Rho kinase inhibition in severe malaria: thwarting parasite-induced collateral damage to endothelia

Acute clinical manifestations of falciparum malaria, such as multiorgan failure and cerebral malaria, occur unpredictably and lead to coma and death within hours if left untreated. Despite the emergency administration of effective antimalarial drugs, 15%-20% of patients die. Other therapeutic approaches are therefore urgently needed. There is increasing evidence that endothelial changes play a key role in the pathogenesis of severe malaria. We therefore used coculture models to study interactions between infected erythrocytes and endothelium. We found that adhesion of Plasmodium falciparum to endothelial cells in vitro activated the Rho kinase signaling pathway, which is strongly involved in various vascular diseases. When added concomitantly with parasites, the Rho kinase inhibitor fasudil (HA-1077), a drug already in clinical use, decreased both NF-kappaB activation and endothelial cell apoptosis. Fasudil also helped to restore endothelial barrier integrity after P. falciparum adhesion. Rho kinase inhibition thus appears to be a promising adjunctive therapeutic approach to the management of severe human malaria.     

Immunostimulant oxidized beta-glucan conjugates

beta-Glucans are polysaccharides that act as nonspecific immune system stimulants. However, many beta-Glucans are sparingly soluble in water. This work describes an oxidative procedure, which solubilizes the beta-Glucan from Saccharomyces cerevisiae and maintains its immunostimulatory properties. Furthermore, the carboxylates at the site of oxidation allow for the conjugation of small molecule immunostimulants. Both the parent oxidized beta-glucan and its conjugates with O-beta-alanyl-5-[6-(N,N'-dimethylamino)purin-9-yl]pentanol stimulate cytotoxic T-lymphocytes (CTLs), B cells and macrophages. In addition, they both stimulate natural killer (NK) cells, a property which the small molecule purine does not possess.     

The strength of donor-specific antibody is a more reliable predictor of antibody-mediated rejection than flow cytometry crossmatch analysis in desensitized kidney recipients

The aim of this study was to evaluate the utility of donor-specific antibodies (DSA) and flow cytometry crossmatch (FCCM) as tools for predicting antibody-mediated rejection (AMR) in desensitized kidney recipients. Sera from 44 patients with DSA at the time of transplant were reviewed. Strength of DSA was determined by single antigen Luminex bead assay and expressed as mean fluorescence intensity (MFI). T- and B-cell FCCM results were expressed as mean channel shift (MCS). AMR was diagnosed by C4d deposition on biopsy. Incidence of early AMR was 31%. Significant differences in the number of DSAs (p = 0.0002), cumulative median MFI in DSA class I (p = 0.0004), and total (class I + class II) DSA (p < 0.0001) were found in patients with and without AMR. No significant difference was seen in MCS of T and B FCCM (p = 0.095 and p = 0.307, respectively). The three-yr graft survival in desensitized patients with DSA having total MFI < 9500 was 100% compared to 76% with those having total MFI > 9500 (p = 0.022). Desensitized kidney transplant recipients having higher levels of class I and total DSA MFI are at high risk for AMR and poor graft survival. Recipient DSA MFI appears to be a more reliable predictor of AMR than MCS of FCCM.     

Influences of family structure dynamics on sexual debut in Africa: implications for research, practice and policies in reproductive health and social development

There is no research on the timing, sequencing and number of changes in family environment and their influences on sexual and reproductive health outcomes in Africa. Using a population-based survey with data on family structure at three points in the life course, this paper examines the influences of these family structure dynamics on the timing of first sex among unmarried males and females aged 12-24 years in Cameroon. The number and timing of family transitions significantly impacted the timing of sexual debut for both males and females. The median age at first sex (18.7 years) is higher among young people without family transition than among those with one transition (18.2 years) or two transitions (17.7 years). Family transitions occurring during childhood were significantly associated with premature sexual initiation for females but not for males. Reproductive health and social development interventions for young people in Africa should integrate the changing contexts and transitions in family structure.     

CLinical Experience Acquired with Raptiva® (CLEAR) trial in patients with moderate‐to‐severe plaque psoriasis: results from extended treatment in an international,Phase III,placebo‐controlled trial

Background: The 12‐week, double‐blind, placebo‐controlled, first‐treatment (FT) CLEAR trial period demonstrated the efficacy/safety of efalizumab in moderate‐to‐severe plaque psoriasis, including refractory or contraindicated patients unsuitable for other systemic treatments. This study assessed the efficacy/safety of open‐label extended treatment (up to 24 weeks' continuous treatment) in patients not achieving ≥75% improvement in Psoriasis Area and Severity Index (PASI‐75) at week 12 of the FT period. Time to relapse after treatment cessation, and efficacy/safety of 12 weeks' open‐label re‐treatment in patients achieving PASI‐75 at week 12 FT were also assessed. Patients and methods: Patients with PASI‐75 at week 12 FT were observed without treatment until relapse, then re‐treated with open‐label efalizumab (1.0 mg/kg/week for 12 weeks). Others received open‐label extended treatment without intervening observation. Results: Among efalizumab‐treated patients (n = 308) who had < 75% PASI improvement at week 12 FT, extended treatment led to PASI‐75 in 26.6%. Among patients with between ≥ 50 and < 75% PASI improvement at week 12 FT (n = 118), 47.5% improved to PASI‐75 with extended treatment. Forpatients achieving PASI‐75 at week 12 FT (n = 164), median time to relapse was 58 days. Re‐treatment after relapse led to mean PASI improvement of 62.3% from study baseline (n = 145). Safety results were consistent with pre‐vious studies, with no new safety concerns. Conclusions: These results demonstrate additional benefit of continuing efali‐zumab. Re‐treatment re‐established disease control in patients with PASI‐75 who relapsed following treatment cessation. The safety profile remained consistent with that seen at 12 weeks.     

Implementation of GA-VirReport,a Web-Based Bioinformatics Toolkit for Post-Entry Quarantine Screening of Virus and Viroids in Plants

High-throughput sequencing (HTS) of host plant small RNA (sRNA) is a popular approach for plant virus and viroid detection. The major bottlenecks for implementing this approach in routine virus screening of plants in quarantine include lack of computational resources and/or expertise in command-line environments and limited availability of curated plant virus and viroid databases. We developed: (1) virus and viroid report web-based bioinformatics workflows on Galaxy Australia called GA-VirReport and GA-VirReport-Stats for detecting viruses and viroids from host plant sRNA extracts and (2) a curated higher plant virus and viroid database (PVirDB). We implemented sRNA sequencing with unique dual indexing on a set of plants with known viruses. Sequencing data were analyzed using GA-VirReport and PVirDB to validate these resources. We detected all known viruses in this pilot study with no cross-sample contamination. We then conducted a large-scale diagnosis of 105 imported plants processed at the post-entry quarantine facility (PEQ), Australia. We detected various pathogens in 14 imported plants and discovered that de novo assembly using 21–22 nt sRNA fraction and the megablast algorithm yielded better sensitivity and specificity. This study reports the successful, large-scale implementation of HTS and a user-friendly bioinformatics workflow for virus and viroid screening of imported plants at the PEQ.