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Biomedical subjects

S F Bolling

Publications and source records attributed to S F Bolling.

At least 91 records · Page 5Linked to original sources
PubMed1994

Inhibition of tumor necrosis factor production by lymphocytes from anti-TNF antibody-treated, cardiac-allografted rats.

Tumor necrosis factor-alpha (TNF) is a multifunctional cytokine involved in the immunopathologic consequences of allograft rejection. We have previously demonstrated that anti-TNF antibody treatment prolongs cardiac allograft survival in rats. To elucidate the mechanism of anti-TNF antibody in modulating the immune response, we investigated TNF production by spleen and lymph node cells from anti-TNF antibody-treated Lewis rats who received MHC-mismatched Brown Norway rat cardiac allografts. In 10 untreated rats, cardiac allografts were rejected at 6.8 +/- 0.6 days after transplantation (mean +/- SD). Anti-TNF antibody treatment enhanced graft survival to 12.7 +/- 1.4 days (P < 0.001 vs controls). In other anti-TNF antibody-treated recipients spleen and lymph node cells were isolated on Day 5 after transplant. TNF production was measured and showed significantly less TNF than those from untreated (no anti-TNF antibody), transplanted recipient rats (28.7 u/10(6) spleen cells vs 76.4 u/10(6) spleen cells at 2 hr and 4.6 u/10(6) lymph node cells vs 9.2 u/10(6) lymph node cells at 24 hr). Furthermore, following lipopolysaccharide stimulation, spleen cells from anti-TNF-treated rats again produced significantly less TNF than those from untreated transplanted rats (68.9 u/10(6) cells vs 189.4 u/10(6) cells at 2 hr). Finally, with allogeneic cell stimulation, anti-TNF treated rats again produced significantly less TNF than untreated transplanted rats (spleen cells, 2.2 u/10(6) cells vs 40.4 u/10(6) cells at 24 hr; lymph node cells, 1.2 u/10(6) cells vs 22.2 u/10(6) cells at 72 hr). These findings suggest that anti-TNF antibody treatment may not only neutralize TNF activity, but also suppress TNF production itself, providing a new insight into the regulation of TNF by anti-TNF antibody.

Animals↗
PubMed1994

The effect of combination cyclosporine and CTLA4-Ig therapy on cardiac allograft survival.

Transplant rejection requires not only T cell receptor/CD3 complex activation by foreign MHC, but also additional costimulatory signals, as T cell receptor activation alone is insufficient for induction of the immune response. The CD28 receptor on helper T cells, interacting with its ligand B7 on activated B cells or macrophages, provides this costimulus to support T cell activity. CTLA4Ig (a soluble CD28 receptor analog), binds B7 and inhibits CD28 activation. As cyclosporine (CsA) has many side effects and CTLA4Ig alone has a significant benefit upon cardiac allograft survival, we theorized that allograft survival could be improved by using CTLA4Ig with lowered dose CsA. In vitro, high-dose CTLA4Ig inhibited the mixed lymphocyte culture reaction (MLR) between MHC-incompatible rat strains. Furthermore, there was synergistic suppression of MLR by low-dose CTLA4Ig combined with low-dose CsA. In vivo studies used a cervical heterotopic transplant model. Control recipients received no immunotherapy. Experimental recipients received low-dose CsA (1.5 mg/kg/day im) x 14 days after transplant or CTLA4Ig (10, 50, or 150 micrograms IP x 7 days). Combination animals received both CTLA4Ig and CsA. These studies showed that low doses of CsA and CTLA4Ig were additive in vivo, although no additional benefit was seen when CsA was combined with high-dose CTLA4Ig. These data suggest that the combination of low-dose CsA plus CTLA4Ig may prove useful in clinical transplantation to maximize immunosuppression and minimize side effects.

Abatacept↗
PubMed1994

Adenosine's effect on myocardial functional recovery: substrate or signal?

During induced ischemia for cardiac surgery, nucleotides are degraded while being used to maintain myocyte integrity. The resulting nucleosides washout upon reperfusion, limiting nucleotide resynthesis resulting in poor postischemic cardiac function. We studied if the mechanism of the beneficial effect of adenosine, a nucleotide precursor, which is known to improve postischemic functional recovery is as a substrate for nucleotide resynthesis or by stimulation of adenosine A1 or A2 receptors. Isolated, retrograde-perfused rabbit hearts received cardioplegia as controls or cardioplegia containing 80 microM [R]-N6-[1-methyl-2-phenylethyl]-adenosine, an A1 receptor agonist, or 200 microM 5'-(N-ethylcarboxamido)adenosine, or 200 microM adenosine alone. To assess functional recovery developed pressure, max dP/dt, pressure-rate product, coronary flow, and myocardial oxygen consumption were compared after 120 min of 34 degrees C global cardioplegic ischemia. Following ischemia and reperfusion, adenosine alone had better developed pressure, dP/dt, and pressure-rate product, while heart rates, wet weights, %H2O, end-diastolic volumes/pressures, and oxygen extraction were not significantly different between groups. While adenosine receptor stimulation may play a role, in this model the beneficial effect of adenosine on functional recovery appears to be mediated more by adenosine's role as a substrate for nucleotide resynthesis.

Adenosine↗
PubMed1994

Incidence, presentation, diagnosis, and management of malfunctioning implantable cardioverter-defibrillator rate-sensing leads.

Recognition of tachyarrhythmia by an implantable cardioverter-defibrillator (ICD) requires an intact rate-sensing lead. We retrospectively examined 266 consecutive patients requiring an ICD to characterize the incidence, clinical presentation, diagnosis, and management of a defective rate-sensing lead. To identify clinical parameters that may contribute to lead complications, we also assessed the effects of age, gender, type of rate-sensing lead, manufacturer of the lead, and surgeon. Over a follow-up period of 30 +/- 22 months (mean +/- standard deviation), a defective lead was found in 9 (3.4%) patients, in 9 (1.7%) of 514 leads over a period of 2 to 39 (mean 17 +/- 15) months after implantation. Except for 1 patient, in whom a lead fracture was incidently found during ICD generator replacement, these patients had multiple inappropriate shocks of recent onset. Clinical parameters were not helpful in identifying patients at risk for lead complication. An abnormal beeping signal obtained while the patients performed various maneuvers was helpful in confirming a defect. All of the defective leads were epicardial. These cases were managed by placement of a transvenous endocardial lead.

Defibrillators, Implantable↗
PubMed1994

Selective lung or heart-lung transplantation for pulmonary hypertension associated with congenital cardiac anomalies.

Fixed pulmonary hypertension has been a contraindication to correction of congenital heart defects. Beginning in February 1991, we pursued a policy of performing single-lung transplantation with intracardiac repair for selected patients with this physiology, reserving heart-lung transplantation for those with unreconstructable heart disease. Of 7 patients treated under this protocol, 5 underwent single-lung transplantation and intracardiac repair. The cardiac anomalies included complete atrioventricular canal (1), aortopulmonary window (1), atrial septal defect (1), and ventricular septal defect (2). One patient died perioperatively. All 4 patients surviving operation remained alive through the first postoperative year, but 3 died 13, 17, and 22 months after operation. Two other patients with pulmonary hypertension (1 with tricuspid atresia, 1 after failed Mustard procedure) received a heart-lung transplant and are well 15 and 18 months after operation. This experience demonstrates that selected patients with major intracardiac defects and pulmonary hypertension may have good early results after cardiac repair and single-lung transplantation, but that long-term results are considerably less favorable.

Adolescent↗
PubMed1994

Extracorporeal life support after heart or lung transplantation.

Extracorporeal life support (ECLS) has been used in 10 patients after heart (5 patients), lung (3 patients), and heart-lung (2 patients) transplantation. The age range was 7 months to 55 years. Cardiopulmonary failure leading to institution of ECLS was due to acute postoperative organ malfunction in 4 patients (2 survived), subacute organ malfunction in 3 patients (none survived), and late rejection or infection in 3 patients (2 survived). Neurologic complications occurred in 3 patients (1 survived) and bleeding, in 5 patients (2 survived). Six patients (60%) were successfully weaned from ECLS, and 4 (40%) survived to leave the hospital. Survival was associated with younger age, shorter duration of ECLS, and longer interval from operation to initiation of ECLS but not to reason for initiating ECLS. Extracorporeal life support is feasible for sustaining both adults and children after heart, lung, or heart-lung transplantation. Best results were obtained in patients with conditions that, in retrospect, were treatable and reversible within days. More experience is needed to predict preoperatively which patients will benefit most from ECLS.

Adolescent↗
PubMed1994

Stunning, preconditioning, and functional recovery after global myocardial ischemia.

Stunning (reversible myocardial ischemia without necrosis) occurs with induced global ischemia during cardiac operations and depresses the ability of the heart to utilize oxygen efficiently because less contractile work is developed per unit of oxygen utilized. Interestingly, regional studies have demonstrated dramatic infarct size reduction with stunning episodes before prolonged ischemia, a phenomenon known as myocardial preconditioning. It is postulated that the postischemic contractile dysfunction noted after stunning causes reduced energy demands, which "preconditions" myocardium to withstand a subsequent longer ischemic episode. Some evidence from regional studies suggests that preconditioning may improve functional recovery after ischemia. This study examined the complex relationship between stunning and preconditioning to functional recovery in a surgical setting of global ischemia. To study the effect of stunning, myocardial oxygen consumption, oxygen extraction, and functional indices of contractility were measured before and after isolated rabbit hearts were subjected to 10, 20, or 45 minutes of normothermic 37 degrees C global ischemic stun intervals. This demonstrated that while oxygen consumption and extraction quickly recover to prestun levels, contractility remains depressed well beyond the stun interval. To study the effect of preconditioning using stunning, isolated hearts were then subjected to 120 minutes of 34 degrees C cardioplegic-induced ischemia after preconditioning. Hearts received either modified St. Thomas cardioplegic solution as a control or cardioplegia administered after preconditioning with 37 degrees C ischemic stunning for 5, 10, 15, 20, or 45 minutes or multiple 5- or 10-minute stuns, with reperfusion before cardioplegic-induced ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Simultaneous traumatic ascending and descending thoracic aortic rupture.

A case of a 56-year-old male blunt trauma victim with combined simultaneous ascending and descending thoracic aortic rupture is presented. He was successfully treated with immediate operation for the ascending aortic rupture and a delayed approach, with nonoperative stabilization and later repair, due to poor pulmonary status and a question in diagnosis, for the descending aortic rupture.

Aorta↗
PubMed1994

The use of dichloroacetate in the treatment of overwhelming hypoxic acidosis.

Overwhelming hypoxic acidosis due to poor tissue oxygen delivery from low cardiac output, pulmonary failure, and other causes has devastating effects postoperatively on patient outcome. Whereas conventional therapeutics often can not reverse the downward spiral of these patients, dichloroacetate (DCA) has been shown to be beneficial. This study investigated the metabolic and hemodynamic effects of DCA given after the onset of overwhelming hypoxic acidosis in a canine model. A hypoxically ventilated canine model of severe induced acidosis was established and dogs surviving the development of acidosis were randomized to receive DCA or sodium chloride (NaCl) treatment. Dogs receiving DCA after development of hypoxic lactic acidosis showed no further change in metabolic parameters during the 90-minute treatment period (pH, 7.24 to 7.23; HCO3, 17.7 to 18 mmol/L; lactate, 2.04 to 1.05 mM/L); whereas animals receiving an equivalent sodium load showed progressive, significant deterioration in all parameters (pH, 7.24 to 7.12; HCO3, 16.8 to 13.2 mM/L; lactate, 2.05 to 3.55 mM/L). Myocardial blood flow was significantly increased by hypoxia in all dogs. Finally, cardiac output and stroke volume were significantly increased at 90 minutes by DCA versus control. Myocardial oxygen utilization efficiency (LV work/M VO2) was improved during DCA treatment. DCA, a carboxylic acid, increases pyruvate dehydrogenase activity, thereby enhancing lactate use a metabolic substrate. DCA had an ameliorative metabolic effect, and benefitted myocardial performance without a direct inotropic effect. DCA treatment appears to enhance myocardial performance on a metabolic and not primarily inotropic basis, does not increase the "cost" of myocardial work, and warrants further study.

Acidosis, Lactic↗
PubMed1994

Dichloroacetate enhances myocardial functional and metabolic recovery following global ischemia.

This study was undertaken to determine the effect of dichloroacetate (DCA) on myocardial functional and metabolic recovery following global ischemia. Sixteen isolated rabbit hearts were subjected to 120 minutes of mildly hypothermic (34 degrees C) cardioplegic arrest with multi-dose, modified St. Thomas' cardioplegia. Following ischemia, hearts were reperfused with either a physiologic salt solution (PSS) as controls, (CON, N = 10), or PSS containing DCA (DCA, N = 6) at a concentration of 1 mmol/L. Functional and metabolic indices were determined at baseline and at 15, 30, and 45 minutes of reperfusion. Results were analyzed using analysis of variance (ANOVA, Sheffe F test) and significance was defined as P < 0.05. Functional recovery was significantly better in hearts reperfused with DCA. Developed pressure (DP) recovered to 62 +/- 4% of baseline in DCA hearts, compared to 37 +/- 8% in CON hearts. Recovery of dP/dt was also improved in DCA versus CON hearts (67 +/- 5 v 43 +/- 10%). Coronary blood flow was not different between groups either at baseline or during reperfusion, but myocardial oxygen consumption (MVO2) was increased in the DCA versus CON hearts (71 +/- 10% of baseline, v 51 +/- 19%). Diastolic compliance during reperfusion was improved in those hearts receiving DCA, as was myocardial mechanical use efficiency (DP/MVO2). Correction of myocardial tissue pH to baseline values was similar in both groups, indicating that the beneficial effect on functional recovery seen with DCA was not solely related to amelioration of acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Pulmonary function in single lung transplantation for chronic obstructive pulmonary disease.

The primary determinants of pulmonary function after heart-lung or double lung transplantation are the volume and compliance of the recipient's thoracic cage. This study evaluated the influence of recipient chest wall factors on static and dynamic lung volumes after single lung transplantation for chronic obstructive pulmonary disease. Fourteen patients with chronic obstructive pulmonary disease received 15 single lung transplants (one retransplant). Posttransplantation follow-up data at 3 and 6 months, in the absence of infection or rejection, were available in nine patients. Overall pulmonary function at 6 months improved from preoperative levels to 55% to 65% of predicted values (forced vital capacity 38% to 55%, forced expiratory volume at 1 second 18% to 55%, maximum voluntary ventilation 21% to 65%), and allograft-specific pulmonary function improved to nearly normal predicted single-lung values (forced vital capacity 89%, forced expiratory volume at 1 second 90%, maximum voluntary ventilation 105%). Postoperative pulmonary function in these patients correlated significantly with preoperative thoracic volume measured by planimetry of chest radiographs. No correlation between postoperative pulmonary function was demonstrated with either the estimated volume of donated lung tissue or relative donor-to-recipient size matching. These findings support the concept that recipient chest wall factors determine postoperative pulmonary function in patients undergoing single lung transplantation for chronic obstructive pulmonary disease. Furthermore, the allograft lung functions at a normal level for the recipient and does not appear to be constrained by hyperinflation of the contralateral lung.

Adult↗
PubMed1994

Developmental differences in myocardial protection in response to 5'-nucleotidase inhibition.

Age-related differences in the activity of 5'-nucleotidase, an enzyme responsible for conversion of high-energy phosphates to their the diffusible precursors, may help to explain age-related differences in tolerance of global myocardial ischemia. Postischemic function and high-energy phosphate content were measured in the hearts of rabbits 7 to 10 days old (neonate), 30 to 40 days old (1 month), and 6 to 12 months old (adult). Hearts in each age group were subjected to 60 minutes of ischemia at 34 degrees C either with no cardioplegia, with unmodified St. Thomas' Hospital cardioplegic solution, or with St. Thomas' Hospital cardioplegic solution with pentoxifylline, a 5'-nucleotidase inhibitor. These groups were compared with one another and with control hearts that were continuously perfused for 1 hour. In adults, addition of pentoxifylline to St. Thomas' Hospital cardioplegic solution restored adenosine triphosphate and total nondiffusible nucleotide levels to control values and improved recovery of cardiac output and developed pressure compared with results with unmodified St. Thomas' Hospital cardioplegic solution. In contrast, biochemical and functional parameters in neonatal hearts were not affected by either unmodified St. Thomas' Hospital cardioplegic solution cardioplegia or St. Thomas' Hospital cardioplegic solution with pentoxifylline. Functional recovery in neonatal hearts subjected to unprotected ischemia was superior to that in the older age groups. In 1-month-old hearts, St. Thomas' Hospital cardioplegia improved recovery compared with recovery after unprotected ischemia, but no incremental improvement in function or high-energy stores was seen with addition of pentoxifylline. The lack of effect of pentoxifylline on neonatal hearts suggest that there is a relative deficiency of 5'-nucleotidase in this age group. This may contribute to the improved functional recovery observed in unprotected hearts. Furthermore, addition of pentoxifylline to adult hearts appears to confer the benefits of low 5'-nucleotidase activity occurring naturally in the neonate.

5'-Nucleotidase↗
PubMed1993

Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion.

Allograft rejection is a T cell-dependent process. Productive T cell activation by antigen requires antigen engagement of the T cell receptor as well as costimulatory signals delivered through other T cell surface molecules such as CD28. Engagement of CD28 by its natural ligand B7 can be blocked using a soluble recombinant fusion protein, CTLA4Ig. Administration of CTLA4Ig blocks antigen-specific immune responses in vitro and in vivo, and we have shown that treatment of rats with a 7-d course of CTLA4Ig at the time of transplantation leads to prolonged survival of cardiac allografts (median 30 d), although most grafts are eventually rejected. Here, we have explored additional strategies employing CTLA4Ig in order to achieve long-term allograft survival. Our data indicate that donor-specific transfusion (DST) plus CTLA4Ig can provide effective antigen-specific immunosuppression. When DST is administered at the time of transplantation followed by a single dose of CTLA4Ig 2 d later, all animals had long-term graft survival (> 60 d). These animals had delayed responses to donor-type skin transplants, compared with normal rejection responses to third-party skin transplants. Furthermore, donor-matched second cardiac allografts were well tolerated with minimal histologic evidence of rejection. These data indicate that peritransplant use of DST followed by subsequent treatment with CTLA4Ig can induce prolonged, often indefinite, cardiac allograft acceptance. These results may be clinically applicable for cadaveric organ and tissue transplantation in humans.

Abatacept↗
PubMed1993

Precursor trapping: a "neonatal" mechanism of myocardial protection.

During induced ischemia for cardiac surgery, 5'-nucleotidase (5NT) catalyzes nucleotide breakdown by dephosphorylating AMP and IMP to diffusible precursors--adenosine and inosine. These precursors become unavailable upon reperfusion washout limiting nucleotide resynthesis, resulting in poor postischemic function. Neonatal hearts, which are more resistant to ischemia than adults, have low 5NT activity, trapping available precursors. Adult rabbit hearts given cardioplegia with a 5NT inhibitor, pentoxifylline, demonstrated improved postischemic contractility, compliance, and myocardial oxygen consumption after 120 min of 34 degrees C ischemia. To determine if this improved function was a result of enhanced nucleotide precursor availability during or following ischemia, total nondiffusible nucleotides, ATP, ADP, AMP, and IMP, and total diffusible nucleotides, adenosine, inosine, hypoxanthine, and xanthine, were measured by HPLC at end ischemia, 1 and 15 min after reperfusion. While all preischemic values were equivalent, pentoxifylline-treated hearts had significantly greater total non-diffusible nucleotides at end ischemia, 1 and 15 min after reperfusion. Additionally, pentoxifylline-treated hearts had significantly greater total diffusible nucleosides at end ischemia and 1 min after reperfusion, but were equal to control at 15 min after reperfusion. Furthermore, coronary sinus effluent had a significantly higher release of total diffusible nucleosides in control vs pentoxifylline-treated hearts. The data indicate that precursor trapping with pentoxifylline prevented nucleotide catabolism to diffusible precursors and enhanced postischemic nucleotide availability. We postulate the increased precursor availability augmented myocardial nucleotide resynthesis and correlated with the improved functional recovery noted. This strategy may have application in adult cardiac surgery.

5'-Nucleotidase↗
PubMed1993

Lipopolysaccharide pretreatment of cyclosporine-treated rats enhances cardiac allograft survival.

Lipopolysaccharide (LPS), the endotoxin in gram-negative bacterial cell walls, is a major factor in septic shock. Tumor necrosis factor (TNF) appears immediately after LPS release or LPS injection in rats, but when these animals have LPS reinjected for up to 7 days, TNF production is inhibited. Because inhibiting TNF with anti-TNF antibodies prolongs cardiac allograft survival and is synergistic with cyclosporine (CsA), enhanced graft survival could result from inhibiting TNF via LPS pretreatment. Accordingly, heterotopic rat heart transplants were performed in: I, untreated controls: II, LPS pretransplant treatment: III, LPS post-transplant treatment; IV, low-dose CsA post-transplant treatment; V, CsA post-transplant treatment and PBS (LPS vehicle); or VI, LPS pretransplant treatment and low-dose CsA post-transplant treatment, using Brown Norway (BN) donors and Lewis (LEW) recipients. Rejection was defined by a lack of contractions. Results showed that while LPS pre- or post-treatment alone had little allograft survival effect, LPS pretreatment combined with CsA significantly prolonged survival vs control or CsA alone (22.0 +/- 1.6 days vs 6.8 +/- 0.6 days or 13.4 +/- 1.1 days; P < 0.001). Primary MLRs of LPS-pretreated LEW splenocytes cocultured with irradiated BN splenocytes had significantly less [3H]thymidine incorporation than untreated LEW splenocytes (3671 +/- 349 vs 7828 +/- 14 cpm). TNF assays of untreated and PBS-treated LEW spleen cells cocultured with irradiated BN spleen cells had 1.3 and 1.1 pg of TNF/10(6) cells, respectively, in 2 hr, but no TNF from LPS-pretreated LEW cells was detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The role of intravascular ultrasound in acute traumatic aortic rupture.

Acute traumatic aortic rupture is a lethal injury and requires immediate diagnosis and surgical repair. The standard of diagnosis for aortic rupture is aortography. In patients in whom the angiographic findings of rupture are subtle or uncertain, intravascular ultrasound (IVUS) imaging of the descending aorta has been useful in confirming or excluding mural injury. However, because IVUS is unable to provide a complete and expeditious survey of the aorta and brachiocephalic arteries, the diagnosis of rupture will continue to rely on aortography or current generation computed tomography.

Acute Disease↗