Biomedical subjects
Publications and source records attributed to J K Harrison.
We describe two unusual cases of hypoxemia after cardiac surgery due to intracardiac right-to-left shunting through a patent foramen ovale or atrial septal defect. The interatrial defects were successfully occluded by placement of a novel, transcather device, the Angelwings Atrial Septal Defect Occluder Device, with resolution of hypoxemia.
Fractalkine is distinguished structurally from other chemokines in that it contains a mucin-like stalk that tethers a CX3C chemokine module to a transmembrane-spanning region; its expression in cultured endothelial cells has been shown to be up-regulated by tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1). The purpose of this study was to determine whether fractalkine is expressed, in a proinflammatory agent-regulated manner, by cardiac endothelial cells in vivo. Steady state levels of fractalkine mRNA were increased in rat cardiac tissues after in vivo treatment with lipopolysaccharide (LPS), IL-1, or TNF-alpha. In situ hybridization and immunohistochemical analysis revealed that endothelial cells of the coronary vasculature and endocardium were the principal source of proinflammatory agent-inducible fractalkine, although some fractalkine immunoreactivity was also found on the myocytes. These data are the first demonstration of in vivo cardiac endothelial cell fractalkine expression and regulation by proinflammatory agents such as LPS, IL-1, or TNF-alpha. Cardiac endothelial cell-expressed fractalkine may contribute to the influx of leukocytes into the heart during inflammation.
Several carbostyril-based beta-agonists have been shown to bind tightly to and slowly dissociate from the beta2-adrenoceptor (beta2AR). In the present study, the structural features of 8-hydroxy-5-[2-[(1-phenyl-2-methylprop-2-yl)amino]-1-hydroxyethyl] -carbostyril (11a) which contribute to its binding properties at the beta2AR were investigated using a series of synthesized analogs. The k(off), estimated by the rate of cAMP decline in DDT1 MF-2 (DDT) cells with a reduced receptor density, Ki and ligand-induced receptor reductions were determined. All of the derivatives stimulated cAMP accumulation in DDT cells in the sub to mid nanomolar range and elicited the same maximal stimulation as (-)isoproterenol. Derivatives of 11a with side chain N-substitutions comprising 2-methylbutyl, phenylethyl and isopropyl had higher k(off)-values and lower affinities as compared to 11a. Increasing the number of methylenes between the side chain tertiary alpha carbon and phenyl from 1 in 11a to 3 or reducing the number to 0 also resulted in derivatives with higher k(off)- and Ki-values. In addition, replacement of the 8-hydroxycarbostyril nucleus of 11a with catechol reduced the affinity of the compound for the beta2AR by 48-fold and increased its k(off). Only those derivatives with the lowest k(off)-values induced a decrease in the receptor density of DDT cell membranes following a preincubation and extensive washing. The data show that the 8-hydroxycarbostyril nucleus in conjunction with substitutions on the tertiary alpha carbon of the side chain and positioning of the phenyl group are important characteristics determining the high affinity and slow dissociation of 11a from the beta2AR.
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BACKGROUND: This study evaluated the correlation and variability between noninvasive and invasive measures of mitral stenosis severity before and after balloon mitral commissurotomy (BMC) in a large group of patients with symptomatic mitral stenosis. Factors related to variability between measurements were determined. METHODS: The Doppler transmitral gradient, Doppler half-time valve area, and 2-dimensional echocardiographic (2D) mitral valve area (MVA) were measured immediately before and 1 day after BMC in 272 consecutive patients with mitral stenosis and compared with their respective measures during cardiac catheterization. RESULTS: The correlation coefficient for the comparison of noninvasive and invasive measurements of the transmitral gradient was 0.63 before BMC and 0.60 after the procedure; for 2D versus Gorlin-derived MVA, 0.39 and 0.57, respectively; and for Doppler half-time versus Gorlin-derived MVA, 0.31 and 0.18, respectively. A large degree of variability in the measurement of MVA was present among the 3 techniques before BMC and increased after BMC. Before BMC, for the comparison of 2D and Gorlin-derived MVA, variables predictive of the discrepancy were age, echocardiographic score, transmitral gradient during catheterization, and cardiac index. For the comparison of Doppler half-time versus Gorlin-derived MVA, age, heart rate during cardiac catheterization and echocardiography, cardiac output and left ventricular end-diastolic pressure predicted the difference between the 2 measures. CONCLUSIONS: In symptomatic patients with mitral stenosis, there is significant variability between noninvasive and invasive measures of mitral stenosis severity despite careful, reproducible measurements. The difference between noninvasive and invasive measures of MVA before BMC is strongly related to cardiac output.
BACKGROUND: Patients presenting for coronary artery bypass graft (CABG) surgery may have concurrent asymptomatic aortic stenosis (AS) or aortic insufficiency (AI). This retrospective study was performed to evaluate outcomes in patients with aortic valve disease undergoing CABG with or without aortic valve replacement (AVR). METHODS: Study groups included 414 patients undergoing combined AVR and CABG (AVR-CABG group) and 62 patients with asymptomatic mild-to-moderate AS, AI, or both undergoing CABG but not AVR (CABG group). End points included 30-day mortality rate, time to cardiac mortality, time to all-cause mortality, and time to aortic valve reoperation. Reoperation refers to surgery for replacement of the native aortic valve in the CABG group or replacement of the prosthetic aortic valve in the AVR-CABG group. Important patient characteristics affecting outcomes were determined by using Cox proportional-hazard analysis. These variables were then included in multivariable analyses by using logistic regression analysis and Cox proportional-hazard modeling to compare outcomes between each patient group. RESULTS: No difference was seen in any of the mortality end points between the CABG group and the AVR-CABG group after controlling for significant differences between the groups. However, the need for reoperation for AVR was significantly higher for the CABG group than the AVR-CABG group. For patients followed for up to 6 years, the estimated need for aortic valve reoperation was 24.3% in the CABG group versus 3% in the AVR-CABG group. CONCLUSION: On the basis of these results, patients with asymptomatic AS or AI should be considered for AVR at the time of CABG.
BACKGROUND: Fractalkine is a newly identified T-cell and monocyte/macrophage (Mphi) chemokine with a transmembrane domain and is a cell-surface protein on activated endothelium. It can mediate adhesion of cells expressing the fractalkine receptor CX3CR1. These unique features make fractalkine well suited for leukocyte recruitment in tissues with high blood flow as in the renal glomerulus. METHODS: Fractalkine expression in glomeruli and response of isolated glomerular inflammatory cells to fractalkine were studied in the Wistar-Kyoto (WKY) crescentic glomerulonephritis model. Antibody was used to confirm the proinflammatory role of fractalkine. RESULTS: Fractalkine was markedly induced in the endothelium of nephritic rat glomeruli, and inflammatory leukocytes infiltrating the glomeruli expressed increased levels of CX3CR1. Anti-CX3CR1 antibody treatment dramatically blocked leukocyte infiltration in the glomeruli, prevented crescent formation, and improved renal function. CONCLUSIONS: Fractalkine plays a central role in leukocyte trafficking at the endothelium in the high-flow glomerular circuit and, in turn, implicates CX3CR1 as a prime drug target for therapeutic intervention of endothelium-related inflammatory diseases.
PURPOSE: To explore how nurses in one U.S. state perceived that managed care influenced professional nursing in that state. The nursing community is challenged to move with haste in demonstrating, through research, the clinical and economic value that nurses add to cost-effective outcomes. DESIGN: A Delphi survey in 1996 of a convenience sample of 84 clinical nurse specialists (CNSs) and nurse practitioners (NPs) in California. METHODS: CNSs and NPs contributed to the list of managed care influences on nursing practice. fifty-seven (68%) completed the third and final round. FINDINGS: Panelist agreement was the highest for (a) exploring new approaches to providing quality care more cost-effectively, (b) expanding nurse practitioners' role in primary care, and (c) more effectively partnering with clients in helping them assume greater self-responsibility for their health. Greatest threats were perceived to be hassles involved in seeking authorization for care and responding to payment denials; the tenuous job market for nurses; and encroachment on nursing practice by others. CONCLUSIONS: The findings can assist nurses in states with low managed-care concentration to create their preferred future within health care delivery. A more highly educated nurse workforce will be needed for 21st century health systems in which more care is likely to be delivered outside hospitals.
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Left atrial v-wave amplitude has been associated with the presence and severity of chronic mitral regurgitation (MR) but it has not been evaluated for the detection of acute MR. We evaluated the left atrial v-wave amplitude of 205 consecutive patients with mitral stenosis immediately before and after stepwise, incremental balloon mitral commissurotomy to determine predictors of large v waves at baseline and an increase in v-wave amplitude after balloon commissurotomy. The sensitivity and specificity of an increase in v-wave amplitude for detecting worsening and severe MR were determined. A large v wave was present in 44% of patients before balloon commissurotomy and was predicted by age, mean left atrial pressure, mean transmitral gradient, mean pulmonary artery pressure, and angiographic severity of MR. There was a strong inverse correlation between v-wave amplitude and calculated left atrial compliance (r = -0.92). An increase in v-wave amplitude after balloon commissurotomy was associated with an increasing probability of worsening or severe MR. This indicator had a sensitivity, specificity, and positive and negative predictive values of 35%, 91%, 64%, 75%, respectively, for detecting any increase in MR. For the detection of severe MR, the sensitivity was 79%, specificity 89%, positive predictive value 42%, and negative predictive value 98%. Thus, left atrial v-wave amplitude reflects left atrial compliance and severity of mitral stenosis before balloon commissurotomy. An increase in v-wave amplitude is an insensitive but very specific indicator of worsening or severe MR during stepwise, incremental balloon mitral commissurotomy.
BACKGROUND: Percutaneous balloon mitral valvuloplasty and durable mitral prostheses have made the role of open mitral commissurotomy (OMC) uncertain. METHODS AND RESULTS: Results from the use of St Jude mitral valve replacement (SJMVR) were compared with those of the use of OMC in 312 consecutive patients with mitral stenosis between 1983 and the present. OMC and SJMVR patients were well matched for age, sex, and comorbidity except that SJMVR patients had more severe stenosis and were more likely to undergo concurrent aortic valve replacement. Compared with OMC, SJMVR without chordal preservation involved a longer pump time (158 +/- 81 versus 87 +/- 41 min, P < 0.05), more frequent in-hospital complications or death (57 of 219 [26%] versus 4 of 52 [8%], P < 0.01), and longer hospital stay (13 +/- 11 versus 10 +/- 6 days, P = 0.001). Preservation of chordae to at least 1 mitral valve leaflet decreased early morbidity and mortality rates of SJMVR to values comparable to those of OMC (3 of 41 [7%]). Survival was greater at 10 years for OMC versus SJMVR (86 +/- 5% versus 67 +/- 4%, P = 0.03). Ten-year freedom from cardiac events was not different between groups (49 +/- 9% for OMC versus 55 +/- 4% for SJMVR, P = 0.7). Freedom from subsequent mitral procedures at 10 years was better for SJMVR (96 +/- 2% versus 58 +/- 8%, P < 0.001). CONCLUSIONS: In the modern era, SJMVR offers significantly greater durability than does OMC. Chordal preservation at the time of SJMVR may reduce perioperative complications to levels comparable to those of OMC.
Many poxviruses express a 35-40-kDa secreted protein, termed "T1" (for leporipoxviruses) or "35kDa" (for orthopoxviruses), that binds CC-chemokines with high affinity but is unrelated to any known cellular proteins. Many previously identified poxvirus cytokine-binding proteins display strict species ligand-binding specificity. Because the T1 and 35kDa proteins share only 40% amino acid identity, we compared the abilities of purified myxoma virus-T1 (M-T1) and vaccinia virus (strain Lister)- and rabbitpox virus-35kDa proteins to inhibit human CC-chemokines in vitro. All three proteins were equally effective in preventing several human CC-chemokines from binding to target chemokine receptors and blocking subsequent intracellular calcium release. The inhibitory affinities were comparable (Ki = 0.07-1.02 nM). These proteins also displayed similar abilities to inhibit (IC50 = 6.3-10.5 nM) human macrophage inflammatory protein-1alpha-mediated chemotaxis of human monocytes. None of the viral proteins blocked interleukin-8-mediated calcium flux or chemotaxis of human neutrophils, confirming that the biological specificity of the T1/35kDa family is targeted inhibition of CC-chemokines. Despite the significant sequence divergence between the leporipoxvirus T1 and orthopoxvirus 35kDa proteins, our data suggest that their CC-chemokine binding and inhibitory properties appear to be species nonspecific and that the critical motifs most likely reside within the limited regions of conservation.
A recently identified chemokine, fractalkine, is a member of the chemokine gene family, which consists principally of secreted, proinflammatory molecules. Fractalkine is distinguished structurally by the presence of a CX3C motif as well as transmembrane spanning and mucin-like domains and shows atypical constitutive expression in a number of nonhematopoietic tissues, including brain. We undertook an extensive characterization of this chemokine and its receptor CX3CR1 in the brain to gain insights into use of chemokine-dependent systems in the central nervous system. Expression of fractalkine in rat brain was found to be widespread and localized principally to neurons. Recombinant rat CX3CR1, as expressed in Chinese hamster ovary cells, specifically bound fractalkine and signaled in the presence of either membrane-anchored or soluble forms of fractalkine protein. Fractalkine stimulated chemotaxis and elevated intracellular calcium levels of microglia; these responses were blocked by anti-CX3CR1 antibodies. After facial motor nerve axotomy, dramatic changes in the levels of CX3CR1 and fractalkine in the facial nucleus were evident. These included increases in the number and perineuronal location of CX3CR1-expressing microglia, decreased levels of motor neuron-expressed fractalkine mRNA, and an alteration in the forms of fractalkine protein expressed. These data describe mechanisms of cellular communication between neurons and microglia, involving fractalkine and CX3CR1, which occur in both normal and pathological states of the central nervous system.
Chemokines play a central role in immune and inflammatory responses. It has been observed recently that certain viruses have evolved molecular piracy and mimicry mechanisms by encoding and synthesizing proteins that interfere with the normal host defense response. One such viral protein, vMIP-II, encoded by human herpesvirus 8, has been identified with in vitro antagonistic activities against CC and CXC chemokine receptors. We report here that vMIP-II has additional antagonistic activity against CX3CR1, the receptor for fractalkine. To investigate the potential therapeutic effect of this broad-spectrum chemokine antagonist, we studied the antiinflammatory activity of vMIP-II in a rat model of experimental glomerulonephritis induced by an antiglomerular basement membrane antibody. vMIP-II potently inhibited monocyte chemoattractant protein 1-, macrophage inflammatory protein 1beta-, RANTES (regulated on activation, normal T cell expressed and secreted)-, and fractalkine-induced chemotaxis of activated leukocytes isolated from nephritic glomeruli, significantly reduced leukocyte infiltration to the glomeruli, and markedly attenuated proteinuria. These results suggest that molecules encoded by some viruses may serve as useful templates for the development of antiinflammatory compounds.
Chemokines are a group of pro-inflammatory peptides that mediate leukocyte migration and activation. Several members of the chemokine family have been shown to be synthesized by cells of the central nervous system (CNS). To begin to address the role of chemokine receptors in CNS physiology, we identified, by molecular cloning techniques, the rat orthologs of the chemokine receptors, CCR2, CCR3, CCR5, and CXCR4. CCR2 and CCR5 expression was detected in rat spleen, lung, kidney, thymus and macrophages; CCR5 mRNA was also detected in rat brain. Primary cultures of rat microglia expressed CCR5 mRNA that was regulated by IFN-gamma, while both cultured astrocytes and microglia were found to contain mRNA for CXCR4 and CX3CR1. Induction of experimental allergic encephalomyelitis (EAE) in the rat was accompanied by increased levels of CCR2, CCR5, CXCR4, and CX3CR1 mRNAs in the lumbar spinal cords of animals displaying clinical signs of the disease. These data identify the rat orthologs of chemokine receptors and demonstrate that brain, spinal cord, and cultured glial cells express chemokine receptors that can be regulated both in vitro and in vivo.
We describe a novel percutaneous approach for correction of partially anomalous pulmonary venous connection. We describe two cases of dual pulmonary venous drainage where embolization of the anomalous pulmonary venous connection was successful.
OBJECTIVES: This study evaluated the effect of aortic insufficiency on the correlation of pressure half-time-derived mitral valve area with each of 2 standards for mitral valve area (planimetry and cardiac catheterization) in a prospectively assembled cohort of patients scheduled for percutaneous balloon mitral commissurotomy. BACKGROUND: Although Doppler pressure half-time has been validated as a method for assessing mitral valve area, most previous studies have suggested that this noninvasive technique overestimates mitral valve area in the setting of coexistent aortic insufficiency. METHODS AND RESULTS: Echocardiography and cardiac catheterization were performed on 212 consecutive patients scheduled for percutaneous balloon mitral commissurotomy. After excluding 35 patients who did not have aortography, the rest were divided into a "no aortic insufficiency [AI] group" (n = 146) including those with trivial or no aortic insufficiency at catheterization and an "AI group" (n = 31 ) including those with mild or moderate aortic insufficiency. The pressure half-time mitral valve area tended to slightly underestimate invasive valve area by 0.04 cm2 in the AI group and to slightly overestimate invasive valve area by 0.06 cm2 in the no AI group. This difference between the groups was not statistically significant (P = .13). The pressure half-time mitral valve area tended to underestimate planimetered valve area by 0.11 cm2 in the AI group and by 0.10 cm2 in the no AI group. There was no difference between the 2 groups (P = .94). Potential confounders that could theoretically mask the effect of aortic insufficiency on the pressure half-time (including age, heart rate, blood pressure, left ventricular diastolic pressure, ejection fraction, mitral regurgitation, and atrial fibrillation) were excluded by multivariable analyses. CONCLUSIONS: The pressure half-time method of determining mitral valve area is not adversely affected by mild to moderate aortic insufficiency. This finding has implications for the utility of this technique in the rheumatic valvular disease population, in which mitral and aortic valve disease frequently coexist.
Superior vena cava syndrome (SVCS) is a distressing manifestation of benign or malignant disease obstructing return of blood flow through the superior vena cava (SVC). Treatment, often centering around management of the underlying illness, may be slow in relieving symptoms, relying on the recruitment of collateral veins to reestablish blood flow. Percutaneous delivery of metallic stents into the vena cava has been used with success to relieve obstruction to blood flow quickly and completely. We present the case of a patient with complete occlusion of the SVC who underwent successful vena caval revascularization with placement of balloon expandable metallic stents. We also review published reports on the use of stents for SVCS. Results from several series demonstrate that stents can be used with excellent results. Response rates in these series reviewed range from 68% to 100%. Recurrence of symptoms occurred in 4% to 45% of patients but could often be treated with anticoagulation, angioplasty of the stented area, or repeat stenting. Stenting has been used successfully in patients with malignant diseases and in the less common cases of SVCS from a benign etiology. Complications are uncommon and usually of minor consequence. Anticoagulation, thrombolytics, and thrombectomy or atherectomy catheters have also been used during or following stent implantation although their use remains primarily empiric. Percutaneous treatment of SVC obstruction offers patients hope for prompt and dramatic relief from the symptoms of SVCS.