BanLec, a banana lectin, is a potent inhibitor of Middle East respiratory syndrome coronavirus in in vitro assays

Poster Abstract Session - Viral Infections: Treatment and Prevention: no. 1159BACKGROUND: Middle East respiratory syndrome coronavirus (MERS-CoV) continues to cause human infections with multiple clusters two years after the onset of the epidemic. Though mild cases have been recognized, the infection is severe in those with co-morbidities and >30% of patients die from the infection. Our recent structure-based development of a fusion inhibitor is one of the few treatment options for MERS and it led us to hypothesize that other existing antivirals that block cellular entry may also be active against MERS-CoV. BanLec is a jacalin-related banana lectin that has potent anti-HIV activity through binding to glycosylated viral envelope proteins and blocking cellular entry. We assessed the anti-MER-CoV activity of BanLec in cell culture assays. METHODS: The anti-MERS-CoV activity of BanLec was assessed by cytopathic effect (CPE) inhibition, viral yield reduction, and plaque reduction (PRA) assays in Vero, Calu-3, and/or HK2 cells. The cytotoxicity of BanLec was also assessed. RESULTS: The CC50 of BanLec was >10 nM in Vero and Calu-3 cells. CPE was completely absent in Vero and HK2 cells infected with MERS-CoV on 3 dpi with 30.00 nM of BanLec. In Calu-3 cells, CPE was completely absent at 90.00 nM of the drug. The EC50 of BanLec ranged from 3.99-4.82 nM (Table 1). The mean viral loads reduced by 7.13, 3.40, and 3.63 log10 copies/ml in Vero, Calu-3, and HK2 cells respectively (Fig. 1A to C). The highest percentage of plaque reduction at a concentration of >10 nM of BanLec were 100% and 59.5% in Vero cells and HK2 cells respectively (Fig. 2A & B). CONCLUSION: BanLec exhibits potent in vitro anti-MERS-CoV activity. The detailed mechanism and in vivo correlation of its antiviral activity should be further tested in animal models. The potential advantages of using BanLec for MERS include its high stability and the prospect of using it as a topical treatment or prophylaxis for exposed patients. (Table see attachment)BACKGROUND: Middle East respiratory syndrome coronavirus (MERS-CoV) continues to cause human infections with multiple clusters two years after the onset of the epidemic. Though mild cases have been recognized, the infection is severe in those with co-morbidities and >30% of patients die from the infection. Our recent structure-based development of a fusion inhibitor is one of the few treatment options for MERS and it led us to hypothesize that other existing antivirals that block cellular entry may also be active against MERS-CoV. BanLec is a jacalin-related banana lectin that has potent anti-HIV activity through binding to glycosylated viral envelope proteins and blocking cellular entry. We assessed the anti-MER-CoV activity of BanLec in cell culture assays. METHODS: The anti-MERS-CoV activity of BanLec was assessed by cytopathic effect (CPE) inhibition, viral yield reduction, and plaque reduction (PRA) assays in Vero, Calu-3, and/or HK2 cells. The cytotoxicity of BanLec was also assessed. RESULTS: The CC50 of BanLec was >10 nM in Vero and Calu-3 cells. CPE was completely absent in Vero and HK2 cells infected with MERS-CoV on 3 dpi with 30.00 nM of BanLec. In Calu-3 cells, CPE was completely absent at 90.00 nM of the drug. The EC50 of BanLec ranged from 3.99-4.82 nM (Table 1). The mean viral loads reduced by 7.13, 3.40, and 3.63 log10 copies/ml in Vero, Calu-3, and HK2 cells respectively (Fig. 1A to C). The highest percentage of plaque reduction at a concentration of >10 nM of BanLec were 100% and 59.5% in Vero cells and HK2 cells respectively (Fig. 2A & B). CONCLUSION: BanLec exhibits potent in vitro anti-MERS-CoV activity. The detailed mechanism and in vivo correlation of its antiviral activity should be further tested in animal models. The potential advantages of using BanLec for MERS include its high stability and the prospect of using it as a topical treatment or prophylaxis for exposed patients

Cognitive and autonomic dysfunction measures in normal controls, white coat and borderline hypertension

<p>Abstract</p> <p>Background</p> <p>White coat hypertension (WCHT) is a significant clinical condition with haemodynamic differences and presence of functional changes. We aim to compare cognitive and autonomic dysfunction variables (heart rate variability) between subjects with normal blood pressure (controls), WCHT, and borderline hypertension (BLH).</p> <p>Methods</p> <p>We performed a cross-sectional study in a cohort of 69 subjects (mean age ± SD; 38.2 ±10.8 years) comprising comparable number of normal controls, WCHT, and BLH. We measured clinic and 24-hour ambulatory blood pressure monitoring (ABPM), cognitive function parameters, and heart rate variability (HRV). All subjects underwent 24-hour ambulatory electrocardiography monitoring which was analyzed for HRV measurements. We performed a routine echocardiography (ECHO) for all subjects.</p> <p>Results</p> <p>Multiple comparison between the three groups revealed significant (p < 0.04) differences in mean day-time ABPM (systolic and diastolic). In the state anxiety inventory (SAI), both subjects with WCHT and BLH had significantly (p < 0.006) higher anxiety levels than the control group. In memory tasks WCHT subjects scored significantly (p < 0.004) lower in comparison with the other two groups. WCHT significantly (p < 0.001) performed less in memory tests, whereas BLH subjects had significantly (p < 0.001) lower reaction time. We found a significant (p < 0.05) difference in the 24-hour RMSSD and SDNN between the three groups. There was significant correlation between 24-hour RMSSD and computer CANTAB scores. The Echocardiography assessment revealed no significant differences in LV mass indices and diastolic function.</p> <p>Conclusions</p> <p>WCHT and BLH subjects showed lower cognitive performance and higher levels of anxiety when compared to controls. Autonomic function reflected by HRV indices was lower in WCHT and BLH in contrast to control, though not significantly. Our results suggest that WCHT may not be a benign condition as it may contribute to the overall risk for cardiovascular disease and LV damage. Longitudinal studies of patients with WCHT should clarify the transient, persistent or the progressive nature of this condition.</p

Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012

OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. DESIGN: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. RESULTS: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO (2)/FiO (2) ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO (2)/FI O (2) 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5-10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). CONCLUSIONS: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients