Intermittent preventive treatment for malaria in pregnancy in Africa: What's new, what's needed?

Falciparum malaria is an important cause of maternal, perinatal and neonatal morbidity in high transmission settings in Sub-Saharan Africa. Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP-IPT) has proven efficacious in reducing the burden of pregnancy-associated malaria but increasing levels of parasite resistance mean that the benefits of national SP-IPT programmes may soon be seriously undermined in much of the region. Hence, there is an urgent need to develop alternative drug regimens for IPT in pregnancy. This paper reviews published safety and efficacy data on various antimalarials and proposes several candidate combination regimens for assessment in phase II/III clinical trials

Levofloxacin versus placebo for the prevention of tuberculosis disease in child contacts of multidrug-resistant tuberculosis: study protocol for a phase III cluster randomised controlled trial (TB-CHAMP)

Background Multidrug-resistant (MDR) tuberculosis (TB) presents a challenge for global TB control. Treating individuals with MDR-TB infection to prevent progression to disease could be an effective public health strategy. Young children are at high risk of developing TB disease following infection and are commonly infected by an adult in their household. Identifying young children with household exposure to MDR-TB and providing them with MDR-TB preventive therapy could reduce the risk of disease progression. To date, no trials of MDR-TB preventive therapy have been completed and World Health Organization guidelines suggest close observation with no active treatment. Methods The tuberculosis child multidrug-resistant preventive therapy (TB-CHAMP) trial is a phase III cluster randomised placebo-controlled trial to assess the efficacy of levofloxacin in young child contacts of MDR-TB cases. The trial is taking place at three sites in South Africa where adults with MDR-TB are identified. If a child aged < 5 years lives in their household, we assess the adult index case, screen all household members for TB disease and evaluate any child aged < 5 years for trial eligibility. Eligible children are randomised by household to receive daily levofloxacin (15–20 mg/kg) or matching placebo for six months. Children are closely monitored for disease development, drug tolerability and adverse events. The primary endpoint is incident TB disease or TB death by one year after recruitment. We will enrol 1556 children from approximately 778 households with an average of two eligible children per household. Recruitment will run for 18–24 months with all children followed for 18 months after treatment. Qualitative and health economic evaluations are embedded in the trial. Discussion If the TB-CHAMP trial demonstrates that levofloxacin is effective in preventing TB disease in young children who have been exposed to MDR-TB and that it is safe, well tolerated, acceptable and cost-effective, we would expect that that this intervention would rapidly transfer into policy. Trial registration ISRCTN Registry, ISRCTN92634082. Registered on 31 March 2016

Intermittent preventive treatment for the prevention of malaria during pregnancy in high transmission areas

Malaria in pregnancy is one of the major causes of maternal morbidity and adverse birth outcomes. In high transmission areas, its prevention has recently changed, moving from a weekly or bimonthly chemoprophylaxis to intermittent preventive treatment (IPTp). IPTp consists in the administration of a single curative dose of an efficacious anti-malarial drug at least twice during pregnancy – regardless of whether the woman is infected or not. The drug is administered under supervision during antenatal care visits. Sulphadoxine-pyrimethamine (SP) is the drug currently recommended by the WHO. While SP-IPTp seems an adequate strategy, there are many issues still to be explored to optimize it. This paper reviewed data on IPTp efficacy and discussed how to improve it. In particular, the determination of both the optimal number of doses and time of administration of the drug is essential, and this has not yet been done. As both foetal growth and deleterious effects of malaria are maximum in late pregnancy women should particularly be protected during this period. Monitoring of IPTp efficacy should be applied to all women, and not only to primi- and secondigravidae, as it has not been definitively established that multigravidae are not at risk for malaria morbidity and mortality. In HIV-positive women, there is an urgent need for specific information on drug administration patterns (need for higher doses, possible interference with sulpha-based prophylaxis of opportunistic infections). Because of the growing level of resistance of parasites to SP, alternative drugs for IPTp are urgently needed. Mefloquine is presently one of the most attractive options because of its long half life, high efficacy in sub-Saharan Africa and safety during pregnancy. Also, efforts should be made to increase IPTp coverage by improving the practices of health care workers, the motivation of women and their perception of malaria complications in pregnancy. Because IPTp is not applicable in early pregnancy, which is a period when malaria may also be deleterious for women and their offspring, there is a necessity to integrate this strategy with other preventive measures which can be applied earlier in pregnancy such as insecticide-treated nets

Reduced glucocerebrosidase is associated with increased &#945;-synuclein in sporadic Parkinsons disease

Heterozygous mutations in GBA1, the gene encoding lysosomal glucocerebrosidase, are the most frequent known genetic risk factor for Parkinsons disease. Reduced glucocerebrosidase and &#945;-synuclein accumulation are directly related in cell models of Parkinsons disease. We investigated relationships between Parkinsons disease-specific glucocerebrosidase deficits, glucocerebrosidase-related pathways, and &#945;-synuclein levels in brain tissue from subjects with sporadic Parkinsons disease without GBA1 mutations. Brain regions with and without a Parkinsons disease-related increase in &#945;-synuclein levels were assessed in autopsy samples from subjects with sporadic Parkinsons disease (n = 19) and age- and postmortem delay-matched controls (n = 10). Levels of glucocerebrosidase, &#945;-synuclein and related lysosomal and autophagic proteins were assessed by Western blotting. glucocerebrosidase enzyme activity was measured using a fluorimetric assay, and glucocerebrosidase and &#945;-synuclein mRNA expression determined by quantitative PCR. Related sphingolipids were analyzed by mass spectrometry. Multivariate statistical analyses were performed to identify differences between disease groups and regions, with non-parametric correlations used to identify relationships between variables. glucocerebrosidase protein levels and enzyme activity were selectively reduced in the early stages of Parkinsons disease in regions with increased &#945;-synuclein levels although limited inclusion formation, while GBA1 mRNA expression was non-selectively reduced in Parkinsons disease. The selective loss of lysosomal glucocerebrosidase was directly related to reduced lysosomal chaperone-mediated autophagy, increased &#945;-synuclein and decreased ceramide. glucocerebrosidase deficits in sporadic Parkinsons disease are related to the abnormal accumulation of &#945;-synuclein and are associated with substantial alterations in lysosomal chaperone-mediated autophagy pathways and lipid metabolism. Our data suggest that the early selective Parkinsons disease changes are likely due to the redistribution of cellular membrane proteins leading to a chronic reduction in lysosome function in brain regions vulnerable to Parkinsons disease pathology

Breath ammonia analysis: Clinical application and measurement

This review covers in detail the complexity of human breath, how the body metabolizes ammonia, clinical conditions which are directly related to the regulation of ammonia concentration, and analysis of current techniques that are capable of detecting breath ammonia. Focusing on these areas provides the information needed to develop a breath ammonia sensor for monitoring dysfunction of the human body. Human breath has been broken down into its key components which are necessary for proper understanding of what to look for when attempting to isolate volatile organic compounds. A pathway has been shown which explains the origin of ammonia in the body and how it is processed within a healthy system. Following this, the hazards of several dysfunctions related to the broken ammonia pathway have been discussed. It is essential that technicians have knowledge of these inner workings of the human body along with current technology. Thus, the advantages and disadvantages of techniques from chemical ionization, gas chromatography, laser spectroscopy, and chemical sensing have been discussed. © Taylor and Francis Group, LLC