Public health activities to identify and monitor persons at risk for Ebola virus disease in the United States include directing persons at risk to assessment facilities that are prepared to safely ...evaluate for Ebola virus disease. Although it is unlikely that a person with Ebola virus disease will unexpectedly present to a nonemergency ambulatory care facility, the Centers for Disease Control and Prevention have provided guidance for this setting that can be summarized as identify, isolate, and inform.
Streptococcus pneumoniae is an important cause of otitis media and invasive disease. Since introduction of the heptavalent pneumococcal conjugate vaccine, there has been an increase in replacement ...disease due to serotype 19A clonal complex (CC)199 isolates. The goals of this study were to 1) describe genetic diversity among nineteen CC199 isolates from carriage, middle ear, blood, and cerebrospinal fluid, 2) compare CC199 19A (n = 3) and 15B/C (n = 2) isolates in the chinchilla model for pneumococcal disease, and 3) identify accessory genes associated with tissue-specific disease among a larger collection of S. pneumoniae isolates. CC199 isolates were analyzed by comparative genome hybridization. One hundred and twenty-seven genes were variably present. The CC199 phylogeny split into two main clades, one comprised predominantly of carriage isolates and another of disease isolates. Ability to colonize and cause disease did not differ by serotype in the chinchilla model. However, isolates from the disease clade were associated with faster time to bacteremia compared to carriage clade isolates. One 19A isolate exhibited hypervirulence. Twelve tissue-specific genes/regions were identified by correspondence analysis. After screening a diverse collection of 326 isolates, spr0282 was associated with carriage. Four genes/regions, SP0163, SP0463, SPN05002 and RD8a were associated with middle ear isolates. SPN05002 also associated with blood and CSF, while RD8a associated with blood isolates. The hypervirulent isolate's genome was sequenced using the Solexa paired-end sequencing platform and compared to that of a reference serotype 19A isolate, revealing the presence of a novel 20 kb region with sequence similarity to bacteriophage genes. Genetic factors other than serotype may modulate virulence potential in CC199. These studies have implications for the long-term effectiveness of conjugate vaccines. Ideally, future vaccines would target common proteins to effectively reduce carriage and disease in the vaccinated population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We examined the effects of ML3000 and several non-steroidal antiinflammatory drugs (NSAIDs) on the synthesis of products of 5-LOX (LTB4, LTC4) and COX-1/2 (TXB2, PGE2) in vitro and ex vivo in order ...to further elucidate the mechanism of action of ML3000.
Using a human whole blood assay the effect of ML3000 on the shunt of arachidonic acid to the lipoxygenase pathway when COX is blocked was studied. ML3000 (0.3, 1, 3, 10, 30 microg/ml) and indomethacin (0.3, 1, 3, 10, 30 microg/ml) concentration-dependently inhibited the synthesis of PGE2 (IC50 = 3.9 and 4.5 microM). In contrast to ML3000, indomethacin produced an increase of LTC4 of up to 155.5% of control. 5-lipoxygenase inhibition was further tested in a basophilic leukemia cell assay using RBL-1 cells. ML3000 (1-10 microM) inhibited the synthesis of LTB4 in a concentration related manner (IC50: 3.6 microM). In carrageenan induced rat paw edema, ML3000 and indomethacin completely blocked the formation of PGE2 in the inflamed tissue. The LTB4 production in the inflamed paw was reduced to basal levels by ML3000 (10 +/- 1.4 pg/paw saline control and 7.5 +/- 1.3-5.9 +/- 3.2 pg/paw ML3000), whereas LTB4 levels remained markedly elevated as compared to saline control by indomethacin (30.7 pg/paw). 5-LOX inhibition in the inflamed rat colon was investigated by measuring LTB4 synthesis. MK-886 and ML3000 at 10 mg/kg p.o. reduced LTB4 production to 29.8 +/- 4.9 and 30.1 +/- 2.8 pg/mg tissue as compared to control (54.2 +/- 7.4 mg/kg tissue). LTB4 levels in the rat stomach were comparable to control (2.5 +/- 0.4 pg/mg protein) after oral administration of ML3000 (10, 30, 100 mg/kg), whereas oral treatment with indomethacin (0.3, 1, 3 mg/kg) or diclofenac (1, 3 mg/kg) increased LTB4 up to 9.2 +/- 2.3 or 8.9 +/- 1.6 pg/mg protein. This effect was significant at 1 mg/kg diclofenac and 0.3 mg/kg indomethacin.
These results provide further evidence, that ML3000 inhibits 5-LOX as well as COX-1 and COX-2 in vitro and in animal experiments. The favourable gastrointestinal (GI) tolerability of the compound is believed to be linked to the mechanism of combined 5-LOX and COX-1/2 inhibition of ML3000.
Background and purpose: A main challenge in the therapy of osteoarthritis (OA) is the development of drugs that will modify the disease. Reliable test systems are necessary to enable an efficient ...screening of therapeutic substances. We therefore established a chondrocyte‐based in vitro cell culture model in order to characterize different p38MAPK inhibitors.
Experimental approach: Interleukin‐1β (IL‐1β)‐stimulated human OA chondrocytes were treated with the p38MAPK inhibitors Birb 796, pamapimod, SB203580 and the new substance CBS‐3868. Birb 796‐ and SB203580‐treated cells were analysed in a genome‐wide microarray analysis. The efficacy of all inhibitors was characterized by quantitative gene expression analysis and the quantification of PGE2 and NO release.
Key results: Microarray analysis revealed inhibitor‐specific differences in gene expression. Whereas SB203580 had a broad effect on chondrocytes, Birb 796 counteracted the IL‐1β effect more specifically. All p38MAPK inhibitors significantly inhibited the IL‐1β‐induced gene expression of COX‐2, mPGES1, iNOS, matrix metalloproteinase 13 (MMP13) and TNFRSF11B, as well as PGE2 release. Birb 796 and CBS‐3868 showed a higher efficacy than SB203580 and pamapimod at inhibiting the expression of COX‐2 and MMP13 genes, as well as PGE2 release. In the case of mPGES1 and TNFRSF11B gene expression, CBS‐3868 exceeded the efficacy of Birb 796.
Conclusions and implications: Our test system could differentially characterize inhibitors of the same primary pharmaceutical target. It reflects processes relevant in OA and is based on chondrocytes that are mainly responsible for cartilage degradation. It therefore represents a valuable tool for drug screening in between functional in vitro testing and in vivo models.
The search for the causes of neurodegenerative disorders is a major theme in brain research. Acquired disturbances of several aspects of cellular metabolism appear pathologically important in ...sporadic Alzheimer's disease (SDAT). Among these brain glucose utilisation is reduced in the early stages of the disease and the regulatory enzymes important for glucose metabolism are reduced. In the brain, insulin, insulin-like growth factors and their receptors regulate glucose metabolism and promote neuronal growth. To detect changes in the functional activity of the brain insulin neuromodulatory system of SDAT patients, we determined the concentrations of insulin and c-peptide as well as insulin receptor binding and IGF-I receptor binding in several regions of postmortem brain cortex during aging and Alzheimer's disease. Additionally, we performed immunohistochemical staining with antibodies against insulin in neocortical brain areas in SDAT and controls. We show for the first time that insulin and c-peptide concentration in the brain are correlated and decrease with aging, as do brain insulin receptor densities. Weak insulin-immunoreactivity could be demonstrated histochemically in pyramidal neurons of controls, whereas in SDAT a stronger insulin-immunoreactivity was found. On a biochemical level, insulin and c-peptide levels were reduced compared to middle-aged controls, but were unchanged compared to age-matched controls. Brain insulin receptor densities in SDAT were decreased compared to middle-aged controls, but increased in comparison to age-matched controls. IGF-I receptor densities were unchanged in aging and in SDAT. Tyrosine kinase activity, a signal transduction mechanism common to both receptor systems, was reduced in SDAT in comparison to middle-aged and age-matched control groups. These data are consistent with a neurotrophic role of insulin in the human brain and a disturbance of insulin signal transduction in SDAT brain and favor the hypothesis that insulin dependent functions may be of pathogenetic relevance in sporadic SDAT.
Directed evolution approaches were used to construct a thermally stabilized variant of Erwinia chrysanthemi pectin methylesterase A. The final evolved enzyme has four amino acid substitutions that ...together confer a Tm value that is approximately 11°C greater than that of the wild-type enzyme, while maintaining near-wild-type kinetic properties. The specific activity, with saturating substrate, of the thermally stabilized enzyme is greater than that of the wild-type enzyme when both are operating at their respective optimal temperatures, 60°C and 50°C. The engineered enzyme may be useful for saccharification of biomass, such as sugar beet pulp, with relatively high pectin content. In particular, the engineered enzyme is able to function in biomass up to temperatures of 65°C without significant loss of activity. Specifically, the thermally stabilized enzyme facilitates the saccharification of sugar beet pulp by the commercial pectinase preparation Pectinex Ultra SPL. Added pectin methylesterase increases the initial rate of sugar production by approximately 50%.
Non-typhoidal Salmonella is estimated to be the most common bacterial cause of foodborne illness in the United States, causing an estimated one million domestically acquired foodborne illnesses ...annually. Recent, large outbreaks have highlighted the importance of ground beef as an important source of multidrug-resistant Salmonella. We analysed the epidemiology of salmonellosis outbreaks that were attributed to beef in the United States reported to the Centers for Disease Control and Prevention (CDC) from 1973 to 2011. During 1973–2011, of the 1965 outbreaks of Salmonella where a food vehicle was implicated, 96 were attributed to beef, accounting for 3684 illnesses. We observed a shift in the type of beef implicated in salmonellosis outbreaks, from roast to ground beef. Delicatessen-style roast beef cooked in commercial processing establishments was the predominant type during the 1970s and early 1980s; regulations on cooking and processing essentially eliminated this problem by 1987. Ground beef emerged as an important vehicle in the 2000s; it was implicated in 17 (45%) of the 38 beef-attributed outbreaks reported during 2002–2011. Although this emergence was likely due in part to increased participation in CDC's PulseNet, which was established in 1996, and proactive decisions by the United States Department of Agriculture's Food Safety and Inspection Service, stronger measures are needed to decrease contamination of ground beef with Salmonella.
To examine sources of repeat Chlamydia trachomatis infections using behavioural and molecular methods.
Women with C. trachomatis had baseline and 4-month follow-up visits consisting of behavioural ...surveys and genotyping of C. trachomatis. Frequencies and population-attributable risk percentages (PAR%) were estimated for possible sources of repeat infections including sex partners not known to be treated, new sex partners, and sex partners not known to be monogamous. Women with different genotypes at baseline and follow-up were classified as different partner sources of infection.
The cumulative incidence of repeat infections in the sample (n=183) was 13% (95% CI 8% to 18%). Predictors of repeat infections included younger age and continued sex with a partner not known to be treated. Frequencies of having partners not known to be treated, new partners, or partners not known to be monogamous at follow-up were 21% (95% CI 15% to 27%), 37% (95% CI 30% to 44%) and 33% (95% CI 28% to 41%), respectively. The PAR% for having a partner not known to be treated was 26% (95% CI 3% to 49%) and for having a new sex partner was 21% (95% CI 0% to 50%). Among eight patients with available genotypes at baseline and follow-up, five had different genotypes and were classified as having a different partner source of infection.
Different sex partner sources of repeat C. trachomatis infections other than untreated sex partners may contribute substantially to the burden of repeat infections.
U.S. Organizational Sentencing Guidelines provide firms with incentives to develop formal ethics programs to promote ethical organizational cultures and thereby decrease corporate offenses. Yet ...critics argue such programs are cosmetic. Here we studied bank employees before and after the introduction of formal ethics training—an important component of formal ethics programs—to examine the effects of training on ethical organizational culture. Two years after a single training session, we find sustained, positive effects on indicators of an ethical organizational culture (observed unethical behavior, intentions to behave ethically, perceptions of organizational efficacy in managing ethics, and the firm's normative structure). While espoused organizational values also rose in importance post-training, the boost dissipated after the second year which suggests perceptions of values are not driving sustained behavioral improvements. This finding conflicts with past theory which asserts that enduring behavioral improvements arise from the inculcation of organizational values. Implications for future research are discussed.
PDF
