Impact of aging on cardiac sympathetic innervation measured by <Superscript>123</Superscript>I-mIBG imaging in patients with systolic heart failure

Purpose

Sympathetic nervous system (SNS) hyperactivity is a salient characteristic of chronic heart failure (HF) and contributes to the progression of the disease. Iodine-123 meta-iodobenzylguanidine (¹²³I-mIBG) imaging has been successfully used to assess cardiac SNS activity in HF patients and to predict prognosis. Importantly, SNS hyperactivity characterizes also physiological ageing, and there is conflicting evidence on cardiac ¹²³I-mIBG uptake in healthy elderly subjects compared to adults. However, little data are available on the impact of ageing on cardiac sympathetic nerve activity assessed by ¹²³I-mIBG scintigraphy, in patients with HF.

Methods and results

We studied 180 HF patients (age?=?66.1?±?10.5 years [yrs]), left ventricular ejection fraction (LVEF?=?30.6?±?6.3 %) undergoing cardiac ¹²³I-mIBG imaging. Early and late heart to mediastinum (H/M) ratios and washout rate were calculated in all patients. Demographic, clinical, and echocardiographic data were also collected. Our study population consisted of 53 patients aged >75 years (age?=?77.7?±?4.0 year), 67 patients aged 62–72 years (age?=?67.9?±?3.2 years) and 60 patients aged ≤61 year (age?=?53.9?±?5.6 years). In elderly patients, both early and late H/M ratios were significantly lower compared to younger patients (p?<?0.05). By multivariate analysis, H/M ratios (both early and late) and washout rate were significantly correlated with LVEF and age.

Conclusions

Our data indicate that, in a population of HF patients, there is an independent age-related effect on cardiac SNS innervation assessed by ¹²³I-mIBG imaging. This finding suggests that cardiac ¹²³I-mIBG uptake in patients with HF might be affected by patient age.

     

Insulin secretion and insulin sensitivity defects are a common feature of mild,clinically homogeneous,recently diagnosed type II (Non-insulin-dependent) diabetics

Summary Alteration in insulin secretion and reduced peripheral sensitivity to the hormone have been reported in type II diabetes. In this paper, a comparison is made of basal glucose production (³H-6 glucose), insulin secretion and insulin sensitivityin vivo (hyperglycemic clamp) andin vitro (binding to circulating monocytes) in 24 patients with recently diagnosed type II diabetes, matched for age and fasting glycemia and divided into non-obese (14 subjects) and moderately obese (10 subjects), and in 9 non-obese controls. The non-obese diabetics were slightly hyperinsulinemic during fasting (10.8±1.0vs 4.8±0.8 μU/ml in controls, p < 0.0005), with a significant reduction in early and late insulin secretion (14.0±1.5vs 20.8 ± 2.0 μU/ml, p<0.01 and 24.8±3.3vs 34.7±2.14 μU/ml, p<0.025). The insulin sensitivity index MCR/I was significantly reduced (2.30±0.32vs 4.14±0.40, p<0.005). Endogenous glucose production was significantly increased (107±10.2vs 84±3.7 mg/m² per min, p<0.025) and displayed a positive correlation with fasting glycemia (r=0.51, p<0.05). Insulin binding to monocytes was significantly lower than in controls (2.36±0.22%vs 4.06±0.32%, p<0.0005). Moderately obese diabetics also were significantly hyperinsulinemic in the fasting state (18.1±2.8 μU/ml, p<0.0005vs controls) but, typically, lacked the early secretory phase (20.6±3.6 μU/mlvs baseline, n.s.). A similar increase of hepatic glucose production (107±11.2 mg/m² per min, p<0.025vs controls, n.s.vs non-obese diabetics) and decrease of peripheral sensitivity to insulin (MCR/I=1.78±0.31, p<0.0005vs controls, n.s.vs non-obese diabetics) was found in moderately obsese diabetics, as well as a significant reduction of insulin binding to insolated monocytes (2.62±0.4% p<0.01vs controls, n.s.vs non-obese diabetics). These results confirm that common defects of both non-obese and moderately obese type II diabetics are: lack of early phase of glucose induced insulin secretion, increase in hepatic glucose production and decrease of peripheral insulin sensitivity together with reduction of insulin binding to circulating monocytes. The hypothesis of a unique defect as a cause of hyperglycemia in type II diabetes in early clinical phase is not borne out by the results of this study. Moderate obesity, even if able to reduce insulin sensitivity, seems to be less important in determining hyperglycemia. This study was supported by a grant fromConsiglio Nazionale delle Ricerche, P.F. Medicina Preventiva, SP4,Malattie Degenerative, N. 84.02449.56.     

Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes

Death-associated protein kinase (DAP-kinase), a proapoptotic serine/threonine kinase, is a candidate tumor suppressor gene. We studied the methylation status of DAP-kinase of 194 bone marrow samples from 160 patients with acute myeloid leukemia (AML) and 34 with a myelodysplastic syndrome (MDS) at the time of initial diagnosis by polymerase chain reaction (PCR). Hypermethylation of DAP-kinase was present in 27.5% (44 of 160) of AML and in 47% (16 of 34) of MDS specimens and significantly correlated to loss of DAP-kinase expression (P =.008). It was significantly more frequent in AML secondary to therapy for other malignancies (s-AML; 14 of 29, 48.3%), as compared to de novo AML (30 of 131, 22.9%, P =.01). DAP-kinase hypermethylation in AML was associated with myelodysplastic changes in the bone marrow at the time of the initial diagnosis (P =.002) and with the presence of cytogenetic abnormalities (P =.02). Alteration in the apoptotic response due to the loss of DAP-kinase function may be an early event in the transformation pathway to secondary leukemia via myelodysplasia.     

Effects of coronary revascularisation on myocardial blood flow and coronary vasodilator reserve in hibernating myocardium

OBJECTIVE—Previous studies have suggested that resting myocardial blood flow is within normal limits in most chronically dysfunctional left ventricular segments which improve function after coronary artery revascularisation (hibernating myocardium). The aim of this study was to assess myocardial blood flow and coronary vasodilator reserve in hibernating myocardium before and after coronary revascularisation.
PATIENTS AND METHODS— 30 patients with multivessel coronary disease undergoing coronary revascularisation (21 patients with bypass grafting and nine with coronary angioplasty), and 21 age and sex matched healthy volunteers (controls). Myocardial blood flow (MBF, ml/min/g) was measured by positron emission tomography using oxygen-15 water at rest and after dipyridamole (MBFdip, 0.56 mg/kg in four minutes). Coronary vasodilator reserve was calculated as MBFdip/MBF. Regional wall motion was assessed with echocardiography.
RESULTS—Before revascularisation there were 48 remote and 275 dysfunctional myocardial segments, of which 163 (59%) improved function after revascularisation (hibernating). In hibernating segments coronary vasodilator reserve before revascularisation was significantly lower than in remote segments (1.97 (0.7), p < 0.0001) and controls (3.2 (1.5), p < 0.0001). In hibernating segments, myocardial blood flow remained unchanged after revascularisation (0.94 (0.3) v 0.95 (0.3) ml/min/g, p = 0.3) while coronary vasodilator reserve increased (1.47 (0.7) v 1.98 (1.0), p < 0.0001). Myocardial blood flow was similar in remote, hibernating segments before and after revascularisation and in controls.
CONCLUSIONS—This study confirms that myocardial blood flow at rest in hibernating myocardium is within normal limits in most segments, and that hibernating myocardium is characterised by an impaired coronary vasodilator reserve which improves significantly after coronary revascularisation.


Keywords: hibernating myocardium; myocardial blood flow; heart failure; positron emission tomography     

Detection of autonomous replicating sequences (ars) in the genome of Epstein-Barr virus.

Epstein-Barr virus (EBV) DNA was analyzed for the presence of autonomous replicating sequences (designated ars) in a eukaryotic system consisting of a uracil auxotroph of Saccharomyces cerevisiae, YNN27, and a pBR322 hybrid plasmid, YIp5, containing the yeast uracil gene but apparently lacking a eukaryotic origin of replication. Cloned EBV DNA EcoRI restriction fragments, A, B, and DIJhet, were judged to function in this capacity by their ability to convert YNN27 cells to the uracil phenotype after transformation with each EBV-specific fragment ligated into YIp5. Additional analyses to confirm and to specify further the location of the ars were performed by cleavage of EcoRI fragments A and B into smaller BamHI fragments, which were subsequently cloned in YIp5 and tested for their ability to function as ars. BamHI fragment X, obtained from EcoRI fragment A, and BamHI fragment R, obtained from EcoRI fragment B, showed ars behavior. The successful recovery of the appropriate virus DNA segments in plasmid form from transformed yeast cells and the ability of these yeast cells to be propagated further substantiated the ars capability of the three EBV fragments.     

Comparative analysis of the incidence of surgical site infections in patients with liver resection for colorectal hepatic metastases after neoadjuvant chemotherapy

Background

The aim of this study was to identify the incidence of surgical site infections (SSIs) and postoperative complications, as defined by the Clavien–Dindo classification, after hepatic resection for metastatic colorectal cancer in patients with and without associated neoadjuvant chemotherapy.

Methods

A total of 181 patients were studied retrospectively. Patients were divided into two groups: the first group comprised patients with associated neoadjuvant chemotherapeutic treatment for liver metastases with a latency time <8 wk and the second group comprised patients without associated neoadjuvant chemotherapy.

Results

Variables of duration of liver surgery, length of total hospital stay, and length of postoperative hospital stay seem to be correlated with SSIs and postoperative complications, P < 0.005 and P < 0.0001, respectively. Duration of surgery is a risk factor for SSIs, with an odds ratio of 1.15, and for complications according to the Clavien–Dindo classification, with an odds ratio of 1.35.

Conclusions

Neoadjuvant chemotherapy was not a significant risk factor for SSIs, whereas the total length of hospital stay, length of postoperative hospital stay, and duration of surgery were independent predictors of SSIs and complications according to the Clavien–Dindo classification.     

Extending cluster lot quality assurance sampling designs for surveillance programs

Lot quality assurance sampling (LQAS) has a long history of applications in industrial quality control. LQAS is frequently used for rapid surveillance in global health settings, with areas classified as poor or acceptable performance on the basis of the binary classification of an indicator. Historically, LQAS surveys have relied on simple random samples from the population; however, implementing two‐stage cluster designs for surveillance sampling is often more cost‐effective than simple random sampling. By applying survey sampling results to the binary classification procedure, we develop a simple and flexible nonparametric procedure to incorporate clustering effects into the LQAS sample design to appropriately inflate the sample size, accommodating finite numbers of clusters in the population when relevant. We use this framework to then discuss principled selection of survey design parameters in longitudinal surveillance programs. We apply this framework to design surveys to detect rises in malnutrition prevalence in nutrition surveillance programs in Kenya and South Sudan, accounting for clustering within villages. By combining historical information with data from previous surveys, we design surveys to detect spikes in the childhood malnutrition rate. Copyright © 2014 John Wiley & Sons, Ltd.     

Novel NAD(P)H oxidase inhibitor suppresses angioplasty-induced superoxide and neointimal hyperplasia of rat carotid artery

Neointimal proliferation occurring after vascular or endovascular procedures is a major complication leading to end-organ or limb ischemia. In experimental models, balloon injury has been shown to induce NAD(P)H oxidase to produce vascular superoxide anion (O2*-) production, which has been implicated in cell proliferation, but a direct link is still unclear. We postulated that inhibition of arterial NAD(P)H oxidase, resulting in decreased O2*-, would lessen the neointimal hyperplasia caused by balloon injury to the common carotid artery (CCA). Sprague-Dawley rats were implanted with osmotic minipumps containing either vehicle, a cell-permeant peptide that inhibits NAD(P)H oxidase (gp91ds-tat, 10 mg/kg per day), or a scrambled peptide control (scrmb-tat). Two days after pump implantation, the left CCA was injured using an intravascular balloon embolectomy catheter (2F Fogarty). Systolic blood pressure was monitored by tail cuff. Fourteen days after injury, CCAs were harvested and analyzed by digital morphometry. Rats in both groups remained normotensive, with no significant differences in systolic blood pressure. Reactive oxygen species measurements after injury indicated a significant reduction in vascular O2*- in rats infused with gp91ds-tat, and the neointima/media area and thickness ratios were significantly lower in their arteries compared with control. On the contrary, no significant change in overall CCA diameter was observed in any group. Our data indicate that in response to balloon injury of the rat carotid artery, NAD(P)H oxidase activity contributes to neointimal hyperplasia and is involved in vascular cell proliferation and migration during restenosis.