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PubMed1993

Chaperonin from Thermus thermophilus can protect several enzymes from irreversible heat denaturation by capturing denaturation intermediate.

Chaperonin isolated from Thermus thermophilus is stable up to 80 degrees C. Taking advantage of this heat stability, we have studied the effects of chaperonin on heat denaturation of several relatively heat labile enzymes. When the enzymes are incubated at their denaturating temperatures, the presence of T. thermophilus chaperonin in the solution has little effect on the rate of apparent inactivation of the enzyme. However, this inactivation is not irreversible since most activity is recovered when the solution is shifted to the second incubation at a moderate temperature with concomitant addition of MgATP. When the chaperonin is omitted from the solution, no recovery is observed. Recovery of the activity is also dependent on MgATP in the second incubation and 50% of recovery is attained at 5 microM MgATP. When the chaperonin is added after starting the incubation at a denaturing temperature, recovery of the activity becomes poorer as the delay of chaperonin addition increases. The critical temperature of the incubation at which irreversible denaturation occurs to the enzymes is elevated 8-15 degrees C by inclusion of T. thermophilus chaperonin in the solution. The heat stability of captured proteins by the chaperonin, assessed as retention of the ability to resume productive folding under optimal conditions, is measured more accurately using chemically produced folding intermediate-chaperonin complexes. The ability is lost at about 78 degrees C being irrespective of variable heat stability of individual enzymes. These results indicate that during heat denaturation proteins assume a common structure which is recognizable by the chaperonin. Once a protein with this structure is captured by T. thermophilus chaperonin, it retains the ability to resume productive folding even after exposure to the otherwise denaturing high temperature. Its heat stability seems to be limited solely by heat stability of chaperonin.

Adenosine Triphosphate↗
PubMed1999

Variability and evolution of Kaposi's sarcoma-associated herpesvirus in Europe and Africa. International Collaborative Group.

OBJECTIVE: To study the evolution of Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus type 8 in Europe and Africa. DESIGN AND METHODS: PCR and sequence analysis of the variable viral membrane glycoprotein gene K1 in 58 tumour and peripheral blood samples from patients with AIDS-related Kaposi's sarcoma (KS), 'classic' (HIV-negative) KS, transplant KS, Multicentric Castleman's Disease, other lymphoproliferative disorders, and healthy KSHV-infected individuals from the UK, Denmark, Sweden, Italy, Spain, Iceland, The Faroe Islands, Greece, The Gambia and Uganda. RESULTS: Three major groups of K1 sequences were found: A, B and C, as defined previously. The K1 gene has evolved, both within and between these three groups, under positive selection. KSHV group B strains predominate in Africa and are more distant from groups A and C, found in Europe, than A and C are from each other. Within group C two subgroups, C' and C", can be identified. Subgroup C" is more closely related to group A in a region of the K1 protein and appears to be phylogenetically close to the branchpoint between A and C. Group A and C strains are currently found in both HIV-1-infected and -uninfected Europeans, and were already present in Europe before the start of the AIDS epidemic. We found some examples of closely related K1 sequences in Italy and Denmark, but in general KSHV strains in Europe did not cluster geographically. CONCLUSION: KSHV strains in East and West Africa are closely related but phylogenetically distant from those in Europe. The two major KSHV groups in Europe are more closely related, with some strains adopting an intermediate phylogenetic position. In Europe, KSHV strains may have been disseminated at least several decades ago. Variability in the K1 region is driven by selection and does not correlate with different KSHV-related pathologies or geographic regions where clinically more aggressive HIV-negative KS ('endemic' KS) is more common.

AIDS-Related Opportunistic Infections↗
PubMed2005

Mortality assessment in intensive care units via adverse events using artificial neural networks.

OBJECTIVE: This work presents a novel approach for the prediction of mortality in intensive care units (ICUs) based on the use of adverse events, which are defined from four bedside alarms, and artificial neural networks (ANNs). This approach is compared with two logistic regression (LR) models: the prognostic model used in most of the European ICUs, based on the simplified acute physiology score (SAPS II), and a LR that uses the same input variables of the ANN model. MATERIALS AND METHODS: A large dataset was considered, encompassing forty two ICUs of nine European countries. The recorded features of each patient include the final outcome, the case mix (e.g. age) and the intermediate outcomes, defined as the daily averages of the out of range values of four biometrics (e.g. heart rate). The SAPS II score requires 17 static variables (e.g. serum sodium), which are collected within the first day of the patient's admission. A nonlinear least squares method was used to calibrate the LR models while the ANNs are made up of multilayer perceptrons trained by the RPROP algorithm. A total of 13,164 adult patients were randomly divided into training (66%) and test (33%) sets. The two methods were evaluated in terms of receiver operator characteristic (ROC) curves. RESULTS: The event based models predicted the outcome more accurately than the currently used SAPS II model (P<0.05), with ROC areas within the ranges 83.9-87.1% (ANN) and 82.6-85.2% (LR) versus 80% (LR SAPS II). When using the same inputs, the ANNs outperform the LR (improvement of 1.3-2%). CONCLUSION: Better prognostic models can be achieved by adopting low cost and real-time intermediate outcomes rather than static data.

Decision Trees↗
PubMed1985

Psychosocial and physiological factors in relation to blood pressure at rest--a study of Swedish men in their upper twenties.

The interrelationships between psychosocial factors, several physiological variables and blood pressure (BP) were investigated in 88 young men (aged 26-32 years) in whom high, intermediate or low BP had been recorded at the age of 18 years. In the original high BP group, venous plasma noradrenaline was normal but adrenaline levels elevated. At the follow-up adrenaline correlated with systolic blood pressure (SBP), and this was also so after controlling for overweight and serum gamma-glutamyltranspeptidase [gamma-GT, a marker for alcohol consumption, which showed an independent association with diastolic blood pressure (DBP)]. Low assertiveness (low scores of verbal and indirect aggression) correlated with high BPs, even after controlling for other psychosocial variables. Several associations between psychosocial job variables and physiological variables were found. Among self-reported job variables, excessive 'demands' and 'bossing others' (but not 'decision latitude' or 'psychosocial conflict') were associated with high SBP. Habitual smoking of cigarettes was not associated with BP at rest, but influenced several associations between psychosocial and physiological variables. Men with high BP at rest and low plasma renin activity (PRA) reported more psychosocial problems at work and lower assertiveness than other groups.

Adult↗
PubMed1999

Pharmacokinetics and pharmacodynamics of Ro 44-3888 after single ascending oral doses of sibrafiban, an oral platelet aggregation inhibitor, in healthy male volunteers.

AIMS: This study constituted the first administration of the oral platelet inhibitor, sibrafiban, to humans. The aim was to investigate the pharmacokinetics and pharmacodynamics of Ro 44-3888, the active principle of sibrafiban, after single ascending oral doses of sibrafiban. Particular emphasis was placed on intersubject variability of the pharmacokinetic and pharmacodynamic parameters of Ro 44-3888. METHODS: The study consisted of three parts. Part I was an open ascending-dose study to determine target effect ranges of sibrafiban. Part II, a double-blind, placebo-controlled, parallel-group study, addressed the intersubject variability of pharmacokinetic and pharmacodynamic parameters of the active principle at a sibrafiban dose achieving an intermediate effect. Part III was a double-blind, placebo-controlled, ascending-dose design covering the complete plasma concentration vs pharmacodynamic response curve of sibrafiban. RESULTS: At sibrafiban doses between 5 mg and 12 mg, the pharmacokinetics of free Ro 44-3888 in plasma were linear whereas those of total Ro 44-3888 were non-linear because of the saturable binding to the glycoprotein IIb-IIIa receptor. Saturation of the GP IIb-IIIa receptor was reached at plasma concentrations of 15.9 ng ml-1. At sibrafiban doses up to 2 mg, ADP-induced platelet aggregation was inhibited by 50%, whereas the inhibition of TRAP-induced platelet aggregation was about 20-30%. At the higher doses, ADP-induced platelet aggregation was almost completely inhibited while a clear dose-response could be observed with TRAP-induced inhibition of platelet aggregation at sibrafiban doses of 5 to 12 mg. Ivy bleeding time increased very steeply with dose with a significant prolongation observed at doses of 5 to 7 mg of sibrafiban (5-7 min, >30 min in one case). At a sibrafiban dose of 12 mg, the stopping criterion for dose escalation (prolongation of the Ivy bleeding time >30 min in three out of four subjects per dose group) was reached. The interindividual coefficients of variation of the integrated pharmacokinetic and pharmacodynamic parameters (AUC and AUE) were below 20%, thus lying well within the pre-set level of acceptance. CONCLUSIONS: With a low intersubject variability of its pharmacokinetic and pharmacodynamic parameters, linear pharmacokinetics and pharmacodynamic effects closely related to its plasma concentrations, Ro 44-3888 has good pharmacological prerequisites for a well controllable therapy of secondary prevention of arterial thrombosis in patients with acute coronary syndrome.

Adenosine Diphosphate↗
PubMed1985

A study of the variability in the febrile responses of rabbits to endogenous pyrogen.

The range of body temperature increases elicited by a standard dose of endogenous pyrogen (0.5 ml/kg iv) was examined in a population of 26 male New Zealand White rabbits. Although the mean maximum increase in rectal temperature was 0.88 +/- 0.06 degree C (SE), individual responses varied from 0.4 degree to 1.5 degree C. Three representative animals that responded to the standard dose of pyrogen with small, intermediate, and large febrile responses were selected and challenged with the same dose of pyrogen on eight separate occasions, and the variability of these responses was examined. There was little variability within the characteristic responses of any particular animal to the repeated challenges. The variability of the febrile responses elicited by both intravenous and intracerebroventricular administration of the same pyrogen was examined and compared using another group of 11 rabbits. The variability in response to the intravenous route was similar to that found in the larger population, whereas the variation in response to the intracerebroventricular route was smaller, and all 11 animals had fevers that were greater than 1 degrees C. It is concluded that the variability of the febrile responses of rabbits to intravenous pyrogen was due to differences between individual sensitivities of animals to the intravenously administered pyrogen. This difference in sensitivity may be due to a difference in the amount of pyrogen that reaches the putative receptor sites, or to a difference in the density or effectiveness of receptor sites in translating the pyrogenic stimulus into a fever response.

Animals↗
PubMed1996

Immediate effects of lung transplantation on right ventricular morphology and function in patients with variable degrees of pulmonary hypertension.

OBJECTIVES: This study sought to determine the immediate effects of lung transplantation on right ventricular morphology and function in patients with variable degrees of pulmonary hypertension and to evaluate these features as potential markers of immediate outcome. BACKGROUND: Selected lung transplant recipients with severe preoperative pulmonary hypertension have previously been shown to have a reduction in right ventricular size and improved function at follow-up evaluation. METHODS: Thirty-two consecutive patients (mean [+/- SD] age 44 +/- 11 years) were prospectively classified into three groups according to their pretransplantation pulmonary artery systolic pressure: severe pulmonary hypertensive group > or = 75 mm Hg, intermediate pulmonary hypertensive group 40 to 74 mm Hg and non-pulmonary hypertensive group < 40 mm Hg. Hemodynamic and transesophageal echocardiographic variables were measured immediately before and after lung transplantation. RESULTS: Pulmonary artery systolic and mean pressures markedly decreased after transplantation in the severe pulmonary hypertensive group (from 115 +/- 26 to 45 +/- 19 mm Hg and from 76 +/- 14 to 31 +/- 11 mm Hg, respectively, both p < 0.05). Mean pulmonary artery pressure decreased in the intermediate group (from 34 +/- 7 to 26 +/- 7 mm Hg, p < 0.05). Right ventricular end-diastolic area, end-systolic area and eccentricity index decreased in the severe pulmonary hypertensive group after transplantation. End-diastolic area also decreased in the intermediate pulmonary hypertensive group. Right ventricular fractional area change was not significantly different between groups and did not change consistently after transplantation. Three patients with severe pulmonary hypertension who had continued depression of right ventricular function after transplantation died in the immediate postoperative period. CONCLUSIONS: Lung transplantation is associated with an immediate decrease in pulmonary artery pressures and right ventricular size and normalization of septal geometry but variable changes in right ventricular function. Continued depression of right ventricular fractional area change may be a potential marker of poor outcome.

Adult↗
PubMed2005

Characterization of a highly variable eutherian microRNA gene.

Mouse microRNAs (miRNAs) miR-290-miR295 are encoded by a cluster of partially homologous pre-miRNA hairpins and are likely to be functionally important in embryonic stem (ES) cells and preimplantation embryos. We present evidence that a spliced, capped, and polyadenylated primary transcript spans this entire Early Embryonic microRNA Cluster (EEmiRC). Partial Drosha processing yields additional large nuclear RNA intermediates. A conserved promoter element containing a TATA-box directs EEmiRC transcription. Sequence analysis shows that the EEmiRC transcription unit is remarkably variable and can only be identified bioinformatically in placental (eutherian) mammals. Consistent with eutherian-specific function, EEmiRC is expressed in trophoblastic stem (TS) cells. When analyzing evolutionary and functional relationships, the organization of the entire miRNA loci should be considered in addition to the mature miRNA sequences. Application of this concept suggests that EEmiRC is a recently acquired rapidly evolving gene important for eutherian development.

Animals↗
PubMed1997

The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia.

The dominant cerebellar ataxias (ADCAs) represent a clinically and genetically heterogeneous group of disorders linked by progressive deterioration in balance and coordination. The utility of genetic classification of the ADCAs has been highlighted by the striking variability in clinical phenotype observed within families and the overlap in clinical phenotype observed between those with different genotypes. The recent demonstration that spinocerebellar ataxia type 2 (SCA2) is caused by a CAG repeat expansion within the ataxin-2 gene has allowed us to determine the frequency of SCA2 compared with SCA1, SCA3/Machado-Joseph disease (MJD), and dentatorubropallidoluysian atrophy (DRPLA) in patients with sporadic and inherited ataxia. SCA2 accounts for 13% of patients with ADCA (without retinal degeneration), intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respectively. Together, SCA1, SCA2, and SCA3/MJD constitute >40% of the mutations leading to ADCA I in our population. No patient without a family history of ataxia, or with a pure cerebellar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3. No overlap in ataxin-2 allele size between normal and disease chromosomes, or intermediate-sized alleles, were observed. Repeat length correlated inversely with age at onset, accounting for approximately 80% of the variability in onset age. Haplotype analysis provided no evidence for a single founder chromosome, and diverse ethnic origins were observed among SCA2 kindreds. In addition, a wide spectrum of clinical phenotypes was observed among SCA2 patients, including typical mild dominant ataxia, the MJD phenotype with facial fasciculations and lid retraction, and early-onset ataxia with a rapid course, chorea, and dementia.

Adolescent↗
PubMed2002

Self-modelling analysis applied to nanosecond transient absorption spectroscopy of flavone: an aid to elucidate and characterise reaction intermediates.

A nanosecond transient absorption spectroscopy study of flavone performed with a 248 nm pump radiation has been investigated with the support of a chemometric treatment: SIMPLISMA. The experimental spectra obtained in various solvent with a pump-probe delay lower than about 2 micros are in quite good concordance with those already presented in the literature. Nevertheless after about 10 micros, the spectrum pattern significantly evolves as a function of time particularly for the methanolic solution. A qualitative analysis together with a SIMPLISMA chemometric treatment of the experimental data allowed to elucidate and characterise two interdependent transient species in the alcoholic medium: the lowest T1 triplet state of flavone and the ketyl radical forming by H-abstraction reaction from the solvent. In cyclohexane and acetonitrile, the same species seem to be produced in the studied time-scale but the radical form is generated with variable quantum yield depending on the solvent polarity. The pure spectrum and the photochemical kinetics of each reaction intermediate could have been determined with the help of the second derivative SIMPLISMA calculation procedure.

Acetonitriles↗
PubMed1981

Carnitine palmityl transferase deficiency: clinical variability, carrier detection, and autosomal-recessive inheritance.

A 21-year-old man had recurrent myoglobinuria; his 28-year-old sister had symptoms of fatigability. During prolonged fasting, serum free fatty acid rose in both siblings, but only the sister produced ketone bodies and had elevated creatine phosphokinase activity. Carnitine palmityl transferase (CPT) activity was less than 30% of normal in muscle and platelets. Liver biopsy disclosed a low level of the enzyme in the brother. The parents had intermediate levels of the enzyme in platelets. CPT deficiency seems to have an autosomal-recessive pattern of inheritance and a variable phenotypic expression.

Acyltransferases↗
PubMed2004

Spectroscopic and quantum chemical characterization of the electronic structure and bonding in a non-heme FeIV[double bond]O complex.

High valent FeIV=O species are key intermediates in the catalytic cycles of many mononuclear non-heme iron enzymes involving the binding and activation of dioxygen. Using variable temperature magnetic circular dichroism (VT MCD) spectroscopy and experimentally calibrated density functional calculations, we are able to present the first detailed description of the electronic structure of a non-heme FeIV=O S = 1 complex. These studies define the nature of the FeIV=O bond and present the basis for understanding high-valent oxygen intermediates in non-heme iron enzymes.

Circular Dichroism↗
PubMed1991

Evolution of compensatory substitutions through G.U intermediate state in Drosophila rRNA.

It has often been suggested that the frequently observed Watson-Crick base-pair compensatory substitutions in RNA helical structures occur mainly through a slightly deleterious G.U intermediate state. We have scored base substitutions in a set of 82 related Drosophila species for the D1 and D2 variable domains of the large rRNA subunit. In all locations where a G-C in equilibrium with A-U compensatory base change occurred, a G.U pair has been observed in one or several species. As this dominant process implies two transitions, their rate was far higher in paired regions (92%) than in unpaired regions (47%). The other types of compensation were rarer and no intermediate states were observed. Most of the G.U base pairs observed in a species are not slightly deleterious. The rate of evolution of compensatory substitution is close to that predicted by a simple model of compensatory substitution through slightly deleterious or slightly advantageous G.U pairs, although some exceptions are presented.

Animals↗
PubMed1999

Cardiac interbeat interval dynamics from childhood to senescence : comparison of conventional and new measures based on fractals and chaos theory.

BACKGROUND: New methods of R-R interval variability based on fractal scaling and nonlinear dynamics ("chaos theory") may give new insights into heart rate dynamics. The aims of this study were to (1) systematically characterize and quantify the effects of aging from early childhood to advanced age on 24-hour heart rate dynamics in healthy subjects; (2) compare age-related changes in conventional time- and frequency-domain measures with changes in newly derived measures based on fractal scaling and complexity (chaos) theory; and (3) further test the hypothesis that there is loss of complexity and altered fractal scaling of heart rate dynamics with advanced age. METHODS AND RESULTS: The relationship between age and cardiac interbeat (R-R) interval dynamics from childhood to senescence was studied in 114 healthy subjects (age range, 1 to 82 years) by measurement of the slope, beta, of the power-law regression line (log power-log frequency) of R-R interval variability (10(-4) to 10(-2) Hz), approximate entropy (ApEn), short-term (alpha(1)) and intermediate-term (alpha(2)) fractal scaling exponents obtained by detrended fluctuation analysis, and traditional time- and frequency-domain measures from 24-hour ECG recordings. Compared with young adults (<40 years old, n=29), children (<15 years old, n=27) showed similar complexity (ApEn) and fractal correlation properties (alpha(1), alpha(2), beta) of R-R interval dynamics despite lower spectral and time-domain measures. Progressive loss of complexity (decreased ApEn, r=-0.69, P<0.001) and alterations of long-term fractal-like heart rate behavior (increased alpha(2), r=0.63, decreased beta, r=-0.60, P<0.001 for both) were observed thereafter from middle age (40 to 60 years, n=29) to old age (>60 years, n=29). CONCLUSIONS: Cardiac interbeat interval dynamics change markedly from childhood to old age in healthy subjects. Children show complexity and fractal correlation properties of R-R interval time series comparable to those of young adults, despite lower overall heart rate variability. Healthy aging is associated with R-R interval dynamics showing higher regularity and altered fractal scaling consistent with a loss of complex variability.

Adolescent↗
PubMed1991

Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree.

By the careful screening of familial dysbetalipoproteinemic (FD) patients, five probands showing heterozygosity for the APOE*3-Leiden allele were found. Genealogical studies revealed that these probands share common ancestry in the 17th century. In a group of 128 family members, spanning three generations, 37 additional heterozygous APOE*3-Leiden gene carriers were detected. Although with a variable degree of severity, all carriers exhibited characteristics of FD such as (a) elevated levels of cholesterol in the very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) fractions, (b) elevated ratios of cholesterol levels in these density fractions over total plasma levels of triglycerides, and (c) strongly increased plasma levels of apolipoprotein E (apoE). Multiple linear regression analysis revealed that most of the variability in expression of FD in APOE*3-Leiden allele carriers can be explained by age. Body mass index showed a less significant influence on the expression of FD. Gender had no effect on the expression in E*3-Leiden allele carriers, nor did it influence the age of onset of FD. In the group of APOE*3-Leiden allele carriers, we found that the E*2 allele enhances the expression of FD, whereas the E*4 allele had the opposite effect. Isoelectric focusing of plasma and of isolated VLDL, IDL, and high density lipoprotein density fractions showed that in E*3-Leiden allele carriers the apoE3-Leiden variant largely predominates over its normal apoE counterpart, especially in the VLDL and IDL density fractions. We conclude that in APOE*3-Leiden allele carriers FD is dominantly inherited with a high rate of penetrance, i.e., the presence of normally functioning apoE molecules in the plasma does not prevent the age-related expression of this disease.

Adolescent↗
PubMed2004

alpha-internexin is present in the pathological inclusions of neuronal intermediate filament inclusion disease.

Neuronal intermediate filament (IF) inclusion disease (NIFID) is a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal, and extrapyramidal signs. Pathologically, in affected areas, there is neuronal loss, astrocytosis, and neuronal intracytoplasmic aggregates of abnormal neuronal IFs that contain neither tau nor alpha-synuclein. Thus, to characterize the neuronal IF protein profile of inclusions in NIFID, immunohistochemistry (IHC) was performed on 10 cases of NIFID, four normal aged controls (NL), and two cases of Alzheimer's disease (AD) using a panel of anti-neuronal IF proteins. Immunoelectron microscopy was performed on selected cases and frozen tissue from the frontal lobe of four cases was used for biochemical studies including sequential extractions and Western blotting. Based on these studies, we report here for the first time that alpha-internexin, a neuronal IF protein, is present within the inclusions of NIFID as are all three neurofilament subunits: heavy, medium, and light. Thus, all class IV neuronal IF proteins are present within the pathological inclusions of this disease. Biochemistry revealed that IF aggregates were soluble in sodium dodecyl sulfate (SDS) and no post-translational modification was detected when compared with Alzheimer's disease or aged control brains. Hence, we conclude that NIFID is characterized by the pathological cytoplasmic aggregation of all class IV neuronal IF proteins in brain. The discovery of alpha-internexin in the cytoplasmic inclusions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological accumulations of IFs.

Adult↗
PubMed2002

Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.

BACKGROUND: The biological basis of frailty has been difficult to establish owing to the lack of a standard definition, its complexity, and its frequent coexistence with illness. OBJECTIVE: To establish the biological correlates of frailty in the presence and absence of concurrent cardiovascular disease and diabetes mellitus. METHODS: Participants were 4735 community-dwelling adults 65 years and older. Frail, intermediate, and nonfrail subjects were identified by a validated screening tool and exclusion criteria. Bivariate relationships between frailty level and physiological measures were evaluated by Pearson chi2 tests for categorical variables and analysis of variance F tests for continuous variables. Multinomial logistic regression was performed to evaluate multivariable relationships between frailty status and physiological measures. RESULTS: Of 4735 Cardiovascular Health Study participants, 299 (6.3%) were identified as frail, 2147 (45.3%) as intermediate, and 2289 (48.3%) as not frail. Frail vs nonfrail participants had increased mean +/- SD levels of C-reactive protein (5.5 +/- 9.8 vs 2.7 +/- 4.0 mg/L), factor VIII (13 790 +/- 4480 vs 11 860 +/- 3460 mg/dL), and, in a smaller subset, D dimer (647 +/- 1033 vs 224 +/- 258 ng/mL) (P< or =.001 for all, chi2 test for trend). These differences persisted when individuals with cardiovascular disease and diabetes were excluded and after adjustment for age, sex, and race. CONCLUSIONS: These findings support the hypothesis that there is a specific physiological basis to the geriatric syndrome of frailty that is characterized in part by increased inflammation and elevated markers of blood clotting and that these physiological differences persist when those with diabetes and cardiovascular disease are excluded.

Aged↗
PubMed1991

Effects of alterations in left ventricular filling, contractility, and systemic vascular resistance on the ascending aortic blood velocity waveform of normal subjects.

OBJECTIVES: To confirm the consistent effects on Doppler-measured aortic blood flow velocity waveform variables of alterations in left ventricular preload, afterload, and inotropy using pharmacologic and physiologic maneuvers. SETTING: Medical school laboratory. SUBJECTS: Healthy volunteers. INTERVENTIONS: Increasing infusion rates of dobutamine (1.25 to 5 micrograms/kg.min), esmolol (1.25 to 5 mg/min), phentolamine (1.25 to 5 mg/min), methoxamine (1.25 to 5 mg/min), metaraminol (1.25 to 5 mg/min), and placebo (1.25 to 5 mL of 0.9% saline/min) and increasing plasma removal (0.5 to 1 L) in awake, rested, supine subjects. MEASUREMENTS AND MAIN RESULTS: Ascending aortic blood flow was measured by the suprasternal Doppler approach allowing calculation of waveform variables of stroke distance and minute distance (linear measures of stroke volume and cardiac output), peak velocity, mean acceleration and flow time corrected for heart rate. An index of systemic vascular resistance was obtained by dividing mean systemic BP by the minute distance. Inotropic changes predominantly affected peak velocity and mean acceleration. Changes in preload mainly affected the flow time corrected for heart rate, whereas afterload changes had an intermediate effect. Unsuspected but subsequently confirmed hemodynamic effects were seen with esmolol and metaraminol. CONCLUSIONS: Aortic blood flow velocity waveform variables measured by Doppler ultrasound can be used to noninvasively follow changes in left ventricular preload, afterload, and inotropy.

Adrenergic beta-Antagonists↗