Long-term outcome in relation to renal sympathetic activity in patients with chronic heart failure.

AIMS: Although cardiac sympathetic activation is associated with adverse outcome in patients with chronic heart failure (CHF), the influence of renal sympathetic activity on outcome is unknown. We assessed the hypothesis that renal noradrenaline (NA) spillover is a predictor of the combined endpoint of all-cause mortality and heart transplantation in CHF. METHODS AND RESULTS: Sixty-one patients with CHF, New York Heart Association (NYHA) I-IV (66% NYHA III-IV), and left ventricular ejection fraction (LVEF) 26+/-9% (mean+/-SD) were studied with cardiac and renal catheterizations at baseline and followed for 5.5+/-3.7 years (median 5.5 years, range 12 days to 11.6 years). Nineteen deaths and 13 cases of heart transplantation were registered. Only renal NA spillover above median, 1.19 (interquartile range 0.77-1.43) nmol/min, was independently associated with an increased relative risk (RR) of the combined endpoint (RR 3.1, 95% CI 1.2-7.6, P=0.01) in a model also including total body NA spillover, LVEF, glomerular filtration rate (GFR), renal blood flow, cardiac index, aetiology, and age. CONCLUSION: Renal noradrenergic activation has a strong negative predictive value on outcome independent of overall sympathetic activity, GFR, and LVEF. These findings suggest that treatment regimens that further reduce renal noradrenergic stimulation could be advantageous by improving survival in patients with CHF.     

Maternal Physical Activity Is Associated With Improved Blood Pressure Regulation During Late Pregnancy

Background

Cardiovagal baroreflex gain (cBRG) reflects an individual's ability to buffer swings in blood pressure. It is not well understood how this mechanism is influenced by physical activity in pregnancy. Because pregnant women tend to engage in low levels of moderate-to-vigorous physical activity (MVPA) and high levels of sedentary behaviour, we sought to determine the influence of MVPA and sedentary behaviour on cBRG and mean arterial pressure (MAP) in pregnancy.

Enhancement of MHC-I Antigen Presentation via Architectural Control of pH-Responsive,Endosomolytic Polymer Nanoparticles

Protein-based vaccines offer a number of important advantages over organism-based vaccines but generally elicit poor CD8⁺ T cell responses. We have previously demonstrated that pH-responsive, endosomolytic polymers can enhance protein antigen delivery to major histocompatibility complex class I (MHC-I) antigen presentation pathways thereby augmenting CD8⁺ T cell responses following immunization. Here, we describe a new family of nanocarriers for protein antigen delivery assembled using architecturally distinct pH-responsive polymers. Reversible addition-fragmentation chain transfer (RAFT) polymerization was used to synthesize linear, hyperbranched, and core-crosslinked copolymers of 2-(N,N-diethylamino)ethyl methacrylate (DEAEMA) and butyl methacrylate (BMA) that were subsequently chain extended with a hydrophilic N,N-dimethylacrylamide (DMA) segment copolymerized with thiol-reactive pyridyl disulfide (PDS) groups. In aqueous solution, polymer chains assembled into 25 nm micellar nanoparticles and enabled efficient and reducible conjugation of a thiolated protein antigen, ovalbumin. Polymers demonstrated pH-dependent membrane-destabilizing activity in an erythrocyte lysis assay, with the hyperbranched and cross-linked polymer architectures exhibiting significantly higher hemolysis at pH ≤ 7.0 than the linear diblock. Antigen delivery with the hyperbranched and cross-linked polymer architecture enhanced in vitro MHC-I antigen presentation relative to free antigen, whereas the linear construct did not have a discernible effect. The hyperbranched system elicited a four- to fivefold increase in MHC-I presentation relative to the cross-linked architecture, demonstrating the superior capacity of the hyperbranched architecture in enhancing MHC-I presentation. This work demonstrates that the architecture of pH-responsive, endosomolytic polymers can have dramatic effects on intracellular antigen delivery, and offers a promising strategy for enhancing CD8⁺ T cell responses to protein-based vaccines.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9697-1) contains supplementary material, which is available to authorized users.KEY WORDS: MHC-I antigen presentation, pH-responsive nanoparticle, polymer architecture, RAFT polymerization, vaccine     

CYP3A isoforms in Ewing's sarcoma tumours: an immunohistochemical study with clinical correlation

Ewing's sarcoma is an aggressive malignancy of bone and soft tissue with high incidence of metastasis and resistance to chemotherapy. Cytochrome P450 (CYP) monooxygenases are a family of enzymes that are involved in the metabolism of exogenous and endogenous compounds, including anti‐cancer drugs, and have been implicated in the aggressive behaviour of various malignancies. Tumour samples and clinical information including age, sex, tumour site, tumour size, clinical stage and survival were collected from 36 adult and paediatric patients with Ewing's sarcoma family tumours. Tissue microarrays slides were processed for immunohistochemical labelling for CYP3A4, CYP3A5 and CYP3A7 using liver sections as positive control. The intensity of staining was scored as negative, low or high expression and was analysed statistically for any association with patients' clinical information. Four cases were later excluded due to inadequate viable tissue. CYP3A4 staining was present in 26 (81%) cases with high expression noted in 13 (40%) of 32 cases. High expression was significantly associated with distant metastases (P < 0.05). CYP3A5 and CYP3A7 were expressed in 5 and 13 cases respectively (15.6%, 40.6%). There was no association between the expression of CYP3A isoforms and age, sex, tumour size, or location (pelvic or extra‐pelvic). None of the biomarkers showed any correlation with overall or disease‐free survival. In conclusion, expression of CYP3A isoforms is noted in Ewing's sarcoma tumours and high CYP3A4 expression may be associated with metastasis. Additional studies are needed to further investigate the role of CYP3A4 in the prognosis of these tumours.     

Comprehensive health status assessment of centenarians: results from the 1999 large health survey of veteran enrollees

BACKGROUND: Information on the health status of centenarians provides a means for understanding the health care needs of this growing population. Therefore, we examined the health status of a national cohort of centenarian veteran enrollees. METHODS: Ninety-three centenarian veteran enrollees returned a complete health history questionnaire, which included questions about sociodemographic information, age-associated conditions, health behaviors, health-related quality of life as measured by the Veterans SF-36, and change in health status. RESULTS: Centenarian veteran enrollees are a group with major impairment across multiple dimensions of health-related quality of life despite having a relatively low prevalence of diseases. They had considerable physical limitations as reflected by their physical health summary scores (26.2 +/- 8.3). However, their mental health was comparatively good (mental health summary score 44.1 +/- 12.5). Compared to younger elderly veterans (ages 85-99), centenarians had a lower prevalence of hypertension, angina or myocardial infarction, diabetes, and chronic low back pain (p <.05). Centenarians had significantly worse physical functioning, role physical, vitality, and social functioning scores than did younger elderly veterans. The two groups did not differ in their general health, bodily pain, role emotional, and mental health scores. Centenarians did not perceive much decline in their physical or mental health during the preceding year. CONCLUSIONS: Centenarian veteran enrollees are a group with a low number of age-associated diseases and good mental health despite substantial physical limitations. These results support future studies of services directed toward improvement of function as opposed to those focused solely on the treatment of diseases.     

Biochemical and clinical manifestations of dopamine-producing paragangliomas: utility of plasma methoxytyramine

Measurements of plasma-free normetanephrine and metanephrine provide a sensitive test for diagnosis of pheochromocytoma but may fail to detect tumors that produce predominantly dopamine. Such tumors are extremely rare, usually found as extraadrenal paragangliomas. This report describes measurements of plasma concentrations of free methoxytyramine, the O-methylated metabolite of dopamine, in 120 patients with catecholamine-producing tumors, including nine with extraadrenal paragangliomas secreting predominantly dopamine. In seven of these nine patients, tumors were found incidentally or secondary to the space-occupying complications of the lesions. Plasma concentrations of free methoxytyramine and dopamine were increased in all nine patients, including two with normal plasma and urinary normetanephrine and metanephrine and normal urinary outputs of dopamine. Relative increases above normal for plasma methoxytyramine (104-fold) and dopamine (56-fold) were much greater (P < 0.001) than those for urinary dopamine (3-fold). Insensitivity of the latter for identification of dopamine-secreting tumors was due to dependence of the urinary amine on renal extraction and decarboxylation of circulating 3,4-dihydroxyphenylalanine. Measurements of plasma-free methoxytyramine, in addition to normetanephrine and metanephrine, are unlikely to improve diagnosis of pheochromocytomas in hypertensive patients with symptoms of catecholamine excess but may be useful in selected patients for identification of tumors that produce predominantly dopamine.     

Narrative inquiry as a research methodology exploring person centred care in nursing

Background

Although, person centred care has for a long time been an important approach to nursing care, it is often not a reality in the clinical environment. The focus of health research has, until recently, been on the physical aspects of a persons’ illness and this has influenced how care is delivered. There is a need to broaden the focus from the illness to the person who is ill. A holistic approach to the persons’ social and cultural experience of their illness will aid health care professions to provide person centred care.This paper will make the argument that narrative inquiry is a well suited to health care research in general and nursing research in particular as it focuses its inquiry on the individual person's experience of their illness – ‘what matters’ from the person's point of view. Narrative inquiry explores the narrative from a temporal, social and spatial view.

Potential challenges facing distributed leadership in health care: evidence from the UK National Health Service

The discourse of leaderism in health care has been a subject of much academic and practical debate. Recently, distributed leadership (DL) has been adopted as a key strand of policy in the UK National Health Service (NHS). However, there is some confusion over the meaning of DL and uncertainty over its application to clinical and non‐clinical staff. This article examines the potential for DL in the NHS by drawing on qualitative data from three co‐located health‐care organisations that embraced DL as part of their organisational strategy. Recent theorising positions DL as a hybrid model combining focused and dispersed leadership; however, our data raise important challenges for policymakers and senior managers who are implementing such a leadership policy. We show that there are three distinct forms of disconnect and that these pose a significant problem for DL. However, we argue that instead of these disconnects posing a significant problem for the discourse of leaderism, they enable a fantasy of leadership that draws on and supports the discourse.     

Management of peripheral arterial disease in the elderly: focus on cilostazol

Symptomatic and asymptomatic peripheral arterial disease (PAD) is a common problem in the elderly. The management of PAD includes the prevention of cardiovascular events and relief of symptoms – most commonly intermittent claudication (IC). Both require treatment of the causes and consequences of atherothrombosis, but some strategies are more effective for prevention of cardiovascular events and others are more effective for the relief of symptoms. Priorities for the prevention of cardiovascular events include smoking cessation, exercise, antiplatelet therapy, and the treatment of dyslipidemia, hypertension, and diabetes. Walking time and ability are improved by exercise. The benefit of numerous drugs in the treatment of IC has been assessed. The results have generally been disappointing, but there is some evidence that statins and cilostazol (an inhibitor of phosphodiesterase 3) are of benefit. Meta-analyses suggest that cilostazol increases maximum walking distance by 40%–50% and improves other objective measures of walking. The safety profile of cilostazol in patients with PAD appears to be acceptable although the mechanism for its effect on IC is unclear. In addition to risk factor management, treatment with cilostazol should be considered in patients with disabling IC.