Preclinical antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-beta-D- arabinofuranosyl)adenine (Cl-F-ara-A)

Cl-F-ara-A, an analog of fludarabine, was evaluated against a spectrum of tumor systems in culture and in mice. The compound exhibited significant cytotoxicity against a variety of human tumor cell lines. More importantly, the compound showed selectivity in vivo, with excellent activity being demonstrated against human colon and renal tumors. Human nonsmall cell lung and prostate tumors were also sensitive in vivo to the compound, albeit at a reduced level.     

Monitoring adenovirus infections with on-line and off-line methods

Several known process monitoring methods were tested for their efficacy in the detection of adenovirus infections. The methods that we explored include several indirect indications of viral infections, including metabolic rate analysis, secondary gauges of respiration, cell size measurement, cell number and cell viability determination, and changes in capacitance. Direct indications of the adenovirus infection were also applied, including total viral particle and infectious particle measurements, as well as a flow cytometry method for detecting infected cells. All of the methods tested in the study provide some positive indication of an adenovirus infection. Many of the methods require repeated sampling, which may limit their utility in a manufacturing process. All of the indirect measures of viral infection may be limited by the fact that they do not uniquely identify an infection. The simplest monitoring methods appear to be detection of changes in respiration or the capacitance of the culture, both of which seem to provide a clear indication of an infection. Further work will be required to demonstrate that these indications are characteristic of only a successful and productive adenovirus infection.     

Sensory processing of water currents by fishes

Water currents are extremely important in the aquatic environment and play a very significant role in the lives of fishes. Sensory processing of water currents involves a number of sensory modalities including the inner ear, vision, tactile sense and the mechanosensory lateral line. The inner ear will detect whole-body accelerations generated by changes in flow, or by turbulence, whereas visual and tactile inputs will signal translational movement with respect to an external visual or tactile reference frame. The superficial neuromasts of the mechanosensory lateral line detect flow over the surface of the body and have the appropriate anatomical distribution and physiological properties to signal the strength and the direction of flow and, hence, contribute to the detection of regional differences in flow over different parts of the body.     

Fatty acid deficiency signs predict the severity of reading and related difficulties in dyslexic children

It has been proposed that developmental dyslexia may be associated with relative deficiencies in certain highly unsaturated fatty acids (HUFA). In children with attention-deficit/hyperactivity disorder, minor physical signs of fatty acid deficiency have been shown to correlate with blood biochemical measures of HUFA deficiency. These clinical signs of fatty acid deficiency were therefore examined in 97 dyslexic children in relation to reading and related skills, and possible sex differences were explored.Children with high fatty acid deficiency ratings showed poorer reading (P<0.02) and lower general ability (P<0.04) than children with few such clinical signs. Within males (n=72) these relationships were stronger, and fatty acid deficiency signs were also associated with poorer spelling and auditory working memory (P<0.05, P<0.005 respectively). Within females (n=25) no associations were significant. These results support the hypothesis that fatty acid deficiency may contribute to the severity of dyslexic problems, although sex differences merit further investigation.     

Evaluation of computer based clinical decision support system and risk chart for management of hypertension in primary care: randomised controlled trial

ObjectivesTo investigate the effect of a computer based clinical decision support system and a risk chart on absolute cardiovascular risk, blood pressure, and prescribing of cardiovascular drugs in hypertensive patients.DesignCluster randomised controlled trial.Setting27 general practices in Avon.Participants614 patients aged between 60 and 79 years with high blood pressure.InterventionsPatients were randomised to computer based clinical decision support system plus cardiovascular risk chart; cardiovascular risk chart alone; or usual care.ResultsPatients in the computer based clinical decision support system and chart only groups were no more likely to have cardiovascular risk reduced to below 10% than patients receiving usual care. Patients in the computer based clinical decision support group were more likely to have a cardiovascular risk ⩾10% than chart only patients, odds ratio 2.3 (95% confidence interval 1.1 to 4.8). The chart only group had significantly lower systolic blood pressure compared with the usual care group (difference in means −4.6 mm Hg (95% confidence interval −8.4 to −0.8)). Reduction of diastolic blood pressure did not differ between the three groups. The chart only group were twice as likely to be prescribed two classes of cardiovascular drugs and over three times as likely to be prescribed three or more classes of drugs compared with the other groups.ConclusionsThe computer based clinical decision support system did not confer any benefit in absolute risk reduction or blood pressure control and requires further development and evaluation before use in clinical care can be recommended. Use of chart guidelines are associated with a potentially important reduction in systolic blood pressure.     

Genomic population structure of Grass Pickerel (Esox americanus vermiculatus) in Canada: management guidance for an at-risk fish at its northern range limit

Eighty nine (42%) of Canada’s 215 freshwater fish species have been assessed as at risk by the Committee on the Status of Endangered Wildlife in Canada. This study examines genomic population structure of the at-risk Grass Pickerel (Esox americanus vermiculatus), a small (≤?33 cm) predatory fish that in Canada has a range spanning approximately 114,000 km² of southern Ontario. Within this range it occupies approximately ten sites that are mostly shallow, weedy, and slow-flowing. Its populations and habitat are declining. This study defines population clusters and quantifies genomic diversity within and between populations based on?>?5500 loci and?>?950 SNPs from genomes of 66 individuals representing the subspecies’ entire Canadian range. Ordination and STRUCTURE analyses revealed four major geographic/genomic clusters centered in the Georgian Bay-Severn River, southeastern shore of Lake Huron, Niagara Peninsula, and upper St. Lawrence River. Major clusters were distinguished by relatively high Hudson Fst values (0.205–0.480), with Georgian Bay-Severn River being consistently most distinct. The Niagara Peninsula major cluster contained an additional three discernable sub-clusters differentiated by Fst values as great or greater than major clusters, despite spanning only ca. 200 km². Genomically distinct Niagara sub-clusters occurred in Abino Drain, Big Forks Creek, and Tea Creek. Samples from sites between both major and minor clusters exhibited admixture from adjacent clusters. Despite current management of Grass Pickerel under a single designatable unit throughout its Canadian range, we map considerable geographic population structure that should help guide the designation of additional conservation units.

     

Age-associated defect in human TLR-1/2 function

The effects of aging on human TLR function remain incompletely understood. We assessed TLR function and expression in peripheral blood monocytes from 159 subjects in 2 age categories, 21-30 and >65 years of age, using a multivariable mixed effect model. Using flow cytometry to assess TLR-induced cytokine production, we observed a substantial, highly significant defect in TLR1/2-induced TNF-alpha (p = 0.0003) and IL-6 (p < 0.0001) production, in older adults compared with young controls. In contrast to findings in aged mice, other TLR (including TLR2/6)-induced cytokine production appeared largely intact. These differences were highly significant even after correcting for covariates including gender, race, medications, and comorbidities. This defect in TLR1/2 signaling may result from alterations in baseline TLR1 surface expression, which was decreased by 36% in older adults (p < 0.0001), whereas TLR2 surface expression was unaffected by aging. Production of IL-6 (p < 0.0001) and TNF-alpha (p = 0.003) after stimulation by N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-Cys-[S]-Ser1-[S]-Lys(4) trihydrochloride was strongly associated with TLR1 surface expression. Diminished TLR1/2 signaling may contribute to the increased infection-related morbidity and mortality and the impaired vaccine responses observed in aging humans.