Rocaglates as dual-targeting agents for experimental cerebral malaria

Cerebral malaria (CM) is a severe and rapidly progressing complication of infection by Plasmodium parasites that is associated with high rates of mortality and morbidity. Treatment options are currently few, and intervention with artemisinin (Art) has limited efficacy, a problem that is compounded by the emergence of resistance to Art in Plasmodium parasites. Rocaglates are a class of natural products derived from plants of the Aglaia genus that have been shown to interfere with eukaryotic initiation factor 4A (eIF4A), ultimately blocking initiation of protein synthesis. Here, we show that the rocaglate CR-1-31B perturbs association of Plasmodium falciparum eIF4A (PfeIF4A) with RNA. CR-1-31B shows potent prophylactic and therapeutic antiplasmodial activity in vivo in mouse models of infection with Plasmodium berghei (CM) and Plasmodium chabaudi (blood-stage malaria), and can also block replication of different clinical isolates of P. falciparum in human erythrocytes infected ex vivo, including drug-resistant P. falciparum isolates. In vivo, a single dosing of CR-1-31B in P. berghei-infected animals is sufficient to provide protection against lethality. CR-1-31B is shown to dampen expression of the early proinflammatory response in myeloid cells in vitro and dampens the inflammatory response in vivo in P. berghei-infected mice. The dual activity of CR-1-31B as an antiplasmodial and as an inhibitor of the inflammatory response in myeloid cells should prove extremely valuable for therapeutic intervention in human cases of CM.We thank Susan Gauthier, Genevieve Perreault, and Patrick Senechal for technical assistance. This work was supported by a research grant (to P.G.) from the Canadian Institutes of Health Research (CIHR) (Foundation Grant). J.P. and P.G. are supported by a James McGill Professorship salary award. D.L. is supported by fellowships from the Fonds de recherche sante Quebec, the CIHR Neuroinflammation training program. J.P. is supported by CIHR Research Grant FDN-148366. M.S. is supported by a CIHR Foundation grant. J.A.P. is supported by NIH Grant R35 GM118173. Work at the Boston University Center for Molecular Discovery is supported by Grant R24 GM111625. K.C.K. was supported by a CIHR Foundation Grant and the Canada Research Chair program. (Canadian Institutes of Health Research (CIHR); James McGill Professorship salary award; Fonds de recherche sante Quebec; CIHR Neuroinflammation training program; FDN-148366 - CIHR Research Grant; CIHR Foundation grant; R35 GM118173 - NIH; Canada Research Chair program; R24 GM111625

Cardiovascular risk factors in adult general out-patient clinics in Nigeria: a country analysis of the Africa and Middle East Cardiovascular Epidemiological (ACE) study.

Background: With globalization and rapid urbanization, demographic and epidemiologic transitions have become important determinants for the emergence of cardiovascular disease (CVD).Objective: To estimate the prevalence of CVD risk factors in adult out-patients attending general practice and non-specialist clinics in urban and rural Nigeria.Methods: As part of the Africa and Middle East Cardiovascular Epidemiological (ACE) study, a cross-sectional epidemiologic study was undertaken for the presence of hypertension, diabetes mellitus, dyslipidemia, obesity, smoking and abdominal obesity in Nigeria.Results: In total, 303 subjects from 8 out-patient general practice clinics were studied, 184 (60.7%) were female and 119 (39.3%) were male. Mean age was 42.7±13.1 years; 51.8% were aged <45 years; 4% ≥65 years. Over 90% of subjects had ≥1 of 6 selected modifiable cardiovascular risk factors: 138 (45.6%) had 1-2; 65 (21.5%) had 3; 60 (19.8%) had 4; and 11 (3.6%) had 5 concurrent risk factors. Screening identified 206 subjects (68.0%) with dyslipidemia who did not have a prior diagnosis.Conclusion: Cardiovascular risk factors are highly prevalent in Nigerian subjects attending out-patient clinics. Moreover, many subjects were undiagnosed and therefore unaware of their cardiovascular risk status. Opportunistic screening alongside intensive national, multisectoral education or risk factor education is needed, should be scaled up nationwide and rolled out in both urban and rural communities in Nigeria.Keywords: Nigeria, cardiovascular risk factors, screening programs, risk factor management, The Africa and Middle East Cardiovascular Epidemiological (ACE) study

Disaster Management in High Risk Regions : A Case Study of the Indian Himalayas Region

The occurrence of several cases of natural disaster and its impact on high-risk regions remains an issue that continues to attract continued research, most especially from a global perspective. Despite the devastating impact of several known natural phenomenon such as flooding, tsunamis, earthquakes, glaciers and tornadoes, there seem not to be well-structured disaster management approach from stakeholders in high-risk disaster-prone regions to cope with eventual disaster cases. The Indian Himalayan region under review within this research article has been conducted investigated, and a review on how the build of poorly constructed residences have impacted the lives of people living within this region. This article addresses this problem in a line with well-structured thematic sections that examines community resilience, effective stakeholder communication and community preparedness can result in effective disaster management approach

Emergency treatment of a ruptured huge omphalocele by simple suture of its membrane

Background: The rupture of a huge omphalocele is an emergency that threatens the newborn baby’s life. It constitutes a therapeutical concern in the absence of prosthesis especially in developing countries. Methods: We are reporting herein the case of a newborn baby that we managed in emergency successfully thanks to a simple treatment. Results: It was a huge omphalocele, ruptured during delivery, in a male newborn baby. We conducted a simple and conservative surgical treatment without prosthesis, which consisted of reconstruction of the omphalocele’s membrane by closing it with absorbable suture materials. The suture of the omphalocele’s membrane was followed by treatment with the Grob’s method. This treatment saved the newborn baby’s life. The total skinning was obtained after 3 months. Conclusions: In case of rupture of huge omphalocele in absence of prosthesis, it is better to suture the membrane, and continue the treatment according to the Grob’s method; the residual disembowelment can be repaired later. Keywords: Ruptured omphalocele, Huge omphalocele, Grob’s method, Developing countries Backgroun

C5 deficiency and C5a or C5aR blockade protects against cerebral malaria

Experimental infection of mice with Plasmodium berghei ANKA (PbA) provides a powerful model to define genetic determinants that regulate the development of cerebral malaria (CM). Based on the hypothesis that excessive activation of the complement system may confer susceptibility to CM, we investigated the role of C5/C5a in the development of CM. We show a spectrum of susceptibility to PbA in a panel of inbred mice; all CM-susceptible mice examined were found to be C5 sufficient, whereas all C5-deficient strains were resistant to CM. Transfer of the C5-defective allele from an A/J (CM resistant) onto a C57BL/6 (CM-susceptible) genetic background in a congenic strain conferred increased resistance to CM; conversely, transfer of the C5-sufficient allele from the C57BL/6 onto the A/J background recapitulated the CM-susceptible phenotype. The role of C5 was further explored in B10.D2 mice, which are identical for all loci other than C5. C5-deficient B10.D2 mice were protected from CM, whereas C5-sufficient B10.D2 mice were susceptible. Antibody blockade of C5a or C5a receptor (C5aR) rescued susceptible mice from CM. In vitro studies showed that C5a-potentiated cytokine secretion induced by the malaria product P. falciparum glycosylphosphatidylinositol and C5aR blockade abrogated these amplified responses. These data provide evidence implicating C5/C5a in the pathogenesis of CM

Profil de l’algodystrophie chez 112 patients en consultation rhumatologique à Lomé (Togo)

Objectives: To determine the frequency and semiological profile of Complex Regional Pain Syndrome (CRPS) in Lomé. Patients and methods: It was the study of a series of cases on files of patients suffering from CRPS and seen in 24 years of rheumatologic practice in Lomé. The diagnosis was mainly radioclinic. Results: 112 from the 22425 examined patients (0.5%) suffered from CRPS. These 112 patients were made of 71 women and 41 men ; and had the mean age of 53.07 years at the diagnosis. The median duration of the disease was 4.29 months. The main risk factors founded in 60 patients were: trauma (53.33%), stroke (23.32%) and diabetes (6.00%). In the 52 others patients, no risk factor was found. The CRPS was preferably located at shoulder (41 cases), and the wrist and hand (15 cases). Shoulder-hand syndrome was observed in 34 patients (30.63%). Inflammatory pain (59 patients) and mechanical pain (49 patients) were mostly observed. The mobilization of the joints was painful in 110 cases. The pain was associated with joint stiffness (51 patients), locoregional swollen joint (39 patients) and cutaneous disorders (15 patients). Among the 52 patients seen in control, the outcome was favorable in 49 cases and a recidivism in three cases. Conclusion: The cases of CRPS observed in Black Africa do not present particularity on semiological and demographic features

Impact of mass distribution of free long-lasting insecticidal nets on childhood malaria morbidity: The Togo National Integrated Child Health Campaign

<p>Abstract</p> <p>Background</p> <p>An evaluation of the short-term impact on childhood malaria morbidity of mass distribution of free long-lasting insecticidal nets (LLINs) to households with children aged 9-59 months as part of the Togo National Integrated Child Health Campaign.</p> <p>Methods</p> <p>The prevalence of anaemia and malaria in children aged zero to 59 months was measured during two cross-sectional household cluster-sample surveys conducted during the peak malaria transmission, three months before (Sept 2004, n = 2521) and nine months after the campaign (Sept 2005, n = 2813) in three districts representative of Togo's three epidemiological malaria transmission regions: southern tropical coastal plains (Yoto), central fertile highlands (Ogou) and northern semi-arid savannah (Tone).</p> <p>Results</p> <p>In households with children <5 years of age, insecticide-treated net (ITN) ownership increased from <1% to >65% in all 3 districts. Reported ITN use by children during the previous night was 35.9%, 43.8% and 80.6% in Yoto, Ogou and Tone, respectively. Rainfall patterns were comparable in both years. The overall prevalence of moderate to severe anaemia (Hb < 8.0 g/dL) was reduced by 28% (prevalence ratio [PR] 0.72, 95% CI 0.62-0.84) and mean haemoglobin was increased by 0.35 g/dL (95% CI 0.25-0.45).</p> <p>The effect was predominantly seen in children aged 18-59 months and in the two southern districts: PR (95% CI) for moderate to severe anaemia and clinical malaria: Yoto 0.62 (0.44-0.88) and 0.49 (0.35-0.75); Ogou 0.54 (0.37-0.79) and 0.85 (0.57-1.27), respectively. Similar reductions occurred in children <18 months in Ogou, but not in Yoto. No effect was seen in the semi-arid northern district despite a high malaria burden and ITN coverage.</p> <p>Conclusions</p> <p>A marked reduction in childhood malaria associated morbidity was observed in the year following mass distribution of free LLINs in two of the three districts in Togo. Sub-national level impact evaluations will contribute to a better understanding of the impact of expanding national malaria control efforts.</p

SdiA, an N-Acylhomoserine Lactone Receptor, Becomes Active during the Transit of Salmonella enterica through the Gastrointestinal Tract of Turtles

encode a LuxR-type AHL receptor, SdiA, they cannot synthesize AHLs. In vitro, it is known that SdiA can detect AHLs produced by other bacterial species..We conclude that the normal gastrointestinal microbiota of most animal species do not produce AHLs of the correct type, in an appropriate location, or in sufficient quantities to activate SdiA. However, the results obtained with turtles represent the first demonstration of SdiA activity in animals