Clinical characteristics and outcomes of COVID-19 patients in Bali, Indonesia.

INTRODUCTION: The spectrum of illness and outcomes of coronavirus disease 2019 (COVID-19) patients may vary. This study reports the characteristics of COVID-19 patients in Bali, Indonesia, and evaluates the diagnostic value of their clinical symptoms. METHOD: This observational study was conducted in eight hospitals. The patients were classified as non-severe COVID-19, severe COVID-19, and non-COVID-19. Demographics, clinical, laboratory, and radiologic characteristics, and outcomes of COVID-19 patients were collected. Factors associated with the severity and outcomes were assessed using the chi-squared test or ANOVA when appropriate. We also compared the clinical features of non-severe COVID-19 and non-COVID-19 patients to evaluate the diagnostic accuracy. RESULTS: This study included 92 patients: 41 non-COVID-19 and 51 COVID-19 patients, comprising 45 non-severe and six severe cases. The most common symptoms of COVID-19 were cough (47.1%), fever (31.0%), and dyspnea (25.3%). Cough, fatigue, and anosmia have high accuracy, and combining these complaints in clinical diagnostics offered a higher accuracy in predicting COVID-19 patients (60.1%). We found lower lymphocyte counts and interleukin-1R levels and higher levels of C-reactive protein, interleukin-6, and interleukin-8 in severe compared than in non-severe COVID-19 patients. Lactate dehydrogenase was associated with intensive care unit admission and ventilator use, while other markers such as neutrophil-lymphocyte ratio, C-reactive protein, and interleukin-6 were not. CONCLUSION: A battery of symptoms, including cough, fatigue, and anosmia, is likely associated with COVID-19 in Bali. Clinicians should be aware of these symptoms to ensure a prompt diagnostic test for COVID-19, beyond other causes of acute febrile illnesses.

Silver Sulfadiazine's Effect on Keratin-19 Expression as Stem Cell Marker in Burn Wound Healing.

BACKGROUND: Burn wounds are one of the causes of cutaneous injury that involve both epidermal and dermal layers of skin. Silver sulfadiazine (SSD) has been widely used to treat burn wounds, however recent studies have found the treatment to have some drawbacks, such as cellular toxicity effects. Cutaneous wound regeneration is known to start from the basal layer of the epidermal epithelial cells, which are enriched with highly proliferative cells. Keratin-19 (K19) is one of the epidermal stem cell biomarkers found in the skin. This study aims to explore the expression of K19 in burn wound tissue and to investigate the effect of SSD on its expression. METHODS: We created a burn wound model in Sprague Dawley rats and randomly divided them into control and SSD groups. Wound closure was evaluated (visitrak) overtime series followed by histological evaluation of K19 expression in the wound tissue (immunohistochemistry staining). RESULTS: Our model successfully represents full-thickness damage caused by a burn wound. The SSD group showed a faster reduction of wound surface area (wound closure) compared to the control group with the peak at day 18 post wounding (p < 0.05). K19 expression was found in both groups and was distributed on epidermal layers, hair follicles and dermis of granulation tissue showing similar patterns. CONCLUSION: Topical application of SSD on burn wounds showed superiority in wound closure and is likely to have no harmful effect on epidermal stem cells. However, further study is required to investigate the effect of silver species on cell viability and toxicity effects during long term treatment.

Dengue viral infection in Indonesia: Epidemiology, diagnostic challenges, and mutations from an observational cohort study.

BACKGROUND: Dengue virus (DENV) infection is a major cause of acute febrile illness in Indonesia. Diagnostic inaccuracy may occur due to its varied and non-specific presentation. Characterization of DENV epidemiology, clinical presentation, and virology will facilitate appropriate clinical management and public health policy. METHODOLOGY/PRINCIPAL FINDINGS: A multicenter observational cohort study was conducted in Indonesia to assess causes of acute fever requiring hospitalization. Clinical information and specimens were collected at enrollment, 14-28 days, and 3 months from 1,486 children and adults. Total of 468 (31.9%) cases of DENV infection were confirmed by reference laboratory assays. Of these, 414 (88.5%) were accurately diagnosed and 54 had been misdiagnosed as another infection by sites. One hundred initially suspected dengue cases were finally classified as 'non-dengue'; other pathogens were identified in 58 of those cases. Mortality of DENV infection was low (0.6%). Prior DENV exposure was found in 92.3% of subjects >12 years. DENV circulated year-round in all cities, with higher incidence from January to March. DENV-3 and DENV-1 were the predominant serotypes. This study identified DENV-1 with TS119(C→T) substitution in the serotyping primer annealing site, leading to failure of serotype determination. CONCLUSIONS/SIGNIFICANCE: DENV is a common etiology of acute febrile illness requiring hospitalization in Indonesia. Diagnostic accuracy at clinical sites merits optimization since misdiagnosis of DENV infection and over-estimation of dengue can negatively impact management and outcomes. Mutation at the annealing site of the serotyping primer may confound diagnosis. Clinicians should consider following diagnostic algorithms that include DENV confirmatory testing. Policy-makers should prioritize development of laboratory capacity for diagnosis of DENV.

The role of Notch signaling in diabetic endothelial progenitor cells dysfunction.

AIMS: To investigate the role of Notch signaling pathway in vasculogenic dysfunction of diabetic EPCs (DM-EPCs). METHODS: The study was performed in mice and diabetes was induced with Streptozotocin. The functional consequences of Notch pathway modulation were studied by assessment of colony forming capacity (EPC colony forming assay), EPC differentiation capacity (% of definitive EPC-CFU (dEPC-CFU)), circulating EPCs (EPC culture assay) and migrated cells (migration assay); in the presence of Notch inhibitor (γ-secretase inhibitors (GSI)) compared to control. Notch pathway and VEGF involvement in DM- EPCs were assessed by gene expression (RT-qPCR). RESULTS: DM demonstrated to increase Notch pathway expression in bone marrow (BM) EPCs followed by lower EPC-CFU number, EPCs differentiation capacity, number of circulating EPCs, migrated cells and VEGF expression compared to control (p<0.05). Inhibition of Notch pathway by GSI rescued vasculogenic dysfunction in DM-EPCs as represented by increase in EPC-CFU number, differentiation capacity and number of circulating EPCs (p<0.05). CONCLUSION: Our findings indicate the involvement of Notch pathway in mediating DM-EPCs dysfunction including less number of EPC-CFU, circulating EPCs and migrated cell number compared to control. Further in vitro inhibition of Notch pathway by GSI rescued DM-EPC dysfunction. Therefore targeting Notch pathway in DM may provide a target to restore DM-EPC dysfunction.

Introduction to next generation of endothelial progenitor cell therapy: a promise in vascular medicine.

The concept of Endothelial Progenitor Cells (EPCs) therapy for adult neovascularization has continuously received attention. They are believed to participate in endothelial repair and post natal angiogenesis due to their abilities in differentiating into endothelial cells and producing protective cytokines and growth factors. Abundant evidence supports the involvement of EPCs in capillary growth and in participating in the formation of collateral vessels, which lead to improved vascular perfusion and functional recovery in target tissue. Autologous EPC now is becoming a novel treatment option for therapeutic revascularization and vascular repair in ischemic diseases. However, various diseases such as diabetes, heart disease and ischemic diseases are related to EPC dysfunction and give rise to additional challenges of autologous EPC therapy. A novel strategy to enhance the number and function of EPCs is needed to be established to provide successful autologous EPCs therapy. Currently, clinical trials for the new generation of EPC therapy in treating peripheral ischemic diseases are underway. In this review we provide an overview and the limitations of current EPCs therapy with an introduction to the new strategies of next generation EPC therapy for more promising vascular and tissue regeneration therapy.

Oxidative stress tolerance of early stage diabetic endothelial progenitor cell.

INTRODUCTION: One of the causes for poor vasculogenesis of diabetes mellitus (DM) is known to rise from the dysfunction of bone marrow-derived endothelial progenitor cells (BM EPCs). However, the origin of its cause is less understood. We aimed to investigate the effect of oxidative stress in early stage of diabetic BM-EPC and whether its vasculogenic dysfunction is caused by oxidative stress. METHODS: Bone marrow c-Kit+Sca-1+Lin- (BM-KSL) cells were sorted from control and streptozotocin-induced diabetic C57BL6J mice by flow cytometry. BM-KSLs were then assessed for vasculogenic potential (colony forming assay; EPC-CFA), accumulation of intracellular ROS (CM-H2DCFDA), carbonylated protein (ELISA), anti-oxidative enzymes expression (RT-qPCR) and catalase activity (Amplex Red). RESULTS: Compared to control, DM BM-KSL had significantly lower EPC-CFUs in both definitive EPC-CFU and total EPC-CFU (p < 0.05). Interestingly, the oxidative stress level of DM BM-KSL was comparable and was not significantly different to control followed by increased in anti-oxidative enzymes expression and catalase activity. CONCLUSIONS: Primitive BM-EPCs showed vasculogenic dysfunction in early diabetes. However the oxidative stress is not denoted as the major initiating factor of its cause. Our results suggest that primitive BM-KSL cell has the ability to compensate oxidative stress levels in early diabetes by increasing the expression of anti-oxidative enzymes.

Anagliptin, a DPP-4 inhibitor, suppresses proliferation of vascular smooth muscles and monocyte inflammatory reaction and attenuates atherosclerosis in male apo E-deficient mice.

Dipeptyl peptidase-4 (DPP-4) inhibitors modulate the progression of atherosclerosis. To gain insights into their mechanism of action, 9-wk-old male apolipoprotein E (apoE)-deficient mice were fed a DPP-4 inhibitor, anagliptin-containing diet. The effects of anagliptin were investigated in, a monocyte cell line, human THP-1 cells, and rat smooth muscle cells (SMCs). Treatment with anagliptin for 16 wk significantly reduced accumulation of monocytes and macrophages in the vascular wall, SMC content in plaque areas, and oil red O-stained area around the aortic valve without affecting glucose tolerance or body weight. Serum DPP-4 concentrations were significantly higher in apoE-deficient mice than control mice, and the levels increased with aging, suggesting the involvement of DPP-4 in the progression of atherosclerosis. Indeed, soluble DPP-4 augmented cultured SMC proliferation, and anagliptin suppressed the proliferation by inhibiting ERK phosphorylation. In THP-1 cells, anagliptin reduced lipopolysaccharide-induced TNF-α production with inhibiting ERK phosphorylation and nuclear translocation of nuclear factor-κB. Quantitative analysis also showed that anagliptin reduced the area of atherosclerotic lesion in apoE-deficient mice. These results indicated that the anti-atherosclerotic effect of anagliptin is mediated, at least in part, through its direct inhibition of SMC proliferation and inflammatory reaction of monocytes.