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  1. Jose S, Tan SW, Ooi YY, Ramasamy R, Vidyadaran S
    J Neuroinflammation, 2014;11:149.
    PMID: 25182840 DOI: 10.1186/s12974-014-0149-8
    Progression of neurodegenerative diseases occurs when microglia, upon persistent activation, perpetuate a cycle of damage in the central nervous system. Use of mesenchymal stem cells (MSC) has been suggested as an approach to manage microglia activation based on their immunomodulatory functions. In the present study, we describe the mechanism through which bone marrow-derived MSC modulate the proliferative responses of lipopolysaccharide-stimulated BV2 microglia.
  2. Ooi YY, Rahmat Z, Jose S, Ramasamy R, Vidyadaran S
    World J Stem Cells, 2013 Jan 26;5(1):34-42.
    PMID: 23362438 DOI: 10.4252/wjsc.v5.i1.34
    To assess the capacity to isolate and expand mesenchymal stem cells (MSC) from bone marrow of CBA/Ca, ICR and Balb/c mice.
  3. Jose S, Tan SW, Tong CK, Vidyadaran S
    Cell Biol Int, 2015 Dec;39(12):1355-63.
    PMID: 26194799 DOI: 10.1002/cbin.10516
    Microglia are resident macrophages of the central nervous system (CNS). Apart from playing vital roles as sentinel cells, they are crucial in physiological processes such as synaptic pruning during brain development. CNS disorders require an understanding of the contribution of each cellular compartment to the pathogenesis. Elucidating the role of microglia in disease development and progression in the intricate CNS environment is technically challenging and requires the establishment of reliable, reproducible techniques to isolate and culture microglia. A number of different protocols have been developed for isolation of neonatal microglia and here we compare two widely used methods, namely, mild trypsinization and EasySep® magnetic separation. EasySep® magnetic separation provided higher microglia yield, and flow cytometric evaluation of CD11b and F4/80 markers revealed that EasySep® separation method also produced significantly higher purity compared to mild trypsinization. Microglia isolated using EasySep® separation method were functional, as demonstrated by the generation of nitric oxide, IL-6, TNF-α, and MCP-1 in response to lipopolysaccharide stimulation. In summary, this study has revealed that magnetic separation is superior to mild trypsinization in terms of yield and purity of microglia.
  4. Liy PM, Puzi NNA, Jose S, Vidyadaran S
    Exp Biol Med (Maywood), 2021 11;246(22):2399-2406.
    PMID: 33715528 DOI: 10.1177/1535370221997052
    Nitric oxide is a versatile mediator formed by enzymes called nitric oxide synthases. It has numerous homeostatic functions and important roles in inflammation. Within the inflamed brain, microglia and astrocytes produce large amounts of nitric oxide during inflammation. Excessive nitric oxide causes neuronal toxicity and death and mesenchymal stem cells can be used as an approach to limit the neuronal damage caused by neuroinflammation. Mesenchymal stem cell therapy ameliorates inflammation and neuronal damage in disease models of Alzheimer's disease, Parkinson's disease, and other neuroinflammatory disorders. Interestingly, we have reported that in vitro, mesenchymal stem cells themselves contribute to a rise in nitric oxide levels through microglial cues. This may be an undesirable effect and highlights a possible need to explore acellular approaches for mesenchymal stem cell therapy in the central nervous system.
  5. Hafez P, Jose S, Chowdhury SR, Ng MH, Ruszymah BH, Abdul Rahman Mohd R
    Cell Biol Int, 2016 Jan;40(1):55-64.
    PMID: 26289249 DOI: 10.1002/cbin.10536
    The alarming rate of increase in myocardial infarction and marginal success in efforts to regenerate the damaged myocardium through conventional treatments creates an exceptional avenue for cell-based therapy. Adult bone marrow mesenchymal stem cells (MSCs) can be differentiated into cardiomyocytes, by treatment with 5-azacytidine, thus, have been anticipated as a therapeutic tool for myocardial infarction treatment. In this study, we investigated the ability of basic fibroblastic growth factor (bFGF) and hydrocortisone as a combined treatment to stimulate the differentiation of MSCs into cardiomyocytes. MSCs were isolated from sternal marrow of patients undergoing heart surgery (CABG). The isolated cells were initially monitored for the growth pattern, followed by characterization using ISCT recommendations. Cells were then differentiated using a combination of bFGF and hydrocortisone and evaluated for the expression of characteristic cardiac markers such as CTnI, CTnC, and Cnx43 at protein level using immunocytochemistry and flow cytometry, and CTnC and CTnT at mRNA level. The expression levels and pattern of the cardiac markers upon analysis with ICC and qRT-PCR were similar to that of 5-azacytidine induced cells and cultured primary human cardiomyocytes. However, flow cytometric evaluation revealed that induction with bFGF and hydrocortisone drives MSC differentiation to cardiomyocytes with a marginally higher efficiency. These results indicate that combination treatment of bFGF and hydrocortisone can be used as an alternative induction method for cardiomyogenic differentiation of MSCs for future clinical applications.
  6. Hafez P, Chowdhury SR, Jose S, Law JX, Ruszymah BHI, Mohd Ramzisham AR, et al.
    Cardiovasc Eng Technol, 2018 09;9(3):529-538.
    PMID: 29948837 DOI: 10.1007/s13239-018-0368-8
    Developing experimental models to study ischemic heart disease is necessary for understanding of biological mechanisms to improve the therapeutic approaches for restoring cardiomyocytes function following injury. The aim of this study was to develop an in vitro hypoxic/re-oxygenation model of ischemia using primary human cardiomyocytes (HCM) and define subsequent cytotoxic effects. HCM were cultured in serum and glucose free medium in hypoxic condition with 1% O2 ranging from 30 min to 12 h. The optimal hypoxic exposure time was determined using Hypoxia Inducible Factor 1α (HIF-1α) as the hypoxic marker. Subsequently, the cells were moved to normoxic condition for 3, 6 and 9 h to replicate the re-oxygenation phase. Optimal period of hypoxic/re-oxygenation was determined based on 50% mitochondrial injury via 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay and cytotoxicity via lactate dehydrogenase (LDH) assay. It was found that the number of cells expressing HIF-1α increased with hypoxic time and 3 h was sufficient to stimulate the expression of this marker in all the cells. Upon re-oxygenation, mitochondrial activity reduced significantly whereas the cytotoxicity increased significantly with time. Six hours of re-oxygenation was optimal to induce reversible cell injury. The injury became irreversible after 9 h as indicated by > 60% LDH leakage compared to the control group cultured in normal condition. Under optimized hypoxic reoxygenation experimental conditions, mesenchymal stem cells formed nanotube with ischemic HCM and facilitated transfer of mitochondria suggesting the feasibility of using this as a model system to study molecular mechanisms of myocardial injury and rescue.
  7. HIV-CAUSAL Collaboration, Cain LE, Phillips A, Olson A, Sabin C, Jose S, et al.
    Clin Infect Dis, 2015 Apr 15;60(8):1262-8.
    PMID: 25567330 DOI: 10.1093/cid/ciu1167
    BACKGROUND: Current clinical guidelines consider regimens consisting of either ritonavir-boosted atazanavir or ritonavir-boosted lopinavir and a nucleoside reverse transcriptase inhibitor (NRTI) backbone among their recommended and alternative first-line antiretroviral regimens. However, these guidelines are based on limited evidence from randomized clinical trials and clinical experience.

    METHODS: We compared these regimens with respect to clinical, immunologic, and virologic outcomes using data from prospective studies of human immunodeficiency virus (HIV)-infected individuals in Europe and the United States in the HIV-CAUSAL Collaboration, 2004-2013. Antiretroviral therapy-naive and AIDS-free individuals were followed from the time they started a lopinavir or an atazanavir regimen. We estimated the 'intention-to-treat' effect for atazanavir vs lopinavir regimens on each of the outcomes.

    RESULTS: A total of 6668 individuals started a lopinavir regimen (213 deaths, 457 AIDS-defining illnesses or deaths), and 4301 individuals started an atazanavir regimen (83 deaths, 157 AIDS-defining illnesses or deaths). The adjusted intention-to-treat hazard ratios for atazanavir vs lopinavir regimens were 0.70 (95% confidence interval [CI], .53-.91) for death, 0.67 (95% CI, .55-.82) for AIDS-defining illness or death, and 0.91 (95% CI, .84-.99) for virologic failure at 12 months. The mean 12-month increase in CD4 count was 8.15 (95% CI, -.13 to 16.43) cells/µL higher in the atazanavir group. Estimates differed by NRTI backbone.

    CONCLUSIONS: Our estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a greater 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for atazanavir compared with lopinavir regimens.

  8. Lodi S, Phillips A, Logan R, Olson A, Costagliola D, Abgrall S, et al.
    Lancet HIV, 2015 Aug;2(8):e335-43.
    PMID: 26423376 DOI: 10.1016/S2352-3018(15)00108-3
    BACKGROUND: Recommendations have differed nationally and internationally with respect to the best time to start antiretroviral therapy (ART). We compared effectiveness of three strategies for initiation of ART in high-income countries for HIV-positive individuals who do not have AIDS: immediate initiation, initiation at a CD4 count less than 500 cells per μL, and initiation at a CD4 count less than 350 cells per μL.

    METHODS: We used data from the HIV-CAUSAL Collaboration of cohort studies in Europe and the USA. We included 55,826 individuals aged 18 years or older who were diagnosed with HIV-1 infection between January, 2000, and September, 2013, had not started ART, did not have AIDS, and had CD4 count and HIV-RNA viral load measurements within 6 months of HIV diagnosis. We estimated relative risks of death and of death or AIDS-defining illness, mean survival time, the proportion of individuals in need of ART, and the proportion of individuals with HIV-RNA viral load less than 50 copies per mL, as would have been recorded under each ART initiation strategy after 7 years of HIV diagnosis. We used the parametric g-formula to adjust for baseline and time-varying confounders.

    FINDINGS: Median CD4 count at diagnosis of HIV infection was 376 cells per μL (IQR 222-551). Compared with immediate initiation, the estimated relative risk of death was 1·02 (95% CI 1·01-1·02) when ART was started at a CD4 count less than 500 cells per μL, and 1·06 (1·04-1·08) with initiation at a CD4 count less than 350 cells per μL. Corresponding estimates for death or AIDS-defining illness were 1·06 (1·06-1·07) and 1·20 (1·17-1·23), respectively. Compared with immediate initiation, the mean survival time at 7 years with a strategy of initiation at a CD4 count less than 500 cells per μL was 2 days shorter (95% CI 1-2) and at a CD4 count less than 350 cells per μL was 5 days shorter (4-6). 7 years after diagnosis of HIV, 100%, 98·7% (95% CI 98·6-98·7), and 92·6% (92·2-92·9) of individuals would have been in need of ART with immediate initiation, initiation at a CD4 count less than 500 cells per μL, and initiation at a CD4 count less than 350 cells per μL, respectively. Corresponding proportions of individuals with HIV-RNA viral load less than 50 copies per mL at 7 years were 87·3% (87·3-88·6), 87·4% (87·4-88·6), and 83·8% (83·6-84·9).

    INTERPRETATION: The benefits of immediate initiation of ART, such as prolonged survival and AIDS-free survival and increased virological suppression, were small in this high-income setting with relatively low CD4 count at HIV diagnosis. The estimated beneficial effect on AIDS is less than in recently reported randomised trials. Increasing rates of HIV testing might be as important as a policy of early initiation of ART.

    FUNDING: National Institutes of Health.

  9. Al Hashmi AM, Shuaib A, Imam Y, Amr D, Humaidan H, Al Nidawi F, et al.
    Front Neurol, 2022;13:1016376.
    PMID: 36408502 DOI: 10.3389/fneur.2022.1016376
    Background: Acute stroke care is complex and requires multidisciplinary networking. There are insufficient data on stroke care in the Middle East and adjacent regions in Asia and Africa.

    Objective: Evaluate the state of readiness of stroke programs in the Middle East North Africa and surrounding regions (MENA+) to treat acute stroke.

    Method: Online questionnaire survey on the evaluation of stroke care across hospitals of MENA+ region between April 2021 and January 2022.

    Results: The survey was completed by 34/50 (68%) hospitals. The median population serviced by participating hospitals was 2 million. The median admission of patients with stroke/year was 600 (250-1,100). The median length of stay at the stroke units was 5 days. 34/34 (100%) of these hospitals have 24/7 CT head available. 17/34 (50%) have emergency guidelines for prehospital acute stroke care. Mechanical thrombectomy with/without IVT was available in 24/34 (70.6%). 51% was the median (IQR; 15-75%) of patients treated with IVT within 60 min from arrival. Thirty-five minutes were the median time to reverse warfarin-associated ICH.

    Conclusion: This is the first large study on the availability of resources for the management of acute stroke in the MENA+ region. We noted the disparity in stroke care between high-income and low-income countries. Concerted efforts are required to improve stroke care in low-income countries. Accreditation of stroke programs in the region will be helpful.

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