Infarct size can be limited by reducing the determinants of infarct size or increasing collateral blood flow by treatment initiated before the ischaemic event. Reperfusion is the definitive treatment for permanently reducing infarct size and restoring some degree of contractile function to the affected myocardium. Innate survival mechanisms in the heart can be stimulated by short, non-lethal periods of ischaemia and reperfusion, applied either before or after the ischaemic event. Preconditioning, a series of transient intervals of ischaemia and reperfusion applied before the lethal ‘index’ ischaemic event, sets in motion molecular and cellular mechanisms that increase cardiomyocyte survival to a degree that had not hitherto been seen before. The cardioprotective ischaemic-reperfusion protocol applied at onset of reperfusion, termed ‘postconditioning’ (Postcon), is also associated with significant cardioprotection that can be applied at the point of reperfusion treatment in the catheterization laboratory or operating room. Both preconditioning and Postcon have been successfully applied to the clinical setting and have been found to reduce infarct size and other attributes of post-ischaemic injury. This review will summarize the physiological preclinical data on preconditioning and Postcon that are relevant to their translation to clinical therapeutics and treatment.
Introduction: Patients with distributive shock who require high dose vasopressors have a high mortality. Angiotensin II (ATII) may prove useful in patients who remain hypotensive despite catecholamine and vasopressin therapy. The appropriate dose of parenteral angiotensin II for shock is unknown. Methods: In total, 20 patients with distributive shock and a cardiovascular Sequential Organ Failure Assessment score of 4 were randomized to either ATII infusion (N =10) or placebo (N =10) plus standard of care. ATII was started at a dose of 20 ng/kg/min, and titrated for a goal of maintaining a mean arterial pressure (MAP) of 65 mmHg. The infusion (either ATII or placebo) was continued for 6 hours then titrated off. The primary endpoint was the effect of ATII on the standing dose of norepinephrine required to maintain a MAP of 65 mmHg. Results: ATII resulted in marked reduction in norepinephrine dosing in all patients. The mean hour 1 norepinephrine dose for the placebo cohort was 27.6 ± 29.3 mcg/min versus 7.4 ± 12.4 mcg/min for the ATII cohort (P =0.06). The most common adverse event attributable to ATII was hypertension, which occurred in 20% of patients receiving ATII. 30-day mortality for the ATII cohort and the placebo cohort was similar (50% versus 60%, P =1.00). Conclusion: Angiotensin II is an effective rescue vasopressor agent in patients with distributive shock requiring multiple vasopressors. The initial dose range of ATII that appears to be appropriate for patients with distributive shock is 2 to 10 ng/kg/min. Trial registration: Clinicaltrials.gov NCT01393782. Registered 12 July 2011.
Background: The restriction factor SAMHD1 regulates intracellular nucleotide level by degrading dNTPs and blocks the replication of retroviruses and DNA viruses in non-cycling cells, like macrophages or dendritic cells. In patients, inactivating mutations in samhd1 are associated with the autoimmune disease Aicardi-Goutières Syndrome (AGS). The accumulation of intracellular nucleic acids derived from endogenous retroelements thriving in the absence of SAMHD1 has been discussed as potential trigger of the autoimmune reaction. In vitro, SAMHD1 has been found to restrict endogenous retroelements, like LINE-1 elements (L1). The mechanism, however, by which SAMHD1 blocks endogenous retroelements, is still unclear. Results: Here, we show that SAMHD1 inhibits the replication of L1 and other endogenous retroelements in cycling cells. By applying GFP- and neomycin-based reporter assays we found that the anti-L1 activity of SAMHD1 is regulated by phosphorylation at threonine 592 (T592). Similar to the block of HIV, the cofactor binding site and the enzymatic active HD domain of SAMHD1 proofed to be essential for restriction of L1 elements. However, phosphorylation at T592 did not correlate with the dNTP hydrolase activity of SAMHD1 in cycling 293T cells suggesting an alternative mechanism of regulation. Interestingly, we found that SAMHD1 binds to ORF2 protein of L1 and that this interaction is regulated by T592 phosphorylation. Together with the finding that the block is also active in cycling cells, our results suggest that the SAMHD1-mediated inhibition of L1 is similar but not identical to HIV restriction. Conclusion: Our findings show conclusively that SAMHD1 restricts the replication of endogenous retroelements in vitro. The results suggest that SAMHD1 is important for maintaining genome integrity and support the idea of an enhanced replication of endogenous retroelements in the absence of SAMHD1 in vivo, potentially triggering autoimmune diseases like AGS. Our analysis also contributes to the better understanding of the activities of SAMHD1 in antiviral defense and nucleotide metabolism. The finding that the phosphorylation of SAMHD1 at T592 regulates its activity against retroelements but not necessarily intracellular dNTP level suggests that the dNTP hydrolase activity might not be the only function of SAMHD1 important for its antiviral activity and for controlling autoimmunity.
Purpose: Psychosocial and sensory factors including anxiety, depression, and pressure pain threshold have been used to cluster chronic symptoms in irritable bowel syndrome (IBS). However, little is known about the contribution of psychosocial sensory factors on pain interference and quality of life (QOL) in this population.
Design: We performed a cross-sectional analysis of baseline data from a randomized controlled trial.
Sample: Eighty young adults with IBS aged 21 ± 2.57 years (76.25% female).
Methods:
Demographic and psychosocial factors including anxiety, depression, fatigue, cognition/general concerns, sleep disturbance, self-efficacy, coping, and food intake were measured as independent variables. Quantitative sensory testing (QST) was conducted to measure mechanical, thermal, and pressure pain thresholds. Self-reported pain measured by the brief pain inventory (BPI) and IBS-QOL were assessed as the outcome variables. Regression analysis and mediation analysis were conducted to determine the associated factors of IBS pain and QOL.
Results: Age, sex, and psychosocial factors including coping, self-efficacy, alcohol intake, mechanical pain sensitivity, and cold pain threshold were significantly associated with pain interference (all p < 0.05). Coping, and self-efficacy were significantly associated with IBS-QOL (all p < 0.05). In the mediation analysis, coping catastrophizing and self-efficacy were indirectly associated with IBS-QOL mediated by fatigue.
Conclusions: Psychosocial factors including coping and self-efficacy, and QST factors significantly correlate with self-reported pain and QOL among young adults with IBS. This preliminary research calls for further interventional studies that target personalized psychosocial and quantitative sensory factors to improve pain management and quality of life in IBS patients.
Objectives:
To estimate the risk of post-vasectomy infections in various settings and across various surgical techniques and sanitization practices.
Patients and Methods:
Retrospective review of the records of 133,044 vasectomized patients from four large practices/network of practices using the no-scalpel vasectomy (NSV) technique in Canada (2011-2021), Colombia (2015-2020), New Zealand (2018-2021), and the United Kingdom (2006-2019). We defined infection as any mention in medical records of any antibiotics prescribed for a genital or urinary condition following vasectomy.
Results:
Post-vasectomy infection risks were 0.8% (219 infections/26,809 procedures), 2.1% (390/18,490), 1.0% (100/10,506), and 1.3% (1,007/77,239) in Canada, Colombia, New Zealand, and the UK, respectively. Audit period comparison suggests a limited effect on the risk of infection of excising a short vas segment, applying topical antibiotic on scrotal opening, wearing a surgical mask in Canada, type of skin disinfectant, and use of non-sterile gloves in New Zealand. Risk of infection was lower in Colombia when mucosal cautery and fascial interposition [FI] were used for vas occlusion compared to ligation, excision, and FI (0.9% vs. 2.1%, p<0.00001). Low level of infection certainty in 56% to 60% of patients who received antibiotics indicates that the true risk might be overestimated. Lack of information in medical records and patients not consulting their vasectomy providers might have led to underestimation of the risk.
Conclusion:
Risk of infection after vasectomy is low, about 1%, among international high-volume vasectomy practices performing NSV and various occlusion techniques. Apart from vasectomy occlusion technique, no other factor modified the risk of post-vasectomy infection.
Sickle cell disease (SCD) is a common hemoglobinopathy which can affect multiple organ systems in the body. Within the digestive tract, the hepatobiliary system is most commonly affected in SCD. The manifestations range from benign hyperbilirubinemia to overt liver failure, with the spectrum of acute clinical presentations often referred to as "sickle cell hepatopathy". This is an umbrella term referring to liver dysfunction and hyperbilirubinemia due to intrahepatic sickling process during SCD crisis leading to ischemia, sequestration and cholestasis. In this review, we detail the pathophysiology, clinical presentation and biochemical features of various acute and chronic hepatobiliary manifestations of SCD and present and evaluate existing evidence with regards to management of this disease process. We also discuss recent advances and controversies such as the role of liver transplantation in sickle cell hepatopathy and highlight important questions in this field which would require further research. Our aim with this review is to help increase the understanding, aid in early diagnosis and improve management of this important disease process.
BACKGROUND: Thrombin generation (TG) is a pivotal process in achieving hemostasis. Coagulation profiles during pregnancy and early neonatal period are different from that of normal (non-pregnant) adults. In this ex vivo study, the differences in TG in maternal and cord plasma relative to normal adult plasma were studied.
METHODS: Twenty consented pregnant women and ten consented healthy adults were included in the study. Maternal and cord blood samples were collected at the time of delivery. Platelet-poor plasma was isolated for the measurement of TG. In some samples, anti-FIXa aptamer, RB006, or a TFPI inhibitor, BAX499 were added to elucidate the contribution of intrinsic and extrinsic pathway to TG. Additionally, procoagulant and inhibitor levels were measured in maternal and cord plasma, and these values were used to mathematically simulate TG.
RESULTS: Peak TG was increased in maternal plasma (393.6±57.9 nM) compared to adult and cord samples (323.2±38.9 nM and 209.9±29.5 nM, respectively). Inhibitory effects of RB006 on TG were less robust in maternal or cord plasma (52% vs. 12% respectively) than in adult plasma (81%). Likewise the effectiveness of BAX499 as represented by the increase in peak TG was much greater in adult (21%) than in maternal (10%) or cord plasma (12%). Further, BAX499 was more effective in reversing RB006 in adult plasma than in maternal or cord plasma. Ex vivo data were reproducible with the results of the mathematical simulation of TG.
CONCLUSION: Normal parturient plasma shows a large intrinsic pathway reserve for TG compared to adult and cord plasma, while TG in cord plasma is sustained by extrinsic pathway, and low levels of TFPI and AT.
Background and objectives: Calcification of the mitral and aortic valves is common in dialysis patients (CKD-5D). However, the prognostic significance of valvular calcification (VC) in CKD is not well established.
Design, setting, participants, & measurements: 144 adult CKD-5D patients underwent bidimensional echocardiography for qualitative assessment of VC and cardiac computed tomography (CT) for quantification of coronary artery calcium (CAC) and VC. The patients were followed for a median of 5.6 years for mortality from all causes.
Results: Overall, 38.2% of patients had mitral VC and 44.4% had aortic VC on echocardiography. Patients with VC were older and less likely to be African American; all other characteristics were similar between groups. The mortality rate of patients with calcification of either valve was higher than for patients without VC. After adjustment for age, gender, race, diabetes mellitus, and history of atherosclerotic disease, only mitral VC remained independently associated with all-cause mortality (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.03 to 2.91). Patients with calcification of both valves had a two-fold increased risk of death during follow-up compared with patients without VC (HR, 2.16; 95% CI, 1.14 to 4.08). A combined CT score of VC and CAC was strongly associated with all-cause mortality during follow-up (HR for highest versus lowest tertile, 2.21; 95% CI, 1.08 to 4.54).
Conclusions: VC is associated with a significantly increased risk for all-cause mortality in CKD-5D patients. These findings support the use of echocardiography for risk stratification in CKD-5D as recently suggested in the Kidney Disease Improving Global Outcomes guidelines.
Exposure to stressful events during development has consistently been shown to produce long-lasting alterations in the hypothalamic-pituitary-adrenal (HPA) axis, which may increase vulnerability to disease, including PTSD and other mood and anxiety disorders. Recently reported genetic association studies indicate that these effects may be mediated, in part, by gene x environment (GxE) interactions involving polymorphisms within two key genes, CRHR1 and FKBP5. Data suggest that these genes regulate HPA axis function in conjunction with exposure to child maltreatment or abuse. In addition, a large and growing body of preclinical research suggests that increased activity of the amygdala-HPA axis induced by experimental manipulation of the amygdala mimics several of the physiological and behavioral symptoms of stress-related psychiatric illness in humans. Notably, interactions between the developing amygdala and HPA axis underlie critical periods for emotional learning which are modulated by developmental support and maternal care. These translational findings lead to an integrated hypothesis: high levels of early life trauma lead to disease through the developmental interaction of genetic variants with neural circuits that regulate emotion, together mediating risk and resilience in adults.
by
John W. Petersen;
B. Della Johnson;
Kevin E. Kip;
R. David Anderson;
Eileen M. Handberg;
Barry Sharaf;
Puja Kiran Mehta;
Sheryl F. Kelsey;
C. Noel Bairey Merz;
Carl J, Pepine
Background: TIMI frame count (TFC) predicts outcomes in patients with obstructive coronary artery disease (CAD); it remains unclear whether TFC predicts outcomes in patients without obstructive CAD. Methods: TFC was determined in a sample of women with no obstructive CAD enrolled in the Women's Ischemia Syndrome Evaluation (WISE) study. Because TFC is known to be higher in the left anterior descending artery (LAD), TFC determined in the LAD was divided by 1.7 to provide a corrected TFC (cTFC). Results: A total of 298 women, with angiograms suitable for TFC analysis and long-term (6-10 year) follow up data, were included in this sub-study. Their age was 55±11 years, most were white (86%), half had a history of smoking, and half had a history of hypertension. Higher resting cTFC was associated with a higher rate of hospitalization for angina (34% in women with a cTFC > 35, 15% in women with a cTFC ≤35, P < 0.001). cTFC provided independent prediction of hospitalization for angina after adjusting for many baseline characteristics. In this cohort, resting cTFC was not predictive of major events (myocardial infarction, heart failure, stroke, or all-cause death), cardiovascular events, all-cause mortality, or cardiovascular mortality. Conclusions: In women with signs and symptoms of ischemia but no obstructive CAD, resting cTFC provides independent prediction of hospitalization for angina. Larger studies are required to determine if resting TFC is predictive of major events in patients without obstructive coronary artery disease.