Acidosis of severe falciparum malaria: heading for a shock?

Severe Plasmodium falciparum malaria encompasses a complex syndrome affecting many organs and causing physiological perturbations that have many features in common with children with sepsis. Among these, metabolic acidosis has emerged as a central feature of severe malaria and is the best independent predictor of a fatal outcome in both adults and children. There is now clear evidence that intravascular hypovolaemia (shock) is common in children with malarial acidosis. How it should be treated presents a therapeutic dilemma because acidosis often coexists with impaired consciousness (cerebral malaria). We summarize the results of recent clinical trials examining the safety and efficacy of volume expansion in children with 'cerebral malaria' complicated by acidosis.     

Associations between Exposure to Intimate Partner Violence,Armed Conflict,and Probable PTSD among Women in Rural C?te d’Ivoire

Background

Objectives were to assess associations between intimate partner violence (IPV), violence during armed conflict (i.e. crisis violence), and probable post-traumatic stress disorder (PTSD).

Methods

Using a sample of 950 women in rural Côte d’Ivoire, logistic generalized estimating equations assessed associations between IPV and crisis violence exposures with past-week probable PTSD.

Results

Over one in 5 (23.4%) women reported past-year IPV, and over one in 4 women (26.5%) reported experiencing IPV prior to the past year (i.e. remote IPV). Crisis violence was experienced by 72.6% of women. In adjusted models including demographics, crisis violence (overall and specific forms), and IPV (remote and past-year), women who reported past-year IPV had 3.1 times the odds of reporting probable past-week PTSD (95%CI: 1.8–5.3) and those who reported remote IPV had 1.6 times the odds (95%CI: 0.9–2.7). Violent exposures during the crisis were not significantly associated with probable PTSD (any crisis violence: aOR: 1.04 (0.7–1.5); displacement: aOR: 0.9 (95%CI: 0.5–1.7); family victimization during crisis: aOR: 1.1 (95%CI: 0.8–1.7); personal victimization during crisis: aOR: 1.7 (95%CI: 0.7–3.7)).

Conclusion

Past-year IPV was more strongly associated with past-week probable PTSD than remote IPV and violence directly related to the crisis. IPV must be considered within humanitarian mental health and psychosocial programming.     

Regulation of the E3 ubiquitin ligase activity of MDM2 by an N-terminal pseudo-substrate motif

The tumor suppressor p53 has evolved a MDM2-dependent feedback loop that promotes p53 protein degradation through the ubiquitin–proteasome system. MDM2 is an E3-RING containing ubiquitin ligase that catalyzes p53 ubiquitination by a dual-site mechanism requiring ligand occupation of its N-terminal hydrophobic pocket, which then stabilizes MDM2 binding to the ubiquitination signal in the DNA-binding domain of p53. A unique pseudo-substrate motif or “lid” in MDM2 is adjacent to its N-terminal hydrophobic pocket, and we have evaluated the effects of the flexible lid on the dual-site ubiquitination reaction mechanism catalyzed by MDM2. Deletion of this pseudo-substrate motif promotes MDM2 protein thermoinstability, indicating that the site can function as a positive regulatory element. Phospho-mimetic mutation in the pseudo-substrate motif at codon 17 (MDM2^S17D) stabilizes the binding of MDM2 towards two distinct peptide docking sites within the p53 tetramer and enhances p53 ubiquitination. Molecular modeling orientates the phospho-mimetic pseudo-substrate motif in equilibrium over a charged surface patch on the MDM2 at Arg⁹⁷/Lys⁹⁸, and mutation of these residues to the MDM4 equivalent reverses the activating effect of the phospho-mimetic mutation on MDM2 function. These data highlight the ability of the pseudo-substrate motif to regulate the allosteric interaction between the N-terminal hydrophobic pocket of MDM2 and its central acidic domain, which stimulates the E3 ubiquitin ligase function of MDM2. This model of MDM2 regulation implicates an as yet undefined lid-kinase as a component of pro-oncogenic pathways that stimulate the E3 ubiquitin ligase function of MDM2 in cells.     

Active Surveillance of Hansen's Disease (Leprosy): Importance for Case Finding among Extra-domiciliary Contacts

Hansen''s disease (leprosy) remains an important health problem in Brazil, where 34,894 new cases were diagnosed in 2010, corresponding to 15.3% of the world''s new cases detected in that year. The purpose of this study was to use home visits as a tool for surveillance of Hansen''s disease in a hyperendemic area in Brazil. A total of 258 residences were visited with 719 individuals examined. Of these, 82 individuals had had a previous history of Hansen''s disease, 209 were their household contacts and 428 lived in neighboring residences. Fifteen new Hansen''s disease cases were confirmed, yielding a detection rate of 2.0% of people examined. There was no difference in the detection rate between household and neighbor contacts (p = 0.615). The two groups had the same background in relation to education (p = 0.510), household income (p = 0.582), and the number of people living in the residence (p = 0.188). Spatial analysis showed clustering of newly diagnosed cases and association with residential coordinates of previously diagnosed multibacillary cases. Active case finding is an important tool for Hansen''s disease control in hyperendemic areas, enabling earlier diagnosis, treatment, decrease in disability from Hansen''s disease and potentially less spread of Mycobacterium leprae.     

Eco-Bio-Social Determinants for House Infestation by Non-domiciliated Triatoma dimidiata in the Yucatan Peninsula,Mexico

Background

Chagas disease is a vector-borne disease of major importance in the Americas. Disease prevention is mostly limited to vector control. Integrated interventions targeting ecological, biological and social determinants of vector-borne diseases are increasingly used for improved control.

Methodology/principal findings

We investigated key factors associated with transient house infestation by T. dimidiata in rural villages in Yucatan, Mexico, using a mixed modeling approach based on initial null-hypothesis testing followed by multimodel inference and averaging on data from 308 houses from three villages. We found that the presence of dogs, chickens and potential refuges, such as rock piles, in the peridomicile as well as the proximity of houses to vegetation at the periphery of the village and to public light sources are major risk factors for infestation. These factors explain most of the intra-village variations in infestation.

Conclusions/significance

These results underline a process of infestation distinct from that of domiciliated triatomines and may be used for risk stratification of houses for both vector surveillance and control. Combined integrated vector interventions, informed by an Ecohealth perspective, should aim at targeting several of these factors to effectively reduce infestation and provide sustainable vector control.     

Efficient suspension bioreactor expansion of murine embryonic stem cells on microcarriers in serum-free medium

Large numbers of cells will be required for successful embryonic stem cell (ESC)-based cellular therapies or drug discovery, thus raising the need to develop scaled-up bioprocesses for production of ESCs and their derived progeny. Traditionally, ESCs have been propagated in adherent cultures in static flasks on fibroblasts layers in serum-containing medium. Direct translation of two-dimensional flatbed cultures to large-scale production of the quantities of cells required for therapy simply by increasing the number of dishes or flasks is not practical or economical. Here, we describe successful scaled-up production of ESCs on microcarriers in a stirred culture system in a serum-free medium. Cells expanded on CultiSpher S, Cytodex 3, and Collagen microcarriers showed superior cell-fold expansions of 439, 193, and 68, respectively, without excessive agglomeration, compared with 27 in static culture. In addition, the ESCs maintained their pluripotency after long-term culture (28 days) in serum-free medium. This is the first time mESCs have been cultured on microcarriers without prior exposure to serum and/or fibroblasts, while also eliminating the excessive agglomeration plaguing earlier studies. These protocols provide an economical, practical, serum-free means for expanding ESCs in a stirred suspension bioprocess.     

The Effects of Silicone Fluid Additives and Silicone Elastomer Matrices on Barnacle Adhesion Strength

Barnacle adhesion strength was used to screen seventy-seven polydimethylsiloxane elastomeric coatings for fouling-release properties. The test coatings were designed to investigate the effect on barnacle adhesion strength of silicone fluid additive type, additive location, additive molecular weight, additive loading level, mixtures of additives, coating matrix type and coating fillers. The type of silicone fluid additive was the primary controlling factor in barnacle fouling-release. The type of silicone matrix in which the fluid resided was found to alter the effect on fouling-release. Two PDMS fluids, DMSC15 and DBE224, significantly reduced the adhesion strength of barnacles compared to unmodified elastomers. Optimum fouling-release performance was dependent on the interaction of fluid type and elastomeric matrix.