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Biomedical subjects

M Epstein

Publications and source records attributed to M Epstein.

At least 55 records · Page 3Linked to original sources
PubMed1999

Role of a third generation calcium antagonist in the management of hypertension.

Calcium antagonists are uniquely suitable for managing hypertension by virtue of their efficacy, metabolic neutrality and their ability to countervail counterregulatory adaptive changes, thereby enhancing blood pressure lowering. Recent evidence has accrued underscoring the concept that calcium antagonists are heterogeneous and consist of chemically dissimilar agents. The difference in formulations and pharmacokinetics affect clinical events including the effect on blood pressure, heart rate and the degree with which sympathetic activity is activated. Lacidipine is a new calcium antagonist that is the prototype of the lipophilic dihydropyridines. Of great importance, lacidipine has a slow onset of vasodilator/antihypertensive effect and does not promote an excessive sympathetic drive. These attributes commend its selection as an antihypertensive agent.

Antihypertensive Agents↗
PubMed1999

Lysophosphatidic acid and mesangial cells: implications for renal diseases.

The last decade has witnessed a phenomenal increase in our understanding of the biological role of lysophosphatidic acid (LPA) and has led to an appreciation of this critical serum-derived growth factor released from platelets. We herein summarize recent observations that collectively support the hypothesis that LPA may play a key role in the pathogenesis of initiation and progression of proliferative glomerulonephritis. LPA synergistically stimulates mesangial cell proliferation in combination with platelet-derived growth factor in primary culture. The mechanism of co-mitogenesis is likely to be mediated by the prolonged activation of mitogen-activated protein kinase which is stimulated by platelet-derived growth factor and LPA through different mechanisms. LPA contracts cultured mesangial cells and has properties in common with other pressor molecules including mobilization of intracellular Ca2+ and promotion of Ca2+ entry through dihydropyridine-sensitive calcium channels. LPA receptor mRNA has been identified in isolated glomeruli dissected from renal biopsy samples of patients with IgA nephropathy. All of these facts have led us to postulate that LPA is produced within glomeruli and that LPA's mitogenic as well as haemodynamic action contribute to the pathological process of mesangial proliferative glomerulonephritis. The possible production of LPA as an autocrine factor from mesangial cells themselves has also been discussed.

Glomerular Mesangium↗
PubMed1998

Evaluation of the finite element software ABAQUS for biomechanical modelling of biphasic tissues.

The biphasic cartilage model proposed by Mow et al. (1980) has proven successful to capture the essential mechanical features of articular cartilage. In order to analyse the joint contact mechanics in real, anatomical joints, the cartilage model needs to be implemented into a suitable finite element code to approximate the irregular surface geometries of such joints. However, systematic and extensive evaluation of the capacity of commercial software for modelling the contact mechanics with biphasic cartilage layers has not been made. This research was aimed at evaluating the commercial finite element software ABAQUS for analysing biphasic soft tissues. The solutions obtained using ABAQUS were compared with those obtained using other finite element models and analytical solutions for three numerical tests: an unconfined indentation test, a test with the contact of a spherical cartilage surface with a rigid plate, and an axi-symmetric joint contact test. It was concluded that the biphasic cartilage model can be implemented into the commercial finite element software ABAQUS to analyse practical joint contact problems with biphasic articular cartilage layers.

Animals↗
PubMed1998

Can a rheological muscle model predict force depression/enhancement?

A new phenomenological model of activated muscle is presented. The model is based on a combination of a contractile element, an elastic element that engages upon activation, a linear dashpot and a linear spring. Analytical solutions for a few selected experiments are provided. This model is able to reproduce the response of cat soleus muscle to ramp shortening and stretching and, unlike standard Hill-type models, computations are stable on the descending limb of the force-length relation and force enhancement (depression) following stretching (shortening) is predicted correctly. In its linear version, the model is consistent with a linear force-velocity law, which in this model is a consequence rather than a fundamental characteristic of the material. Results show that the mechanical response of activated muscle can be mimicked by a viscoelastic system. Conceptual differences between this model and standard Hill-type models are analyzed and the advantages of the present model are discussed.

Algorithms↗
PubMed1998

Material and functional properties of articular cartilage and patellofemoral contact mechanics in an experimental model of osteoarthritis.

The purposes of this study were to determine the in situ functional and material properties of articular cartilage in an experimental model of joint injury, and to quantify the corresponding in situ joint contact mechanics. Experiments were performed in the anterior cruciate ligament (ACL) transected knee of the cat and the corresponding, intact contralateral knee, 16 weeks following intervention. Cartilage thickness, stiffness, effective Young's modulus, and permeability were measured and derived from six locations of the knee. The total contact area and peak pressures in the patellofemoral joint were obtained in situ using Fuji Pressensor film, and comparisons between experimental and contralateral joint were made for corresponding loading conditions. Total joint contact area and peak pressure were increased and decreased significantly (alpha=0.01), respectively, in the experimental compared to the contralateral joint. Articular cartilage thickness and stiffness were increased and decreased significantly (alpha=0.01), respectively, in the experimental compared to the contralateral joint in the four femoral and patellar test locations. Articular cartilage material properties (effective Young's modulus and permeability) were the same in the ACL-transected and intact joints. These results demonstrate for the first time the effect of changes in articular cartilage properties on the load transmission across a joint. They further demonstrate a substantial change in the joint contact mechanics within 16 weeks of ACL transection. The results were corroborated by theoretical analysis of the contact mechanics in the intact and ACL-transected knee using biphasic contact analysis and direct input of cartilage properties and joint surface geometry from the experimental animals. We conclude that the joint contact mechanics in the ACL-transected cat change within 16 weeks of experimental intervention.

Animals↗
PubMed1998

Pathophysiology of diabetic nephropathy.

Diabetic nephropathy (DN) is now the commonest cause of end-stage renal failure in the Western world. Recent studies examining the pathogenesis of diabetic complications have focused on the complex interaction between genetic and hemodynamic mechanisms in addition to metabolic factors such as advanced glycation, protein kinase C (PKC) activation, and polyol production. The importance of the various components, particularly with regard to the progression of DN, is currently being explored with the assistance of targeted drug intervention studies.

Diabetic Nephropathies↗
PubMed1998

Potential of dopamine A-1 agonists in the management of acute renal failure.

Many therapeutic approaches have been undertaken both to prevent acute ischemic or nephrotoxic renal injury and, once acute renal failure (ARF) has developed, to improve renal function and reduce mortality. To date, most therapeutic studies have investigated the effects of diuretics (eg, mannitol, furosemide), vasoactive agents (calcium channel blockers, atrial natriuretic peptide), or dopamine (a nonselective dopaminergic agent [DAA]) in one or more phases of ARF. Unfortunately, studies of the use of DAA in ARF are complicated by the existence of at least two different DAA receptors (DA-1 and DA-2), and by the stimulation of alpha- and/or beta-adrenergic receptors by high doses of DAA. The undesirable side effects of high doses of dopamine and the inconclusive results using low doses (ie, "renal doses") of dopamine (a nonselective DAA) have prompted consideration of the use of more selective dopaminergic agonists for the prophylaxis and treatment of ARF. Selective DA-1 agonists exhibit many desirable renal effects that theoretically support their use for the prophylaxis and/or treatment of ARF, including decreases in renal vascular resistance accompanied by increases in renal blood flow and glomerular filtration rate, and increases in sodium excretion and urine volume. Even at high doses, some selective DA-1 agonists, such as fenoldopam, do not stimulate DA-2 receptors, or adrenergic alpha- or beta-receptors, and thus are free of unwanted side effects (eg, arrhythmias). Results of several studies in normal and hypertensive humans, and a few studies in animal models, are consistent with the notion that DA-1 agonists may be useful in preventing or treating ARF. Careful randomized prospective clinical trials of DA-1 agonists in human ARF are needed to test this hypothesis.

Acute Kidney Injury↗
PubMed1998

Nested expression and sequential downregulation of the Xenopus caudal genes along the anterior-posterior axis.

Expression of the Xenopus Xcad-1 and Xcad-2 genes initiates during early gastrulation exhibiting a dorsoventral asymmetry in their domains of transcription. At mid-gastrulation the ventral preference becomes stronger and the caudal genes take up a posterior localization in their expression, which they will maintain until their downregulation along the dorsal midline. Comparison of the three Xenopus caudal genes revealed a temporal and spatial nested set of expression patterns. The transcription of the caudal genes is sequentially downregulated with the one expressed most caudally (Xcad-2) being shut down first, this sequence is most evident along the dorsal midline. This pattern of expression suggests a role for the caudal genes as posterior determinants along the anteroposterior axis. In chicken, mouse, man and Xenopus three members of the caudal family have been identified in the genome. Even though in Xenopus the Xcad-3 gene has been previously described, in order to obtain a better insight on the role of the caudal genes a comparative study of all three frog genes was performed.

Animals↗
PubMed1998

The Xcad-2 gene can provide a ventral signal independent of BMP-4.

Patterning of the marginal zone in the Xenopus embryo has been attributed to interactions between dorsal genes expressed in the organizer and ventral-specific genes. In this antagonistic interplay of activities, BMP-4, a gene that is not expressed in the organizer, provides a strong ventralizing signal. The Xenopus caudal type homeobox gene, Xcad-2, which is expressed around the blastopore with a gap over the dorsal lip, was analyzed as part of the ventral signal. Xcad-2 was shown to efficiently repress during early gastrula stages the dorsal genes gsc, Xnot-2, Otx-2, XFKH1 and Xlim-1, while it positively regulates the ventral genes, Xvent-1 and Xvent-2, with Xpo exhibiting a strong positive response to Xcad-2 overexpression. Xcad-2 was also capable of inducing BMP-4 expression in the organizer region. Support for a ventralizing role for Xcad-2 was obtained from co-injection experiments with the dominant negative BMP receptor which was used to block BMP-4 signaling. Under lack-of-BMP-signaling conditions Xcad-2 could still regulate dorsal and ventral gene expression and restore normal development, suggesting that it can act downstream of BMP-4 signaling or independently of it. Xcad-2 could also inhibit secondary axis formation and dorsalization induced by the dominant negative BMP receptor. Xcad-2 was also shown to efficiently reverse the dorsalizing effects of LiCl. These results place Xcad-2 as part of the ventralizing gene program which acts during early gastrula stages and can execute its ventralizing function in the absence of BMP signaling.

Animals↗
PubMed1998

A numerical study of the stiffness of a sarcomere.

Relatively recent experimental findings of the significant compliance of the thin (actin) and thick (myosin) filaments have brought into question a number of conclusions based on the assumption of perfect myofilament rigidity. A new model based on a discrete representation of the relevant structures was used to calculate the theoretical stiffness of a sarcomere with compliant myofilaments. Because of the discrete nature of the model, it can be applied to situations in which either the number of links between filaments is low (i.e. partial overlap or partial activation) or the spatial distribution of links is not uniform. The results of this model are discussed and compared to the predictions given by the previously published model by Ford et al. (Ford, L. E., Huxley, A. F. and Simmons, R. M., Journal of Physiology, 1981, 311, 219--249). Although it can be shown that both models give identical results for an infinite number of links, our model consistently predicts a stiffer sarcomere for partial overlap. The differences in the stiffness values as calculated by a model with rigid filaments, the continuous model by Ford et al. and the discrete model presented here would lead to differences in the interpretation of experimental results, especially in the case of partial overlap and partial activation. An explanation for the discrepancies between models is presented together with a way to correct the continuous model to approximate discrete model results.

Actin Cytoskeleton↗
PubMed1998

The temporal profile and morphologic features of neuronal death in human stroke resemble those observed in experimental forebrain ischemia: the potential role of apoptosis.

Although neuronal death has been studied in experimental models of ischemia, the precise mechanisms regulating cell death remain unclear. Furthermore, the timing and pattern of neuronal death in human stroke has not been extensively studied. To further our understanding of ischemia-induced neuronal death, we examined the temporal profile of histochemical and morphologic characteristics of hippocampal neuronal death following experimental forebrain ischemia and compared these findings to human brain specimens obtained from subjects suffering cerebral infarction. Transient forebrain ischemia (TFI) was induced in normothermic adult rats by bilateral carotid artery occlusion combined with hypotension. Animals were sacrificed at 6, 12, 18, 24, 48, and 72 h and 7, 14, and 28 days following ischemia (n = 4 at each time point). Experimental tissue was analyzed using light and electron microscopy as well as TUNEL histochemistry. A total of 27 human brain specimens with neuropathological confirmation of ischemic damage and appropriate controls were also examined using light microscopy and TUNEL histochemistry. Dense TUNEL staining in hippocampal CA-1 neurons was present at 48 and 72 h following experimental ischemia. Prior to these times, little or no nuclear staining was noted and after 72 h nuclear staining diminished rapidly. Ultrastructural findings at these time points demonstrated many features similar to those seen in cells undergoing apoptosis, such as cell shrinkage with increased electron density, chromatin condensation with formation of heterochromatin, intact plasma membranes, and intact intracellular organelles. In a similar fashion, human stroke specimens during the subacute period showed dense nuclear TUNEL staining in penumbral neurons, whereas in the acute or chronic stages little or no staining was noted. Our results demonstrate that the timing of morphologic changes and TUNEL histochemistry following human stroke resembles that observed in experimental TFI. Furthermore, neuronal death in both experimental ischemia and human stroke share several features characteristic of apoptotic cell death.

Adolescent↗
PubMed1998

Calcium antagonists and the progression of chronic renal failure.

End-stage renal disease, which signifies irreversible renal failure, constitutes a major and growing public health problem worldwide. The striking increase in end-stage renal disease has catalyzed clinical and investigative focus on pharmacologic interventions to retard progression to this condition. Increasing evidence indicates that some classes of antihypertensive medications may confer a greater effect than others in slowing progression of renal disease despite similar levels of blood pressure reduction. Substantive data indicate that angiotensin converting enzyme inhibition preferentially retards the progression of renal disease, primarily by protecting the injured kidney from hemodynamically mediated glomerular damage. Newer studies suggest that calcium antagonists also have diverse properties, which are independent of their renal microcirculatory effects that might afford renal protection.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

University of Miami Division of Clinical Pharmacology Therapeutic Rounds: ischemic renal disease.

Ischemic renal disease (IRD) is defined as a significant reduction in glomerular filtration rate and/or loss of renal parenchyma caused by hemodynamically significant renal artery stenosis. IRD is a common and often overlooked clinical entity that presents in the setting of extrarenal arteriosclerotic vascular disease in older individuals with azotemia. IRD is an important cause of chronic renal failure and end-stage renal disease (ESRD), and many patients with a presumed diagnosis of hypertensive nephrosclerosis may actually have undiagnosed ischemic nephropathy as the cause of their ESRD. The primary reason for establishing the diagnosis of IRD is the hope that correction of a renal artery stenosis will lead to improvement of renal function or a delay in progression to ESRD. There are six typical clinical settings in which the clinician could suspect IRD: acute renal failure caused by the treatment of hypertension, especially with angiotensin-converting enzyme inhibitors; progressive azotemia in a patient with known renovascular hypertension; acute pulmonary edema superimposed on poorly controlled hypertension and renal failure; progressive azotemia in an elderly patient with refractory or severe hypertension; progressive azotemia in an elderly patient with evidence of atherosclerotic disease; and unexplained progressive azotemia in an elderly patient. It is important for the clinician to identify IRD, because IRD represents a potentially reversible cause of chronic renal failure in a hypertensive patient.

Aged↗
PubMed1998

Articular joint mechanics with biphasic cartilage layers under dynamic loading.

The composition and amount of extracellular matrix produced by chondrocytes are thought to be influenced by the stress and strain states in the vicinity of the chondrocytes. During daily activities, such as walking and running, articular joints are loaded dynamically. In the present study, a solution is proposed to simulate the responses of a joint under dynamic loading. In order to show the characteristics of the proposed solution, numerical simulations were carried out, in which the contact radius, the relative approach displacement between the centers of the contacting bodies, or the contact force were controlled. As a result of the history-dependent material properties of the articular cartilage, the predicted parameters changed nonperiodically, when the controlled parameters varied periodically. For a constant load, the contact radius and the relative displacement between the contacting bodies were predicted to increase at decreasing rates. When the contact force was varied dynamically, the predicted mean values of the contact radius, the relative displacement between the contacting bodies, and the contact pressure at the center of the contact area depended on the amplitude and the duration of the loading. When the relative displacement between the contacting bodies was controlled, the amplitudes and the cycling frequency must be limited to avoid a loss of contact between the articular joint surfaces. The proposed solution is valid for a long but limited time period, the exact extent of which is yet to be determined. It can be used to simulate the effects associated with cartilage degeneration in diseases such as osteoarthritis.

Biomechanical Phenomena↗
PubMed1998

Effects of inserting a pressensor film into articular joints on the actual contact mechanics.

Fuji film has been widely used in studies aimed at obtaining the contact mechanics of articular joints. Once sealed for practical use in biological joints, Fuji Pressensor film has a total effective thickness of 0.30 mm, which is comparable to the cartilage thickness in the joints of many small animals. The average effective elastic modulus of Fuji film is approximately 100 MPa in compression, which is larger by a factor of 100-300 compared to that of normal articular cartilage. Therefore, inserting a Pressensor film into an articular joint will change the contact mechanics of the joint. The measurement precision of the Pressensor film has been determined systematically; however, the changes in contact mechanics associated with inserting the film into joints have not been investigated. This study was aimed at quantifying the changes in the contact mechanics associated with inserting sealed Fuji Pressensor film into joints. Spherical and cylindrical articular joint contact mechanics with and without Pressensor film and for varying degrees of surface congruency were analyzed and compared by using finite element models. The Pressensor film was taken as linearly elastic and the cartilage was assumed to be biphasic, composed of a linear elastic solid phase and an inviscid fluid phase. The present analyses showed that measurements of the joint contact pressures with Fuji Pressensor film will change the maximum true contact pressures by 10-26 percent depending on the loading, geometry of the joints, and the mechanical properties of cartilage. Considering this effect plus the measurement precision of the film (approximately 10 percent), the measured joint contact pressures in a joint may contain errors as large as 14-28 percent.

Animals↗