Biomedical subjects

Stephen J Lewis

Publications and source records attributed to Stephen J Lewis.

34 records · Page 2Linked to original sources

PubMed2005

Differentiation of L- and D-S-nitrosothiol recognition sites in vivo.

The main aim of this study was to determine the effects of the lipophobic electron acceptor, nitroblue tetrazolium (NBT), on the vasodilator responses elicited by femoral vein injections of L- and D-S-nitrosocysteine (L- and D-SNC), L- and D-S-nitroso-beta,beta-dimethylcysteine (L- and D-SNPEN) and the nitric oxide (NO) donor, MAHMA NONOate, in pentobarbital-anesthetized rats. L- and D-SNC, L- and D-SNPEN, and MAHMA NONOate elicited dose-dependent falls in mean arterial blood pressure (MAP), and hindquarter (HQR), renal (RR), and mesenteric (MR) vascular resistances. The L-SNC- and L-SNPEN-induced depressor and vasodilator responses were markedly attenuated after injection of NBT. The D-SNC- and D-SNPEN-induced falls in mean arterial pressure, hindquarter, and mesenteric vascular resistances were also reduced after injection of nitroblue tetrazolium whereas the falls in renal resistances were not affected. However, nitroblue tetrazolium inhibited the L-SNC and L-SNPEN responses much more profoundly than the D-SNC and D-SNPEN responses in each vascular bed. In contrast, the MAHMA NONOate-induced responses were not attenuated by nitroblue tetrazolium. This study demonstrates that nitroblue tetrazolium attenuates L- and D-SNC-and L- and D-SNPEN- mediated but not NO-mediated vasodilation. The lack of effects of NBT on the NO responses suggests that NBT does not interfere with the intracellular mechanisms by which NO relaxes vascular smooth muscle. The more pronounced effects of NBT on the vasodilator effects of L-SNC and L-SNPEN than D-SNC and D-SNPEN suggests that these stereoisomers differentially interact with stereoselective S-nitrosothiol recognition sites in the vasculature and that these sites (or their signaling elements) contain thiol residues that may be susceptible to occupation and/or oxidation (ie, disulfide-bond formation) by nitroblue tetrazolium.

Animals↗

PubMed2005

Role of ATP-sensitive K+ -channels in hemodynamic effects of peroxynitrite in anesthetized rats.

The aim of this study was to determine whether the hypotensive and vasodilator actions of peroxynitrite in pentobarbital-anesthetized rats involve the activation of ATP-sensitive K+-channels (K+ATP-channels). The effects of the K+ATP-channel agonist, cromakalim (9-36 microg/kg, iv), peroxynitrite (0.5-10 micromol/kg iv), and L-S-nitrosocysteine (12.5-200 nmol/kg, iv) on mean arterial blood pressure (MAP) and mesenteric (MR) and hindquarter (HQR) vascular resistances were determined before and after injection of the K+ATP-channel blocker, glibenclamide (40 micromol/kg, iv). Cromakalim, peroxynitrite, and L-S-nitrosocysteine produced dose-dependent reductions in MAP, MR, and HQR. Administration of glibenclamide did not affect resting hemodynamic parameters but markedly attenuated the hemodynamic actions of cromakalim. The maximal falls in MAP and HQR produced by peroxynitrite were attenuated by glibenclamide whereas the maximal falls in MR were not affected. In addition, the duration of the hypotensive and vasodilator effects of peroxynitrite in the mesenteric and hindquarter beds were markedly diminished by glibenclamide. In contrast, glibenclamide did not affect the maximal hypotensive or vasodilator effects of L-S-nitrosocysteine or the duration of these responses. These results suggest that the hypotensive and vasodilator actions of peroxynitrite in anesthetized rats involve the activation of K+ATP-channels whereas the hemodynamic actions of L-S-nitrosocysteine do not.

Adenosine Triphosphate↗

PubMed2005

Loss of K+ATP-channel-mediated vasodilation after induction of tachyphylaxis to peroxynitrite.

Systemic injections of peroxynitrite elicit pronounced vasodilator responses in rats by activation of ATP-dependent K+ channels (K+ATP-channels). The aim of this study was to determine whether development of tachyphylaxis to the vasodilator actions of peroxynitrite involves the loss of K+ATP-channel function. The falls in mean arterial blood pressure (MAP) and mesenteric and hindquarter vascular resistances produced by the K+ATP-channel agonist, cromakalim (3-18 microg/kg, iv), and the nitric oxide (NO) donor, sodium nitroprusside (SNP; 1-4 microg/kg, iv), were determined in pentobarbital-anesthetized rats before and after induction of tachyphylaxis to peroxynitrite induced by the administration of 10 injections of peroxynitrite (10 micromol/kg, iv). The first dose of peroxynitrite elicited pronounced falls in MAP and vascular resistances whereas the tenth injection elicited much smaller responses that were equivalent to those of decomposed peroxynitrite. Before induction of tachyphylaxis to peroxynitrite, cromakalim and SNP produced dose-dependent reductions in MAP and vascular resistances. The hemodynamic actions of cromakalim were markedly attenuated after induction of tachyphylaxis to peroxynitrite whereas the SNP-induced responses were only slightly attenuated. These results suggest that tachyphylaxis to the vasodilator actions of peroxynitrite involves the loss of K+ATP-channel function whereas tachyphylaxis to peroxynitrite minimally affects NO-mediated vasodilation. Taken together, these findings raise the possibility that peroxynitrite inhibits K+ATP-channel function by oxidation and/or nitration of amino acids in these channels.

Adenosine Triphosphate↗

PubMed2005

Peroxynitrite elicits dysfunction of stereoselective s-nitrosocysteine recognition sites.

The aim of this study was to determine whether induction of tachyphylaxis to peroxynitrite (induced by giving 10 intravenous injections of a 10-micromol/kg dose) differentially affects the vasodilator responses elicited by systemic injections of the L- and D-isomers of S-nitrosocysteine (L-SNC and D-SNC), in pentobarbital-anesthetized rats. L- and D-SNC (12.5-200 nmol/kg, iv) elicited dose-dependent reductions in hindquarter, mesenteric, and renal vascular resistances. The L-SNC-induced vasodilator responses in the hindquarter and renal vascular beds were virtually abolished whereas the vasodilator responses in mesenteric bed were markedly diminished after administration of peroxynitrite. The D-SNC-induced vasodilator responses in the hindquarter and renal beds were slightly attenuated whereas the vasodilator responses in the mesenteric bed were not diminished after administration of peroxynitrite. The vasodilator responses elicited by the nitric oxide donor, MAHMA NONOate (5-50 nmol/kg, iv), were not attenuated by peroxynitrite. The finding that induction of tachyphylaxis to peroxynitrite diminishes the effects of L- and D-SNC but not MAHMA NONOate suggests that the stereoisomers exert their vasodilator effects by mechanisms other than their decomposition to nitric oxide. Moreover, the finding that induction of tachyphylaxis to peroxynitrite causes a more pronounced attenuation of the vasodilator effects of L- than D-SNC supports evidence that the stereoisomers differentially interact with stereoselective S-nitrosothiol recognition sites in the vasculature. Taken together, these novel results support the possibility that peroxynitrite diminishes the vasodilator potencies of L- and D-SNC by oxidation and/or nitration of amino acids in these recognition sites.

Animals↗

PubMed2005

Effects of thiol chelation on alpha1-adrenoceptor-induced vasoconstriction in vivo.

The aims of this study were to determine whether systemic injections of the lipophobic thiol chelator, para-hydroxymercurobenzoic acid (PHMBA) would reduce the vasoconstrictor responses elicited by the alpha1-adrenoceptor agonist, phenylephrine, in urethane-anesthetized rats by chelation of thiol residues in alpha1-adrenoceptors in vascular smooth muscle rather than voltage-sensitive Ca(2+)-channels (Ca(2+)VERSUS-channels). The magnitudes and durations of the vasoconstrictor responses elicited by phenylephrine were markedly reduced after the injections of PHMBA. In contrast, the maximal phenylephrine-induced responses were not affected whereas the durations of these responses were markedly attenuated after injection of the Ca(2+)VERSUS-channel blocker, nifedipine. Nifedipine elicited pronounced and sustained falls in mean arterial blood pressure and vascular resistances in PHMBA-treated rats. Moreover, the vasodilator actions of the nitric oxide-donor, sodium nitroprusside were minimally attenuated by PHMBA whereas they were markedly attenuated by nifedipine. These findings support evidence that the vasoconstrictor responses due to activation of alpha1-adrenoceptors are initiated by mobilization of intracellular pools of Ca(2+) whereas they are sustained by opening of Ca(2+)VERSUS-channels. These findings also suggest that PHMBA diminishes the vasoconstrictor effects of phenylephrine by chelation of thiol residues in alpha1-adrenoceptors rather than by blockade of Ca(2+)VERSUS-channels, and that chelation of these thiol residues prevents agonist occupation and/or activation of these receptors and subsequent mobilization of intracellular pools of Ca(2+).

Adrenergic alpha-Agonists↗

PubMed2005

Vasodilator actions of the endothelium-derived relaxing factor L-S-nitrosocysteine in anaesthetized rats are markedly diminished by peroxynitrite.

The aim of the present study was to assess the effects of the potent oxidant and nitrating agent peroxynitrite on the haemodynamic actions of the endothelium-derived S-nitrosothiol L-S-nitrosocysteine. The haemodynamic actions of L-S-nitrosocysteine (12.5-100 nmol/kg, i.v.) were determined in pentobarbital-anaesthetized rats before and after the induction of tachyphylaxis to peroxynitrite achieved by giving 10 intravenous injections of a 10 micromol/kg dose. L-S-Nitrosocysteine elicited dose-dependent reductions in mean arterial blood pressure and in hindquarter and mesenteric vascular resistance. The L-S-nitrosocysteine-induced responses were substantially attenuated after administration of peroxynitrite. We have reported previously that nitric oxide-mediated vasodilation is not diminished after the induction of tachyphylaxis to peroxynitrite. Taken together, these findings support the concept that peroxynitrite reduces the vasodilator actions of L-S-nitrosocysteine via oxidation and/or nitration of putative membrane-bound S-nitrosothiol recognition sites.

Anesthesia↗

PubMed2005

Effects of induction of capacitative calcium entry on equine laminar microvessels.

OBJECTIVE: To determine the effects of induction of capacitative Ca2+ entry on tone in equine laminar arteries and veins. SAMPLE POPULATION: Laminar arteries and veins from 6 adult mixed-breed horses. PROCEDURE: Arteries and veins were isolated and mounted on small vessel myographs for the measurement of isometric tension. Capacitative Ca2+ entry was induced by incubating the vessels with the specific Ca2+-ATPase inhibitor thapsigargin (100nM) in a Ca2+-free physiologic salt solution. Capacitative Ca2+ entry-associated contractile responses were determined by the subsequent addition of 2mM Ca2+ to the solution bathing the vessels; in some experiments, either the voltage-gated Ca2+ blocker diltiazem (10microM) or the putative capacitative Ca2+ entry inhibitor trifluoromethylphenylimidazole (300microM) was added to the bathing solution 15 minutes prior to a second 2mM Ca2+ exposure. The Sr2+ permeability of the capacitative Ca2+ entry pathway in laminar vessels was assessed by exposing the vessels to 4mM Sr2+ after induction of capacitative Ca2+ entry with thapsigargin. RESULTS: Induction of capacitative Ca2+ entry elicited robust contractile responses in laminar veins but did not increase tone in laminar arteries. In laminar veins, capacitative Ca2+ entry-induced contractile responses were unaffected by preincubation with diltiazem, attenuated by trifluoromethylphenylimidazole, and were impermeable to Sr+. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that induction of capacitative Ca2+ entry elicits vasoconstriction in equine laminar veins but not in laminar arteries and should therefore be considered a potential mechanism by which selective venoconstriction occurs in horses during the development of acute laminitis.

Animals↗

PubMed2005

Using 3D animations to teach intracellular signal transduction mechanisms: taking the arrows out of cells.

Traditional methods of teaching intracellular biological processes and pathways use figures or flowcharts with the names of molecules linked with arrows. Many veterinary students, presented with such material, simply memorize the names or chemical structures of the molecules and are then likely to forget the material once the examination is completed. To address this problem, the authors designed, created, and field-tested new teaching media that incorporate realistic three-dimensional (3D) animations depicting the dynamic changes that occur in intracellular molecules during cellular activation. Testing found that veterinary students taught using traditional teaching media (e.g., lectures, handouts, textbooks) are proficient in memorizing the names and order of intracellular molecules but unable to appreciate the interactions between these elements or their spatial relationships within cells. In contrast, more than 90% of veterinary students taught using 3D animations not only recall the facts about the intracellular elements but also develop accurate mental images of the interactions among these molecules and their spatial relationships. These findings strongly suggest that the comprehension of complex biological processes by veterinary students can be enhanced by the use of dynamic 3D depictions of these processes in the classroom.

Cell Physiological Phenomena↗

PubMed2004

Pedicle subtraction osteotomy for the treatment of fixed sagittal imbalance. Surgical technique.

BACKGROUND: Fixed sagittal imbalance (a syndrome in which the patient is only able to stand with the weight-bearing line in front of the sacrum) has many etiologies. The most commonly reported technique for correction is the Smith-Petersen osteotomy. Few reports on pedicle subtraction procedures (resection of the posterior elements, pedicles, and vertebral body through a posterior approach) are available in the peer-reviewed literature. We are aware of no report involving a substantial number of patients with coexistent scoliosis who underwent pedicle/vertebral body subtraction for the treatment of fixed sagittal imbalance. METHODS: Twenty-seven consecutive patients in whom sagittal imbalance was treated with lumbar pedicle subtraction osteotomy at one institution were analyzed. Radiographic analysis included assessment of thoracic kyphosis, lumbar lordosis, lordosis through the pedicle subtraction osteotomy site, and the C7 sagittal plumb line. Outcomes analysis was performed with use of a before-and-after pain scale, items from the Oswestry questionnaire, and the Scoliosis Research Society (SRS) questionnaire after a minimum duration of follow-up of two years. Complications and radiographic findings were also analyzed for the entire group. RESULTS: Overall, the average increase in lordosis was 34.1 degrees and the average improvement in the sagittal plumb line was 13.5 cm. One patient had development of a lumbar pseudarthrosis through the area of pedicle subtraction osteotomy, and six patients had development of a thoracic pseudarthrosis. Two patients had development of increased kyphosis at L5/S1, caudad to the fusion, resulting in some loss of sagittal correction. There were significant improvements in the overall Oswestry score (p < 0.0001) and the pain-scale score (p = 0.0002). Most patients reported improvement in terms of pain and self-image as well as overall satisfaction with the procedure. CONCLUSIONS: Pedicle subtraction osteotomy is a useful procedure for patients with fixed sagittal imbalance. A worse clinical result is associated with increasing patient comorbidities, pseudarthrosis in the thoracic spine, and subsequent breakdown caudad to the fusion.

Humans↗

PubMed2003

Complications and outcomes of pedicle subtraction osteotomies for fixed sagittal imbalance.

STUDY DESIGN: Radiographic analysis, outcomes analysis (pain scale, Oswestry, SRS-24), and accumulation of complications. Outcomes and complications collected prospectively. Radiographic analysis performed retrospectively. OBJECTIVES: To assess the benefits and stress complications of pedicle subtraction osteotomies for patients with fixed sagittal imbalance. SUMMARY OF BACKGROUND DATA: Few reports on pedicle subtraction osteotomies exist in the peer-review literature for conditions other than trauma and ankylosing spondylitis. MATERIALS AND METHODS: Thirty-three consecutive patients with sagittal imbalance treated with lumbar pedicle subtraction osteotomy at one institution (minimum 2-year follow-up) were analyzed. Complications were also analyzed for the entire group of consecutive pedicle subtraction osteotomies done at our institution to date (n = 66). RESULTS: For the 33 patients with minimum 2-year follow-up, there were significant improvements in the overall Oswestry score (P 0.0001) and pain score (P = 0.0001). Most patients reported improvement in pain and self-image and reported overall satisfaction based on ultimate SRS-24 questionnaire. There was one pseudarthrosis in the lumbar spine through an area of pedicle subtraction osteotomy (area of previous laminectomy and nonunion), and six patients had thoracic pseudarthroses (levels other than the osteotomy level) and one patient had a pseudarthrosis at L5-S1. Two patients had acute angular kyphosis at the thoracolumbar junction at the proximal end of the construct. Five patients who experienced transient neurologic deficits resolved their deficits after central canal enlargement. CONCLUSIONS: The clinical result with pedicle subtraction osteotomy is reduced with pseudarthrosis in the thoracic or lumbar spine and subsequent breakdown adjacent to the fusion. For patients with a degenerative sagittal imbalance etiology the results were worse and the complications were higher. Central canal enlargement is critical.

Adult↗

PubMed2003

Comparison of left ventriculography and coronary arteriography with positron emission tomography in assessment of myocardial viability.

BACKGROUND: Assessment of viability of myocardium after an ischemic insult is an important clinical question that affects decisions pertaining to potential revascularization. The results of contrast left ventriculograms and coronary angiography were compared to positron emission tomography (PET) in 64 patients with coronary artery disease and reduced left ventricular function. HYPOTHESIS: The study was undertaken to determine the relative utility of the invasive studies in the assessment of viability. METHODS: Right anterior oblique ventriculograms were assessed for hypokinesis, akinesis, or dyskinesis in six segments. The PET scans were assessed for viability by visual estimation of flourodeoxyglucose (FDG) uptake in six segments that corresponded to the segments analyzed on the ventriculograms. RESULTS: Of a total of 373 segments successfully analyzed by PET, 272 were judged to be viable (normal or hypokinetic) by contrast ventriculography. Of these, 253 (93%) were considered viable by PET. Of 177 segments deemed either normal or mild-to-moderately hypokinetic by ventriculography, 170 (94%) were viable by PET. Of 95 severely hypokinetic segments, 83 (84%) were viable by PET. Of 79 akinetic segments, 44 (56%) were considered viable by PET. For segments that were dyskinetic and thought to be nonviable by ventriculography, 19 of 22 (86%) were also considered nonviable by PET. For 294 segments for which a determination on viability was made based on the presence of wall motion on the ventriculogram (normal, hypokinetic, ordyskinetic; not akinetic), there was excellent agreement with PET (93%; p < 0.001). In 49 patients there was akinesis in no more than one segment in either the anterior or inferior territories, indicating the potential for assessment of viability by ventriculography in at least two of three segments in each territory. Coronary anatomy was analyzed to assess whether coronary patency could help in assessing viability. Segments supplied by patent arteries were more likely to be viable by PET than segments supplied by occluded arteries (p < 0.001). Akinetic segments were more likely to be supplied by occluded arteries (56 vs. 23, 72%). Dyskinetic segments were predominantly nonviable by PET (86%) and were usually supplied by occluded arteries (77%). CONCLUSION: In patients in whom the assessment of viability is clinically relevant, the presence of systolic inward motion on the contrast left ventriculogram correlates well with segment viability by PET, while outward or dyskinetic movement correlates well with nonviability. Thus, the use of PET to assess viability in many patients may be unnecessary.

Coronary Angiography↗

PubMed2003

Frequency and significance of antibodies to chromatin in autoimmune hepatitis.

Our aims were to determine the frequency and prognostic implications of antibodies to chromatin in autoimmune hepatitis. Three hundred seventy-one serum samples from 172 patients were tested by enzyme-linked immunosorbent assay. Sixty-seven patients (39%) had antibodies to chromatin. Percent positivity was greater in men than women (58% vs 34%, P = 0.008), and seropositivity was associated with higher serum levels of gamma-globulin and immunoglobulin G. Antibodies to chromatin disappeared in 25 of 60 patients who were tested successively (42%), and they were more common in samples obtained during active than inactive disease (32% vs 19%, P = 0.01). Relapse after drug withdrawal occurred more often in seropositive patients (91% vs 66%, P = 0.002). We conclude that antibodies to chromatin occur commonly in autoimmune hepatitis, and they are associated with disease activity. Percent positivity is greater in men than women, and seropositivity identifies individuals who commonly relapse after drug withdrawal.

Adolescent↗

PubMed2003

Pedicle subtraction osteotomy for the treatment of fixed sagittal imbalance.

Adult↗

PubMed2003

Casebook: diarrhoea.

Explore the source record for details and available documents.

Adolescent↗

PubMed2002

Biomechanical evaluation of lumbosacral reconstruction techniques for spondylolisthesis: an in vitro porcine model.

STUDY DESIGN: Biomechanical evaluation of lumbosacral fixation using a porcine model. OBJECTIVES: The primary objective of the current study was to quantify and compare the changes in lumbosacral range of motion produced by four different methods of surgical stabilization, as well as comparing the relative effects of the four constructs in destructive testing. SUMMARY OF BACKGROUND DATA: The lumbosacral junction continues to be a difficult region to obtain a successful spinal arthrodesis and is one of the primary regions for construct failure. METHODS: Twenty-four fresh-frozen porcine lumbosacral spines were used in this investigation. Following intact analysis, the specimens were radically destabilized at the lumbosacral junction and randomized into four treatment groups based on reconstruction: 1) L7-S1 pedicle screws alone (n = 6); 2) L7-S1 pedicle screws and interbody cage (titanium mesh) (n = 6); 3) L7-S1 pedicle screws and iliac screws (n = 6); and 4) L7-S1 pedicle/iliac screws and interbody cage (n = 6). Nondestructive, multidirectional flexibility analyses included four loading methods and fatigue component followed by a destructive flexural load to failure. Lumbosacral peak range of motion (millimeters or degrees) and ultimate failure load (Nm) of the four reconstruction techniques were statistically compared using a one-way analysis of variance combined with Fisher's PLSD. RESULTS: 1) Axial compression: There were no differences in lumbosacral flexibility among the four treatment groups (P > 0.05). 2) Axial rotation: Iliac screw constructs, with or without cages, decreased flexibility at the lumbosacral junction compared with pedicle screws alone (P < 0.05). However, interbody cage reconstructions did not significantly reduce motion. 3) Flexion-extension: Iliac screws with interbody cages reduced segmental motion about the lumbosacral junction, which was significantly different from the remaining treatments (P < 0.05). 4) Lateral bending: The iliac screw constructs afforded significantly less lumbosacral motion compared with bothpedicle screw constructs (with or without cages). With destructive testing, pullout for L7-S1 constructs occurred at the sacrum, whereas failure for the L7-S1/iliac screw, with and without cages, occurred at the proximal adjacent level. CONCLUSION: Iliac screw constructs reduced lumbosacral flexibility levels in three of four loading methods (axial rotation, flexion-extension, and lateral bending) compared with pedicle screw reconstructions. The addition of interbody cages decreased lumbosacral motion for the iliac screw treatments under flexion-extension loading and pedicle screw constructs under axial rotation but did not protect the sacral screws in destructive testing as the iliac screws did. Based on evaluation using an porcine model, both iliac screws and interbody cages effectively reduce the multidirectional flexibility properties of the lumbosacral junction; however, iliac screws are more restrictive of motion (at the lumbosacral joint) and protective of the S1 screws.

Animals↗

PubMed2002

Usefulness of rest and low-dose dobutamine wall motion scores in predicting survival and benefit from revascularization in patients with ischemic cardiomyopathy.

This study examined the value of wall motion scores at rest and with low- and high-dose dobutamine infusion for prediction of outcome and benefit from revascularization in patients with ischemic cardiomyopathy. Follow-up was obtained in 139 patients with ischemic cardiomyopathy who had echocardiography at rest, and during low- (10 microg/kg/min) and high-dose dobutamine (maximal dose 50 microg/kg/min) infusion. Both rest and low-dose wall motion scores were multivariate predictors of cardiac death, but ischemia and peak dose scores were not predictors. Rest scores risk stratified patients into 3 groups: score (1.00 to 1.99) with 11% cardiac death; score (2.00 to 2.49) with 30% death; and score > or =2.50 with 47% death. One third of patients with rest scores > or =2.50 had improvement in scores to < 2.50 with low-dose dobutamine. Their frequency of cardiac death was reduced to 23% compared with 60% (p = 0.04) in those who remained with low-dose scores > or =2.50. Low-dose scores also identified those who benefited from revascularization. In patients with low-dose scores (1.00 to 1.99), the frequency of cardiac death was marginally lower in revascularized than nonrevascularized patients (10% vs 21%, p = 0.28). In patients with scores (2.00 to 2.49), revascularized patients had a significantly lower frequency of cardiac death than nonrevascularized patients (15% vs 41%, p < 0.05). The frequency of death in those with low-dose scores > or =2.50 was very high in both revascularized (75%) and nonrevascularized (56%, p = 0.42) patients. Thus, rest and low-dose wall motion scores enable risk stratification of patients with ischemic cardiomyopathy and identify those who do and do not benefit from revascularization.

Adrenergic beta-Agonists↗