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Biomedical subjects

I Klein

Publications and source records attributed to I Klein.

At least 91 records · Page 5Linked to original sources
PubMed1995

Lack of association between smoking and inflammatory bowel disease in Jewish patients in Israel.

BACKGROUND/AIMS: An excess of smokers in patients with Crohn's disease (CD) and a paucity of smokers in patients with ulcerative colitis (UC) were reported in many studies. The aim of this study was to examine the association between smoking and inflammatory bowel disease (IBD) in Israel. METHODS: Two independent studies were performed. Patients with recent IBD in comparison with matched population and outpatient controls and patients with chronic UC and CD were studied. Altogether, 475 subjects were investigated. RESULTS: In both studies, the presence of current smokers was lower in CD (9% and 18%) than in UC (24% and 26%). The proportions of nonsmokers in both studies were similar (UC, 61% and 65%; CD, 67% and 70%) and comparable to those found in their two control groups (57% and 61%; 63% and 68%, respectively) and to the general population of Israel. All differences in smoking habits between patient groups and their controls were not statistically significant, except for the paucity of current smokers in the small group of patients with newly diagnosed CD (P < 0.05). A matched analysis produced similar results. CONCLUSIONS: The expected associations between smoking and IBD could not be confirmed. Two hypotheses are considered: (1) the association between smoking and IBD may not be universal, and (2) our findings may be related to the higher genetic predisposition to IBD in Jewish people.

Adult↗
PubMed1995

The effects of long-term aerobic exercise and energy restriction on protein synthesis.

Long-term aerobic exercise and energy intake regulate body composition in a complex manner. To study the combined effects of exercise and energy restriction on muscle mass, we measured skeletal and cardiac muscle protein synthesis after 28 days of two levels of energy restriction with or without daily running-wheel exercise in female rats. Protein synthesis was measured as 3H-Phe incorporation 10 minutes' postbolus of a flooding pulse injection. The two exercise plus energy-restriction groups had greater skeletal muscle and cardiac muscle mass compared with their food-matched groups. Cardiac, gastrocnemius, and soleus muscle protein synthetic rates were proportional to their muscle masses. Exercise-induced energy deficits preserved cardiac and soleus mass to a greater extent than gastrocnemius mass, whereas the effects of energy restriction were similar in all three muscles. These findings suggest that energy intake and exercise have independent effects on the regulation of muscle mass and protein synthesis.

Animals↗
PubMed1995

Triiodothyronine improves left ventricular function without oxygen wasting effects after global hypothermic ischemia.

Cardiopulmonary bypass results in a "euthyroid sick" state. Recently, interest has focused on the relationship between low serum triiodothyronine levels and postoperative cardiovascular hemodynamics. The present study was undertaken to more clearly define the acute effects of triiodothyronine on myocardial mechanics and energetics after hypothermic global ischemia using an ex-vivo canine heart preparation to model the clinical condition. Experiments were performed on isolated hearts subjected to hyperkalemic arrest with 90 minutes of hypothermic (10 degrees C) ischemia. Isolated hearts were cross-perfused by euthyroid support dogs in which triiodothyronine levels spontaneously decreased by 65% to 75% (p < 0.01) after the initiation of cross-perfusion. In nine heart preparations, triiodothyronine (Triostat) was given as a bolus dose (0.2 micrograms/kg) after 1 hour of baseline data collection with a subsequent measurable rise in serum triiodothyronine levels (p < 0.01). In six postischemic hearts, reverse triiodothyronine was given as a 0.2 micrograms/kg bolus. Triiodothyronine was also administered to a group of eight nonischemic, continuously perfused isolated hearts. Intrinsic myocardial contractility was assessed by analysis of the preload recruitable stroke work area, energetic efficiency from the myocardial oxygen consumption-pressure-volume area relationship, and coronary vascular resistance from analysis of coronary flow and perfusion pressure. Acute administration of triiodothyronine to postischemic hearts improved the preload recruitable stroke work area from 9.5 +/- 1.42 to 14.9 +/- 2.03 x 10(7) erg/ml, a 56% increase from baseline (p < 0.001), but had no effect on the preload recruitable stroke work area of the nonischemic hearts. The inotropic response resulting from triiodothyronine treatment did not alter the myocardial oxygen consumption-pressure-volume area relationship. Triiodothyronine treatment was associated with significantly decreased coronary resistance and increased coronary flow through a range of diastolic loading conditions in the postischemic hearts. The biologically inactive thyroid hormone metabolite reverse triiodothyronine was without effect on any of the measured parameters. On the basis of these results, we conclude that the low triiodothyronine state of cardiopulmonary bypass can be reproduced in this isolated heart model and that acute triiodothyronine treatment results in a unique inotropic action manifest only in the postischemic reperfused myocardium and is accomplished without oxygen wasting effects.

Animals↗
PubMed1995

Acquired von Willebrand's syndrome causing a hemorrhagic diathesis in a patient with hypothyroidism.

The occurrence of bleeding diathesis with menorrhagia and easy bruising may occur in patients with moderate to severe hypothyroidism sometimes linked to acquired von Willebrand's disease (VWD). We describe a patient with profound hypothyroidism in whom the diagnosis of hypothyroidism was established while evaluating uncontrolled gingival bleeding after a dental procedure. Thyroid hormone replacement led to a rise in von Willebrand factor, factor VIIIC, and a significant fall in the elevated bleeding time from 15 to 8 min. Acquired von Willebrand's disease is an unusual manifestation of hypothyroidism and is reversible.

Adult↗
PubMed1994

Treatment of hyperthyroid disease.

PURPOSE: To evaluate treatments for hyperthyroid disease. DATA SOURCES: Selected studies published during the last 20 years addressing the diagnosis, causes, and treatment of hyperthyroid disease. STUDY SELECTION: Studies were chosen based on their usefulness in addressing specific points in the treatment of hyperthyroid disease. DATA EXTRACTION: Various treatment principles extracted from the references form the basis for the conclusions and recommendations made here. RESULTS: Hyperthyroid disease is a common endocrine disease. Although Graves disease is the most common cause of thyrotoxicosis, other primary and secondary causes exist. With classic signs and symptoms accompanied by confirmatory laboratory measures of thyroid hyperfunction, the diagnosis can be established firmly. Radioiodine is the preferred method to treat Graves disease; however, recent data concerning treatment with a combination of propylthiouracil and thyroxine require further evaluation to establish its efficacy. Radioiodine is also the preferred treatment for the other forms of hyperthyroid disease; however, patient-specific considerations in both may require patient-tailored therapies. CONCLUSIONS: Hyperthyroid disease can be treated definitively for most patients. Palliative therapy with beta-adrenergic blockade is useful in some patients. Further studies are needed to determine whether more recently described treatments have improved efficacy and whether therapy directed specifically at the underlying immunologic cause of Graves disease can be used successfully.

Graves Disease↗
PubMed1994

Posttranscriptional modification of myosin heavy-chain gene expression in the hypertrophied rat myocardium.

Hypertrophy of the myocardium in response to pressure or volume overload elicits a change in myofibrillar protein content as a result of changes in both transcriptional and translational regulation of gene expression. Hemodynamic overload caused by aortic constriction produced changes in the expression of the two isoforms of myosin heavy chain (MHC) with a 319% increase in beta-MHC mRNA and a 54% decrease in alpha-MHC mRNA (P < 0.01). Cardiac unloading as a result of heterotopic transplantation resulted in a decrease in cardiac mass and a similar shift in MHC isoform expression. In this study. We investigated cardiac gene transcription to understand how different hemodynamic stimuli produce similar cardiac phenotypes. We studied the in vivo activity of the alpha-MHC promoter (-2564 to +421 bp of the transcriptional start site) by directly injecting a recombinant expression plasmid (pAM3LUC) into the ventricular tissue of coarctated animals as well as into the unloaded heterotopic transplanted heart. When expressed as a function of the activity of a constitutively active viral promoter (pSVCAT), pAM3LUC activities were 18.4 +/- 2.9, 24.6 +/- 2.6, and 25.0 +/- 4.5 (x10(4)) luciferase/chloramphenicol acetyltransferase units in the hypertrophied ventricles of 2-, 3-, and 7-day coarctated animals, respectively. These values were not statistically different from pAM3LUC activity in control hearts of sham operated animals even though alpha-MHC mRNA content was decreased by 54% in the hypertrophied myocardium. This disparity between transcriptional activity and mRNA content suggests that alpha-MHC expression in the hypertrophic ventricle is in part regulated by a posttranscriptional mechanism. In contrast, alpha-MHC promoter activity in the unloaded transplanted hearts decreased significantly by 37% compared to control working hearts and suggests that a transcriptional mechanism of regulation of the alpha-MHC gene may account for the phenotypic expression observed in the unloaded myocardium.

Animals↗
PubMed1994

Regulation of rat ventricular myosin heavy chain expression by serum and contractile activity.

To quantitatively analyze the effects of serum stimulation and contractile activity and their interaction on cellular growth and cardiac myosin heavy chain (MHC) gene expression, spontaneously contracting neonatal rat ventricular myocytes in primary culture were maintained in serum-free growth medium or growth medium supplemented with fetal bovine serum. Contractile activity in paired cultures was inhibited by addition of the calcium channel blocker verapamil (10 microM) to the culture medium. Both serum stimulation and contractile activity produced myocyte hypertrophy as assessed by increases in total protein, total RNA, protein-to-DNA ratios, and total MHC protein content. MHC isoenzyme analysis indicated that both MHC-alpha and MHC-beta proteins accumulated in response to serum stimulation and/or contractile activity. The increases in MHC-beta protein resulting from serum stimulation and contractile activity occurred in parallel with increases in MHC-beta mRNA. In contrast, MHC-alpha mRNA levels were relatively unaffected by serum stimulation but appeared to decrease in response to contractile activity. The protein kinase inhibitor staurosporine (5 nM) reduced MHC-beta expression in serum-free, contracting cultures and also prevented the serum-induced increase in MHC-beta mRNA observed in both contracting and arrested myocytes. Staurosporine also increased MHC-alpha mRNA levels in serum-free, contracting, and verapamil-arrested myocytes. These data suggest that both humoral and mechanical factors regulate MHC isoenzyme expression and cellular growth in neonatal ventricular myocytes.

Alkaloids↗
PubMed1994

Effects of exercise on protein synthesis and myosin heavy chain gene expression in hypothyroid rats.

Hypothyroidism suppresses muscle growth and alters myosin heavy chain (MHC) gene expression. To study the role of thyroid hormones in exercise-induced muscle growth and protein synthesis, we measured skeletal and cardiac muscle protein synthesis and MHC gene expression in hypothyroid rats allowed to exercise voluntarily. Female Sprague-Dawley rats (200-210 g) were separated into four groups for 28 days of treatment: control, hypothyroid (TX), hypothyroid plus running-wheel exercise (TX+Ex), and hypothyroid plus 25% overfed (TX+OF). Fractional protein synthesis rates (% incorporation/day) were measured using [3H]phenylalanine incorporation 10 min postinjection. The heart weight-to-body weight ratios of the TX and the TX+OF groups showed marked cardiac atrophy over the 28-day period (2.76 +/- 0.12 and 2.50 +/- 0.22 vs. 3.37 +/- 0.18 mg/g, respectively; P < 0.01). However, the TX+Ex group prevented heart, gastrocnemius, and soleus muscle atrophy over the same time period. Heart, gastrocnemius, and soleus muscles had markedly suppressed protein synthesis rates in the TX and TX+OF groups vs. the euthyroid controls (mean fall -72%; P < 0.01, analysis of variance). However, exercise increased protein synthesis rate by 50% (P < 0.05) compared with TX alone in all three muscle groups. Exercise did not modify hypothyroid-induced alterations of cardiac myosin isoform expression. Exercise-mediated effects on skeletal and cardiac muscle growth but not cardiac MHC gene expression appear to be independent of thyroid hormones.

Animals↗
PubMed1994

Effects of adrenergic agonists on the growth and gene expression of the transplanted heart.

Cardiac growth occurs in response to changes in hemodynamic demand and results primarily from cellular hypertrophy without cellular hyperplasia. In addition to changes in cardiac work, various reports have demonstrated that adrenergic stimulation, specifically of the alpha 1 adrenergic receptor of cultured myocytes, can produce changes in cardiac-specific gene expression and increases in protein synthesis and cell growth. To study the effects of adrenergic stimulation in the absence of alterations in cardiac work we have used the model of the heterotopically transplanted heart, which is a spontaneously beating, vascularly perfused, and histologically normal heart that is hemodynamically unloaded. Seventy-two hours after transplantation, the hemodynamically unloaded transplanted heart had decreased in size by 20% when compared with the control host heart that was growing in situ. Treatment with either the alpha-adrenergic agonist phenylephrine (2.5 mg/kg/day) or the beta-adrenergic agonist isoproterenol (250 micrograms/kg/day) while increasing the spontaneous heart rate had no effect on the size of the transplanted heart. Simultaneous measurements demonstrated that both of these drugs produced a 10% increase in weight of the corresponding hemodynamically loaded host heart. We previously demonstrated that cardiac unloading caused a change in the expression of the myosin heavy chain (MHC) genes with a significant increase in the beta MHC isoform. In the present studies treatment with either isoproterenol or phenylephrine did not alter MHC gene expression either in the in situ host or transplanted hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic Agonists↗
PubMed1993

Determination of Elsamitrucin (BMY-28090) in plasma and urine by high-performance liquid chromatography with fluorescence detection.

The cytostatic agent Elsamitrucin is a new fermentation product active in a variety of in vivo tumor models of murine and human origin. To determine its pharmacokinetics during the clinical phase I trial, an HPLC procedure was developed and validated. Plasma samples were extracted after addition of the internal standard, i.e. the analog Chartreusin. Urine samples were injected without extraction of the samples. Because of the wide concentration range of Elsamitrucin in the plasma samples two standard curves were used: up to 100 nM and from 100-1000 nM. Recoveries of Elsamitrucin from plasma were 87% and 74% for concentrations lower and higher than 100 nM, respectively. The detection limits were 1 nM in plasma and 7.5 nM in urine at a signal-to-noise ratio of 3. The accuracy ranged from 95-107% for plasma and from 96-104% for urine. The within-day precision was < or = 4.8% and < or = 2.8% in plasma and urine, respectively. The between-day precision was < or = 4.4% and < or = 7.1% in plasma and urine, respectively. The method proved to be sufficiently sensitive, specific and accurate for analysis of clinical samples for pharmacokinetic purposes.

Aminoglycosides↗
PubMed1993

Thyroid carcinoma presenting as an enlarged cervical lymph node.

Differentiated thyroid cancer most commonly presents as a thyroid nodule. Cervical node metastases are commonly observed. In the present report, we describe the clinical presentation, pathologic findings, surgical approach, and follow-up of 43 patients in whom the initial presentation of thyroid cancer was that of an enlarged cervical lymph node. At surgery, 65% of the patients had additional lymph node involvement. The thyroid pathology was papillary carcinoma in all patients, and, in two thirds of patients, the thyroid primary was 1 cm or smaller in size. Forty patients underwent thyroidectomy and modified neck dissection; 3 were treated by thyroidectomy alone. One patient died of disease, 7 were lost to follow-up after 4 to 27 years, 5 died of unrelated causes, and the remaining 30 are alive and free of disease 1.5 to 33.5 years after surgery (mean: 14.8 years).

Adolescent↗
PubMed1993

A mild form of mucolipidosis type III in four Baluch siblings.

Four Baluch siblings with mucolipidosis type III (pseudo-Hurler polydystrophy) are described. The patients had features commonly found in mucolipidosis III, including claw hands, joint stiffness, aortic valve involvement and radiological dysostosis multiplex. However, intelligence was normal, there were no eye abnormalities on slit-lamp examination and skin elasticity was normal. Many lysosomal enzymes were elevated in serum and diminished in cultured fibroblasts, although the findings for beta-galactosidase were atypical. Assays for the two enzymes involved in formation of the phosphomannose recognition marker revealed normal activity of the phosphotransferase with alpha-methylmannoside as an acceptor, and normal activity of the phosphodiester glycosidase. Metabolic labelling of fibroblasts with 32P followed by immunoprecipitation of cathepsin D, electrophoresis and fluorography showed that this enzyme was not labelled in the patients' cells, although some label was detected in the secreted precursor polypeptide. The data are consistent with the assumption that activity of the phosphotransferase is low towards lysosomal enzymes as substrates, and that the patients belong to complementation group C.

Arylsulfatases↗
PubMed1993

In vivo regulation of recombinant cardiac myosin heavy chain gene expression by thyroid hormone.

Cardiac myocytes have the unique ability to express exogenous genes that have been injected directly into the heart tissue in vivo. This technique makes it possible to identify cis-acting DNA sequences responsible for the regulation of myocyte-specific genes in a working heart. In these studies we introduced recombinant plasmids containing 5'-flanking sequences of the alpha-myosin heavy chain (alpha MHC) gene into the rat myocardium in order to identify sufficient promoter/enhancer sequences that faithfully reproduced the activity of the endogenous gene. The transcriptional activity of the alpha MHC promoter sequence was measured by the level of activity of the firefly luciferase reporter gene and was reported as the activity relative to a coinjected constitutively active viral promoter construct (pRSVCAT) which corrected for variations in DNA uptake and posttranscriptional events. We report that a recombinant plasmid containing 5'-flanking sequences -2560 to +421 basepairs of the transcriptional start site of the alpha MHC gene was appropriately inactive in the hypothyroid rat heart, in which expression of the endogenous gene was also inhibited. The activity of this promoter sequence was increased 44-fold by thyroid hormone in the hearts of thyroidectomized rats. In contrast, although this recombinant plasmid was appropriately active in the euthyroid myocardium, its activity could not be further stimulated by thyroid hormone. The observation that regulation of the transcriptional activity of the alpha MHC promoter by thyroid hormone was different in euthyroid and hypothyroid hearts suggests that the participation of nuclear regulatory factors, including the thyroid hormone/retinoid family of receptors, may differ according to thyroid status.

Animals↗
PubMed1992

Analysis and pharmacokinetics of N-l-leucyldoxorubucin and metabolites in tissues of tumor-bearing BALB/c mice.

Leucyldoxorubicin (Leu-Dox) was developed as a prodrug of doxorubicin (Dox) with the aim of lowering the cardiotoxicity and improving the therapeutic index produced by Dox. To support the preclinical findings on its antitumor activity and cardiotoxicity, concentrations of Leu-Dox and its metabolites were determined in plasma, heart, and tumor after the administration of Leu-Dox to tumor-bearing mice. A liquid-liquid extraction procedure employing a chloroform/2-propanol/dimethylsulfoxide (DMSO) mixture was developed. By means of high-performance liquid chromatography (HPLC) with fluorescence detection, Leu-Dox and six of its metabolites could be assayed in the tissues with high sensitivity. Detection limits ranged from 0.01 nmol/g tissue for the aglycons to 0.06 nmol/g for Dox. Recoveries were in the range of 82%-110%, and calibration curves were linear over the concentration range tested (0.1-10 nmol/g tissue, r > or = 0.998). Concentration versus time curves were constructed for plasma, heart, and tumor over the first 72 h, and areas under the curves (AUCs) for the first 48 h were determined by the trapezoidal rule. Dox was rapidly formed from Leu-Dox, reaching peak levels in plasma within 5 min and in tissues within 1 h after i.v. administration of Leu-Dox (12 mg/kg). The elimination of Leu-Dox was also fast as illustrated by final half-lives of 1.1, 0.8, and 0.9 h in the plasma, heart, and tumor, respectively. For Dox, the final half-lives were 16.7 h in plasma, 15.3 h in heart tissues, and 27.4 h in tumor tissues. AUC values determined for Leu-Dox and Dox were 221 and 51 nmol ml-1 min, 443 and 4,262 nmol g-1 min, and 153 and 1,466 nmol g-1 min in the plasma, heart, and tumor, respectively. Comparison of these values with those obtained after an equimolar dose of Dox indicated 26%, 30%, and 16% of Leu-Dox appeared as Dox in the plasma, heart, and tumor, respectively. Thus, not only is the plasma compartment not representative for calculations of the conversion of Leu-Dox into Dox in tissue, but differences in its appearance also exist between the tissue compartments. The AUC values found for Dox in the heart may explain the reduced cardiotoxicity elicited by Leu-Dox as compared with Dox; however, the values obtained for Dox in the insensitive murine colon tumor cannot explain the enhanced antitumor activity exerted by Leu-Dox in the sensitive human tumor xenografts in nude mice.

Animals↗
PubMed1992

Thyroid hormone effects on cardiac gene expression independent of cardiac growth and protein synthesis.

Prior studies have demonstrated the importance of hemodynamic loading in mediating thyroxine (T4)-induced cardiac hypertrophy. Direct cellular effects of thyroid hormone have been implicated in modulating the expression of the myosin heavy chain (MHC) genes and the slow sarcoplasmic reticulum calcium adenosine triphosphatase (SR Ca(2+)-ATPase) gene. In the present report, administration of T4 for 72 h did not stimulate growth of the hemodynamically unloaded heterotopic isograft. The synthetic rates of total cardiac proteins and MHC in the isograft remained significantly lower at 64 and 53% of the respective rates measured simultaneously in the in situ working heart. Although total left ventricle RNA content in the isograft was unchanged by T4, alpha-MHC and SR Ca(2+)-ATPase mRNA concentrations were increased 181 and 208%, respectively, and the previously observed beta-MHC expression was completely prevented. These data indicate that, although T4 requires an increased hemodynamic load to stimulate cardiac protein synthesis, it is capable of directly altering the expression of at least two myocyte-specific genes. Therefore some of the phenotypic alterations observed with thyroid hormone treatment are the result of direct effects of the hormones on specific cardiac genes and independent of changes in cardiac growth.

Animals↗