Abstract
HYpothesis testing using PHYlogenies (HyPhy) is a scriptable, open-source package for fitting a broad range of evolutionary models to multiple sequence alignments, and for conducting ...subsequent parameter estimation and hypothesis testing, primarily in the maximum likelihood statistical framework. It has become a popular choice for characterizing various aspects of the evolutionary process: natural selection, evolutionary rates, recombination, and coevolution. The 2.5 release (available from www.hyphy.org) includes a completely re-engineered computational core and analysis library that introduces new classes of evolutionary models and statistical tests, delivers substantial performance and stability enhancements, improves usability, streamlines end-to-end analysis workflows, makes it easier to develop custom analyses, and is mostly backward compatible with previous HyPhy releases.
Spinal cord injury (SCI) provokes an inflammatory response that generates substantial secondary damage within the cord but also may contribute to its repair. Anti-inflammatory treatment of human SCI ...and its timing must be based on knowledge of the types of cells participating in the inflammatory response, the time after injury when they appear and then decrease in number, and the nature of their actions. Using post-mortem spinal cords, we evaluated the time course and distribution of pathological change, infiltrating neutrophils, monocytes/macrophages and lymphocytes, and microglial activation in injured spinal cords from patients who were ‘dead at the scene’ or who survived for intervals up to 1 year after SCI. SCI caused zones of pathological change, including areas of inflammation and necrosis in the acute cases, and cystic cavities with longer survival (Zone 1), mantles of less severe change, including axonal swellings, inflammation and Wallerian degeneration (Zone 2) and histologically intact areas (Zone 3). Zone 1 areas increased in size with time after injury whereas the overall injury (size of the Zones 1 and 2 combined) remained relatively constant from the time (1–3 days) when damage was first visible. The distribution of inflammatory cells correlated well with the location of Zone 1, and sometimes of Zone 2. Neutrophils, visualized by their expression of human neutrophil α-defensins (defensin), entered the spinal cord by haemorrhage or extravasation, were most numerous 1–3 days after SCI, and were detectable for up to 10 days after SCI. Significant numbers of activated CD68-immunoreactive ramified microglia and a few monocytes/macrophages were in injured tissue within 1–3 days of SCI. Activated microglia, a few monocytes/macrophages and numerous phagocytic macrophages were present for weeks to months after SCI. A few CD8+ lymphocytes were in the injured cords throughout the sampling intervals. Expression by the inflammatory cells of the oxidative enzymes myeloperoxidase (MPO) and nicotinamide adenine dinucleotide phosphate oxidase (gp91phox), and of the pro-inflammatory matrix metalloproteinase (MMP)-9, was analysed to determine their potential to cause oxidative and proteolytic damage. Oxidative activity, inferred from MPO and gp91phox immunoreactivity, was primarily associated with neutrophils and activated microglia. Phagocytic macrophages had weak or no expression of MPO or gp91phox. Only neutrophils expressed MMP-9. These data indicate that potentially destructive neutrophils and activated microglia, replete with oxidative and proteolytic enzymes, appear within the first few days of SCI, suggesting that anti-inflammatory ‘neuroprotective’ strategies should be directed at preventing early neutrophil influx and modifying microglial activation.
Concerns regarding pain constitute a large component of dental anxiety, and patients with high dental anxiety are likely to have exaggerated memory and prediction of dental pain. It remains to be ...investigated, however, if memory of anxiety is exaggerated in a manner similar to that of pain, and if anxiety and pain assimilate in memory over time. A sample of 79 patients presenting for emergency extraction rated their anxiety and pain before, during, and two weeks after the procedure. Measures of trait dental anxiety and fear of pain also were collected. All patients exaggerated their recall of procedure pain, but only those high in trait dental anxiety exaggerated their recall of anxiety. Highly anxious patients reported more pain prior to the procedure and expected more pain; ratings of anxiety and pain for all participants assimilated over time.
Summary
Background
Tumour necrosis factor‐α inhibitors (TNFαIs) are used for treatment of inflammatory disorders. There is evidence linking these agents with occurrence of malignancies. For four out ...of five TNFαIs the Food and Drug Administration (FDA) label states, ‘melanoma has been reported in patients treated with these agents’.
Objectives
To determine whether a statistically significant association exists between administration of TNFαIs and development of malignant melanoma.
Methods
We searched the FDA Adverse Event Reporting System (FAERS) database for terms related to melanoma and TNFαIs for detection of safety signals. We also searched a large urban academic electronic medical record (EMR) database for which we calculated the relative risk (RR) of melanoma in subjects exposed to TNFαIs vs. nonexposed subjects.
Results
There were 972 reports of melanoma associated with a TNFαI identified in the FAERS database, with 69 reports among individuals using more than one TNFαI. A safety signal was detected for infliximab, golimumab, etanercept and adalimumab, but not certolizumab pegol. For TNFαIs as a class of drugs, a safety signal was detectable in the FAERS database, and RR was significant in the EMR database. For the EMR cohort, 6045 patients were exposed to TNFαIs and 35 cases of melanoma were detected. Significance for RR was detected for adalimumab (RR 1·8, P = 0·02) and etanercept (RR 2·35, P = 0·0004 < 0·001).
Conclusions
We identified a significant association between exposure to TNFαIs and malignant melanoma in two different analyses. Our findings add to existing evidence linking these agents with the occurrence of malignant melanoma. Additional investigations are required to explore this association further along with the risk of melanoma with TNFαI therapy.
What's already known about this topic?
Tumour necrosis factor‐α inhibitors (TNFαIs) have been linked with the occurrence of malignancies, including melanoma.
A statistical association has not yet been clarified.
What does this study add?
A safety signal was detected in the Food and Drug Administration Adverse Event Reporting System database.
Enhanced monitoring for patients receiving TNFαIs is therefore warranted.
Rapid time to treatment with thrombolytic therapy is associated with lower mortality in patients with acute myocardial infarction (MI). However, data on time to primary angioplasty and its ...relationship to mortality are inconclusive.
To test the hypothesis that more rapid time to reperfusion results in lower mortality in the strategy of primary angioplasty.
Prospective observational study of data collected from the Second National Registry of Myocardial Infarction between June 1994 and March 1998.
A total of 661 community and tertiary care hospitals in the United States.
A cohort of 27,080 consecutive patients with acute MI associated with ST-segment elevation or left bundle-branch block who were treated with primary angioplasty.
In-hospital mortality, compared by time from acute MI symptom onset to first balloon inflation and by time from hospital arrival to first balloon inflation (door-to-balloon time).
Using a multivariate logistic regression model, the adjusted odds of in-hospital mortality did not increase significantly with increasing delay from MI symptom onset to first balloon inflation. However, for door-to-balloon time (median time 1 hour 56 minutes), the adjusted odds of mortality were significantly increased by 41% to 62% for patients with door-to-balloon times longer than 2 hours (for 121-150 minutes: odds ratio OR, 1.41; 95% confidence interval CI, 1.08-1.84; P=.01; for 151-180 minutes: OR, 1.62; 95% CI, 1.23-2.14; P<.001; and for >180 minutes: OR, 1.61; 95% CI, 1.25-2.08; P<.001).
The relationship in our study between increased mortality and delay in door-to-balloon time longer than 2 hours (present in nearly 50% of this cohort) suggests that physicians and health care systems should work to minimize door-to-balloon times and that door-to-balloon time should be considered when choosing a reperfusion strategy. Door-to-balloon time also appears to be a valid quality-of-care indicator. JAMA. 2000.
The chronic intake of naturally multi-mycotoxin contaminated feed by broilers with or without titers of Yeast Cell Wall Extract (YCWE, a.k.a Mycosorb A+
), was investigated. Day-old male Cobb chicks ...(1600 birds, 64 pens, 25 birds/pen) were randomly allocated to diets of control (CON); diet containing mycotoxins (MT); CON + 0.2% YCWE; MT + 0.025% YCWE; MT + 0.05% YCWE; MT + 0.1% YCWE; MT + 0.2% YCWE; and MT + 0.4% YCWE. Growth performance, blood biochemical parameters and gut health were recorded over 42 days. Compared with CON, MT had reduced body weight (BW) and increased feed conversion ratio (FCR) on days 35 and 42 with increased duodenal crypt depth and fewer goblet cells. Furthermore, European Poultry Production Efficiency (EPEF) was reduced for MT versus CON. Feeding MT + 0.2% YCWE improved BW, lowered FCR, reduced crypt depth, increased goblet cell count and improved EPEF. Considering titration of YCWE (0 to 0.4%) during mycotoxin challenge, a cubic effect was observed for FCR with NC + 0.2% YCWE having the lowest FCR. These findings suggest that chronic consumption of multiple
mycotoxins present in common field concentrations can negatively impact broiler performance and gut health while inclusion of YCWE, particularly 0.2%, could be effective in counteracting mycotoxins.
A prominent feature of most cancers including Barrett's adenocarcinoma (BAC) is genetic instability, which is associated with development and progression of disease. In this study, we investigated ...the role of recombinase (hsRAD51), a key component of homologous recombination (HR)/repair, in evolving genomic changes and growth of BAC cells. We show that the expression of RAD51 is elevated in BAC cell lines and tissue specimens, relative to normal cells. HR activity is also elevated and significantly correlates with RAD51 expression in BAC cells. The suppression of RAD51 expression, by short hairpin RNA (shRNA) specifically targeting this gene, significantly prevented BAC cells from acquiring genomic changes to either copy number or heterozygosity (P<0.02) in several independent experiments employing single-nucleotide polymorphism arrays. The reduction in copy-number changes, following shRNA treatment, was confirmed by Comparative Genome Hybridization analyses of the same DNA samples. Moreover, the chromosomal distributions of mutations correlated strongly with frequencies and locations of Alu interspersed repetitive elements on individual chromosomes. We conclude that the hsRAD51 protein level is systematically elevated in BAC, contributes significantly to genomic evolution during serial propagation of these cells and correlates with disease progression. Alu sequences may serve as substrates for elevated HR during cell proliferation in vitro, as they have been reported to do during the evolution of species, and thus may provide additional targets for prevention or treatment of this disease.
Aims We examined the clinical characteristics and outcome of patients with early (<2h), intermediate (2–4h) and late (>4h) presentation treated by primary angioplasty or thrombolytic therapy for ...acute myocardial infarction. Methods and Results We studied 2635 patients enrolled in 10 randomized trials of primary angioplasty (n=1302) vs thrombolytic therapy (n=1333) in acute myocardial infarction, and baseline characteristics of the two groups were comparable. Increase in presentation delay is associated with older age, female gender, diabetes and an increased heart rate. We classified the patients according to the time delay from symptom onset to presentation into three categories: early presentation (<2h), intermediate presentation (2–4h), and late presentation (≥4h). At 30 days the combined rate of death, non-fatal reinfarction and stroke in patients presenting early was 5·8% in the angioplasty group vs 12·5% in the thrombolysis group, in patients with intermediate presentation, 8·6% vs 14·2%, respectively, and in patients presenting late 7·7% vs 19·4%, respectively. With increasing time from symptom onset to presentation, all major adverse cardiac event rates show a trend to a larger increase in the thrombolysis group compared to the angioplasty group, both at 30 days and at 6 months after the acute event. Conclusions Major adverse cardiac event rates are lower after angioplasty compared to thrombolysis, irrespective of time to presentation. With increasing time to presentation major adverse cardiac event rates increase after thrombolysis but appear to remain relatively stable after angioplasty.
Complement, activated during myocardial ischemia and reperfusion, causes myocardial damage through multiple processes. The COMplement inhibition in Myocardial infarction treated with Angioplasty ...(COMMA) trial was performed to determine the effect of pexelizumab, a C5 complement inhibitor, on infarct size in patients with ST-segment-elevation myocardial infarction (MI) undergoing primary percutaneous coronary intervention.
In COMMA, 960 patients with MI (20% isolated inferior MI) were randomized to placebo, pexelizumab 2.0-mg/kg bolus, or pexelizumab 2.0-mg/kg bolus and 0.05-mg/kg per h infusion for 20 hours. Infarct size by creatine kinase-MB area under the curve, the primary outcome, did not differ significantly between groups (placebo median, 4393; bolus pexelizumab, 4526; bolus plus infusion pexelizumab, 4713 ng/mL x h; P=0.89 for bolus versus placebo; P=0.76 for bolus plus infusion versus placebo), nor did the composite of 90-day death, new or worsening heart failure, shock, or stroke (placebo, 11.1%; bolus, 10.7%; bolus plus infusion, 8.5%). The ninety-day mortality rate was significantly lower with pexelizumab bolus plus infusion (1.8% versus 5.9% with placebo; nominal P=0.014); the bolus-only group had an intermediate mortality rate (4.2%).
In patients with ST-elevation MI undergoing percutaneous coronary intervention, pexelizumab had no measurable effect on infarct size. However, the significant reduction in mortality suggests that pexelizumab may benefit patients through alternative novel mechanisms and provides impetus for additional investigation.
Dental patients generally recall more pain than they originally report, with ratings of pain related to state anxiety and dental fear, but the role of depression in recall of dental pain remains ...uncertain. This study examined the relative contributions of different variables in explaining dental pain recalled after tooth extraction. Patients presenting for tooth extraction, prior to extraction, rated their current dental pain and state anxiety, prediction of pain and state anxiety during extraction, depression, and dental fear. Immediately postprocedure and then 1 mo later, patients rated their pain and state anxiety during extraction. Hierarchical linear regression equations were used to explain variance in recalled pain and state anxiety. In addition, patients were divided into high and low dental fear and depression groups and compared on ratings of pain and state anxiety across time. In a final sample of 157 patients, the most important predictors of recalled pain were pain reported during extraction (β = .53) and recalled state anxiety (β = .52). Dental fear and depression had a significant interaction: only when patients reported less depression did those patients who reported more dental fear also report more pain than patients who reported less dental fear (P < 0.05, ω2 = .07). Patients who reported more depression entered the dental operatory reporting more pain, but all patients generally reported less pain during extraction than they predicted or recalled. Memory of state anxiety and pain reported during tooth extraction, not depression or state anxiety at the time of extraction, were critical factors in memory of the pain associated with the procedure. At higher levels of depression, patients higher and lower in dental fear did not differ in report of pain. Future studies are needed to further clarify interactions of depression and dental fear over time.
PDF
