication, symptom management, marital relationship, palliative care, and everyday life made easier. (2) Well-being of the spouse caregivers: well-being of the spouse caregivers, self-care, mental health, supporting carers in palliative care, where to find help. Conclusion: The guidelines can be developed as a manual for the caregivers and for training healthcare professionals working with neurodegenerative conditions.

COVID-19 vaccine associated demyelination & its association with MOG antibody.

BACKGROUND: ChAdOx1-S (Covishield™/Vaxzervria, AstraZeneca) and BBV152 (Covaxin) SARS-CoV-2 vaccines are proven to be safe and effective, but rare complications have been reported. OBJECTIVE: To describe reports of central nervous system (CNS) demyelination following ChAdOx1-S and BBV152 vaccinations. METHODS & RESULTS: We report 29 (17 female; mean 38 years) cases of CNS demyelination; twenty-seven occurred in temporal association with ChAdOx1-S vaccine; two in association with BBV152 vaccine. Eleven patients had presentation with myelitis, six patients developed optic neuritis, five had acute demyelinating encephalomyelitis, three presented with brainstem demyelination, and four had multiaxial involvement. Myelin oligodendrocyte glycoprotein (MOG) antibodies were positive in ten patients. One patient with ADEM and tumefactive demyelinating lesions died after a prolonged intensive care unit stay and superimposed infection. As compared to the control group (87); the postvaccinial cases were found to have a significantly higher mean age, presence of encephalopathy (p value:0.0007), CSF pleocytosis (p value: 0.0094) and raised CSF protein (p value: 0.0062). CONCLUSIONS: It is difficult to establish a causal relationship between vaccination and neurological adverse events such as demyelination. The temporal association with the vaccination and the presence of MOG antibodies raises the possibility of an immunogenic process triggered by the vaccine in susceptible individuals.

Evidence of endoplasmic reticular stress in the spinal motor neurons exposed to CSF from sporadic amyotrophic lateral sclerosis patients.

We have earlier reported that intrathecal injection of cerebrospinal fluid (CSF) from sporadic Amyotrophic Lateral Sclerosis patients (ALS-CSF) into neonatal rats and supplementation of rat spinal cord cultures with ALS-CSF induces motor neuron degeneration via aberrant neurofilament phosphorylation and Golgi apparatus fragmentation. Intracellular aggregates immunoreactive to ubiquitin, phosphorylated neurofilaments and choline acetyl transferase (ChAT) were prominently seen in NSC-34 cells exposed to ALS-CSF. Protein aggregation could cause stress on endoplasmic reticulum (ER) and may precede Golgi fragmentation. Here we assessed the effect of ALS-CSF on the expression of GRP-78 and caspase-12 proteins, the markers of ER stress responses, in NSC-34 cells and rat spinal cords by immunochemistry and immunoblotting. Both in vitro and in vivo, increased expression of these proteins accompanied elevated active caspase-12 levels. Apoptotic nuclei and nuclear translocation of caspase-12 were noted in some cells. In vitro, the occurrence of ER stress was supported by electron microscopic observations of numerous free polyribosomes and fragmented ER cisternae. Aggregated mSOD1 protein causes ER stress in familial ALS. ER stress is also reported in the autopsy samples of sporadic ALS. Thus our observation of ER stress may be linked to the protein aggregation, viz. phosphorylated neurofilaments and ChAT, reported earlier.

Down regulation of trophic factors in neonatal rat spinal cord after administration of cerebrospinal fluid from sporadic amyotrophic lateral sclerosis patients.

Accumulating evidence supports neuroprotective role of trophic factors in amyotrophic lateral sclerosis (ALS). Previous studies from our laboratory report that the CSF of patients with sporadic ALS (ALS-CSF) induces degenerative changes in the rat spinal motor neurons and reactive astrogliosis in the surrounding gray matter. The present study was aimed to investigate if the ALS-CSF affected the expression of trophic factors namely, brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2) and insulin-like growth factor 1 (IGF1) in the newborn rat spinal cords. ALS-CSF was intrathecally injected into the neonatal rats and the mRNA levels of the trophic factors were determined by quantitative real-time polymerase chain reaction. Here, we report significant down regulation in the gene expression of trophic factors for BDNF, FGF2 and IGF1. BDNF mRNA levels were found to be reduced by 6.8-fold in the ALS-CSF injected group compared to control groups. The levels of IGF1 and FGF2 mRNA were also decreased by 3.91- and 2.13-fold, respectively, in the ALS group. We further found that exogenous supplementation of BDNF considerably reduced the aberrant phosphorylation of neurofilaments, complementing our earlier findings of restored expression of voltage gated sodium channel. Reduced expression of trophic factors indicates an altered microenvironment of the motor neurons and could possibly be one of the contributing factors in the degeneration process.

Congenital myopathies: clinical and immunohistochemical study.

Congenital myopathies (CMs), a group of relatively non-progressive disorders presents with weakness and hypotonia of varying severity, morphologically recognized by specific structural abnormalities within the myofiber. This report presents the clinical and Histopathological features of 40 patients with CMs. Centronuclear myopathy was the commonest (40%) followed by congenital fiber type disproportion (37.5%). Other less common CMs included: myotubular myopathy (5%), nemaline myopathy (5%), central core disease (5%), multicore disease (2.5%) and congenital myopathy with tubular aggregate (5%). Immunolabeling to desmin corresponded to morphological changes within the myofibers while vimentin was negative in all the patients. There is no combined role of these proteins in the disease process.

Transmethylamine-N-Oxide Is Associated With Diffuse Cardiac Fibrosis in People Living With HIV.

Background People living with HIV are at increased risk of developing diastolic dysfunction, heart failure, and sudden cardiac death, all of which have been characterized by higher levels of myocardial fibrosis. Transmethylamine-N-oxide (TMAO), a dietary gut metabolite, is linked to the development of myocardial fibrosis in animal models. However, it is unclear whether TMAO plays a role in the development of myocardial fibrosis in people living with HIV. Methods and Results The study population consisted of participants enrolled in the multisite cross-sectional study called CHART-HIV (Characterizing Heart Function on Anti-Retroviral Therapy). Participants underwent echocardiography, cardiac magnetic resonance imaging, biomarker analysis, and targeted assessment of gut-related circulating metabolites; diastolic dysfunction was determined by study-specific criteria. Multivariable linear regression models were performed to examine the relationship of gut-related metabolites with serum and imaging measures of myocardial fibrosis. Models were adjusted for traditional cardiovascular, inflammatory, and HIV-related risk factors. Diastolic dysfunction was present in 94 of 195 individuals (48%) in CHART-HIV; this cohort demonstrated higher prevalence of hypertension, hyperlipidemia, and chronic kidney disease as well as higher plasma levels of both TMAO and choline. TMAO levels were associated with parameters reflecting increased left ventricular filling pressures and with a marker of the innate immune system. TMAO levels correlated with diffuse myocardial fibrosis (R=0.35; P<0.05) as characterized by myocardial extracellular volume fraction as well as biomarkers reflective of myocardial fibrosis. Conclusions In this study of people living with HIV, the gut metabolite TMAO was associated with underlying diffuse myocardial fibrosis and found to be a potential marker of early structural heart disease. The mechanistic role of the gut microbiome in HIV-associated cardiovascular disease warrants further investigation. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT02860156.