Peroxisome proliferator-activated receptor-gamma protects against hepatic ischemia/reperfusion injury in mice

The function of peroxisome proliferator-activated receptor-gamma (PPARgamma) in hepatic inflammation and injury is unclear. In this study, we sought to determine the role of PPARgamma in hepatic ischemia/reperfusion injury in mice. Male mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 8 hours of reperfusion. PPARgamma was found to be constitutively activated in hepatocytes but not in nonparenchymal cells. Upon induction of ischemia, hepatic PPARgamma activation rapidly decreased and remained suppressed throughout the 8-hour reperfusion period. This reduced activation was not a result of decreased protein availability as hepatic nuclear PPARgamma, retinoid X receptor-alpha (RXRalpha), and PPARgamma/RXRalpha heterodimer expression was maintained. Accompanying the decrease in PPARgamma activation was a decrease in the expression of the natural ligand 15-deoxy-Delta(12,14)-prostaglandin J(2). This was associated with reduced interaction of PPARgamma and the coactivator, p300. To determine whether PPARgamma activation is hepatoprotective during hepatic ischemia/reperfusion injury, mice were treated with the PPARgamma agonists, rosiglitazone and connecting peptide. These treatments increased PPARgamma activation and reduced liver injury compared to untreated mice. Furthermore, PPARgamma-deficient mice had more liver injury after ischemia/reperfusion than their wild-type counterparts. Conclusion: These data suggest that PPARgamma is an important endogenous regulator of, and potential therapeutic target for, ischemic liver injury.     

Women at Risk for Cardiovascular Disease Lack Knowledge of Heart Attack Symptoms

Background:

It is not known whether cardiovascular disease (CVD) risk level is related to knowledge of the leading cause of death of women or heart attack symptoms.

Hypothesis:

Women with higher CVD risk estimated by Framingham Risk Score (FRS) or metabolic syndrome (MS) have lower CVD knowledge.

Methods:

Women visiting primary care clinics completed a standardized behavioral risk questionnaire. Blood pressure, weight, height, waist size, fasting glucose, and lipid profile were assessed. Women were queried regarding CVD knowledge.

Results:

Participants (N = 823) were Hispanic women (46%), non‐Hispanic white (37%), and non‐Hispanic black (8%). FRS was determined in 278: low (63%), moderate (29%), and high (8%); 24% had ≥3 components of MS. The leading cause of death was answered correctly by 54%, heart attack symptoms by 67%. Knowledge was lowest among racial/ethnic minorities and those with less education (both P< 0.001). Increasing FRS was inversely associated with knowing the leading cause of death (low 72%, moderate 68%, high 45%, P = 0.045). After multivariable adjustment, moderate/high FRS was inversely associated with knowing symptoms (moderate odds ratio [OR] 0.52, 95% confidence interval [CI]: 0.28‐0.98; high OR 0.29, 95% CI: 0.11–0.81), but not the leading cause of death. MS was inversely associated with knowing the leading cause of death (P< 0.001) or heart attack symptoms (P = 0.018), but not after multivariable adjustment.

Conclusions:

Women with higher FRS were less likely to know heart attack symptoms. Efforts to target those at higher CVD risk must persist, or the most vulnerable may suffer disproportionately, not only because of risk factors but also inadequate knowledge. Clin. Cardiol. 2011 DOI: 10.1002/clc.22092 This work was supported in part by the US Department of Health and Human Services (1HHCWH05003‐01‐11); Arlene and Joseph Taub Foundation, Paterson, New Jersey; Edwina and Charles Adler Foundation; and by Columbia University's CTSA grant, UL1‐RR024156 from the NCRR/NIH. The authors have no other funding, financial relationships, or conflicts of interest to disclose.     

Radioactive choline metabolism in guinea pig gallbladder

Acetylcholine may be released from gallbladder intrinsic nerves in response to cholecystokinin stimulation. This study characterized metabolites of [¹⁴C]choline produced in the gallbladder and released during incubation, with or without cholecystokinin-octapeptide. Radiolabeled [¹⁴C]choline was applied to the mucosal or muscle surface of intact guinea pig gallbladders in an organ bath. After radiolabeling, gallbladders were incubated with or without the contractile agonist cholecystokinin-octapeptide. Metabolites of [¹⁴C]choline were identified in gallbladder tissue and incubation buffers using HPLC and thin-layer chromatography. The major metabolites of [¹⁴C]choline were betaine and phosphocholine. [¹⁴C]Phosphocholine was incorporated slowly into [¹⁴C]phosphatidylcholine. [¹⁴C]Choline was released into buffers during incubation. [¹⁴C]Acetylcholine constituted less than 1% of radiolabel in the gallbladder. There was no identifiable [¹⁴C]acetylcholine released in buffers. Cholecystokinin-octapeptide did not affect choline metabolism. These studies showed that choline in the gallbladder is metabolized along pathways similar to those in the liver. Gallbladders released mostly choline, rather than acetylcholine, even during hormonally induced contraction.This project was supported by the Research and Development Office of the Department of Veterans Affairs.     

Association of granulocyte-macrophage colony-stimulating factor with the crystalloid granules of human eosinophils

We have previously shown that normal-density human peripheral blood eosinophils transcribe and translate mRNA for granulocyte-macrophage colony-stimulating factor (GM-CSF) and that the intracellular distribution was granular as assessed by light microscopy immunocytochemistry. The present study was conducted to confirm this apparent association between GM-CSF and the crystalloid granule using a subcellular fractionation method for human eosinophils and immunogold electron microscopy (EM). Highly purified (> 99%, by negative selection using anti-CD16 immunomagnetic microbeads) human peripheral blood eosinophils were obtained from four asthmatic subjects (not taking systemic medication), homogenized and density fractionated (5 x 10(7) cells/subject) on linear Nycodenz gradients. Twenty-four fractions were collected from each cell preparation and analyzed for marker enzyme activities as well as total protein. Dot blot analysis with specific monoclonal antibodies (MoAbs) was used to detect the eosinophil granule proteins major basic protein (MBP) and eosinophil cationic protein (ECP). An anti-CD9 MoAb was used as an eosinophil plasma membrane marker. Lactate dehydrogenase (LDH) was used as a cytosolic marker. Immunoreactivity for GM-CSF was detected by a specific enzyme-linked immunosorbent assay using a polyclonal antihuman GM-CSF antibody and confirmed by dot blot. GM-CSF coeluted with the cellular fractions containing granule markers (MBP, ECP, eosinophil peroxidase, hexosaminidase, and arylsulphatase), but not those containing cytoplasm (LDH+) or membrane (CD9+) markers. EM examination of pooled fractions associated with the peak of GM-CSF immunoreactivity confirmed that they contained crystalloid and small granules, but not plasma membrane. In addition, quantification, using immunogold labeling with an anti/GM-CSF MoAb, indicated preferential localization of gold particles over the eosinophil granule cores of intact cells. Thus, our results indicate that GM-CSF resides as a granule-associated, stored mediator in unstimulated human eosinophils.     

Prevalence and prognostic significance of atrial arrhythmias after orthotopic cardiac transplantation

Objectives. We studied the duration and prognostic significance of atrial arrhythmias in the denervated transplanted heart, specifically the occurrence of atrial fibrillation in the absence of vagal modulation.

Background. Substantial animal data indicate that vagally induced dispersion of atrial refractoriness plays a central role in the induction and maintenance of atrial fibrillation.

Methods. We studied the occurrence of atrial arrhythmias in the denervated hearts of 88 consecutive orthotopic transplantations in 85 patients by means of continuous telemetry and all available electrocardiographic tracings.

Results. Fifty percent of recipients (44 of 88) developed at least one atrial arrhythmia. Atrial fibrillation occurred 23 times (21 recipients), atrial flutter 39 times (26 recipients), ectopic atrial tachycardia 3 times (3 recipients) and supraventricular tachycardia 18 times (11 recipients). The number of atrial fibrillation and atrial flutter episodes did not differ (23 vs. 39, p = 0.072), but the fibrillation (37.0 ± 10 vs. 6.6 ± 3.6 h, p = 0.014). Atrial fibrillation was associated with an increased risk of subsequent death (10 of 21 recipients with vs. 15 of 67 without atrial fibrillation, risk ratio 3.15 ± 0.18, p = 0.005 by Cox proportional hazards model). All 5 recipients who developed “late” atrial fibrillation (>2 weeks after transplantation) died versus 5 of 16 who developed atrial fibrillation within the first 2 weeks (p = 0.007). Causes of death included rejection (three recipients), allograft failure (two recipients), infection (three recipients) and multiorgan failure (two recipients). Atrial fibrillation was not associated with age, gender, ischemic time, reason for transplantation, echocardiographic variables, invasive hemodynamic variables or biopsy grade. Mean time from atrial arrhythmia to echocardiography was 2.7 ± 3.3 days; that to biopsy was 4.8 ± 6.3 days. Atrial flutter was not associated with subsequent death. Only 7 (15.9%) of 44 recipients demonstrated moderate or severe allograft rejection at the time of the arrhythmia.

Conclusions. Atrial arrhythmias occur frequently in the denervated transplanted heart, often in the absence of significant rejection. Late atrial fibrillation may be associated with an increased all-cause mortality.     

Is Patients’ Preferred Involvement in Health Decisions Related to Outcomes for Patients with HIV?

BACKGROUND Previous studies suggest that patients who are more involved in their medical care have better outcomes. OBJECTIVES We sought to compare health care processes and outcomes for patients with HIV based on their preferred level of involvement in health decisions. DESIGN Cross-sectional analysis of audio computer-assisted interviews with patients at an urban HIV clinic. PATIENTS One thousand and twenty-seven patients awaiting an appointment with their primary care provider. MEASURES Patients were asked how they preferred to be involved in decisions (doctor makes most or all decisions, doctor and patient share decisions, patient makes all decisions). We also asked patients to rate the quality of communication with their HIV provider, and their self-reported receipt of and adherence to HAART. RESULTS Overall, 23% patients preferred that their doctor make all or most decisions, 63% preferred to share decisions with their doctor, and 13% preferred to make all final decisions alone. Compared to patients who prefer to share decisions with their HIV provider, patients who prefer that their provider make all/most decisions were significantly less likely to adhere to HAART (OR [odds ratio] 0.57, 95% CI 0.38–0.86) and patients who preferred to make decisions alone were significantly less likely to receive HAART or to have undetectable HIV RNA in unadjusted analyses (OR 0.52, 95% CI 0.31–0.87 for receipt of HAART; OR 0.64, 95% CI 0.44–0.95 for undetectable HIV RNA). After controlling for potentially confounding patient characteristics and differences in patient ratings of communication quality, patients who preferred that their provider make all/most decisions remained significantly less likely to adhere to HAART (OR 0.58, 95% CI 0.38–0.89); however, the associations with receipt of HAART and undetectable HIV RNA were no longer significant (OR 0.60, 95% CI 0.34–1.05 for receipt of HAART; OR 0.80, 95% C.I 0.53–1.20 for undetectable HIV RNA). CONCLUSIONS Although previous research suggests that more patient involvement in health care decisions is better, this benefit may be reduced when the patient wants to make decisions alone. Future research should explore the extent to which this preference is modifiable so as to improve outcomes.