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PubMed2002

Endemic hepatitis C virus infection in a Sicilian town: further evidence for iatrogenic transmission.

The prevalence of and risk factors for HCV and HBV infections in the general population and the predictive value of ALT screening in identifying anti-HCV positive subjects have been evaluated in a small Sicilian town. A random 1:4 sampling from the census of the general population was performed. Anti-HCV, HCV-RNA, HCV genotype, HBsAg, and anti-HBc were tested. The linkage between HCV infection and potential risk factors was evaluated by multiple logistic regression analysis. Among 721 subjects studied, 75 (10.4%) were anti-HCV positive. The HCV infection rate increased from 0.4% in subjects 10-29 years of age to 34% in those > 60 years of age. Among the 75 anti-HCV positive subjects, 66.7% were HCV-RNA positive and 36% had abnormal ALT, in contrast abnormal ALT levels were found in 4.3% of the 646 anti-HCV negative subjects (P < 0.01). HCV genotype 1b infected the majority (88.0%) of viremic subjects. Exposure to HBV infection (anti-HBc positivity) was found in 11.2% of subjects; HBsAg positivity was 0.7%. At multivariate analysis, two variables were associated with HCV infection: age > or = 45 years (OR 27.8; CI 95% = 11.0-70.2) and previous hospitalization (OR 2.5; CI 95% = 1.3-4.7). ALT testing had low positive predictive value (PPV = 49.1%) for HCV infection. The positive predictive value was good (88%) in people > or = 60 years of age, but minimal (16.7%) in those below 60. These findings indicate that HCV infection is common in the elderly, perhaps as a result of past iatrogenic transmission. The present low rate of HCV infection among the younger generations coupled with the low progression of the viral related liver damage does not support the projection of a future increasing incidence in the next decades of the burden of HCV-related chronic disease. HBV infection, formerly common in this area, is already in sharp decline. In an area of high HCV endemicity, screening of the general population by ALT cannot be used a surrogate marker to detect HCV infection in those susceptible to treatment.

Adolescent↗

PubMed1995

Can the long-term outcomes of percutaneous balloon mitral valvotomy and surgical commissurotomy be expected to be similar?

The ultimate role of percutaneous balloon mitral valvotomy will depend on its potential for sustained improvement. Long-term outcome data including survival, reoperation and thromboembolism are available for surgical commissurotomy. However, length of follow up for percutaneous balloon mitral valvotomy is inadequate to acquire similar end-point data. We therefore hypothesized that comparison of changes in mitral valve area following balloon or surgical commissurotomy would serve as a useful surrogate end-point by which the long-term benefit of percutaneous balloon mitral valvotomy could be determined. Mitral valve area was determined by Doppler echocardiography following percutaneous balloon mitral valvotomy (N = 230) and surgical commissurotomy (N = 241, 130 closed and 111 open mitral commissurotomy). Regression lines of mitral valve area versus interval from intervention were constructed for each of the two groups. Nine clinical and echocardiographic variables were also analyzed to determine their predictive value for low mitral valve areas. Both groups showed similar and significant negative correlations for mitral valve area versus time (r = -0.48, r = -0.6, balloon vs. surgical commissurotomy respectively, p = 0.001 for both groups). The slopes of the regression lines for both groups were also similar (y = -0.007 x +1.9, y = -0.005 x +1.8, y = -0.006 x +1.8, p = NS). There were no differences in the prevalence of mitral regurgitation. Independent predictors of mitral restenosis according to multivariate analysis were time interval from surgery (p < 0.03), composite mitral valve morphology score (p < 0.04) and subvalvular disease (p < 0.04). Thus, there is a progressive decrease in mitral valve area following percutaneous mitral balloon valvotomy that, at least for the available duration of follow up, appears to parallel changes in valve area following closed or open mitral commissurotomy. A less pliable valve and more subvalvular disease are independent predictors of smaller valve areas. These data suggest that the long term clinical outcome following percutaneous balloon mitral valvotomy may be expected to be similar to the available data for surgical commissurotomy.

Adult↗

PubMed1996

Tmax: an unconfounded metric for rate of absorption in single dose bioequivalence studies.

PURPOSE: While peak drug concentration (Cmax) is recognized to be contaminated by the extent of absorption, it has long served as the indicator of change in absorption rate in bioequivalence studies. This concentration measure per se is a measure of extreme drug exposure, not absorption rate. This paper redirects attention to Tmax as the absorption rate variable. METHODS: We show that the time to peak measure (Tmax), if obtained from equally spaced sampling times during the suspected absorption phase, defines a count process which encapsulates the rate of absorption. Furthermore such count data appear to follow the single parameter Poisson distribution which characterizes the rate of many a discrete process, and which therefore supplies the proper theoretical basis to compare two or more formulations for differences in the rate of absorption. This paper urges limiting the use of peak height measures based on Cmax to evaluate only for dose-dumping, a legitimate safety concern with any formulation. These principles and techniques are illustrated by a bioequivalence study in which two test suspensions are compared to a reference formulation. RESULTS: Appropriate statistical evaluation of absorption rate via Tmax supports bioequivalence, whereas the customary analysis with Cmax leads to rejection of bioequivalence. This suggests that the inappropriate use of Cmax as a surrogate metric for absorption rate contributes to the unpredictable and uncertain outcome in bioequivalence evaluation today.

Absorption↗

PubMed2004

Oxidative stress - a link between endothelial injury, coagulation activation, and atherosclerosis in haemodialysis patients.

BACKGROUND/AIM: Recently emerging evidence suggests that oxidative stress (SOX) may participate in atherogenesis. The aim of the present study was to establish whether enhanced SOX, involving endothelial injury, activation of coagulation, and inflammatory reaction, could be implicated in atherosclerotic diseases in haemodialysis (HD) patients. METHODS: Markers of SOX, endothelial injury, coagulation, and cytokines, were measured in the plasma of HD patients with and without cardiovascular disease (CVD), and of healthy controls by ELISA methods. Remodeling of the carotid arteries was assessed by measuring the intima-media thickness (IMT) as a surrogate of atherosclerotic disease in all groups. RESULTS: Markers of SOX, endothelial injury, and extrinsic coagulation pathway activation and IMT values were significantly elevated in HD patients, especially in those with CVD when compared with the control group. The von Willebrand factor antigen (vWF:Ag) levels were more increased in the patients with CVD than in those without. Furthermore, the plasma levels of tumour necrosis factor alpha, monocyte chemo-attractant protein 1, and macrophage inflammatory protein 1 beta were significantly higher only in the HD group with CVD when compared with the controls. The IMT was strongly and directly correlated with Cu/Zn superoxide dismutase. Both IMT and Cu/Zn superoxide dismutase were positively correlated with age, thrombomodulin, vWF:Ag, tissue factor, tissue factor pathway inhibitor, prothrombin fragment F1 + 2, monocte chemo-attractant protein 1, macrophage inflammatory protein 1 beta, and tumour necrosis factor alpha levels. Multivariate analysis identified vWF:Ag as the only independent variable significantly associated with an increased IMT. CONCLUSIONS: The present study suggests that enhanced SOX, involved pro-atherogenic cytokine and chemokines levels, endothelial injury, and coagulation activation may constitute a pathway for accelerated atherosclerosis in HD patients. The significant, independent association between IMT and vWF:Ag should be assessed in future studies to determine whether vWF:Ag elevation is causative or a by-product of the increased IMT.

Biomarkers↗

PubMedDate not supplied

Kinetic and efficacy analysis of RNA interference in stably and transiently expressing cell lines.

RNA interference, particularly through the use of small interfering RNA (siRNA), has become an important laboratory tool for both fundamental and applied investigations. However, it is currently unknown whether siRNA-mediated knockdown of transiently expressed proteins is an acceptable quantitative surrogate for stably expressed proteins. Further, the best means by which to transfect cells with functionally active siRNA are poorly defined, and determination of the best reagent and transfection conditions for a particular cell line is a burdensome prerequisite for RNA interference studies. We therefore established the optimal transfection conditions for six commercial siRNA delivery reagents in three cell lines (HR5-CL11, HeLa, and NIH/3T3) transiently or stably expressing the firefly luciferase gene. The delivery efficiency, knockdown kinetics, and cytotoxicity of the reagents were evaluated. siPORT Amine, X-tremeGENE, and TransIT-siQUEST achieved the best knockdown and consistency of performance among the three cell lines. Delivery efficiency varied and was cell line dependent in some cases. The knockdown kinetics were reagent-dependent, and knockdown was generally more rapid in the stably transfected cells. Cytotoxicity of the reagents was variable. GeneSilencer was the least cytotoxic reagent for all three cell lines, and TransIT-siQUEST was the most cytotoxic to the HeLa and HR5-CL11 cell lines. These comparative results provide an initial basis for reagent selection and experimental design for RNA interference studies in HeLa, NIH/3T3, and their respective derivative cell lines.

Animals↗

PubMed2005

Prognostic usage of V(H) gene mutation status and its surrogate markers and the role of antigen selection in chronic lymphocytic leukemia.

B-cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease with many patients surviving for decades with minimal or no treatment, whereas others succumb rapidly to their disease despite therapy. In recent years, new molecular prognostic factors have emerged in CLL that have significantly improved the subgrouping of the disease. One of the most important molecular predictors, the immunoglobulin V(H) gene mutation status, divides CLL into two prognostic groups, depending on the presence or absence of somatic hypermutation, where unmutated V(H) genes are associated with considerably worse prognosis than mutated V(H) genes. An exception to this appears to be CLL patients utilizing the V(H)3-21 gene as they have poor outcome irrespective of mutation status. Surrogate markers for the VH gene mutation status have been suggested, such as CD38 and ZAP-70 expression. However, the CD38 level was later shown to display poor correlation to the mutation status, although it may still serve as an independent prognostic factor. More promising is the expression levels of ZAP-70, which appears to be both a strong surrogate marker for V(H) gene mutation status, although discrepancies have been reported, as well as an independent prognostic marker. Immunoglobulin gene analysis has also indicated the possibility of antigen selection in CLL considering the significant bias in V(H) gene usage. Intriguingly, the V(H)3-21+ group and several other CLL subsets using certain V(H) genes was recently reported to display strikingly restricted immunoglobulin gene features, in both their heavy and light chain gene rearrangements, thus further high-lighting the possible role of antigen involvement in CLL development.

Antigens, Neoplasm↗

PubMed2003

Latent transition regression for mixed outcomes.

Health status is a complex outcome, often characterized by multiple measures. When assessing changes in health status over time, multiple measures are typically collected longitudinally. Analytic challenges posed by these multivariate longitudinal data are further complicated when the outcomes are combinations of continuous, categorical, and count data. To address these challenges, we propose a fully Bayesian latent transition regression approach for jointly analyzing a mixture of longitudinal outcomes from any distribution. Health status is assumed to be a categorical latent variable, and the multiple outcomes are treated as surrogate measures of the latent health state, observed with error. Using this approach, both baseline latent health state prevalences and the probabilities of transitioning between the health states over time are modeled as functions of covariates. The observed outcomes are related to the latent health states through regression models that include subject-specific effects to account for residual correlation among repeated measures over time, and covariate effects to account for differential measurement of the latent health states. We illustrate our approach with data from a longitudinal study of back pain.

Back Pain↗

PubMed2005

Relationship of QT interval duration with carotid intima media thickness in a clinically healthy population undergoing cardiovascular risk screening.

OBJECTIVES: To investigate the relationship between cardiac repolarization (QT interval duration) and intima media thickness (IMT) of the carotid arteries as surrogate measures of subclinical atherosclerosis. DESIGN: Prospective study with consecutive subjects enrolled in the SAPHIR program (Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk). SETTING: The analysis of the material was performed at the departments of medicine and neurology of a university hospital. SUBJECTS: The study cohort comprises a population-based sample of 1199 clinically healthy subjects (851 men and 348 women; age 39-66 years). Exclusion criteria were cardiovascular disease, diabetes, atrial fibrillation, bundle branch block and use of medication affecting QT interval duration. MAIN OUTCOME MEASURES: IMT of common (CCA) and internal carotid arteries (ICA) was measured by B-mode ultrasound. QT interval duration was determined in the resting 12-lead electrocardiogram by an automatic analysis program. The QT intervals were corrected for heart rate with five standard equations (QTc-Bazett, -Fridericia, -Framingham, -Hodges and -Rautaharju) and tested for their relationship with carotid IMT after adjustment for clinical and metabolic variables. Results. Females had higher heart rates than males (64 +/- 10 b min(-1) vs. 60 +/- 9 b min(-1), P <0.0005), with longer mean QT (410 +/- 28 ms vs. 404 +/- 28 ms, P=0.003) and QTc intervals in all correction formulae (P <0.0005). Significant correlations between QT/QTc and ICA IMT (r=0.14-0.16) were found in males. In the general linear model the association between QTc (except for Bazett) and ICA IMT remained significant after adjusting for age, BMI and further cardiovascular risk factors. In females the crude correlations between QT/QTc and ICA IMT were lower than those with CCA IMT. Only the correlation between uncorrected QT and CCA IMT (r=0.15, P=0.006) remained significant after adjustment for covariates. CONCLUSIONS: The results of the present study demonstrate that QT and QTc prolongation are in part associated with IMT of carotid arteries, which is an established risk marker of subclinical atherosclerosis. In men the data support the hypothesis of an association between QTc and ICA IMT. In women a statistically significant relationship was found between the uncorrected QT interval and CCA IMT. These findings suggest that differences in carotid IMT and ventricular repolarization between genders might be related to hormonal and nonhormonal effects.

Adult↗

PubMed2000

Characterisation of a mouse monoclonal anti-idiotype reactive with a V region sequence commonly used by human immunoglobulins.

BACKGROUND: A mouse monoclonal antibody (2C7/IgG2b kappa) has been described recently, which is directed against the major house dust mite allergen Der p 1, and whose epitope specificity is representative of a major component of the human IgE anti-Der p 1 response. AIMS: To characterise an anti-idiotypic antibody (2G10/IgG1 kappa) raised against monoclonal antibody 2C7 as surrogate human IgE anti-Der p 1. METHODS: The specificity of the anti-idiotype antibody 2G10 was determined by competitive inhibition experiments using human and mouse immunoglobulins of known VH gene families. The epitope recognised by monoclonal antibody 2G10 was located on the molecular model of the Fv (fragment variable) region of monoclonal antibody 2C7. RESULTS: The data suggest that monoclonal antibody 2G10 is directed against a crossreactive idiotype on human IgE that is shared by polyclonal IgG. Competitive inhibition studies against human immunoglobulins, representative of VH2, VH3, and VH4 gene families, showed that monoclonal antibody 2G10 is mostly likely to be directed against sequences encoded by either VH3 or VH4 genes. The fact that monoclonal antibody 2G10 binds to the humanized (complementarity determining region (CDR) grafted) CAMPATH-1H antibody, but not to the original rat CAMPATH-1 YTH34.5.6 antibody, indicates that it is directed against a framework region rather than the CDRs. Analysis of amino acids in the VH region for charge, hydrophobicity, and accessibility suggests that reactivity with monoclonal antibody 2G10 is defined by a hexapeptide spanning residues 74-79 within framework region 3. CONCLUSION: The anti-idiotype monoclonal antibody 2G10 could potentially be used as a probe for determining the contribution of the VH3 and VH4 gene segments to antigenic specificity.

Amino Acid Sequence↗

PubMed2006

Validation of a new technique for the quantitation of edema in the experimental setting.

BACKGROUND: An inherent limitation to the study of in vivo animal models of lymphedema is the potential inaccuracy or unreliability of existing methods for the quantification of edema volume as a surrogate functional measure of lymphatic transport capacity. Circumference-based techniques have been proposed and validated as a suitable alternative to volume displacement measurements in human clinical studies; accordingly, we have elaborated a new application of this approach that can be applied to small animal studies. METHODS: Acute postsurgical lymphedema was created experimentally in the murine tail. Both normal and lymphedematous murine tails were examined. Tail volume was quantitated both by water displacement and by a digital photographic technique. In selected mice, after sacrificed on postsurgical day 7, a 6 cm segment was resected from the midportion of the tail and cauterized to create a closed space. Known incremental volumes of saline (20-100 microL) were injected for subsequent digital photographic volumetry. RESULTS: The coefficients of variation for volume assessment by water displacement and by digital imaging were 0.08+/-0.09 and 0.01+/-0.009, respectively. The two techniques were poorly correlated: while serial water displacement analysis yielded highly variable measurements within the same tail, concurrent digital imaging of the tail circumference was quite reproducible. Furthermore, after parenteral injection of known incremental volumes of saline, the correlation between the injectate volumes and the digitally measured increases in volume was high, both in the normal and the lymphedematous tail. CONCLUSION: In the murine tail, when compared to water displacement volumetry, digital photography yields highly reproducible data. We can conclude that the lack of correlation between the two methods, with the relatively flat slope of the linear regression relationship, reflects inherent inaccuracies of the water displacement method.

Animals↗

PubMed1994

Surrogate and auxiliary endpoints in clinical trials, with potential applications in cancer and AIDS research.

Surrogate endpoints have been defined by Prentice as response variables that can substitute for a 'true' endpoint for the purpose of comparing specific interventions or treatments in a clinical trial. The applicability of this definition, and of related surrogate endpoint criteria, is discussed, with emphasis on cancer and AIDS research settings. Auxiliary endpoints are defined as response variables, or covariates, that can strengthen true endpoint analyses. Specifically, such response variables provide some additional information on true endpoint occurrence times for study subjects having censored values for such times. Auxiliary variables will very frequently be available, and they may be able to be used without making additional strong assumptions. Approaches to the use of auxiliary variables using ideas based on augmented score and augmented likelihood methods are described.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study.

BACKGROUND: Depression is associated with interpersonal difficulties related to abnormalities in affective facial processing. OBJECTIVES: To map brain systems activated by sad facial affect processing in patients with depression and to identify brain functional correlates of antidepressant treatment and symptomatic response. DESIGN: Two groups underwent scanning twice using functional magnetic resonance imaging (fMRI) during an 8-week period. The event-related fMRI paradigm entailed incidental affect recognition of facial stimuli morphed to express discriminable intensities of sadness. SETTING: Participants were recruited by advertisement from the local population; depressed subjects were treated as outpatients. PATIENTS AND OTHER PARTICIPANTS: We matched 19 medication-free, acutely symptomatic patients satisfying DSM-IV criteria for unipolar major depressive disorder by age, sex, and IQ with 19 healthy volunteers. Intervention After the baseline assessment, patients received fluoxetine hydrochloride, 20 mg/d, for 8 weeks. MAIN OUTCOME MEASURES: Average activation (capacity) and differential response to variable affective intensity (dynamic range) were estimated in each fMRI time series. We used analysis of variance to identify brain regions that demonstrated a main effect of group (depressed vs healthy subjects) and a group x time interaction (attributable to antidepressant treatment). Change in brain activation associated with reduction of depressive symptoms in the patient group was identified by means of regression analysis. Permutation tests were used for inference. RESULTS: Over time, depressed subjects showed reduced capacity for activation in the left amygdala, ventral striatum, and frontoparietal cortex and a negatively correlated increase of dynamic range in the prefrontal cortex. Symptomatic improvement was associated with reduction of dynamic range in the pregenual cingulate cortex, ventral striatum, and cerebellum. CONCLUSIONS: Antidepressant treatment reduces left limbic, subcortical, and neocortical capacity for activation in depressed subjects and increases the dynamic range of the left prefrontal cortex. Changes in anterior cingulate function associated with symptomatic improvement indicate that fMRI may be a useful surrogate marker of antidepressant treatment response.

Affect↗

PubMed2003

Late renal allograft failure between 1990 and 1998 in Spain: a changing scenario.

BACKGROUND: Our aim was to study time-dependent modifications in the characteristics of renal transplants in Spain during the 1990s and risk factors associated with death-censored graft failure after the first year. METHODS: A total of 3,365 adult patients who underwent transplantation in 1990, 1994, and 1998 with a functioning graft after the first year were included. RESULTS: Ten-year patient and graft survival rates were 82% and 70%. Major modifications between 1990 and 1998 were increases in donor age (32 +/- 15 to 43 +/- 18 years, P<0.0001) and number of HLA mismatches (2.8 +/- 1.2 to 3.2 +/- 1.2, P<0.0001). Acute rejection decreased from 39% to 25% (P<0.0001), and the prevalence recipients with hepatitis C virus decreased from 29% to 10% (P<0.0001). The use of lipid-lowering agents during the first year increased from 6% to 41% (P<0.0001). Projected renal allograft half-life estimate was 15.4 (range, 14.1-16.8) years in 1990 and 17.7 (range, 14.0-21.4) in 1998 (P=0.007). Independent variables associated with graft survival were as follows: recipient age, last panel-reactive antibodies, acute rejection, hepatitis C virus antibodies in the recipient, triglycerides, serum creatinine and proteinuria at 3 months, and the increase of serum creatinine and proteinuria between the 3rd and 12th month. The use of statins during the first year was associated with a decreased risk for graft loss. CONCLUSION: Despite worsening of surrogate parameters of renal quality and poorer HLA matching, graft survival improved during the 1990s in Spain.

Adult↗

PubMed2002

Noninvasive assessment of cardiac pumping capacity during exercise predicts prognosis in patients with congestive heart failure.

BACKGROUND: Prognostic parameters in patients with congestive heart failure (CHF) are important for guiding therapeutic options. Maximal oxygen uptake (O(2)max) is a widely used parameter for prognostic assessment in patients with CHF and correlates with exercise cardiac output; however, afterload is not taken into account. METHODS: The concept of a noninvasive surrogate of cardiac power output combines exercise systolic BP (SBP), as an estimate of afterload, with O(2)max, as an estimate of exercise cardiac output neglecting preload. Thus, a variable termed exercise cardiac power (ECP) is defined as the product of O(2)max (expressed as a percent predicted value) and SBP (ECP, expressed as %mm Hg, is the product of O(2)max, expressed as percentage of predicted maximum, times systolic pressure. The prognostic value of ECP obtained during routine treadmill ergospirometry was assessed in patients referred to our heart failure clinic. Patients undergoing heart transplantation were censored at the time of transplantation. RESULTS: One hundred fifty-four patients were followed prospectively for a mean (+/- SE) duration of 625 +/- 32 days. Thirty-two patients (21%) died. ECP was the most powerful predictor of mortality, was the combined end point of mortality or hospitalization for worsening heart failure (all p < 0.001), and was an independent predictor in multivariate analysis. An ECP of < 5,000 %mm Hg indicated a poor prognosis with a 1-year mortality rate of 37%, whereas only 2% of the patients having an ECP of > 9,000 %mm Hg died during the first year. CONCLUSION: The integration of afterload and O(2)max improves the prognostic value of each indicator, and provides an easily available and independent predictor of mortality and morbidity in CHF patients. This integrative concept of cardiac hydraulic performance is superior to O(2)max and can be used in routine ergospirometry.

Analysis of Variance↗

PubMed2000

Nonlinear time series analysis of normal and pathological human walking.

Characterizing locomotor dynamics is essential for understanding the neuromuscular control of locomotion. In particular, quantifying dynamic stability during walking is important for assessing people who have a greater risk of falling. However, traditional biomechanical methods of defining stability have not quantified the resistance of the neuromuscular system to perturbations, suggesting that more precise definitions are required. For the present study, average maximum finite-time Lyapunov exponents were estimated to quantify the local dynamic stability of human walking kinematics. Local scaling exponents, defined as the local slopes of the correlation sum curves, were also calculated to quantify the local scaling structure of each embedded time series. Comparisons were made between overground and motorized treadmill walking in young healthy subjects and between diabetic neuropathic (NP) patients and healthy controls (CO) during overground walking. A modification of the method of surrogate data was developed to examine the stochastic nature of the fluctuations overlying the nominally periodic patterns in these data sets. Results demonstrated that having subjects walk on a motorized treadmill artificially stabilized their natural locomotor kinematics by small but statistically significant amounts. Furthermore, a paradox previously present in the biomechanical literature that resulted from mistakenly equating variability with dynamic stability was resolved. By slowing their self-selected walking speeds, NP patients adopted more locally stable gait patterns, even though they simultaneously exhibited greater kinematic variability than CO subjects. Additionally, the loss of peripheral sensation in NP patients was associated with statistically significant differences in the local scaling structure of their walking kinematics at those length scales where it was anticipated that sensory feedback would play the greatest role. Lastly, stride-to-stride fluctuations in the walking patterns of all three subject groups were clearly distinguishable from linearly autocorrelated Gaussian noise. As a collateral benefit of the methodological approach taken in this study, some of the first steps at characterizing the underlying structure of human locomotor dynamics have been taken. Implications for understanding the neuromuscular control of locomotion are discussed. (c) 2000 American Institute of Physics.

Journal Article↗

PubMed1993

Joint impairment and self-reported disability in elderly persons.

Recent findings indicating that arthritis is a major contributor to disability in elderly persons are based on self-reported diagnostic information. We conducted physical examinations of the joints at baseline on 541 older persons. We then tested a multivariate model of total/generic disability which included respondent group, demographic and chronic disease variables (joint impairment and comorbid conditions), arthritis pain, and psychological status. Hierarchical multiple regression found that the model explained 55 percent (adjusted R2 = .55) of the variance in baseline disability with joint impairment accounting for 15 percent (change in R2 = .15) of the variance. When joint impairment was removed from the model, arthritis pain worked well as a surrogate. Together, these findings strongly support the importance of musculoskeletal disease in explaining disability in the elderly population.

Activities of Daily Living↗

PubMed2006

A general multivariate extension of Fisher's geometrical model and the distribution of mutation fitness effects across species.

The evolution of complex organisms is a puzzle for evolutionary theory because beneficial mutations should be less frequent in complex organisms, an effect termed "cost of complexity." However, little is known about how the distribution of mutation fitness effects (f(s)) varies across genomes. The main theoretical framework to address this issue is Fisher's geometric model and related phenotypic landscape models. However, it suffers from several restrictive assumptions. In this paper, we intend to show how several of these limitations may be overcome. We then propose a model of f(s) that extends Fisher's model to account for arbitrary mutational and selective interactions among n traits. We show that these interactions result in f(s) that would be predicted by a much smaller number of independent traits. We test our predictions by comparing empirical f(s) across species of various gene numbers as a surrogate to complexity. This survey reveals, as predicted, that mutations tend to be more deleterious, less variable, and less skewed in higher organisms. However, only limited difference in the shape of f(s) is observed from Escherichia coli to nematodes or fruit flies, a pattern consistent with a model of random phenotypic interactions across many traits. Overall, these results suggest that there may be a cost to phenotypic complexity although much weaker than previously suggested by earlier theoretical works. More generally, the model seems to qualitatively capture and possibly explain the variation of f(s) from lower to higher organisms, which opens a large array of potential applications in evolutionary genetics.

Animals↗

PubMed2003

Utility of automated brachial ankle pulse wave velocity measurements in hypertensive patients.

BACKGROUND: We examined whether pulse wave velocity (PWV), determined by brachial ankle arterial pressure wave measurements, using a newly developed, fully automated device could be a surrogate measure for carotid femoral PWV. METHODS & RESULTS: This device (AT-form PWV/ABI, Nippon Colin, Komaki, Japan) can simultaneously monitor bilateral brachial and ankle pressure wave forms using the volume plethysmographic method, with two optional tonometry sensors for carotid and femoral arterial wave measurements. We examined the right brachial-right ankle PWV and left carotid-left femoral PWV in 89 normotensive and untreated hypertensive patients. The brachial ankle PWV correlated well with carotid femoral PWV (r = 0.755, P <.00001). The Bland-Altman plots of the two variables, however, showed a significant difference exists between the two techniques over the range of measurement. The within-observer and between-observer coefficients of variation of the brachial ankle PWV were 6.5% +/- 4.1% and 3.6% +/- 3.9%, respectively. To determine the factors affecting brachial ankle PWV, we studied treated and untreated hypertensive patients with World Health Organization stage I (n = 146), stage II (n = 74), or stage III (n = 54). In multiple regression analysis, age, brachial ankle PWV, and the presence of diabetes were significant predictors of the severity of hypertensive organ damage. Age, systolic blood pressure, and the stage of hypertensive organ damage were major determinants of brachial ankle PWV. CONCLUSIONS: Although the brachial ankle PWV does not agree with the carotid femoral PWV, this parameter may yet become a new, useful measure for arterial stiffness. Further longitudinal studies are necessary to confirm the clinical significance of the brachial ankle PWV.

Aged↗