For virtually three decades wound drains were used almost routinely in total joint replacement without question and were considered essential. On reviewing the literature, however, the scientific ...evidence for their use is scanty. More recently, a number of relatively small studies have questioned their value. It was therefore decided to carry out a large, definitive study to determine whether or not the use of a wound drain affected the outcome in primary total hip replacement. In July 1994, a prospective, randomized control trial began in Musgrave Park Hospital. A total of 872 primary total hip replacements were included (440 with a drain and 432 without). A number of different parameters were measured in thepostoperative period including blood loss, wound and drain site ooze, haematoma formation and wound infection. The study found no evidence to suggest that drains are actually harmful to patients, but they do not appear to be necessary. Consequently, it is proposed that postoperative drainage systems offer little advantage in the outcome of primary total hip replacements. A saving of £ 12 508 could be made over the course of a year if no drains at all were used for patients undergoing total hip replacement surgery in the study hospital (drain per unit cost £7. 16×1747, 1995/96).
Epigenetic therapy is emerging as a potential therapy for solid tumors. To investigate its mechanism of action, we performed integrative expression and methylation analysis of 63 cancer cell lines ...(breast, colorectal, and ovarian) after treatment with the DNA methyltransferase inhibitor 5-azacitidine (AZA). Gene Set Enrichment Analysis demonstrated significant enrichment for immunomodulatory pathways in all three cancers (14.4-31.3%) including interferon signaling, antigen processing and presentation, and cytokines/chemokines. Strong upregulation of cancer testis antigens was also observed. An AZA IMmune gene set (AIMs) derived from the union of these immunomodulatory pathway genes classified primary tumors from all three types, into "high" and "low" AIM gene expression subsets in tumor expression data from both TCGA and GEO. Samples from selected patient biopsies showed upregulation of AIM genes after treatment with epigenetic therapy. These results point to a broad immune stimulatory role for DNA demethylating drugs in multiple cancers.
The Paisley Caves in Oregon record the oldest directly dated human remains (DNA) in the Western Hemisphere. More than 100 high-precision radiocarbon dates show that deposits containing artifacts and ...coprolites ranging in age from 12,450 to 2295 ¹⁴C years ago are well stratified. Western Stemmed projectile points were recovered in deposits dated to 11,070 to 11,340 ¹⁴C years ago, a time contemporaneous with or preceding the Clovis technology. There is no evidence of diagnostic Clovis technology at the site. These two distinct technologies were parallel developments, not the product of a unilinear technological evolution. "Blind testing" analysis of coprolites by an independent laboratory confirms the presence of human DNA in specimens of pre-Clovis age. The colonization of the Americas involved multiple technologically divergent, and possibly genetically divergent, founding groups.
BACKGROUND: Left atrial (LA) enlargement, congestive heart failure (CHF), and aortic thromboembolism (ATE) are associated with decreased survival in cats with hypertrophic cardiomyopathy (HCM), but ...the prognostic value of echocardiographic variables has not been well characterized. HYPOTHESIS/OBJECTIVES: We hypothesized that LA echocardiographic variables and assessment of left ventricular (LV) diastolic and systolic function would have prognostic value in cats with HCM. ANIMALS: Two hundred eighty‐two cats diagnosed with HCM. METHODS: Clinical and echocardiographic records of affected cats seen at the Royal Veterinary College from 2004 to 2009 were retrospectively analyzed. Only cats with echocardiographic confirmation of LV diastolic wall thickness ≥6 mm were included. Outcomes were obtained from clinical records or referring veterinarians and owners. RESULTS: Deaths occurred in 164 cats, of which 107 were believed to have been cardiac deaths. Univariable predictors of an increased risk of cardiac death included older age, absence of a murmur, presence of a gallop sound or arrhythmia, presentation with either CHF or ATE, extreme LV hypertrophy (≥9.0 mm), LV fractional shortening (FS%) ≤30%, regional wall hypokinesis, increased left atrial size, decreased left atrial function, spontaneous echo‐contrast/thrombus or both, absence of left ventricular outflow tract obstruction, and a restrictive diastolic filling pattern. Cox's proportional hazard analysis identified LA dysfunction, low LV systolic function, and extreme LV hypertrophy as independent predictors of decreased cardiac survival time. CONCLUSIONS AND CLINICAL IMPORTANCE: Echocardiographic measurement of LA function, extreme LV hypertrophy, and LV systolic function provides important prognostic information in cats with HCM.
Ovarian carcinoma is the fifth leading cause of death among women in the United States. Persistent activation of STAT3 is frequently detected in ovarian carcinoma. STAT3 is activated by Janus family ...kinases (JAK) via cytokine receptors, growth factor receptor, and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses antitumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on ovarian carcinoma cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small-molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration, and adhesion of ovarian carcinoma cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity, and immune cell populations in a transgenic mouse model of ovarian carcinoma. AZD1480 treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured ovarian carcinoma cells and ovarian tumor growth rate, volume, and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal TME of tumor-bearing mice than control mice. Taken together, our results show pharmacologic inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy.
Temporal lobe epilepsy is the most common drug-resistant form of epilepsy in adults. The reorganization of neural networks and the gene expression landscape underlying pathophysiologic network ...behavior in brain structures such as the hippocampus has been suggested to be controlled, in part, by microRNAs. To systematically assess their significance, we sequenced Argonaute-loaded microRNAs to define functionally engaged microRNAs in the hippocampus of three different animal models in two species and at six time points between the initial precipitating insult through to the establishment of chronic epilepsy. We then selected commonly up-regulated microRNAs for a functional in vivo therapeutic screen using oligonucleotide inhibitors. Argonaute sequencing generated 1.44 billion small RNA reads of which up to 82% were microRNAs, with over 400 unique microRNAs detected per model. Approximately half of the detected microRNAs were dysregulated in each epilepsy model. We prioritized commonly up-regulated microRNAs that were fully conserved in humans and designed custom antisense oligonucleotides for these candidate targets. Antiseizure phenotypes were observed upon knockdown of miR-10a-5p, miR-21a-5p, and miR-142a-5p and electrophysiological analyses indicated broad safety of this approach. Combined inhibition of these three microRNAs reduced spontaneous seizures in epileptic mice. Proteomic data, RNA sequencing, and pathway analysis on predicted and validated targets of these microRNAs implicated derepressed TGF-β signaling as a shared seizure-modifying mechanism. Correspondingly, inhibition of TGF-β signaling occluded the antiseizure effects of the antagomirs. Together, these results identify shared, dysregulated, and functionally active microRNAs during the pathogenesis of epilepsy which represent therapeutic antiseizure targets.
Topological insulator (TI) nanoribbons with proximity-induced superconductivity are a promising platform for Majorana bound states (MBSs). In this work, we consider a detailed modeling approach for a ...TI nanoribbon in contact with a superconductor via its top surface, which induces a superconducting gap in its surface-state spectrum. The system displays a rich phase diagram with different numbers of end-localized MBSs as a function of chemical potential and magnetic flux piercing the cross section of the ribbon. These MBSs can be
or
upon consideration of electrostatic disorder. We simulate a tunneling spectroscopy setup to probe the different topological phases of top-proximitized TI nanoribbons. Our simulation results indicate that a
TI nanoribbon is ideally suited for realizing fully gapped topological superconductivity, in particular when the Fermi level is pinned near the Dirac point. In this regime, the setup yields a single pair of MBSs, well separated at opposite ends of the proximitized ribbon, which gives rise to a robust quantized zero-bias conductance peak.
The Sertoli cells of the testes secrete anti-Müllerian hormone (Müllerian inhibiting Substance, AMH) and inhibin B (InhB). AMH triggers the degeneration of the uterine precursor in male embryos, ...whereas InhB is part of the gonadal-pituitary axis for the regulation of sperm production in adults. However, both hormones are also putative regulators of homeostasis, and age-related changes in these hormones may therefore be important to the health status of elderly men. The levels of AMH in elderly men are unknown, with limited information being available about age-related changes in InhB. We have therefore used ELISAs to measure Sertoli cell hormone levels in 3 cohorts of community-dwelling men in New Zealand. In total, 615 men were examined, 493 of which were aged 65 or older. Serum AMH and InhB levels inversely correlated with age in men older than 50 years (p<0.001) but not in the younger men. A minority of elderly men had undetectable levels of AMH and InhB. The variation in hormone levels between similarly aged men increased with the age of men. AMH and InhB partially correlated with each other as expected (r = 0.48, p<0.001). However, the ratio of the two Sertoli hormones varied significantly between men, with this variation increasing with age. Elderly men selected for the absence of cardiovascular disease had AMH levels similar to those of young men whereas their InhB levels did not differ from aged-matched controls. These data suggests that Sertoli cell number and function changes with age, but with the extent and nature of the changes varying between men.
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