Future of medical research in Sri Lanka: amidst economic chaos.

Sri Lanka is facing an economic crisis and medical research is significantly affected at present with researchers facing many obstacles. Urgent remedial measures are required to overcome the current situation if medical research is to continue in Sri Lanka.

A comparison of changes in venous lactate and haematocrit during fluid resuscitation of dengue haemorrhagic fever.

BACKGROUND: Judicious fluid resuscitation and stringent monitoring of clinical parameters improve the outcome of dengue haemorrhagic fever (DHF). The usefulness of serum lactate to monitor adequate fluid therapy has not been adequately explored. METHODS: An observational study was conducted in Sri Lanka, recruiting 162 DHF patients within 12 h of diagnosis of the critical phase. Venous lactate level was measured at each time of performing haematocrit (HCT), using a prevalidated handheld lactate analyser. RESULTS: The median venous lactate level was 1.3 (range 0.3-6) mmol/L in the study population and 154 (95.2%) patients had median lactate levels of <2 mmol/L. The HCT values in the study participants ranged from 28 to 62, with a median value of 43. There was no statistically significant correlation between the lactate and HCT values obtained at the same time. A significant reduction in venous lactate was not observed following the administration of fluid boluses. The expected reduction in HCT was seen following the administration of dextran and crystalloid/dextran combination. The maximum recorded lactate level positively correlated with the duration of hospital stay. CONCLUSIONS: This study concludes that venous lactate is not an appropriate parameter with which to monitor the response to fluid therapy in uncomplicated DHF.

An international multidisciplinary consensus statement on MAFLD and the risk of CVD.

BACKGROUND: Fatty liver disease in the absence of excessive alcohol consumption is an increasingly common condition with a global prevalence of ~ 25-30% and is also associated with cardiovascular disease (CVD). Since systemic metabolic dysfunction underlies its pathogenesis, the term metabolic (dysfunction)-associated fatty liver disease (MAFLD) has been proposed for this condition. MAFLD is closely intertwined with obesity, type 2 diabetes mellitus and atherogenic dyslipidemia, which are established cardiovascular risk factors. Unlike CVD, which has received attention in the literature on fatty liver disease, the CVD risk associated with MAFLD is often underestimated, especially among Cardiologists. METHODS AND RESULTS: A multidisciplinary panel of fifty-two international experts comprising Hepatologists, Endocrinologists, Diabetologists, Cardiologists and Family Physicians from six continents (Asia, Europe, North America, South America, Africa and Oceania) participated in a formal Delphi survey and developed consensus statements on the association between MAFLD and the risk of CVD. Statements were developed on different aspects of CVD risk, ranging from epidemiology to mechanisms, screening, and management. CONCULSIONS: The expert panel identified important clinical associations between MAFLD and the risk of CVD that could serve to increase awareness of the adverse metabolic and cardiovascular outcomes of MAFLD. Finally, the expert panel also suggests potential areas for future research.

Polymyalgia rheumatica presenting as sternoclavicular arthritis: a case report.

BACKGROUND: Polymyalgia rheumatica and giant cell arteritis are systemic inflammatory conditions of the elderly. Polymyalgia rheumatica classically presents as a bilateral proximal muscle pain and stiffness syndrome. Biceps tenosynovitis is the commonest pathology in polymyalgia rheumatica. However according to literature, erosive sternoclavicular arthritis is a rare association of polymyalgia rheumatica. Giant cell arteritis is an inflammatory granulomatous arteritis predominantly involving large cerebral arteries. Thus, its classic clinical presentation includes severe headache with scalp tenderness, jaw claudication, and sudden painless loss of vision. Urological manifestations (prostatic vasculitis and epididymo-orchitis) were seldom reported in giant cell arteritis. CASE PRESENTATION: A 53-year-old Sinhalese man presented with progressive right-sided shoulder joint pain and neck pain associated with constitutional symptoms and episodic generalized headache. Examination revealed restricted movements of the right shoulder joint with nontender pulsatile bilateral temporal arteries. Blood testing showed elevated erythrocyte sedimentation rate and C-reactive protein. Color Doppler ultrasound of the superficial temporal artery revealed "halo sign." The temporal artery showed infiltration of mononuclear cells in the arterial media and adventitia. Computed tomography revealed right sternoclavicular arthritis with incidental finding of ureteric stricture. The patient was treated with high-dose oral prednisolone, and good clinical and biochemical response was observed during follow-up. CONCLUSION: Polymyalgia rheumatica-giant cell arteritis may rarely present as erosive sternoclavicular arthritis as the initial manifestation, mimicking many rheumatological conditions. Urological involvement such as ureteric strictures may be rare associations of primary systemic vasculitis. A high degree of suspicion combined with targeted investigations would allow early identification the polymyalgia rheumatica-giant cell arteritis syndrome in the presence of atypical manifestations, leading to improved patient outcomes.

Neutrophil Lymphocyte Ratio as a Marker of In-Hospital Deterioration in COVID-19: Observations From a Resource Constraint Setting.

Introduction and Objectives: The study was conducted to assess the association of neutrophil lymphocyte ratio (NLR) in COVID-19 and to identify the cut-off value that predicts mortality, need of respiratory support and admission to high-dependency or intensive care. Methods: A retrospective observational study was conducted to collect demographic data, clinical variables, the neutrophil-lymphocyte ratio on-admission and the outcome of confirmed COVID-19 patients admitted to a tertiary care center in Sri Lanka. Results: There were 208 patients with a median age of 56 years (IQR 43-67) and 98 (47.1%) males. The median neutrophil count was 4.07 × 103/µL (IQR 2.97-6.79) and the median lymphocyte count was 1.74 × 103/µL (IQR 1.36-4.75). The calculated NLR ranged from 0.12 to 48.28 with a median value of 2.32 (IQR 1.37-4.76). A NLR value >3.6 predicted development of severe disease requiring respiratory support, transfer to a high-dependency or an intensive care unit and/or succumbing to the illness with a sensitivity 80% and specificity 80% (area under the curve 0.8, 95% CI 0.72-0.88, P < .0001). The adjusted odds ratio of NLR > 3.6 on predicting severe disease was 11.1, 95% CI 4.5- 27.0, P < .0001. Conclusions: A NLR > 3.6 is a useful variable to be included in risk prediction scores in Sri Lanka.

Antiviral effects of deoxynojirimycin (DNJ)-based iminosugars in dengue virus-infected primary dendritic cells.

Dendritic cells (DCs) are important targets for dengue virus (DENV) infection and play a significant role in the early immune response. Antiviral effects of iminosugars against DENV in primary cells have been demonstrated previously in monocyte-derived macrophages (MDMΦs). Given the important role played by DCs in innate immune defense against DENV, the antiviral effects of three deoxynojirimycin (DNJ) derivatives (NN-DNJ, EOO-DNJ and 2THO-DNJ) and a deoxygalactonojirimycin (DGJ) negative control were evaluated in DENV-infected primary human monocyte-derived immature DCs (imDCs). DNJ- but not DGJ-derivatives elicited antiviral activity in DENV-infected imDCs, similar to that observed in MDMΦs. The DNJ-derivatives inhibited DENV secretion in a dose-dependent manner. Endoplasmic reticulum (ER) α-glucosidase I inhibition by DNJ-derived iminosugars, at concentrations of 3.16 µM, correlated with a reduction in the specific infectivity of virions that were still secreted, as well as a reduction in DENV-induced tumour necrosis factor alpha secretion. This suggests iminosugar-mediated ER α-glucosidase I inhibition may give rise to further benefits during DENV infection, beyond the reduction in viral secretion associated with ER α-glucosidase II inhibition.

Pathogen-induced inflammation is attenuated by the iminosugar MON-DNJ via modulation of the unfolded protein response.

Sepsis is a life-threatening condition involving a dysregulated immune response to infectious agents that cause injury to host tissues and organs. Current treatments are limited to early administration of antibiotics and supportive care. While appealing, the strategy of targeted inhibition of individual molecules in the inflammatory cascade has not proved beneficial. Non-targeted, systemic immunosuppression with steroids has shown limited efficacy and raises concern for secondary infection. Iminosugars are a class of small molecule glycomimetics with distinct inhibition profiles for glycan processing enzymes based on stereochemistry. Inhibition of host endoplasmic reticulum resident glycoprotein processing enzymes has demonstrated efficacy as a broad-spectrum antiviral strategy, but limited consideration has been given to the effects on host glycoprotein production and consequent disruption of signalling cascades. This work demonstrates that iminosugars inhibit dengue virus, bacterial lipopolysaccharide and fungal antigen-stimulated cytokine responses in human macrophages. In spite of decreased inflammatory mediator production, viral replication is suppressed in the presence of iminosugar. Transcriptome analysis reveals the key interaction of pathogen-induced endoplasmic reticulum stress, the resulting unfolded protein response and inflammation. Our work shows that iminosugars modulate these interactions. Based on these findings, we propose a new therapeutic role for iminosugars as treatment for sepsis-related inflammatory disorders associated with excess cytokine secretion.

Aseptic meningitis as the initial presentation of Leptospira borgpetersenii serovar Tarassovi: two case reports and a literature review.

BACKGROUND: Leptospirosis is a zoonotic illness caused by pathogenic spirochetes of the genus Leptospira. The disease spectrum ranges from a mild influenza-like presentation to a more serious Weil's syndrome. Leptospirosis rarely presents as a primary neurological syndrome. We report two cases of Leptospira borgpetersenii serovar Tarasssovi presenting as aseptic meningitis in Sri Lanka. CASE PRESENTATION: We describe case reports of two patients presenting as symptomatic aseptic meningitis due to neuroleptospirosis. Both patients had significant neurological involvement at presentation in the absence of common clinical features of leptospirosis. These patients were initially managed as bacterial or viral meningitis and leptospirosis was suspected due to a history of exposure to contaminated water. Subsequently, they were diagnosed to have neuroleptospirosis by positive Leptospira serology and both patients gained full recovery. CONCLUSION: Our report highlights the importance of considering leptospirosis as a differential diagnosis in patients with aseptic meningitis in endemic settings. Obtaining a detailed occupational and recreational history is helpful in diagnosing neuroleptospirosis promptly. We report the association of Leptospira borgpetersenii serovar (sv.) Tarassovi (strain bakeri) in causing aseptic meningitis, which has not been reported to the best of our knowledge.

The role of the unfolded protein response in dengue virus pathogenesis.

Symptomatic dengue virus (DENV) infections range from mild fever to severe haemorrhagic disease and death. Host-viral interactions play a significant role in deciding the fate of the infection. The unfolded protein response (UPR) is a prosurvival cellular reaction induced in response to DENV-mediated endoplasmic reticulum stress. The UPR has complex interactions with the cellular autophagy machinery, apoptosis, and innate immunity. DENV has evolved to manipulate the UPR to facilitate its replication and to evade host immunity. Our knowledge of this intertwined network of events is continuously developing. A better understanding of the UPR mediated antiviral and proviral effects will shed light on dengue disease pathogenesis and may help development of anti-DENV therapeutics. This review summarizes the role of the UPR in viral replication, autophagy, and DENV-induced inflammation to describe how a host response contributes to DENV pathogenesis.

Non alcoholic fatty liver disease increases the mortality from acute coronary syndrome: an observational study from Sri Lanka.

BACKGROUND: Non alcoholic fatty liver disease is an independent risk factor for coronary artery disease. But its effect on acute coronary syndrome is not clear. We performed this study to identify the prevalence of NAFLD in patients with ACS admitted to a tertiary care center in Sri Lanka. We also described the association of NAFLD with the severity of ACS predicted by the GRACE score. METHODS: We performed a descriptive study including all consecutive patients with non-fatal ACS admitted to Colombo South Teaching Hospital from 01/02/2014 to 30/04/2014. Patients with excessive alcohol consumption, established cirrhosis and patients with identified risk factors for liver disease were excluded from the study. All patients underwent ultrasound scan of liver. RESULTS: There were 120 participants, 75 (62.5%) males and 45 (37.5%) females with acute coronary syndrome. Average age was 61.28 ± 11.83 years. NAFLD was seen in 56 (46.7%) patients with ACS. Patients with NAFLD had a higher GRACE score than patients without NAFLD (120.2 ± 26.9 Vs 92.3 ± 24.2, p < 0.001). Increased age and presence of NAFLD conferred a higher mortality risk from ACS as predicted by GRACE score. Patients with NAFLD had a higher predicted mortality during in-ward stay (adjusted OR 31.3, CI 2.2-439.8, p = 0.011) and at 6 months after discharge (adjusted OR 15.59, CI 1.6-130.6, p = 0.011). CONCLUSIONS: Patients with NAFLD have a higher predicted mortality from acute coronary syndrome and thus require aggressive treatment of CAD. It is important to consider this novel risk factor when risk stratifying patients with ACS.

Myocarditis causing severe heart failure--an unusual early manifestation of leptospirosis: a case report.

BACKGROUND: Leptospirosis is the most widespread zoonosis in the world. Cardiac involvement is a frequent complication of leptospirosis although significant left ventricular dysfunction is rare. We report a case of fatal leptospira myocarditis leading to cardiogenic shock on the second day of illness. This early occurrence of myocarditis is not previously reported. CASE PRESENTATION: A 36-yr-old previously healthy Sri Lankan male who takes care of a horse presented to the medical casualty ward with a one day history of fever, arthralgia and severe myalgia. He developed hypotension on the second day of illness. Electrocardiogram showed sinus tachycardia with ST segment depression in lateral leads which evolved in to rapid atrial fibrillation in the subsequent days. 2D echocardiogram showed dilated cardiac chambers with severe global hypokinesia and an ejection fraction of 20%. His renal and liver functions were within normal limits. He developed multi organ dysfunction syndrome and refractory shock, later in the course of illness. Leptospirosis was confirmed by positive leptospira IgM and negative IgG. Patient died on the fifth day of illness despite optimal medical treatment with intravenous penicillin, meropenem, levofloxacin, inotropes and supportive care in the intensive care unit. CONCLUSIONS: We describe a rare and unusual early complication of leptospirosis which has not been reported before. It is important to bear in mind that leptospirosis could present as myocarditis during the early phase of illness.