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Swann O.,University of Malawi | Swann O.,Center for Immunity | Everett D.B.,University of Malawi | Everett D.B.,University of Liverpool | And 5 more authors.
Pediatric Infectious Disease Journal | Year: 2014

BACKGROUND: Neonatal meningitis is an important cause of morbidity in sub-Saharan Africa and requires urgent empiric treatment with parenteral administered antibiotics. Here we describe the etiology, antimicrobial susceptibility and suitability of the World Health Organization first-line recommended antibiotics (penicillin and gentamicin) for bacterial meningitis in young infants in Malawi. METHODS: We reviewed all cerebrospinal fluid samples received from infants ≤2 months of age with clinically suspected meningitis between January 1, 2002, and December 31, 2008, at the Queen Elizabeth Central Hospital in Blantyre, Malawi. RESULTS: We identified 259 culture-positive isolates from 259 infants ≤2 months of age. Sixty isolates were from neonates ≤7 days old, in whom the most common pathogens were Group B Streptococcus (27/60; 45.0%), Streptococcus pneumoniae (13/60; 21.7%) and nontyphoidal Salmonella enterica (7/60; 11.7%). One hundred and ninety one isolates were from young infants who were >7 days and ≤2 months of age. In this group, the most common isolates were S. pneumoniae (80/191; 41.9%), Group B Streptococcus (38/191; 19.9%) and nontyphoidal Salmonella enterica (34/191; 17.8%). More isolates were susceptible to ceftriaxone than to the combination of penicillin and gentamicin (218/220; 99.1% vs. 202/220; 91.8%, Fisher's exact test P = 0.006). In particular, Gram-negative isolates were significantly more susceptible to ceftriaxone than to gentamicin (72/74; 97.3% vs. 63/74; 85.1%, Fisher's exact test P = 0.020). Penicillin and gentamicin provided less coverage for Gram-negative than Gram-positive isolates (74/86; 86.0% vs. 155/163; 95.1%, χ = 6.24, P = 0.012). CONCLUSIONS: In view of these results, the World Health Organization recommendations for empiric penicillin and gentamicin for suspected neonatal meningitis should be reevaluated. © 2013 by Lippincott Williams & Wilkins.


Ramiro R.S.,Institute of Evolutionary Biology | Khan S.M.,Leiden Malaria Research Group | Franke-Fayard B.,Leiden Malaria Research Group | Janse C.J.,Leiden Malaria Research Group | And 5 more authors.
Proceedings of the Royal Society B: Biological Sciences | Year: 2015

Sexual reproduction is an obligate step in the life cycle of many parasites, including the causative agents of malaria (Plasmodium). Mixed-species infections are common in nature and consequently, interactions between heterospecific gametes occur. Given the importance of managing gene flow across parasite populations, remarkably little is understood about how reproductive isolation between species is maintained. We use the rodent malaria parasites P. berghei and P. yoelii to investigate the ecology of mixed-species mating groups, identify proteins involved in pre-zygotic barriers, and examine their evolution. Specifically, we show that (i) hybridization occurs, but at low frequency; (ii) hybridization reaches high levels when female gametes lack the surface proteins P230 or P48/45, demonstrating that these proteins are key for pre-zygotic reproductive isolation; (iii) asymmetric reproductive interference occurs, where the fertility of P. berghei gametes is reduced in the presence of P. yoelii and (iv) as expected for gamete recognition proteins, strong positive selection acts on a region of P230 and P47 (P48/45 paralogue). P230 and P48/45 are leading candidates for interventions to block malaria transmission. Our results suggest that depending on the viability of hybrids, applying such interventions to populations where mixed-species infections occur could either facilitate or hinder malaria control. © 2015 The Author(s) Published by the Royal Society. All rights reserved.


Atkins K.E.,Center for Immunity | Atkins K.E.,The New School | Read A.F.,Pennsylvania State University | Walkden-Brown S.W.,University of New England of Australia | And 2 more authors.
Epidemics | Year: 2013

Marek's disease virus (MDV), a poultry pathogen, has been increasing in virulence since the mid twentieth century. Since multiple vaccines have been developed and widely implemented, losses due to MDV have decreased. However, vaccine failure has occurred in the past and vaccine breakthroughs remain a problem. Failure of disease control with current vaccines would have significant economic and welfare consequences. Nevertheless, the epidemiology of the disease during a farm outbreak is not well understood. Here we present a mathematical model to predict the effectiveness of vaccines to reduce the outbreak probability and disease burden within a barn. We find that the chance of an outbreak within a barn increases with the virulence of an MDV strain, and is significantly reduced when the flock is vaccinated, especially when there the contaminant strain is of low virulence. With low quantities of contaminated dust, there is nearly a 100% effectiveness of vaccines to reduce MDV outbreaks. However, the vaccine effectiveness drops to zero with an increased amount of contamination with a middle virulence MDV strain. We predict that the larger the barn, and the more virulent the MDV strain is, the more virus is produced by the time the flock is slaughtered. With the low-to-moderate virulence of the strains studied here, the number of deaths due to MDV is very low compared to all-cause mortality regardless of the vaccination status of the birds. However, the cumulative MD incidence can reach 100% for unvaccinated cohorts, and 35% for vaccinated cohorts. These results suggest that death due to MDV is an insufficient metric to assess the prevalence of MDV broiler barns regardless of vaccine status, such that active surveillance is required to successfully assess the probability of MDV outbreaks, and to limit transmission of MDV between successive cohorts of broiler chickens. © 2013 The Authors.


Nackiewicz D.,Center for Immunity | Dey P.,Center for Immunity | Szczerba B.,Center for Immunity | Mohammad S.,Center for Immunity | And 6 more authors.
Nephron - Experimental Nephrology | Year: 2014

Background: Lipoprotein abnormalities are associated with a rapid decline in renal function in patients of chronic kidney disease. In addition, hyperlipidemia is associated with an increased risk of developing renal insufficiency. The underlying molecular mechanisms for these clinical findings are unclear. We have previously reported a role for inhibitor of differentiation 3 (ID3), a transcription factor, in regulating kidney disease in hyperlipidemia. Introducing a genetic deficiency of Id3 in spontaneously hyperlipidemic apolipoprotein E knockout (Apoe-/-) mice led to accelerated mesangioproliferative glomerulonephritis. The present study was carried out to further investigate the contribution of ID3 in hyperlipidemia-associated kidney disease. Methods: Female C57BL/6 mice that were ID3-sufficient wild-type (WT) or ID3-deficient (Id3-/-) were fed a Western diet and evaluated for proteinuria, glomerular pathology, and immune infiltrating cells. Primary mesangial cell lines were generated from both mouse strains and stimulated with oxidized phospholipids. Cytokines and chemokines produced were measured by multiplex assays, ELISA, and QPCR. Glomerular isolates were studied for CXCL1 expression by QPCR. Results:Id3-/- mice on a Western diet developed accelerated proteinuria and mesangioproliferative glomerulonephritis compared to WT controls. In vitro, Id3-/- glomerular mesangial cell lines produced higher levels of the monocyte chemoattractant CXCL1 in response to oxidized phospholipids. This was consistent with the rapid increase in glomerular CXCL1 expression followed by macrophage infiltration in Id3-/- mice fed a Western diet. Conclusions: A functional ID3 influences susceptibility to kidney disease and prevents glomerular injury by regulating local chemokine production and inflammatory cell recruitment. © 2014 S. Karger AG, Basel.


Scindia Y.,Center for Immunity | Nackiewicz D.,Center for Immunity | Dey P.,Center for Immunity | Szymula A.,Center for Immunity | And 9 more authors.
Nephron - Experimental Nephrology | Year: 2012

Aims: The role of kidney infiltrating T cells in the pathology of lupus nephritis is unclear. This study was undertaken to investigate whether CD4+ T cell responses to a surrogate mesangial antigen can initiate glomerulonephritis. Methods: Ovalbumin (OVA) was deposited in the glomerular mesangium of C57BL/6 (B6) mice using anti-α8-integrin immunoliposomes (α8ILs). This was followed by injection of activated OVA-reactive CD4+ transgenic OT2 T cells. Trafficking of antigen-specific OT2 T cells to kidneys and lymph nodes was studied by flow cytometry. Glomerular pathology and immune cell infiltration was characterized by immunostaining. Role of CCR2 deficiency on T cell-mediated glomerulonephritis was investigated using B6.ccr2-/- mice. Results: α8ILs delivered OVA specifically to the renal glomeruli. Adoptively transferred OT2 T cells preferentially accumulated in renal lymph nodes and in the renal cortex. Kidneys showed glomerular inflammation with recruitment of endogenous T cells, dendritic cells and macrophages. T cell-mediated inflammation induced mesangial cell activation and an increase in glomerular MCP1 and fibronectin. The formation of inflammatory foci was driven by Ly6C monocytes and was CCR2 dependent. Conclusions: The findings from this study show that T cells reactive with antigens in the mesangium are sufficient to initiate glomerular pathology. Antigen-specific CD4 T cells act by inducing glomerular MCP1 production which mediates recruitment of inflammatory monocytes resulting in glomerulonephritis. Thus, downmodulation of T cell responses within the kidneys of lupus patients will be a beneficial therapeutic approach. © 2012 S. Karger AG, Basel.

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