Feasibility to detect severe coronary artery stenoses with upright treadmill exercise magnetic resonance imaging

We performed treadmill exercise magnetic resonance imaging in 27 patients with exertional chest pain who were referred for contrast coronary angiography to determine the feasibility of this method to identify severe coronary artery stenoses. The sensitivity and specificity for detecting >70% coronary artery luminal diameter narrowings on contrast coronary angiography were 79% and 85%, respectively.     

Effects of aging and dietary restriction on tissue protein synthesis: relationship to plasma insulin-like growth factor-1.

Insulin-like growth factor-1 (IGF-1) decreases with age in many species and appears to have an important role in the age-related decline in capacity for protein synthesis with age. The goals of these studies were to determine whether (a) ad libitum fed mice demonstrate age-related decreases in IGF-1, (b) the relationship between IGF-1 and age-related changes in protein synthetic capacity in ad libitum fed animals, and (c) whether moderate dietary restriction (which increases both life span and protein synthetic capacity) delays age-related changes in protein synthesis and plasma IGF-1. These studies indicate that (a) in ad libitum fed animals, plasma IGF-1 decreases with age between 10 and 15 months and moderate dietary restriction decreases plasma IGF-1 in young but not older animals, and (b) the temporal changes in protein synthesis are tissue specific; moderate dietary restriction either increases or prevents the age-related decline in tissue protein synthesis. Results suggest that in normal aging, decreases in IGF-1 are associated with the decline in protein synthesis but that other regulatory mechanisms appear to have an important role in this process. Dietary restriction decreases plasma IGF-1 in young animals and either increases protein synthesis or prevents the age-related decline in protein synthesis, suggesting that the effects of dietary restriction are not mediated via increases in plasma IGF-1.     

Periostin is required for maturation and extracellular matrix stabilization of noncardiomyocyte lineages of the heart

The secreted periostin protein, which marks mesenchymal cells in endocardial cushions following epithelial-mesenchymal transformation and in mature valves following remodeling, is a putative valvulogenesis target molecule. Indeed, periostin is expressed throughout cardiovascular morphogenesis and in all 4 adult mice valves (annulus and leaflets). Additionally, periostin is expressed throughout the fibrous cardiac skeleton and endocardial cushions in the developing heart but is absent from both normal and/or pathological mouse cardiomyocytes. Periostin (peri(lacZ)) knockout mice exhibit viable valve disease, with neonatal lethality in a minority and latent disease with leaflet abnormalities in the viable majority. Surviving peri(lacZ)-null leaflets are truncated, contain ectopic cardiomyocytes and smooth muscle, misexpress the cartilage proteoglycan aggrecan, demonstrate disorganized matrix stratification, and exhibit reduced transforming growth factor-beta signaling. Neonatal peri(lacZ) nulls that die (14%) display additional defects, including leaflet discontinuities, delamination defects, and deposition of acellular extracellular matrix. Assessment of collagen production, 3D lattice formation ability, and transforming growth factor-beta responsiveness indicate periostin-deficient fibroblasts are unable to support normal valvular remodeling and establishment of a mature cardiac skeleton. Furthermore, pediatric stenotic bicuspid aortic valves that have lost normal extracellular matrix trilaminar stratification have greatly reduced periostin. This suggests that loss of periostin results in inappropriate differentiation of mesenchymal cushion cells and valvular abnormalities via a transforming growth factor-beta-dependent pathway during establishment of the mature heart. Thus, peri(lacZ) knockouts provide a new model of viable latent valve disease.     

Aged mice exhibit greater mortality concomitant to increased brain and plasma TNF-alpha levels following intracerebroventricular injection of lipopolysaccharide

BACKGROUND: Age-related defects in the development of peripheral inflammatory responses have been observed in rodents and humans. OBJECTIVE: We examined the effects of age on a centrally injected endotoxin-induced cytokine production and cellular activation in mice. METHODS: Male C57BL/6J (B6) mice, C3H/HeN mice, and C3H/HeJ mice received an intracerebroventricular injection of lipopolysaccharide (LPS) and were sacrificed at various times (2, 4, 8 h) thereafter. ELISA for IL-1beta, IL-6, IL-12, and TNF-alpha were conducted on forebrain tissue homogenates as well as plasma samples, and lectin staining to detect activated microglia was prepared for selected brain slices. RESULTS: Intracerebroventricular injection of LPS in B6 mice produced an age-associated increase in mortality which was paralleled with a significant increase in brain and plasma levels of TNF-alpha. AntiTNF-alpha- and IL-6-immunoreactive cells possessed macrophagelike morphologies and were observed along the LPS injection tract and scattered throughout the hilus of the dorsal hippocampus and cerebral cortices. This LPS-mediated response was found to be specific in that the LPS-hyporesponsive mouse strain (C3H/HeJ) failed to demonstrate significant brain or plasma levels of TNF-alpha after LPS administration compared to C3H/HeN mice. CONCLUSION: These results suggest that the age-related increases in TNF-alpha production and mortality following the intracerebroventricular administration of LPS may be due to an increased endotoxin hypersensitivity of brain microglia/macrophages within aged animals.     

What counts in brain aging? Design-based stereological analysis of cell number

The advent and implementation of new design-based stereological techniques allows the quantification of cell number without the assumptions required when obtaining areal densities. These new techniques are rapidly becoming the standard for quantifying cell number, particularly in aging studies. Recently, studies using stereological techniques have failed to confirm earlier findings regarding age-associated neural loss. This newly emerging view of retained cell number during aging is having a major impact on biogerontology, prompting revaluation of long-standing hypotheses of age-related cell loss as causal for age-related impairments in brain functioning. Rather than focus on neuronal loss as the end-result of a negative cascade of neuronal injury, research has begun to consider that age-related behavioral declines may reflect neuronal dysfunction (e.g., synaptic or receptor loss, signal transduction deficits) instead of neuronal death. Here we discuss design-based stereology in the context of age-related change in brain cell number and its impact on consideration of structural change in brain aging. Emergence of this method of morphometrics, however, can have relevance to many areas of gerontological research.     

Binding of intact and cleaved human growth hormone to hepatic receptors and plasma binding proteins.

The binding of intact (i) and cleaved (c) 125I-labeled human GH to the hepatic GH-binding sites and to the plasma GH-binding protein (GH-BP) of rabbits was compared. The c-hGH label was prepared by incubation of the iodinated hormone with the plasmalemal fraction of pregnant rat liver. Unlabeled c-hGH was prepared in milligram quantities by digestion with plasmin. The c-hGH label revealed both high and low affinity binding sites on the rabbit liver membranes when it was displaced by unlabeled c-hGH. Cleavage of the hGH label caused a substantial decrease in its affinity for the low affinity site. When i-hGH was used to displace either i-hGH or c-hGH tracers, it failed to discriminate between the two classes of binding sites, as it had equally high affinity for both. The c-hGH had a substantilly lower affinity for the plasma GH-BP than did the i-hGH. This difference is consistent with the c-hGH having an increased bioactivity, but not with its reported slow clearance rate. If cleavage of GH occurs at its sites of action, the lowered affinity for the plasma GH-BP, with retention of high affinity for the high affinity site, could increase its potency relative to that of the i-hGH.     

Serological evidence of Helicobacter pylori infection in UK South Asian and European populations: implications for gastric cancer and coronary heart disease

OBJECTIVES: To describe the prevalence of serological evidence of infection with Helicobacter pylori among people of South Asian and European ethnic origins and to assess its association with prevalent coronary heart disease (CHD). METHODS: We used a quantitative method to compare IgG antibodies to H. pylori in a population sample of 300 South Asians and 302 Europeans in Newcastle upon Tyne, UK. RESULTS: For men and women, respectively, H. pylori IgG (95% confidence interval) was 16.7 microg/ml (13.9, 20.2) and 11.3 (9.4, 13.5) among Europeans and 11.6 (9.8, 13.7) and 14.3 (12.1, 16.9) among South Asians. Levels were higher in older participants and in those of lower socioeconomic status. The ratio of geometric mean IgG, (95% confidence interval) adjusted for age, sex and socioeconomic status, in those with and without CHD was 1.02 (0.49, 2.11) among Europeans and 1.79 (1.01, 3.17) among South Asians. Antibodies against staphylococcal enterotoxins A and B were higher among South Asians than Europeans. CONCLUSIONS: The prevalence of H. pylori infection among UK South Asians does not reflect that of their countries of origin, nor their lower prevalence of gastric cancer. The association with CHD in South Asians requires corroboration in other studies.     

Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy.

OBJECTIVES: The purpose of our study was to characterize the penetrance of PKP2 mutations among family members of people with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and to examine clinical features and predictors of disease among PKP2 mutation carriers. BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy is an inherited cardiomyopathy characterized by fatty-fibrous myocardial replacement of the right ventricle, ventricular arrhythmias, and right ventricular dysfunction. Mutations in PKP2, the gene encoding plakophilin-2, are found in 11% to 43% of ARVD/C probands. METHODS: The study population was composed of 64 individuals in 9 families with an ARVD/C proband previously shown to carry a pathogenic PKP2 mutation. The diagnosis of ARVD/C was established based on task force criteria (TFC) set by the European Society of Cardiology. RESULTS: In addition to the probands, PKP2 mutations were present in 52% of relatives screened. Forty-nine percent of PKP2 mutation carriers met TFC. Among mutation carriers who did not meet full TFC, 50% met at least some TFC criteria besides family history. Pedigrees showed wide intra-familial variability, ranging from severe disease with early death to individuals who were completely asymptomatic late in life. Male PKP2 mutation carriers were more likely to have structural and conduction abnormalities as determined by imaging studies, signal-averaged electrocardiography, and 24-h ambulatory electrocardiography (p < 0.05). CONCLUSIONS: PKP2 mutations in a group of North American families with ARVD/C have both reduced penetrance and variable expressivity. Gender may have an influence on penetrance of PKP2 mutations, with male mutation carriers more likely to develop specific phenotypic manifestations of this disease.     

Cardiac pacemaker lead extraction using conventional techniques:a single centre experience

BACKGROUND: New methods of lead extraction using laser sheath devices are under evaluation but these techniques are not available in the majority of centres and have cost implications. Furthermore, in the absence of comparative randomised trials, registry experience with new devices must be judged against contemporary data using conventional methods. We report a single centre series of pacemaker lead extraction using conventional methods. METHODS: Study Population: Attempted extraction of 165 leads during 95 procedures in 80 patients. Leads had been in place (dwell time) for a mean of 76 months (range 0.2-248.4 months). Indications for lead extraction: infection (41.1%), skin erosion (9.5%), advisory leads (12.6%), faulty leads (12.6%), other (24.2%). Extraction techniques: traction and/or locking stylets and dilator sheaths (89.7%), Byrd workstation (6.1%) and open thoracotomy (4.8%). RESULTS: Complete removal was achieved for 143 leads (86.7%), partial removal in 12 leads (7.3%) and 10 (6.1%) could not be removed. A shorter lead dwell time was associated with extraction success in both univariate (p=0.0004) and multivariate analyses (p<0.0001). There was a trend for a higher rate of success in atrial rather than ventricular leads (93.2% v 80.9%, p=0.052). Active fixation, patient gender, age and indication for lead extraction had no bearing on outcome. Complications: There were no deaths. Major complications occurred in 3 patients (3.2%): pericardial tamponade (1), pulmonary embolus (1) and stroke (1). Significant bleeding (requiring blood transfusion) occurred in 11 procedures (12%). CONCLUSIONS: Cardiac lead extraction using conventional methods has a high success rate of 86.7%. Success was significantly related to a shorter lead dwell time. Further prospective randomised trials are needed to compare traditional techniques with laser extraction both in terms of clinical outcome and cost-effectiveness.     

Ethanol Suppresses Growth Hormone-Mediated Cellular Responses in Liver Slices

Previous studies indicate that both acute and chronic ethanol administration inhibit protein synthesis and decrease the secretion of insulin-like growth factor-1 (IGF-1). Although IGF-1 synthesis and secretion are regulated by growth hormone secretion from the pituitary gland, we assessed whether ethanol inhibits tissue response to growth hormone. Liver slices from male Sprague-Dawley rats were prepared, placed into F-12 media, and incubated at 37°C with [³H]leucine, and either 0.25 or 1 nM rat growth hormone and 0, 37 (physiological levels), or 175 mM (toxic levels) ethanol. Tissues were removed at 0,15,30, and 60 min. Protein synthesis increased linearly during this time period, and administration of growth hormone (1 nM) significantly increased protein synthetic rate by 48% ( p < 0.01), whereas addition of 37 or 175 mM ethanol attenuated the effects of growth hormone ( p < 0.01). Analysis of IGF-1 mRNA indicated a 2-fold increase in response to growth hormone ( p < 0.01), whereas ethanol administration decreased the growth hormone-induced rise of IGF-1 mRNA. Ethanol (175 mM) inhibited the release of IGF-1 into the media ( p < 0.05). Ethanol did not alter growth hormone receptor binding, and exposure of tissue slices to ethanol did not influence the number of growth hormone receptors or the affinity of growth hormone for its receptor.
Our results demonstrate that (1) growth hormone is a potent acute regulator of IGF-1 mRNA and IGF-1 peptide release, (2) ethanol inhibits growth hormone-induced protein synthesis and induction of IGF-1 gene expression, and (3) the inhibitory effects of ethanol on growth hormone occur without changing growth hormone receptor number or binding characteristics. We conclude that ethanol suppresses growth hormone-induced signal transduction, resulting in a decrease in IGF-1 gene expression.