The effect of cortisol on the synthesis of prostaglandins (PGF2 alpha, PGE2) by human endometrial fibroblasts in vitro with and without addition of estradiol-17 beta or progesterone

Cortisol is known as a potent inhibitor of phospholipase A2 activity in several tissues. In fibroblast monolayer cell cultures from proliferative human endometrium cortisol alone does not affect the basal PGF2 alpha or PGE2 synthesis. After stimulation of PGF2 alpha production by 10(-7) mol/l estradiol-17 beta increasing concentrations of cortisol up to 10(-5) mol/l dosedependently reduce the PGF2 alpha production. Also the progesterone (10(-4) mol/l) stimulated increase of PGF2 alpha and PGE2 synthesis is inhibited by cortisol (10(-7) mol/l).     

Effect of Footwear Modifications on Oscillations at the Achilles Tendon during Running on a Treadmill and Over Ground: A Cross-Sectional Study

Background

Achilles tendon injuries are known to commonly occur in runners. During running repeated impacts are transferred in axial direction along the lower leg, therefore possibly affecting the oscillation behavior of the Achilles tendon. The purpose of the present study was to explore the effects of different footwear modifications and different ground conditions (over ground versus treadmill) on oscillations at the Achilles tendon.

Methods

Oscillations were measured in 20 male runners using two tri-axial accelerometers. Participants ran in three different shoe types on a treadmill and over ground. Data analysis was limited to stance phase and performed in time and frequency space. Statistical comparison was conducted between oscillations in vertical and horizontal direction, between running shoes and between ground conditions (treadmill versus over ground running).

Results

Differences in the oscillation behavior could be detected between measurement directions with peak accelerations in the vertical being lower than those in the horizontal direction, p < 0.01. Peak accelerations occurred earlier at the distal accelerometer than at the proximal one, p < 0.01. Average normalized power differed between running shoes (p < 0.01) with harder damping material resulting in higher power values. Little to no power attenuation was found between the two accelerometers. Oscillation behavior of the Achilles tendon is not influenced by ground condition.

Conclusion

Differences in shoe configurations may lead to variations in running technique and impact forces and therefore result in alterations of the vibration behavior at the Achilles tendon. The absence of power attenuation may have been caused by either a short distance between the two accelerometers or high stiffness of the tendon. High stiffness of the tendon will lead to complete transmission of the signal along the Achilles tendon and therefore no attenuation occurs.     

The UGDP controversy: thirty-four years of contentious ambiguity laid to rest

The University Group Diabetes Program (UGDP), launched in 1960, was an early placebo-controlled, multi-center clinical trial devised to determine which, if any, of the treatments for type 2 diabetes was efficacious. Because of an excess of cardiac deaths in patients treated with tolbutamide, a sulfonylurea drug, investigators terminated this limb of the study. This decision was met with strong resistance from the parent drug company and many in the medical community. Subsequent clinical studies both supported and conflicted with the UDGP findings, so that the controversy has persisted. A rationale for sulfonylurea-induced cardiotoxicity emerged with the observation that these drugs block ischemic preconditioning, a protective maneuver that reduces myocardial damage after temporary blockage of coronary blood flow; this action of sulfonylureas provided laboratory support for the UGDP findings. The development of newer sulfonylurea drugs that do not block ischemic preconditioning has rendered the UGDP controversy moot and has preserved a place for sulfonylureas in the treatment of type 2 diabetes.     

Meta-analyses of studies on the association between electromagnetic fields and childhood cancer

During the last 15 years several studies have investigated a possible relationship between exposure to electromagnetic fields (EMF) and childhood cancer. There is considerable variation between these studies with respect to methods of exposure assessment and reported results. Methods of exposure assessment range from simple visual criteria to costly and time consuming measurements or estimations of electric flux density. Additional individual refinements further hinder the comparability of results. We carried out several meta-analyses of data published so far taking into account the heterogeneity between studies as far as possible. Our particular interest was to investigate a potential dose-response-like relationship by comparing analyses for different cut-off points of exposure. Our meta-analyses suggest a marginal association between all cancer diagnoses combined and EMF exposure assessed by the two-level wire code (odds ratio, OR= 1.37, 95% confidence interval, CI: 0.94–2.00). Based on this criterion a significant effect was found for cases of leukemia (OR= 1.66, CI: 1.11–2.49) but not for central nervous system (CNS) tumors (OR= 1.5, CI: 0.69–3.26) or lymphomas (OR= 1.32, CI: 0.52–3.37). A significant increase in overall cancer risk with increasing stages of the four-level wire code (P=0.003) could not be confirmed when data of the initial study performed by Wertheimer and Leeper were excluded (P=0.17). When the exposure criterion was based on distance to the transmission line, estimated ORs for all cancers combined and for leukemias increased with distances decreasing from 100 to 25 m. Those analyses incorporating data on measured or calculated EMFs demonstrated also an increase of overall cancer risk with higher cut-off points. However, regarding individual diagnoses, this finding was reflected only in the group of brain tumors. One possible explanation for the high degree of heterogeneity between studies - especially with respect to methods of exposure assessment and choice of the respective cutpoint relevant for an increase in cancer risk - could be that published cut-off points were not always chosen in advance, but were selected because in exploratory analyses the most striking results were obtained with these specific cut-off values. Should this speculation be true at least partially, any meta-analysis will yield a false-positive finding. Further results of comparable studies with strictly a priori planned analyses are necessary to properly investigate a possible link between EMF and childhood cancer.     

Carbohydrate uptake in Advenella mimigardefordensis strain DPN7T is mediated by periplasmic sugar oxidation and a TRAP‐transport system

In this study, we investigated an SBP (DctP_Am) of a tripartite ATP‐independent periplasmic transport system (TRAP) in Advenella mimigardefordensis strain DPN7^T. Deletion of dctP_Am as well as of the two transmembrane compounds of the tripartite transporter, dctQ and dctM, impaired growth of A. mimigardefordensis strain DPN7^T, if cultivated on mineral salt medium supplemented with d ‐glucose, d ‐galactose, l ‐arabinose, d ‐fucose, d ‐xylose or d ‐gluconic acid, respectively. The wild type phenotype was restored during complementation studies of A. mimigardefordensis ΔdctP_Am using the broad host vector pBBR1MCS‐5::dctP_Am. Furthermore, an uptake assay with radiolabeled [¹⁴C(U)]‐d ‐glucose clearly showed that the deletion of dctP_Am, dctQ and dctM, respectively, disabled the uptake of this aldoses in cells of either mutant strain. Determination of K_D performing thermal shift assays showed a shift in the melting temperature of DctP_Am in the presence of d ‐gluconic acid (K_D 11.76 ± 1.3 µM) and the corresponding aldonic acids to the above‐mentioned carbohydrates d ‐galactonate (K_D 10.72 ± 1.4 µM), d ‐fuconic acid (K_D 13.50 ± 1.6 µM) and d ‐xylonic acid (K_D 8.44 ± 1.0 µM). The sugar (glucose) dehydrogenase activity (E.C.1.1.5.2) in the membrane fraction was shown for all relevant sugars, proving oxidation of the molecules in the periplasm, prior to transport.     

TNF receptors 1 and 2 exert distinct region‐specific effects on striatal and hippocampal grey matter volumes (VBM) in healthy adults

Tumour necrosis factor alpha (TNFα) has been implicated in the pathophysiology of neurodegenerative and neuropsychiatric disease, with research highlighting a role for TNFα in hippocampal and striatal regulation. TNFα signals are primarily transduced by TNF receptors 1 and 2 (TNFR1 and TNFR2), encoded by TNFRSF1A and TNFRSF1B, which exert opposing effects on cell survival (TNFR1, neurodegenerative; TNFR2, neuroprotective). We therefore sought to explore the respective roles of TNFR1 and TNFR2 in the regulation of hippocampal and striatal morphology in an imaging genetics study. Voxel‐based morphometry was used to analyse the associations between TNFRSF1A (rs4149576 and rs4149577) and TNFRSF1B (rs1061624) genotypes and grey matter structure. The final samples comprised a total of 505 subjects (mean age = 33.29, SD = 11.55 years; 285 females and 220 males) for morphometric analyses of rs1061624 and rs4149576, and 493 subjects for rs4149577 (mean age = 33.20, SD = 11.56 years; 281 females and 212 males). Analyses of TNFRSF1A single nucleotide polymorphisms (SNPs) rs4149576 and rs4149577 showed highly significant genotypic associations with striatal volume but not the hippocampus. Specifically, for rs4149576, G homozygotes were associated with reduced caudate nucleus volumes relative to A homozygotes and heterozygotes, whereas for rs4149577, reduced caudate volumes were observed in C homozygotes relative to T homozygotes and heterozygotes. Analysis of the TNFRSF1B SNP rs1061624 yielded a significant association with hippocampal but not with striatal volume, whereby G homozygotes were associated with increased volumes relative to A homozygotes and heterozygotes. Our findings indicate a role for TNFR1 in regulating striatal but not hippocampal morphology, as well as a complementary role for TNFR2 in hippocampal but not in striatal morphology.     

Structure of the Mature Streptococcal Cysteine Protease Exotoxin mSpeB in Its Active Dimeric Form

Invasive infections of Streptococcus pyogenes are dependent on the cysteine protease streptococcal pyrogenic exotoxin B. Previous structures of the enzyme have not disclosed the proper active-site configuration. Here, the crystal structure of the mature enzyme is presented to 1.55 Å, disclosing a homodimer. A serine from one subunit inserts into the active site of the other to donate to the oxyanion hole and coordinates the ligand proximal to the active-site cysteine. Dimerization is unique to the mature form and is clearly a prerequisite for catalysis. The present structure supports a tripartite switch system that is triggered upon dimerization and substrate binding: (1) liberation of the active-site histidine from an inactive configuration, (2) relocation of residues blocking the substrate binding pockets and (3) repositioning of two active-site tryptophans to settle in the active configuration. Based on the present structure, the active site of clan CA cysteine proteases is expanded and a detailed mechanism of the deacylation mechanism is proposed. The results may have applications for the development of protease inhibitors specific to bacterial cysteine proteases.