Association of serum digoxin concentration and outcomes in patients with heart failure

Context  The Digitalis Investigation Group (DIG) trial reported that digoxin provided no overall mortality benefit and only a modest reduction in hospitalizations among patients with heart failure and depressed left ventricular systolic function. The clinical outcomes associated with digoxin therapy at different serum concentrations in the DIG trial have not been assessed. Objective  To assess variations in serum digoxin concentration (SDC) and their association with mortality and hospitalization in patients with heart failure. Design, Setting, and Patients  Post hoc analysis of the randomized, double-blinded, placebo-controlled DIG trial, conducted from August 1991 to December 1995, with the main analysis restricted to men with a left ventricular ejection fraction of 45% or less (n = 3782). Patients randomly assigned to receive digoxin were divided into 3 groups based on SDC at 1 month (0.5-0.8 ng/mL, n = 572; 0.9-1.1 ng/mL, n = 322; and 1.2 ng/mL, n = 277) and compared with patients randomly assigned to receive placebo (n = 2611). Main Outcome Measure  All-cause mortality at a mean follow-up of 37 months. Results  Higher SDCs were associated with increased crude all-cause mortality rates (0.5-0.8 ng/mL, 29.9%; 0.9-1.1 ng/mL, 38.8%; and 1.2 ng/mL, 48.0%; P = .006 for trend). Patients with SDCs of 0.5 to 0.8 ng/mL had a 6.3% (95% confidence interval [CI], 2.1%-10.5%) lower mortality rate compared with patients receiving placebo. Digoxin was not associated with a reduction in mortality among patients with SDCs of 0.9 to 1.1 ng/mL (2.6% increase; 95% CI, - 3.0% to 8.3%), whereas patients with SDCs of 1.2 ng/mL and higher had an 11.8% (95% CI, 5.7%-18.0%) higher absolute mortality rate than patients receiving placebo. The association between SDC and mortality persisted after multivariable adjustment (SDC 0.5-0.8 ng/mL hazard ratio [HR] 0.80, 95% CI, 0.68-0.94; SDC 0.9-1.1 ng/mL HR 0.89, 95% CI, 0.74-1.08; SDC 1.2 ng/mL HR 1.16, 95% CI, 0.96-1.39; and HR of 1.00 [referent] for placebo). Conclusions  Our findings demonstrate that higher SDCs were associated with increased mortality and suggest that the effectiveness of digoxin therapy in men with heart failure and a left ventricular ejection fraction of 45% or less may be optimized in the SDC range of 0.5 to 0.8 ng/mL.      

The obesity paradox: body mass index and outcomes in patients with heart failure

BACKGROUND: In the general population, obesity is associated with increased risk of adverse outcomes. However, studies of patients with chronic disease suggest that overweight and obese patients may paradoxically have better outcomes than lean patients. We sought to examine the association of body mass index (BMI) and outcomes in stable outpatients with heart failure (HF). METHODS: We analyzed data from 7767 patients with stable HF enrolled in the Digitalis Investigation Group trial. Patients were categorized using baseline BMI (calculated as weight in kilograms divided by the square of height in meters) as underweight (BMI <18.5), healthy weight (BMI, 18.5-24.9, overweight (BMI, 25.0-29.9), and obese (BMI > or =30.0). Risks associated with BMI groups were evaluated using multivariable Cox proportional hazards models over a mean follow-up of 37 months. RESULTS: Crude all-cause mortality rates decreased in a near linear fashion across successively higher BMI groups, from 45.0% in the underweight group to 28.4% in the obese group (P for trend <.001). After multivariable adjustment, overweight and obese patients were at lower risk for death (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.80-0.96, and HR, 0.81; 95% CI, 0.72-0.92, respectively), compared with patients at a healthy weight (referent). In contrast, underweight patients with stable HF were at increased risk for death (HR 1.21; 95% CI, 0.95-1.53). CONCLUSIONS: In a cohort of outpatients with established HF, higher BMIs were associated with lower mortality risks; overweight and obese patients had lower risk of death compared with those at a healthy weight. Understanding the mechanisms and impact of the "obesity paradox" in patients with HF is necessary before recommendations are made concerning weight and weight control in this population.     

Mucosal and systemic antibody responses and protection induced by a prime/boost rotavirus-DNA vaccine in a gnotobiotic pig model

A live rotavirus prime/DNA boost vaccine regimen was evaluated in a gnotobiotic pig model for human rotavirus (HRV) diarrhea. Plasmid DNA expressing rotavirus inner capsid VP6 was administered to pigs intramuscularly (IM) twice after oral priming with attenuated (Att) Wa strain HRV (AttHRV/VP6DNA2x). Other groups included: (1) VP6 DNA IM 2x then AttHRV orally (VP6DNA2x/AttHRV); (2) VP6 DNA IM 3x (VP6DNA3x) and controls. Significant protection (70%) against virus shedding, but lower protection against diarrhea (30%) was achieved only in the AttHRV/VP6DNA2x group after challenge (virulent Wa HRV). The other vaccines (VP6DNA2x/AttHRV and VP6DNA3x) were less effective. Higher protection rates were associated with the highest IgA antibody responses induced by the AttHRV/VP6DNA2x regimen. Interestingly, the VP6 DNA vaccine, although not effective when administered alone, boosted neutralizing and VP4 antibody titers in pigs previously primed with AttHRV, possibly mediated by cross-reactive T helper cells.     

Animal coronaviruses: what can they teach us about the severe acute respiratory syndrome?

In 2002, a new coronavirus (CoV) emerged in the People's Republic of China, associated with a severe acute respiratory syndrome (SARS) and mortality in humans. The epidemic rapidly spread throughout the world before being contained in 2003, although sporadic cases occurred thereafter in Asia. The virus is thought to be of zoonotic origin from a wild animal reservoir (Himalayan palm civets [Paguma larvata] are suspected), but the definitive host is unknown. There is concern about possible transmission of SARS CoV to rodents or domestic cats (as proven experimentally) with perpetuation of the disease in these species. In livestock and poultry, CoVs are recognised causes of enteric and respiratory infections that are often fatal in young animals. Although the emergence of SARS surprised the medical community, veterinary coronavirologists had previously isolated CoVs from wildlife and documented their interspecies transmission to livestock. Furthermore, scientists were aware of compelling evidence pointing to the emergence of new CoV strains and the mutation of existing strains resulting in new disease syndromes in animals, but the evolution and disease impact of CoVs was not widely appreciated before SARS. This review focuses on the comparative pathogenesis of CoV infections, including the factors that accentuate CoV respiratory disease, with emphasis on livestock and poultry. The goal is to provide insights into CoV transmission and disease mechanisms that could potentially be applicable to SARS, highlighting the contributions of veterinary scientists to this area of study. Such examples illustrate the need for communication and collaboration between the veterinary and medical communities to understand and control emerging zoonotic diseases of the 21st Century.     

MicroRNA-145 is regulated by DNA methylation and p53 gene mutation in prostate cancer

MiR-145 is downregulated in various cancers including prostate cancer. However, the underlying mechanisms of miR-145 downregulation are not fully understood. Here, we reported that miR-145 was silenced through DNA hypermethylation and p53 mutation status in laser capture microdissected (LCM) prostate cancer and matched adjacent normal tissues. In 22 of 27 (81%) prostate tissues, miR-145 was significantly downregulated in the cancer compared with the normal tissues. Further studies on miR-145 downregulation mechanism showed that miR-145 is methylated at the promoter region in both prostate cancer tissues and 50 different types of cancer cell lines. In seven cancer cell lines with miR-145 hypermethylation, 5-aza-2'-deoxycytidine treatment dramatically induced miR-145 expression. Interestingly, we also found a significant correlation between miR-145 expression and the status of p53 gene in both LCM prostate tissues and 47 cancer cell lines. In 29 cell lines with mutant p53, miR-145 levels were downregulated in 28 lines (97%), whereas in 18 cell lines with wild-type p53 (WT p53), miR-145 levels were downregulated in only 6 lines (33%, P < 0.001). Electrophoretic mobility shift assay showed that p53 binds to the p53 response element upstream of miR-145, but the binding was inhibited by hypermethylation. To further confirm that p53 binding to miR-145 could regulate miR-145 expression, we transfected WT p53 and MUT p53 into PC-3 cells and found that miR-145 is upregulated by WT p53 but not with MUTp53. The apoptotic cells are increased after WT p53 transfection. In summary, this is the first report documenting that downregulation of miR-145 is through DNA methylation and p53 mutation pathways in prostate cancer.     

OVARIAN ACTINOMYCOSIS PRESENTING AS ACUTE PERITONITIS

Book reviews in this article: A patient with acute peritonitis due to ovarian actinomycosis and the association of this disease with the intrauterine contraceptive device is discussed. Because adequate treatment requires prolonged antibiotics the diagnosis should be sure. Unfortunately if antibiotics are given pre-operatively culture is usually unsuccessful and thus careful examination of all removed material is essential. As many of these women are of child bearing age surgical intervention should aim to preserve fertility wherever possible.     

The in vivo response of invariant natural killer T cells to glycolipid antigens

Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that recognizes glycolipid antigens presented by the major histocompatibility complex class I-related protein CD1d. Although iNKT cells have received a lot of attention as targets for the development of immunotherapies, few studies have investigated the in vivo response of iNKT cells to glycolipid antigen activation. Accumulating evidence indicates that iNKT cells generate a dynamic response to in vivo activation by glycolipid antigens that is characterized by surface receptor downmodulation, expansion, cytokine production, cross talk with other cells, homeostatic contraction, and acquisition of an anergic phenotype. These studies provide new insight into the biology of iNKT cells and have important implications for designing safe and effective iNKT cell-based vaccines and therapies.     

HSP70 as a Diagnostic and Prognostic Marker in Egyptian Women With Breast Cancer

BackgroundHeat shock protein 70 (HSP70) is a significant cellular stress response protein that has intrinsic and extrinsic pathways to protect cells against apoptosis. It is one of the most induced proteins in cancer cells. The aim of the present study is to investigate the significant role of the HSP70 expression in Egyptian patients with breast cancer (BC) and its potential to be as a diagnostic and prognostic marker.Materials and MethodsHSP70 was examined in 155 cases in this prospective study; patients were subdivided into 3 groups: 60 patients with malignant metastatic disease, 60 patients with malignant non-metastatic disease, and 35 patients with benign lesions as control. HSP70 expression was detected using enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC).ResultsMost cases of breast cancer expressed HSP70 in both serum (98.3%) and tumor tissue (90%). A strong positive correlation was found between HSP70 IHC and ELISA (r = 0.811). The mean HSP70 levels, as detected in both patients’ serum by ELISA and tumor tissue by IHC, was significantly higher in patients with BC than in benign cases (P = .001). HSP70 was significantly higher in patients with metastatic BC than in those with non-metastatic BC (P = .001). HSP70 showed positive correlation with tumor size (pT stage) and number of lymph node metastases (P ≤ .001).ConclusionHSP70 is over-expressed in patients with metastatic and non-metastatic BC than in benign cases. A high level of HSP70 either in patient’s serum or in tumor tissue correlated significantly with advanced disease in patients with BC. This present study suggests that HSP70 can serve as a BC biomarker for early screening, diagnosis, and follow-up.