Dietary omega-3 supplementation exacerbates left ventricular dysfunction in an ovine model of anthracycline-induced cardiotoxicity

BackgroundCumulative dose-dependent nonischemic cardiomyopathy (NICM) remains a significant risk with the use of some chemotherapeutic agents. In this context, omega-3 polyunsaturated fatty acids (PUFA) have been investigated for their cardioprotective potential in rodent and in vitro models of anthracycline toxicity, with conflicting results. This study evaluated prophylactic omega-3 PUFA supplementation in a large-animal model of anthracycline-induced NICM.Methods and ResultsMerino sheep were randomized to oral drenching with omega-3 PUFA (fish oil; n = 8) or olive oil placebo (n = 9) 3 weeks before commencing repeated intracoronary infusions of doxorubicin (DOX) to induce cardiac dysfunction. Cumulative DOX dose was 3.6 mg/kg. Drenching was continued for 12 weeks after final DOX exposure. Despite significant increases in tissue omega-3 PUFA levels (P < .05 vs placebo), omega-3–treated sheep displayed greater signs of anthracycline cardiotoxicity than placebo animals, consisting of left ventricular dilatation and a greater decline in ejection fraction (P < .05), although myocardial fibrosis burden was similar in both groups.ConclusionsDietary intake of omega-3 PUFA fails to prevent and may indeed exacerbate DOX-induced cardiotoxicity. Clinical use of omega-3 supplementation during chemotherapy should be deferred until more information is available regarding the mechanisms of interaction between fatty acids and the myocardium during anthracycline exposure.     

Abnormalities of Calcium Handling Proteins in Skeletal Muscle Mirror Those of the Heart in Humans With Heart Failure: A Shared Mechanism?

BackgroundIn the failing human heart, abnormalities of Ca²⁺ cycling have been described, but there is scant knowledge about Ca²⁺ handling in the skeletal muscle of humans with heart failure (HF). We tested the hypothesis that in humans with HF, Ca²⁺ cycling proteins in skeletal muscle are abnormal.Methods and ResultsTen advanced HF patients (50.4 ± 3.7 years), and 9 age-matched controls underwent vastus lateralis biopsy. Western blot analysis showed that sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA)2a, which is responsible for Ca²⁺ sequestration into the sarcoplasmic reticulum(SR), was lower in HF versus controls (4.8 ± 0.5 vs 7.5 ± 0.8 AU, P = .01). Although phospholamban (PLN), which inhibits SERCA2a, was not different in HF versus controls, phosphorylation (SER16 site) of PLN, which relieves this inhibition, was reduced (0.8 ± 0.1 vs 3.9 ± 0.9 AU, P = .004). Dihydropyridine receptors were reduced in HF, (2.1 ± 0.4 vs 3.6 ± 0.5 AU, P = .04). We tested the hypothesis that these abnormalities of Ca²⁺ handling protein content and regulation were due to increased oxidative stress, but oxygen radical scavenger proteins were not elevated in the skeletal muscle of HF patients.ConclusionIn chronic HF, marked abnormalities of Ca²⁺ handling proteins are present in skeletal muscle, which mirror those in failing heart tissue. This suggests a common mechanism, such as chronic augmentation of sympathetic activity and autophosphorylation of Ca²⁺-calmodulin-dependent-protein kinase II.     

Obstructive sleep apnea and diabetic neuropathy: a novel association in patients with type 2 diabetes

Rationale: Diabetic peripheral neuropathy is common and causes significant morbidity. Obstructive sleep apnea (OSA) is also common in patients with type 2 diabetes. Because OSA is associated with inflammation and oxidative stress, we hypothesized that OSA is associated with peripheral neuropathy in type 2 diabetes. Objectives: To assess the relationship between OSA and peripheral neuropathy in patients with type 2 diabetes. Methods: A cross-sectional study of adults with type 2 diabetes recruited randomly from the diabetes clinic of two UK hospitals. Measurements and Main Results: Peripheral neuropathy was diagnosed using the Michigan Neuropathy Screening Instrument. OSA (apnea-hypopnea index ≥ 5 events/h) was assessed using home-based, multichannel respiratory monitoring. Serum nitrotyrosine was measured by ELISA, lipid peroxide by spectrophotometer, and microvascular function by laser speckle contrast imaging. Two hundred thirty-four patients (mean [SD] age, 57 [12] yr) were analyzed. OSA prevalence was 65% (median apnea-hypopnea index, 7.2; range, 0-93), 40% of which were moderate to severe. Neuropathy prevalence was higher in patients with OSA than those without (60% vs. 27%, P < 0.001). After adjustment for possible confounders, OSA remained independently associated with diabetic neuropathy (odds ratio, 2.82; 95% confidence interval, 1.44-5.52; P = 0.0034). Nitrotyrosine and lipid peroxide levels (n = 102, 74 with OSA) were higher in OSA and correlated with hypoxemia severity. Cutaneous microvascular function (n = 71, 47 with OSA) was impaired in OSA. Conclusions: We describe a novel independent association between diabetic peripheral neuropathy and OSA. We identified increased nitrosative/oxidative stress and impaired microvascular regulation as potential mechanisms. Prospective and interventional studies are needed to assess the impact of OSA and its treatment on peripheral neuropathy development and progression in patients with type 2 diabetes.     

A 44-year-old man with bilateral eyelid swelling

Swollen eyelids are commonly ascribed to allergic conjunctivitis, contact dermatitis, eczema, angioedema, or acute sinusitis. The differential diagnosis extends to thyroid eye disease; blepharitis; Sj?gren's syndrome; Churg-Strauss vasculitis; Wegener's granulomatosis; Gleich syndrome; orbital and ocular lymphoid hyperplasia or adnexal lymphoma; idiopathic orbital inflammatory disease/idiopathic sclerosing orbital inflammation; rarely, orbital parasitosis; and IgG4-related diseases. The likely diagnosis proceeds from the more to the less common in patients without a history of allergy or infection. Both ocular lymphoid hyperplasia and ocular adnexal lymphoma must be considered in the differential diagnosis of persistent disease, and neither of these entities can be recognized or differentiated from one another clinically or radiologically. Early diagnosis is essential because therapy may consist of frequent follow-up and/or active intervention. Outcomes in patients treated early and appropriately are often favorable.     

Sexual Behavior and HIV Testing Among Bisexual Men: A Nationwide Comparison of Australian Bisexual-Identifying and Gay-Identifying Men

Men who have sex with men (MSM) are typically studied as though they were a homogeneous population. This has resulted in a lack of knowledge about the sexual health and behavior of bisexual men as distinct from gay men. In this study, patterns of sexual behavior and rates of HIV testing were compared between 854 gay-identifying and 164 bisexual-identifying men who participated in an Australian nationwide online survey. Approximately half of both groups engaged in unprotected anal intercourse (UAI) at their most recent sexual encounter, but bisexual-identifying men were more likely to have had sex with a partner who was either serodiscordant or with whom their seroconcordance was unknown. Despite these patterns, only 62% of bisexual-identifying men had ever been tested for HIV compared to 84% of gay-identifying men. Multivariate logistic regression focused on rates of UAI and HIV testing among bisexual-identifying men. Patterns were similar across all age groups and educational backgrounds. However, bisexual-identifying men were less likely to engage in UAI with a casual partner and were more likely to have been tested for HIV if they had multiple partners or had disclosed their sexual orientation to their social networks. In all, these data reveal important differences between gay- and bisexual-identifying men, particularly with regard to HIV testing, and highlight a need for HIV prevention strategies to focus more strategically on finding ways of promoting safer sex and HIV testing among all MSM.     

Theories of the pathogenesis of hepatic encephalopathy

The earliest hypothesis of the pathogenesis of HE implicated ammonia, although effects of appreciable concentrations of this neurotoxin did not resemble HE. Altered eurotransmission in the brain was suggested by similarities between increased GABA-mediated inhibitory neurotransmission and HE, specifically decreased consciousness and impaired motor function. Evidence of increased GABAergic tone in models of HE has accumulated; potential mechanisms include increased synaptic availability of GABA and accumulation of natural benzodiazepine receptor ligands with agonist properties. Pathophysiological concentrations of ammonia associated with HE, have the potential of enhancing GABAergic tone by mechanisms that involve its interactions with the GABAa receptor complex.     

Clinical Outcome of Acute Upper Gastrointestinal Hemorrhage among Patients Admitted to a Government Hospital in Egypt

Background/Aim:

Acute upper gastrointestinal hemorrhage (AUGIH) is a life-threatening emergency that results in high morbidity and mortality. The mortality rate varies between 4% and 14%. The aim of the study was to determine the clinical outcome of AUGIH among patients admitted to a government hospital in Egypt.

Patients and Methods:

This was a cross-sectional hospital-based study performed in 1000 patients presenting with AUGIH over a 7-year period between January 2004 and January 2011.

Results:

One thousand patients were analyzed. Fifty-four percent were male. Mean age was 52 ± 17 years. Eighty-eight percent were emergency admissions and 12% were inpatients at the time of bleeding. At presentation 68% had major comorbidity and 50% had liver disease. Seven hundred and twenty-four patients (72%) underwent endoscopy. Bleeding varices accounted for 31% of AUGIH and peptic ulcer 28%. Two hundred and thirty-two patients had endoscopically diagnosed bleeding varices or peptic ulcer with a visible vessel or active bleeding. These received endoscopic therapy. Initial hemostasis was achieved in 207 (89%). Thirteen patients (6%) had therapy at a subsequent endoscopy for further bleeding. Surgery was performed on 9 patients (0.9%) with AUGIH. Complications were reported in 70 patients (7%) mainly liver failure (4%). Six hundred and eighty-four patients (68%) were discharged improved, 162 (16%) left hospital without a diagnosis and 4 (0.4%) were referred to another facility. The overall mortality was 15%. Mortality was 24% in patients ≥60 years, 37% among inpatients, and 21% in those who had a major comorbidity. Mortality was 22% in patients who had liver disease and 9% in variceal bleeding.

Conclusion:

The most common cause of AUGIH was variceal in origin. Endoscopic therapy was successful in most cases. Mortality after AUGIH was particularly high among elderly patients, inpatients, and patients who had a major comorbidity, liver disease, and variceal bleeding.     

Simvastatin Reduces Endothelial NOS: Caveolin-1 Ratio but not the Phosphorylation Status of eNOS In Vivo

In vivo evidence for the pleiotropic effects of simvastatin on the nitric oxide synthase system is limited.Aims: To determine if simvastatin can affect the endothelial nitric oxide synthase cascade.Methods: New Zealand white rabbits (n=15) were divided: Group 1 (control) was fed a normal rabbit diet; Group 2 (MC) received a normal rabbit diet with 1% methionine (M) plus 0.5% cholesterol (C) and 5% peanut oil (atherogenic diet); Group 3 received the same diet as the MC group plus 5 mg/kg/ day simvastatin (S) orally (MCS). After 4 weeks, the abdominal aorta was collected and analyzed.Results: Total cholesterol (TC) and total homocysteine (tHcy) were not significantly different between MCS and MC. Endothelial function was only reduced in MC (p<0.05). Although eNOS significantly increased in MC and MCS (p<0.01), simvastatin treatment significantly reduced endothelial caveolin-1 by 35% (p=0.038), causing a 2.5-fold (p=0.026) increase in the eNOS: caveolin-1 ratio. The phosphorylation of eNOS at the threonine 495 site or serine 1177 site was not affected by diet or treatment; however, a positive correlation between the two phosphorylation sites was observed (r(2)= 0.5, p=0.01).Conclusion: in vivo pleiotropic effects of statin therapy include decreasing endothelial caveolin-1. Other therapies designed to affect eNOS phosphorylation in vivo might be useful in further preventing CVD.