Synthesis and Structure-Activity Relationships of Imidazopyridine/Pyrimidine- and Furopyridine-Based Anti-infective Agents against Trypanosomiases.

Neglected tropical diseases remain among the most critical public health concerns in Africa and South America. The drug treatments for these diseases are limited, which invariably leads to fatal cases. Hence, there is an urgent need for new antitrypanosomal drugs. To address this issue, a large number of diverse heterocyclic compounds were prepared. Straightforward synthetic approaches tolerated pre-functionalized structures, giving rise to a structurally diverse set of analogs. We report on a set of 57 heterocyclic compounds with selective activity potential against kinetoplastid parasites. In general, 29 and 19 compounds of the total set could be defined as active against Trypanosoma cruzi and T. brucei brucei, respectively (antitrypanosomal activities <10 µM). The present work discusses the structure-activity relationships of new fused-ring scaffolds based on imidazopyridine/pyrimidine and furopyridine cores. This library of compounds shows significant potential for anti-trypanosomiases drug discovery.

Leishmania donovani tyrosyl-tRNA synthetase structure in complex with a tyrosyl adenylate analog and comparisons with human and protozoan counterparts.

The crystal structure of Leishmania donovani tyrosyl-tRNA synthetase (LdTyrRS) in complex with a nanobody and the tyrosyl adenylate analog TyrSA was determined at 2.75 Å resolution. Nanobodies are the variable domains of camelid heavy chain-only antibodies. The nanobody makes numerous crystal contacts and in addition reduces the flexibility of a loop of LdTyrRS. TyrSA is engaged in many interactions with active site residues occupying the tyrosine and adenine binding pockets. The LdTyrRS polypeptide chain consists of two pseudo-monomers, each consisting of two domains. Comparing the two independent chains in the asymmetric unit reveals that the two pseudo-monomers of LdTyrRS can bend with respect to each other essentially as rigid bodies. This flexibility might be useful in the positioning of tRNA for catalysis since both pseudo-monomers in the LdTyrRS chain are needed for charging tRNATyr. An "extra pocket" (EP) appears to be present near the adenine binding region of LdTyrRS. Since this pocket is absent in the two human homologous enzymes, the EP provides interesting opportunities for obtaining selective drugs for treating infections caused by L. donovani, a unicellular parasite causing visceral leishmaniasis, or kala azar, which claims 20,000 to 30,000 deaths per year. Sequence and structural comparisons indicate that the EP is a characteristic which also occurs in the active site of several other important pathogenic protozoa. Therefore, the structure of LdTyrRS could inspire the design of compounds useful for treating several different parasitic diseases.

Characterization of particles, ammonia and endotoxin in swine confinement operations.

To define the atmospheres swine confinement operations, we measured concentrations of total and respirable dust particles, ammonia and endotoxin in the nursery and grower areas of 4 swine confinement houses. Increased ventilation in spring-summer relative to that in winter reduced concentrations of large dust particles more rapidly than it did smaller particles or ammonia. The greater decrease in large particles correlating to increased room air velocity may reflect larger particles' momentum causing impaction on surfaces. There was significant spatial variation in the concentration of airborne endotoxin within individual swine rooms and pens reflecting different mixing of large feed and smaller manure particles. Smaller particles had 4-fold higher concentrations of endotoxin than did larger particles, suggesting they had higher fecal material concentrations. Total airborne endotoxin and total suspended particulates correlated to the fraction of functional endotoxin contained in large particles, suggesting that small particles (0.5-2.0 micrometers) collide with large particles (50 micrometers). These data suggest that large non-respirable particles remove smaller respirable particles from indoor atmospheres due to kinematic coagulation.

Clinical and electrophysiological assessments in ALS patients.

Since the relationships between traditional assessments in ALS patients have not been defined, three clinical and four electrophysiological assessments were performed in a cross-sectional study of 87 ALS patients. The clinical assessments produced Norris ALS scores, muscle strength scores and illness durations (DUR). The electrophysiological assessments produced scores for motor unit interference pattern, denervation potentials, compound muscle action potential, and fasciculations. The individual muscle scores were averaged to produce mean scores, and Spearman rank correlations were performed on the mean scores. The association between Norris ALS and mean muscle strength (MMS) scores is significant (p less than .001, rs = 0.84), and these scores are significantly correlated with mean interference pattern (0.77, 0.82), mean denervation potential (-0.63, -0.70), and mean compound muscle action potential scores (0.55, 0.60), respectively. Correlations between IP and DP scores (-0.71), IP and CMAP scores (0.62), and DP and CMAP (-0.56) scores are also significant. Scatterplots of the data and regression lines suggest linear relationships between each of these assessments. Illness duration and fasciculation scores are not strongly correlated (rs less than 0.55) with any of the other clinical or electrophysiological assessments.

The distribution of small ions during the early development of Xenopus laevis and Ambystoma mexicanum embryos.

The free ion concentrations of Na+, K+ and Cl- have been measured in the cells and intercellular spaces of developing amphibian embryos using ion-sensitive microelectrodes. Ca2+, H+ and buffering capacity have also been measured in the intercellular spaces. The free intracellular Na+ and K+ concentrations in the early cleavage stages remain approximately constant at 21 mM and 90 mM respectively. The free intracellular Cl- concentration, approximately 60 mM during the egg to 4-cell stage, falls during development to around 30 mM by the 128-cell stage. Embryos from different batches show a wide variation in intracellular free ion content. A strong correlation was observed between the ion content, particularly of K+, and the viability of the embryo. If the intracellular K+ concentration was less than 60 mM, embryos invariably died between late blastula and early gastrula stages; if greater than 80 mM the embryo generally survived. The intercellular free Na+, K+, Cl- and Ca2+ concentrations in Xenopus mid-blastula embryos are 91 mM, 4 mM, 59 mM and 1.5 mM respectively. The intercellular potential at late neurula stages is +3.5 mV when the embryo is bathed in 5% Ringer solution; changing to Ringer solution reduced the potential to -4 mV. Before gastrulation the intercellular Ca2+ concentration in Xenopus falls to approximately 0.5 mM, where it remains throughout gastrulation before returning to its mid-blastula value during neurulation. In Xenopus, the intercellular Na+ concentration falls to around 75 mM and the intercellular K+ concentration rises to around 17 mM at the end of gastrulation. These changes are not maintained and both Na+ and K+ concentrations return to their earlier values. In Ambystoma, the intercellular K+ concentration falls steadily from 7 mM at the mid-blastula stage to 2 mM at the end of neurulation. The Na+ concentration is constant at approximately 93 mM up to stage 14; between stages 14 and 16 the measurements show some scatter (minimum value 60 mM, maximum value 100 mM), and beyond stage 16 the Na+ concentration increases to 123 mM.

Low vitamine A and zinc concentrations in Mexican-American migrant children with growth retardation.

Nutritional evaluations were undertaken on 102 Mexican-American preschool children who were below the 3rd percentile for height, weight, or head circumference. Serum vitamin A concentrations were low in 36 of 102 children (35%). Hair zinc concentrations were low in 28 of 96 children (29%) and plasma zinc concentrations were low in 35 of 94 children (37%). Children with only low height had a mean hair zinc level of 87.5 microgram/g, whereas those with only low weight had a mean level of 108.6 microgram/g and those with only low head circumference had a mean level of 100.1 microgram/g. There was no correlation of height percentiles with plasma zinc, hair zinc, or serum vitamin A. However, further studies are needed to determine if there is a relationship between growth retardation and zinc and/or vitamin A status in this population.

Problem children

Brief notes on problem children are presented. The importance of environment is stressed and the fact that treatment, often of simple character, is frequently effective. (AU)