Human Umbilical Cord-Derived Mesenchymal Stem Cells in the Treatment of Multiple Sclerosis Patients: Phase I/II Dose-Finding Clinical Study.

Multiple sclerosis (MS) is a chronic neuro-inflammatory disease resulting in disabilities that negatively impact patients' life quality. While current treatment options do not reverse the course of the disease, treatment using mesenchymal stromal/stem cells (MSC) is promising. There has yet to be a consensus on the type and dose of MSC to be used in MS. This work aims to study the safety and efficacy of two treatment protocols of MSCs derived from the umbilical cord (UC-MSCs) and their secretome. The study included two groups of MS patients; Group A received two intrathecal doses of UC-MSCs, and Group B received a single dose. Both groups received UC-MSCs conditioned media 3 months post-treatment. Adverse events in the form of a clinical checklist and extensive laboratory tests were performed. Whole transcriptome analysis was performed on patients' cells at baseline and post-treatment. Results showed that all patients tolerated the cellular therapy without serious adverse events. The general disability scale improved significantly in both groups at 6 months post-treatment. Examining specific aspects of the disease revealed more parameters that improved in Group A compared to Group B patients, including a significant increase in the (CD3+CD4+) expressing lymphocytes at 12 months post-treatment. In addition, better outcomes were noted regarding lesion load, cortical thickness, manual dexterity, and information processing speed. Both protocols impacted the transcriptome of treated participants with genes, transcription factors, and microRNAs (miRNAs) differentially expressed compared to baseline. Inflammation-related and antigen-presenting (HLA-B) genes were downregulated in both groups. In contrast, TNF-alpha, TAP-1, and miR142 were downregulated only in Group A. The data presented indicate that both protocols are safe. Furthermore, it suggests that administering two doses of stem cells can be more beneficial to MS patients. Larger multisite studies should be initiated to further examine similar or higher doses of MSCs.

Facemask wearing does not impact neuro-electrical brain activity.

Given the massive use of facemasks (FMs) during the covid-19 pandemic, concerns have been raised regarding the effect of FMs wearing on overall health. This study aimed at evaluating the effect of surgical FM on brain neuro-electrical activity. Electroencephalography (EEG) background frequency (BGF) and background amplitude (BGA) was performed on 30 volunteers before (baseline), during and after wearing a FM for 60 min. Measurements were done during normal ventilation, hyperventilation and post-hyperventilation (PHVR). Blood gas levels were assessed at baseline and after FM use. EEG analysis concerning baseline (without FM) (BGA), was 47.69 ± 18.60 µV, wearing FM, BGA was 48.45 ± 17.79 µV, post FM use BGA was 48.08 ± 18.30 µV. There were no statistically significant differences between baseline BGA and BGA under FM and post FM. BGF, Baseline data were 10.27 ± 0.79, FM use 10.30 ± 0.76 and post FM use was 10.33 ± 0.76. There were no statistically significant differences between baseline BGF and BGF under FM and post FM. Venous blood gases, and peripheral oxygen saturation were not significantly affected by FM use. Short-term use of FM in young healthy individuals has no significant alteration impact on brain's neuro-electrical activity.

A New Tool for Safety Evaluation and a Combination of Measures for Efficacy Assessment of Cotransplanting Human Allogenic Neuronal Stem Cells and Mesenchymal Stem Cells for the Treatment of Parkinson Disease: Protocol for an Interventional Study.

BACKGROUND: Parkinson disease (PD) is a neurodegenerative disorder associated with a broad spectrum of motor and nonmotor symptoms. Any proposed cure needs to address the many aspects of the disease. Stem cell therapy may have potential in this regard as indicated in recent preclinical and clinical studies. OBJECTIVE: This protocol aims to examine the safety and therapeutic benefit of human Wharton jelly-derived mesenchymal stem cells (WJ-MScs) and their derivatives, neuronal stem cells (NSCs) in PD. METHODS: This clinical trial is a double-arm, single-blinded, phase I-II interventional study. Participants have been allocated to 1 of 2 groups: one receiving allogeneic WJ-MSCs alone, the other receiving NSCs and WJ-MScs. Participants are being followed-up and assessed over a period of 6 months. To assess safety, an incidence of treatment-emergent adverse events (TEAEs) tool tailored for PD is being used immediately and up to 6 months after treatment. For efficacy assessment, a number of factors are being used, including the gold standard severity test and the Unified Parkinson Disease Rating Scale. In addition, the following standardized assessments for different common symptoms in PD are being included: motor (both subjectively and objectively assessed with wearable sensors), sensory, quality of life and psychological well-being, cognition, and sleep quality. Furthermore, immune-modulatory cytokines and neuronal damage versus regeneration markers in PD, including the neuronal protein linked to PD, α-synuclein, are being monitored. RESULTS: Ten patients have been enrolled in this study and thus participant recruitment has been completed. The study status is active and beyond the recruiting stage. Study chart implementation, data collection, and analysis are ongoing. CONCLUSIONS: The combination of NSCs and MSCs in PD may be useful for harnessing the best of the immunomodulation and neural repair characteristics of these cell types. The tailored comprehensive and scaled TEAEs and the variety of evaluation tools used enables a comprehensive assessment of this cellular therapy treatment protocol. A consideration of this expanded tool set is important in the design of future clinical studies for PD. TRIAL REGISTRATION: ClinicalTrials.gov NCT03684122; https://clinicaltrials.gov/ct2/show/NCT03684122. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/29695.

Could vagus nerve stimulation influence bone remodeling?

OBJECTIVES: To investigate the effect of vagus nerve stimulation (VNS) on the bone mineral density (BMD) in epileptic patients. METHODS: A prospective cohort study was conducted on individuals with refractory seizures who underwent VNS surgery between January 2012 and December 2018. BMD was measured preoperatively and between 6 months and one year after surgery. RESULTS: Twenty-one patients (mean age (±SD)=23.6±12.3 years) were recruited for the implantation of a VNS device. The mean absolute increase in lumbar BMD in the 21 patients was 0.04±0.04 g/cm2 resulting in an overall percent increase from baseline of 4.7±6.1%. BMD increased by an amount ≥ the least significant change (LSC) for the lumbar spine in 13 patients (61.9%). The lumbar Z score also increased in these patients from -1.22±1.15 to -0.88±1.22, P=0.006). Pre and Post VNA femoral BMD was measured in only 11 patients and, of those 3 showed a significant increase in BMD, 1 a significant decrease and 7 no change. CONCLUSION: The implantation of a VNS was associated with an increase in lumbar BMD. This study could lead to a new application for VNS in the treatment of osteoporosis.

Mini-mental state examination (MMSE) scores in elderly Jordanian population.

Background: The Mini-Mental State Examination (MMSE) is a simple informative and validated screening test of cognitive functions. No data of MMSE scores has been published about elderly Jordanian population. Objective: To study the MMSE scores in the elderly Jordanian population (defined as age of 50 years or more). Methods: This was a cross sectional study. A 250 healthy elderly Jordanians were interviewed and tested for their MMSE score. Their scores were analyzed and the effect of age, gender, education, marital status, diabetes mellitus (DM), hypertension (HTN), smoking, dyslipidemia, heart disease (HD), and family history of dementia (FHD) on the score was studied. Results: MMSE scores of 236 elderly subjects, aged 63±8.4 years (range 50-86 years) were analyzed. There were 111 (47%) males. There was a direct correlation between MMSE score and education level. People with a higher education (college) had the highest scores in comparison with people who are illiterates or have a high school level. The score correlated negatively with age (Pearson correlation r = -0.23, p = 0.00). Other studied variables did not correlate with score on multivariate analysis. Conclusion: Jordanians ≥50 years old with no previous brain disease scored 26.7 ± 3.2. Education was the most important determining factor of this score. the score showed also a negative correlation with age. We suggest that in this population a cut off score of 24 for those with high education beyond high school and 21 for those with up to high school education and it is not appropriate for illiterate.

Correction to: The prevalence and risk factors of peripheral neuropathy among patients with type 2 diabetes mellitus; the case of Jordan.

[This corrects the article DOI: 10.1186/s13098-018-0309-6.].

The prevalence and risk factors of peripheral neuropathy among patients with type 2 diabetes mellitus; the case of Jordan.

BACKGROUND: Peripheral neuropathy is one of the most common microvascular complication of diabetes mellitus. This study is conducted to determine the prevalence of diabetic peripheral neuropathy (DPN) and its associated factors among patients with type 2 diabetes mellitus in Jordan. METHODS: A cross-sectional study was conducted at the National Center for Diabetes, Endocrinology and Genetics, Jordan. A total of 1003 patients with type 2 diabetes were recruited. Data were collected from participants during a face-to-face structured interview. DPN was assessed using the translated version of Michigan Neuropathy Screening Instrument (MNSI). RESULTS: The overall prevalence of DPN based on MNSI was 39.5%. The most frequently reported symptoms were numbness (32.3%) and pain with walking (29.7%), while the least reported symptoms were the history of amputation (1.3%) and loss of sensation in legs/feet while walking (3.8%). Logistic regression analysis revealed that unemployment, cardiovascular disease, dyslipidemia, diabetic retinopathy and long standing DM (diabetes of ≥ 5 years) were significantly associated with DPN. CONCLUSION: Peripheral Neuropathy is highly prevalent among Jordanian patients with type 2 diabetes mellitus. DPN was significantly associated with duration of DM, dyslipidemia, diabetic retinopathy, cardiovascular disease, and unemployment. Early detection and appropriate intervention are mandatory among high-risk groups.

Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: Clinical, ophthalmological and radiological assessments of safety and efficacy.

AIMS: This open-label prospective phase I/IIa clinical study used autologous bone marrow-derived mesenchymal stromal cells (BM-MSCs) followed by mesenchymal stromal cells conditioned media (MSC-CM) for the first time to treat multiple sclerosis (MS) patients. The primary goal was to assess the safety and feasibility and the secondary was efficacy. The correlation between the MSC-CM content and treatment outcome was investigated. METHODS: Ten MS patients who failed conventional therapy were enrolled. Adverse events were recorded to assess safety. The Expanded Disability Status Scale (EDSS) was the primary efficacy measurement, the secondary included clinical (25WFT, 9-PHT), cognitive (MMS), ophthalmology (OCT, VEP), and radiological (MRI lesion and volume) tests. The MSCs-CM concentration of 27 inflammatory biomarkers was investigated. RESULTS: The treatment protocol was well tolerated by patients. There was an overall trend of improvement in all the tests, except the lesion volume which increased significantly. A decrease of 4 and 3.5 points on the EDSS was achieved in two patients. We report a correlation between a decreased lesion number at baseline and higher IL-6, IL-8, and VEGF MSC-CM content. CONCLUSION: The used protocol was safe and feasible with possible efficacy. The addition of MSC-CM could be related to the magnitude of EDSS improvement observed.

Treatment of MuSK-Associated Myasthenia Gravis.

OPINION STATEMENT: Approximately 5-8 % of myasthenia gravis (MG) patients test positive for antibodies against muscle- specific tyrosine kinase (MuSK) receptors. Except in extremely rare reports, all are acetylcholine receptor (AChR) antibody-negative. While MuSK myasthenia gravis (MMG) patients have distinct clinical phenotypes and may differ from AChR-positive patients in diagnostic testing and response to treatment, goals for the treatment of MMG are similar to those in non-MMG. Priority of treatment should be directed toward reducing weakness as much and as quickly as possible. This is particularly true in patients with bulbar or respiratory weakness in order to avoid progression to respiratory failure. After this initial phase, medications should be slowly tapered to the minimum effective dose. Considering the natural history of MMG, a small proportion of patients can be completely taken off treatment at some point, but the vast majority will require treatment for life. Response to acetylcholinesterase inhibitors (ACEi) is usually poor, and the likelihood of side effects is relatively high. However, considering the benign nature of this line of treatment and the potential for rapid response, an initial trial of ACEi is reasonable. Unless clearly contraindicated by other medical conditions, we recommend initiating corticosteroid treatment for all MMG patients, starting at a dose of 1.5-2 mg /kg/ day of prednisone, followed by gradual and slow taper to the minimum effective dose. A steroid-sparing agent such as azathioprine - and, less often, mycophenolate mofetil or cyclosporine - may be added. When prednisone is used in combination with another immunosuppressive agent, reducing and then tapering off prednisone may be tried after maximum improvement is achieved. It should be emphasized that response to immunosuppressive medications can be delayed for months, although most patients eventually show marked and sustained response. Cyclophosphamide may be used sparingly in select patients who do not respond to the above medications. Rituximab has shown promising results in MMG, and should be considered in severe and refractory cases or in situations where other options are contraindicated or not tolerated by patients. Acute exacerbations may be treated by plasma exchange, which most reports indicate is superior to IVIg, although IVIg may still be used. To date, there is no convincing evidence for the role of thymectomy in MMG.

Towards establishing a multiple sclerosis biobank in Jordan.

Genome-wide association studies (GWAS) have been a promising approach in unraveling genetic associations to multiple sclerosis (MS), a complex, multifactorial disease. Biobanks are repositories of patient biospecimens and information that can promote GWAS research. However, the success of GWAS and biobanking is dependent on the level of participation of MS patients in genetic research. In order to initiate MS-based biobanking and GWAS research in Jordan, the willingness of MS patients to participate in long-term, genetic research in Jordan and their preferred type of a consent form were investigated. MS patients (289) were recruited for genetic studies. Personal and clinical information were collected from those who enrolled in the study. Approximately 96% of MS patients agreed to participate in genetic studies. The female:male ratio among patients was 2:1 with most patients being diagnosed with relapsing-remitting MS (88%). The mean age of onset was 28.3 years, the mean duration of illness was 6 years, and the mean Expanded Disability Status Scale was 2.8. Relatedness of parents was significantly associated with having secondary-progressive MS. Approximately 85% of the patients preferred open consent with 37% of them preferring to renew their consent. All the patients approved to be recontacted and update their information via accessing their medical files or physicians. These observations support the establishment of a specialized MS biobank in Jordan and pave the way to participate in international large-scale genetic initiatives.

The promoter SNP, but not the alternative splicing SNP, is linked to multiple sclerosis among Jordanian patients.

Multiple sclerosis is a chronic inflammatory autoimmune disease of the human central nervous system. A number of studies with compelling evidence have provided correlation between single nucleotide polymorphisms in interleukin-7 receptor alpha and multiple sclerosis (MS) in several populations. One such variation, rs6897932, is located within the coding region and results in the generation of a soluble receptor, whereas another one, rs11567685, is located in the promoter region and affects gene expression. In this study, we investigated the frequencies of these two SNPs and their association to MS in 200 healthy controls and 200 MS patients based on a simple PCR-RFLP strategy not reported previously. The frequencies of the high risk alleles for both SNPs were in a high range among healthy and MS subjects relative to previous studies. In addition, whereas no association was found between the alternative splicing SNP, rs6897932, and MS, a significant link was found between the promoter SNP, rs11567685, and MS. These results are in contrast to other studies and may have important implications as to the molecular contribution of IL-7Rα in multiple sclerosis.

Clinical characteristics and outcomes of patients with idiopathic inflammatory myopathies from Jordan 1996-2009.

To describe demographic characteristics, clinical features and outcome of Jordanian patients with idiopathic inflammatory myopathies (IIM), a retrospective chart review of all patients diagnosed with IIM at Jordan University Hospital between 1996 and 2009 was carried out. Thirty patients with IIM were identified. Female to male ratio was 1.7:1, with mean age at diagnosis 34.3 ± 9.2 (10-72) years with bimodal presentation at 21 and 49 years and a mean follow-up of 6.5 ± 5.7 years. Eleven patients had polymyositis (PM); 19 patients had dermatomyositis (DM); 1 patient had DM with malignancy; 2 patients had juvenile DM; and 2 patients had DM/PM with other rheumatologic diseases. Raynaud's phenomenon was present in 26% of patients, dysphagia in 40%, fever in 16%, arthralgia/arthritis in 26%, and dyspnea was present in 26% patients. Positive muscle biopsy and EMG were present in 81% and 92% of patients, respectively. Elevated serum creatinine kinase (CK), AST/ALT and LDH were found in 90%, 72%, and 88% of patients at presentation, respectively. Interstitial fibrosis identified on high-resolution computed tomography (HRCT) was found in 7/14 (50%) patients. Restrictive lung disease was present in 16/21 (76%), low diffusion capacity of lung of carbon monoxide (DLCO) in 10/17 (59%) and pulmonary hypertension in only 3/19 (16%) patients tested. Arab Jordanian patients with IIM showed very low prevalence of malignancy, lower mean age than previous reports, and similar other clinical, laboratory and serologic markers, and survival rate to previous reports. Of interest, we found that extra-muscular manifestations were mainly associated with dermatomyositis.

Mini mental status examination (MMSE) in stable chronic renal failure patients on hemodialysis: The effects of hemodialysis on the MMSE score. A prospective study.

Cognitive impairment is common in hemodialysis (HD) patients. The mini mental status examination is a simple screening test for dementia. The objectives of this study were to (1) study and compare the predialysis and postdialysis mini mental status examination score and 2 subscores and compare them with those of a control group and (2) determine the factors affecting these scores. This was a prospective study of 54 HD patients, which involved calculation of their predialysis (PrHDSc) and (2-4 weeks later) postdialysis (PoHDSc) scores and comparison of these with the control scores (CoSc). The mean scores for PreHDSc and PoHDSc were 26.5+/-2.7 and 26.4+/-3.3, respectively. Both were significantly lower than CoSc, 28.4+/-1.6 (95% CI for score difference 0.99-2.97, P<0.001). The subscores for orientation, registration, and recall (ORR) and attention (ATT) before and after HD were 14.2+/-1.3, 14.3+/-1.8, and 3.5+/-1.7, 3.2+/-1.8, respectively. Both were significantly lower than the CoSc, 15.2+/-1.2 and 4.2+/-1.1 (P=0.001 and 0.004, respectively). There were no significant differences between the PrHDSc and PoHDSc (P values of 0.87, 0.63, and 0.45, respectively). Patients' PrHDSc correlated positively with PoHDSc and dialysis efficiency measured by the urea reduction ratio and Kt/V (r=0.58, 0.4, and 0.34, respectively). Education level correlated positively with PrHDSc r=0.41 but not PoHDSc. Hemodialysis duration correlated negatively with PrHDSc r=-0.3. There was no correlation among age, chronic renal failure duration, HD frequency, weight loss, systolic or diastolic blood pressure drop, and PrHDSc or PoHDSc. Hemodialysis patients scored significantly less than the control patients. Their score was not affected by HD. This may reflect the stable cognitive function/dysfunction or the mild sensitivity of the test.

MRI documented acute myelitis in a patient with Vogt-Koyanagi-Harada syndrome: first report.

MRI findings in transverse myelitis complicating Vogt-Koyanagi-Harada (VKH) syndrome have not been documented before. Here, we present a case with acute myelitis complicating VKH syndrome and show the MRI findings.

Lipid profile in Jordanian patients with first ever ischemic stroke.

OBJECTIVE: To study the relationship between lipid profile, total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides (TG) in Jordanian patients admitted with first ever ischemic stroke (IS) to a teaching hospital over a 3-year-period, and compared them to a control group. METHODS: A retrospective case control study of all patients with diagnosis of IS who were admitted to the Jordan University Hospital, Amman, Jordan from January 2004 to December 2006 and had a documented fasting lipid profile within 48 hours of their admission. They were compared to controls without IS. RESULTS: Ninety-eight patients with IS were studied and compared to 98 control subjects. Both patients and control groups were similar regarding age, gender distribution, prevalence of hypertension, diabetes mellitus, ischemic heart disease (IHD), and smoking. The lipid profile showed a significantly lower HDL level in IS patients compared to the control group. There were no significant differences between the patients and control regarding TC, LDL, or TG levels. Control group used statins more frequently than patients (28% versus 10%, p=0.002). Both groups had high prevalence of risk factors. CONCLUSION: Though this study is limited by its retrospective design, it suggests that IS patients have significantly lower levels of HDL.

Nonconvulsive status epilepticus: high incidence in dialysis-dependent patients.

Nonconvulsive status epilepticus is defined as a mental status change from baseline of at least a 30-min duration associated with constant or near-continuous ictal discharges on an electroencephalogram (EEG). Nonconvulsive status epilepticus is an often-overlooked diagnosis as a cause of acute confusional state. There are few case reports in dialysis patients. We are reporting 5 patients on chronic dialysis treatment who presented with an acute confusional state. Nonconvulsive status epilepticus was diagnosed by EEG and response to intravenous benzodiazepines. We recommend early EEG to be considered in the evaluation of dialysis patients with an acute confusional state.