Pharmacokinetics/Pharmacodynamics findings after repeated Administration of ARTESUNATE thermostable suppositories (RECTOCAPS) in Vietnamese patients with uncomplicated malaria

Summary: In recent years, Artemisinin and particularly one of its derivatives — Artesunate (ART — has become an essential alternative for treatment of both uncomplicated and severe falciparum malaria in Asia and Africa as well. Therefore, these compounds are still and inccreasingly in the focus of interest because of quick acting of this drug, is able to help even unconscious to overcome the malaria attack, when administered by injection. As an alternative, RECTOCAPS have been developed and their use is meanwhile well established. From earlier studies in children, suffering from Plasmodium falciparum malaria, we obtained a high level of DHART in the blood, but as expected also a rapid decline in the levels of both DHART and ART. A second administration of ART was additionally applied 4 hours after the first administration. DHART and ART plasma levels were found to last longer on an assumed therapeutic level than those obtained after one administration only. The fever clearance and the parasitemia reduction rates were found to be effective according to this dosing regimen. In view of these findings, we decided to conduct the actual described study by administering 200 mg of ART every 3 hours (0, 3, 6 and 9 h) by the rectal route. Soft geiatine capsules (RECTOCAPS) containing 200 mg of ART GMP — type each (Artesunic acid) were administered by rectal route. Each patient received four RECTOCAPS capsules (4×200 mg of ART) over a 3 h period. 12 adult patients with uncomplicated malaria were selected. Age, weight, height, body temperature, parasite counts before treatment and their evolution until 96 h are determined. Blood samples were taken at short time intervals after starting with the first medication: 0, 30 min, 60 min, 3 h, 6 h, 9 h, 12 h, 24 h, 36 h, 48 h, 60 h, 72 h, 84 h, 96 h and 108 h. The aliquots of all the blood samples were used for performing parasite counts. Plasma obtained following the traditional procedure was kept at −40°C until analysis. HPLC technique with electrochemical detector was used for quantification of ART and DHART. From the blood concentration values of ART and DHART, the following observation can be derived: the onset of action is observed within the first half hours, therapeutic levels of the drug obtained (89 μg/ml ART compared to 84 μg/ml DHART). The DHART levels are somewhat higher than those of ART (a peak concentration after 6 h starting medication of 151 μg/ml ART as compared to 276 μg/ml DHART). The variations as a function of frequency of DHART uptake are much less marked than those observed for ART. Another finding is that after the administration, some sort of a plateau of DHART and ART is built up, lasting at least from 9 to 12 hours with DHART level of about 190 μg/ml and ART of 90 μg/ml. In the case of single-dose administration, the levels of both compounds were below the detection threshold after three hours. With regard to the parasite counts, although there were inter-individual variations, it should be noted that after 48 hours a high proportion of the patients (8 out of 12) was completely clear of parasites. Similar results were observed with regard to the body temperature (7 out of 12 returned to normal temperature 36 hours after starting the therapy). The findings of the study support the RECTOCAPS application principle resulting in effectiveness both for the velocity of drug uptake as well as for the height of plasma levels. Repeated administration of ART can extend the duration of therapeutic plasma levels of the dru

Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution

Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative and neuroinflammatory diseases of the central nervous system(1-4). These highly diverse and specialized functions may be executed by subsets of microglia that already exist in situ, or by specific subsets of microglia that develop from a homogeneous pool of cells on demand. However, little is known about the presence of spatially and temporally restricted subclasses of microglia in the central nervous system during development or disease. Here we combine massively parallel single-cell analysis, single-molecule fluorescence in situ hybridization, advanced immunohistochemistry and computational modelling to comprehensively characterize subclasses of microglia in multiple regions of the central nervous system during development and disease. Single-cell analysis of tissues of the central nervous system during homeostasis in mice revealed specific time- and region-dependent subtypes of microglia. Demyelinating and neurodegenerative diseases evoked context-dependent subtypes of microglia with distinct molecular hallmarks and diverse cellular kinetics. Corresponding clusters of microglia were also identified in healthy human brains, and the brains of patients with multiple sclerosis. Our data provide insights into the endogenous immune system of the central nervous system during development, homeostasis and disease, and may also provide new targets for the treatment of neurodegenerative and neuroinflammatory pathologies

Women out, children out : the effect of female labor on portuguese preschool enrollment rates

This article tests whether Portuguese female activity rates have increased preschool enrollment rates. Particularly during the last 20 years, Portuguese women have assumed new roles in the marketplace and have become active workers outside of the home environment. This change has encouraged more sensible decisions with respect to preschool enrollment. Using cointegration techniques, we concluded that female activity rates and real income per capita caused a long-term increase in preschool enrollment rates. Although the percentage of agricultural gross value added to the gross domestic product and the number of preschool institutes were also found to be significant in the estimated vector error correction model, their causal relationship with preschool enrollment was only short term.COMPETE; QREN; FEDER; Fundação para a Ciência e a Tecnologia (FCT

Adherence to dietary recommendations for preschoolers: clinical trial with teenage mothers

ABSTRACT OBJECTIVE To assess the effect of educational dietary intervention offered in the child’s first year of life, as well as teenage mothers and grandmothers in carrying out the dietary recommendations at four to seven years. METHODS Randomized clinical trial initiated in 2006, in Porto Alegre, RS, involving 323 teenage mothers and grandmothers who cohabited. The intervention consisted of six counseling sessions on breastfeeding and healthy complementary feeding. The first session occurred in the maternity ward and the other ones in the households of mothers at seven, 15, 30, 60, and 120 days of the child’s life. The information about the child’s diet were obtained on a monthly basis in the first six months, every two months in the second half-year, and at four to seven years, using a food frequency questionnaire. To assess the adequacy of food consumption to the recommendations from the Ministry of Health, we elaborated a score system that would reflect the compliance with the Ten Steps for Healthy Toddlers from 2 to 10 Years. The average scores of intervention and control groups were compared using the t-test. RESULTS Low adherence to recommendations on child nutrition was found in the study population, with no difference in implementation the steps between the groups. The score on the compliance with the steps was similar in both groups (9.6 [SD = 1.63] and 9.3 [SD = 1.60] in the intervention and control groups, respectively) and no influence of the cohabitation with the grandmother was found. CONCLUSIONS Educational dietary intervention in the first four months of the child’s life for teenage mothers and grandmothers had no effect on the compliance with the recommendations at four to seven years of the child’s life

Freiburg Neuropathology Case Conference

Purpose!#!After coil embolization of intracranial aneurysms, it is currently not well understood whether the initial coil packing density or the type of aneurysm residual perfusion, depicted by the modified Raymond-Roy occlusion classification, primarily effects the rate of aneurysm recurrence. We hypothesized that these factors interact and only one remains an independent risk factor.!##!Methods!#!In this single center retrospective study, 440 patients with intracranial ruptured and unruptured aneurysms between 2010 and 2017 were screened. A total of 267 patients treated with stand-alone coiling, with or without stent or balloon assistance were included (age 54.1 ± 12.2 years, sex 70.4% female). Flow diverter or Woven EndoBridge (WEB) device implantation were exclusion criteria.!##!Results!#!Using a binary logistic regression model, independent risk factors for aneurysm recurrence were postinterventional modified Raymond-Roy occlusion classification class (Odds ratio [OR] 1.747, 95% confidence interval [CI] 1.231-2.480) and aneurysm diameter (OR 1.145, CI 1.032-1.271). A trend towards a higher recurrence in ruptured aneurysms did not reach significance (OR 1.656, CI 0.863-3.179). Aneurysm localization, packing density, and neck width were not independently associated with aneurysm recurrence.!##!Conclusion!#!Independent risk factors for aneurysm recurrence after coil embolization with and without stent or balloon assistance were aneurysm diameter and postinterventional grading within the modified Raymond-Roy occlusion classification. Packing density interacted with the latter and was not independently associated to recurrence