Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance

Antimalarial chloroquine (CQ) prevents haematin detoxication when CQ-base concentrates in the acidic digestive vacuole through protonation of its p-aminopyridine (pAP) basic aro- matic nitrogen and sidechain diethyl-N. CQ export through the variant vacuolar membrane export channel, PFCRT, causes CQ-resistance in Plasmodium falciparum but 3-methyl CQ (sontochin SC), des-ethyl amodiaquine (DAQ) and bis 4-aminoquinoline piperaquine (PQ) are still active. This is determined by changes in drug accumulation ratios in parasite lipid (LAR) and in vacuolar water (VAR). Higher LAR may facilitate drug binding to and blocking PFCRT and also aid haematin in lipid to bind drug. LAR for CQ is only 8.3; VAR is 143,482. More hydrophobic SC has LAR 143; VAR remains 68,523. Similarly DAQ with a phenol sub- stituent has LAR of 40.8, with VAR 89,366. In PQ, basicity of each pAP is reduced by distal piperazine N, allowing very high LAR of 973,492, retaining VAR of 104,378. In another bis quinoline, dichlorquinazine (DCQ), also active but clinically unsatisfactory, each pAP retains basicity, being insulated by a 2-carbon chain from a proximal nitrogen of the single linking piperazine. While LAR of 15,488 is still high, the lowest estimate of VAR approaches 4.9 million. DCQ may be expected to be very highly lysosomotropic and therefore potentially hepatotoxic. In 11 pAP antimalarials a quadratic relationship between logLAR and logRe- sistance Index (RI) was confirmed, while log (LAR/VAR) vs logRI for 12 was linear. Both might be used to predict the utility of structural modifications

Unexpected removal of the most neutral cationic pharmaceutical in river waters

Contamination of surface waters by pharmaceuticals is now widespread. There are few data on their environmental behaviour, particularly for those which are cationic at typical surface water pH. As the external surfaces of bacterio-plankton cells are hydrophilic with a net negative charge, it was anticipated that bacterio-plankton in surface-waters would preferentially remove the most extensively-ionised cation at a given pH. To test this hypothesis, the persistence of four, widely-used, cationic pharmaceuticals, chloroquine, quinine, fluphenazine and levamisole, was assessed in batch microcosms, comprising water and bacterio-plankton, to which pharmaceuticals were added and incubated for 21 days. Results show that levamisole concentrations decreased by 19 % in microcosms containing bacterio-plankton, and by 13 % in a parallel microcosm containing tripeptide as a priming agent. In contrast to levamisole, concentrations of quinine, chloroquine and fluphenazine were unchanged over 21 days in microcosms containing bacterio-plankton. At the river-water pH, levamisole is 28 % cationic, while quinine is 91–98 % cationic, chloroquine 99 % cationic and fluphenazine 72–86 % cationic. Thus, the most neutral compound, levamisole, showed greatest removal, contradicting the expected bacterio-plankton preference for ionised molecules. However, levamisole was the most hydrophilic molecule, based on its octanol–water solubility coefficient (K ow). Overall, the pattern of pharmaceutical behaviour within the incubations did not reflect the relative hydrophilicity of the pharmaceuticals predicted by the octanol–water distribution coefficient, D ow, suggesting that improved predictive power, with respect to modelling bioaccumulation, may be needed to develop robust environmental risk assessments for cationic pharmaceuticals

Data from an International Multi-Centre Study of Statistics and Mathematics Anxieties and Related Variables in University Students (the SMARVUS Dataset)

This large, international dataset contains survey responses from N = 12,570 students from 100 universities in 35 countries, collected in 21 languages. We measured anxieties (statistics, mathematics, test, trait, social interaction, performance, creativity, intolerance of uncertainty, and fear of negative evaluation), self-efficacy, persistence, and the cognitive reflection test, and collected demographics, previous mathematics grades, self-reported and official statistics grades, and statistics module details. Data reuse potential is broad, including testing links between anxieties and statistics/mathematics education factors, and examining instruments’ psychometric properties across different languages and contexts

Malaria vectors in the municipality of Serra do Navio, State of Amapá, Amazon Region, Brazil.

We conducted a survey to determine the vectors of malaria in six localities of Serra do Navio municipality, State of Amapá, from 1990 to 1991. Malaria infection rates of 29.3%, 6.2% and 20.4% were detected by human blood smears in Colônia Agua Branca, Porto Terezinha and Arrependido, respectively. There was no malaria infection detected in Serra do Navio. Fifteen species were identified among 3,053 anopheline mosquitoes collected by human bait and 64.4% were identified as Anopheles albitarsis s.l., 16.7% An. braziliensis, 9.5% An. nuneztovari and 5.8% An. triannulatus. An. darlingi, the main vector of malaria in the Amazon region of Brazil, was scare. Using enzyme-linked immunosorbent assay (ELISA), a total positive rate of 0.8% (23/2876) was found for six species: fifteen An. albitarsis s.l., four An. nuneztovari, and one of each: An. braziliensis, An. triannulatus, An. oswaldoi and An. rangeli. Nine of 23 positive mosquitoes were infected with Plasmodium malariae, eight with P. vivax VK210, three with P. vivax VK247 and three with P. falciparum. Since An. albitarsis s.l. was collected feeding on humans, was present in the highest density and was positive by ELISA for malaria sporozoites, it probably plays an important role in malaria transmission in this area

Toll-like receptors-2, -3 and -4 expression patterns on human colon and their regulation by mucosal-associated bacteria

The colonic epithelium provides an interface between the host and micro-organisms colonising the gastrointestinal tract. Molecular recognition of bacteria is facilitated through Toll-like receptors (TLR). The colonic epithelium expresses relatively high levels of mRNA for TLR3 and less for TLR2 and -4. Little is known of the expression patterns and mode of induction of expression for these pattern recognition receptors in human colon. The aim of this study was to investigate their localization in the gut and induction of expression in epithelial cell lines by mucosal bacteria. TLR2 and -4 were expressed only in crypt epithelial cells, expression was lost as the cells matured and moved towards the gut lumen. In contrast, TLR3 was only produced in mature epithelial cells. HT29 and CACO-2 had different levels of expression for TLR1–4. Co-culture of HT29 cells with different mucosal isolates showed that they were highly responsive to bacterial challenge, with up-regulation of mRNA for TLR1–4. In contrast, CACO-2 cells were refractive to bacterial challenge, showing little difference in mRNA levels. TLR3 was induced in HT29 only by Gram-positive commensals with up-regulation of both mRNA and protein and an enhancement of the antiviral immune response. This pattern of expression allows induction of responsiveness to bacteria only by the crypt epithelium so that tolerance to commensal organisms can be maintained. In contrast, mature columnar epithelium is able to respond to viral pathogens, which are not part of the normal gut commensal microbiota