Handgrip Strength Predicts Longitudinal Changes in Clock Drawing Test Performance. An Observational Study in a Sample of Older Non-Demented Adults.

OBJECTIVE: Impairment of physical performance might identify older people at higher risk of dementia over time. The present study evaluated handgrip strength as independent predictor of cognitive decline. DESIGN: Observational, prospective. Follow-up duration: 11.2 ± 0.8 months. SETTING AND PARTICIPANTS: Geriatric outpatients center. 104 consecutive stroke- and dementia-free older adults (44% men, ages 80.2 ± 5.4 years). METHODS: The Clinical Dementia Rating scale and the Clock Drawing Test (CDT) were administered. Handgrip strength was assessed using a Jamar hand dynamometer. Brain magnetic resonance imaging studies at 1.5 T were performed. White matter damage was expressed as severity of white matter hyperintensities (WMHs). Longitudinal changes in cognitive function were expressed as 1-year decline in CDT performance. RESULTS: A robust association was observed between baseline handgrip strength and 1-year cognitive decline after multiple adjustment. Of note, the strength of such association was only minimally attenuated after adjusting for deep WMHs extent (ß coefficient for handgrip strength = 0.183, SE= 0.038, p= 0.007, R2= 0.58). CONCLUSIONS: Handgrip strength predicted accelerated 1-year decline in cognitive function, assessed by CDT, in a sample of older adults. Future studies are needed to elucidate the causal mechanisms linking limitations in physical function with dementia risk.

Insulin effects on the left ventricle in older hypertensive subjects.

BACKGROUND: To evaluate the effects of hyperinsulinemia on left ventricular (LV) structure and function in older hypertensive subjects METHODS: Thirty-seven hypertensive subjects (17 men/20 women) aged 50 to 80, were studied. LV mass were evaluated echocardiographically according to the Penn convention. A 75-g oral glucose tolerance test (OGTT) was performed after overnight fasting, and both blood glucose and insulin concentrations were assayed at 0, 30, 60, 90, 120, and 180 minutes. Comparison between groups was performed by analysis of variance. A P value of .05 was considered statistically significant. RESULTS: When the hypertensive patients were divided into two groups according to the median value of 2-hour post-loading plasma insulin, there was no difference in blood pressure levels between the groups. However, hyperinsulinemic hypertensive subjects had an increased LV mass (P < .05), mean wall thickness, and interventricular septum thickness (P < .05 for both parameters) and had better systolic function-ejection and shortening fractions (P < .0001 for both indices). CONCLUSIONS: Hyperinsulinemia may be associated with increased left ventricular mass and with a better systolic performance in older hypertensive subjects.

Sex differences in correlates of steady state and pulsatile component of blood pressure.

1. The aim of the present study was to evaluate whether metabolic factors are linked to the steady component and the pulsatile component of blood pressure, evaluated as mean arterial pressure and pulse pressure respectively, in a sex-specific manner. 2. A cohort of 299 subjects (152 males, 147 females; 25-80 years of age) was studied. Patients presenting congestive heart failure, coronary insufficiency, severe valvular heart disease, neurological accident in the last 6 months, renal or respiratory failure, cancer, diabetes mellitus or acute infectious disease were excluded. None of the women was taking oral contraceptives or oestrogen supplementation. All cardioactive drugs were withdrawn at least 2 weeks before the subjects entered the study. 3. Men presented higher mean arterial pressure (120 +/- 15 compared with 115 +/- 16 mmHg, P < 0.01) and lower pulse pressure values (63 +/- 16 compared with 67 +/- 18 mmHg, P < 0.05) than women. In men, no significant relation between mean arterial pressure and the tested variables was detected; multiple regression analysis demonstrated that age contributed independently to the model for pulse pressure with a multiple r2 of 0.10 (P < 0.01). In women, body mass index contributed independently to the model for mean arterial pressure, with a multiple of 0.12 (P < 0.005); age and, to a lesser extent, body mass index, glycaemia and triglyceridaemia persisted as independent determinants of pulse pressure at the multiple regression analysis, with a multiple r2 of 0.20 (P < 0.001). 4. Our findings suggest that metabolic risk factors are associated differently with pulse pressure and mean arterial pressure values in the two sexes.

Is blood pressure the major determinant of left ventricular mass in subjects over 50 years of age?

The weak relation of systolic blood pressure to left ventricular (LV) mass in hypertension has frequently been regarded as evidence of non-hemodynamic stimuli to muscle growth. Anyway, left ventricular hypertrophy (LVH) is associated with a significantly increased risk for cardiovascular events. Data were obtained from M-mode echocardiograms in 10 normotensives and 58 hypertensives over 50 years (range 50-85 years); 18 hypertensives; were without (LVH -) and 40 were with LVH (LVH +) - when LV mass, normalized for body surface area, was calculated according to the Penn's Convention. Cardiac output was derived by Teicholz formula for LV volumes. End-systolic stress/end-systolic dimension ratio (ESS/ ESD r), an index of myocardial contractility, was calculated as previously validated in the literature. We found that, in subjects ranging from 50 to 85 years of age, the presence of LV hypertrophy is not necessarily associated with raised blood pressure levels. Systolic function was substantially preserved among the study groups, irrespective of their age, hypertensive condition and/or presence of LVH. The increased wall thickness in subjects with LVH was associated with a significant reduction in wall stress (thus suggesting an adequateness of the compensatory role of LVH - at least at the observed stage of the hypertrophy process) and with a significant decrease of the contractile performance. On the multivariate analysis, the observed relation of LV mass to blood pressure and myocardial contractility (r = 0.621, P < 0.001) may explain some apparently conflicting findings, such as the lack of LV hypertrophy in a number of hypertensive patients.

Platelet size and left ventricular hypertrophy in hypertensive patients over 50 years of age.

Both mean platelet volume (MPV) and left ventricular hypertrophy have been described as associated with increased risk for vascular events. Seventy-six hypertensive patients (37 M and 39 F) over 50 years of age were studied. They were divided into subgroups according to the presence of left ventricular hypertrophy (LVH = LV mass index > 125 g m-2, when LV mass was assessed by M-mode echocardiography according to Penn's Convention). MPV was 3% higher in hypertensive patients with LVH compared with those without LVH (P > 0.05) and it was associated with the occurrence of LVH (chi-square = 8.44, P = 0.042). MPV significantly correlated with left ventricular mass index (r = 0.298, P = 0.004) and interventricular septum thickness (r = 0.231, P = 0.022). Both correlations remained significant after adjustment for age, blood pressure and glycaemia. MPV seemed to be associated with increased left ventricular mass and interventricular septum thickness in middle-aged to elderly hypertensive patients.

Pulsatile versus steady-state component of blood pressure in elderly females: an independent risk factor for cardiovascular disease?

OBJECTIVE: To evaluate whether the pulsatile component of blood pressure can be a risk factor independent of the steady component in elderly females. DESIGN: Fifty-two elderly hypertensive female patients were compared with 32 normotensive control subjects of the same age. According to the results of that first study, a cohort of 126 elderly females was studied over a 3-year period to evaluate whether the pulsatile and steady-state components of blood pressure correlated with the same parameters and could predict the occurrence of cardiovascular events. RESULTS: In the first study the hypertensive patients with elevated pulse pressure had significantly higher triglycerides level and lower urinary sodium excretion than the hypertensive patients with lower pulse pressure and than the control subjects of the same age. The incidence of cardiovascular events over a 3-year period was significantly higher in the elderly hypertensive females with increased pulse pressure. In the cohort of 126 females mean arterial pressure (MAP) and pulse pressure did not show the same degree of correlation with the biological parameters tested (plasma triglycerides: MAP r = 0.162, P < 0.05; pulse pressure r = 0.314, P < 0.0005; urinary sodium excretion: MAP r = -0.365, P < 0.0001; pulse pressure r = -0.257, P < 0.002). Furthermore, for the same MAP level, patients with cardiovascular accidents in a 3-year period had significantly higher pulse pressure values. Pulse pressure (and not MAP) was a strong predictor of cardiovascular accidents. CONCLUSIONS: In elderly hypertensive females the pulsatile and the steady-state components of blood pressure did not correlate with the same biological parameters. Furthermore, the pulsatile component, when explored by pulse pressure, seemed to be a strong independent cardiovascular risk factor.

Plasma triglycerides and 24 hour urinary sodium excretion in elderly hypertensives. A pathogenetic connection?

Hypertension among the elderly generally represents a salt- sensitive state. However this salt-sensitivity does not appear to result from age-related increase in either sodium or salt intake. Since 20 years new trends seem to relate the role of sodium in the genesis of hypertension to a primary abnormality of electrolyte transport of cell membrane. Lipid abnormalities have also been described in untreated patients with high blood pressure. Plasma triglycerides were considerably higher (p < 0.01) in the hypertensives than in the controls. 24 hour sodium excretion was significantly lower (p < 0.0001) in hypertensives than in the controls. We have found a strong correlation among reduced sodium excretion, higher triglycerides and elevated blood pressure in the elderly. The blood pressure correlated negatively with 24 hour sodium excretion (p < 0.0001 for systolic and p < 0.002 for diastolic) and positively with plasma triglycerides (p < 0.0001 for systolic and p < 0.001 for diastolic). The poor literature regarding an association of these two alterations in human hypertensives makes our results provocative. We speculated that these alterations may be a facet of the insulin resistance commonly detectable in human hypertensives. However, further investigations are required to answer to this intriguing hypothesis.

Hypertension and atherosclerosis in the elderly: pathogenetic common mechanism and intervention strategies.

Hypertension is the leading cause of death in the elderly in Western countries. The Authors remark that hypertension is not only a purely hemodynamic phenomenon, but is a multifaceted disease frequently associated with metabolic disorders in the elderly. Among the latter, hyperinsulinism could be the linking pathogenetic factor with atherosclerosis progression. Then the Authors suggest a unitary pathogenetic hypothesis of hypertension and atherosclerosis. The crucial points are the inborn alteration of cellular sodium transport systems and the modulating action of environmental factors, first of all insulin. According to this hypothesis, the goal of the management of elderly hypertensives is the prevention of the fatal or invalidant cerebro- and cardiovascular event. To follow a good "pathogenetic" treatment of elderly hypertension and atherosclerotic process evolution, the first step is a dietetic approach avoiding acute load of sodium and lipids. Furthermore, the pharmacological treatment with calcium antagonists and ACE inhibitors is respectful of associated metabolic disorder and positively modulate the cellular sodium transport systems activity.

Cis-acting elements of the sea urchin histone H2A modulator bind transcriptional factors.

Functional tests, performed by microinjection into Xenopus laevis oocytes, show that a DNA fragment containing the modulator of the early histone H2A gene of Paracentrotus lividus enhances transcription of a reporter gene when located, in the physiological orientation, upstream of the tk basal promoter. Gel retardation and DNase I footprinting assays further reveal that the H2A modulator contains at least two binding sites [upstream sequence elements 1 and 2 (USE 1 and USE 2)] for nuclear factors extracted from sea urchin embryos, which actively transcribe the early histone gene set. Interestingly, USE 1 is highly homologous to a cis-acting element previously identified in the H2A modulator of Psammechinus miliaris [Grosschedl, R., Mächler, M., Rohrer, U. & Birnstiel, M. L. (1983) Nucleic Acids Res. 11, 8123-8136]. Finally, a cloned oligonucleotide containing the USE 1 sequence competes efficiently in Xenopus oocytes with the H2A modulator to prevent enhancement of transcription of the reporter gene. From these results, we conclude that USE 1 and perhaps USE 2 in the H2A modulator are upstream transcriptional elements that are recognized by trans-acting factors common to Xenopus and sea urchin.

DNA sequence and pattern of expression of the sea urchin (Paracentrotus lividus) alpha-tubulin genes.

To study the molecular aspects of the regulation of transcription of a multigene family, we have isolated and sequenced cDNA and genomic clones coding for the alpha-tubulin of the sea urchin Paracentrotus lividus. Two cDNA clones, P alpha 10 and P alpha 4, contain respectively the coding information for 391 C-terminal and for 338 N-terminal amino acids of the 452 residues that constitute the complete protein. They show silent nucleotide substitutions only, suggesting that P alpha 10 and P alpha 4 represent the cloned copies of two allelic gene transcripts, which encode for two alpha-tubulin isoforms with identical amino acid sequence in the region of the overlap. The comparison of the predicted amino acid sequence of the composite P alpha 4-10 and of the mouse M alpha-6 (Villasante et al., Mol Cell Biol 1986; 6:2409-2419) reveals a conservation of 97% between the two polypeptides. By RNA blotting hybridization six major alpha-tubulin transcripts were identified. Two, of 3.5 kb and 2.0 kb, are expressed in the unfertilized eggs and during early cleavage. The other two maternal mRNAs, of 2.4 kb and 1.8 kb, are expressed in both early and late cleavage embryos, but in the intestine the 1.8 kb RNA, which specifically reacted with the 3' specific probe of the P alpha 10 cDNA, is the only transcript detected. Finally, the 1.5 kb and 1.9 kb mRNAs represent the transcription of stage- and tissue-specific genes, respectively. In fact, the former becomes detectable at blastula stage and accumulates during late development, whereas the latter is found in the testis only. The sequence data of the 3' terminus of the alpha-3 genomic clone suggests that it encodes for a divergent alpha-tubulin, and it most probably corresponds to the testis-specific gene.

Different micrococcal nuclease cleavage patterns characterize transcriptionally active and inactive sea-urchin histone genes.

The micrococcal nuclease cleavage sites have been mapped in the H2A coding and flanking regions of the sea-urchin histone DNA chromatin. A hypersensitive area, centered around - 100 base pairs from the H2A starting site, is found only in embryos actively transcribing the alpha-subtype histone genes. In mesenchyme blastula embryos, upon inactivation of the H2A gene, this region becomes protected while two other areas, near the transcription starting site and in the proximity of the 3' palindromic sequence, become preferential targets for the enzyme. Analysis of the pattern of micrococcal nuclease cleavage on the same region of the histone gene cluster in sperm and late blastula chromatin and on the corresponding segment of protein-free DNA indicates that distinct nucleosomal arrangements characterize the histone genes in the two cell populations.

Synthesis of heat shock proteins in dissociated sea urchin embryonic cells.

Embryos dissociated into cells retain the stage-specific response to heat shock. The dissociated cells, irrespectively of whether they are reaggregated or not, undergo the developmental changes in their ability to respond to heat shock, at the same time as the entire embryos. The conclusion of the present experiments is that sea urchin embryonic cells become responsive to heat shock and produce heat shock proteins even in the absence of cell interactions.

Heat-shock proteins in sea urchin embryos. Transcriptional and posttranscriptional regulation.

The production of heat-shock proteins in sea urchin embryos is accompanied by the appearance at the polysomal level of their relative mRNAs, as shown by their translation in a cell-free system; thus suggesting that the regulation of their production occurs at a transcriptional level. The mechanism for the inhibition of the bulk protein synthesis and for its reversal on the other hand should be looked for at a posttranscriptional level, since both these phenomena occur also in the presence of actinomycin D. The heat-shock proteins produced as early as at the mesenchyme blastula stage persist within the embryo at least till the pluteus stage.

Archenteron cells are responsible for the increase in ribosomal RNA synthesis in sea urchin gastrulae.

Paracentrotus lividus embryos were continuously labeled with P32 from hatching blastula to pluteus. The archenteron cells were then separated from the rest of the embryo and the radioactivity accumulated into the ribosomal RNA of the two cell groups measured. The results clearly indicate that the bulk of ribosomal RNA is mainly if not entirely, synthesized in this time interval by the archenteron cells.

DNA amplification in sea urchin oocytes.

In situ hybridization of ribosomal RNA withParacentrotus lividus ovaries suggests that ribosomal DNA undergoes amplification in the mononucleolate oocytes of this sea urchin.