Programmed cell death as a defence against infection

Eukaryotic cells can die from physical trauma, resulting in necrosis. Alternately, they can die via programmed cell death upon stimulation of specific signalling pathways. Here we discuss the utility of four cell death pathways in innate immune defence against bacterial and viral infection: apoptosis, necroptosis, pyroptosis and NETosis. We describe the interactions that interweave different programmed cell death pathways, which create complex signalling networks that cross-guard each other in the evolutionary arms race with pathogens. Finally, we describe how the resulting cell corpses — apoptotic bodies, pore-induced intracellular traps (PITs) and neutrophil extracellular traps (NETs) — promote clearance of infection

Unusual case of failure to thrive: Type III Bartter syndrome.

Bartter syndrome Type III is a rare autosomal recessive disorder resulting from an inherited defect in the thick ascending limb of the loop of henle of the nephrons in kidney. The typical clinical manifestations in childhood are failure to thrive and recurrent episodes of vomiting. Typical laboratory findings which help in the diagnosis are hypokalemic metabolic alkalosis, hypomagnesemia and hypercalciuria. We report a case of Type III Bartter syndrome not responding to repeated conventional treatment of failure to thrive

TOWARDS IMPROVING THE MANAGEMENT OF ACUTE ENCEPHALITIS SYNDROME IN NEPAL

Acute Encephalitis Syndrome (AES) is a group of clinical symptoms and signs, used by the World Health Organisation (WHO) and clinicians, to screen for acute encephalitis. Viruses are the most important cause of AES worldwide. Japanese encephalitis virus (JEV), which causes Japanese encephalitis (JE), accounts for approximately one-quarter of AES cases in Nepal. In the absence of definite treatments for JE and many other viral enecpahlitides, improvements in supportive management are vital. In my thesis, the predictors of bad outcome (neurological sequelae or death) among patients with AES and JE were investigated. The relationships between weight-for-age (WFA), hydration status, intravenous fluids and outcome were studied. In addition, a preliminary randomised double blind placebo controlled trial of intravenous immunoglobulin (IVIG), as a novel adjunctive treatment for JE, was conducted. Prolonged fever duration was identified to be a significant predictor of bad outcome in both AES and JE patients. Prolonged fever, low Glasgow coma score (GCS) and focal neurological deficit at hospital admission were significantly associated with bad outcome in AES patients. AES patients with focal neurological deficit were significantly more likely to have a final diagnosis of JE. JE patients presented with a significantly lower body weight and higher respiratory rate. They also presented with a trend for higher urea and potassium levels compared to other AES patients. These findings led me to investigate further whether children with JE were more likely to suffer from dehydration during acute illness. When children are grouped into different weight categories by WFA (Z score), low WFA can indicate dehydration or malnutrition. I found a significant association between frequency of bad outcome and low WFA among both AES and JE patients at hospital admission. To help distinguish dehydration and malnutrition in low WFA children, I then studied additional indicators of malnutrition and dehydration status, including midupper arm circumference, blood lactate levels and fluid status at admission and during hospital stay. I found AES patients suffering a bad outcome had significantly higher admission serum lactate levels, drunk a lower volume of oral fluids, and were more likely to be prescribed a restricted regimen of intravenous fluids. These results suggest AES patients with bad outcome were more likely to be dehydrated. The implications of my findings are that earlier hospital admission during the course of the illness and better in hospital administration of adequate and appropriate fluids may improve outcome among AES and JE patients. Since the majority of families self-refer to hospitals, provision of this simple message into the community, could help improve the lives of people living in high risk areas for JE, like Nepal. Improvement in the treatment of JE is necessary to improve the outcome of the disease in Nepal. Intravenous immunoglobulin, which contains anti-JE virus neutralising antibodies and has anti-inflammatory properties, may be a useful adjunctive treatment. In a preliminary Phase II study, I showed IVIG could be safely administered to JE patients, without any significant increase in drug related adverse events. JE patients treated with IVIG exhibited higher levels of neutralising antibodies and higher IL-4 and IL-6 cytokine levels compared with placebo (saline) treated patients. Although, there was no difference in clinical outcome, the data from this small pilot study suggests IVIG may be an appealing adjunctive treatment option for a phase III trial in the future

Village Baseline Study: Site Analysis Report for Khulna - Morrelganj, Bangladesh

The Gabgachhia village is located in the coastal region of Bangladesh’s Khulna district. The population is rising and living with high levels of poverty and food insecurity. Local resources that are not critically strained from climate change and poor resource management are few, beyond mosques, roads and schools. The community has seen dramatic changes in resources, as early as 1990, which they attribute to increased population pressures and climate change impacts. Forests have been depleted, rivers are full of silt and lacking life, farmlands have low productivity due to rising salinity, flooding and inappropriate varieties, drinking water is insufficient to meet human, crop and animal needs, and infrastructure is weak and unable to withstand the environmen

The functional, social and economic impact of acute encephalitis syndrome in Nepal--a longitudinal follow-up study.

notes: PMCID: PMC3772013Open Access JournalOver 133,000 children present to hospitals with Acute Encephalitis Syndrome (AES) annually in Asia. Japanese encephalitis (JE) accounts for approximately one-quarter of cases; in most cases no pathogen is identified and management is supportive. Although JE is known to result in neurological impairment, few studies have examined the wider impact of JE and AES on patients and their families.Wellcome TrustUniversity of Liverpool Clinical Fellowshi

Cutting Edge: Mouse NAIP1 Detects the Type III Secretion System Needle Protein

The NAIP/NLRC4 inflammasomes activate caspase-1 in response to bacterial type III secretion systems (T3SS). Inadvertent injection of the T3SS rod protein and flagellin into the cytosol are detected through murine NAIP2 and NAIP5/6, respectively. Here, we identify the agonist for the orphan murine NAIP1 receptor as the T3SS needle protein. NAIP1 is poorly expressed in resting mouse bone marrow-derived macrophages (BMMs), however, priming with poly(I:C) induces it, and confers needle protein sensitivity. Further, overexpression of NAIP1 in immortalized BMMs by retroviral transduction enabled needle detection. In contrast, peritoneal cavity macrophages basally express NAIP1 and respond to needle protein robustly independent of priming. Human macrophages are known to only express one NAIP gene, which detects the needle protein, but not rod or flagellin. Thus, murine NAIP1 is functionally analogous to human NAIP

A preliminary randomized double blind placebo-controlled trial of intravenous immunoglobulin for Japanese encephalitis in Nepal

BACKGROUND: Japanese encephalitis (JE) virus (JEV) is a mosquito-borne flavivirus found across Asia that is closely related to West Nile virus. There is no known antiviral treatment for any flavivirus. Results from in vitro studies and animal models suggest intravenous immunoglobulin (IVIG) containing virus-specific neutralizing antibody may be effective in improving outcome in viral encephalitis. IVIG's anti-inflammatory properties may also be beneficial. METHODOLOGY/PRINCIPAL FINDINGS: We performed a pilot feasibility randomized double-blind placebo-controlled trial of IVIG containing anti-JEV neutralizing antibody (ImmunoRel, 400mg/kg/day for 5 days) in children with suspected JE at two sites in Nepal; we also examined the effect on serum neutralizing antibody titre and cytokine profiles. 22 children were recruited, 13 of whom had confirmed JE; 11 received IVIG and 11 placebo, with no protocol violations. One child (IVIG group) died during treatment and two (placebo) subsequently following hospital discharge. Overall, there was no difference in outcome between treatment groups at discharge or follow up. Passive transfer of anti-JEV antibody was seen in JEV negative children. JEV positive children treated with IVIG had JEV-specific neutralizing antibody titres approximately 16 times higher than those treated with placebo (p=0.2), which was more than could be explained by passive transfer alone. IL-4 and IL-6 were higher in the IVIG group. CONCLUSIONS/SIGNIFICANCE: A trial of IVIG for JE in Nepal is feasible. IVIG may augment the development of neutralizing antibodies in JEV positive patients. IVIG appears an appealing option for JE treatment that warrants further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01856205

Adherence to secondary prophylaxis and disease recurrence in 536 Brazilian children with rheumatic fever

<p>Abstract</p> <p>Background</p> <p>More than 15 million people worldwide have rheumatic fever (RF) and rheumatic heart disease due to RF. Secondary prophylaxis is a critical cost-effective intervention for preventing morbidity and mortality related to RF. Ensuring adequate adherence to secondary prophylaxis for RF is a challenging task. This study aimed to describe the rates of recurrent episodes of RF, quantify adherence to secondary prophylaxis, and examine the effects of medication adherence to the rates of RF in a cohort of Brazilian children and adolescents with RF.</p> <p>Methods</p> <p>This retrospective study took place in the Pediatric Rheumatology outpatient clinic at a tertiary care hospital (Instituto de Puericultura e Pediatria Martagão Gesteira) in Rio de Janeiro, Brazil, and included patients with a diagnosis of RF from 1985 to 2005.</p> <p>Results</p> <p>536 patients with RF comprised the study sample. Recurrent episodes of RF occurred in 88 of 536 patients (16.5%). Patients with a recurrent episode of RF were younger (p < 0.0001), more frequently males (p = 0.003), and less adherent (p < 0.0001) to secondary prophylaxis than patients without RF recurrence. Non-adherence to medication at any time during follow-up was detected in 35% of patients. Rates of non-adherence were higher in the group of patients that were lost to follow-up (42%) than in the group of patients still in follow-up (32%) (p = 0.027). Appointment frequency was inadequate in 10% of patients. Higher rates of inadequate appointment frequency were observed among patients who were eventually lost to follow-up (14.5%) than in patients who were successfully followed-up (8%) (p = 0.022). 180 patients (33.5%) were lost to follow up at some point in time.</p> <p>Conclusions</p> <p>We recommend implementation of a registry, and a system of active search of missing patients in every service responsible for the follow-up of RF patients. Measures to increase adherence to secondary prophylaxis need to be implemented formally, once non-adherence to secondary prophylaxis is the main cause of RF recurrence. Detection of irregularity in secondary prophylaxis or in appointments should be an alert about the possibility of loss of follow-up and closer observation should be instituted.</p