Prognostic value of cardiac troponin I assay in hospitalized elderly patients.

BACKGROUND: Cardiac troponin I (cTnI) has been poorly studied in elderly inpatients. AIM: This study wanted to assess factors influencing the increase in cTnI and its prognostic value in hospitalized elderly patients. METHODS: 354 elderly (mean age of 84.8 ± 6.9 years) patients consecutively admitted in the Geriatrics Division in Padua were tested for cTnI levels assay during the hospital stay. Number of subsequent patient deaths at 6 months and 2 years were registered. RESULTS: Of the 354 patients, 27 (7.6%) died in hospital; their levels were not significantly higher or more frequently positive on cTnI than those of the remainder of the sample. 71 (20.01%) patients died within 6 months of being discharged, and in-hospital positive cTnI levels emerged as a mortality risk factor in this group [unadjusted HR 1.13 (1.04-1.23); p = 0.004]. At 2 years, a total of 174 patients (49.2%) had died, but in-hospital pathological cTnI levels were not a mortality risk factor in this group. DISCUSSION: It should be noted that cTnI level was a risk factor for mortality at 6 months but no longer at 2 years after an elderly patient's hospitalization. This finding may relate to patients' limited physiological reserves or be driven by the fact that the elderly tend to receive fewer evidence-based treatments, and to be managed more conservatively than younger patients. CONCLUSIONS: In the multidimensional analysis of older patients, troponin I can be used to stratify patients and assess mortality risk at 6 months, but not at 2 years.

Effect of restoring sinus rhythm in hypertensive patients with atrial fibrillation undergoing electrical cardioversion.

INTRODUCTION: Little is known about the effects of atrial fibrillation (AF) on blood pressure (BP) levels in hypertensive patients. Some studies suggest a role for rhythm control in managing such patients' BP, but the improvement observed in cardiac performance after restoring sinus rhythm (SR) may coincide with an increase in BP. The aim of this study was to apply ambulatory BP monitoring to analyze BP changes in hypertensive patients after electrical cardioversion for persistent AF. METHODS AND RESULTS: The study included 54 hypertensive patients with persistent AF. Ambulatory BP monitoring was performed on the day before electrical cardioversion and again about a month later under conditions of stable medical treatment.Patients with a SR at follow-up (n=34) had significantly higher 24-h, night-time (P<0.05), and daytime (P=0.074) systolic BP, and significantly lower 24-h, daytime (P<0.05), and night-time (P=0.078) DBP. The number of patients with nocturnal dipping decreased from 20 to 14 and the number of those with reverse dipping increased from 1 to 7. Patients with recurrent AF at follow-up (n=20) showed no significant BP changes, except for a decrease in the mean night-time DBP. CONCLUSION: Restoring SR in hypertensive patients with AF led to a significant increase in their systolic BP (especially at night) and a decrease in their DBP. Hypertensive patients with AF should consequently undergo ambulatory BP monitoring after electrical cardioversion for the purpose of adjusting their antihypertensive treatment.

Reliability of Oscillometric Blood Pressure Monitoring in Atrial Fibrillation Patients Admitted for Electric Cardioversion.

The reliability of automated oscillometric blood pressure (BP) monitors in atrial fibrillation (AF) has been poorly investigated, only comparing different patients with AF and sinus rhythm (SR), and is a method influenced by individual characteristics. This study compared the reliability of the oscillometric device A&D TM-2430 (A&D Company, Tokyo, Japan) with that of a mercury sphygmomanometer in AF patients whose SR was restored after electric cardioversion (ECV). Three consecutive BP measurements were obtained on the day before and about 30 days after ECV in stable treatment conditions. Of the 100 patients studied, 63 reported an SR at follow-up, with a significant increase in systolic BP and a significant decrease in diastolic BP according to both devices. There were no significant differences between the systolic and diastolic biases before and after ECV using Bland Altman analysis (P > .05 each). The oscillometric device analyzed, using three repeated measurements, is reliable in measuring BP in AF patients.

Ambulatory blood pressure monitoring in elderly patients with chronic atrial fibrillation: is it absolutely contraindicated or a useful tool in clinical practice and research?

The aim of this study was to test whether ambulatory blood pressure monitoring (ABPM) in elderly patients with atrial fibrillation (AF) is as feasible and reliable as ABPM is in patients with normal sinus rhythm (SR). Studies of ABPM in the elderly remain limited, and the use of this method in patients with AF remains controversial. The Italian SIIA 2008 guidelines consider ABPM 'absolutely contraindicated' for AF patients. This study was conducted on 200 hospitalized patients aged ≥ 65 years (68% females; mean age 82.4 ± 6.3 years): 100 patients with SR and 100 patients with permanent AF. Each patient completed serial blood pressure (BP) measurements with a clinical sphygmomanometer (Sphyg) and ABPM. Differences in mean heart rate (HR) between patient groups were not statistically significant. A total of 99.5% of patients were hypertensive. There were no significant differences between SR and AF patients in mean systolic BP (SBP) and diastolic BP (DBP) values, as measured with the Sphyg or by ABPM. Compared with the Sphyg, errors associated with BP measurements obtained by ABPM did not significantly differ between the two groups. ABPM proved to be as feasible as Sphyg measurements in both AF patients (intraclass correlation coefficients=0.73, 0.67 and 0.74 for SBP, DBP and HR, respectively) and SR patients (intraclass correlation coefficients=0.74, 0.58 and 0.67 for SBP, DBP and HR, respectively). A Bland-Altman plot analysis confirmed that there was good agreement between the two methods. Stable AF (HR 60-100 b.p.m.) should not be considered as an absolute contraindication for the use of ABPM, even in the elderly; it could be a 'relative' contraindication for very unstable AF patients.

Full penetrance of Morgagni-Stewart-Morel syndrome in a 75-year-old woman: case report and review of the literature.

CONTEXT: Morgagni-Stewart-Morel syndrome is defined as the presence of hyperostosis frontalis interna, variably associated with metabolic, endocrine, and neuropsychiatric disorders. The possible cause-effect relationship of these associations remains uncertain. CASE PRESENTATION: A 75-year-old woman presented with severe frontal headache and a history of psychotic disorders. On instrumental examination she was found to have extensive frontal hyperostosis and cortical atrophy. These findings, associated to the metabolic and neuropsychiatric pattern of the patient, are consistent with a high penetrance of Morgagni-Stewart-Morel syndrome. EVIDENCE ACQUISITION AND SYNTHESIS: In this clinical case seminar, we summarize the current understanding of the association between hyperostosis frontalis interna and Morgagni-Stewart-Morel, based on a MEDLINE search (case reports, original articles, and reviews published between 1928 and 2011) on this topic. Possible pathophysiological mechanisms underlying both the headache and the hyperostosis frontalis interna are discussed. CONCLUSION: A case of full penetrance of Morgagni-Stewart-Morel syndrome is reported, presenting many of the clinical features described in the literature. Metabolic and endocrine dysfunctions should be interpreted not only as isolated components of the syndrome, but also as the reason behind its pathogenesis. Endocrine or nutritional disorders may have led to an altered bone metabolism with frontal bone apposition. On the other hand, the severity of our patient's neurological and psychiatric symptoms correlates well with the severity of her hyperostosis frontalis interna and the cortical atrophy.

Intracellular NAD(H) levels control motility and invasion of glioma cells.

Oncogenic transformation involves reprogramming of cell metabolism, whereby steady-state levels of intracellular NAD(+) and NADH can undergo dramatic changes while ATP concentration is generally well maintained. Altered expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD(+)-salvage, accompanies the changes in NAD(H) during tumorigenesis. Here, we show by genetic and pharmacological inhibition of NAMPT in glioma cells that fluctuation in intracellular [NAD(H)] differentially affects cell growth and morphodynamics, with motility/invasion capacity showing the highest sensitivity to [NAD(H)] decrease. Extracellular supplementation of NAD(+) or re-expression of NAMPT abolished the effects. The effects of NAD(H) decrease on cell motility appeared parallel coupled with diminished pyruvate-lactate conversion by lactate dehydrogenase (LDH) and with changes in intracellular and extracellular pH. The addition of lactic acid rescued and knockdown of LDH-A replicated the effects of [NAD(H)] on motility. Combined, our observations demonstrate that [NAD(H)] is an important metabolic component of cancer cell motility. Nutrient or drug-mediated modulation of NAD(H) levels may therefore represent a new option for blocking the invasive behavior of tumors.

Cancer cell metabolism regulates extracellular matrix degradation by invadopodia.

Transformed cancer cells have an altered metabolism, characterized by a shift towards aerobic glycolysis, referred to as 'the Warburg phenotype'. A change in flux through mitochondrial OXPHOS and cytosolic pathways for ATP production and a gain of capacity for biomass production in order to sustain the needs for altered growth and morphodynamics are typically involved in this global rewiring of cancer cell metabolism. Characteristically, these changes in metabolism are accompanied by enhanced uptake of nutrients like glucose and glutamine. Here we focus on the relationship between cell metabolism and cell dynamics, in particular the formation and function of invadopodia, specialized structures for focal degradation of the extracellular matrix. Since we recently found presence of enzymes that are active in glycolysis and associated pathways in invadopodia, we hypothesize that metabolic adaptation and invadopodia formation are linked processes. We give an overview on the background for this idea and show for the first time that extracellular matrix degradation by invadopodia can be differentially manipulated, without effects on cell proliferation, by use of metabolic inhibitors or changes in nutrient composition of cell culture media. We conclude that cell metabolism and carbohydrate availability, especially pyruvate, are involved in fuelling of invadopodia formation and activity.

Diabetes in a geriatric ward: efficacy and safety of new insulin analogs in very old inpatients.

AIMS: 1) to evaluate the prevalence of diabetes mellitus (DM) in a geriatric ward; 2) to assess the efficacy and safety of insulin analogs in elderly inpatients over 65 years of age. METHODS: We analysed the medical records of 1851 elderly inpatients admitted to our geriatric clinic from March 2009 to September 2011, to identify patients with DM. The efficacy and safety of insulin analogs were measured in patients with a hospital stay of at least 9 days, by assessing the means of all glycemic sticks (4-7 sticks/day), number of hyperglycemic events (>250 mg/dL) and number of hypoglycemic events (<70 mg/dL) daily. RESULTS: DM prevalence was 25% (463/1851). Diabetic patients' mean age was 82.9 ± 7.5 years. DM mortality during hospital stay was 10.8% vs 6.7% for non-diabetics (p<0.05). 206/463 diabetic inpatients were treated with insulin, and 85.9% of them received analogs (Rapid and Longer-Acting). Decreases in mean daily glycemia values (from 218.8 ± 81.6 mg/dL to 170.9 ± 42.9 mg/dL, p<0.001) and in number of hyperglycemic events (from 118 to 47) (p<0.012) were noted in 128 insulin analog-treated patients over the 9-day hospitalization. Only 35 hypoglycemic events were found out of 4745 sticks (0.7%). CONCLUSIONS: 1) DM prevalence and mortality in our very old inpatients are high and similar to data reported in the literature. 2) Insulin therapy with analogs is effective (achieves good glycemic control) and safe (low rate of hypoglycemia) even in these frail, very old inpatients.

Novel invadopodia components revealed by differential proteomic analysis.

When highly invasive cancer cells are cultured on an extracellular matrix substrate, they extend proteolytically active membrane protrusions, termed invadopodia, from their ventral surface into the underlying matrix. Our understanding of the molecular composition of invadopodia has rapidly advanced in the last few years, but is far from complete. To accelerate component discovery, we resorted to a proteomics approach by applying DIfference Gel Electrophoresis (DIGE) to compare invadopodia-enriched sub-cellular fractions with cytosol and cell body membrane fractions and the whole cell lysate. The fractionation procedure was validated through step-by-step monitoring of the enrichment in typical actin-related invadopodia-associated proteins. After statistical analysis, 129 protein spots were selected for peptide mass fingerprinting analysis; of these 76 were successfully identified and found to correspond to 58 proteins belonging to different functional classes including aerobic glycolysis and other metabolic pathways, protein synthesis, degradation and folding, cytoskeletal components and membrane-associated proteins. Finally, validation of a number of identified proteins was carried out by a combination of immuno-blotting on cell fractions and immunofluorescence localization at invadopodia. These results reveal newly identified components of invadopodia and open further avenues to the molecular study of invasive growth behavior of cancer cells.

Outcome after acute ischemic stroke (AIS) in older patients: effects of age, neurological deficit severity and blood pressure (BP) variations.

The goal of this study was to examine the relationship between BP variations and neurological deficit outcome in old-old patients after AIS. Fifty-four patients (66-96 years), admitted consecutively for stroke were assessed, using a non-invasive BP monitoring (NIBPM), measuring mean systolic (SBP) and diastolic (DBP) blood pressure and their variation between days 1 and 7. Neurological assessment and cognitive function were evaluated using the NIH stroke Scale (NIHSS) and the short portable mental status Questionnaire (SPMSQ), respectively. Functional status was assessed using the modified Rankin scale (RS) and the Barthel index (BI). NIHSS on the 1st day positively correlated with SPMSQ score and with BI on day 21. The NIHSS variation (ΔNIHSS) between days 21 and 1 negatively correlated with mean 24-h BP change between days 7 and 1 (r=-0.59 for DBP and r=-0.54 for SBP; p<0.001). Age, severity of stroke at admission, history of hypertension, atrial fibrillation (AF) and BP levels at admission were not correlated to ΔNIHSS. An inverse correlation between the decrease of 24-h BP within the first week and ΔNIHSS suggests prudence in lowering BP in the acute phase of stroke in elderly.

Lignin chemistry: biosynthetic study and structural characterisation of coniferyl alcohol oligomers formed in vitro in a micellar environment.

Model coniferyl alcohol lignin (the so-called dehydrogenative polymerisate, DHP) was produced in water under homogeneous conditions guaranteed by the presence of a micellised cationic surfactant. A complete study of the activity of the enzymatic system peroxidase/H(2)O(2) under our reaction conditions was reported and all the reaction products up to the pentamer were characterised by (1)H NMR spectroscopy and ESI mass spectrometry. Our system, and the molecules that have been generated in it, represent a closer mimicry of the natural microenvironment since an enzyme, under micellar conditions, reproduces the cell system better than in buffer alone. On the basis of the oligomers structures a new biosynthetic perspective was proposed that focused attention on a coniferyl alcohol dimeric quinone methide as the key intermediate of the reaction. A formal, strictly alternate sequence of a radical and an ionic step underlines the reaction, thus generating ordered oligolignols structures. Alternatively to other model lignins, our olignols present a lower degree of radical coupling between oligomeric units. This offers a closer biosynthetic situation to the observation of a low rate of radical generation in the cell wall.

Cell and molecular biology of invadopodia.

The controlled degradation of the extracellular matrix is crucial in physiological and pathological cell invasion alike. In vitro, degradation occurs at specific sites where invasive cells make contact with the extracellular matrix via specialized plasma membrane protrusions termed invadopodia. Considerable progress has been made in recent years toward understanding the basic molecular components and their ultrastructural features; generating substantial interest in invadopodia as a paradigm to study the complex interactions between the intracellular trafficking, signal transduction, and cytoskeleton regulation machineries. The next level will be to understand whether they may also represent valid biological targets to help advance the anticancer drug discovery process. Current knowledge will be reviewed here together with some of the most important open questions in invadopodia biology.

Faciogenital dysplasia protein Fgd1 regulates invadopodia biogenesis and extracellular matrix degradation and is up-regulated in prostate and breast cancer.

Invadopodia are proteolytically active membrane protrusions that extend from the ventral surface of invasive tumoral cells grown on an extracellular matrix (ECM). The core machinery controlling invadopodia biogenesis is regulated by the Rho GTPase Cdc42. To understand the upstream events regulating invadopodia biogenesis, we investigated the role of Fgd1, a Cdc42-specific guanine nucleotide exchange factor. Loss of Fgd1 causes the rare inherited human developmental disease faciogenital dysplasia. Here, we show that Fgd1 is required for invadopodia biogenesis and ECM degradation in an invasive cell model and functions by modulation of Cdc42 activation. We also find that Fgd1 is expressed in human prostate and breast cancer as opposed to normal tissue and that expression levels matched tumor aggressiveness. Our findings suggest a central role for Fgd1 in the focal degradation of the ECM in vitro and, for the first time, show a connection between Fgd1 and cancer progression, proposing that it might function during tumorigenesis.

Invadopodia biogenesis is regulated by caveolin-mediated modulation of membrane cholesterol levels.

Invadopodia are proteolytically active protrusions formed by invasive tumoural cells when grown on an extracellular matrix (ECM) substratum. Clearly, invadopodia are specialized membrane domains acting as sites of signal transduction and polarized delivery of components required for focalized ECM degradation. For these reasons, invadopodia are a model to study focal ECM degradation by tumour cells. We investigated the features of invadopodia membrane domains and how altering their composition would affect invadopodia biogenesis and function. This was achieved through multiple approaches including manipulation of the levels of cholesterol and other lipids at the plasma membrane, alteration of cholesterol trafficking by acting on caveolin 1 expression and phosphorylation. We show that cholesterol depletion impairs invadopodia formation and persistence, and that invadopodia themselves are cholesterol-rich membranes. Furthermore, the inhibition of invadopodia formation and ECM degradation after caveolin 1 knock-down was efficiently reverted by simple provision of cholesterol. In addition, the inhibitory effect of caveolin 3(DGV) expression, a mutant known to block cholesterol transport to the plasma membrane, was similarly reverted by provision of cholesterol. We suggest that invadopodia biogenesis, function and structural integrity rely on appropriate levels of plasma membrane cholesterol, and that invadopodia display the properties of cholesterol-rich membranes. Also, caveolin 1 exerts its function in invadopodia formation by regulating cholesterol balance at the plasma membrane. These findings support the connection between cholesterol, cancer and caveolin 1, provide further understanding of the role of cholesterol in cancer progression and suggest a mechanistic framework for the proposed anti-cancer activity of statins, tightly related to their blood cholesterol-lowering properties.