An unusual case of left ventricular aneurysm in duchenne muscular dystrophy

Various structural anomalies of the left ventricular papillary muscles have been observed in recent years. Many of these have been linked to electrocardiographic aberrations. Recently two reports have appeared where the base of the posterior papillary muscle was identified as the source of frequent premature ventricular complexes. In some of these patients these frequent premature ventricular complexes have led to left ventricular dysfunction. In this report a newly discovered structural variant of the anterior papillary muscle is described--the bifid papillary muscle. Furthermore, it is proposed that this bifid papillary muscle is the source of frequent ventricular premature complexes, presenting as bigeminy in a patient with normal left ventricular function.     

Inhaled nitric oxide decreases infarction size and improves left ventricular function in a murine model of myocardial ischemia-reperfusion injury

To learn whether nitric oxide (NO) inhalation can decrease myocardial ischemia-reperfusion (I/R) injury, we studied a murine model of myocardial infarction (MI). Anesthetized mice underwent left anterior descending coronary artery ligation for 30, 60, or 120 min followed by reperfusion. Mice breathed NO beginning 20 min before reperfusion and continuing thereafter for 24 h. MI size and area at risk were measured, and left ventricular (LV) function was evaluated using echocardiography and invasive hemodynamic measurements. Inhalation of 40 or 80 ppm, but not 20 ppm, NO decreased the ratio of MI size to area at risk. NO inhalation improved LV systolic function, as assessed by echocardiography 24 h after reperfusion, and systolic and diastolic function, as evaluated by hemodynamic measurements 72 h after reperfusion. Myocardial neutrophil infiltration was reduced in mice breathing NO, and neutrophil depletion prevented inhaled NO from reducing myocardial I/R injury. NO inhalation increased arterial nitrite levels but did not change myocardial cGMP levels. Breathing 40 or 80 ppm NO markedly and significantly decreased MI size and improved LV function after ischemia and reperfusion in mice. NO inhalation may represent a novel method to salvage myocardium at risk of I/R injury.     

Discovery of an intravenous hepatoselective glucokinase activator for the treatment of inpatient hyperglycemia

Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties.     

Delta12-prostaglandin D2 is a potent and selective CRTH2 receptor agonist and causes activation of human eosinophils and Th2 lymphocytes

Prostaglandin D2 (PGD2) is a lipid mediator produced by mast cells, macrophages and Th2 lymphocytes and has been detected in high concentrations in the airways of asthmatic patients. There are two receptors for PGD2, namely the D prostanoid (DP) receptor and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). The proinflammatory effects of PGD2 leading to recruitment of eosinophils and Th2 lymphocytes into inflamed tissues is thought to be predominantly due to action on CRTH2. Several PGD2 metabolites have been described as potent and selective agonists for CRTH2. In this study we have characterized the activity of delta12-PGD2, a product of PGD2 isomerization by albumin. Delta12-PGD2 induced calcium mobilization in CHO cells expressing human CRTH2 receptor, with efficacy and potency similar to those of PGD2. These effects were blocked by the TP/CRTH2 antagonist ramatroban. delta12-PGD2 bound to CRTH2 receptor with a pKi of 7.63, and a 55-fold selectivity for CRTH2 compared to DP. In Th2 lymphocytes, delta12-PGD2 induced calcium mobilization with high potency and an efficacy similar to that of PGD2. delta12-PGD2 also caused activation of eosinophils as measured by shape change. Taken together, these results show that delta12-PGD2 is a potent and selective agonist for CRTH2 receptor and can cause activation of eosinophils and Th2 lymphocytes. These data also confirm the selective effect of other PGD2 metabolites on CRTH2 and illustrate how the metabolism of PGD2 may influence the pattern of leukocyte infiltration at sites of allergic inflammation.     

A comparison of the effects of fish oil and flaxseed oil on cardiac allograft chronic rejection in rats

Both fish and flaxseed oils are major sources of different n-3 fatty acids. Beneficial effects of fish oil on posttransplantation complications have been reported. The current study aimed to compare the effects of flaxseed and fish oils in a rat cardiac allograft model. Male Fischer and Lewis rats were used as donors and recipients, respectively, to generate a heterotopic cardiac allograft model. Animals were randomly assigned into three groups and fed a diet supplemented with 1) 5% (wt/wt) safflower oil (control, n = 7), 2) 5% (wt/wt) flaxseed oil (n = 8), or 3) 2% (wt/wt) fish oil (n = 7), and an intraperitoneal injection of cyclosporine A (CsA; 1.5 mg.kg(-1).day(-1)) over 12 wk. Body weight, blood pressure, plasma levels of lipids, CsA, select cytokines, as well as graft function and chronic rejection features were assessed. Body weight and blood CsA levels were similar among the groups. Relative to controls, both treated groups had lower systolic and diastolic blood pressure and plasma levels of macrophage chemotactic protein-1. Treatment with fish oil significantly (P < 0.05) lowered plasma levels of triglycerides, total cholesterol, and LDL-cholesterol. HDL-cholesterol concentrations were significantly higher (P < 0.05) in the flaxseed oil-treated group compared with the other two groups. Both flaxseed oil and fish oil may provide similar biochemical, hemodynamic, and inflammatory benefits after heart transplantation; however, neither of the oils was able to statistically significantly impact chronic rejection or histological evidence of apparent cyclosporine-induced nephrotoxicity in this model.     

Changes in survival among elderly patients initiating dialysis from 1990 to 1999

Background

Over the past decade, there has been a steep rise in the number of people with complex medical problems who require dialysis. We sought to determine the life expectancy of elderly patients after starting dialysis and to identify changes in survival rates over time.

Methods

All patients aged 65 years or older who began dialysis in Canada between 1990 and 1999 were identified from the Canadian Organ Replacement Register. We used Cox proportional hazards models to examine the effect that the period during which dialysis was initiated (era 1, 1990–1994; era 2, 1995–1999) had on patient survival, after adjusting for diabetes, sex and comorbidity. Patients were followed from initiation of dialysis until death, transplantation, loss to follow-up or study end (Dec. 31, 2004).

Results

A total of 14 512 patients aged 65 years or older started dialysis between 1990 and 1999. The proportion of these patients who were 75 years or older at the start of dialysis increased from 32.7% in era 1 (1990–1994) to 40.0% in era 2 (1995–1999). Despite increased comorbidity over the 2 study periods, the unadjusted 1-, 3- and 5-year survival rates among patients aged 65–74 years at dialysis initiation rose from 74.4%, 44.9% and 25.8% in era 1 to 78.1%, 51.5% and 33.5% in era 2. The respective survival rates among those aged 75 or more at dialysis initiation increased from 67.2%, 32.3% and 14.2% in era 1 to 69.0%, 36.7% and 20.3% in era 2. This survival advantage persisted after adjustment for diabetes, sex and comorbidity in both age groups (65–74 years: hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.72–0.81; 75 years or more: HR 0.86, 95% CI 0.80–0.92).

Interpretation

Survival after dialysis initiation among elderly patients has improved from 1990 to 1999, despite an increasing burden of comorbidity. Physicians may find these data useful when discussing prognosis with elderly patients who are initiating dialysis.Within general medical and subspecialty areas, chronic kidney disease is increasingly recognized as an important comorbid condition that is often associated with prolonged hospital stays and increased morbidity and mortality.^1–3 As a result, internists and other specialists are more likely than before to be involved with the care of patients for whom dialysis needs to be started because of end-stage kidney disease. The majority of patients starting dialysis are 65 years or older at the time of their first treatment, and many are over 75 years.⁴ Given the heightened awareness of chronic kidney disease, its high prevalence, the association with multiple comorbidity, and the impact of dialysis on survival and quality of life, we sought to calculate the mean life expectancy of elderly patients who began dialysis at either 65–74 years of age or at 75 years or more, and to identify whether there was any change in survival probability, or in the effect of comorbidity characteristics, on dialysis over the past decade.