Biomedical subjects

A Horowitz

Publications and source records attributed to A Horowitz.

At least 37 records · Page 2Linked to original sources

PubMed1998

Regulation of syndecan-4 phosphorylation in vivo.

Recent studies suggest that some of the heparan sulfate-carrying proteoglycans may directly participate in signaling via their cytoplasmic tail. The present investigation addresses the potential involvement of syndecan-4, a widely expressed transmembrane proteoglycan, in this process. We found that the cytoplasmic tail of syndecan-4 is phosphorylated on a single serine residue (Ser183) in growth-arrested NIH 3T3 fibroblasts, with a stoichiometry of 0.3 mol Pi/mol syndecan-4. Treatment of the cells with a protein kinase C (PKC)-activating phorbol ester lead to a 2.5-fold increase in Ser183 phosphorylation. This increase was inhibited by a generic PKC inhibitor but not by an inhibitor specific to the calcium-dependent conventional PKCs, suggesting that the cytoplasmic tail of syndecan-4 is phosphorylated by a calcium-independent novel PKC isozyme. Application of 10-30 ng/ml basic fibroblast growth factor (bFGF) produced a 2-3-fold reduction in the phosphorylation of syndecan-4. Because treatment with the phosphatase inhibitor calyculin prevented the bFGF-induced decrease in syndecan-4 phosphorylation, the effect of bFGF appears to be mediated by a protein serine/threonine phosphatase type 1 or 2A. We conclude that the cytoplasmic tail of syndecan-4 is subject to in vivo phosphorylation on Ser183, which is regulated by the activities of a novel PKC isozyme and a bFGF-dependent serine/threonine phosphatase.

3T3 Cells↗

PubMed1998

Diagnostic value of AgNOR staining in thyroid cytology.

OBJECTIVE: To determine the value of the argyrophil nucleolar organizer region (AgNOR) technique on scrape cytology of thyroid lesions. STUDY DESIGN: AgNOR counts were evaluated in smears of 70 thyroid lesions that were sent for frozen section and included 15 cases of follicular adenoma, 10 cases of follicular carcinoma, 13 cases of papillary carcinoma, 23 cases of nodular goiter and 9 cases of Hashimoto's thyroiditis. Forty-one slides out of 70 were freshly prepared, and 29 slides had been previously stained with hematoxylin and eosin and then destained with alcohol. The number of AgNOR dots was recorded for 50 cells, and the mean number was calculated. RESULTS: The mean AgNOR counts were statistically significantly higher in malignant lesions in comparison to benign lesions. CONCLUSION: AgNOR staining could be of use in cytologic material from thyroid lesions.

Adenocarcinoma, Follicular↗

PubMed1997

The role of integrins in saphenous vein vascular smooth muscle cell migration.

PURPOSE: Smooth muscle cell (SMC) migration is an essential feature of the intimal hyperplastic process that so frequently limits the patency of vascular reconstructions. The purpose of this investigation was to evaluate the effect of a series of integrins, or cell surface receptors that mediate cellular attachment, on platelet-derived growth factor (PDGF) and extracellular matrix (ECM) protein-induced migration of human SMCs. METHODS: Immunofluorescence staining was used to search for various integrins and subunits on the surface of SMCs derived from human saphenous vein. Chemotaxis and haptotaxis of SMCs to various matrix proteins and PDGF were assayed using a 48-well microchemotaxis chamber in the presence or absence of antibodies that blocked the function of these integrins. RESULTS: Several subunits (beta 1, alpha 2, alpha 5) and one integrin (alpha v beta 3) were identified in saphenous vein SMCs. The beta 1 integrin antibody inhibited chemotaxis to collagen I and IV, laminin, and PDGF. The alpha 2 integrin antibody inhibited collagen I and IV, and laminin-induced chemotaxis. The alpha 5 integrin antibody had no effect on SMC migration. The alpha v beta 3 integrin antibody inhibited chemotaxis to PDGF but not to the ECM proteins. CONCLUSIONS: Integrins are necessary for SMC migration induced by PDGF and ECM proteins. The integrin or subunits responsible for facilitating migration varies with the stimulant. Agonists designed to inhibit integrin function might be used to suppress SMC migration and suppress the formation of intimal hyperplasia.

Cell Movement↗

PubMed1997

The relationship between vision impairment and the assessment of disruptive behaviors among nursing home residents.

This study examines the relationship between vision impairment, defined as best corrected distance acuity, and disruptive behaviors among nursing home residents (N = 89). All data were collected from nursing home records. Vision impairment was significantly related on the bivariate level to the disruptive behavior index (r = .21; p < .05). Hierarchical regression analyses, with disruptive behaviors as the criterion and age and comorbid conditions as covariates, indicate that vision status is a significant independent contributor to disruptive behaviors among long-term care residents. Several interpretations for this observed relationship are discussed, as are implications for nursing home services and future research.

Aged↗

PubMed1997

Benign osteonecrosis of the external ear canal.

Benign osteonecrosis (BON) of the external ear canal (EEC), also termed as focal or circumscribed necrotizing lesion, is an infrequent phenomenon with distinctive features and of an obscure origin. Five patients with BON of the EEC presented with aggressiveness and extension of varying degree including involvement of the middle ear. It seems that the disease might have a self limited course (two patients) though, at times, extensive measures including hyperbarric oxygen therapy (one patient) should be applied.

Adult↗

PubMed1996

Hyperechogenic fetal bowel and elevated serum alpha-fetoprotein: a poor fetal prognosis.

OBJECTIVE: To evaluate the clinical significance of increased fetal bowel echogenicity in women with elevated maternal serum alpha-fetoprotein (MSAFP) during the second trimester. METHODS: The study group comprised six pregnant women with elevated second-trimester MSAFP (greater than 2.5 multiples of the median), whose ultrasonographic evaluations indicated hyperechogenic fetal bowel. They were compared with six pregnant women whose fetuses, during routine second-trimester ultrasonographic screening for fetal anomalies, were found to have a hyperechogenic bowel without elevated MSAFP, according to natural history, pregnancy outcome, and associated features. RESULTS: All six fetuses with the combination of elevated MSAFP and echogenic bowel were growth-restricted; four died in utero and one of the two live-born infants died during the neonatal period. The single survivor in this group was born prematurely; necrotizing enterocolitis was diagnosed at 30 days of life and surgery was performed. None of the cases had associated congenital anomalies. Only one of the six controls had associated anomalies (trisomy 21), and this pregnancy was terminated. The pregnancy course of the remaining five fetuses was normal; all were appropriate for gestational age and were delivered at term. No perinatal mortality occurred in this group; however, in one infant, cerebral palsy was diagnosed at 10 months of age. CONCLUSION: Fetal bowel hyperechogenicity found in women with elevated second-trimester MSAFP levels is associated with poor fetal outcome, particularly fetal growth restriction with fetal and neonatal death, and should be considered an ominous prenatal finding.

Adult↗

PubMed1996

Analysis of load transfer and stress distribution by an implant-supported fixed partial denture.

This study simultaneously examined the load transfer and stress distribution by an implant-supported fixed partial denture. A mandibular implant framework with implants connected to the abutments was embedded in a three-dimensional photoelastic model of a mandible. Strain gauges were attached on the superior surface of the framework, and a vertical load of 7.5 kg was applied to seven points on the framework. The measurements derived from this simulation revealed that (1) there was a direct proportion between the stress distribution in the metal framework and stresses created in the supporting structure around the implants; (2) the mode of load transfer and stress distribution was directly proportional to the distance of the components from the loading point; and (3) when the cantilever was loaded, the major part of the stress was distributed within the cantilever in the connection to the distal abutment. In this simulation, stress was distributed over the two, or maximum three, closest implants with the distal implant the most stressed.

Birefringence↗

PubMed1996

Protein kinase C mediation of Ca(2+)-independent contractions of vascular smooth muscle.

Tumour-promoting phorbol esters induce slow, sustained contractions of vascular smooth muscle, suggesting that protein kinase C (PKC) may play a role in the regulation of smooth muscle contractility. In some cases, e.g., ferret aortic smooth muscle, phorbol ester induced contractions occur without a change in [Ca2+]i or myosin phosphorylation. Direct evidence for the involvement of PKC came from the use of single saponin-permeabilized ferret aortic cells. A constitutively active catalytic fragment of PKC induced a slow, sustained contraction similar to that triggered by phenylephrine. Both responses were abolished by a peptide inhibitor of PKC. Contractions of similar magnitude occurred even when the [Ca2+] was reduced to close to zero, implicating a Ca(2+)-independent isoenzyme of PKC. Of the two Ca(2+)-independent PKC isoenzymes, epsilon and zeta, identified in ferret aorta, PKC epsilon is more likely to mediate the contractile response because (i) PKC epsilon, but not PKC zeta, is responsive to phorbol esters; (ii) upon stimulation with phenylephrine, PKC epsilon translocates from the sarcoplasm to the sarcolemma, whereas PKC zeta, translocates from a perinuclear localization to the interior of the nucleus; and (iii) when added to permeabilized single cells of the ferret aorta at pCa 9, PKC epsilon, but not PKC zeta, induced a contractile response similar to that induced by phenylephrine. A possible substrate of PKC epsilon is the smooth muscle specific, thin filament associated protein, calponin. Calponin is phosphorylated in intact smooth muscle strips in response to carbachol, endothelin-1, phorbol esters, or okadaic acid. Phosphorylation of calponin in vitro by PKC (a mixture of alpha, beta, and gamma isoenzymes) dramatically reduces its affinity for F-actin and alleviates its inhibition of the cross-bridge cycling rate. Calponin is phosphorylated in vitro by PKC epsilon but is a very poor substrate of PKC zeta. A signal transduction pathway is proposed to explain Ca(2+)-independent contraction of ferret aorta whereby extracellular signals trigger diacylglycerol production without a Ca2+ transient. The consequent activation of PKC epsilon would result in calponin phosphorylation, its release from the thin filaments, and alleviation of inhibition of cross-bridge cycling. Slow, sustained contraction then results from a slow rate of cross-bridge cycling because of the basal level of myosin light chain phosphorylation (approximately 0.1 mol Pi/mol light chain). We also suggest that signal transduction through PKC epsilon is a component of contractile responses triggered by agonists that activate phosphoinositide turnover; this may explain why smooth muscles often develop more force in response, e.g., to alpha 1-adrenergic agonists than to K+.

Amino Acid Sequence↗

PubMed1996

Epsilon-isoenzyme of protein kinase C induces a Ca(2+)-independent contraction in vascular smooth muscle.

We provide here the first direct evidence for in situ functional specificity of protein kinase C (PKC)-epsilon as a regulator of smooth muscle contractility. PKC is known to cause a Ca(2+)-independent contraction of ferret aortic smooth muscle, and the expression of two Ca(2+)-independent PKC isoenzymes, epsilon and zeta, has been demonstrated in this tissue. To test directly the hypothesis that one of these isoenzymes regulates contractility, constitutively active forms of PKC-epsilon and PKC-zeta were applied to saponin-permeabilized single ferret aortic smooth muscle cells. PKC-zeta caused no significant force response, but PKC-epsilon induced contraction of a magnitude (105 +/- 8 micrograms) similar to that produced by phenylephrine (110 +/- 10 micrograms), a relatively selective alpha 1-adrenergic agonist that triggers a PKC-dependent contraction. The PKC-epsilon-induced contraction was reversed by the PKC pseudosubstrate inhibitory peptide, PKC19-31. The myosin light chain kinase inhibitor 1-(5-chloronaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine (ML-9) did not affect the force response of PKC-epsilon-activated cells, suggesting that PKC-epsilon may induce this contraction solely via thin filament disinhibition. In support of this conclusion, calponin and caldesmon were shown to be good in vitro substrates of PKC-epsilon but not of PKC-zeta.

Animals↗

PubMed1996

Effects of calponin on force generation by single smooth muscle cells.

Although the actin-binding and actomyosin adenosinetriphosphatase (ATPase) inhibitory properties of calponin are well documented in vitro, its function in the smooth muscle cell has not been elucidated. To address this question, we utilized the ferret aortic smooth muscle cell, which shows a protein kinase C-dependent contraction even at pCa (-log [Ca2+]) 9.0 in the absence of a change in myosin light chain phosphorylation. Force was recorded from single, briefly permeabilized cells stimulated via a Ca(2+)-independent pathway by either phenylephrine or the epsilon isoenzyme of protein kinase C. Treatment of stimulated cells with wild-type recombinant calponin reduced steady-state contractile force by 45-60%. When calponin application preceded protein kinase C epsilon treatment, contraction was completely suppressed. On the other hand, calponin phosphorylated at Ser175 or mutant calponin with a Ser175 --> Ala replacement had no effect on contractile force. A peptide corresponding to Leu166-Gly194 of calponin, which included an actin-binding domain but excluded the actomyosin ATPase inhibitory region, was synthesized. Treatment of aortic smooth muscle cells with this peptide triggered a concentration-dependent contraction, presumably by alleviating the inhibitory effect of endogenous calponin. A control peptide with a scrambled sequence of the same residues produced no detectable contractile response. Although other interpretations are possible, these results are consistent with the view that calponin participates in thin filament-mediated regulation of smooth muscle contraction and that it may be part of a Ca(2+)-independent pathway downstream of protein kinase C epsilon.

Animals↗

PubMed1996

Mechanisms of smooth muscle contraction.

Work performed with differentiated contractile smooth muscle tissue over the last two decades has made clear that covalent modification of myosin by phosphorylation of the 20-kDa myosin light chains is a significant mode of regulation of contractile activity in smooth muscle, particularly in regard to the generation of phasic contractions and the initial development of tonic contractions. This regulatory mechanism appears to be of unique importance in smooth muscle compared with striated muscle. It is equally clear, however, that there is an important role for protein kinase C in the regulation of smooth muscle tone maintenance, particularly in vascular smooth muscle. Several possible signal transduction cascades involving protein kinase C are outlined. Increasing evidence suggests a link between protein kinase C and actin-based regulatory mechanisms. This review places emphasis on relating up-to-date biochemical facts to the physiological realities of the smooth muscle cell.

Animals↗

PubMed1996

Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia.

BACKGROUND: It has been proposed that schizophrenia is associated with underactivity of brain glutamatergic neurotransmission, especially at the level of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Glycine potentiates NMDA receptor-mediated neurotransmission, indicating that it may serve as an effective therapeutic agent in the treatment of schizophrenia. METHOD: Eleven treatment-resistant patients with chronic schizophrenia completed a double-blind, placebo-controlled, six-week, randomly assigned, crossover treatment trial of 0.8 g/kg body weight/day of glycine, added to their prior antipsychotic treatment. RESULTS: Glycine was well tolerated, resulted in significantly increased serum glycine levels and induced a mean 36 (7%) reduction in negative symptoms (P < 0.0001). Significant improvements were also induced in depressive and cognitive symptoms. The greatest reduction in negative symptoms was registered in the patients who had the lowest baseline serum glycine levels. CONCLUSIONS: These results extend previous findings and suggest an additional approach to the pharmacotherapy of negative symptoms and cognitive deficits in schizophrenia.

Adult↗

PubMed1996

Rate of keratinization of the wall segment of the hoof and its relation to width and structure of the zona alba (white line) with respect to claw disease in cattle.

OBJECTIVES: To determine contribution of the wall segment of bovine cattle hoof to horn production, and relevance of structural differences of the wall segment and its horn production rate to claw disease. DESIGN: Epidermis and papillary body of the wall segment were examined by mesoscopy, light microscopy, and transmission and scanning electron microscopy. Morphometry of the entire length of the zona alba was examined, and the horn production rate of the wall segment was calculated. ANIMALS: Mixed-breed, dual purpose (beef and dairy) cattle of either sex, and young (20 months) Holstein-Friesian beef bulls. PROCEDURE: Blocks of a strip of the hoof from the coronary segment to the sole margin, including epidermis and dermis, were prepared for light and transmission electon microscopy. Prepared specimens of the wall-sole border were examined by scanning electron microscopy. Morphometry was performed on the outer, middle, and inner parts of the zona alba structures on unfixed horn specimens of beef bull claws. After removal of the zona alba specimens, the claw was removed and the proximodistal extent of the epidermal leaflets was measured and analyzed statistically. RESULTS: Horn production increased in the distal half of the wall segment, was greatest at the wall-sole border, and highest above the abaxial end of the zona alba. High horn production resulted in an incompletely keratinized, softer horn. CONCLUSIONS AND CLINICAL RELEVANCE: High horn production at the zona alba increases susceptibility to vascular disturbance. Claw dyskeratoses appear first in areas of high horn production, areas which are also subject to a greater frequency of claw lesions.

Animals↗

PubMed1995

Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: biodistribution and therapeutic efficacy.

Anthracyclines entrapped in small-sized, sterically stabilized liposomes have the advantage of long circulation time, reduced systemic toxicity, increased uptake into systemic tumors, and gradual release of their payload. To date, there is no information on the behavior of these liposomes in brain tumors. The objective of this study was to compare the biodistribution and clinical efficacy of free doxorubicin (F-DOX) and stealth liposome-encapsulated DOX (SL-DOX) in a secondary brain tumor model. Nine days after tumor inoculation Fischer rats with a right parietal malignant sarcoma received an intravenous dose of 6 mg/kg of either F-DOX or SL-DOX for evaluation of drug biodistribution. For therapeutic trials a single dose of 8 mg/kg was given 6 or 11 days after tumor induction, or alternatively, weekly doses (5 mg/kg) were given on Days 6, 13, and 20. Liposome-encapsulated DOX was slowly cleared from plasma with a t1/2 of 35 hours. Free-DOX maximum tumor drug levels reached a mean value of 0.8 microgram/g and were identical in the adjacent brain and contralateral hemisphere. In contrast, SL-DOX tumor levels were 14-fold higher at their peak levels at 48 hours, declining to ninefold increased levels at 120 hours. A gradual increase in drug levels in the brain adjacent to tumor was noted between 72 and 120 hours (up to 4 micrograms/g). High-performance liquid chromatography analysis identified a small amount of aglycone metabolites within the tumor mass from 96 hours and beyond, after SL-DOX injection. Cerebrospinal fluid levels were barely detectable in tumor-bearing rats treated with F-DOX up to 120 hours after drug injection (< or = 0.05 microgram/ml), whereas the levels found after SL-DOX were 10- to 30-fold higher. An F-DOX single-dose treatment given 6 days after tumor inoculation increased the rats' life span (ILS) by 135% over controls (p < 0.05) but was not effective if given on Day 11. In contrast, SL-DOX treatment resulted in an ILS of 168% (p < 0.0003) with no difference when given after 6 or 11 days. Treatment with three weekly doses of SL-DOX produced an ILS of 189% compared to 126% by F-DOX (p < 0.0002). The authors conclude that the use of long-circulating liposomes as cytotoxic drug carriers in brain tumor results in enhanced drug exposure and improved therapeutic activity, with equal effectiveness against early small- and large-sized brain tumors.

Animals↗

PubMed1994

Tamoxifen enhances cell death in implanted MCF7 breast cancer by inhibiting endothelium growth.

Magnetic resonance imaging at high spatial resolution and histochemical staining were applied to monitor the influence of tamoxifen versus estrogen on the growth, endothelial density, and extent of necrosis in tumors of MCF7 human breast cancer cells implanted in nude mice. Concomitantly with tamoxifen growth arrest, a highly significant decrease, by more than 2-fold, in the endothelial density of viable tumor regions had occurred, together with a significant increase in the extent of necrosis. The results suggest that the antiestrogenic activity of tamoxifen in breast cancer, which results in enhanced necrosis and tumor regression, is due to the inhibition of angiogenesis and of endothelial growth, thus reducing vascularization and impairing tumor perfusion.

Animals↗

PubMed1994

Antibodies probe for folded monomeric myosin in relaxed and contracted smooth muscle.

Regulatory light chain phosphorylation is required for assembly of smooth and non-muscle myosins in vitro, but its effect on polymerization within the cell is not understood. Relaxed smooth muscle cells contain dephosphorylated thick filaments, but this does not exclude the presence of a pool of folded myosin monomers which could be recruited to assemble when phosphorylated, thus forming part of smooth muscle's activation pathway. To test this hypothesis, relaxed and contracted avian gizzard cryosections were labeled with a fluorescently conjugated monoclonal antibody specific for the folded monomeric conformation, or with an antibody against the tip of the tail whose epitope is accessible in the monomeric but not the filamentous state. Fluorescence intensity observed in the two physiological states was quantitated by digital imaging microscopy. Only trace amounts of folded monomeric myosin were detected in both the relaxed and contracted states. The amount of monomer also did not increase when alpha-toxin permeabilized gizzard was equilibrated in a solvent that disassembles filaments in vitro. Assembly/disassembly is therefore unlikely to play a major role in regulating the contraction/relaxation cycle in smooth muscle cells.

Animals↗

PubMed1994

Vision impairment and functional disability among nursing home residents.

The relationship was explored between vision impairment, defined by best corrected distance acuity, and functional dependency among nursing home residents. All data, including clinical information on visual acuity, were collected from nursing home records. Almost one-fourth of all residents were found to have at least a moderate vision impairment (20/70 or worse) even after best correction with refractive lenses. Findings from hierarchical regression analyses indicate that vision status is an independent significant predictor of activities of daily living (ADL) functional dependency even after age, gender, and comorbidity are accounted for. Implications for nursing home services and future research are discussed.

Activities of Daily Living↗

PubMed1994

Total proctocolectomy, pancreaticoduodenectomy and total gastrectomy for multiple carcinomas in a patient with familial adenomatous polyposis.

A unique case of familial adenomatous polyposis presenting with simultaneous adenocarcinoma of the periampullary region, gallbladder and several gastric lesions, 10 years after a total proctocolectomy, is reported. Multiple gastrointestinal carcinomas associated with familial polyposis have been reported sporadically. However, this is the only known patient who successfully underwent a pancreaticoduodenectomy (Whipple procedure) and a total gastrectomy in addition to a previous total proctocolectomy.

Adenocarcinoma↗