In vitro biosynthesis of plasma proteins under ischemic conditions of closed-circuit perfusion of healthy and intoxicated rabbit liver

We are elaborating on the kinetics and mechanisms of septic rabbit liver to de novo biosynthesize acute-phase response (APR) proteins under in vitro conditions of deepening ischemia in reference to their in vivo prevalence in serum and cerebrospinal fluids (CSF) collected at predetermined times. The significance of the data is interpreted as relevant to grafting cadaveric liver into end-stage liver diseased patients and APR-induced ischemic heart diseases (IHD). Hepatic APR was induced by CCl(4)-intubation, and the administration of cholera toxin (CT) or scorpion venom (SV), or both, to rabbits. Hepatic functional efficiency, in terms of biosynthesis of APR proteins in closed circuit perfusion of the isolated intoxicated liver with oxygenated saline or L-15 media paralleled the two-dimensional immunoelectrophoresis (2D-IEP) spectrum of APR serum proteins at time of liver isolation. We are suggesting: (a) in vitro biosynthesis of plasma proteins by isolated perfused liver is the result of in vivo decoded and retained APR inflammatory signals; and (b) decoded inflammatory signals are expressed not withstanding the perfusate's organic composition. Furthermore, 90 min of ischemic perfusion in saline or L-15 medium precipitated mitochondrial aberrations which resulted in further deterioration of de novo biosynthesis of APR plasma proteins. Regardless of the nature of the inflammatory stimuli, mitochondrial aberrations rendered the perfused organ a biologically inert tissue mass that was incapable of resuming biological function upon perfusion with oxygenated L-15 medium. This is most likely due to ischemia-induced irreversible hepatic necrosis. Thus, in vitro aberrations of mitochondrial function(s) critically limit the capability of the isolated liver to resume its organic function to sustain biosynthesis of de novo plasma proteins. Extrapolation of these results to the surgical management of end-stage liver diseases points to the importance of the status and the handling protocol(s) of the cadaver donor liver prior to successful grafting. We conclude that although histology of a cadaver liver may reveal well-preserved hepatic cellular organelles with at least minimal intra- and intercellular communication required for viable hepatic function, we deem it essential to further define acceptable minimal capabilities to de novo biosynthesize plasma proteins by a cadaver liver as a measure of its functional viability and suitability for transplantation. Ultimately, this measure may improve the success of liver transplants with minimal surgical and drug interventions.     

Estimating the decline in excess risk of chronic obstructive pulmonary disease following quitting smoking – A systematic review based on the negative exponential model

We quantified the decline in COPD risk following quitting using the negative exponential model, as previously carried out for other smoking-related diseases. We identified 14 blocks of RRs (from 11 studies) comparing current smokers, former smokers (by time quit) and never smokers, some studies providing sex-specific blocks. Corresponding pseudo-numbers of cases and controls/at risk formed the data for model-fitting. We estimated the half-life (H, time since quit when the excess risk becomes half that for a continuing smoker) for each block, except for one where no decline with quitting was evident, and H was not estimable. For the remaining 13 blocks, goodness-of-fit to the model was generally adequate, the combined estimate of H being 13.32 (95% CI 11.86–14.96) years. There was no heterogeneity in H, overall or by various studied sources. Sensitivity analyses allowing for reverse causation or different assumed times for the final quitting period little affected the results. The model summarizes quitting data well. The estimate of 13.32 years is substantially larger than recent estimates of 4.40 years for ischaemic heart disease and 4.78 years for stroke, and also larger than the 9.93 years for lung cancer. Heterogeneity was unimportant for COPD, unlike for the other three diseases.     

Sex Differences in Platelet Reactivity and Cardiovascular and Psychological Response to Mental Stress in Patients With Stable Ischemic Heart Disease: Insights From the REMIT Study

BackgroundAlthough emotional stress is associated with ischemic heart disease (IHD) and related clinical events, sex-specific differences in the psychobiological response to mental stress have not been clearly identified.ObjectivesWe aimed to study the differential psychological and cardiovascular responses to mental stress between male and female patients with stable IHD.MethodsPatients with stable IHD enrolled in the REMIT (Responses of Mental Stress–Induced Myocardial Ischemia to Escitalopram) study underwent psychometric assessments, transthoracic echocardiography, and platelet aggregation studies at baseline and after 3 mental stress tasks. Mental stress–induced myocardial ischemia (MSIMI) was defined as the development or worsening of regional wall motion abnormality, reduction of left ventricular ejection fraction (LVEF) ≥8% by transthoracic echocardiography, and/or ischemic ST-segment change on electrocardiogram during 1 or more of the 3 mental stress tasks.ResultsIn the 310 participants with known IHD (18% women, 82% men), most baseline characteristics were similar between women and men (including heart rate, blood pressure, and LVEF), although women were more likely to be nonwhite, living alone (p < 0.001), and unmarried (p < 0.001); they also had higher baseline depression and anxiety (p < 0.05). At rest, women had heightened platelet aggregation responses to serotonin (p = 0.007) and epinephrine (p = 0.004) compared with men. Following mental stress, women had more MSIMI (57% vs. 41%; p < 0.04), expressed more negative (p = 0.02) and less positive emotion (p < 0.001), and demonstrated higher collagen-stimulated platelet aggregation responses (p = 0.04) than men. Men were more likely than women to show changes in traditional physiological measures, such as blood pressure (p < 0.05) and double product.ConclusionsIn this exploratory analysis, we identified clear, measurable, and differential responses to mental stress in women and men. Further studies should test the association of sex differences in cardiovascular and platelet reactivity in response to mental stress and long-term outcomes. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847)     

Hormones and health outcomes in aging men

Increasing age is a predictor of ill-health and mortality related to cardiovascular disease and to frailty, a syndrome characterized by deterioration of multiple organ systems leading to loss of physiological reserve, diminished capacity to cope with stressors, and increased risk of disability and death. As men grow older, their levels of testosterone decline while the prevalence of ill-health increases. Observational studies have linked lower testosterone levels with cardiovascular disease and mortality in middle-aged and older men. More recently, lower testosterone has been shown to predict reduced sexual activity and frailty in aging men. Additional studies are needed to determine whether lower testosterone is a biomarker or a potentially treatable risk factor for poorer health outcomes in older men. During aging, the response of the pituitary–thyroid axis alters to manifest higher thyrotropin levels. The presences of subclinical hypo- and hyper-thyroidism predict adverse cardiovascular outcomes. Newer results indicate that in euthyroid older men, differences in free thyroxine levels within the normal range predict specific health outcomes including frailty. Clarification of the roles of endogenous testosterone and thyroxine in the genesis of ill-health during male aging offers the prospect of future intervention to preserve health and well-being in this growing population.     

A Reappraisal of Exercise Electrocardiographic Indexes of the Severity of Ischemic Heart Disease: Angiographic and Scintigraphic Correlates

Objectives. We explored how the exercise electrocardiographic (ECG) indexes generally presumed to signify severe ischemic heart disease (IHD) correlate with coronary angiographic and scintigraphic myocardial perfusion findings.

Background. In exercise testing, it is generally assumed that the early onset of ST segment depression and its occurrence at a low rate–pressure product (ischemic threshold); the amount of maximal ST segment depression; and a horizontal or downsloping ST segment and its prolonged recovery after exercise signify more severe IHD. However, the relation of these indexes to coronary angiographic and exercise myocardial perfusion findings in patients with IHD is unclear.

Methods. We prospectively carried out a symptom-limited 12-lead Bruce protocol thallium-201 single-photon emission computed tomographic (SPECT) exercise test in 66 consecutive subjects with stable angina, ≥70% stenosis of at least one coronary artery, normal rest ECG and left ventricular wall motion and a prior positive exercise ECG. The above ECG indexes, vessel disease (VD), a VD score and the quantitative thallium-SPECT measures of the extent, maximal deficit and redistribution gradient of the perfusion abnormality were characterized.

Results. Maximal ST segment depression could not differentiate the number of diseased vessels; was not related to VD score, maximal thallium deficit or redistribution gradient; but was related to the extent of perfusion abnormality (r = 0.29, 95% confidence interval [CI] 0.08 to 0.52, p = 0.02). Time of onset of ST segment depression correlated inversely only with VD (r = −0.22, 95% CI −0.44 to −0.05, p < 0.05), whereas the ischemic threshold had low inverse correlation only with VD score (r = −0.25, 95% CI −0.47 to −0.01, p < 0.05) and the redistribution gradient (r = −0.33, 95% CI −0.53 to −0.10, p < 0.01). A horizontal or downsloping compared with an upsloping ST segment did not demonstrate more severe angiographic and scintigraphic disease. Recovery time did not correlate with angiographic and scintigraphic findings, and correlations between angiographic and scintigraphic findings were also low or absent.

Conclusions. In this homogeneous study group, the exercise ECG indexes did not necessarily signify more severe IHD by angiographic and scintigraphic criteria. Lack of concordance between the exercise ECG, angiography and myocardial scintigraphy suggests that these diagnostic modalities examine different facets of myocardial ischemia, underscoring the need for caution in the interpretation of their results.

(J Am Coll Cardiol 1997;29:1497–504)     

Cardioprotective effects of saponins from Panax japonicus on acute myocardial ischemia against oxidative stress-triggered damage and cardiac cell death in rats

Aim

To study the cardioprotective effects of saponins from Panax japonicus (SPJ) on acute myocardial ischemia injury rats induced by ligating of the left anterior descending branch (LAD), on the basis of this investigation, the possible mechanism of SPJ was elucidated.

Materials and methods

SPJ was identified by high performance liquid chromatography-evaporative light scattering detection. Male Sprague-Dawley rats (200–220 g) were randomly divided into four groups: sham-operated, LAD, LAD + l-SPJ (SPJ, 50 mg/kg/day, orally) and LAD + h-SPJ (SPJ, 100 mg/kg/day, orally). Before operation, the foregoing groups were pretreated with homologous drug once a day for 7 days, respectively. After twelve hours in LAD, the cardioprotective effects of SPJ were evaluated by infarct size, biochemical values, hemodynamic, and histopathological observations and the antioxidative and antiapoptotic relative gene expressions.

Results

SPJ significantly improved heart function and decreased infarct size; remarkably decreased levels of serum lactate dehydrogenase, creatine kinase, xanthine oxide and malondialdehyde content, increased contents of serum total antioxidant capacity, superoxide dismutase (SOD), glutathione peroxidase, catalase; quantitative real-time PCR results showed that SPJ might markedly reverse the down-regulated mRNA expressions of the SOD1, SOD2 and SOD3, ameliorate the increased Bax and caspase-3 mRNA expressions and decreased Bcl-2 mRNA expression and ratios of Bcl-2 to Bax. Histopathological observations provided supportive evidence for biochemical analyses, and with the dose of SPJ increasing, the aforesaid improvement became more and more strong.

Conclusions

The studies demonstrated that in ischemic myocardium, oxidative stress caused the overgeneration and accumulation of reactive oxygen species (ROS), which was central of cardiac ischemic injury. SPJ exerted beneficially cardioprotective effects on myocardial ischemia injury rats, mainly scavenging oxidative stress-triggered overgeneration and accumulation of ROS, alleviating myocardial ischemia injury and cardiac cell death.     

Intense lipid peroxidation in premature clinical coronary atherosclerosis is associated with metabolic abnormalities

Increased oxidative stress is associated with rapid progression of atherosclerosis. In this study we sought to determine whether premature onset of clinical coronary atherosclerosis is associated with increased levels of lipid peroxidation. We measured plasma levels of malondialdehyde (MDA), using high-pressure liquid chromatography, in 42 male patients with early- (<56 years) or late-onset (>64 years) unstable angina and in 2 age-matched control groups (n=20). Plasma MDA levels were higher in the patients with unstable angina than in the control groups (1.57 +/- 0.07 vs 1.14 +/- 0.03 nmol/mL; P<.001). Patients with early-onset angina showed higher MDA levels than those in late-onset patients (1.75 +/- 0.11 vs 1.44 +/- 0.097 nmol/mL; P<.05), despite a similar prevalence of risk factors for atherothrombosis. The inflammatory component, measured with the use of a high-sensitivity enzyme-linked immunosorbent assay for C-reactive protein, and platelet activity, measured as prothrombin fragment 1+2, failed to predict MDA level. Fasting glucose (P<.05) was the best predictor of MDA level in patients with early-onset unstable angina; uric acid (P=.09) and body-mass index (P=.15) showed trends toward significant correlation with MDA level in the same group of patients. Metabolic abnormalities related to insulin resistance in patients with premature coronary atherosclerosis appear to be important mediators of major plasma oxidative damage.     

AIDS-related cholangiopancreatographic changes

The cholangiographic and pancreatographic appearances of the acquired immunodeficiency syndrome (AIDS) associated cholangitis were evaluated in 26 patients. Twenty-four patients were diagnosed by retrograde cholangiography or endoscopic cholangiopancreatography (ERC or ERCP). One patient was diagnosed by T-tube cholangiography and another patient by transhepatic cholangiography. The radiographic findings ranged from intrahepatic ductal abnormalities with or without involvement of the extrahepatic biliary tree (eight patients) to irregularities and strictures involving the ampulla of Vater or the intrapancreatic portion of the common bile duct (CBD) with proximal dilatation (18 patients). Significant strictures involving the juxta-ampullary pancreatic duct were identified in six of 12 patients. Twenty-one of the 26 patients had associated infections which included: Cryptosporidium (CS), Mycobacterium avium intracellulare (MAI), cytomegalovirus (CMV), Microsporidium (MSP), and Isospora (ISP). Three patients were operated upon for acute acalculous cholecystitis. In each instance, organisms were identified in both the bile duct and the inflamed gallbladder.An editorial commentary on this article follows on pp. 423–424.