Current thinking attributes the balance between T helper 1 (Th1) and Th2 cytokine response patterns in immune responses to the nature of the antigen, the genetic composition of the host, and the ...cytokines involved in the early interaction between T cells and antigen-presenting cells. Here we introduce glutathione, a tripeptide that regulates intracellular redox and other aspects of cell physiology, as a key regulatory element in this process. By using three different methods to deplete glutathione from T cell receptor transgenic and conventional mice and studying in vivo and/or in vitro responses to three distinct antigens, we show that gultathione levels in antigen-presenting cells determine whether Th1 or Th2 response patterns predominate. These findings present new insights into immune response alterations in HIV and other diseases. Further, they potentially offer an explanation for the well known differences in immune responses in ``Th1'' and ``Th2'' mouse strains.
Despite increased attention to understanding risk factors for sexual aggression, knowledge regarding the emotional and sexual arousal patterns of sexually aggressive men remains limited. The current ...study examined whether sexually aggressive men exhibit unique profiles of affective responsivity, in particular to negatively valenced stimuli, as well as sexual arousal patterns that differentiate them from nonaggressive men. We presented 78 young men (38 sexually aggressive; 40 nonaggressive) with a series of videos designed to induce positive, sad, or anxious affect. Affect and subjective sexual arousal were assessed following each film and erectile responses were measured continuously. Sexually aggressive men reported significantly higher levels of sexual arousal following both the positive and negative conditions as compared to nonaggressive men. Erectile responses of sexually aggressive men were significantly greater than nonaggressive men's following the positive affect induction. Self-reported positive affect, but not negative affect, was a significant predictor of subjective sexual arousal for both groups of men. Compared to nonaggressive men, sexually aggressive men showed significantly weaker correlations between subjective and physiological sexual arousal. Findings suggest that generalized heightened propensity for sexual arousal may be a risk factor for sexually aggressive behavior.
To examine the effects of the DPP-4i sitagliptin on CV outcomes during and after incident MI in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).
TECOS randomized 14,671 ...participants with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) to sitagliptin or placebo, in addition to usual care. For those who had a within-trial MI, we analyzed case fatality, and for those with a nonfatal MI, we examined a composite cardiovascular (CV) outcome (CV death or hospitalization for heart failure hHF) by treatment group, using Cox proportional hazards models left-censored at the time of the first within-trial MI, without and with adjustment for potential confounders, in intention-to-treat analyses.
During TECOS, 616 participants had ≥ 1 MI (sitagliptin group 300, placebo group 316, HR 0.95, 95% CI 0.81-1.11, P = 0.49), of which 25 were fatal 11 and 14, respectively). Of the 591 patients with a nonfatal MI, 87 (15%) died subsequently, with 66 (11%) being CV deaths, and 57 (10%) experiencing hHF. The composite outcome occurred in 58 (20.1%; 13.9 per 100 person-years) sitagliptin group participants and 50 (16.6%; 11.7 per 100 person-years) placebo group participants (HR 1.21, 95% CI 0.83-1.77, P = 0.32, adjusted HR 1.23, 95% CI 0.83-1.82, P = 0.31). On-treatment sensitivity analyses also showed no significant between-group differences in post-MI outcomes.
In patients with type 2 diabetes and ASCVD experiencing an MI, sitagliptin did not reduce subsequent risk of CV death or hHF, contrary to expectations derived from preclinical animal models. Trial registration clinicaltrials.gov no. NCT00790205.
Background Cardioversion is a class I procedure for symptomatic atrial fibrillation (AF) patients pursuing rhythm control. There are few contemporary reports on quality of life and outcomes following ...cardioversion. Methods Using the nationwide prospective ORBIT-AF registry, cardioversion patients were propensity matched 3-to-1 to non-cardioverted patients and Cox proportional hazards modeling evaluated hospitalization at 1-year in those with and without cardioversion. Cardiovascular outcomes, AF progression, and quality of life were evaluated for the matched cohorts with and without cardioversion. Results Among 9642 patients, 817 patients (8%) underwent 906 cardioversions during median follow-up of 12 (IQR 6–18) months. Among matched cardioverted and non-cardioverted patients, 1-year cardiovascular hospitalization rates were 43% versus 21%, (adjusted hazard ratio 2.2, 95% CI 1.8–2.8, P < .001), and sinus rhythm at both first and second follow-up was 36% versus 27% ( P = .042), respectively. Findings were similar among first-time cardioversion patients. Matched cardioversion patients did not exhibit greater symptom improvement (34% vs 42%) or less symptomatic progression (15% vs 4%) by EHRA scores. Cardioversion was associated with AF progression with an odds ratio of 1.6 (95% CI 1.2–2.2, P = .001) after cardioversion and 2.7 ( P < .001) after first cardioversion versus matched non-cardioversion patients. After cardioversion only 18% of patients not previously on an antiarrhythmic started one, less than 5% underwent ablation, and 22% stopped their antiarrhythmic. Conclusions Cardioversion was not associated with improved AF related quality of life or less progression. Many patients who undergo cardioversion do not receive adjunctive rhythm control therapies. These findings may help to better inform therapeutic decision-making.
We describe a mechanism of light activation that initiates protein inhibitory action of a biologically inert Co(III) Schiff base (Co(III)-sb) complex. Photoinduced electron transfer (PET) occurs from ...a Ru(II) bipyridal complex to a covalently attached Co(III) complex and is gated by conformational changes that occur in tens of nanoseconds. Reduction of the Co(III)-sb by PET initiates displacement of the inert axial imidazole ligands, promoting coordination to active site histidines of α-thrombin. Upon exposure to 455 nm light, the rate of ligand exchange with 4-methylimidazole, a histidine mimic, increases by approximately 5-fold, as observed by NMR spectroscopy. Similarly, the rate of α-thrombin inhibition increases over 5-fold upon irradiation. These results convey a strategy for light activation of inorganic therapeutic agents through PET utilizing redox-active metal centers.
: 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) reduction is one of the most frequently used methods for measuring cell proliferation and neural cytotoxicity. It is widely ...assumed that MTT is reduced by active mitochondria in living cells. By using isolated mitochondria from rat brain and B12 cells, we indeed found that malate, glutamate, and succinate support MTT reduction by isolated mitochondria. However, the data presented in this study do not support the exclusive role of mitochondria in MTT reduction by intact cells. Using a variety of approaches, we found that MTT reduction by B12 cells is confined to intracellular vesicles that later give rise to the needle‐like MTT formazan at the cell surface. Some of these vesicles were identified as endosomes or lysosomes. In addition, MTT was found to be membrane impermeable. These and other results suggest that MTT is taken up by cells through endocytosis and that reduced MTT formazan accumulates in the endosomal/lysosomal compartment and is then transported to the cell surface through exocytosis.
Background Chest pain/discomfort (CP) is the hallmark symptom of acute myocardial infarction (MI), but some patients with MI present without CP. We hypothesized that MI type (ST-segment elevation MI ...STEMI or non-STEMI NSTEMI) may be associated with the presence or absence of CP. Methods We investigated the association between CP at presentation and MI type, hospital care, and mortality among 1,143,513 patients with MI in the National Registry of Myocardial Infarction (NRMI) from 1994 to 2006. Results Overall, 43.6% of patients with NSTEMI and 27.1% of patients with STEMI presented without CP. For both MI type, patients without CP were older, were more frequently female, had more diabetes or history of heart failure, were more likely to delay hospital arrival, and were less likely to receive evidence-based medical therapies and invasive cardiac procedures. Multivariable analysis indicated that NSTEMI (vs STEMI) was the strongest predictor of atypical symptoms (adjusted odds ratio 95% CI, 1.93 1.91-1.95). Within the 4 CP/MI type categories, hospital mortality was highest for no CP/STEMI (27.8%), followed by no CP/NSTEMI (15.3%) and CP/STEMI (9.6%), and was lowest for CP/NSTEMI (5.4%). The adjusted odds ratio of mortality was 1.38 (1.35-1.41) for no CP (vs CP) in the STEMI group and 1.31 (1.28-1.34) in the NSTEMI group. Conclusions Hospitalized patients with NSTEMI were nearly 2-fold more likely to present without CP than patients with STEMI. Patients with MI without CP were less quickly diagnosed and treated and had higher adjusted odds of hospital mortality, regardless of whether they had ST-segment elevation.
Abstract Objectives Modifications in reimbursement rates by Medicare in 2008 have led to peripheral vascular interventions (PVI) being performed more commonly in outpatient and office-based clinics. ...The objective of this study was to determine the effects of this shift in clinical care setting on clinical outcomes after PVI. Background Modifications in reimbursement have led to peripheral vascular intervention (PVI) being more commonly performed in outpatient hospital settings and office-based clinics. Methods Using a 100% national sample of Medicare beneficiaries from 2010 to 2012, we examined 30-day and 1-year rates of all-cause mortality, major lower extremity amputation, repeat revascularization, and all-cause hospitalization by clinical care location of index PVI. Results A total of 218,858 Medicare beneficiaries underwent an index PVI between 2010 and 2012. Index PVIs performed in inpatient settings were associated with higher 1-year rates of all-cause mortality (23.6% vs. 10.4% and 11.7%; p < 0.001), major lower extremity amputation (10.1% vs. 3.7% and 3.5%; p < 0.001), and all-cause repeat hospitalization (63.3% vs. 48.5% and 48.0%; p < 0.001), but lower rates of repeat revascularization (25.1% vs. 26.9% vs. 38.6%; p < 0.001) when compared with outpatient hospital settings and office-based clinics, respectively. After adjustment for potential confounders, patients treated in office-based clinics remained more likely than patients in inpatient hospital settings to require repeat revascularization within 1 year across all specialties. There was also a statistically significant interaction effect between location of index revascularization and geographic region on the occurrence of all-cause hospitalization, repeat revascularization, and lower extremity amputation. Conclusions Index PVI performed in office-based settings was associated with a higher hazard of repeat revascularization when compared with other settings. Differences in clinical outcomes across treatment settings and geographic regions suggest that inconsistent application of PVI may exist and highlights the need for studies to determine optimal delivery of PVI in clinical practice.
The effects of lightning and other meteorological factors on wildfire activity in the North American boreal forest are statistically analyzed during the fire seasons of 2000-2006 through an ...integration of the following data sets: the MODerate Resolution Imaging Spectroradiometer (MODIS) level 2 fire products, the 3-hourly 32-km gridded meteorological data from North American Regional Reanalysis (NARR), and the lightning data collected by the Canadian Lightning Detection Network (CLDN) and the Alaska Lightning Detection Network (ALDN). Positive anomalies of the 500 hPa geopotential height field, convective available potential energy (CAPE), number of cloud-to-ground lightning strikes, and the number of consecutive dry days are found to be statistically important to the seasonal variation of MODIS fire counts in a large portion of Canada and the entirety of Alaska. Analysis of fire occurrence patterns in the eastern and western boreal forest regions shows that dry (in the absence of precipitation) lightning strikes account for only 20% of the total lightning strikes, but are associated with (and likely cause) 40% of the MODIS observed fire counts in these regions. The chance for ignition increases when a threshold of at least 10 dry strikes per NARR grid box and at least 10 consecutive dry days is reached. Due to the orientation of the large-scale pattern, complex differences in fire and lightning occurrence and variability were also found between the eastern and western sub-regions. Locations with a high percentage of dry strikes commonly experience an increased number of fire counts, but the mean number of fire counts per dry strike is more than 50% higher in western boreal forest sub-region, suggesting a geographic and possible topographic influence. While wet lightning events are found to occur with a large range of CAPE values, a high probability for dry lightning occurs only when 500 hPa geopotential heights are above ~5700 m and CAPE values are near the maximum observed level, underscoring the importance of low-level instability to boreal fire weather forecasts.
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