Re-emerging Vitamin D deficiency epidemic and its implications on the public health in the US

Vitamin D is essential in maintaining the bone health and Calcium homeostasis in the body. These actions are mediated through the Vitamin D receptors (VDR) present in cells through which the activated vitamin D acts [1]. In the past, it was known that these receptors existed in the intestine and bone cell. However, recent discovery of VDR in other tissues as well, has broadened the action of Vitamin D and increased its adequate intake [1].^ In the past, Vitamin D deficiency was most common among institutionalized, elderly patients and children and thought to be extinct in the healthy population. However, recent evidence has shown that, prevalence of vitamin D deficiency is increasing into an epidemic status in the overall population of the United States, including the healthy individuals [2-3]. The increased daily-recommended requirement and other multiple factors are responsible for the re-emergence of this epidemic [4-5]. Some of these factors could be used to control the epidemic. Studies have also shown the association between vitamin D deficiency and increased risk for developing chronic diseases such as diabetes, hypertension, multiple sclerosis, arthritis, and some fatal cancers like prostate, colon and breast cancers [1, 4, 6-14]. This issue results in increased disease burden, morbidity and mortality in the community [15-20].^ Methods: The literature search was conducted using the University of Texas Health Science Center at Houston (UTHSC) and University of Texas Southwestern Medical Center (UTSW) online library. The key search terms used are “vitamin D deficiency And prevalence Or epidemiology”, “vitamin D deficiency And implication And public health” using PubMed and Mesh database and “vitamin D deficiency” using systematic reviews. The search is limited to Humans and the English language. The articles considered for the review are limited to Healthy US population to avoid health conditions that predispose the population to vitamin D deficiency. Only US population is considered to narrow down the study.^ Results: There is an increased prevalence of low levels of Vitamin D levels below the normal range in the US population regardless of age and health status. Vitamin D deficiency is also associated with increased risk of chronic illnesses and fatal cancers.^ Conclusion: This increased prevalence and the association of the deficiency with increased all-cause mortality has increased the economic burden and compromised the quality of life among the population. This necessitates the health care providers to routinely screen their patients for the Vitamin D status and counsel them to avoid the harmful effects of the Vitamin D deficiency. ^

Experimental diabetes in rats causes hippocampal dendritic and synaptic reorganization and increased glucocorticoid reactivity to stress

We report that 9 d of uncontrolled experimental diabetes induced by streptozotocin (STZ) in rats is an endogenous chronic stressor that produces retraction and simplification of apical dendrites of hippocampal CA3 pyramidal neurons, an effect also observed in nondiabetic rats after 21 d of repeated restraint stress or chronic corticosterone (Cort) treatment. Diabetes also induces morphological changes in the presynaptic mossy fiber terminals (MFT) that form excitatory synaptic contacts with the proximal CA3 apical dendrites. One effect, synaptic vesicle depletion, occurs in diabetes as well as after repeated stress and Cort treatment. However, diabetes produced other MFT structural changes that differ qualitatively and quantitatively from other treatments. Furthermore, whereas 7 d of repeated stress was insufficient to produce dendritic or synaptic remodeling in nondiabetic rats, it potentiated both dendritic atrophy and MFT synaptic vesicle depletion in STZ rats. These changes occurred in concert with adrenal hypertrophy and elevated basal Cort release as well as hypersensitivity and defective shutoff of Cort secretion after stress. Thus, as an endogenous stressor, STZ diabetes not only accelerates the effects of exogenous stress to alter hippocampal morphology; it also produces structural changes that overlap only partially with those produced by stress and Cort in the nondiabetic state.

Factors to consider in Micronesian food-based interventions: a case study of preventing Vitamin A deficiency

Background: Many factors need to be considered in a food-based intervention. Vitamin A deficiency and chronic diseases, such as diabetes, heart disease and cancer, have become serious problems in the Federated States of Micronesia (FSM) following the decreased production and consumption of locally grown foods. However, agricultural and social conditions are still favourable for local food production. Aim: To identify key factors to consider in a Micronesian food-based intervention focusing on increased production and consumption of four major Micronesian staple foods: banana, breadfruit, giant swamp taro and pandanus. Methods: Ethnographic methods including key informant interviews and a literature review. Results: Pacific and Micronesian values, concepts of food and disease, and food classifications differ sharply from Western concepts. There are few FSM professionals with nutrition expertise. Traditional foods and food cultivars vary in nutrient content, consumption level, cost, availability, status, convenience in growing, storing and cooking, and organoleptic factors. Conclusions: A systematic consideration of the factors that relate to a food-based intervention is critical to its success. The evaluation of which food and cultivar of that food that might be most effectively promoted is also critical. Regional differences, for example FSM inter-island differences between the staple foods and cultivars, must be considered carefully. The evaluation framework presented here may be relevant to Pacific island and other countries with similar foods where food-based interventions are being planned. An ethnographic approach was found to be essential in understanding the cultural context and in data collection and analysis.

CRISE DE IDENTIDADE EM ADOLESCENTES PORTADORES DO DIABETES MELLITUS DO TIPO I

A adolescência é um processo dinâmico entre a infância e a idade adulta: inicia-se com a puberdade e termina com a aquisição da identidade, da autonomia, bem como da elaboração de projetos de vida e de integração na sociedade. Os modelos de identidade são transferidos dos pais para os adolescentes, de modo a permitir a construção de idéias e afetos próprios. Este estudo tem como objetivo identificar como o adolescente vivencia tornar-se portador da doença crônica o diabetes. Para tanto, recorremos a abordagem qualitativa, utilizando como instrumento de coleta a entrevista semi-estruturada. Participaram do estudo cinco sujeitos, com idade variando de 10 a 17 anos, com diagnóstico do diabetes mellitus tipo 1 há pelo menos um ano. A partir das entrevistas, organizamos os dados em três temas: o impacto do diagnóstico no adolescente, convivendo com mudanças e a busca de identidade. Considerando-se que a adolescência é um período de vida marcado pela busca da identidade, no qual o adolescente esta revendo suas posições infantis frente a incerteza dos papéis adultos que se apresentam a ele, e aliado a este momento vem a doença crônica o diabetes. Parece-nos importante que haja compreensão, um grande apoio social e um efetivo trabalho de educação em diabetes que possibilitará a integração social e psicológica do portador do diabetes.

An investigation of the relationships among self-care behaviors, health beliefs, and metabolic control in the non-insulin-dependent diabetic adult

Self-care and health beliefs have been found to be important concepts in the management of chronic diseases such as diabetes mellitus. Poor metabolic control has been associated with a higher incidence of complications in diabetic patients. This study sought to explore any relationships among perceptions of self-care behaviors, health beliefs and metabolic control. The sample consisted of 52 outpatients with non-insulin-dependent diabetes from a large teaching medical center. Interviews were done to obtain the patients' perceptions of their self-care behaviors, and their health beliefs concerning diabetes. Results of glycosylated hemoglobin and/or serum glucose levels were obtained from the medical records. Data were analyzed using Cochran-Mantel-Haenzel statistics, and Pearson's r. Results indicated no significant relationships among perceptions of self-care behaviors, health beliefs and metabolic control. Ethnicity, education and gender were found to be significantly associated with self-care behaviors and health beliefs.

Modelling socially optimal land allocations for sugar cane growing in North Queensland: a linked mathematical programming and choice modelling study

A modelling framework is developed to determine the joint economic and environmental net benefits of alternative land allocation strategies. Estimates of community preferences for preservation of natural land, derived from a choice modelling study, are used as input to a model of agricultural production in an optimisation framework. The trade-offs between agricultural production and environmental protection are analysed using the sugar industry of the Herbert River district of north Queensland as an example. Spatially-differentiated resource attributes and the opportunity costs of natural land determine the optimal tradeoffs between production and conservation for a range of sugar prices.

Prognostic Value of a New Cardiopulmonary Exercise Testing Parameter in Chronic Heart Failure: Oxygen Uptake Efficiency at Peak Exercise - Comparison with Oxygen Uptake Efficiency Slope

INTRODUCTION: A growing body of evidence shows the prognostic value of oxygen uptake efficiency slope (OUES), a cardiopulmonary exercise test (CPET) parameter derived from the logarithmic relationship between O(2) consumption (VO(2)) and minute ventilation (VE) in patients with chronic heart failure (CHF). OBJECTIVE: To evaluate the prognostic value of a new CPET parameter - peak oxygen uptake efficiency (POUE) - and to compare it with OUES in patients with CHF. METHODS: We prospectively studied 206 consecutive patients with stable CHF due to dilated cardiomyopathy - 153 male, aged 53.3±13.0 years, 35.4% of ischemic etiology, left ventricular ejection fraction 27.7±8.0%, 81.1% in sinus rhythm, 97.1% receiving ACE-Is or ARBs, 78.2% beta-blockers and 60.2% spironolactone - who performed a first maximal symptom-limited treadmill CPET, using the modified Bruce protocol. In 33% of patients an cardioverter-defibrillator (ICD) or cardiac resynchronization therapy device (CRT-D) was implanted during follow-up. Peak VO(2), percentage of predicted peak VO(2), VE/VCO(2) slope, OUES and POUE were analyzed. OUES was calculated using the formula VO(2) (l/min) = OUES (log(10)VE) + b. POUE was calculated as pVO(2) (l/min) / log(10)peakVE (l/min). Correlation coefficients between the studied parameters were obtained. The prognosis of each variable adjusted for age was evaluated through Cox proportional hazard models and R2 percent (R2%) and V index (V6) were used as measures of the predictive accuracy of events of each of these variables. Receiver operating characteristic (ROC) curves from logistic regression models were used to determine the cut-offs for OUES and POUE. RESULTS: pVO(2): 20.5±5.9; percentage of predicted peak VO(2): 68.6±18.2; VE/VCO(2) slope: 30.6±8.3; OUES: 1.85±0.61; POUE: 0.88±0.27. During a mean follow-up of 33.1±14.8 months, 45 (21.8%) patients died, 10 (4.9%) underwent urgent heart transplantation and in three patients (1.5%) a left ventricular assist device was implanted. All variables proved to be independent predictors of this combined event; however, VE/VCO2 slope was most strongly associated with events (HR 11.14). In this population, POUE was associated with a higher risk of events than OUES (HR 9.61 vs. 7.01), and was also a better predictor of events (R2: 28.91 vs. 22.37). CONCLUSION: POUE was more strongly associated with death, urgent heart transplantation and implantation of a left ventricular assist device and proved to be a better predictor of events than OUES. These results suggest that this new parameter can increase the prognostic value of CPET in patients with CHF.

Protocole pour l'évaluation et la prise en charge des plaies chroniques [Protocol for the evaluation and treatment of chronic wounds in the home care setting]

In 2001, it became evident that the domiciliary care nurses needed a tool to assist them in treating patients with chronic wounds. A protocol was therefore developed which could be used not only by the nurses but also by doctors and other health care professionals working in home care. As a parallel measure, a network of nurses specialised in wound care and available for advice and consultation was established.

Effects of arterial oxygen tension and cardiac output on venous saturation: a mathematical modeling approach

OBJECTIVES: Hemodynamic support is aimed at providing adequate O-2 delivery to the tissues; most interventions target O-2 delivery increase. Mixed venous O-2 saturation is a frequently used parameter to evaluate the adequacy of O-2 delivery. METHODS: We describe a mathematical model to compare the effects of increasing O-2 delivery on venous oxygen saturation through increases in the inspired O-2 fraction versus increases in cardiac output. The model was created based on the lungs, which were divided into shunted and non-shunted areas, and on seven peripheral compartments, each with normal values of perfusion, optimal oxygen consumption, and critical O-2 extraction rate. O-2 delivery was increased by changing the inspired fraction of oxygen from 0.21 to 1.0 in steps of 0.1 under conditions of low (2.0 L.min(-1)) or normal (6.5 L.min(-1)) cardiac output. The same O-2 delivery values were also obtained by maintaining a fixed O-2 inspired fraction value of 0.21 while changing cardiac output. RESULTS: Venous oxygen saturation was higher when produced through increases in inspired O-2 fraction versus increases in cardiac output, even at the same O-2 delivery and consumption values. Specifically, at high inspired O-2 fractions, the measured O-2 saturation values failed to detect conditions of low oxygen supply. CONCLUSIONS: The mode of O-2 delivery optimization, specifically increases in the fraction of inspired oxygen versus increases in cardiac output, can compromise the capability of the "venous O-2 saturation" parameter to measure the adequacy of oxygen supply. Consequently, venous saturation at high inspired O-2 fractions should be interpreted with caution.

Efficacy of graded activity versus supervised exercises in patients with chronic non-specific low back pain: protocol of a randomised controlled trial

Abstract Background Low back pain is a relevant public health problem, being an important cause of work absenteeism worldwide, as well as affecting the quality of life of sufferers and their individual functional performances. Supervised active physical routines and of cognitive-behavioral therapies are recommended for the treatment of chronic Low back pain, although evidence to support the effectiveness of different techniques is missing. Accordingly, the aim of this study is to contrast the effectiveness of two types of exercises, graded activity or supervised, in decreasing symptoms of chronic low back pain. Methods/design Sample will consist of 66 patients, blindly allocated into one of two groups: 1) Graded activity which, based on an operant approach, will use time-contingent methods aiming to increase participants’ activity levels; 2) Supervised exercise, where participants will be trained for strengthening, stretching, and motor control targeting different muscle groups. Interventions will last one hour, and will happen twice a week for 6 weeks. Outcomes (pain, disability, quality of life, global perceived effect, return to work, physical activity, physical capacity, and kinesiophobia) will be assessed at baseline, at treatment end, and three and six months after treatment end. Data collection will be conducted by an investigator blinded to treatment allocation. Discussion This project describes the randomisation method that will be used to compare the effectiveness of two different treatments for chronic low back pain: graded activity and supervised exercises. Since optimal approach for patients with chronic back pain have yet not been defined based on evidence, good quality studies on the subject are necessary. Trial registration NCT01719276

Development of Clinical Decision Support Systems based on Mathematical Models of Physiological Systems

In the last years of research, I focused my studies on different physiological problems. Together with my supervisors, I developed/improved different mathematical models in order to create valid tools useful for a better understanding of important clinical issues. The aim of all this work is to develop tools for learning and understanding cardiac and cerebrovascular physiology as well as pathology, generating research questions and developing clinical decision support systems useful for intensive care unit patients. I. ICP-model Designed for Medical Education We developed a comprehensive cerebral blood flow and intracranial pressure model to simulate and study the complex interactions in cerebrovascular dynamics caused by multiple simultaneous alterations, including normal and abnormal functional states of auto-regulation of the brain. Individual published equations (derived from prior animal and human studies) were implemented into a comprehensive simulation program. Included in the normal physiological modelling was: intracranial pressure, cerebral blood flow, blood pressure, and carbon dioxide (CO2) partial pressure. We also added external and pathological perturbations, such as head up position and intracranial haemorrhage. The model performed clinically realistically given inputs of published traumatized patients, and cases encountered by clinicians. The pulsatile nature of the output graphics was easy for clinicians to interpret. The manoeuvres simulated include changes of basic physiological inputs (e.g. blood pressure, central venous pressure, CO2 tension, head up position, and respiratory effects on vascular pressures) as well as pathological inputs (e.g. acute intracranial bleeding, and obstruction of cerebrospinal outflow). Based on the results, we believe the model would be useful to teach complex relationships of brain haemodynamics and study clinical research questions such as the optimal head-up position, the effects of intracranial haemorrhage on cerebral haemodynamics, as well as the best CO2 concentration to reach the optimal compromise between intracranial pressure and perfusion. We believe this model would be useful for both beginners and advanced learners. It could be used by practicing clinicians to model individual patients (entering the effects of needed clinical manipulations, and then running the model to test for optimal combinations of therapeutic manoeuvres). II. A Heterogeneous Cerebrovascular Mathematical Model Cerebrovascular pathologies are extremely complex, due to the multitude of factors acting simultaneously on cerebral haemodynamics. In this work, the mathematical model of cerebral haemodynamics and intracranial pressure dynamics, described in the point I, is extended to account for heterogeneity in cerebral blood flow. The model includes the Circle of Willis, six regional districts independently regulated by autoregulation and CO2 reactivity, distal cortical anastomoses, venous circulation, the cerebrospinal fluid circulation, and the intracranial pressure-volume relationship. Results agree with data in the literature and highlight the existence of a monotonic relationship between transient hyperemic response and the autoregulation gain. During unilateral internal carotid artery stenosis, local blood flow regulation is progressively lost in the ipsilateral territory with the presence of a steal phenomenon, while the anterior communicating artery plays the major role to redistribute the available blood flow. Conversely, distal collateral circulation plays a major role during unilateral occlusion of the middle cerebral artery. In conclusion, the model is able to reproduce several different pathological conditions characterized by heterogeneity in cerebrovascular haemodynamics and can not only explain generalized results in terms of physiological mechanisms involved, but also, by individualizing parameters, may represent a valuable tool to help with difficult clinical decisions. III. Effect of Cushing Response on Systemic Arterial Pressure. During cerebral hypoxic conditions, the sympathetic system causes an increase in arterial pressure (Cushing response), creating a link between the cerebral and the systemic circulation. This work investigates the complex relationships among cerebrovascular dynamics, intracranial pressure, Cushing response, and short-term systemic regulation, during plateau waves, by means of an original mathematical model. The model incorporates the pulsating heart, the pulmonary circulation and the systemic circulation, with an accurate description of the cerebral circulation and the intracranial pressure dynamics (same model as in the first paragraph). Various regulatory mechanisms are included: cerebral autoregulation, local blood flow control by oxygen (O2) and/or CO2 changes, sympathetic and vagal regulation of cardiovascular parameters by several reflex mechanisms (chemoreceptors, lung-stretch receptors, baroreceptors). The Cushing response has been described assuming a dramatic increase in sympathetic activity to vessels during a fall in brain O2 delivery. With this assumption, the model is able to simulate the cardiovascular effects experimentally observed when intracranial pressure is artificially elevated and maintained at constant level (arterial pressure increase and bradicardia). According to the model, these effects arise from the interaction between the Cushing response and the baroreflex response (secondary to arterial pressure increase). Then, patients with severe head injury have been simulated by reducing intracranial compliance and cerebrospinal fluid reabsorption. With these changes, oscillations with plateau waves developed. In these conditions, model results indicate that the Cushing response may have both positive effects, reducing the duration of the plateau phase via an increase in cerebral perfusion pressure, and negative effects, increasing the intracranial pressure plateau level, with a risk of greater compression of the cerebral vessels. This model may be of value to assist clinicians in finding the balance between clinical benefits of the Cushing response and its shortcomings. IV. Comprehensive Cardiopulmonary Simulation Model for the Analysis of Hypercapnic Respiratory Failure We developed a new comprehensive cardiopulmonary model that takes into account the mutual interactions between the cardiovascular and the respiratory systems along with their short-term regulatory mechanisms. The model includes the heart, systemic and pulmonary circulations, lung mechanics, gas exchange and transport equations, and cardio-ventilatory control. Results show good agreement with published patient data in case of normoxic and hyperoxic hypercapnia simulations. In particular, simulations predict a moderate increase in mean systemic arterial pressure and heart rate, with almost no change in cardiac output, paralleled by a relevant increase in minute ventilation, tidal volume and respiratory rate. The model can represent a valid tool for clinical practice and medical research, providing an alternative way to experience-based clinical decisions. In conclusion, models are not only capable of summarizing current knowledge, but also identifying missing knowledge. In the former case they can serve as training aids for teaching the operation of complex systems, especially if the model can be used to demonstrate the outcome of experiments. In the latter case they generate experiments to be performed to gather the missing data.

Selecting candidate predictor variables for the modelling of post-discharge mortality from sepsis: a protocol development project.

Background: Post-discharge mortality is a frequent but poorly recognized contributor to child mortality in resource limited countries. The identification of children at high risk for post-discharge mortality is a critically important first step in addressing this problem. Objectives: The objective of this project was to determine the variables most likely to be associated with post-discharge mortality which are to be included in a prediction modelling study. Methods: A two-round modified Delphi process was completed for the review of a priori selected variables and selection of new variables. Variables were evaluated on relevance according to (1) prediction (2) availability (3) cost and (4) time required for measurement. Participants included experts in a variety of relevant fields. Results: During the first round of the modified Delphi process, 23 experts evaluated 17 variables. Forty further variables were suggested and were reviewed during the second round by 12 experts. During the second round 16 additional variables were evaluated. Thirty unique variables were compiled for use in the prediction modelling study. Conclusion: A systematic approach was utilized to generate an optimal list of candidate predictor variables for the incorporation into a study on prediction of pediatric post-discharge mortality in a resource poor setting.

Modelling the Distribution of Ischaemic Stroke-Specific Survival Time Using an EM-based Mixture Approach with Random Effects Adjustment

A two-component survival mixture model is proposed to analyse a set of ischaemic stroke-specific mortality data. The survival experience of stroke patients after index stroke may be described by a subpopulation of patients in the acute condition and another subpopulation of patients in the chronic phase. To adjust for the inherent correlation of observations due to random hospital effects, a mixture model of two survival functions with random effects is formulated. Assuming a Weibull hazard in both components, an EM algorithm is developed for the estimation of fixed effect parameters and variance components. A simulation study is conducted to assess the performance of the two-component survival mixture model estimators. Simulation results confirm the applicability of the proposed model in a small sample setting. Copyright (C) 2004 John Wiley Sons, Ltd.

Initial hepatosplanchnic blood flow distribution and oxygen metabolism in experimental model of hypotensive brain death

Background: Organs from the so-called marginal donors have been used with a significant higher risk of primary non function than organs retrieved from the optimal donors. We investigated the early metabolic changes and blood flow redistribution in splanchnic territory in an experimental model that mimics marginal brain-dead (BD) donor. Material/Methods: Ten dogs (21.3 +/- 0.9 kg), were subjected to a brain death protocol induced by subdural balloon inflation and observed for 30 min thereafter without ally additional interventions. Mean arterial and intracranial pressures, heart rate, cardiac output (CO), portal vein and hepatic artery blood flows (PVBF and HABF, ultrasonic flowprobe), and O(2)-derived variables were evaluated. Results: An increase in arterial pressure, CO, PVBF and HABF was observed after BD induction. At the end, an intense hypotension with normalization in CO (3.0 +/- 0.2 VS. 2.8 +/- 2.8 L/min) and PVBF (687 +/- 114 vs. 623 +/- 130 ml/min) was observed, whereas HABF (277 33 vs. 134 28 ml/min, p<0.005) remained lower than baseline values. Conclusions: Despite severe hypotension induced by sudden increase of intracranial pressure, the systemic and splanchnic blood flows were partially preserved without signs of severe hypoperfusion (i.e. hyperlactatemia). Additionally, the HABF was mostly negatively affected in this model of marginal BD donor. Our data suggest that not only the cardiac output, but the intrinsic hepatic microcirculatory mechanism plays a role in the hepatic blood flow control after BD.

Use of cyclic variation of integrated backscatter to assess contractile reserve and myocardial viability in chronic ischemic left ventricular dysfunction

The detection of viable myocardium has important implications for management, but use of stress echocardiography to detect this is subjective and requires exposure to dobutamine. We investigated whether cyclic variation (CV) of integrated backscatter (IB) from the apical views could provide a resting study for detection of contractile reserve (CR) and prediction of myocardial viability in 27 patients with chronic ischemic left ventricular (LV) dysfunction. Repeat echocardiography was performed after 6.7 +/- 3.8 months of follow-up; 14 patients underwent revascularization and 13 were treated medically. Using a standardized dobutamine echocardiography (DbE) protocol, images from three apical views were acquired at 80-120 frames/sec at rest and during stress. CR was identified if improvement of wall motion was observed at low dose (5 or 10 mug/kg/min) DbE. Myocardial viability was characterized by improvement at follow-up echocardiography in patients with revascularization. CVIB at rest and low dose dobutamine were assessed in 194 segments with resting asynergy (severe hypokinesis or akinesis), of which 88 (45%) were in patients who underwent revascularization. Of these, CVIB could be measured in 190 (98%) segments at rest and 185 (95%) at low dose dobutamine. Sixty-two (33%) segments had CR during low dose DbE and 50 (57%) segments showed wall-motion recovery (myocardial viability) at follow-up echocardiography. Segments with CR had significantly higher CVIB at rest (P < 0.001) and low dose dobutamine (P = 0.005) than segments without CR. Using optimal thresholds of CVIB (> 8.2 dB) at rest, the accuracy of CVIB for detecting CR was 70%. Compared with nonviable segments, viable segments had significantly higher CVIB at rest (P < 0.001) and low dose dobutamine (P < 0.001). Using optimal thresholds of CVIB (> 5.3 dB) at rest, the accuracy of CVIB for detecting myocardial viability was 85%, which was higher than that in conventional DbE (62%, P < 0.01). Thus, assessment of CV.TB from the apical views is a feasible and accurate tool for detecting CR and predicting myocardial viability in chronic LV dysfunction.