Long-term impact of changing childhood malnutrition on rotavirus diarrhoea: Two decades of adjusted association with climate and socio-demographic factors from urban Bangladesh.

BACKGROUND: There is strong association between childhood rotavirus, diarrhoea, climate factors and malnutrition. Conversely, a significant nutritional transition (reduced under-nutrition) with a concurrent increasing trend of rotavirus infection in last decade was also observed among under 5 children, especially in developing countries including Bangladesh. Considering the pathophysiology of rotavirus, there might be an interaction of this nutrition transition which plays a pivotal role in increasing rotavirus infection in addition to climate and other man-made factors in urban areas such as Dhaka, Bangladesh. METHODS: Relevant monthly data from 1993-2012 were extracted from the archive of the Diarrhoeal Disease Surveillance System of icddr, b and linked with data collected from the Dhaka station of the Bangladesh Meteorological Department (mean temperature, rainfall, sea level pressure and humidity). Seasonal autoregressive integrated moving average time series models were deployed to determine the association between the monthly proportion of rotavirus infection and underweight, stunting and wasting adjusting for climate, socio-demographic and sanitation factors. FINDING: The proportion of rotavirus cases among all causes diarrhoea increased from 20% in 1993 to 43% in 2012 (Chi squared for trend p = 0.010). In contrast, underweight, stunting and wasting decreased from 59%-29% (p<0.001); 53%-21% (p<0.001) and 32%-22% (p<0.001) respectively over the same period. Mean ambient temperature increased from 25.76°C-26.62°C (p = 0.07); mean rainfall, sea level pressure and mean humidity decreased from 234.92-111.75 mm (p = 0.5), 1008.30-1006.61 mm of hg (p = 0.02) and 76.63%-70.26% (p<0.001), respectively. In the adjusted model, a decrease in monthly proportion of underweight [coef.: -0.189 (95% CI:-0.376, -0.003)] and wasting [-0.265 (-0.455, -0.075)] were significantly and inversely associated with rotavirus infection. However, an inverse but insignificant association was observed for stunting [-0.070 (-0.249, 0.109)]. INTERPRETATION: The reduction of acute childhood malnutrition is significantly associated with increasing rotavirus diarrhoea among under-5 children. Thus mass vaccination in addition to interventions directed at man-made modifiable predictors for prevention and control is warranted.

Nora's Story.

In this column, Nora Gibbons, 16 years old, describes the home births of four of her siblings. Nora's story captures the wonder and simplicity of home birth and demonstrates the impact the experience of being present at home birth can have on children. Nora's joy and confidence in birth because of her experiences will influence her own birth choices.

Rrp2, a prokaryotic enhancer-like binding protein, is essential for viability of Borrelia burgdorferi.

The Lyme disease spirochete, Borrelia burgdorferi, exists in two diverse niches (i.e., an arthropod tick vector and mammalian host) during its enzootic life cycle. To effectively adapt to these unique environments, the bacterium alters the expression of numerous genes, including several major outer surface (lipo)proteins that are required for infection and transmission. An enhancer-binding protein (EBP), known as Rrp2, is one identified activator of the RpoN/RpoS alternative sigma factor cascade. Because initial efforts to generate an rrp2 deletion strain were unsuccessful, the role of Rrp2 in the activation of the RpoN/RpoS pathway was first defined using a strain of B. burgdorferi carrying an rrp2 point mutant that was defective in its ability to activate RpoN-dependent transcription. The fact that subsequent attempts to disrupt rrp2 have also been unsuccessful has led investigators to hypothesize that Rrp2 has other undefined functions which are essential for B. burgdorferi survival and independent of its EBP function. We used a lac-based inducible expression system to generate a conditional rrp2 mutant in virulent B. burgdorferi. In this strain, an isopropyl-ß-D-thiogalactopyranoside-inducible copy of the rrp2 gene is expressed in trans from a borrelial shuttle vector. We found that the chromosomal copy of rrp2 could be inactivated only when rrp2 was induced, and the maintenance of rrp2 expression was required for the growth of the mutants. In addition, the overexpression of rrp2 is detrimental to B. burgdorferi growth in a manner that is independent of the RpoN/RpoS pathway. These studies provide the first direct evidence that rrp2 is an essential gene in B. burgdorferi.

Relationship between dialysate oxidized protein and peritoneal membrane transport properties in patients on peritoneal dialysis.

BACKGROUND: Increased levels of oxidized proteins have been reported in the serum of patients with end-stage renal disease, though little is known regarding the oxidized protein content of the dialysate in patients on peritoneal dialysis (PD) and no information is available as to how this may correlate with important clinical and laboratory variables, including abnormal peritoneal membrane function. In this study we attempted to identify oxidized proteins in the dialysate of patients on PD using western blot analysis, and examined the relationship between these proteins and the function of the peritoneal membrane and other clinical and laboratory variables. METHODS: Peritoneal dialysate and serum samples were obtained from 18 patients on PD, and western blot analysis using an antibody to oxidized protein was carried out with reprobing for albumin. Oxidized protein/albumin ratios were determined and compared with various clinical and laboratory variables including peritoneal equilibration test results. RESULTS: Oxidized protein/albumin ratios were higher in the dialysate of patients who were high/high average transporters compared to low/low average transporters. Oxidized protein ratios were also found to be higher in the dialysate of patients who had diminished urine output as a reflection of loss of residual renal function. Negative correlations were noted between oxidized protein ratios in the dialysate and serum albumin levels and creatinine clearance. CONCLUSIONS: Higher levels of oxidized protein in the dialysate appear to be correlated with high/high average peritoneal membrane transport characteristics and may be related to loss of residual renal function. These preliminary findings suggest that it is plausible that oxidized proteins in the dialysate might play a contributory role in complications including membrane damage and ultrafiltration failure in patients on PD.

Dexamethasone attenuates oxidation of extracellular matrix proteins by human monocytes.

In response to infection or in immune complex-mediated diseases, inflammatory cells may oxidatively damage extracellular matrix (ECM) proteins. In this study we evaluated whether human monocytes could oxidize ECM and whether this could be modulated by exposure to LPS, IgG complexes, and dexamethasone (DEX). Wells in tissue culture plates were coated with the ECM preparation Matrigel. Porous inserts with or without the human monocyte cell line THP-1 were placed into ECM-containing wells and cells were exposed to control conditions or to LPS (10 ng/ml), IgG complexes (200 and 500 microg/ml), or DEX (10(-7) and 10(-6) M). ECM was then subjected to Western blot analysis using an antibody to oxidized protein. In addition, Western blot analysis was carried out on DEX-treated cells to evaluate expression of the NADPH oxidase components p67-phox and gp91-phox. THP-1 cells enhanced ECM oxidation and this effect was augmented by LPS and by IgG aggregates. Preincubation of cells with DEX attenuated ECM oxidation and was also associated with decreased expression of p67-phox and gp91-phox. These findings suggest that human monocytes can oxidize ECM proteins and that this may be modulated by IgG complexes and LPS. Dexamethasone appears to attenuate ECM oxidation and a better understanding of this mechanism might allow for interventions to minimize oxidative damage to ECM proteins by monocytes in infectious and inflammatory states.

Oxidized immunoglobulin G in patients with end-stage renal disease treated by hemodialysis.

Patients with end-stage renal disease treated by hemodialysis have enhanced oxidative stress that may result in oxidation of IgG and resultant functional changes. In this study, Western blot analysis was used to assess the oxidized protein content of IgG samples purified from plasma of 8 controls and 11 patients on hemodialysis. In certain experiments, oxidized IgG was digested with papain and Western blot analysis was performed to identify oxidized Fc fragments. Compared to plasma IgG from controls, the IgG from hemodialysis patients had greater oxidized protein content, evidenced by more intense antibody binding to both the heavy and light chains. Western blot analysis of papain digests of oxidized IgG samples that were reprobed with an anti-Fc fragment antibody showed oxidative modification of the Fc fragment. These results suggest that patients with end-stage renal disease treated by hemodialysis have increased oxidized IgG in their plasma, including the Fc portion. Further studies are needed to see if this is due to enhanced production and/or decreased clearance of oxidized IgG.

Angiotensin II induces apoptosis in rat glomerular epithelial cells.

ANG II has been shown to modulate kidney cell growth and contribute to the pathobiology of glomerulosclerosis. Glomerular visceral epithelial cell (GEC) injury or loss is considered to play a pivotal role in the initiation and progression of glomerulosclerosis. In the present study, we investigated the effect of ANG II on GEC apoptosis. Rat GECs were incubated with increasing doses of ANG II for variable time periods. Apoptosis was evaluated by cell nucleus staining and DNA fragmentation assay. ANG II induced GEC apoptosis in a dose- and time-dependent manner. The proapoptotic effect was attenuated by the ANG II receptor type 1 antagonist losartan or the ANG II receptor type 2 antagonist PD-123319 and was completely blocked by incubation with the combined antagonists. Moreover, ANG II stimulated transforming growth factor (TGF)-beta1 production as measured by ELISA. GECs exposed to TGF-beta1 demonstrated a dose- and time-dependent increase in apoptosis. ANG II-induced apoptosis was significantly inhibited by addition of anti-TGF-beta1 antibody. ANG II also upregulated the expression of Fas, FasL, and Bax and downregulated the expression of Bcl-2 in GECs. These studies suggest that ANG II induces GEC apoptosis by a mechanism involving TGF-beta1 expression that may, importantly, contribute to the pathogenesis of glomerulosclerosis.

Metal-catalyzed oxidation of extracellular matrix proteins promotes human mesangial cell apoptosis and is associated with enhanced expression of Bax and caspase activation.

Oxidative injury in glomerular disease may oxidize extracellular matrix proteins which might modulate their interaction with mesangial cells and thereby account for the hypocellularity seen in advanced glomerulosclerosis. In this study we evaluated whether oxidation of extracellular matrix could modulate human mesangial cell apoptosis. Human mesangial cells were seeded onto plates coated with unmodified (control) or oxidized Matrigel, laminin, or type IV collagen. Mesangial cell apoptosis was increased on oxidized Matrigel as well as on oxidized laminin and type IV collagen. Mesangial cells behaved similarly on plates coated with control and oxidized forms of the integrin ligand-containing peptide GRGDSP. Cells on oxidized matrix demonstrated enhanced expression of Bax, increased fragmentation of PARP, and diminished apoptosis in the presence of the interleukin-1 beta converting enzyme inhibitor Ac-Tyr-Val-Ala-Asp-aldehyde. These data suggest that oxidation of extracellular matrix proteins may enhance human mesangial cell apoptosis via a mechanism that appears to involve enhanced expression of Bax and caspase activation. This may account for irreversible mesangial hypocellularity in glomerulosclerosis.

Extracellular matrix oxidation modulates survival, NF-kappaB translocation, and MAPK activity in mesangial cells.

Inflammatory injury to the kidney may oxidize extracellular matrix proteins. These changes appear to impair adhesion of glomerular mesangial cells and might impact signaling mechanisms in these cells. In this study we evaluated how extracellular matrix oxidation could modulate the development of apoptosis as well as the activity of the transcription factor NF-kappaB and that of the MAPK family members ERK-1,2 and JNK. Exposure of mesangial cells to oxidized matrix enhanced the percentage of apoptotic cells. Western blot analysis revealed diminished levels of the phosphorylated form of ERK-1,2 in cells on oxidized matrix, while levels of phosphorylated JNK were increased. Cells on unmodified matrix were found to have rapid translocation of the p65 subunit of NF-kappaB, which was attenuated in cells on oxidized matrix. These findings suggest that extracellular matrix oxidation may impair survival of mesangial cells in association with decreased levels of pERK-1,2, increased levels of pJNK, and diminished nuclear translocation of the transcription factor NF-kappaB.