Identifying potential drug targets in the kinomes of two monogenean species.

Protein kinases are enzymes involved in essential biological processes such as signal transduction, transcription, metabolism, and the cell cycle. Human kinases are targets for several drugs approved by the US Food and Drug Administration. Therefore, the identification and classification of kinases in other organisms, including pathogenic parasites, is an interesting subject of study. Monogeneans are platyhelminths, mainly ectoparasites, capable of causing health problems in farmed fish. Although some genomes and transcriptomes are available for monogenean species, their full repertoire of kinases is unknown. The aim of this study was to identify and classify the putative kinases in the transcriptomes of two monogeneans, Rhabdosynochus viridisi and Scutogyrus longicornis, and then to predict potential monogenean drug targets (MDTs) and selective inhibitor drugs using computational approaches. Monogenean kinases having orthologs in the lethal phenotype of C. elegans but not in fish or humans were considered MDTs. A total of 160 and 193 kinases were identified in R. viridisi and S. longicornis, respectively. Of these, 22 kinases, belonging mainly to the major groups CAMK, AGC, and TK, were classified as MDTs, five of which were evaluated further. Molecular docking analysis indicated that dihydroergotamine, ergotamine, and lomitapide have the highest affinity for the kinases BRSK and MEKK1. These well-known drugs could be evaluated in future studies for potential repurposing as anti-monogenean agents. The present study contributes valuable data for the development of new antiparasitic candidates for finfish aquaculture.

Susceptibility of Pacific white snook Centropomus viridis to Vibrio species.

To examine the pathogenicity of Vibrio strains, several doses of Vibrio harveyi (CAIM 1622 and CAIM 1508), Vibrio ponticus (CAIM 1751) and Vibrio anguillarum (CAIM 8) were used to challenge Pacific white snook Centropomus viridis Lockington, 1877 juveniles, and survival, gross signs and histological lesions were observed. Susceptibility of pathogenic vibrios CAIM 1508 and CAIM 1751 to antibiotics used in aquaculture was also evaluated. The growth ability of the tested strains was not related to their pathogenicity. One of the V. harveyi strains (CAIM 1508) was the most virulent, causing per-acute septicaemia in C. viridis even at a low dose (1.4 × 104 CFU g-1). Although the V. ponticus strain (CAIM 1751) was less virulent, this is the first report of it as a pathogen of white snook. Fish challenged with V. ponticus displayed external, generalized haemorrhaging. Necrosis of the digestive tract and intravascular haemosiderosis were the most remarkable histological lesions in fish challenged with both strains. Multifocal necrosis of the internal organs and bacterial masses was also observed. The lowest minimum inhibitory concentration of the pathogenic strains (CAIM 1508 and CAIM 1751) was calculated for enrofloxacin (20 and 10 µg ml-1, respectively), and both bacteria were resistant to amoxicillin, ampicillin and trimethoprim-sulfamethoxazole.

Track structure modeling in liquid water: A review of the Geant4-DNA very low energy extension of the Geant4 Monte Carlo simulation toolkit.

Understanding the fundamental mechanisms involved in the induction of biological damage by ionizing radiation remains a major challenge of today's radiobiology research. The Monte Carlo simulation of physical, physicochemical and chemical processes involved may provide a powerful tool for the simulation of early damage induction. The Geant4-DNA extension of the general purpose Monte Carlo Geant4 simulation toolkit aims to provide the scientific community with an open source access platform for the mechanistic simulation of such early damage. This paper presents the most recent review of the Geant4-DNA extension, as available to Geant4 users since June 2015 (release 10.2 Beta). In particular, the review includes the description of new physical models for the description of electron elastic and inelastic interactions in liquid water, as well as new examples dedicated to the simulation of physicochemical and chemical stages of water radiolysis. Several implementations of geometrical models of biological targets are presented as well, and the list of Geant4-DNA examples is described.

Antigliadin antibodies in Cuban patients with spinocerebellar ataxia type 2.

OBJECTIVE: To evaluate the significance of antigliadin antibodies (AGA) levels for spinocerebellar ataxia type 2. METHODS: We determined AGA levels in 64 patients with spinocerebellar ataxia type 2 and in 65 healthy matched controls. The clinical assessment was carried out using the International Cooperative Ataxia Rating Scale and CAG repeat number was assessed by PCR. RESULTS: Antibodies were positive in 23.4% of the ataxia patients and 9.09% of the controls. Statistical comparison using chi2 test with Yates's correction reveals significant differences between these two groups (chi2 = 3.94; p = 0.047). The same was obtained for strongly positive AGA (chi2 = 4.62; p = 0.032). There were no significant differences between AGA positive and AGA negative patients in age at onset, disease duration, ataxia score or CAG repeat number, neither in the prevalence of gastrointestinal symptoms, prevalence of wheat intolerance or body weight. CONCLUSIONS: These results demonstrate an association between antigliadin antibodies serum levels and SCA2. However, more work has to be done to clarify the clinical consequences of such an association.

Antigliadin antibodies in Cuban patients with spinocerebellar ataxia type 2

Antibodies were positive in 23.4 percent of the ataxiapatients and 9.09 percent of the controls. Statistical comparisonusing x2 test with Yatess correction reveals significantdifferences between these two groups (x2=3.94; p=0.047). The same was obtained for strongly positiveAGA (x2=4.62; p=0.032). There were no significant differences between AGA positive and AGA negativepatients in age at onset, disease duration, ataxia score orCAG repeat number, neither in the prevalence of gastrointestinal symptoms, prevalence of wheat intolerance or body weight. These results demonstrate anassociation between antigliadin antibodies serum levels and SCA2. However, more work has to be done to clarify the clinical consequences of such an association...(AU)

Genetic targets for the detection and identification of Venezuelan equine encephalitis viruses.

Rt-PCR probes targeted to different gene sequences of VEE (Venezuelan equine encephalitis) virus strain TC-83 were assessed for their sensitivity, specificity and non-specific cross-reactivity. A generic VEE virus amplimer (VNSP4F2/VNSP4R2), targeted against nsP4 was identified, which was sensitive (detected at least 10 pfu) and robust (worked over a wide range of salt concentrations and annealing temperatures). An E2 amplimer designed against TC-83, (VE2F/VE2R), identified VEE strains TRD (1AB), P676 (1C), 3880 (1D) Everglades (2) vRNA whilst a second E2 primer pair designed against strain 68U201, (68UF/68UR), identified all the remaining VEE viruses in the sero-complex. This would suggest that the VEE virus E2 gene can be sub-divided at the genetic level into two separate groups making it a useful target for differentiation of serosubtypes 1 and 2 from the other VEE virus subtypes. Using a panel of amplimers targeted to different VEE genes and strains it was possible to distinguish between most of the serotypes, but most importantly, we were able to detect the epizootic strains TRD and P676 as well as other VEE viruses implicated in human disease (sero-subtypes 1D and 1E).

New Nocardia taxon among isolates of Nocardia brasiliensis associated with invasive disease.

Nocardia brasiliensis, the second most frequently isolated aerobic actinomycete in the clinical laboratory, is usually associated with localized cutaneous infections. However, 22% of 238 N. brasiliensis isolates from the United States and 12% of 66 isolates from Queensland, Australia, which had been collected over a 17-year period, were associated with extracutaneous and/or disseminated diseases. Of the 62 invasive isolates, 37 (60%) were susceptible to ciprofloxacin and/or were susceptible to clarithromycin and resistant to minocycline, compared with only 6 (3%) of 242 localized cutaneous isolates. The 43 isolates with this susceptibility pattern appeared to define a new taxon. They were similar to Nocardia asteroides complex isolates clinically in proportions from persons with pulmonary (70%), central nervous system (23%), and/or disseminated diseases (37%) in the setting of corticosteroids (74%) or AIDS (14%). This putative new taxon differed from N. brasiliensis in the hydrolysis of adenine (92 versus 4%), beta-lactamase patterns on isoelectric focusing, and the presence of two early mycolic acid-ester peaks by high-performance liquid chromatography. Restriction analysis of a 439-bp fragment of the 65-kDa heat shock protein gene revealed that N. brasiliensis and the new taxon had different restriction patterns with 8 of the 11 enzymes tested. Screening of invasive isolates of N. brasiliensis for susceptibility to ciprofloxacin will identify most isolates of the new taxon, which likely represents a new Nocardia species.

Portage guide to early intervention: cross-cultural aspects and intra-cultural variability.

The issues arising from implementing an early intervention service, developed in the rural United States in the late 1960s in a range of different cultural contexts over a period of a quarter of a century, are explained. Services from India, Bangladesh, Jamaica and the United Kingdom are compared. As well as considering cross-cultural aspects of Portage, variability within one country, the United Kingdom, is considered by comparing one service in an inner-city area and one in a rural area.

PIP: In the late 1960s in rural Wisconsin, the Portage Guide to Early Intervention was developed to manage development delay in preschool children. A parent, usually the mother, teaches the child each day and keeps a record. A home visitor monitors progress weekly and teaches the parent by modelling the program with the child. It operates under basic assumptions, some of which many countries cannot meet. For example, services available in developed countries (e.g., health services) are not available in Bangladesh and India, because resources are limited and the population is so large. Further, there are considerable differences in culture between these countries and the West (e.g., extended family vs. nuclear family). Moreover, the major causes of developmental delay in these South Asian countries are different than in developed countries (birth asphyxia, malnutrition, and deficiency diseases vs. genetic causes). Professionals in India and Bangladesh have incorporated Portage into a variety of early intervention services, thereby modifying the model considerably. In Jamaica, however, professionals use the Portage model with only a few modifications. Fore example, they use it with all disabled children rather than just those with learning disabilities. A problem with using the model is the lack of manufactured toys and play materials listed in the curriculum. Jamaica has a training program for child development aides. Portage services exist throughout the UK. Urban programs serve many more immigrants from developing countries than do the rural programs. This requires modifying the Portage model. In all countries, costs pose a constraint. This overview of Portage services in various countries indicates that these services alone are relatively unimportant as direct agents of social change and may be an important element of broader social changes.

Urea kinetic analysis and clinical outcome on CAPD. A five year longitudinal study.

The present study, along with some recent studies, suggests that there is an organic link between the amount of dialysis a patient receives and his/her nutritional status. The latter, as reflected by serum albumin, is predictive of survival on CAPD. It is clear, therefore, that urea kinetic analysis is a powerful tool for prescribing and monitoring therapy in CAPD patients.

Increased responsiveness of intestinal and vascular smooth muscle to agonists in rats infected with Nippostrongylus brasiliensis.

Rats were infected with the nematode parasite, N. brasiliensis. During infection, the responsiveness of intestinal and vascular smooth muscle to agonists changed. For example, the maximum response of isolated segments of intestine to acetylcholine were increased. In part, this enhanced responsiveness was due to hypertrophy of intestinal smooth muscle. In addition, there was an almost two-fold increase in the tension developed per unit of cross-sectional area, indicating that the contractile capacity of the muscle was also increased during infection. The responsiveness of vascular smooth muscle to agonists was also enhanced. In the perfused rat hindquarters, the maximum response to phenylephrine increased throughout infection, reaching a peak at a time (day 14 of infection) when the rate of worm expulsion was maximal. The possibility is considered that these changes in the responsiveness of intestinal and vascular smooth muscle are the result of an immune response.