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.

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.

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.

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.

Influence of age and gender on the function of postganglionic sympathetic sudomotor axons.

BACKGROUND: The quantitative sudomotor axon reflex test (QSART) is an autonomic function test to evaluate the function of postganglionic sympathetic sudomotor axons. The QSART is used for research and in clinical assessment of various neurological diseases, but few studies have assessed the influence of age, gender and reported a normative range. We assessed the influence of age and gender on QSART parameters. METHODS: We recruited 61 healthy volunteers (41 men and 20 women) after obtaining written informed consent. The QSART was recorded as per standard protocol after iontophoretic stimulation (using acetylcholine) for 5 minutes. We analysed the sweat response to obtain total sweat production, rate of sweat production and latency time from the start of stimulation to sweat response. We assessed these parameters in the right medial forearm, right proximal leg, right distal leg and right proximal foot. RESULTS: Men had significantly higher evoked sweat volume and sweat latency period compared to women. A positive correlation was observed between age and evoked total sweat volume. An inverse correlation was noted between age and evoked sweat latency period. CONCLUSION: Postganglionic sudomotor function increased significantly with age. Men had significantly higher sweat volume suggesting sympathetic predominance. These results might help establish normative data for the Indian population.

Demonstration of autonomic dysfunction in traumatic brachial plexus injury using quantitative sudomotor axon reflex test: Preliminary results.

OBJECTIVE: To objectively document autonomic dysfunction in the affected arm with traumatic brachial plexus injury (TBPI) using quantitative sudomotor axon reflex test (QSART). MATERIALS AND METHODS: Patients with TBPI presenting to the neurosurgical outpatient department from August 2013 to November 2014 were included in the study. The QSART was administered to each patient with prior informed consent detailing the procedure. A total of 20 patients with TBPI were included in the study. The age, sex, mode of injury, date of injury, side of injury, and type of injury (pan brachial plexus vs preserved distal function) were recorded. The presence of any pain was also recorded. The injuries were also grouped as preganglionic and postganglionic injuries based on clinical, electroneuromyography (ENMG) and magnetic resonance imaging (MRI) findings. The results of the test for the affected and normal limb were recorded and analyzed with appropriate statistical tests to determine any significant differences. RESULTS: The study included 20 patients, with their age ranging from 15 to 50 years. Out of the 20 patients, one was female and the rest 19 were males. Seven (35%) of the injuries were complete (pan brachial plexus) and 13 (65%) were incomplete (preserved distal function). All patients had preganglionic TBPI. There was no evidence of any statistically significant difference between the affected and normal arm for total sweat volume (P = 0.20) and latency period (P = 0.42). However, the average mean values for the same were lower in the affected arm as compared to the normal. The baseline sweat output (P = 0.010), however, was significantly lower in the affected arm as compared to the normal arm. CONCLUSION: QSART has demonstrated reduced baseline sweat output in the affected arm in patients with TBPI. This indicates the presence of autonomic dysfunction in the injured arm.

Cerebrospinal Fluid from Sporadic Amyotrophic Lateral Sclerosis Patients Induces Mitochondrial and Lysosomal Dysfunction.

In our laboratory, we have developed (1) an in vitro model of sporadic Amyotrophic Lateral Sclerosis (sALS) involving exposure of motor neurons to cerebrospinal fluid (CSF) from sALS patients and (2) an in vivo model involving intrathecal injection of sALS-CSF into rat pups. In the current study, we observed that spinal cord extract from the in vivo sALS model displayed elevated reactive oxygen species (ROS) and mitochondrial dysfunction. Quantitative proteomic analysis of sub-cellular fractions from spinal cord of the in vivo sALS model revealed down-regulation of 35 mitochondrial proteins and 4 lysosomal proteins. Many of the down-regulated mitochondrial proteins contribute to alterations in respiratory chain complexes and organellar morphology. Down-regulated lysosomal proteins Hexosaminidase, Sialidase and Aryl sulfatase also displayed lowered enzyme activity, thus validating the mass spectrometry data. Proteomic analysis and validation by western blot indicated that sALS-CSF induced the over-expression of the pro-apoptotic mitochondrial protein BNIP3L. In the in vitro model, sALS-CSF induced neurotoxicity and elevated ROS, while it lowered the mitochondrial membrane potential in rat spinal cord mitochondria in the in vivo model. Ultra structural alterations were evident in mitochondria of cultured motor neurons exposed to ALS-CSF. These observations indicate the first line evidence that sALS-CSF mediated mitochondrial and lysosomal defects collectively contribute to the pathogenesis underlying sALS.

Partial Body Weight-Supported Treadmill Training in Patients With Parkinson Disease: Impact on Gait and Clinical Manifestation.

OBJECTIVE: To evaluate the effect of conventional gait training (CGT) and partial weight-supported treadmill training (PWSTT) on gait and clinical manifestation. DESIGN: Prospective experimental research design. SETTING: Hospital. PARTICIPANTS: Patients with idiopathic Parkinson disease (PD) (N=60; mean age, 58.15±8.7y) on stable dosage of dopaminomimetic drugs were randomly assigned into the 3 following groups (20 patients in each group): (1) nonexercising PD group, (2) CGT group, and (3) PWSTT group. INTERVENTIONS: The interventions included in the study were CGT and PWSTT. The sessions of the CGT and PWSTT groups were given in patient's self-reported best on status after regular medications. The interventions were given for 30min/d, 4d/wk, for 4 weeks (16 sessions). MAIN OUTCOME MEASURES: Clinical severity was measured by the Unified Parkinson Disease Rating Scale (UPDRS) and its subscores. Gait was measured by 2 minutes of treadmill walking and the 10-m walk test. Outcome measures were evaluated in their best on status at baseline and after the second and fourth weeks. RESULTS: Four weeks of CGT and PWSTT gait training showed significant improvements of UPDRS scores, its subscores, and gait performance measures. Moreover, the effects of PWSTT were significantly better than CGT on most measures. CONCLUSIONS: PWSTT is a promising intervention tool to improve the clinical and gait outcome measures in patients with PD.

Spirometry Changes in Cold Climatic Conditions of Antarctica.

BACKGROUND: Pulmonary function is one of the important physiological measures that is known to be affected during the changes in the altitude. There is dearth of literature on changes in the pulmonary function variables in the cold climate conditions of Antarctica. We carried out spirometry before, during and after one year stay at Antarctica in members of the Indian expedition. METHODS: Spirometry was carried out on 23 members of the XXVI Indian Scientific Expedition to Antarctica at baseline, after six months of expedition and at the end of one year, using standard guidelines. The tests were carried out indoor in temperature controlled laboratory. RESULTS: The pulmonary function test parameters did not vary across the period. Although, both forced vital capacity (FVC) and forced expiratory volume in first second (FEV1) showed a decreasing trend but did not attain any statistical significance. However, peak expiratory flow (PEFR) rate was reduced significantly. CONCLUSION: Our study did not show consistently significant change in the pulmonary function parameters in the members of the Indian Antarctic expedition.

Treadmill gait training improves baroreflex sensitivity in Parkinson's disease.

BACKGROUND: Partial weight supported treadmill gait training (PWSTT) is widely used in rehabilitation of gait in patient with Parkinson's Diseases (PD). However, its effect on blood pressure variability (BPV) and baroreflex sensitivity (BRS) in PD has not been studied. AIM: To evaluate the effect of conventional and treadmill gait training on BPV components and BRS. METHODS: Sixty patients with idiopathic PD were randomized into three groups. Twenty patients in control group were on only stable medication, 20 patients in conventional gait training (CGT) group (Stable medication with CGT) and 20 patients in PWSTT group (Stable medication with 20 % PWSTT). The CGT and PWSTT sessions were given for 30 min per day, 4 days per week, for 4 weeks (16 sessions). Groups were evaluated in their best 'ON' states. The beat-to-beat finger blood pressure (BP) was recorded for 10 min using a Finometer instrument (Finapres Medical Systems, The Netherlands). BPV and BRS results were derived from artifact-free 5-min segments using Nevrocard software. RESULTS: BRS showed a significant group with time interaction (F = 6.930; p = 0.003). Post-hoc analysis revealed that PWSTT group showed significant improvement in BRS (p < 0.001) after 4 weeks of training. No significant differences found in BPV parameters; systolic BP, diastolic BP, co-variance of systolic BP and low frequency component of systolic BP. CONCLUSIONS: Four weeks of PWSTT significantly improves BRS in patients with PD. It can be considered as a non-invasive method of influencing BRS for prevention of orthostatic BP fall in patients with PD.

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.

Chitotriosidase - a putative biomarker for sporadic amyotrophic lateral sclerosis.

BACKGROUND: Potential biomarkers to aid diagnosis and therapy need to be identified for Amyotrophic Lateral Sclerosis, a progressive motor neuronal degenerative disorder. The present study was designed to identify the factor(s) which are differentially expressed in the cerebrospinal fluid (CSF) of patients with sporadic amyotrophic lateral sclerosis (SALS; ALS-CSF), and could be associated with the pathogenesis of this disease. RESULTS: Quantitative mass spectrometry of ALS-CSF and control-CSF (from orthopaedic surgical patients undergoing spinal anaesthesia) samples showed upregulation of 31 proteins in the ALS-CSF, amongst which a ten-fold increase in the levels of chitotriosidase-1 (CHIT-1) was seen compared to the controls. A seventeen-fold increase in the CHIT-1 levels was detected by ELISA, while a ten-fold elevated enzyme activity was also observed. Both these results confirmed the finding of LC-MS/MS. CHIT-1 was found to be expressed by the Iba-1 immunopositive microglia. CONCLUSION: Elevated CHIT-1 levels in the ALS-CSF suggest a definitive role for the enzyme in the disease pathogenesis. Its synthesis and release from microglia into the CSF may be an aligned event of neurodegeneration. Thus, high levels of CHIT-1 signify enhanced microglial activity which may exacerbate the process of neurodegeneration. In view of the multifold increase observed in ALS-CSF, it can serve as a potential CSF biomarker for the diagnosis of SALS.

Influence of age and gender on autonomic regulation of heart.

Heart rate variability (HRV) is a non-invasive method to measure cardiac autonomic function. Impairments in HRV have been proposed as independent risk factor for increased cardiac mortality and morbidity. Cardio protective phenomenon in females has been hypothesized to be due to differential autonomic tone. Age related loss of vagal control has been reported as predisposing factor for the development of cardiovascular disease. In this study we assessed effect of age and gender on autonomic regulation of heart in healthy volunteers. HRV data of 189 subjects (114 males and 75 females) were analyzed in time and frequency domains using customized program. Artifact free 5 min electrocardiogram segment was used for analysis. It was ensured that none of the subject had medical illness such as diabetes, hypertension, thyroid disorders, cardiac disorders, diseases potentially related with autonomic neuropathy and major psychiatric illness by careful history and clinical examination. HRV recordings were done under standard laboratory condition. On correlation analysis SDNN, RMSSD, total power negatively correlated with age suggesting reduced autonomic regulation of heart with increase in age (SDNN: r = -0.444, p < 0.01; RMSSD: r = -0.552, p < 0.01; total power: r = -0.474, p < 0.01); similarly High frequency power (HF.nu) negatively correlated with age (r = -0.167, p = 0.02), denoting loss of vagal tone with aging. LF/HF ratio correlated positively with age (r = 0.19, p < 0.01) suggesting a relative increase of sympathetic activity with increase in age. On multiple regression analysis to control for effect of age and heart rate while comparing males and females, LF.nu showed significant reduction suggesting lower sympathetic tone in females (ß = -6.64; p < 0.01) and HF.nu showed increase at trend level (ß = 4.47; p = 0.053). In conclusion, there is overall reduction in autonomic control of heart with increase in the age. Sympathetic tone predominates and vagal tone diminishes with aging process. Females showed greater vagal tone than male. This differential autonomic tone indicate age, gender related predisposition to cardiovascular disease.

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 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.

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.

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.

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).

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.