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The question of whether gender-related disparities still exist in the treatment and outcomes of patients presenting with acute coronary syndromes (ACS) remains controversial. Using data from 4 registries spanning a decade, we sought to determine whether sex-related differences have persisted over time and to examine the treating physician's rationale for adopting a conservative management strategy in women compared with men. From 1999 to 2008, 14,196 Canadian patients with non–ST-segment elevation ACS were recruited into the Acute Coronary Syndrome I (ACSI), ACSII, Global Registry of Acute Coronary Events (GRACE/GRACE2), and Canadian Registry of Acute Coronary Events (CANRACE) prospective multicenter registries. Women in the study population were found to be significantly older than men and were more likely to have a history of heart failure, diabetes, or hypertension. Fewer women were treated with thienopyridines, heparin, and glycoprotein IIb/IIIa inhibitors compared with men in GRACE and CANRACE. Female gender was independently associated with a lower in-hospital use of coronary angiography (adjusted odds ratio 0.76, 95% CI 0.69-0.84, P < .001) and higher in-hospital mortality (adjusted odds ratio 1.26, 95% CI 1.02-1.56, P = .036), irrespective of age (P for interaction =.76). Underestimation of patient risk was the most common reason for not pursuing an invasive strategy in both men and women. Despite temporal increases in the use of invasive cardiac procedures, women with ACS are still more likely to be treated conservatively, which may be due to underestimation of patient risk. Furthermore, they have worse in-hospital outcomes. Greater awareness of this paradox may assist in bridging the gap between current guidelines and management practices.

Chemicals in food are widely used leading to significant human exposure. Allura Red AC (AR) is a highly common synthetic colorant; however, little is known about its impact on colitis. Here, we show chronic exposure of AR at a dose found in commonly consumed dietary products exacerbates experimental models of colitis in mice. While intermittent exposure is more akin to a typical human exposure, intermittent exposure to AR in mice for 12 weeks, does not influence susceptibility to colitis. However, exposure to AR during early life primes mice to heightened susceptibility to colitis. In addition, chronic exposure to AR induces mild colitis, which is associated with elevated colonic serotonin (5-hydroxytryptamine; 5-HT) levels and impairment of the epithelial barrier function via myosin light chain kinase (MLCK). Importantly, chronic exposure to AR does not influence colitis susceptibility in mice lacking tryptophan hydroxylase 1 (TPH1), the rate limiting enzyme for 5-HT biosynthesis. Cecal transfer of the perturbed gut microbiota by AR exposure worsens colitis severity in the recipient germ-free (GF) mice. Furthermore, chronic AR exposure elevates colonic 5-HT levels in naïve GF mice. Though it remains unknown whether AR has similar effects in humans, our study reveals that chronic long-term exposure to a common synthetic colorant promotes experimental colitis via colonic 5-HT in gut microbiota-dependent and -independent pathway in mice. Allura Red AC is a dye used in food products. Here the authors report that chronic, long-term exposure to Allura Red AC increases susceptibility to experimental colitis in mice dependent on the serotonin biosynthetic enzyme TPH1, while intermittent exposure more typical for the human setting did not increase susceptibility to experimental colitis.

Rationale and objective Repeated and/or heightened elevations in glucocorticoids (e.g., repeated stress) can promote escalated drug-taking behaviors and induce compromised HPA axis function. Given that interoceptive/subjective drug cues are a fundamental factor in drug-taking behavior, we sought to determine the effects of exposure to repeated elevations in the glucocorticoid corticosterone (CORT) on the interoceptive effects of alcohol in rats using drug discrimination techniques. Methods Male Long Evans rats trained to discriminate alcohol (1 g/kg, IG) vs. water were exposed to CORT (300 μg/ml) in the home cage drinking water for 7 days. The interoceptive effects of experimenter- and self-administered alcohol were assessed and HPA axis function was determined. Results The interoceptive effects of experimenter- and self-administered alcohol were blunted following CORT. Control experiments determined that this decreased sensitivity was unrelated to discrimination performance impairments or decreased CORT levels at the time of testing and was dependent on repeated CORT exposure. Susceptibility to compromised HPA axis function following CORT exposure was suggested by an altered pattern of CORT secretion and blunted CORT response following injection of the synthetic glucocorticoid dexamethasone. Conclusions These findings present a possible behavioral mechanism for escalated alcohol drinking during episodes of heightened elevations in glucocorticoids (e.g., stress). That is, during these episodes, individuals may consume more alcohol to achieve the desired interoceptive effects. Understanding these behavioral mechanisms may lead to a better understanding of factors that promote alcoholism and alcohol abuse in at risk populations.

In red algae, the most abundant principal cell wall polysaccharides are mixed galactan agars, of which agarose is a common component. While bioconversion of agarose is predominantly catalyzed by bacteria that live in the oceans, agarases have been discovered in microorganisms that inhabit diverse terrestrial ecosystems, including human intestines. Here we comprehensively define the structure–function relationship of the agarolytic pathway from the human intestinal bacterium Bacteroides uniformis ( Bu ) NP1. Using recombinant agarases from Bu NP1 to completely depolymerize agarose, we demonstrate that a non-agarolytic Bu strain can grow on GAL released from agarose. This relationship underscores that rare nutrient utilization by intestinal bacteria is facilitated by the acquisition of highly specific enzymes that unlock inaccessible carbohydrate resources contained within unusual polysaccharides. Intriguingly, the agarolytic pathway is differentially distributed throughout geographically distinct human microbiomes, reflecting a complex historical context for agarose consumption by human beings. Polysaccharides are the primary structural cell wall and energy storage molecules of seaweed. Here, the authors show how the geographically restricted dietary polysaccharide agarose is selectively utilized by the human intestinal bacterium Bacteroides uniformis , providing insight into how carbohydrate metabolism evolves within the human microbiome.

The Global Registry of Acute Coronary Event (GRACE) risk score was developed in a large multinational registry to predict in-hospital mortality across the broad spectrum of acute coronary syndromes (ACS). Because of the substantial regional variation and temporal changes in patient characteristics and management patterns, we sought to validate this risk score in a contemporary Canadian population with ACS. The main GRACE and GRACE 2 registries are prospective, multicenter, observational studies of patients with ACS (June 1999 to December 2007). For each patient, we calculated the GRACE risk score and evaluated its discrimination and calibration by the c statistic and the Hosmer-Lemeshow goodness-of-fit test, respectively. To assess the impact of temporal changes in management on the GRACE risk score performance, we evaluated its discrimination and calibration after stratifying the study population into prespecified subgroups according to enrollment period, type of ACS, and whether the patient underwent coronary angiography or revascularization during index hospitalization. A total of 12,242 Canadian patients with ACS were included; the median GRACE risk score was 127 (25th and 75th percentiles were 103 and 157, respectively). Overall, the GRACE risk score demonstrated excellent discrimination ( c statistic 0.84, 95% CI 0.82-0.86, P < .001) for in-hospital mortality. Similar results were seen in all the subgroups (all c statistics ≥0.8). However, calibration was suboptimal overall (Hosmer-Lemeshow P = .06) and in various subgroups. GRACE risk score is a valid and powerful predictor of adverse outcomes across the wide range of Canadian patients with ACS. Its excellent discrimination is maintained despite advances in management over time and is evident in all patient subgroups. However, the predicted probability of in-hospital mortality may require recalibration in the specific health care setting and with advancements in treatment.

Melanoma is the deadliest form of skin cancer and considered intrinsically resistant to chemotherapy. Nearly all melanomas harbor mutations that activate the RAS/mitogen-activated protein kinase (MAPK) pathway, which contributes to drug resistance via poorly described mechanisms. Herein we show that the RAS/MAPK pathway regulates the activity of cyclin-dependent kinase 12 (CDK12), which is a transcriptional CDK required for genomic stability. We find that melanoma cells harbor constitutively high CDK12 activity, and that its inhibition decreases the expression of long genes containing multiple exons, including many genes involved in DNA repair. Conversely, our results show that CDK12 inhibition promotes the expression of short genes with few exons, including many growth-promoting genes regulated by the AP-1 and NF-κB transcription factors. Inhibition of these pathways strongly synergize with CDK12 inhibitors to suppress melanoma growth, suggesting promising drug combinations for more effective melanoma treatment. In patients with melanoma, increased RAS/mitogen-activated protein kinase (MAPK) pathway activity is known to drive chemotherapy resistance. Here, the authors identify CDK12 as a downstream effector of the RAS/MAPK pathway and therapeutic target which mediates chemotherapy resistance through increased expression of DNA repair associated genes.

Metabotropic glutamate receptor subtypes (mGlu2/3) regulate a variety of alcohol-associated behaviors, including alcohol reinforcement, and relapse-like behavior. To date, the role of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol has not been examined. Given that the discriminative stimulus effects of drugs are determinants of abuse liability and can influence drug seeking, we examined the contributions of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol. In male Long-Evans rats trained to discriminate between alcohol (1 g/kg, IG) and water, the mGlu2/3 agonist LY379268 (0.3–10 mg/kg) did not produce alcohol-like stimulus effects. However, pretreatment with LY379268 (1 and 3 mg/kg; in combination with alcohol) inhibited the stimulus effects of alcohol (1 g/kg). Systemic LY379268 (3 mg/kg, i.p.) was associated with increases in neuronal activity within the amygdala, but not the nucleus accumbens, as assessed by c-Fos immunoreactivity. Intra-amygdala activation of mGlu2/3 receptors by LY379268 (6 μg) inhibited the discriminative stimulus effects of alcohol, without altering response rate. In contrast, intra-accumbens LY379268 (3 μg) profoundly reduced response rate; however, at lower LY379268 doses (0.3, 1 μg), the discriminative stimulus effects of alcohol and response rate were not altered. These data suggest that amygdala mGlu2/3 receptors have a functional role in modulating the discriminative stimulus properties of alcohol and demonstrate differential motor sensitivity to activation of mGlu2/3 receptors in the amygdala and the accumbens. Understanding the neuronal mechanisms that underlie the discriminative stimulus effects of alcohol may prove to be important for future development of pharmacotherapies for treating alcoholism.

Stomatal movements in response to environmental stimuli critically control the plant water status. Although these movements are governed by osmotically driven changes in guard cell volume, the role of membrane water channels (aquaporins) has remained hypothetical. Assays in epidermal peels showed that knockout Arabidopsis thaliana plants lacking the Plasma membrane Intrinsic Protein 2;1 (PIP2;1) aquaporin have a defect in stomatal closure, specifically in response to abscisic acid (ABA). ABA induced a 2-fold increase in osmotic water permeability (Pf) of guard cell protoplasts and an accumulation of reactive oxygen species in guard cells, which were both abrogated in pip2;1 plants. Open stomata 1 (OST1)/Snf1-related protein kinase 2.6 (SnRK2.6), a protein kinase involved in guard cell ABA signaling, was able to phosphorylate a cytosolic PIP2;1 peptide at Ser-121. OST1 enhanced PIP2;1 water transport activity when coexpressed in Xenopus laevis oocytes. Upon expression in pip2;1 plants, a phosphomimetic form (Ser121Asp) but not a phosphodeficient form (Ser121Ala) of PIP2;1 constitutively enhanced the Pf of guard cell protoplasts while suppressing its ABA-dependent activation and was able to restore ABA-dependent stomatal closure in pip2;1. This work supports a model whereby ABA-triggered stomatal closure requires an increase in guard cell permeability to water and possibly hydrogen peroxide, through OST1-dependent phosphorylation of PIP2;1 at Ser-121.

To examine the quadriceps strength (QUADS) on the surgical (SURG) and non-surgical (Non-SURG) limbs in adolescent male and female athletes at pre-operative (PRE), 12 weeks post-operative (12WK), and return to sport (RTS) time points following ACL injury and reconstruction. Prospective cohort study design. Clinical Research Laboratory. 66 adolescent athletes. Isokinetic QUADS of the SURG and Non-SURG limbs at the PRE, 12WK, and RTS time points were assessed and compared between each time point. Both male and female participants had significantly lower 12 WK QUADS in the SURG limb than the PRE QUADS, but the RTS QUADS was significantly greater than the 12WK QUAD (p < 0.05). However, only female participants had greater RTS QUADS as compared to the PRE QUADS (p < 0.001). For the Non-SURG limb, only male participants had a significant improvement over time (PRE vs RTS; p < 0.001). Adolescent males and females differ in their QUADS recovery across the continuum of care following ACLR. Clinicians should consider this pattern of recovery when treating adolescent males and females. •Adolescent males and females differ in their QUADS recovery in SURG and Non-SURG limbs following ACLR.•For the SURG limb, only female athletes made a significant improvement of the QUAD strength from PRE to RTS.•For the Non-SURG limb, only male athletes made significant improvement of the QUAD strength from PRE to RTS.•The LSI may overestimate the QUAD strength of the SURG limb.

One of the most widely used tasks for investigating psychological time, time reproduction, requires from participants the reproduction of the duration of a previously presented stimulus. Although prior studies have investigated the effects of different cognitive processes on time reproduction performance, no studies have looked into the effects of different reproduction methods on these performances. In the present study, participants were randomly assigned to one of three reproduction methods, which included (a) just pressing at the end of the interval, (b) pressing to start and stop the interval, and (c) maintaining continuous pressing during the interval. The study revealed that the three reproduction methods were not equivalent, with the method involving keypresses to start and stop the reproduction showing the highest accuracy, and the method of continuous press generating less variability.