Enhanced levels of fractalkine and HSP60 in cerebrospinal fluid of sporadic amyotrophic lateral sclerosis patients.

Amyotrophic Lateral Sclerosis (ALS) is a multifactorial neurodegenerative disorder with a significant contribution of non-cell autonomous mechanisms to motor neuronal degeneration. Amongst a plethora of molecules, fractalkine (C-X3-C motif chemokine ligand 1), and Heat Shock Protein 60 (HSP60), are key modulators of microglial activation. The contribution of these molecules in Sporadic ALS (SALS) remains unexplored. To investigate this, fractalkine levels were estimated in Cerebrospinal fluid (CSF) of SALS patients (ALS-CSF; n = 44) by Enzyme-linked Immunosorbent Assay (ELISA) and correlated with clinical parameters including disease severity and duration. CSF HSP60 levels were estimated by Western blotting (ALS-CSF; n = 19). Also, CSF levels of Chitotriosidase-1 (CHIT-1), a microglia-specific neuroinflammatory molecule, were measured and its association, if any, with fractalkine and HSP60 was investigated. Both fractalkine and HSP60 levels were significantly elevated in ALS-CSF. Similar to our earlier observation, CHIT-1 levels were also upregulated. Fractalkine showed a moderate negative correlation with the ALS-Functional Rating Scale (ALSFRS) score indicating its significant rise in mild cases which plateaued in cases with high disease severity. However, no obvious correlation was found between fractalkine, HSP60, and CHIT-1. Our study hints that high fractalkine levels in mild cases might be conferring neuroprotection by combating microglial activation and highlights its importance as a novel therapeutic target for SALS. On the other hand, significantly enhanced levels of HSP60, a pro-inflammatory molecule, hint towards its role in accentuating microgliosis, although, it doesn't act synergistically with CHIT-1. Our study suggests that fractalkine and HSP60 act independently of CHIT-1 to suppress and accentuate neuroinflammation, respectively.

Association of Insulin-like Growth Factor-1 and Neurofilament Light Chain in Patients with Progressive Supranuclear Palsy.

Background: Progressive supranuclear palsy (PSP) is the most common primary tauopathy. The definite diagnosis of PSP is established by histopathologic changes in the brain. There are no reliable blood-based biomarkers to aid the diagnosis of this fatal disease at an early stage. Also, the precise etiopathology of PSP and its variants is inadequately understood. Objective: Blood-based molecules such as neurofilament light chain (NfL) and insulin-like growth factor-1 (IGF-1) are shown as important markers of neurodegenerative and aging processes, respectively. These two biomarkers have not been analyzed simultaneously in PSP patients. Methods: To address this knowledge gap, 40 PSP patients and equal number of healthy individuals were recruited and serum levels of NfL and IGF-1 were assayed in all the study participants by enzyme-linked immunosorbent assay (ELISA). Motor and nonmotor symptoms were evaluated in PSP patients using various scales/questionnaires. Cardiac autonomic function tests were performed in a subset of patients (n = 27). Results: A significantly high serum level of NfL (P < 0.01) and a reduced level of IGF-1 (P = 0.02) were observed in PSP patients compared to healthy controls. Besides, a negative correlation (r = -0.54, P < 0.01) between NfL and IGF-1 levels was observed in PSP patients. Conclusion: The finding of this study reinforces the important role of blood NfL level as a potential biomarker of PSP. Further, the current study provides novel insights into the reciprocal correlation between NfL and IGF-1 in PSP patients. Combined analysis of blood levels of these two functionally relevant markers might be useful in the prediction and diagnosis of PSP.

Qualitative and Quantitative Electrocardiogram Parameters in a Large Cohort of Children with Duchenne Muscle Dystrophy in Comparison with Age-Matched Healthy Subjects: A Study from South India.

Background: Electrocardiography (ECG) remains an excellent screening tool for cardiac assessment in Duchenne muscular dystrophy (DMD), but an accurate interpretation requires comparison with age-matched healthy controls. Objective: We examined various ECG parameters in children with DMD, in comparison with age-matched controls. Methods: Standard 12-lead ECG tracings of serial patients were screened for quality and selected. Controls were healthy, age-matched school-going children. Both quantitative and qualitative ECG parameters were analyzed. Results: After screening, ECGs from 252 patients with DMD (8.32 ± 3.12 years, 2-21 years) and ECGs from 151 age-matched healthy controls (9.72 ± 2.23, 4-19 years) were included. A significantly higher heart rate, shorter R-R interval, and taller R wave in V1 were seen across all age group of DMD in comparison to controls, with the difference increasing with age. While QT prolongation was seen in all age groups of DMD, QTc prolongation was seen only at 10 years or more. Incomplete right bundle branch block (RBBB) and pathological Q waves in inferolateral leads were exclusive in DMD, with the latter declining with age. Evidence for left ventricular (LV) pathology, such as tall R in V5/V6, increase in SV1 + RV6 height, and QRS complex duration, were seen only in the age group of 10 years or more. Conclusion: Stratification based on age and comparison with age-matched healthy subjects showed that several ECG parameters were influenced by age, and it also identified age-dependent evidence for LV pathology and QTc prolongation in DMD.

Investigation of Autonomic Dysfunction in Alzheimer's Disease-A Computational Model-Based Approach.

(1) Background and Objective: Alzheimer's disease (AD) is commonly accompanied by autonomic dysfunction. Investigating autonomic dysfunction's occurrence patterns and severity may aid in making a distinction between different dementia subtypes, as cardiac autonomic dysfunction and AD severity are correlated. Heart rate variability (HRV) allows for a non-invasive assessment of the autonomic nervous system (ANS). AD is characterized by cholinergic depletion. A computational model of ANS based on the kinetics of acetylcholine and norepinephrine is used to simulate HRV for various autonomic states. The model has the flexibility to suitably modulate the concentration of acetylcholine corresponding to different autonomic states. (2) Methods: Twenty clinically plausible AD patients are compared to 20 age- and gender-matched healthy controls using HRV measures. Statistical analysis is performed to identify the HRV parameters that vary significantly in AD. By modulating the acetylcholine concentration in a controlled manner, different autonomic states of Alzheimer's disease are simulated using the ANS model. (3) Results: In patients with AD, there is a significant decrease in vagal activity, sympathovagal imbalance with a dominant sympathetic activity, and change in the time domain, frequency domain, and nonlinear HRV characteristics. Simulated HRV features corresponding to 10 progressive states of AD are presented. (4) Conclusions: There is a significant difference in the HRV features during AD. As cholinergic depletion and autonomic dysfunction have a common neurological basis, autonomic function assessment can help in diagnosis and assessment of AD. Quantitative models may help in better comprehending the pathophysiology of the disease and assessment of its progress.

Effects of an 18-Week Integrated Yoga Program on Cardiac Autonomic Function in Breast Cancer Patients Undergoing Adjuvant Chemotherapy: A Randomized Controlled Trial.

BACKGROUND: Cardiotoxicity is a commonly observed adverse effect seen in breast cancer (BC) patients undergoing chemotherapy with attributes toward cardiac autonomic dysfunction (CAD). Yoga, a mind-body system of medicine that has been shown to improve cardiac autonomic nervous system (ANS) activity in various health conditions, could be an effective adjuvant approach in addressing CAD. OBJECTIVE: This study aims to investigate the protective effects of Integrated Yoga Therapy (IYT) on ANS functioning, assessed using Heart rate variability (HRV) in breast cancer patients undergoing chemotherapy. METHODS: A total of 68 (stage I-III) BC patients were randomly assigned into 2 groups: Treatment as Usual group (TAU) and TAU with Yoga Therapy group (TAUYT). All patients underwent anthracycline-based adjuvant chemotherapy for a total of 6 cycles with 21 days/cycle. During chemotherapy, the TAUYT group received IYT 5 days a week for 18 weeks, compared with usual care alone in the TAU group. Resting heart rate (RHR) and HRV, measured in both the time and frequency domains, were used to assess the cardiac ANS function of each patient before and after 6 cycles of chemotherapy. RESULTS: A total of 30 subjects in the TAU group and 29 subjects in the TAUYT group were included in the analysis. At baseline (before chemotherapy), there were no significant differences between the TAU and TAUYT groups in terms of RHR and HRV indices. However, after chemotherapy, patients in the TAU group had a significantly higher average RHR (P < .02) and lower HRV indices with reduced parasympathetic indices: RMSSD (P < .01), pNN50% (P < .04), high-frequency power (P < .001) and increased sympathetic indices: low-frequency power (P < .001) with sympathovagal imbalance: LF/HF (P < .001) compared with patients in the TAUYT group. CONCLUSION: The study showed the protective effects of yoga therapy on CAD in patients receiving anthracycline-based chemotherapy for BC, proposing yoga as a potential adjuvant intervention in improving cardiac health and preventing cardiovascular-related morbidities. TRIAL REGISTRATION: This trial is registered with the Clinical Trials Registry-India (CTRI) database (CTRI/2020/10/028446; October 16, 2020).

Oligodendroglia Confer Neuroprotection to NSC-34 Motor Neuronal Cells Against the Toxic Insults of Cerebrospinal Fluid from Sporadic Amyotrophic Lateral Sclerosis Patients.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder with multifactorial pathomechanisms affecting not only motor neurons but also glia. Both astrocytes and microglia get activated and contribute significantly to neurodegeneration. The role of oligodendroglia in such a situation remains obscure, especially in the sporadic form of ALS (SALS), which contributes to 90% of cases. Here, we have investigated the role of oligodendroglia in SALS pathophysiology using a human oligodendroglial cell line, MO3.13, by exposing the cells to cerebrospinal fluid from SALS patients (ALS-CSF; 10% v/v for 48 h). ALS-CSF significantly reduced the viability of MO3.13 cells and down-regulated the expression of oligodendroglia-specific proteins, namely, CNPase and Olig2. Furthermore, to investigate the effect of the observed oligodendroglial changes on motor neurons, NSC-34 motor neuronal cells were co-cultured/supplemented with conditioned/spent medium of MO3.13 cells upon exposure to ALS-CSF. Live cell imaging experiments revealed protection to NSC-34 cells against ALS-CSF toxicity upon co-culture with MO3.13 cells. This was evidenced by the absence of neuronal cytoplasmic vacuolation and beading of neurites, which instead resulted in better neuronal differentiation. Enhanced lactate levels and increased expression of its transporter, MCT-1, with sustained expression of trophic factors, namely, GDNF and BDNF, by MO3.13 cells hint towards metabolic and trophic support provided by the surviving oligodendroglia. Similar metabolic changes were seen in the lumbar spinal cord oligodendroglia of rat neonates intrathecally injected with ALS-CSF. The findings indicate that oligodendroglia are indeed rescuer to the degenerating motor neurons when the astrocytes and microglia turn topsy-turvy.

Opioid versus Nonopioid Analgesia for Craniotomy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Despite the use of intraoperative opioid analgesia, postoperative pain is often reported by patients undergoing craniotomies. Opioids also cause undesirable side effects in neurosurgical patients. Hence, the role of nonopioid analgesia has been explored for craniotomies in recent years. METHODS: This systematic review evaluated evidence from randomized controlled trials (RCTs) comparing opioid and nonopioid analgesia during craniotomies regarding postoperative pain, recovery, and adverse events. RESULTS: Of the 10,459 records obtained by searching MEDLINE, Embase, and Web of Science databases, 6 RCTs were included. No difference was observed in pain scores between opioid and nonopioid analgesia at 1 and 24 hours after surgery: mean difference (MD), 1.11 units; 95% confidence interval [CI], -0.16 to 2.38, P = 0.09 and MD, -0.06 units; 95% CI, -1.14 to 1.01, P = 0.91, respectively. The time for first postoperative analgesic requirement was shorter with opioids but was not statistically significant (MD, -84.77 minutes; 95% CI, -254.65 to 85.11; P = 0.33). Postoperative nausea and vomiting (relative risk = 1.60; 95% CI, 0.96-2.66; P = 0.07) was similar but shivering (relative risk = 2.01; 95% CI, 1.09-3.71; P = 0.03) was greater in the opioid group than nonopioid group. CONCLUSIONS: There were no important differences in clinical outcomes between the groups in our review. The GRADE certainty of evidence was rated low for most outcomes. Available evidence does not suggest superiority of intraoperative nonopioid over opioid analgesia for postoperative pain in patients undergoing craniotomy. More studies are needed to firmly establish the role of nonopioid intraoperative analgesics as an alternative to opioids in this population.

Neuro-Cardio-Autonomic Modulations in Children with Duchenne Muscular Dystrophy.

BACKGROUND AND OBJECTIVE: Duchenne muscular dystrophy (DMD) is a degenerative X-linked muscle disease. Death frequently results from complications in cardiopulmonary systems. Preclinical/early diagnosis of cardiac autonomic abnormalities may aid initiate cardioprotective therapy and enhance prognosis. METHODS: A cross sectional, prospective study of 38 DMD boys compared with 37 age-matched healthy controls was conducted. Lead II electrocardiography and beat-to-beat blood pressure were recorded to assess heart rate variability (HRV), blood pressure variability (BPV), and baroreceptor sensitivity (BRS) in a standardized environment. Data were analysed and correlated with disease severity and genotype. RESULTS: In the DMD group, the median age at assessment was 8 years [IQR 7-9 years], the median age at disease onset was 3 years [IQR, 2-6 years], and the mean duration of illness was 4 years [IQR, 2.5-5]. DNA sequencing showed deletions in 34/38 (89.5 %) and duplications in 4/38 (10.5%) patients. The median heart rate in DMD children was significantly higher [101.19 (Range, 94.71-108.49)] /min compared to controls [81 (Range, 76.2-92.76)] /min (p < 0.05). All the assessed HRV and BPV parameters were significantly impaired in DMD cases except for the coefficient of variance of systolic blood pressure. Further, BRS parameters were also significantly reduced in DMD, excluding alpha-LF. A positive correlation was found between alpha HF with age at onset and duration of illness. CONCLUSION: This study demonstrates a distinct early impairment of neuro-cardio-autonomic regulation in DMD. Simple yet effective non-invasive techniques such as HRV, BPV, and BRS may help identify cardiac dysfunction in a pre-clinical state, paving the way for early cardio-protective therapies and limiting disease progression in DMD patients.

Resting heart rate variability as a diagnostic marker of cardiovascular dysautonomia in postural tachycardia syndrome.

OBJECTIVES: Postural orthostatic tachycardia syndrome (POTS) is a disorder of the autonomic nervous system characterised by orthostatic intolerance and orthostatic tachycardia without hypotension. Heart rate variability (HRV) is the most reliable and objective tool for assessing autonomic dysfunction severity. In the present study, we aimed to investigate HRV changes in resting supine position, predicting severity and cardiovascular risk in patients with POTS. METHODS: We compared 100 POTS patients with 160 healthy controls matched for age and gender in a case-control design. Along with clinical characterization, heart rate variability was evaluated using ambulatory 5 min ECG in lead II and expressed in frequency and time-domain measures. RESULTS: The resting heart rate of patients with POTS was significantly higher than that of healthy controls. In HRV measures, root mean square successive difference of RR intervals (RMSSD), total and high frequency (HF) powers were statistically lower with an increased low frequency (LF) to high-frequency ratio in patients with POTS compared to healthy controls. Further, stepwise logistic regression analysis showed increased basal HR and LF/HF as significant predictors of POTS and its severity. CONCLUSIONS: This is the first study on a large cohort of patients with POTS from India wherein HRV was assessed. The study showed reduced parasympathetic activity and increased sympathetic activity in patients with POTS compared to healthy controls. These findings of increased resting heart rate and LF/HF were found to be potential predictors of POTS and future cardiovascular risks, which need to be replicated in a larger and more homogenized cohort.

Opioid versus non-opioid analgesia for spine surgery: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Opioids are the primary analgesics used in patients undergoing spine surgery. Postoperative pain is common despite their liberal use and so are opioid-associated side effects. Non-opioid analgesics are gaining popularity as alternative to opioids in spine surgery. METHODS: This systematic review evaluated current evidence regarding opioid and non-opioid intraoperative analgesia and their influence on immediate postoperative pain and adverse events in spine surgery. RESULTS: A total of 10,459 records were obtained by searching Medline, EMBASE and Web of Science databases and six randomized controlled trials were included. Differences in postoperative pain scores between opioid and non-opioid groups were not significant at 1 h: 4 studies, mean difference (MD) = 0.65 units, 95% confidence intervals (CI) [-0.12 to 1.41], p = 0.10, but favored non-opioid at 24 h after surgery: 3 studies, MD = 0.75 units, 95%CI [0.03 to 1.46], p = 0.04. The time for first postoperative analgesic requirement was shorter (MD = -45.06 min, 95%CI [-72.50 to -17.62], p = 0.001), and morphine consumption during first 24 h after surgery was higher in opioid compared to non-opioid group (MD = 4.54 mg, 95%CI [3.26 to 5.82], p < 0.00001). Adverse effects of postoperative nausea and vomiting (Relative risk (RR) = 2.15, 95%CI [1.37 to 3.38], p = 0.0009) and shivering (RR = 2.52, 95%CI [1.08 to 5.89], p = 0.03) were higher and bradycardia was lower (RR = 0.35, 95%CI [0.17 to 0.71], p = 0.004) with opioid analgesia. CONCLUSION: The certainty of evidence on GRADE assessment is low for studied outcomes. Available evidence supports intraoperative non-opioid analgesia for overall postoperative pain outcomes in spine surgery. More research is needed to find the best drug combination and dosing regimen. Prospero Registration: CRD42020209042.

Impact of integrated yoga therapy on cognitive impairment and cardiac dysfunction in relation to quality of life in breast cancer patients undergoing chemotherapy: Study protocol for a two-arm randomized controlled trial.

Background: Chemotherapy-related cognitive impairment (CRCI) and cardiac dysfunction (CRCD) are common adverse effects seen in breast cancer patients undergoing chemotherapy. Even though these effects significantly influence daily functioning and overall quality of life, effective strategies to avoid and/or mitigate these adverse effects remain elusive. Yoga as a Mind-body intervention has been used increasingly by cancer patients and has undergone empirical investigations as a potential intervention for patients with cancer. Furthermore, yoga is associated with improved cognition and cardiac functioning in healthy older adults and subjects with cognitive and cardiac impairments. Accordingly, in the current study, yoga holds promise as an intervention to prevent/manage CRCI and CRCD with improved overall QOL in women receiving chemotherapy for breast cancer. Methods: The study is a two-arm, randomized controlled trial. Women diagnosed with stage I-III breast cancer and awaiting neo-adjuvant or adjuvant chemotherapy will be recruited from a tertiary care center in Bangalore, India. Following recruitment, subjects are randomized to the intervention group (integrated yoga therapy intervention during chemotherapy) or the control group (standard care during chemotherapy). The study's primary outcome is to measure the quality of life (cognitive domain) using European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The other primary objectives will include cognitive functioning using neuropsychological test battery and cardiac autonomic function testing using heart rate variability. Secondary outcomes are Brain-derived neurotrophic factor (BDNF), brain function (functional MRI), Echocardiography, serum cortisol, Functional assessment of cancer therapy-cognition (FACT-Cog V3), perceived stress scale and Ryff Scales of Psychological Well-Being. Assessments take place before, during and after chemotherapy; 16-weeks post chemotherapy and 1-year post-baseline. Discussion: Yoga is a promising intervention for preventing and/or managing chemotherapy-related adverse effects (CRAE) and enhancing the quality of life among breast cancer patients. The findings from this study may also help understand the inner mechanisms involved in the protective and restorative effects of yoga on CRAE and support the use of yoga prophylactically for breast cancer patients. In addition, the results of this study could help chemotherapy-exposed individuals with other solid cancer types who have cognitive and cardiac issues. Ethics and Dissemination: The study is approved by the ethics committee of the HealthCare Global Enterprises Ltd. Hospital (EC/434/19/01) and National Institute of Mental Health and Neurosciences (NIMH/DO/ETHICS SUB-COMMITTEE (BS&NS) 9th MEETING/2018). Clinical Trial Registration: http://ctri.nic.in/Clinicaltrials/advancesearchmain.php, identifier CTRI/2020/10/028446.

Enhanced dehydroepiandrosterone levels are positively correlated with N3 sleep stage in long-term mindfulness meditation practitioners.

Objectives: Meditation practices positively influence the neural, hormonal and autonomic systems. We have demonstrated that long-term practice of mindfulness meditation increases N3 and rapid eye movement (REM) sleep stages and bring efficient autonomic modulation during sleep. In the present study, the probable humoral correlation that could bring about these changes is evaluated. Material and Methods: Long-term Vipassana meditators (n=41) and controls (n=24) (males, 30-60 years of age) underwent a two-day consecutive whole night polysomnography recording. During the second day, with exposure to 100Lux brightness, blood was sampled from the antecubital vein between 8-9 PM and in subsequent early morning. Sleep stage was scored as per American Society of Sleep Medicine (ASSM) guidelines for the second-day recording. Sleep-related hormones were estimated - melatonin by radioimmunoassay; dehydroepiandrosterone (DHEA), cortisol, growth hormone (GH) and prolactin with enzyme-linked immunosorbent assay (ELISA); DHEA/cortisol ratio was calculated. Percentage of sleep stages and hormonal levels were compared between both groups using independent 't' test and Pearson's correlation was estimated between sleep stages and hormonal levels. Results: Meditators showed increased N3, REM sleep stages. Though evening cortisol was comparable between the two groups; early morning cortisol, diurnal DHEA and melatonin were significantly higher in meditators. Diurnal DHEA correlated significantly with the N3 sleep stage in meditators. Discussion: Higher diurnal DHEA despite variations in corresponding cortisol in meditators demonstrates that long-term Vipassana meditation practice modulates the hypothalamicpituitary-adrenal (HPA) axis and thereby influences sleep. Thus, the study provides evidence to explore the mechanism most likely involved with mindfulness meditation intervention in insomnia.

Diaphragmatic ultrasound: Prospects as a tool to assess respiratory muscle involvement in amyotrophic lateral sclerosis.

BACKGROUND: Ultrasonography (USG) of the diaphragm is a promising alternative to pulmonary function tests (PFT) for assessing respiratory function in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). METHODS: We studied 33 patients fulfilling Awaji criteria (definite = 14; probable = 12; possible = 7) and 33 age and gender-matched controls. Diaphragm thickness was measured using USG at the end of expiration (DTex) and end of inspiration (DTin). The thickness ratio (TR) was calculated as DTin/DTex. The mean age at onset and duration were 49.73 ± 12.7 years and 13.57 ± 9.7 months, respectively. Men = 25 (75.8%); Limb onset ALS/MND = 24 patients (72.7%); bulbar onset = 9 (27.3%). RESULTS: Compared to controls, ALS/MND patients had reduced mean DTex (2.22 ± 0.29 mm vs. 2.02 ± 0.32 mm, p = .012) and DTin (4.0 ± 0.71 mm vs. 3.41 ± 0.38 mm, p < .001). PFTs done in 31 patients showed restrictive abnormality in 80.6%. Significant positive correlation was seen between percentage of predicted forced vital capacity (FVC%) and DTin (p = .009) and TR (p = .037) but not with DTex (p = .852). No significant correlation was seen between diaphragmatic thickness and other PFT parameters or ALSFRS scores. CONCLUSION: The diaphragmatic thickness showed a significant decrease in ALS/MND as compared to controls. End-inspiratory diaphragmatic thickness and TR correlated well with %FVC. Thus, diaphragmatic USG could be a potential alternative to PFTs in assessing respiratory function in ALS/MND patients having the advantage of less patient participation and ease of performing in late stages of ALS/MND.

Corpus callosum morphometry in children with prenatal alcohol exposure.

Alcohol is known to have a neurotoxic effect on the brain of offspring of mothers consuming alcohol during pregnancy. Impact on the neurodevelopment in children who were exposed to alcohol specifically during the antenatal period without any clinically detectable features of fetal alcohol syndrome is less well studied. In this cross-sectional study, structural magnetic resonance imaging (MRI) of the brain was acquired in 28 children whose mothers had consumed alcohol during pregnancy and 30 children of mothers who did not consume alcohol during pregnancy. Areas of Corpus callosum (CC) and its parts in the mid-sagittal section were calculated using morphometric analysis of MRI through Witelson's method. Midbody of CC was found to be significantly smaller in children exposed to alcohol during the prenatal period. CC is a sensitive white matter structure to neurotoxic effects of alcohol during prenatal life. This impact could be visible in developmental age even in those without any clinically detectable features of alcohol exposure.

Effect of Yoga and Physiotherapy on Pulmonary Functions in Children with Duchenne Muscular Dystrophy - A Comparative Study.

CONTEXT: Abnormal respiratory function is known to be detectable almost as soon as it can be measured reliably. Studies have identified the effect of respiratory muscle training as well as breathing exercises in improving pulmonary functions in children with Duchenne muscular dystrophy (DMD). AIMS: This study aims to identify the add-on effect of yoga over physiotherapy on pulmonary functions in children with DMD. SETTINGS AND DESIGN: One hundred and twenty-four patients with DMD were randomized to two groups. Group I received home-based physiotherapy and Group II received physiotherapy along with yoga intervention. MATERIALS AND METHODS: Pulmonary function test (PFT) was assessed before the intervention (baseline data) and at regular intervals of 3 months for a period of 1 year. STATISTICAL ANALYSIS USED: Normality was assessed using Shapiro-Wilk normality test. The baseline data were analyzed using Mann-Whitney U-test to identify the homogeneity. Repeated measures analysis of variance was used to assess significant changes in study parameters during the assessment of every 3 months, both within and between the two groups of patients. RESULTS: A total of 88 participants completed all the 5 assessments, with a mean age of 7.9 ± 1.5 years. PFT parameters such as forced vital capacity (FVC), peak expiratory flow rate, maximum voluntary ventilation (MVV), and tidal volume during maximum voluntary ventilation (MVt) demonstrated significant improvements in Group I. In Group II, FVC and MVt significantly improved from baseline up to 1 year, whereas MVV improved from baseline up to 9 months. Tidal volume did not show any changes in both the groups. CONCLUSIONS: The findings suggest that introduction of yoga with physiotherapy intervention at an early age can be considered as one of the therapeutic strategies in improving pulmonary functions in patients with DMD.

Chitotriosidase, a biomarker of amyotrophic lateral sclerosis, accentuates neurodegeneration in spinal motor neurons through neuroinflammation.

BACKGROUND: Cerebrospinal fluid from amyotrophic lateral sclerosis patients (ALS-CSF) induces neurodegenerative changes in motor neurons and gliosis in sporadic ALS models. Search for identification of toxic factor(s) in CSF revealed an enhancement in the level and enzyme activity of chitotriosidase (CHIT-1). Here, we have investigated its upregulation in a large cohort of samples and more importantly its role in ALS pathogenesis in a rat model. METHODS: CHIT-1 level in CSF samples from ALS (n = 158), non-ALS (n = 12) and normal (n = 48) subjects were measured using ELISA. Enzyme activity was also assessed (ALS, n = 56; non-ALS, n = 10 and normal-CSF, n = 45). Recombinant CHIT-1 was intrathecally injected into Wistar rat neonates. Lumbar spinal cord sections were stained for Iba1, glial fibrillary acidic protein and choline acetyl transferase to identify microglia, astrocytes and motor neurons respectively after 48 h of injection. Levels of tumour necrosis factor-α and interleukin-6 were measured by ELISA. FINDINGS: CHIT-1 level in ALS-CSF samples was increased by 20-fold and it can distinguish ALS patients with a sensitivity of 87% and specificity of 83.3% at a cut off level of 1405.43 pg/ml. Enzyme activity of CHIT-1 was also 15-fold higher in ALS-CSF and has a sensitivity of 80.4% and specificity of 80% at cut off value of 0.1077989 µmol/µl/min. Combining CHIT-1 level and activity together gave a positive predictive value of 97.78% and negative predictive value of 100%. Administration of CHIT-1 increased microglial numbers and astrogliosis in the ventral horn with a concomitant increase in the levels of pro-inflammatory cytokines. Amoeboid-shaped microglial and astroglial cells were also present around the central canal. CHIT-1 administration also resulted in the reduction of motor neurons. CONCLUSIONS: CHIT-1, an early diagnostic biomarker of sporadic ALS, activates glia priming them to attain a toxic phenotype resulting in neuroinflammation leading to motor neuronal death.

Parkinsonian and Cerebellar Phenotypes of Probable MSA: An Insight in to Prognostic Factors Based on Autonomic Functions.

BACKGROUND: Multiple system atrophy is an adult-onset, sporadic, neurodegenerative disorder with parkinsonian (MSA-P) and cerebellar (MSA-C) subtypes. OBJECTIVE: We aimed to elucidate differences in prognostic factors between MSA subtypes. METHODS: The study population comprised 45 probable MSA patients (MSA-P = 22; MSA-C = 23) and 45 healthy controls. Clinical parameters, heart rate variability (HRV), and conventional cardiac autonomic function testing (AFT) were the study tools. RESULTS: Mean age of onset of MSA was 54.7 ± 9 years for MSA-P and 51.9 ± 7 years for MSA-C subgroups. Median disease duration was 2 years in both subgroups. A greater percentage of MSA-P patients (45.5%) had beneficial response to levodopa (P < 0.01). Patients in both subgroups reported significant autonomic disturbances, such as postural symptoms, bladder disturbances, and erectile dysfunction. MSA-P patients had a trend for a greater number of falls and bladder disturbances than MSA-C patients (P = 0.05). Cardiac AFT showed that in MSA-P, 22.2% had definitive and 77.7% had severe autonomic dysfunction, whereas in MSA-C, 9.5% had early, 28.5% had definitive, and 57.1% had severe autonomic dysfunction. HRV analysis showed significant reduction in overall HRV, sympathetic activity, and parasympathetic activity in MSA patients as compared with controls (P < 0.0001). The sympathetic limb was more severely affected in MSA-P patients as compared with MSA-C patients (P < 0.05). CONCLUSION: Autonomic dysfunction and postural instability, negative prognostic markers, were relatively more common in the MSA-P than in the MSA-C patients. This implies that MSA-P patients have poorer prognosis as compared with MSA-C. Dopaminergic medications can be beneficial in MSA-P patients.

Mutation pattern in 606 Duchenne muscular dystrophy children with a comparison between familial and non-familial forms: a study in an Indian large single-center cohort.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is induced by a wide spectrum of mutations such as exon deletions, duplications and small mutations in the dystrophin gene. This is the first study on the mutational spectrum in a cohort of DMD children from India, with an emphasis to compare the mutations in familial and sporadic forms. RESULTS: Multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS) identified 525 and 70 cases of DMD, respectively, while 11 cases showed absent dystrophin staining with no mutations detected. Families with two or more affected males contributed to 12% of the entire cohort. The mutations comprised of exonic deletions in 492/606 (81.2%), duplications in 33/606 (5.4%) and small mutations (point mutations and INDELs) in 70/606 (11.5%) cases. MLPA identified significantly more larger mutations in sporadic (88.2%) than in familial cases (75.3%). The mutations in NGS were: [nonsense = 40 (57.1%); frameshift = 17 (24.3%); splice variant = 12 (17.1%)]. Nonsense mutations were more common in familial than in sporadic cases: 17.8% vs 10.7%. The familial group reported an earlier onset of disease (2.8 ± 1.7 years) as compared to sporadic cases (3.8 ± 1.6 years). CONCLUSION: MLPA could identify mutations in a high percentage of our DMD children. The preponderance of small mutations was noted to be distinctly higher in the familial group. Intriguingly, the familial form of DMD formed a small percentage of the entire cohort. The reasons could be increasing awareness among parents and physicians with early identification of DMD cases, genetic counseling and prenatal testing.

Human placental extract ameliorates cytokine and cytokine receptor signaling in the rat hippocampus upon Benzo[a]Pyrene exposure.

Benzo[alpha]Pyrene (B[a]P) causes toxicity via Cytochrome P450 1A1 (CYP1A1) metabolic activity in the brain. Studies have shown that neuronal IL-2 and TNF-α are associated with the hippocampus development and regulation, but their association with the CYP1A1 activity remains unidentified. Limited action of human placental extract (HPE) in the activation of tissue repair and wound healing is known, but their role in B[a]P clearance in the hippocampus is not known so far. Our study has focused on two novel concepts: (1) association of CYP1A1 activity with the inflammatory response in the brain hippocampus and (2) role of HPE in the immunomodulatory mechanisms in the hippocampus upon B[a]P exposure at cytokine receptor and nuclear level. Intrathecal administration of different concentrations of B[a]P and HPE into male wistar rat pups has been conducted. An increased CYP1A1 activity was observed in the presence of 0.25 µM B[a]P alone but in case of HPE followed by 0.25 µM B[a]P, it was equal to control. Herein we report that 5 µl of 0.1 gm HPE followed by 0.25 µM B[a]P administration enabled down-regulation of IL-2 and TNF-α levels in the hippocampus thereby modulating TNFR2 and IL2Rγc signals via NF-κB activation. Besides, localization of IL-2, TNF-α, IL2Rγc, TNFR1 and TNFR2 in the CA1, CA3 and DG regions of the hippocampus are also depicted. Altogether, these findings will project the clinical importance of HPE in the neuroinflammation suppression in the hippocampus developed due to B[a]P toxicity.

Effect of Yoga as an Add-on Therapy in the Modulation of Heart Rate Variability in Children with Duchenne Muscular Dystrophy.

BACKGROUND: Duchene muscular dystrophy (DMD) is a progressive muscular disorder. Cardiac disorder is the second-most common cause of death in children with DMD, with 10%-20% of them dying of cardiac failure. Heart rate variability (HRV) is shown to be a predictor of cardio-autonomic function. Physiotherapy (PT) is advised for these children as a regular treatment for maintaining their functional status. The effect of yogic practices on the cardio-autonomic functions has been demonstrated in various neurological conditions and may prove beneficial in DMD. MATERIALS AND METHODS: In this study, 124 patients with DMD were randomized to PT alone or PT with yoga intervention. Home-based PT and yoga were advised. Adherence was serially assessed at a follow-up interval of 3 months. Error-free, electrocardiogram was recorded in all patients at rest in the supine position. HRV parameters were computed in time and frequency domains. HRV was recorded at baseline and at an interval of 3 months up to 1 year. Repeated-measures ANOVA was used to analyze longitudinal follow-up and least significant difference for post hoc analysis and P < 0.05 was considered statistically significant. RESULTS: In our study, with PT protocol, standard deviation of NN, root of square mean of successive NN, total power, low frequency, high-frequency normalized units (HFnu), and sympathovagal balance improved at varying time points and the improvement lasted up for 6-9 months, whereas PT and yoga protocol showed an improvement in HFnu during the last 3 months of the study period and all the other parameters were stable up to 1 year. Thus, it is evident that both the groups improved cardiac functions in DMD. However, no significant difference was noted in the changes observed between the groups. CONCLUSION: The intense PT and PT with yoga, particularly home-based program, is indeed beneficial as a therapeutic strategy in DMD children to maintain and/or to sustain HRV in DMD.