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Biomedical subjects

S J Allen

Publications and source records attributed to S J Allen.

At least 55 records · Page 3Linked to original sources
PubMed2001

Effect of sialyl Lewis(x) selectin blockade on myocardial protection during cardioplegic arrest and reperfusion.

PURPOSE: Selectins play a crucial role in the neutrophil-mediated myocardial injury associated with ischemia/reperfusion. We investigated the effect of selectin inhibition on neutrophil-endothelial cell adhesion, myocardial water content, and left ventricular (LV) recovery after cardiopulmonary bypass (CPB) and cardioplegia. METHODS: Dogs were subjected to CPB and 60 minutes of hypothermic cardioplegia. A selectin inhibitor (SI) (25 mg/kg) was given five minutes prior to CPB and as a continuous infusion (5 mg/kg/h) throughout CPB (n = 6). Saline-treated controls (n = 6) received identical volumes. Preload recruitable stroke work (PRSW) was calculated by sonomicrometry and micromanometry. Myocardial water content was determined by microgravimetry. Myeloperoxidase (MPO) activity was measured to quantify polymorphonuclear neutrophil (PMN) infiltration. RESULTS: SI did not attenuate PRSW as well as post-CPB MPO tissue activity. While we found no difference in myocardial water gain between groups 120 minutes post-CPB, there was better edema resolution with SI. CONCLUSIONS: Selectin antagonism does not reduce CPB-associated myocardial injury, and contractile recovery is not enhanced.

Animals↗
PubMed2000

Galanin regulates the postnatal survival of a subset of basal forebrain cholinergic neurons.

The neuropeptide galanin colocalizes with choline acetyltransferase, the synthetic enzyme for acetylcholine, in a subset of cholinergic neurons in the basal forebrain of rodents. Chronic intracerebroventricular infusion of nerve growth factor induces a 3- to 4-fold increase in galanin gene expression in these neurons. Here we report the loss of a third of cholinergic neurons in the medial septum and vertical limb diagonal band of the basal forebrain of adult mice carrying a targeted loss-of-function mutation in the galanin gene. These deficits are associated with a 2-fold increase in the number of apoptotic cells in the forebrain at postnatal day seven. This loss is associated with marked age-dependent deficits in stimulated acetylcholine release, performance in the Morris water maze, and induction of long-term potentiation in the CA1 region of the hippocampus. These data provide unexpected evidence that galanin plays a trophic role to regulate the development and function of a subset of septohippocampal cholinergic neurons.

Animals↗
PubMed2000

Extracorporeal circulation exacerbates microvascular permeability after endotoxemia.

BACKGROUND: Extracorporeal life support without prior inflammatory stimuli results in a modest increase in microvascular permeability. Initiating ECLS after shock, sepsis, or hypoxia results in marked increases in interstitial fluid and total body water. We sought to determine whether an inflammatory stimulus prior to initiating ECLS increases microvascular permeability to protein. METHODS: An anesthetized canine lymphatic fistula model was used to study Starling forces. LPS + ECLS received 1 mg/kg LPS 1 h prior to initiating ECLS, and the group ECLS received saline vehicle. To determine mesenteric microvascular permeability, mesenteric venous pressure was elevated to 32 +/- 1 mm Hg to reach a minimal lymph protein concentration (C(L)). With simultaneous measurement of plasma protein concentration (C(P)), the reflection coefficient, sigma, was calculated using the formula sigma = 1 - C(L)/C(P). Transvascular protein clearance and filtration coefficient (K(f)) were calculated from the measured Starling variables. After a steady state was achieved, normothermic right atrial-to-femoral artery ECLS was initiated and continued for 2 h and then discontinued. Measurements were continued for 30 min after ECLS was discontinued. Measurements were continued for 30 min after ECLS was discontinued. Within-group comparisons were made with ANOVA and Fisher's LSD, and between-group comparisons were made with Student's t tests where appropriate. RESULTS: The reflection coefficient (sigma) decreased significantly from 0.77 +/- 0.02 to 0.53 +/- 0.07 with LPS + ECLS and was lower compared to ECLS alone (0.77 +/- 0.02 to 0.65 +/- 0.03). Transvascular protein clearance increased to a greater extent in LPS + ECLS from 266 +/- 46 to 819 +/- 125 microl/min compared to ECLS alone (284 +/- 49 to 819 +/- 125 microl/min) (P = 0. 06). K(f) increased in both groups after initiation of ECLS, but to a significantly greater extent in LPS + ECLS at 60 min (30.7 +/- 2.2 microl/min/mm Hg/g in ECLS and 50.0 +/- 8.9 microl/min/mm Hg/g in LPS + ECLS). Ileal tissue water increased in both groups, but there were no differences between groups. CONCLUSIONS: Initiation of ECLS after exposure to LPS increases ileal microvascular permeability to protein and water to a greater extent than ECLS alone.

Animals↗
PubMed2000

Identification of syntaxin 1A as a novel binding protein for presenilin-1.

Mutations in the presenilin 1 gene have been shown to result in Alzheimer's disease. Presenilin 1 is a multi-transmembrane protein with a large hydrophilic loop near the C-terminus. This region is required for known functions of presenilin 1. We have constrained this loop within the active site of the bacterial protein, thioredoxin, to mimic its native conformational state. This hybrid protein was used as bait in a yeast two hybrid screen in an attempt to identify presenilin binding proteins. By this method syntaxin 1A, a synaptic plasma membrane protein, was identified as a novel binding protein for presenilin 1. In vitro experiments confirm the two-hybrid results suggesting that PS1 binds syntaxin under physiological conditions.

Alzheimer Disease↗
PubMed2000

Myocardial protection with high-dose beta-blockade in acute myocardial ischemia.

OBJECTIVE: The risk of postoperative cardiac dysfunction is markedly increased by emergency coronary artery bypass grafting in the presence of acute myocardial ischemia. High dose beta-blockade during continuous coronary perfusion has been suggested as an alternative to conventional cardioplegia and this technique has been applied successfully in high risk patients for coronary artery bypass grafting (CABG) surgery. This study compared high dose beta-blockade with esmolol to continuous warm blood cardioplegia in a clinically oriented model of acute left ventricular (LV) ischemia and reperfusion. METHODS: Twelve dogs were subjected to 60 min of regional LV ischemia by left anterior descending branch (LAD) ligation. Cardiopulmonary bypass (CPB) and aortic crossclamp were applied after 45 min of ischemia. Thereafter, high dose beta-blockade during continuous coronary perfusion (ESMO, n = 6) or antegrade continuous warm blood cardioplegia (WBC, n = 6) were maintained for 60 min. Myocardial water content (measured from endomyocardial biopsies using a microgravimetric technique), global LV function (preload recruitable stroke work: PRSW), and regional LV function (echocardiographic wall motion score) were determined at baseline and after weaning from CPB. RESULTS: During aortic crossclamp interstitial edema formation was significantly higher in the WBC group with an average water gain of 2.2 +/- 0.49 vs. 0.76 +/- 0.12% in the ESMO group. Thereafter, edema resolved in both groups, but myocardial water gain remained significantly higher in the WBC group at 60 and 120 min post CPB (0.98 +/- 0.19 and 1.13 +/- 0.32% vs. 0.07 +/- 0.25 and 0.04 +/- 0.08%). Global LV function was significantly higher in the ESMO group at 60 and 120 min post CPB (PRSW 103 +/- 6 and 94.7 +/- 4.6% of baseline vs. 85.3 +/- 4.9 and 74.7 +/- 7.6% of baseline). However, regional LV function showed no significant difference between groups. CONCLUSIONS: High-dose beta-blockade during continuous coronary perfusion may allow the surgeon to utilize the advantages of warm heart surgery, while avoiding the interstitial edema formation and temporary cardiac dysfunction associated with continuous warm blood cardioplegia. In high risk patients such as patients with unstable angina or after failed PTCA, high-dose beta-blockade may be an applicable alternative to cardioplegic arrest.

Acute Disease↗
PubMed2000

Systematic root cause analysis of adverse drug events in a tertiary referral hospital.

BACKGROUND: Adverse drug events (ADEs) occur frequently, and serious ADEs are associated with mortality or prolonged morbidity. As many ADEs are preventable, identification and modification of systems and processes that permit ADEs has the potential to reduce the rate of ADEs. METHODS: Root cause analysis was systematically employed in a blame-free fashion to investigate the patterns of serious ADEs that occurred during a 29-month period at Hermann Hospital (Houston), and process improvements were implemented on the basis of these findings. The consistently nonpunitive responses to the results of the initial and subsequent root cause analyses was gradually seen, accepted, and ultimately embraced by the hospital staff. RESULTS: The most commonly identified root causes were environmental factors (for example, increased census, increased acuity, change of shift) and staffing issues (for example, personnel new to a unit). Policy changes that led to increased use of forcing or constraining functions (for example, removal of concentrated intravenous potassium solutions from floor stocks) and better personnel support (for example, early awareness and response to localized increases in census and acuity) were particularly effective. Although limited by our lack of active surveillance and not necessarily directly due to the process changes that we implemented, the rate of voluntarily reported serious ADEs/100,000 patient days decreased during this time from 7.2 to 4.0, a decline of 45% (p < 0.001). CONCLUSION: Systematic application of root cause analysis followed by implementation of process changes that target the underlying cause(s) of each event can be successfully implemented in a large hospital.

Adverse Drug Reaction Reporting Systems↗
PubMed2000

Effects of selectin-sialyl Lewis blockade on mesenteric microvascular permeability associated with cardiopulmonary bypass.

OBJECTIVES: Cardiopulmonary bypass is associated with an inflammatory response that is associated with a neutrophil-mediated microvascular barrier injury. We studied the effects of blocking neutrophil-endothelial tethering on microvascular permeability and edema formation during cardiopulmonary bypass. Using a selectin antagonist that prevents interactions with their ligands, we hypothesized that there would be less neutrophil infiltration into the tissue and a reduction in microvascular permeability and edema formation. METHODS: A canine mesenteric lymphatic fistula was created to measure Starling forces and to determine microvascular permeability. Normothermic, atrial-femoral cardiopulmonary bypass was initiated (70-90 mL. kg(-1). min(-1)). Intestinal tissue water was determined with microgravimetry. Ileal tissue myeloperoxidase was measured as an index of neutrophil tissue infiltration. One experimental group received the selectin antagonist TBC 1269 before the initiation of bypass, and the control group received saline solution. RESULTS: There was a modest increase in microvascular permeability in both groups, as evidenced by significantly increased transvascular protein clearance and a trend toward a decrease in reflection coefficient. There were no differences in the experimental group compared with the control group. Ileal tissue myeloperoxidase levels were lower in the experimental group than in the control group. CONCLUSIONS: The selectin antagonist TBC 1269 reduces neutrophil infiltration into the ileum without altering ileal microvascular permeability or edema associated with cardiopulmonary bypass.

Animals↗
PubMed2000

Production of an activated form of Bacillus stearothermophilus L-2-hydroxyacid dehydrogenase by directed evolution.

Bacillus stearothermophillus lactate dehydrogenase (bsLDH) is activated in the presence of fructose 1,6 bisphosphate (FBP). The activator is expensive and representative of the sort of co-factor complications that are undesirable in industrial processes. Three rounds of random mutagenesis and screening produced a mutant (6A) which is almost fully activated in the absence of FBP. Wild-type bsLDH has a K(pyr)(M) of 5 mM in the absence of FBP but when activated (+FBP) the K(pyr)(M) drops to 0.05 mM. The mutant 6A has a K(pyr)(M) of 0.07 mM in the absence of FBP. 6A has three amino acid substitutions-R118C, Q203L and N307S-resulting in a 70-fold activation, none of the mutations are near the active site. The activation of wild type bsLDH is due to an FBP induced tetramerization of dimeric bsLDH bringing about a structural rearrangement of key active site residues. The most likely explanation for the activation of 6A is derived from the position of Q203L, which is at the dimer-dimer interface. The suggestion is that the hydrophilic to hydrophobic change has altered the dimer-tetramer equilibrium position towards that of the tetramer. What is significant is the activation of bsLDH by a subtle long range event produced by the 'blind' directed evolution approach.

Alcohol Oxidoreductases↗
PubMed2000

Protein washdown as a defense mechanism against myocardial edema.

Myocardial edema occurs in many pathological conditions. We hypothesized that protein washdown at the myocardial microvascular exchange barrier would change the distribution of interstitial proteins from large to small molecules and diminish the effect of washdown on the colloid osmotic pressure (COP) of interstitial fluid and lymph. Dogs were instrumented with coronary sinus balloon-tipped catheters and myocardial lymphatic cannulas to manipulate myocardial lymph flow and to collect lymph. Myocardial venous pressure was elevated by balloon inflation to increase transmicrovascular fluid flux and myocardial lymph flow. COP of lymph was measured directly and was also calculated from protein concentration. Decreases occurred in both protein concentration and COP of lymph. The proportion of lymph protein accounted for by albumin increased significantly, whereas that accounted for by beta-lipoprotein decreased significantly. The change in the calculated plasma-to-lymph COP gradient was significantly greater than the change in the measured COP gradient. We conclude that the change in the distribution of interstitial fluid protein species decreases the effect of protein washdown on interstitial fluid COP and limits its effectiveness as a defense mechanism against myocardial edema formation.

Animals↗
PubMed2000

Impact of hetastarch on the intestinal microvascular barrier during ECLS.

The effects of hetastarch on microvascular fluid flux were determined in anesthetized dogs undergoing extracorporeal life support (ECLS) with a roller pump and membrane oxygenator. ECLS with a lactated Ringer priming solution resulted in a decrease in microvascular protein reflection coefficient and an increase in transvascular protein clearance. Use of a 6% hetastarch priming solution attenuated the decrease in microvascular protein reflection coefficient and blunted the increase in transvascular protein clearance. Ileal tissue water increased in the group treated with the lactated Ringer priming solution compared with the group treated with 6% hetastarch. The effective plasma-to-interstitial colloid osmotic pressure gradient was greater in the group treated with hetastarch than in the group treated with lactated Ringer solution. Hetastarch decreases the edema associated with ECLS. The reduction in edema is due to the maintenance of the plasma-to-interstitial colloid osmotic pressure gradient and the reduction in the microvascular permeability to protein.

Animals↗
PubMed2000

Effects of myocardial edema on the development of myocardial interstitial fibrosis.

OBJECTIVE: The mechanism by which chronic myocardial edema causes cardiac dysfunction is poorly understood. We hypothesized that myocardial edema triggers cardiac fibrosis development resulting in cardiac dysfunction. Since collagen is the most abundant constituent of the interstitial matrix, we examined the effects of edema development on cardiac collagen metabolism. METHODS: We utilized a chronic pulmonary artery banded rat model that produces right ventricular hypertrophy with myocardial edema and left ventricular edema without hypertrophy or hyperplasia. Wet to dry ratios (index of edema), collagen type I and III concentrations, prolyl 4-hydroxylase (P4-H) and collagen type I and III mRNA levels, collagenase activity and transforming growth factor-beta were measured in both ventricles. RESULTS: Right and left ventricular wet to dry ratios were significantly elevated from 1 to 28 days after pulmonary artery banding compared to sham rats. Right and left ventricular collagen types I and III and P4-H mRNA levels increased significantly at 3 days followed by significant increases in right and left ventricular collagen concentration 7 days after pulmonary artery banding. Right ventricular collagenase activity increased at 3 days while left ventricular collagenase activity decreased 7 days after PA banding. CONCLUSIONS: We conclude that myocardial edema preceded the observed increase in collagen deposition and that edema may have triggered increased collagen synthesis by fibroblasts. leading to fibrosis development.

Animals↗
PubMed1999

Profound and selective loss of catalytic TrkB immunoreactivity in Alzheimer's disease.

Brain-derived neurotrophic factor (BDNF) is known to have trophic effects on various neurons, throughout the brain and spinal cord, via its high-affinity tyrosine kinase receptor TrkB. It has been reported that the mRNA for this neurotrophin is reduced in Alzheimer's disease (AD) brain. We have examined, by Western blotting, the catalytic (p145) and noncatalytic or truncated (p95) forms of TrkB and find that, in both the temporal and frontal cortex, there is a selective loss of immunoreactive-positive staining for the catalytic or kinase form compared with the truncated form. This may have important consequences for the neurotrophic support of vulnerable neurons in AD.

Aged↗
PubMed1999

Analysis of intestinal microvascular permeability associated with cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with a generalized inflammatory response and splanchnic edema formation that are thought to be related to microvascular barrier injury. In particular, intestinal edema and dysfunction have been associated with sepsis and post-CPB complications. The purpose of this study was to measure the forces determining fluid flux induced by CPB across the intestinal microvascular barrier. MATERIALS AND METHODS: An anesthetized canine model was used for this study (n = 12). To determine mesenteric microvascular permeability, a mesenteric lymphatic was cannulated and mesenteric venous pressure was elevated to 33 +/- 1 mm Hg to reach a minimal lymph protein concentration (CL). With simultaneous measurement of plasma protein concentrations (CP), the reflection coefficient, sigma, was calculated using the formula: sigma = 1 - CL/CP. Capillary pressures (PC), lymph flow (QL), lymph protein flux, transvascular protein flux, and intestinal tissue water were all measured using standard techniques. Normothermic cardiopulmonary bypass with flows of 75-80 ml/kg/min was initiated after a steady state was achieved, and CPB was continued for 2 h and then discontinued. Measurements were repeated 30 min after CPB was discontinued. A second group (n = 5) was studied without mesenteric venous pressure elevation to evaluate the role of capillary pressure on the increased fluid flux seen with the initiation of CPB. RESULTS: Initiation of CPB was associated with an increase in intestinal microvascular permeability. Sigma decreased from 0.77 +/- 0.01 to 0.68 +/- 0.01 (P < 0.05) with the initiation of CPB. This corresponded with statistically significant increases in both transvascular protein flux from 310 +/- 22 to 465 +/- 39 ml/min at 30 min and intestinal tissue water from 82.8 +/- 0.7 to 84.3 +/- 0.5% after weaning from CPB. Capillary pressure did not significantly increase with the initiation of CPB. CONCLUSIONS: Initiation of CPB results in a moderate increase in intestinal microvascular permeability to protein and an increase in intestinal tissue water. The increases in tissue water are not due to increased capillary pressure. A better understanding of the microvascular changes associated with extracorporeal circulation will facilitate the search for clinical interventions to minimize the impact of CPB.

Animals↗
PubMed1999

The Radiofrequency Radiation Dosimetry Handbook: reminiscences.

This paper traces the history of the development of the Radiofrequency Radiation Dosimetry Handbook and its subsequent impact on radio frequency radiation exposure standards. The author's recollections are used to illustrate the behind the scenes efforts of the individuals involved in this project. The development of models at the University of Utah and confirmation of these results by various experimenters led to the publication of four editions of the Radiofrequency Radiation Dosimetry Handbook, i.e., "The RFR Experimenters Bible."

History, 20th Century↗
PubMed1999

Variation in tau, the time constant for isovolumic relaxation, along the left ventricular base-to-apex axis.

Tau (tau), the time constant for isovolumic relaxation, is often used as a measure of cardiac diastolic function. However, several methods of calculating tau have been published which may produce different results and, thereby, different conclusions. The purpose of this study was to determine if the method of tau calculation effects the results when left ventricular pressure (LVP) is measured at different positions along the base-to-apex axis. In 16 dogs, we measured LVP at 6 positions along the base-to-apex axis. We calculated tau using three different methods: 1) a monoexponential model (P(t) = [P0-Pasym]eAt + Pasym, where t = time, P0 = LVP at t = 0, Pasym is asymptotic pressure as t-->infinity, A is -1/tau) with a zero asymptote 2) a monoexponential model with a variable asymptote in which the monoexponential decay equation is differentiated with respect to time and substituted into the original equation so that dP/dt vs. LVP is A (-1/tau), and 3) a monoexponential decay model with variable asymptote in which Pasym and A are varied until the best fit line is reached by minimizing the residual sum of squares. When tau is calculated using method 1, tau measured at the LV base is 98.01% +/- 8.85% of tau at the apex. If calculated using method 2, tau measured at the LV base was 75.46 +/- 39.4% of tau measured at the apex. When method 3 is used for tau calculations, base tau increases to 117.76 +/- 4.91% of the apical tau. We conclude: 1) the method used to calculate tau will effect the results and, thus, conclusions drawn from tau data. 2) When using Method 3, which appears to be the best method for tau calculation, tau increases at the LV base compared to the apex.

Animals↗
PubMed1999

Myocardial beta-blockade as an alternative to cardioplegic arrest during coronary artery surgery.

The authors' recent experimental work has demonstrated that myocardial protection using continuous coronary perfusion with warm beta-blocker-enriched blood avoids myocardial ischaemia and minimizes myocardial oedema formation, thus completely preserving left ventricle function. The purpose of this clinical study was to compare this alternative technique in terms of structural and functional myocardial protection with the routinely used crystalloid Bretschneider cardioplegia. Sixty coronary artery surgery patients were randomized to receive either crystalloid cardioplegia or continuous coronary perfusion with warm blood enriched with the ultra-short acting beta-blocker esmolol. Cardiac function was evaluated using transoesophageal echocardiography (fractional area of contraction) and cardiac metabolism using arterial-coronary sinus lactate concentration difference (a - csD(LAC)). From left ventricular biopsies, the authors determined myocardial oedema, heat-shock-protein-70, intercellular-adhesion-molecule and actin pattern. Patients with crystalloid cardioplegia received 3.6 +/- 0.8 grafts during 64 +/- 20 min cross-clamp time (beta-blocker: 3.5 +/- 0.9 grafts during 68 +/- 22 min; NS). Following cross-clamp removal crystalloid cardioplegia hearts released significant lactate amounts (a- csD(LAC)) - 1.0 +/- 0.6 versus - 0.1 +/- 0.2 mmol/litre in beta-blocker hearts; P < 0.05). In crystalloid cardioplegia hearts, myocardial water content increased from 82.1 +/- 2.1% pre-cardiopulmonary bypass to 83.2 +/- 1.7% at the end of cardiopulmonary bypass (P < 0.05); in beta-blocker hearts myocardial water content remained unchanged (pre-cardiopulmonary bypass: 82.3 +/- 1.9%; end of cardiopulmonary bypass: 82.4 +/- 1.7%; NS). At the end of cardiopulmonary bypass, left ventricular biopsies of beta-blocker hearts showed less structural damage as determined by heat shock protein-70, intercellular adhesion molecule-I and deranged actin cross-striation pattern as compared with crystalloid cardioplegia hearts (P < 0.05). The post-cardiopulmonary bypass fractional area of contraction was similar in both groups (beta-blocker: 65 +/- 14%; crystalloid cardioplegia: 62 +/- 16%); however, beta-blocker patients required less inotropic stimulation (dopamine: beta-blocker: 2.9 +/- 2.5 versus crystalloid cardioplegia: 5.0 +/- 2.3 microg/kg per min; P < 0.05). The data suggest that continuous coronary perfusion with warm esmolol-enriched blood results in better myocardial protection compared with crystalloid cardioplegia. It is concluded that the concept of beta-blocker-induced cardiac surgical conditions may be a useful alternative for myocardial protection during coronary artery surgery.

Adrenergic beta-Antagonists↗
PubMed1999

CD44 is involved in selective leucocyte extravasation during inflammatory central nervous system disease.

Clinical signs of experimental autoimmune encephalomyelitis (EAE) are associated with the selective recruitment of CD4+ memory (CD45RBlow CD44high) T cells into the central nervous system (CNS). However, we have found that many of these recently recruited memory cells are CD44low, suggesting that the CD44 antigen may be involved in, and transiently lost during, the extravasation process. Indeed, administration of a CD44-specific antibody (IM7.8.1) induced leucocyte CD44 shedding and both prevented the development and ameliorated the severity of established EAE by inhibiting mononuclear cell infiltration into the CNS. Trafficking of cells into lymph nodes, however, a property mainly of naïve cells, was essentially unaffected. In contrast, treatment with antibody to very late activation antigen-4 (VLA-4) prevented homing to both the CNS and to lymph nodes. This study contests previous reports that dismissed a role for CD44 in inflammation of the CNS and, coupled with observations in murine dermatitis and arthritis, suggests that CD44 is involved in the homing of primed lymphocytes to sites of inflammation. CD44 should therefore be considered a target for immunotherapy of T-cell-mediated inflammatory diseases, such as multiple sclerosis.

Animals↗