Reversal of cardiovascular remodelling with candesart

Cardiovascular remodelling, defined as ventricular and vascular hypertrophy together with fibrosis, characterises hypertension following inhibition of the production of the endogenous vasodilator, nitric oxide (NO). This study has determined whether the cardiovascular remodelling following chronic NO synthase inhibition can e reversed by administration of the selective angiotensin II AT(1)-receptor antagonist, candesartan. Male Wistar rats were treated with L-nitroarginine methyl ester (L-NAME, 400 mg/l in drinking water) for eight weeks and with candesartan cilexetil (2 mg/kg/day by oral gavage) for the last four weeks. L-NAME-treated rats became hypertensive with systolic blood pressure increasing from 110 +/- 4 mmHg (control) to 170 +/- 10 mmHg. Rats developed left ventricular hypertrophy (control 1.70 +/- 0.06; L-NAME 2.10 +/- 0.04 mg/kg body wt) with markedly increased deposition of perivascular and interstitial collagen. Candesartan returned blood pressure, left ventricular weights and collagen deposition to control values. Echo cardiographic assessment showed concentric hypertrophy with an increased fractional shortening; this was reversed by candesartan treatment. Heart failure was not evident. In the isolated Langendorff heart, diastolic stiffness increased in L-NAME-treated rats while the rate of increase in pressure (+dP/dt) increased after eight weeks only; candesartan reduced collagen deposition and normalised +dP/dt. In isolated left ventricular papillary muscles, the potency (negative log EC50) of noradrenaline as a positive inotropic compound was unchanged, (control 6.56 +/- 0.14); maximal increase in force before ectopic beats was reduced from 5.0 +/- 0.4 mN to 2.0 +/- 0.2 mN. Noradrenaline potency as a vasoconstrictor in thoracic aortic rings was unchanged, but maximal contraction was markedly reduced from 25.2 +/- 2.0 mN to 3.0 +/- 0.3 mN; this was partially reversed by candesartan treatment. Thus, chronic inhibition of NO production with L-NAME induces hypertension, hypertrophy and fibrosis with increased toxicity and significant decreases in vascular responses to noradrenaline. These changes were at least partially reversible by treatment with candesartan, implying a significant role of AT(1)-receptors in L-NAME-induced cardiovascular changes.

Molecular clocks in reptiles: Life history influences rate of molecular evolution

Life history has been implicated as a determinant of variation in rate of molecular evolution amongst vertebrate species because of a negative correlation between bode size and substitution rate for many Molecular data sets. Both the generality and the cause of the negative bode size trend have been debated, and the validity of key studies has been questioned (particularly concerning the failure to account for phylogenetic bias). In this study, a comparative method has been used to test for an association between a range of life-history variables-such as body size age at maturity, and clutch size-and DNA substitution rate for three genes (NADH4, cytochrome b, and c-mos). A negative relationship between body size and rate of molecular evolution was found for phylogenetically independent pairs of reptile species spanning turtles. lizards. snakes, crocodile, and tuatara. Although this Study was limited by the number of comparisons for which both sequence and lite-history data were available, the results, suggest that a negative bode size trend in rate of molecular evloution may be a general feature of reptile molecular evolution. consistent with similar studies of mammals and birds. This observation has important implications for uncovering the mechanisms of molecular evolution and warns against assuming that related lineages will share the same substitution rate (a local molecular clock) in order to date evolutionary divergences from DNA sequences.

Vascular dysfunction and heart failure: Epiphenomenon or etiologic agent?

Endothelial function plays a key role in the local regulation of vascular tone. Alterations in endothelial function may result in impaired release of endothelium-derived relaxing factors or increased release of endothelium-derived contracting factors. Heart failure may impair endothelial function by means of reduced synthesis and release of nitric oxide (NO) or by increased degradation of NO and increased production of endothelin-1. Endothelial dysfunction may worsen heart function by means of peripheral effects, causing increased afterload and central effects such as myocardial ischemia and inducible nitric oxide synthase (iNOS)-induced detrimental effects. Evidence from clinical studies has suggested that there is a correlation between decreased endothelial function and increasing severity of congestive heart failure (CHF). Treatments that improve heart function may also improve endothelial dysfunction. The relationship between endothelial dysfunction and heart failure may be masked by the stage of endothelial dysfunction, the location of vessels being tested, and the state of endothelial-dependent vasodilatation response.

Stress correlation function evolution in lattice solid elasto-dynamic models of shear and fracture zones and earthquake prediction

It has been argued that power-law time-to-failure fits for cumulative Benioff strain and an evolution in size-frequency statistics in the lead-up to large earthquakes are evidence that the crust behaves as a Critical Point (CP) system. If so, intermediate-term earthquake prediction is possible. However, this hypothesis has not been proven. If the crust does behave as a CP system, stress correlation lengths should grow in the lead-up to large events through the action of small to moderate ruptures and drop sharply once a large event occurs. However this evolution in stress correlation lengths cannot be observed directly. Here we show, using the lattice solid model to describe discontinuous elasto-dynamic systems subjected to shear and compression, that it is for possible correlation lengths to exhibit CP-type evolution. In the case of a granular system subjected to shear, this evolution occurs in the lead-up to the largest event and is accompanied by an increasing rate of moderate-sized events and power-law acceleration of Benioff strain release. In the case of an intact sample system subjected to compression, the evolution occurs only after a mature fracture system has developed. The results support the existence of a physical mechanism for intermediate-term earthquake forecasting and suggest this mechanism is fault-system dependent. This offers an explanation of why accelerating Benioff strain release is not observed prior to all large earthquakes. The results prove the existence of an underlying evolution in discontinuous elasto-dynamic, systems which is capable of providing a basis for forecasting catastrophic failure and earthquakes.

Present and future pharacotherapy for heart failure

The pharmacotherapy currently recommended by the American College of Cardiology and the American Heart Association for heart failure (HF) is a diuretic, an angiotensin-converting enzyme inhibitor (ACEI), a β-adrenoceptor antagonist and (usually) digitalis. This current treatment of HF may be improved by optimising the dose of ACEI used, as increasing the dose of lisinopril increases its benefits in HF. Selective angiotensin receptor-1 (AT1) antagonists are effective alternatives for those who cannot tolerate ACEIs. AT1 antagonists may also be used in combination with ACEIs, as some studies have shown cumulative benefits for the combination. In addition to being used in Stage IV HF patients, in whom it has a marked benefit, spironolactone should be studied in less severe HF and in the presence of β-blockers. The use of carvedilol, extended-release metoprolol and bisoprolol should be extended to severe HF patients as these agents have been shown to decrease mortality in this group. The ancillary properties of carvedilol, particularly antagonism at prejunctional β-adrenoceptors, may give it additional benefits to selective β1-adrenoceptor antagonists. Celiprolol and bucindolol are not the β-blockers of choice in HF, as they do not decrease mortality. Although digitalis does not reduce mortality, it remains the only option for a long-term positive inotropic effect, as the long-term use of the phosphodiesterase inhibitors is associated with increased mortality. The calcium sensitising drug levosimendan may be useful in the hospital treatment of decompensated HF to increase cardiac output and improve dyspnoea and fatigue. The antiarrhythmic drug amiodarone should probably be used in patients at high risk of arrhythmic or sudden death, although this treatment may soon be superseded by the more expensive implanted cardioverter defibrillators, which are probably more effective and have fewer side effects. The natriuretic peptide nesiritide has recently been introduced for the hospital treatment of decompensated HF. Novel drugs that may be beneficial in the treatment of HF include the vasopeptidase inhibitors and the selective endothelin-A receptor antagonists but these require much more investigation. However, disappointing results have been obtained in a large clinical trial of the tumour necrosis factor α antagonist etanercept, where no likelihood of a difference between placebo and etanercept was observed. Small clinical trials with recombinant growth hormone to thicken ventricles in dilated cardiomyopathy have given variable results.

The effect of heat transfer mode on heart rate responses and hysteresis during heating and cooling in the estuarine crocodile Crocodylus porosus

The effect of heating and cooling on heart rate in the estuarine crocodile Crocodylus porosus was studied in response to different heat transfer mechanisms and heat loads. Three heating treatments were investigated. C. porosus were: (1) exposed to a radiant heat source under dry conditions; (2) heated via radiant energy while half-submerged in flowing water at 23degreesC and (3) heated via convective transfer by increasing water temperature from 23degreesC to 35degreesC. Cooling was achieved in all treatments by removing the heat source and with C. porosus half-submerged in flowing water at 23degreesC. In all treatments, the heart rate of C. porosus increased markedly in response to heating and decreased rapidly with the removal of the heat source. Heart rate during heating was significantly faster than during cooling at any given body temperature, i.e. there was a significant heart rate hysteresis. There were two identifiable responses to heating and cooling. During the initial stages of applying or removing the heat source, there was a dramatic increase or decrease in heart rate ('rapid response'), respectively, indicating a possible cardiac reflex. This rapid change in heart rate with only a small change or no change in body temperature (

An EM-based Semi-Parametric Mixture Model Approach to the Regression Analysis of Competing-Risks Data

We consider a mixture model approach to the regression analysis of competing-risks data. Attention is focused on inference concerning the effects of factors on both the probability of occurrence and the hazard rate conditional on each of the failure types. These two quantities are specified in the mixture model using the logistic model and the proportional hazards model, respectively. We propose a semi-parametric mixture method to estimate the logistic and regression coefficients jointly, whereby the component-baseline hazard functions are completely unspecified. Estimation is based on maximum likelihood on the basis of the full likelihood, implemented via an expectation-conditional maximization (ECM) algorithm. Simulation studies are performed to compare the performance of the proposed semi-parametric method with a fully parametric mixture approach. The results show that when the component-baseline hazard is monotonic increasing, the semi-parametric and fully parametric mixture approaches are comparable for mildly and moderately censored samples. When the component-baseline hazard is not monotonic increasing, the semi-parametric method consistently provides less biased estimates than a fully parametric approach and is comparable in efficiency in the estimation of the parameters for all levels of censoring. The methods are illustrated using a real data set of prostate cancer patients treated with different dosages of the drug diethylstilbestrol. Copyright (C) 2003 John Wiley Sons, Ltd.

Abnormal left ventricular filling with increasing age reflects abnormal myocardial characteristics independent of ischemia or hypertrophy

Abnormal left ventricular (IV) filling may occur with increasing age despite apparently normal IV size and function, and is usually attributed to IV hypertrophy and coronary artery disease. The purpose of this study was to determine whether myocardial abnormalities could be identified in 67 such patients (36 men, mean age 57 +/- 9 years) whose IV hypertrophy and coronary artery disease were excluded by dobutamine echocardiography. All patients underwent gray scale and color tissue Doppler imaging from 3 apical views, which were stored and analyzed off line. Disturbances in structure and function were assessed by averaging the cyclic variation of integrated backscatter, strain rate, and peak systolic strain from each myocardial segment. Calibrated integrated backscatter (corrected for pericardial backscatter intensity) was measured in the septum and posterior wall from the parasternal long-axis view. Abnormal IV filling was present in 36 subjects (54%). Subjects with and without abnormal IV filling had similar IV mass, but differed in age (p <0.01), cyclic variation (p = 0.001), strain rate (p <0.01), and peak systolic strain (p <0.001). Multivariate logistic regression analysis demonstrated that age (p = 0.016) and cyclic variation (p = 0.042) were the most important determinants of abnormal IV filling in these apparently normal subjects. (C) 2003 by Excerpta Medica, Inc.

Nonbreeding Eastern Curlews Numenius madagascariensis Do Not Increase the Rate of Intake or Digestive Efficiency before Long-Distance Migration because of an Apparent Digestive Constraint

The possibility of premigratory modulation in gastric digestive performance was investigated in a long-distance migrant, the eastern curlew (Numenius madagascariensis), in eastern Australia. The rate of intake in the curlews was limited by the rate of digestion but not by food availability. It was hypothesized that before migration, eastern curlews would meet the increased energy demand by increasing energy consumption. It was predicted that (1) an increase in the rate of intake and the corresponding rate of gastric throughput would occur or (2) the gastric digestive efficiency would increase between the mid-nonbreeding and premigratory periods. Neither crude intake rate (the rate of intake calculated including inactive pauses; 0.22 g DM [grams dry mass] or 3.09 kJ min(-1)) nor the rate of gastric throughput (0.15 g DM or 2.85 kJ min(-1)) changed over time. Gastric digestive efficiency did not improve between the periods (91%) nor did the estimated overall energy assimilation efficiency (63% and 58%, respectively). It was concluded that the crustacean-dominated diet of the birds is processed at its highest rate and efficiency throughout a season. It appears that without a qualitative shift in diet, no increase in intake rate is possible. Accepting these findings at their face value poses the question of how and over what time period the eastern curlews store the nutrients necessary for the ensuing long, northward nonstop flight.

Confirmation: Increasing resource availability for transactional workflows

The notion of compensation is widely used in advanced transaction models as means of recovery from a failure. Similar concepts are adopted for providing transaction-like behaviour for long business processes supported by workflows technology. In general, it is not trivial to design compensating tasks for tasks in the context of a workflow. Actually, a task in a workflow process does not have to be compensatable in the sense that the forcibility of reverse operations of the task is not always guaranteed by the application semantics. In addition, the isolation requirement on data resources may make a task difficult to compensate. In this paper, we first look into the requirements that a compensating task has to satisfy. Then we introduce a new concept called confirmation. With the help of confirmation, we are able to modify most non-compensatable tasks so that they become compensatable. This can substantially increase the availability of shared resources and greatly improve backward recovery for workflow applications in case of failures. To effectively incorporate confirmation and compensation into a workflow management environment, a three level bottom-up workflow design method is introduced. The implementation issues of this design are also discussed. (C) 2003 Elsevier Science Inc. All rights reserved.

Method for determining reaction rate of mild steel containers during melting of magnesium-aluminium alloys and effect of aluminium content on directionally solidified microstructures

A magnesium alloy of eutectic composition (33 wt-'%Al) was directionally solidified in mild steel tubes at two growth rates, 32 and 580 mum s(-1,) in a temperature gradient between 10 and 20 K mm(-1). After directional solidification, the composition of each specimen varied dramatically, from 32'%Al in the region that had remained solid to 18%Al (32 mum s(-1) specimen) and 13%Al (580 mum s(-1) specimen) at the plane that had been quenched from the eutectic temperature. As the aluminium content decreased, the microstructure contained an increasing volume fraction of primary magnesium dendrites and the eutectic morphology gradually changed from lamellar to partially divorced. The reduction in aluminium content was caused by the growth of an Al-Fe phase ahead of the Mg-Al growth front. Most of the growth of the Al-Fe phase occurred during the remelting period before directional solidification. The thickness of the Al-Fe phase increased with increased temperature and time of contact with the molten Mg-Al alloy. (C) 2003 Maney Publishing.

Renal function and cardiovascular risk markers in a remote Australian Aboriginal community

Background. Australian Aborigines living in remote areas have exceedingly high rates of renal failure together with increased cardiovascular morbidity and mortality. To examine the basis of this association, we studied markers of renal function and cardiovascular (CV) risk in a coastal Aboriginal community in a remote area of the Northern Territory of Australia. End-stage renal disease (ESRD) incidence rates in that community are 15 times the national non-Aboriginal rate and CV mortality rates in the region are increased 5-fold. Methods. A cross-sectional community survey was conducted. Markers of early renal disease examined included urine albumin/creatinine ratio (ACR), serum creatinine concentration and calculated glomerular filtration rate (GFR). CV risk markers included blood pressure as well as measures of glycaemia, diabetes and serum lipids. Results. The study group included 237 people, 58% of the adult population of the community. The crude prevalence of microalbuminuria (urine ACR: 3.4-33.9 g/mol, 30-299 mg/g) was 31% and of overt albuminuria (urine ACR: greater than or equal to34 g/mol, greater than or equal to300 mg/g), 13%. The prevalence of overt albuminuria increased with age, but the prevalence of microalbuminuria was greatest in the 45-54 year age group. Microalbuminuria was associated with increasing body mass index, whereas overt albuminuria was associated with increasing glycated haemoglobin (HbA1c) and systolic blood pressure and a history of diabetes. The prevalence of elevated serum creatinine concentration (greater than or equal to120 mumol/l) was 10%. GFR (calculated using the MDRD equation) was <60 ml/min/1.73m(2) in 12% and 60-79 ml/min/1.73 m(2) in a further 36% of the study population. Although many people with albuminuria had well preserved GFRs, mean GFR was lower in people with higher levels of albuminuria. Conclusions. The high prevalence of markers of renal disease in this community was consistent with their high rates of ESRD. The distribution of microalbuminuria suggested a 'cohort effect', representing a group who will progress to overt albuminuria. The powerful association of renal disease markers with CV risk factors confirms a strong link between renal and CV disease in the early, asymptomatic stages of each. Thus, pathologic albuminuria, in part, might be a manifestation of the metabolic/haemodynamic syndrome and both conditions might arise out of a common menu of risk factors. Hence, a single agenda of primary and secondary intervention may benefit both.

Comparative proteomic analysis of GS-NSO murine myeloma cell lines with varying recombinant monoclonal antibody production rate

We have employed an inverse engineering strategy based on quantitative proteome analysis to identify changes in intracellular protein abundance that correlate with increased specific recombinant monoclonal antibody production (qMab) by engineered murine myeloma (NSO) cells. Four homogeneous NSO cell lines differing in qMab were isolated from a pool of primary transfectants. The proteome of each stably transfected cell line was analyzed at mid-exponential growth phase by two-dimensional gel electrophoresis (2D-PAGE) and individual protein spot volume data derived from digitized gel images were compared statistically. To identify changes in protein abundance associated with qMab clatasets were screened for proteins that exhibited either a linear correlation with cell line qMab or a conserved change in abundance specific only to the cell line with highest qMab. Several proteins with altered abundance were identified by mass spectrometry. Proteins exhibiting a significant increase in abundance with increasing qMab included molecular chaperones known to interact directly with nascent immunoglobulins during their folding and assembly (e.g., BiP, endoplasmin, protein disulfide isomerase). 2D-PAGE analysis showed that in all cell lines Mab light chain was more abundant than heavy chain, indicating that this is a likely prerequisite for efficient Mab production. In summary, these data reveal both the adaptive responses and molecular mechanisms enabling mammalian cells in culture to achieve high-level recombinant monoclonal antibody production. (C) 2004 Wiley Periodicals, Inc.

Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure

Background - Specific treatments targeting the pathophysiology of hypertensive heart disease are lacking. As aldosterone has been implicated in the genesis of myocardial fibrosis, hypertrophy, and dysfunction, we sought to determine the effects of aldosterone antagonism on myocardial function in hypertensive patients with suspected diastolic heart failure by using sensitive quantitative echocardiographic techniques in a randomized, double-blinded, placebo-controlled study. Methods and Results - Thirty medically treated ambulatory hypertensive patients (19 women, age 62 +/- 6 years) with exertional dyspnea, ejection fraction >50%, and diastolic dysfunction (E/A 250m/sec) and without ischemia were randomized to spironolactone 25 mg/d or placebo for 6 months. Patients were overweight (31 +/- 5 kg/m(2)) with reduced treadmill exercise capacity (6.7 +/- 2.1 METS). Long-axis strain rate (SR), peak systolic strain, and cyclic variation of integrated backscatter (CVIB) were averaged from 6 walls in 3 standard apical views. Mean 24-hour ambulatory blood pressure at baseline (133 +/- 17/80 +/- 7mm Hg) did not change in either group. Values for SR, peak systolic strain, and CVIB were similar between groups at baseline and remained unchanged with placebo. Spironolactone therapy was associated with increases in SR (baseline: -1.57 +/- 0.46 s(-1) versus 6-months: -1.91 +/- 0.36 s(-1), P < 0.01), peak systolic strain (-20.3 &PLUSMN; 5.0% versus -26.9 &PLUSMN; 4.3%, P < 0.001), and CVIB (7.4 +/- 1.7dB versus 8.6 +/- 1.7 dB, P = 0.08). Each parameter was significantly greater in the spironolactone group compared with placebo at 6 months (P = 0.05, P = 0.02, and P = 0.02, respectively), and the increases remained significant after adjusting for baseline differences. The increase in strain was independent of changes in blood pressure with intervention. The spironolactone group also exhibited reduction in posterior wall thickness (P = 0.04) and a trend to reduced left atrial area (P = 0.09). Conclusions - Aldosterone antagonism improves myocardial function in hypertensive heart disease.

Optimisation of strain rate imaging for application to stress echocardiography

We sought to improve the feasibility of strain rate imaging (SRI) during dobutamine stress echocardiography (DSE) in 56 subjects at low risk of coronary disease. The impact of several SRI changes during acquisition were studied, including: (1) changing from fundamental to harmonic imaging; (2) parallel beam-forming; (3) alteration of spatial resolution and (4) narrow sector acquisition. We assessed SR signal quality, a quantitative measure of signal noise and measurements of SRI. Of 1462 segments evaluated, 6% were uninterpretable at rest and 8% at peak stress. Signal quality was optimised by increasing temporal (p = 0.01) and spatial resolution (p<0.0001 vs. baseline imaging) at rest and peak. Increasing spatial resolution also minimised signal noise (p<0.0001). Inter-observer variability of time to peak SR and peak SR were less with high temporal and spatial resolution. SRI quality can be improved with harmonic imaging and higher temporal resolution but optimisation of spatial resolution is critical. (C) 2004 World Federation for Ultrasound in Medicine Biology.