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Biomedical subjects

R A Levine

Publications and source records attributed to R A Levine.

At least 19 recordsLinked to original sources
PubMed2005

Inhibition of TNF-alpha improves indomethacin-induced enteropathy in rats by modulating iNOS expression.

TNF-alpha, including other proinflammatory cytokines alone or in combination, induces iNOS expression and upregulates inflammatory responses. We evaluated the relationship between TNF-alpha and iNOS expression in indomethacin-induced jejunoileitis in male Sprague-Dawley rats. Rats were fed a daily dose of a phosphodiesterase inhibitor-either theophylline or pentoxifylline-for 2 days. Jejunoileitis was induced with two subcutaneous injections of indomethacin (7.5 mg/kg) 24 hr apart and theophylline or pentoxifylline continued for 12 hr or 4 days. Other rats received a single intraperitoneal injection of anti-TNF-alpha monoclonal antibody (TNF-Ab) 30-min before indomethacin. At 4 days TNF-Ab, theophylline, or pentoxifylline treatment significantly decreased indomethacin-induced ulceration, myeloperoxidase activity, and disease activity index. Although indomethacin significantly increased serum TNF-alpha and nitrate/nitrite levels over the control value as early as 12 hr, iNOS expression was detected only after 4 days. Serum IL-1beta level did not change at 12 hr but increased fourfold at 4 days. Treatment with TNF-Ab, theophylline, or pentoxifylline significantly reduced serum/tissue TNF-alpha, IL-1beta, nitrate/nitrite, and iNOS expression. The downregulation of nitrate/nitrite by these inhibitors suggests that TNF-alpha modulates iNOS expression.

Animals↗
PubMed2003

CNS somatosensory-auditory interactions elicit or modulate tinnitus.

Evidence has accumulated linking clinical tinnitus to the somatosensory system. Most clinical tinnitus patients can change the psychoacoustic attributes of their tinnitus with forceful head and neck contractions. The significance of such somatic modulation of tinnitus was assessed by testing non-clinical subjects. Like clinical tinnitus patients, about 80% of non-clinical subjects who had ongoing tinnitus at the time of testing (whether or not they had been previously aware of it) could modulate their tinnitus with head and neck contractions. Almost 60% of those with no tinnitus at the time of testing could elicit a tinnitus-like auditory percept with head and neck contractions. Because similar results were found in the profoundly deaf, we conclude that somatosensory-auditory interactions within the central nervous system account for most, if not all, somatic modulation of tinnitus as well as the development of auditory percepts with somatic testing. Other observations implicate the muscle spindle as initiating the neural activation that ultimately modulates the central auditory pathway, including the dorsal cochlear nucleus. Somatic influences upon auditory perception are not limited to tinnitus subjects but are a fundamental property of the auditory system.

Adolescent↗
PubMed2003

Impact of tissue harmonic imaging in patients with distorted left ventricles: improvement in accuracy and reproducibility of visual, manual and automated echocardiographic assessment of left ventricular ejection fraction.

AIMS: The aim of this study was to assess the incremental value of tissue harmonic imaging vs conventional echocardiography for evaluating left ventricular ejection fraction by manual and automated quantitation as well as visual estimation in patients with distorted left ventricles. METHODS AND RESULTS: In 25 patients unselected for image quality and with distorted left ventricles who underwent a nuclear study, digital cineloops of standard apical views were acquired by both tissue harmonic imaging and conventional echocardiography and sent to six observers for analysis of visual and quantitative left ventricular ejection fraction. Tissue harmonic imaging improved both the correlation and agreement of all echo techniques with nuclear measures, compared with conventional echocardiography echo, reducing standard errors (SE) to below 10%: for the visual estimate SE=7.5%, for manual tracing SE=6.3% and for automated tracing SE=8%. Tissue harmonic imaging decreased inter-observer variability compared with conventional echocardiography echo for both visual assessment (12.4% vs 18.4%, P<0.05) and quantitative measures (for manual tracing, 8.2% vs 11.8%, P<0.05; for automated tracing, 7.8% vs 16.8%, P<0.05). CONCLUSIONS: In patients with distorted left ventricles unselected for image quality, tissue harmonic imaging improves accuracy and reproducibility of both visual and quantitative echocardiographic assessment of left ventricular ejection fraction. In particular, it promotes automated quantitation by reducing its high standard error into a clinically reasonable range.

Aged↗
PubMed2002

Tumor suppressor PTEN is mutated in canine osteosarcoma cell lines and tumors.

Canine osteosarcoma (OS) cell lines contain mutations that directly or indirectly inactivate the tumor suppressor genes p53 and retinoblastoma. Another important tumor suppressor, PTEN, is mutated in many human cancers. To determine whether inactivation of PTEN plays a role in the pathogenesis of canine OS, we studied its expression in canine OS cell lines and tumors. Four of five canine OS cell lines (CO2, C03, CO5, and CO7) constitutively express high levels of the phosphorylated form of Akt, an indirect indicator of aberrant PTEN expression. PTEN protein is essentially absent from three of these cell lines (CO2, CO5, and CO7), whereas C03 contains a potentially inactivating amino acid substitution in PTEN at codon 340. Genomic hybridization experiments indicate that CO2, CO5, and CO7 contain large deletions within the PTEN gene. Ten of 15 OS tumors exhibit variable or negative PTEN staining. Evaluation of a PTEN-negative staining tumor by Southern blotting indicates that the PTEN gene is deleted in this tumor. These results indicate that PTEN is mutated or downregulated in a high percentage of canine OS cell lines and tumors and likely plays an important role in the pathogenesis of the disease.

Animals↗
PubMed2002

Overexpression of the sis oncogene in a canine osteosarcoma cell line.

Specific oncogenes that contribute to the pathogenesis of canine osteosarcoma (OS) have not been identified. In the process of characterizing four OS cell lines, we have found one cell line, CO8, that overexpresses the sis oncogene, which encodes the platelet-derived growth factor (PDGF)-beta. The expression of an important downstream transcriptional target of the PDGF signaling pathway, c-myc, is also elevated fourfold. Conditioned medium from CO8 alone specifically induces tyrosine phosphorylation and therefore the activation of the PDGF-alpha and PDGF-beta receptors on murine 3T3 cells. All of the canine OS lines tested contain PDGF receptors and therefore are capable of responding to PDGE Given the importance of PDGF in promoting cell proliferation, migration, and cell survival, the activation of the sis oncogene and the resultant growth factor autocrine loop potentially contribute to the pathogenesis of a subset of canine osteosarcomas.

3T3 Cells↗
PubMed2001

Paradoxic decrease in ischemic mitral regurgitation with papillary muscle dysfunction: insights from three-dimensional and contrast echocardiography with strain rate measurement.

BACKGROUND: Ischemic mitral regurgitation (MR) was first ascribed to papillary muscle (PM) contractile dysfunction. Current theories include apical leaflet tethering caused by left ventricular (LV) distortion, but PM dysfunction is still postulated and commonly diagnosed. PM contraction, however, parallels apical tethering, suggesting the hypothesis that PM contractile dysfunction can actually diminish MR due to ischemic distortion of the inferior base alone. METHODS AND RESULTS: We therefore occluded the proximal circumflex circulation in 7 sheep while maintaining PM perfusion, confirmed by contrast echocardiography. By 3D echocardiography, we measured the tethering distance between the ischemic medial PM tip and anterior annulus and LV ejection volume to give MR (by subtracting flowmeter LV outflow). In 6 sheep without initial MR, inferior ischemia alone produced PM tip retraction with restricted leaflet closure and mild-to-moderate MR (regurgitant fraction, 25.2+/-2.8%). Adding PM ischemia consistently decreased MR and tethering distance (5.2+/-0.3 to 1.4+/-0.3 mL; +3.8+/-0.5 mm to -2.2+/-0.7 mm axially relative to baseline; P<0.001) as PM strain rate decreased from +0.78+/-0.07 per second (contraction) to -0.42+/-0.06 per second (elongation, P<0.001) and leaflet tenting decreased. In one sheep, prolapse and MR resolved with inferior ischemia and recurred with PM ischemia. CONCLUSIONS: PM contractile dysfunction can paradoxically decrease MR from inferobasal ischemia by reducing leaflet tethering to improve coaptation. This emphasizes the role of geometric factors in ischemic MR mechanism and potential therapy.

Animals↗
PubMed2001

Chordal cutting: a new therapeutic approach for ischemic mitral regurgitation.

BACKGROUND: Mitral regurgitation (MR) conveys adverse prognosis in ischemic heart disease. Because such MR is related to increased leaflet tethering by displaced attachments to the papillary muscles (PMs), it is incompletely treated by annular reduction. We therefore addressed the hypothesis that such MR can be reduced by cutting a limited number of critically positioned chordae to the leaflet base that most restrict closure but are not required to prevent prolapse. This was tested in 8 mitral valves: a porcine in vitro pilot with PM displacement and 7 sheep with acute inferobasal infarcts studied in vivo with three-dimensional (3D) echo to quantify MR in relation to 3D valve geometry. METHODS AND RESULTS: In all 8 valves, PM displacement restricted leaflet closure, with anterior leaflet angulation at the basal chord insertion, and mild-to-moderate MR. Cutting the 2 central basal chordae reversed this without prolapse. In vivo, MR increased from 0.8+/-0.2 to 7.1+/-0.5 mL/beat after infarction and then decreased to 0.9+/-0.1 mL/beat with chordal cutting (P<0.0001); this paralleled changes in the 3D leaflet area required to cover the orifice as dictated by chordal tethering (r(2)=0.76). CONCLUSIONS: Cutting a minimum number of basal chordae can improve coaptation and reduce ischemic MR. Such an approach also suggests the potential for future minimally invasive implementation.

Animals↗
PubMed2001

Bax, Bcl-2, and cyclin expression and apoptosis in rat substantia nigra during development.

Naturally occurring cell death via apoptosis has been reported in the substantia nigra of rats during development, culminating during the perinatal period. Cellular pathways leading to apoptotic death of developing nigral dopamine neurons remain unknown, although the apoptotic mediator, caspase 3, has been shown to be activated during this process. Our previous results demonstrated the inability of antioxidants to rescue the nigral dopamine neurons that undergo apoptosis during development. In the present study, we investigated using immunohistochemistry the expression of cyclins D1, D3, and E in the substantia nigra during pre- and postnatal development, since their re-expression in postmitotic neurons has been proposed to contribute to developmental apoptosis. We also investigated by Western blot analysis of nigral tissue isolated during the first postnatal week the expression of the anti- and pro-apoptotic proteins, Bcl-2 and Bax, respectively, since altered Bcl-2 expression during developmental apoptosis has been described. During apoptotic death of nigral dopamine neurons in development, we detected a significant increase in the Bax:Bcl-2 ratio, which is consistent with enhanced apoptosis. There were no changes in the expression of the cyclins during the same apoptotic period. These novel findings suggest that nigral dopamine neurons undergo developmental apoptotic death through a Bax:Bcl-2-sensitive pathway that does not involve cyclin mediation.

Animals↗
PubMed2001

Lipid peroxidation-mediated oxidative stress and dopamine neuronal apoptosis in the substantia nigra during development.

The cellular pathways underlying naturally occurring neuronal apoptosis in the rat substantia nigra (SN) during the perinatal period remain largely unknown. Determining the mediators of this process in development may shed light on causes of premature neuronal death in adult neurodegenerative disorders, including the loss of dopamine neurons in Parkinson's disease. In the present study, we investigated whether lipid peroxidation-mediated oxidative stress mediates developmental death of nigral neurons by (1) establishing the profile of lipid peroxidation and other oxidative stress markers throughout the postnatal period both in the SN and striatum, and (2) examining whether the inhibitor of lipid peroxidation, alpha-tocopherol, protects these neurons from death. In addition to monitoring, the level of lipid peroxidation throughout development, we also measured the activities of three antioxidant enzymes, namely superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx). We have shown that lipid peroxidation and SOD activity progressively increased from postnatal day (PND) 3 to PND 42 in both SN and striatum. During this period, GPx activity remained stable, while catalase activity transiently increased at PND 8 only in the SN. Furthermore, alpha-tocopherol treatment from embryonic day 18 to PND 2 did not reduce the number of apoptotic neurons at PND 3. These results do not support the hypothesis that lipid peroxidation-mediated oxidative stress is the major mediator of nigral dopamine neuronal apoptosis during the perinatal period.

Animals↗
PubMed2001

Mechanism of ischemic mitral regurgitation with segmental left ventricular dysfunction: three-dimensional echocardiographic studies in models of acute and chronic progressive regurgitation.

OBJECTIVES: This study aimed to separate proposed mechanisms for segmental ischemic mitral regurgitation (MR), including left ventricular (LV) dysfunction versus geometric distortion by LV dilation, using models of acute and chronic segmental ischemic LV dysfunction evaluated by three-dimensional (3D) echocardiography. BACKGROUND: Dysfunction and dilation-both mechanisms with practical therapeutic implications-are difficult to separate in patients. METHODS: In seven dogs with acute left circumflex (LCX) coronary ligation, LV expansion was initially restricted and then permitted to occur. In seven sheep with LCX branch ligation, LV expansion was also initially limited but became prominent with remodeling over eight weeks. Three-dimensional echo reconstruction quantified mitral apparatus geometry and MR volume. RESULTS: In the acute model, despite LV dysfunction with ejection fraction = 23 +/- 8%, MR was initially trace with limited LV dilation, but it became moderate with subsequent prominent dilation. In the chronic model, MR was also initially trace, but it became moderate over eight weeks as the LV dilated and changed shape. In both models, the only independent predictor of MR volume was increased tethering distance from the papillary muscles (PMs) to the anterior annulus, especially medial and posterior shift of the ischemic medial PM, measured by 3D reconstruction (r2 = 0.75 and 0.86, respectively). Mitral regurgitation volume did not correlate with LV ejection fraction or dP/dt. CONCLUSIONS: Segmental ischemic LV contractile dysfunction without dilation, even in the PM territory, fails to produce important MR. The development of MR relates strongly to changes in the 3D geometry of the mitral apparatus, with implications for approaches to restore a more favorable configuration.

Animals↗
PubMed2001

Nitric oxide inhibitors ameliorate indomethacin-induced enteropathy in rats.

The role of nitric oxide (NO) synthase inhibitors in indomethacin (INDO) -induced enteropathy was investigated in male Sprague-Dawley rats. Rats were subcutaneously administered 5% sodium bicarbonate (controls), two doses of INDO 7.5 mg/kg, and three different inducible NO synthase (iNOS) inhibitors at various concentrations 24 hr, apart; aminoguanidine (AG), guanidinoethyldisulfide (GED), and n-(3-aminomethyl)benzylacetamidine (1400W). Rats were killed four days after the initial injection and small intestinal mucosa was assayed for myeloperoxidase (MPO) activity and iNOS expression by western blot analysis. Serum nitrite/nitrate (NOx) concentration was measured colorimetrically. INDO produced acute ulcers along the mesenteric border from the ileum to proximal jejunum. Rats treated with AG (25 and 50 mg/kg), GED (2.5 mg/kg), and 1400W (0.1 mg/kg) showed decreased total ulcer length and MPO activity by 51, 72, 53, and 61% and by 58, 88, 68, and 70%, respectively, compared to INDO alone. All inhibitors similarly reduced INDO-enhanced serum NOx concentrations to its basal levels. Significant iNOS expression was detected in INDO-treated rats, but the inhibitors did not alter iNOS expression. Our data suggest that NO derived from iNOS may be a key factor in the pathogenesis of acute INDO-induced enteropathy in rats.

Amidines↗
PubMed2001

A semiautomated objective technique for applying the proximal isovelocity surface area method to quantitate mitral regurgitation: Clinical studies with the digital flow map.

BACKGROUND: Clinical application of the color Doppler proximal isovelocity surface area (PISA) method to quantify mitral regurgitation (MR) has been limited by the often inaccurate assumption that isovelocity surfaces are hemispheric. This study applied an objective method for selecting the region where the hemispheric geometry holds best on the basis of mathematic analysis of results at different distances from the orifice. We aimed to demonstrate this approach can be applied accurately in the clinical setting and can be semiautomated to promote routine use by extracting velocities from the digital Doppler output and then performing all the calculations automatically. METHODS: In 75 patients with isolated MR, centerline velocities (V(r)) at each distance (r) from the orifice in the proximal flow field were extracted digitally. The automated analysis calculated peak MR flow rates as 2pir(2)V(r) and plotted these against their respective velocities. The optimal value for peak flow rate was obtained mathematically at the site where the slope of this curve was minimal (least inaccuracy). This value was combined with continuous wave Doppler data to provide regurgitant stroke volume (RSV) and orifice area (ROA), which were compared with quantitative Doppler in 75 patients and angiography in 42. RESULTS: RSV and ROA by this optimized, semiautomated PISA method correlated and agreed well with values from quantitative Doppler (y = 0.9x + 1.9, r = 0.90, standard error of the estimate [SEE] = 8.1 mL, mean difference = -0.7 +/- 8.5 mL for RSV; y = 0.9x + 0.02, r = 0.90, SEE = 0.048 cm(2), mean difference = -0.005 +/- 0.1 cm(2) for ROA) and correlated well with angiography (rho = 0.90 for both RSV and ROA). CONCLUSIONS: This objective PISA method for quantifying MR is accurate in the clinical setting and has been semiautomated by use of analysis of digital velocity data to provide a rapid and practical technique suitable to facilitate more extensive application in routine practice.

Algorithms↗
PubMed2001

Role of nitric oxide in acidosis-induced intestinal injury in anesthetized rats.

We investigated the pathogenic mechanism(s) of small intestinal injury during acidosis in relation to circulating nitric oxide (NO) in an experimental rat model. Rats were anesthetized, paralyzed, and mechanically ventilated with room air. Hydrochloric acid (0.16 mmol bolus followed by 0.132 mmol/kg/h) was infused through the jugular vein for 5 hours. Control rats received a saline infusion. Arterial blood gases, blood pressure, and blood pH were measured every 30 minutes. The involvement of NO in this acidosis model was assessed by measuring plasma concentration of nitrite/nitrate (NOx) and by evaluating inducible NO synthase (iNOS) expression in small intestinal mucosa. Intestinal injury was assessed by measuring myeloperoxidase (MPO) activity, thiobarbituric acid reactants (TBARS), and histologic scores. HCl infusion was associated with hypotension, decreased blood pH, increased plasma concentration of NOx, augmented intestinal mucosal iNOS expression, MPO activity, TBARS, and histopathologic injury scores. Pretreatment with an iNOS inhibitor, aminoguanidine (AG, 50 mg/kg), reversed HCl-induced hypotension without a change in blood pH. HCl-induced lesions, MPO activity, TBARS, and plasma NOx production were decreased by AG. Our data show that the pathogenic mechanisms of acidosis-induced small intestinal lesions involve up-regulation of NO production by increased expression of iNOS and augmentation of superoxide radicals and MPO activity.

Acidosis↗
PubMed2001

Culture and personality studies, 1918-1960: myth and history.

The field known as "culture and personality studies" in the middle decades of the 20th century was a precursor of contemporary cross-cultural research on personality. Its rejection by anthropologists and sociologists after 1950 was accompanied by stereotypes that have hardened into myth and obscured its character and relevance for contemporary investigators. This article dispels some prevalent misconceptions (concerning its chronology, its theoretical unity, its positions on individual differences and its relationship to Freudian psychoanalysis) and proposes a tentative explanation of its decline.

Culture↗
PubMed2001

Short report: Detection of borrelia (relapsing fever) in rural Ethiopia by means of the quantitative buffy coat technique.

The diagnosis of louse-borne relapsing fever is commonly made on the basis of the detection of Borrelia spirochetes on Giemsa-stained thin blood films. In the present study, we used acridine orange-coated quantitative buffy coat (QBC) tubes, centrifugation, and fluorescence microscopy to detect Borrelia. Between July and August 1998, we used the QBC technique to diagnose 7 patients with borreliosis who visited a rural clinic in southwest Ethiopia. In laboratory studies that used Borrelia burgdorferi as a model, we detected spirochetes at concentrations as low as 10 organisms/mm3, whereas the number of positive readings assessed by means of stained blood films fell significantly at dilutions below 3,263 organisms/mm3. The greater sensitivity of the QBC technique is important in areas where Borrelia is endemic, as in the Horn of Africa. It may also prove useful in evaluating relapsing fevers in travelers.

Acridine Orange↗