Search PubMed⌕ Search

Biomedical subjects

M Epstein

Publications and source records attributed to M Epstein.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1998

New chart to evaluate weight faltering.

A new chart was designed to aid accurate identification of weight faltering and failure to thrive. It provides guidance on the lower limits of expected weight gain for children, whatever their initial centile position. The chart's theoretical basis, the process of its construction, and its evaluation are described in this paper. Evaluation was by a self completion questionnaire, where respondents answered questions about a range of standardised growth patterns, plotted on old and new charts. Forty five health visitors, 28 general practitioner principals and registrars, and nine community paediatricians provided 328 chart ratings. These showed that the new format significantly increased the proportion of correctly rated charts (old: 45 (28%); new: 82 (51%)), with the greatest impact in severe cases. This suggests that the new chart improves the precision of judgments made about weight gain in infancy.

Child, Preschool↗
PubMed1998

Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism.

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disease characterized by neoplasia of the parathyroid glands, the endocrine pancreas, and the anterior pituitary gland. In addition, families with isolated endocrine neoplasia, notably familial isolated hyperparathyroidism (FIHP) and familial acromegaly, have also been reported. However, whether these families constitute MEN 1 variants or separate entities remains speculative as the genetic bases for these diseases are unclear. The gene for MEN 1 has recently been cloned and characterized. Using single strand conformation analysis (SSCA) and sequencing, we performed mutation analysis in: a) a total of 55 MEN 1 families from 7 countries, b) 13 isolated MEN 1 cases without family history of the disease, c) 8 acromegaly families, and d) 4 FIHP families. Mutations were identified in 27 MEN 1 families and 9 isolated cases. The 22 different mutations spread across most of the 9 translated exons and included frameshift (11), nonsense (6), splice (2), missense mutations (2), and in-frame deletions (1). Among the 19 Finnish MEN 1 probands, a 1466del12 mutation was identified in 6 families with identical 11q13 haplotypes and in 2 isolated cases indicating a common founder. One frameshift mutation caused by 359del4 (GTCT) was found in 1 isolated case and 4 kindreds of different origin and haplotypes; this mutation therefore represents a common "warm" spot in the MEN1 gene. By analyzing the DNA of the parents of an isolated case one mutation was confirmed to be de novo. No mutation was found in any of the acromegaly and small FIHP families, suggesting that genetic defects other than the MEN1 gene might be involved and that additional such families need to be analyzed.

Acromegaly↗
PubMed1998

Calcium antagonists and renal protection: emerging perspectives.

During the past two decades, major investigative interest has focused on the determinants of chronic renal disease and interventions that retard the inexorable progression to end-stage renal disease. Recent studies have provided a theoretic framework for anticipating that angiotensin-converting enzyme (ACE) inhibitors, and possibly calcium antagonists, may preferentially retard the progression of renal disease. Whereas the majority of available clinical trials have assessed the effects of ACE inhibitors in patients with insulin-dependent diabetes mellitus, relatively few long-term studies have evaluated the renoprotective effects of ACE inhibitors and calcium antagonists in patients with nondiabetic renal disease. Recent observations suggest that the two classes of drugs act in a complementary manner to countervail pathogenetic mechanisms at the level of the mesangium. Such observations recently prompted randomized prospective studies that compare the renoprotective effects of calcium antagonist versus ACE inhibitor monotherapy in both diabetic patients and patients with nondiabetic renal disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

The calcium antagonist controversy: the emerging importance of drug formulation as a determinant of risk.

Calcium antagonists are one of the widely available classes of antihypertensive agents. Their broad appeal is attributable to several features, including their efficacy, their beneficial characteristics such as metabolic neutrality, and the occurrence of relatively few nuisance-type side effects. Despite these attributes, a number of retrospective analyses have suggested that calcium antagonists may be detrimental and may both promote adverse cardiovascular events and increase the risk of cancer by interfering with cellular apoptosis. On the basis of this and other retrospective analyses, Furberg and Psaty (Am J Hypertens 1996; 9: 122-125) have proposed that the use of calcium antagonists as first-line antihypertensive agents should be discontinued. I have previously countered these allegations and have suggested that they are not relevant to the newer calcium antagonist formulations in current use. It is not widely appreciated that different formulations of the same chemical moiety can produce markedly different hemodynamic and neurohormonal effects, due to differences in the rate of drug delivery into the systemic circulation. During chronic treatment with dihydropyridine calcium antagonists, major fluctuations in blood pressure (rapid onset and offset of antihypertensive effects) during the dosing interval may occur for drugs and formulations that are short acting. In contrast, slow-release formulations of otherwise rapidly absorbed dihydropyridines achieve a more gradual and sustained antihypertensive effect. It is probable that newer calcium antagonist formulations that are truly once daily and do not provoke intermittent sympathetic activation or a cardioacceleratory response will not promote adverse cardiovascular events.

Calcium Channel Blockers↗