Systematic review of statins in sepsis: There is no evidence of dose response.

OBJECTIVES: Sepsis is a common cause of morbidity and mortality and is associated with significant costs to the healthcare organizations. We performed a systematic review and meta-analysis to assess whether high or low-dose statin therapy improved mortality in patients with sepsis. METHODS: The trials analyzed in this study were multicenter or single center randomized control studies using statins for sepsis in a hospital setting. The patients included were adults with suspected or confirmed infection. INTERVENTIONS: This study found eight randomized controlled trials where participants were given either a statin or placebo daily for 14-28 days, the duration of their illness, or until their death or discharge, which ever occurred first. PRIMARY AND SECONDARY OUTCOMES MEASURED: This meta-analysis measured the effect of statin therapy on in hospital and 28 days mortality. RESULTS: In unselected patients, there was no demonstrable difference in the 28 days mortality (relative risk [RR] 0.88 95% confidence interval [CI], 0.70-1.12 and P = 0.16). There was also no significant difference between statin versus placebo for in-hospital mortality (RR 0.98 95% CI, 0.85-1.14 P = 0.36). When the studies where divided into low-dose and high-dose groups, there were no statistically significant differences for in-hospital mortality between low-dose statin versus placebo for (RR 0.81 CI 0.44-1.49 P = 0.27) or high-dose statin versus placebo (RR 0.99 95% CI 0.85-1.16, P = 0.28). There was no significant difference in adverse effects between the high- and low-dose groups. CONCLUSIONS: In this meta-analysis, we found that the use of statins did not significantly improve either in-hospital mortality or 28-day mortality in patients with sepsis. In the low-dose group, there were fewer quality multicenter studies; hence, conclusions based on the results of this subgroup are limited.

Effects of implied physical effort in sensory-motor and pre-frontal cortex during language comprehension.

Embodied theories of conceptual knowledge suggest that sensory-motor representations of actions similar to those involved in the performance of the action described are recruited during language comprehension. The extent of this recruitment, however, and the brain mechanisms supporting this process remain unknown. Using fMRI, we investigated these issues by examining how people understand sentences that convey three different degrees of physical effort and by comparing this process to action execution. To understand the effort implied by the stimulus sentences, object and action properties associated with nouns and verbs respectively needed to be integrated: pushing the piano implies more physical effort than pushing the chair. Results indicated that a pre-motor region, which was also active in action execution, was sensitive to the degree of effort implied by the language. Interestingly, the anterior inferior frontal gyrus, a region typically associated with semantic processing, was not active in action execution but was nevertheless modulated by the effort implied. Inter-region correlations also suggested that this region was strongly correlated with pre-motor and posterior temporal regions. Overall, results suggest that (a) language understanding elicits action representations retaining a degree of specificity that was previously unsuspected, including unique properties of interactions with objects, and (b) these representations, which result from integrating the words' semantic information, may be computed within a collaborative neural network that includes the anterior inferior frontal gyrus.

PTP1B inhibitors: synthesis and evaluation of difluoro-methylenephosphonate bioisosteres on a sulfonamide scaffold.

We have synthesized and evaluated a series of triaryl sulfonamide-based PTP1B inhibitors in which a difluoro-methylenephosphonate group of a potent lead has been replaced by potential bioisosteric replacements. Several mono- or di-charged compounds (8a, 8b, and 15a) were shown exhibit inhibitory activity in the low micromolar range, demonstrating the feasibility of using this approach in identifying non-phosphonate pTyr mimetics in a small molecular scaffold. These results also provide a useful indication of the relative effectiveness of these pTyr mimetics.

Discovery and structure-activity relationships of novel sulfonamides as potent PTP1B inhibitors.

A series of novel sulfonamides containing a single difluoromethylene-phosphonate group were discovered to be potent inhibitors of protein tyrosine phosphatase 1B. Structure-activity relationships around the scaffold were investigated, leading to the identification of compounds with IC50 or Ki values in the low nanomolar range. These sulfonamide-based inhibitors exhibit 100 and 30 times higher inhibitory activity than the corresponding tertiary amines and carboxamides, respectively.