Aberrant Herpesvirus-Induced Polyadenylation Correlates With Cellular Messenger RNA Destruction

Inhibition of host cell gene expression by the human herpesvirus KSHV occurs via a novel mechanism involving polyadenylation-linked RNA turnover

Spinal Cord Injury Causes Sustained Disruption of the Blood-Testis Barrier in the Rat

There is a high incidence of infertility in males following traumatic spinal cord injury (SCI). Quality of semen is frequently poor in these patients, but the pathophysiological mechanism(s) causing this are not known. Blood-testis barrier (BTB) integrity following SCI has not previously been examined. The objective of this study was to characterize the effects of spinal contusion injury on the BTB in the rat. 63 adult, male Sprague Dawley rats received SCI (n = 28), laminectomy only (n = 7) or served as uninjured, age-matched controls (n = 28). Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), BTB permeability to the vascular contrast agent gadopentate dimeglumine (Gd) was assessed at either 72 hours-, or 10 months post-SCI. DCE-MRI data revealed that BTB permeability to Gd was greater than controls at both 72 h and 10 mo post-SCI. Histological evaluation of testis tissue showed increased BTB permeability to immunoglobulin G at both 72 hours- and 10 months post-SCI, compared to age-matched sham-operated and uninjured controls. Tight junctional integrity within the seminiferous epithelium was assessed; at 72 hours post-SCI, decreased expression of the tight junction protein occludin was observed. Presence of inflammation in the testes was also examined. High expression of the proinflammatory cytokine interleukin-1 beta was detected in testis tissue. CD68+ immune cell infiltrate and mast cells were also detected within the seminiferous epithelium of both acute and chronic SCI groups but not in controls. In addition, extensive germ cell apoptosis was observed at 72 h post-SCI. Based on these results, we conclude that SCI is followed by compromised BTB integrity by as early as 72 hours post-injury in rats and is accompanied by a substantial immune response within the testis. Furthermore, our results indicate that the BTB remains compromised and testis immune cell infiltration persists for months after the initial injury

Corticosteroids for severe sepsis: an evidence-based guide for physicians

Septic shock is characterized by uncontrolled systemic inflammation that contributes to the progression of organ failures and eventually death. There is now ample evidence that the inability of the host to mount an appropriate hypothalamic-pituitary and adrenal axis response plays a major in overwhelming systemic inflammation during infections. Proinflammatory mediators released in the inflamed sites oppose to the anti-inflammatory response, an effect that may be reversed by exogenous corticosteroids. With sepsis, via nongenomic and genomic effects, corticosteroids restore cardiovascular homeostasis, terminate systemic and tissue inflammation, restore organ function, and prevent death. These effects of corticosteroids have been consistently found in animal studies and in most recent frequentist and Bayesian meta-analyses. Corticosteroids should be initiated only in patients with sepsis who require 0.5 μg/kg per minute or more of norepinephrine and should be continued for 5 to 7 days except in patients with poor hemodynamic response after 2 days of corticosteroids and with a cortisol increment of more than 250 nmol/L after a standard adrenocorticotropin hormone (ACTH) test. Hydrocortisone should be given at a daily dose of 200 mg and preferably combined to enteral fludrocortisone at a dose of 50 μg. Blood glucose levels should be kept below 150 mg/dL

GATA2 Mediates Thyrotropin-Releasing Hormone-Induced Transcriptional Activation of the Thyrotropin β Gene

Thyrotropin-releasing hormone (TRH) activates not only the secretion of thyrotropin (TSH) but also the transcription of TSHβ and α-glycoprotein (αGSU) subunit genes. TSHβ expression is maintained by two transcription factors, Pit1 and GATA2, and is negatively regulated by thyroid hormone (T3). Our prior studies suggest that the main activator of the TSHβ gene is GATA2, not Pit1 or unliganded T3 receptor (TR). In previous studies on the mechanism of TRH-induced activation of the TSHβ gene, the involvements of Pit1 and TR have been investigated, but the role of GATA2 has not been clarified. Using kidney-derived CV1 cells and pituitary-derived GH3 and TαT1 cells, we demonstrate here that TRH signaling enhances GATA2-dependent activation of the TSHβ promoter and that TRH-induced activity is abolished by amino acid substitution in the GATA2-Zn finger domain or mutation of GATA-responsive element in the TSHβ gene. In CV1 cells transfected with TRH receptor expression plasmid, GATA2-dependent transactivation of αGSU and endothelin-1 promoters was enhanced by TRH. In the gel shift assay, TRH signal potentiated the DNA-binding capacity of GATA2. While inhibition by T3 is dominant over TRH-induced activation, unliganded TR or the putative negative T3-responsive element are not required for TRH-induced stimulation. Studies using GH3 cells showed that TRH-induced activity of the TSHβ promoter depends on protein kinase C but not the mitogen-activated protein kinase, suggesting that the signaling pathway is different from that in the prolactin gene. These results indicate that GATA2 is the principal mediator of the TRH signaling pathway in TSHβ expression

CYFRA 21-1 is a prognostic determinant in non-small-cell lung cancer: results of a meta-analysis in 2063 patients

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Systematic review of the evidence relating FEV1 decline to giving up smoking

<p>Abstract</p> <p>Background</p> <p>The rate of forced expiratory volume in 1 second (FEV₁) decline ("beta") is a marker of chronic obstructive pulmonary disease risk. The reduction in beta after quitting smoking is an upper limit for the reduction achievable from switching to novel nicotine delivery products. We review available evidence to estimate this reduction and quantify the relationship of smoking to beta.</p> <p>Methods</p> <p>Studies were identified, in healthy individuals or patients with respiratory disease, that provided data on beta over at least 2 years of follow-up, separately for those who gave up smoking and other smoking groups. Publications to June 2010 were considered. Independent beta estimates were derived for four main smoking groups: never smokers, ex-smokers (before baseline), quitters (during follow-up) and continuing smokers. Unweighted and inverse variance-weighted regression analyses compared betas in the smoking groups, and in continuing smokers by amount smoked, and estimated whether beta or beta differences between smoking groups varied by age, sex and other factors.</p> <p>Results</p> <p>Forty-seven studies had relevant data, 28 for both sexes and 19 for males. Sixteen studies started before 1970. Mean follow-up was 11 years. On the basis of weighted analysis of 303 betas for the four smoking groups, never smokers had a beta 10.8 mL/yr (95% confidence interval (CI), 8.9 to 12.8) less than continuing smokers. Betas for ex-smokers were 12.4 mL/yr (95% CI, 10.1 to 14.7) less than for continuing smokers, and for quitters, 8.5 mL/yr (95% CI, 5.6 to 11.4) less. These betas were similar to that for never smokers. In continuing smokers, beta increased 0.33 mL/yr per cigarette/day. Beta differences between continuing smokers and those who gave up were greater in patients with respiratory disease or with reduced baseline lung function, but were not clearly related to age or sex.</p> <p>Conclusion</p> <p>The available data have numerous limitations, but clearly show that continuing smokers have a beta that is dose-related and over 10 mL/yr greater than in never smokers, ex-smokers or quitters. The greater decline in those with respiratory disease or reduced lung function is consistent with some smokers having a more rapid rate of FEV₁decline. These results help in designing studies comparing continuing smokers of conventional cigarettes and switchers to novel products.</p

Serum biomarkers in idiopathic pulmonary fibrosis

International audienceWithin the group of Idiopathic Interstitial Pneumonias (IIPs), above all Idiopathic Pulmonary Fibrosis (IPF) poses a considerable diagnostic and therapeutic problem. Although genetic profiling indicates that IPF, Non Specific Interstitial Pneumonia (NSIP), and chronic hypersensitivity pneumonitis (HP) are distinctly different diseases, in every day practice these diseases can be difficult to tell apart. Furthermore, treatment of these diseases is notoriously difficult. Serum biomarkers reflect our understanding of the underlying pathogenesis and potentially fulfill a role in establishing a diagnosis, prognosis and therapy. While no single biomarker is currently able to accurately predict the presence or absence of an IIP, a composite of several markers holds promise for the future. Several biomarkers, such as KL-6, surfactant proteins and circulating fibrocytes, appear to contribute to our insight into disease progression and prognosis. It is however uncertain whether these markers give us additional information to common diagnostic tests and their value has as yet to be validated for every day practice. Fortunately, the potential of biomarkers is increasingly recognized and biomarker data are prospectively gathered in current placebo-controlled therapeutic trials