Development of the First Oral Bioprecursors of Bis‐alkylguanidine Antimalarial Drugs

Plasmodium falciparum is responsible of the most severe form of malaria, and new targets and novel chemotherapeutic scaffolds are needed to fight emerging multidrug‐resistant strains of this parasite. Bis‐alkylguanidines have been designed to mimic choline, resulting in the inhibition of plasmodial de novo phosphatidylcholine biosynthesis. Despite potent in vitro antiplasmodial and in vivo antimalarial activities, a major drawback of these compounds for further clinical development is their low oral bioavailability. To solve this issue, various modulations were performed on bis‐alkylguanidines. The introduction of N‐disubstituents on the guanidino motif improved both in vitro and in vivo activities. On the other hand, in vivo pharmacological evaluation in a mouse model showed that the N‐hydroxylated derivatives constitute the first oral bioprecursors in bis‐alkylguanidine series. This study paves the way for bis‐alkylguanidine‐based oral antimalarial agents targeting plasmodial phospholipid metabolism.     

Simplification of a complex microbial antilisterial consortium to evaluate the contribution of its flora in uncooked pressed cheese

A complex microbial consortium derived from raw milk and composed of populations classified in 4 groups (lactic acid bacteria (A), Gram positive catalase positive bacteria (B), Gram negative bacteria (C) and yeasts (D)) can contribute to the inhibition of Listeria monocytogenes in the core of an uncooked pressed cheese. To identify what groups may be involved in the inhibition, the consortium was simplified by successively omitting one group at a time. Pasteurized milk was inoculated with these more or less complex consortia and their effects on L. monocytogenes count, pH, acids and volatile compounds in the core of uncooked pressed cheese were evaluated. The growth of L. monocytogenes was the highest in cheeses prepared with pasteurized milk and only St. thermophilus. Inhibition in other cheeses was expressed by comparison with growth in these ones. All the consortia containing both lactic acid bacteria (group A) and Gram positive catalase positive bacteria (group B)--ABCD, ABD, ABC, AB--were more inhibitory than those containing lactic acid bacteria on its own (A) or associated only with yeasts (AD) or/and Gram negative (ADC). Consortia without lactic acid bacteria were weakly inhibitory or had no effect. Gram positive catalase positive bacteria alone were not inhibitory although most of the species became established in the cheeses. The Lactobacillus population (Lb. casei, Lb. plantarum, Lb. curvatus and Lb. farciminis) was predominant in cheeses (9 log CFU/g) with a higher count than Leuconostoc (7 log CFU/g) and Enterococcus (7 log CFU/g). Lactobacillus counts were negatively correlated with those of L. monocytogenes (r=-0.84 at 18 days) and with the level of D-lactic acid. There was no correlation between L. monocytogenes and Leuconostoc or Enterococcus counts. Complex consortium ABCD and AB not only had a stronger inhibitory power in cheeses than consortium AD, they were also associated with the highest levels of L-lactic and acetic acids. All cheeses inoculated with lactic acid bacteria differed from those without by higher levels of ethyl formiate, pentane and alcohols (2-butanol, 2-pentanol), and lower levels of ketones (2-hexanone, 2,3-butanedione) and aldehydes (2-methyl-butanal). Levels of 2-methyl-butanal, 2-butanol and 2-pentanol were higher in ABCD and AB cheeses than in AD cheeses. Beside their contribution to the inhibition, their effect on cheese flavour must be evaluated.     

Bioluminescent Optogenetics: A Novel Experimental Therapy to Promote Axon Regeneration after Peripheral Nerve Injury

Functional recovery after peripheral nerve injury (PNI) is poor, mainly due to the slow and incomplete regeneration of injured axons. Experimental therapies that increase the excitability of the injured axons have proven remarkably successful in promoting regeneration, but their clinical applicability has been limited. Bioluminescent optogenetics (BL-OG) uses luminopsins, fusion proteins of light-generating luciferase and light-sensing ion channels that could be used to increase neuronal excitability if exposed to a suitable substrate. Excitatory luminopsins were expressed in motoneurons of transgenic mice and in wildtype mice transduced with adeno-associated viral vectors. Intraperitoneal administration of coelenterazine (CTZ), a known luciferase substrate, generated intense bioluminescence in peripheral axons. This bioluminescence increased motoneuron excitability. A single administration of CTZ immediately after sciatic nerve transection and repair markedly enhanced motor axon regeneration. Compound muscle action potentials were 3–4 times larger than controls by 4 weeks after injury. The results observed with transgenic mice were comparable to those of mice in which the luminopsin was expressed using viral vectors. Significantly more motoneurons had successfully reinnervated muscle targets four weeks after nerve injury in BL-OG treated mice than in controls. Bioluminescent optogenetics is a promising therapeutic approach to enhancing axon regeneration after PNI.     

Acute airway obstruction in the hospitalized infant: four hard lessons in the distal trachea

Acute obstructing lesions of the distal (lower) trachea present a unique challenge to the pediatric otolaryngologist. The small caliber of the airway and tenuous medical status of such patients test the ingenuity of the surgeon and the limits of instrumentation. This report presents the operative findings and management of four hospitalized infants with worsening respiratory distress. Difficulties encountered in maintaining airway control while diagnosing and correcting these lesions are described.     

Coping With Downsizing: A Comparison of Executive-Level and Middle Managers.

A longitudinal study compared the reactions of executive-level and middle managers prior to a large-scale downsizing, during initial and final phases, and following the downsizing. Compared with executives, middle managers perceived greater job insecurity, were more likely to use escape coping, and reported lower job performance and higher levels of health symptoms. Over time, both executives and middle managers reported a decline in perceived threat of job loss but an increase in sense of powerlessness, a decrease in the use of control-oriented coping strategies, and reduced job performance in the initial phase of downsizing. Although less so, executive-level managers were also adversely affected by the downsizing, suggesting that this group should be included in stress management interventions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Malignancy may adversely influence the quality and behaviour of oocytes

A case series of eight cycles of in-vitro fertilization (IVF) in five women diagnosed with malignant disorders is presented. These patients chose to defer definitive treatment for a chance for preservation of potential fertility. The response of these patients to ovarian stimulation, and the outcome, was compared with 17 IVF cycles in 12 age-matched patients with isolated tubal infertility. An apparent adverse influence of malignant disease on the quality and behaviour of oocytes was observed. Despite a comparable total number of oocytes per cycle in the two groups, a significantly reduced percentage of mature oocytes was retrieved per cycle from patients with malignant diseases. The oocytes from patients with malignant disorders were of a poorer quality and exhibited a significantly impaired fertilization rate compared to the controls. We propose that neoplastic processes, irrespective of the site or cell of origin, may have a detrimental impact on the biology of oocytes, an effect akin to that seen on spermatozoa in men with certain malignancies.     

Development of a psychosocial program on a dialysis unit.

By actively seeking involvement, psychologists were able to develop an intervention program on a dialysis unit. Significant aspects of the program as well as problems encountered are described, and suggestions are made for the application of this approach to other medical settings. (15 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The microanalysis of light elements using transmitted energy loss electrons.

The use of transmitted energy loss electrons is shown to hold considerable promise for the elemental analysis of light elements. In this technique, those electrons which have lost energy in exciting characteristic inner shell atomic levels are detected rather than X-rays resulting from the decay of the excited levels. The advantages of this technique are (1) a large fraction (0.1-1) of the information-carrying energy loss electrons can be detected, and (2) for each excited level, one energy loss electron is produced independent of the fluorescent yield. Thus the technique potentially offers higher sensitivity than X-ray analysis. We have begun a program to evaluate this technique both theoretically and experimentally for electron probe devices. First, we have developed the necessary theoretical framework to make predictions concerning relevant quantities of elemental analysis such as the minimum detectable mass (MDM) and mimimum detectable mass fraction (MMF). The results of these calculations for thin specimens indicate a potential reduction in the MDM by up to three orders of magnitude and in the MMF by up to 500 through the use of transmitted energy loss electrons rather than X-rays; the advantages over X-ray detection being greater for lower atomic number. Second, we have begun experimental measurements to verify our predictions. These experiments were performed in a field emission scanning microscope with known limitations in collection efficiency, but the results indicate the validity of the basic assumptions and also aid in the design of an instrument which can fully exploit this technique. The experimental results obtained indicate the ease of detection of characteristic K-shell energy levels in elements as light as lithium and indicate the mass detectability of less than 10(-18)g.