Severity of muscle impairment and its progression assessed using musculoskeletal magnetic resonance imaging and diffusion tension imaging in 78 boys with Duchenne muscular dystrophy: a retrospective study.

Purpose: Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy. Current diagnostic tests like genetic testing, needle electromyography, and muscle biopsy are either not easily available or invasive, and they are impractical for assessing disease progression and treatment outcomes. Therefore, there is a need for a non-invasive and accurate investigative modality for DMD. In recent years, musculoskeletal magnetic resonance imaging (MRI-MSK) along with fractional anisotropy (FA) and diffusion tensor imaging (DTI) have become major non-invasive tools. Material and methods: T1-weighted MRI-MSK and FA measures of DTI of 78 DMD patients were retrospectively studied to identify the distinct pattern of muscle involvement and fatty infiltration as age and/or disease progresses. Correlation analysis was performed between MRI-MSK grade score vs. age, muscle strength, and Vignos scale. Spearman's rank correlation coefficient was used. Results: As age increased, the MRI grade score and Vignos score increased. There was a statistically significant high positive correlation between MRI-MSK grade score and age, and low positive correlation with Vignos scores. With increasing age, the muscle strength on manual muscle testing (MMT) and FA value decreased. There was high negative correlation with muscle strength on MMT and low positive correlation between FA values and MMT score. Conclusions: On T1-weighted MRI, a distinct pattern, extent, and distribution of lower limb muscle involvement can be seen. MRI-MSK grade score worsens with progressing age, reducing strength, and increasing functional impairment. FA alone may not be an accurate marker in assessing progression of DMD. MRI-MSK and other DTI measures should be further explored as diagnostic and prognostic tools for DMD.

Phase 1 clinical trial for intravenous administration of mesenchymal stem cells derived from umbilical cord and placenta in patients with moderate COVID-19 virus pneumonia: results of stage 1 of the study.

OBJECTIVE: Mesenchymal stem cells can serve as a therapeutic option for COVID-19. Their immunomodulatory and anti-inflammatory properties can regulate the exaggerated inflammatory response and promote recovery of lung damage. METHOD: Phase-1, single-centre open-label, prospective clinical trial was conducted to evaluate the safety and efficacy of intravenous administration of mesenchymal stem cells derived from umbilical cord and placenta in moderate COVID-19. The study was done in 2 stages with total 20 patients. Herein, the results of stage 1 including first 10 patients receiving 100 million cells on day 1 and 4 with a follow up of 6 months have been discussed. RESULTS: No adverse events were recorded immediately after the administration of MSCs or on follow up. There was no deterioration observed in clinical, laboratory and radiological parameters. All symptoms of the study group resolved within 10 days. Levels of inflammatory biomarkers such as NLR, CRP, IL6, ferritin and D-dimer improved in all patients after intervention along with improved oxygenation demonstrated by improvement in the SpO2/FiO2 ratio and PaO2/FiO2 ratio. None of the patients progressed to severe stage. 9 out of 10 patients were discharged within 9 days of their admission. Improvements were noted in chest x-ray and chest CT scan scores at day 7 in most patients. No post-covid fibrosis was observed on chest CT 28 days after intervention and Chest X ray after 6 months of the intervention. CONCLUSION: Administration of 100 million mesenchymal stem cells in combination with standard treatment was found to be safe and resulted in prevention of the cytokine storm, halting of the disease progression and acceleration of recovery in moderate COVID-19. This clinical trial has been registered with the Clinical Trial Registry- India (CTRI) as CTRI/2020/08/027043. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=43175.

A pilot study for treatment of COVID-19 patients in moderate stage using intravenous administration of ozonized saline as an adjuvant treatment-registered clinical trial.

OBJECTIVE: Ozone therapy has tremendous therapeutic potential owing to its antiviral, anti-inflammatory and antioxidant properties, and potential to improve oxygenation. A pilot clinical trial was conducted to evaluate the safety and efficacy ofintravenous ozonised saline treatment in patients with moderate COVID-19 pneumonia. PATIENTS AND METHODS: 10 patients were administered 200 ml freshly prepared ozonised saline intravenously over 1 h once a day for 8 days along with standard medical treatment. Clinical symptoms were monitored everyday and laboratory biomarkers, radiological findings at 1,3,6,10 days. Telephonic follow up was done for all after discharge till Day 14. 7 out of 10 patients required oxygen supplementation at recruitment. RESULTS: There was severe adverse event recorded in the study group.All patients improved from moderate to mild category in average 8 days and were discharged in average 9.7 days. None deteriorated to severe stage. All clinical symptoms resolved within 6 days and oxygen supplementation requirement reduced to none within 4.1 days. There wasstatistically significant reduction inCRP (p = 0.003), D-Dimer (p = 0.049), IL6 (p = 0.002)and statistically significant improvement (p = 0.001) in SpO2/FiO2 ratio. Change in LDH was borderline statistically not significant (p = 0.058).All patients showed significant resolution of bilateral interstitial infiltrates at the end of 10 days. CONCLUSION: Resolved clinical symptoms, improved oxygenation, clearance of infiltrates on Chest X-ray and improvement in biomarkers in a short period with non-progression of the disease showed that IV ozonised saline therapy was safe and effective to prevent disease progression in COVID-19, making it an effective novel therapeutic tool.

Multiple doses of cell therapy and neurorehabilitation in amyotrophic lateral sclerosis: A case report.

Cell therapy, along with intensive rehabilitation has been shown to significantly improve outcomes in amyotrophic lateral sclerosis (ALS), in addition to standard therapy. We present a 40-years-old male ALS patient, suffering for the past four years, who underwent multiple doses of cell therapy at our institution. Along with riluzole treatment and lithium co-administration, his treatment involved multiple intrathecal transplants of autologous bone marrow-derived mononuclear cells, followed by multidisciplinary neurorehabilitation. The outcome measures of ALSFunctional Rating Scale Revised score remained stable, and importantly, Six Minute Walk Test distance improved from 475.2 m to 580.8 m, over a span of 16 months. Improved outcomes are indicative of slowing down of disease progression. Multiple doses of intrathecal autologous cell therapy along with rehabilitation and lithium, in addition to standard riluzole treatment is a novel approach for decelerating disease progression and qualitatively improving living conditions for ALS patients and their caregivers.

The Baseline Pattern and Age-related Developmental Metabolic Changes in the Brain of Children with Autism as Measured on Positron Emission Tomography/Computed Tomography Scan.

[18F] 2-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography scan was performed on 45 children with autism to study the baseline pattern and age-related developmental changes in the brain metabolism. Median standardized uptake values (SUVs) were compared with published healthy control data. Results showed that, in contrary to control data, the median SUVs in children with autism decrease linearly with increase in age. As compared to controls, autism children below 5 years showed greater metabolism and older children showed lower metabolism. In autism group, comparison of absolute SUVs within different regions of the brain revealed relatively lower metabolism in amygdala, hippocampus, parahippocampal gyrus, caudate nucleus, cerebellum, mesial temporal lobe, thalamus, superior and middle temporal pole, and higher metabolic uptake in calcarine fissure and Heschl's gyrus. These results help in understanding the baseline metabolism and developmental changes of brain among different age groups in autism.

Effect of Cellular Therapy in Progression of Becker's Muscular Dystrophy: A Case Study.

Becker muscular dystrophy (BMD) is an inherited disorder due to deletions of the dystrophin gene that leads to muscle weakness. Effects of bone marrow mononuclear cell (BMMNC) transplantation in Muscular Dystrophy have shown to be safe and beneficial. We treated a 20-year-old male suffering from BMD with autologous BMMNC transplantation followed by multidisciplinary rehabilitation. He presented with muscle weakness and had difficulty in performing his activities. The BMMNCs were transplanted via intrathecal and intramuscular routes. The effects were measured on clinical and functional changes. Over 9 months, gradual improvement was noticed in muscle strength, respiratory functions and North Star Ambulatory Assessment Scale. Functional Independence Measure, Berg Balance Score, Brooke and Vignos Scale remained stable indicating halting of the progression. The case report suggests that cellular therapy combined with rehabilitation may have possibility of repairing and regenerating muscle fibers and decreasing the rate of progression of BMD.

The effect of autologous bone marrow mononuclear cell transplantation on the survival duration in Amyotrophic Lateral Sclerosis - a retrospective controlled study.

Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disorder with fatal prognosis. Cellular therapy has been studied for ALS in various animal models and these advances have highlighted its potential to be a treatment modality. This is a retrospective controlled cohort study of total 57 patients. Out of these, 37 patients underwent autologous bone marrow mononuclear cell transplantation in addition to standard rehabilitation and Riluzole. Control group consisted of 20 patients who did not receive cell transplantation. The survival duration since the onset of the disease for both the groups was computed using a Kaplan-Meier Survival analysis and compared using log-rank test. Effect of age at onset, type of onset and lithium on survival duration in the intervention group was analyzed. Mean survival duration of patients in intervention group was 87.76 months which was higher than the control group mean survival duration of 57.38 months. Survival duration was significantly (p = 0.039) higher in people with the onset of the disease below 50 years of age. Limb onset and lithium also showed positive influence on the survival duration. Mean survival duration of the intervention group was also higher than the survival duration of ALS patients in previous epidemiological studies. In addition to the standard treatment with Riluzole, early intervention with combination of BMMNCs transplantation and Lithium may have a positive effect on the survival duration in ALS. Prospective randomized controlled studies with a larger sample size and rigorous methodology are required for conclusive findings.

A clinical study of autologous bone marrow mononuclear cells for cerebral palsy patients: a new frontier.

Cerebral palsy is a nonprogressive heterogeneous group of neurological disorders with a growing rate of prevalence. Recently, cellular therapy is emerging as a potential novel treatment strategy for cerebral palsy. The various mechanisms by which cellular therapy works include neuroprotection, immunomodulation, neurorestoration, and neurogenesis. We conducted an open label, nonrandomized study on 40 cases of cerebral palsy with an aim of evaluating the benefit of cellular therapy in combination with rehabilitation. These cases were administered autologous bone marrow mononuclear cells intrathecally. The follow-up was carried out at 1 week, 3 months, and 6 months after the intervention. Adverse events of the treatment were also monitored in this duration. Overall, at six months, 95% of patients showed improvements. The study population was further divided into diplegic, quadriplegic, and miscellaneous group of cerebral palsy. On statistical analysis, a significant association was established between the symptomatic improvements and cell therapy in diplegic and quadriplegic cerebral palsy. PET-CT scan done in 6 patients showed metabolic improvements in areas of the brain correlating to clinical improvements. The results of this study demonstrate that cellular therapy may accelerate the development, reduce disability, and improve the quality of life of patients with cerebral palsy.

The role of cell transplantation in modifying the course of limb girdle muscular dystrophy: a longitudinal 5-year study.

Limb girdle muscular dystrophy (LGMD), a group of progressive degenerative disorders, causes functional limitation affecting the quality of life. Cell therapy is being widely explored and preliminary studies have shown beneficial effects. Cell therapy induces trophic-factors release, angiogenesis, anti-inflammation, and protein synthesis, which helps in the reparative process at the microcellular level. In this 5-year longitudinal study, the effect of autologous bone marrow mononuclear cells is studied on the natural course of 65 patients with LGMD. Functional Independence Measure and manual muscle testing showed statistically significant improvement, post-cell transplantation. The key finding of this study was demonstration of a plateau phase in the disease progression of the patients. No adverse events were noted. Autologous bone marrow mononuclear cells may be a novel, safe, and effective treatment approach to control the rate of progression of LGMD, thus improving the functional outcomes. Further randomized controlled trials are required.

Autologous bone marrow mononuclear cells intrathecal transplantation in chronic stroke.

Cell therapy is being widely explored in the management of stroke and has demonstrated great potential. It has been shown to assist in the remodeling of the central nervous system by inducing neurorestorative effect through the process of angiogenesis, neurogenesis, and reduction of glial scar formation. In this study, the effect of intrathecal administration of autologous bone marrow mononuclear cells (BMMNCs) is analyzed on the recovery process of patients with chronic stroke. 24 patients diagnosed with chronic stroke were administered cell therapy, followed by multidisciplinary neurorehabilitation. They were assessed on functional independence measure (FIM) objectively, along with assessment of standing and walking balance, ambulation, and hand functions. Out of 24 patients, 12 improved in ambulation, 10 in hand functions, 6 in standing balance, and 9 in walking balance. Further factor analysis was done. Patients of the younger groups showed higher percentage of improvement in all the areas. Patients who underwent cell therapy within 2 years after the stroke showed better changes. Ischemic type of stroke had better recovery than the hemorrhagic stroke. This study demonstrates the potential of autologous BMMNCs intrathecal transplantation in improving the prognosis of functional recovery in chronic stage of stroke. Further clinical trials are recommended. This trial is registered with NCT02065778.

Autologous bone marrow mononuclear cell transplantation in Duchenne muscular dystrophy - a case report.

PATIENT: Male, 9 FINAL DIAGNOSIS: Duchenne muscular dystrophy Symptoms: Hyporeflexia • hypotonia • weaknes of lower limbs MEDICATION: - Clinical Procedure: - Specialty: Neurology. OBJECTIVE: Congenital defects/diseases. BACKGROUND: Duchenne muscular dystrophy (DMD) is a fatal, genetic, progressive, degenerating muscle disorder. Current treatment options are palliative. Newer options of cellular therapy promise to alter the disease process. Preclinical studies have successfully tested myogenic, neurogenic potential and dystrophin expression of bone marrow mononuclear cells. CASE REPORT: We treated a 9-year-old boy suffering from DMD with serial autologous bone marrow mononuclear cell transplantations followed by multidisciplinary rehabilitation. Brooke-Vignos score was 10 and he was wheelchair-bound. Over 36 months, gradual progressive improvement was noticed in muscle strength, ambulation with assistive devices, fine motor movements, Brooke-Vignos score, and functional independence measure score. Nine months after the transplantation, electromyography findings showed development of new normal motor unit potentials of the vastus medialis muscle. CONCLUSIONS: Magnetic resonance imaging scan of musculoskeletal systems showed no increase in fatty infiltration. This case report provides early investigative findings or the restorative effects of cellular therapy in DMD.

Autologous bone marrow mononuclear cells in ischemic cerebrovascular accident paves way for neurorestoration: a case report.

In response to acute ischemic stroke, large numbers of bone marrow stem cells mobilize spontaneously in peripheral blood that home onto the site of ischemia activating the penumbra. But with chronicity, the numbers of mobilized cells decrease, reducing the degree and rate of recovery. Cellular therapy has been explored as a new avenue to restore the repair process in the chronic stage. A 67-year-old Indian male with a chronic right middle cerebral artery ischemic stroke had residual left hemiparesis despite standard management. Recovery was slow and partial resulting in dependence to carry out activities of daily living. Our aim was to enhance the speed of recovery process by providing an increased number of stem cells to the site of injury. We administered autologous bone marrow mononuclear cells intrathecally alongwith rehabilitation and regular follow up. The striking fact was that the hand functions, which are the most challenging deficits, showed significant recovery. Functional Independence Measure scores and quality of life improved. This could be attributed to the neural tissue restoration. We hypothesize that cell therapy may be safe, novel and appealing treatment for chronic ischemic stroke. Further controlled trials are indicated to advance the concept of Neurorestoration.

Autologous bone marrow mononuclear cell therapy for autism: an open label proof of concept study.

Cellular therapy is an emerging therapeutic modality with a great potential for the treatment of autism. Recent findings show that the major underlying pathogenetic mechanisms of autism are hypoperfusion and immune alterations in the brain. So conceptually, cellular therapy which facilitates counteractive processes of improving perfusion by angiogenesis and balancing inflammation by immune regulation would exhibit beneficial clinical effects in patients with autism. This is an open label proof of concept study of autologous bone marrow mononuclear cells (BMMNCs) intrathecal transplantation in 32 patients with autism followed by multidisciplinary therapies. All patients were followed up for 26 months (mean 12.7). Outcome measures used were ISAA, CGI, and FIM/Wee-FIM scales. Positron Emission Tomography-Computed Tomography (PET-CT) scan recorded objective changes. Out of 32 patients, a total of 29 (91%) patients improved on total ISAA scores and 20 patients (62%) showed decreased severity on CGI-I. The difference between pre- and postscores was statistically significant (P < 0.001) on Wilcoxon matched-pairs signed rank test. On CGI-II 96% of patients showed global improvement. The efficacy was measured on CGI-III efficacy index. Few adverse events including seizures in three patients were controlled with medications. The encouraging results of this leading clinical study provide future directions for application of cellular therapy in autism.

Cellular Transplantation Alters the Disease Progression in Becker's Muscular Dystrophy.

Becker's Muscular Dystrophy (BMD) is a dystrophinopathy manifested as progressive muscle degeneration. Autologous Bone Marrow Mononuclear Cells (BMMNCs) have shown some myogenic potential. The paracrine effects of the BMMNCs reduce the inflammation and are thought to reduce muscle degeneration. We treated a 39 year old dental surgeon suffering from BMD. Muscle strength was reduced when measured using modified Medical Research Council's Manual Muscle Testing (mMRC-MMT). Static sitting balance was poor. He was wheelchair dependent for ambulation and moderately independent in Activities of Daily Living (ADL). Functional Independence Measure (FIM) score was 93. Musculoskeletal Magnetic Resonance Imaging (MRI-MSK) showed moderate fatty infiltration in the muscles. Three cellular transplantations were carried out. Clinical assessment and the investigations were repeated. Progressive increase in the muscle strength was noted. Ambulation was independent using push-knee splints and minimal assistance when weary. Static and dynamic balance in sitting and standing improved. FIM score increased from 93 to 105. There was no increase in the degree of fatty infiltration, as seen on the MRI-MSK. The case study provides evidence for the putative benefits of cellular therapy in altering the disease progression in BMD. It also suggests augmented clinical benefits of combination of cellular therapy and rehabilitation.

Positron emission tomography-computer tomography scan used as a monitoring tool following cellular therapy in cerebral palsy and mental retardation-a case report.

Cerebral palsy (CP) is one of the non-progressive neurological diseases caused by damage to the brain tissue at birth, which leads to physical, cognitive and perceptive symptoms. Even after lifelong medical and therapeutic management there are residual deficits which affect the quality of life of the patients and their families. We examined a maximally rehabilitated, 20 year old male suffering from CP and Mental Retardation (MR). He had diplegic gait and Intelligence Quotient (IQ) score of 44 with affected fine motor activities, balance, speech and higher functions. Positron Emission Tomography-Computer Tomography (PET-CT) scan identified frontal, temporal, parietal, occipital, left cerebellar lobes, amygdala, hippocampus, and parahippocampus as the affected areas. He was treated with cellular therapy of Autologous Bone Marrow Derived Mono-Nuclear Cells (MNCs) transplantation followed by multidisciplinary rehabilitation. Six months following therapy, PET-CT scan showed significant increase in metabolic activity in all four lobes, mesial temporal structures and left cerebellar hemisphere, also supported by clinical improvement in IQ, social behavior, speech, balance and daily functioning. These findings provide preliminary evidence to support the efficacy of cellular therapy for the treatment of CP with MR. PET-CT scan can also be viewed as an impressive tool to monitor the effects of cellular therapy.