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S M Palmer

Publications and source records attributed to S M Palmer.

At least 19 recordsLinked to original sources
PubMed2007

Genetic regulation of rejection and survival following human lung transplantation by the innate immune receptor CD14.

We have developed the hypothesis that genetic polymorphisms which alter the expression or function of innate immune receptors contribute to the marked interindividual differences in the onset and severity of lung transplant rejection. In this analysis, we considered the effects of a common promotor polymorphism of the lipopolysaccharide receptor CD14 associated with increased transcriptional activity upon the development of posttransplant rejection and graft survival. Genotyping was performed in 226 lung transplant recipients well characterized with regards to clinical outcomes. An earlier onset of acute rejection, bronchiolitis obliterans syndrome (BOS) and worse posttransplant graft survival due to greater BOS related deaths was evident in patients with the CD14 -159 TT genotype (TT). The adverse effect upon graft survival of the TT genotype remained significant in a multivariate Cox model (Hazard Ratio 1.65, 95% CI, 1.03-2.64, p-value = 0.04) after adjusting for other important covariates. Furthermore, TT patients have significantly greater sCD14, TNF-alpha and IFN-gamma in the peripheral blood implying a heightened state of innate immune activation drives the development of increased post-transplant rejection. Inhibition of innate immune activation through CD14 represents a novel and potentially important therapeutic target to prevent post-transplant rejection and improve outcomes after human lung transplantation.

Adult↗
PubMed2006

A distinct anatomical network of cortical areas for analysis of motion in far peripheral vision.

We defined cortical areas involved in the analysis of motion in the far peripheral visual field, a poorly understood aspect of visual processing in primates. This was accomplished by small tracer injections within and around the representations of the monocular field of vision ('temporal crescents') in the middle temporal area (MT) of marmoset monkeys. Quantitative analyses demonstrate that the representation of the far periphery receives specific connections from the retrosplenial cortex (areas 23v and prostriata), as well as comparatively stronger inputs from the primary visual area (V1) and from areas surrounding MT (in particular, the medial superior temporal area, MST). In contrast, the far peripheral representation receives little or no input from most other extrastriate areas, including the second visual area (V2), the densely myelinated areas of the dorsomedial cortex, and ventral stream areas; these areas are shown to have robust projections to other parts of MT. Our results demonstrate that the responses of cells in different parts of a same visual area can be determined by different combinations of synaptic inputs, in terms of areas of origin. They also suggest that the interconnections responsible for motion processing in the far periphery of the visual field convey information that is crucial for rapid-response aspects of visual function such as orienting, postural and defensive reactions.

Afferent Pathways↗
PubMed2006

Impact of lung transplant operation on bronchiolitis obliterans syndrome in patients with chronic obstructive pulmonary disease.

Previous studies suggest that bilateral (BLT) compared with single lung transplantation (SLT) for patients with chronic obstructive pulmonary disease (COPD) results in improved long-term survival. The effect of transplant operation on bronchiolitis obliterans syndrome (BOS) is unknown. A retrospective study of all lung transplant recipients with pre-transplant diagnoses of COPD at the University of Toronto and at Duke University was performed. Data collected were age, gender, date and type of transplant, acute rejection, survival, presence and time of BOS. 221 (bilateral n = 101, single n = 120) patients met our criteria. Patients with BLT were younger (53.0 vs. 55.3 years; p = 0.034), more likely to be male (56.3% vs. 42.4%; p = 0.039) and more likely to be transplanted at the University of Toronto (79.6% vs. 16.1%; p < 0.001). Freedom from BOS was similar at 1 year post-transplant. However, BLT recipients were more commonly free from BOS 3 years (57.4% vs. 50.7%) and 5 years (44.5% vs. 17.9%) post-transplant (p = 0.024). Survival of BLT was better than SLT recipients at 3 and 5 years post-transplant (BLT vs. SLT: 67.5% vs. 61.1% and 60.7% vs. 34.1%, respectively; p = 0.018). Similar trends on survival were observed after development of BOS. BLT results in lower rates of BOS in patients with COPD that are eligible for both SLT and BLT.

Bronchiolitis Obliterans↗
PubMed2006

The role of hyaluronan degradation products as innate alloimmune agonists.

Dendritic cells (DCs) play a key role in initiating alloimmunity yet the substances that activate them during the host response to transplantation remain elusive. In this study we examined the potential roles of endogenous innate immune agonists in activating dendritic cell-dependent alloimmunity. Using a murine in vitro culture system, we show that 135 KDa fragments of the extracellular matrix glycosaminoglycan hyaluronan induce dendritic cell maturation and initiate alloimmunity. Priming of alloimmunity by hyaluronan-activated DCs was dependent on signaling via TIR-associated protein, a Toll-like receptor (TLR) adaptor downstream of TLRs 2 and 4. However, this effect was independent of alternate TLR adaptors, MyD88 or Trif. Using an in vivo murine transplant model, we show that hyaluronan accumulated during skin transplant rejection. Examination of human lung transplant recipients demonstrated that increased levels of intragraft hyaluronan were associated with bronchiolitis obliterans syndrome. In conclusion, our study suggests that fragments of hyaluronan can act as innate immune agonists that activate alloimmunity.

Animals↗
PubMed2002

Laparoscopic antireflux surgery in the lung transplant population.

BACKGROUND: Lung transplantation has emerged as a viable therapeutic option for patients with a variety of end-stage pulmonary diseases. As immediate posttransplant surgical outcomes have improved, the greatest limitation of lung transplantation remains chronic allograft dysfunction. Gastroesophageal reflux disease (GERD) with resultant aspiration has been implicated as a potential contributing factor in allograft dysfunction. GERD is prevalent in end-stage lung disease patients, and it is even more common in patients after transplantation. We report here on the safety of laparoscopic fundoplication surgery for the treatment of GERD in lung transplant patients. METHODS: Eighteen of the 298 lung transplants performed at Duke University Medical Center underwent antireflux surgery for documented severe GERD. The safety and benefit of laparoscopic fundoplications in this population was evaluated. RESULTS: The antireflux surgeries included 13 laparoscopic Nissen fundoplications, four laparoscopic Toupets, and one open Nissen (converted secondary to extensive adhesions). Two of the 18 patients reported recurrence of symptoms (11%), and two others reported minor GI complaints postoperatively (nausea, bloating). There were no deaths from the antireflux surgery. After fundoplication surgery, 12 of the 18 patients showed measured improvement in pulmonary function (67%). CONCLUSIONS: GERD occurs commonly in the posttransplant lung population. Laparoscopic fundoplication surgery, when indicated, can be done safely with minimal morbidity and mortality. In addition to the resolution of reflux symptoms, improvement in pulmonary function may be seen in this population after fundoplication. Lung transplant patients with severe GERD should be strongly considered for antireflux surgery.

Adolescent↗
PubMed2001

Safety of aerosolized amphotericin B lipid complex in lung transplant recipients.

BACKGROUND: Fungal infections remain an important cause of morbidity and mortality in lung transplant recipients. Aerosolized amphotericin B lipid complex (ABLC) may be more efficacious than conventional amphotericin B in the prevention of fungal infections in animal models, but experience with aerosolized ABLC in humans is lacking. METHODS: We conducted a prospective, noncomparative study designed to evaluate safety of aerosolized ABLC in lung or heart-lung transplant recipients. RESULTS: A total of 381 treatments were administered to 51 patients. Complete spirometry records were available for 335 treatments (69 in intubated patients, 266 in extubated patients). ABLC was subjectively well tolerated in 98% of patients. Pulmonary mechanics worsened by 20% or more posttreatment in less than 5% of all treatments. There were no significant adverse events related to study medication in any patient, and 1-year survival for all enrolled patients was 78%. CONCLUSION: Administration of nebulized ABLC is safe in the short-term and well-tolerated in lung transplant recipients. Additional prospective, randomized studies are needed to determine the efficacy of aerosolized ABLC alone or in conjunction with systemic therapies in the prevention of fungal infections in lung transplant recipients.

Adult↗
PubMed2001

Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection.

BACKGROUND: Although the use of mycophenolate mofetil (MMF) has reduced the incidence of acute rejection in heart and kidney allograft recipients, its role in lung transplantation remains controversial. Therefore, we conducted a randomized, prospective, open-label, multicenter study in lung transplant recipients to determine whether MMF decreases episodes of acute allograft rejection when compared with azathioprine (AZA). METHODS: Between March of 1997 and January of 1999, 81 consecutive lung transplant recipients from two centers were prospectively randomized to receive cyclosporine, corticosteroids, and either 2 mg/kg per day of AZA or 1 g twice daily of MMF. The primary study endpoint was biopsy-proven acute allograft rejection over the first 6 months posttransplant. Secondary endpoints included clinical rejection, cytomegalovirus (CMV) infection, adverse events, and survival. Surveillance bronchoscopies were performed at 1, 3, and 6 months, or if clinically indicated. Pathologists interpreting the biopsy results were blinded to the randomization. Results were analyzed according to intention-to-treat. Between group comparisons of means and proportions were made by using two sample t tests and Fisher's exact tests, respectively. Six-month survival was calculated by the Kaplan-Meier method and compared by the log rank test. RESULTS: Thirty-eight patients were prospectively randomized to receive AZA, and 43 MMF. The incidence of biopsy proven grade II or greater acute allograft rejection at 6 months was 58% in the AZA group and 63% in the MMF group (P=0.82). The 6-month survival rates in the MMF and AZA groups were 86% and 82%, respectively (P=0.57). Rates of CMV infection and adverse events were not significantly different between the two groups. CONCLUSIONS: Acute rejection rates and overall survival at 6 months are similar in lung transplant recipients treated with either MMF- or AZA-based immunosuppression.

Acute Disease↗
PubMed2001

Prognostic value of serum carcinoembryonic antigen levels in patients who undergo lung transplantation.

BACKGROUND: Potential candidates for lung transplantation undergo a rigorous evaluation before transplant. Serum carcinoembryonic antigen (CEA) levels are used as a screening tool for occult malignancy in many lung transplant centers. We reviewed the pre-transplant CEA levels in lung transplant recipients in our institution to determine their prognostic significance. MATERIALS AND METHODS: We performed a retrospective database review of the first 200 patients that had undergone lung or heart-lung transplant at our institution (dates were 1/20/92-7/25/98). Data extracted included CEA levels (in ng/ml) at the time of lung transplant evaluation, demographic data, and survival. Patients had one of the following diagnoses: alpha-1-anti-trypsin deficiency, cystic fibrosis, chronic obstructive pulmonary disease, Eisenmenger's syndrome, idiopathic pulmonary fibrosis, primary pulmonary hypertension, sarcoidosis, or other. RESULTS: After excluding re-transplants, CEA results were available for 174 of 193 (90.2%) patients. CEA levels were elevated in 85 patients (48.9%) with a mean value of 3.15 +/- 2.55 (normal < 2.5). Solid organ cancers developed in 6 patients, at a median follow-up of 27.5 months after transplant. Their mean pre-transplant CEA level was similar to the rest of the group (3.52 +/- 2.05). Pre-transplant CEA levels did not predict post-transplant survival. Patients with idiopathic pulmonary fibrosis had the highest pre-transplant CEA levels, whereas patients with primary pulmonary hypertension and Eisenmenger's syndrome had the lowest (5.36 +/- 4.59, 0.83 +/- 0.56, and 1.43 +/- 0.81, respectively; p = 0.0001). CONCLUSIONS: CEA levels are high in patients with end-stage lung disease, especially IPF. Their levels appear to be a marker of the underlying disease and do not predict the post-transplant survival or development of malignancy.

Adult↗
PubMed2001

Reperfusion edema after lung transplantation: effect of daclizumab.

PURPOSE: To determine if daclizumab, an interleukin-2 antagonist, reduced the severity of reperfusion edema in lung transplant recipients. MATERIALS AND METHODS: Eighty-five patients who were to undergo 86 consecutive lung transplants were included; 43 (50%) received daclizumab in addition to conventional immunosuppression. Patients were assigned to one of the following groups: control, right allograft; control, left allograft; daclizumab treated, right allograft; daclizumab treated, left allograft. Radiographs obtained in the first 5 postoperative days were evaluated for degree of edema. Mean daily edema scores and curves for control and daclizumab-treated groups were compared. Differences in survival at 1, 3, 6, and 12 months after transplantation, days of mechanical ventilation, and the ratio of arterial oxygenation to inspired oxygen level at 1, 3, and 5 days after transplantation were also compared. RESULTS: Mean daily edema scores, edema curves, survival, days of mechanical ventilation, and ratio of arterial oxygenation to inspired oxygen level at 1 and 3 days after transplantation did not significantly differ between daclizumab-treated and control groups. A trend toward improved survival in the daclizumab-treated group was noted. CONCLUSION: Daclizumab had no effect on the radiographic or immediate clinical manifestations of reperfusion edema in lung transplant recipients. Additional follow-up is needed to determine if daclizumab offers any long-term benefit in terms of reduced rejection rates or survival.

Adolescent↗
PubMed2001

Complications (excluding hyperinflation) involving the native lung after single-lung transplantation: incidence, radiologic features, and clinical importance.

PURPOSE: To determine the incidence, importance, and radiologic features of native lung complications after single-lung transplantation. MATERIALS AND METHODS: Seventeen (15%) of 111 single-lung transplant recipients developed native lung complications (excluding hyperinflation) 0-58 months (mean, 17 months) after transplantation. Complaints at presentation, culture or histopathologic results, diagnostic or therapeutic procedures, and outcome were recorded. Chest radiographs (n = 17) and computed tomographic (CT) scans (n = 8) obtained at time of diagnosis were reviewed. Serial radiographs were assessed for disease progression or improvement. RESULTS: The most common complications were infection (n = 10), caused by bacteria (n = 4), fungi (n = 4), or mycobacteria (n = 2), typically manifested as lobar or segmental opacities on chest radiographs or CT scans. Lung cancer manifested as a solitary well-circumscribed nodule (n = 1), multiple nodules (n = 1), or a hilar mass (n = 1). Five (29%) of 17 patients died of native lung complications. Seven patients underwent mediastinoscopy (n = 3), lobectomy (n = 2), thoracoscopic wedge resection (n = 2), tube thoracostomy (n = 2), or pneumonectomy (n = 1) for diagnosis or treatment. CONCLUSION: Native lung complications occurred in 17 (15%) single-lung transplant recipients, were most commonly due to infection or lung cancer, and caused serious morbidity or mortality in 12 (71%) of 17 patients affected.

Adult↗
PubMed2001

Lung transplantation after long-term mechanical ventilation : results and 1-year follow-up.

BACKGROUND: Long-term mechanical ventilation is considered as a relative or absolute contraindication for lung transplantation by most centers. We report on the results of transplantation in nine patients requiring long-term mechanical ventilation at two lung transplant centers. METHODS: The study group (group 1) consisted of nine patients receiving mechanical ventilation who underwent lung transplantation at either Duke University Medical Center or the University of Florida between 1992 and 1997. Patients in group 1 met the following criteria: they underwent exercise therapy with a physical therapist, and they were without panresistant bacterial airway colonization. The study patients that met these criteria spent at least 13 days receiving mechanical ventilation prior to transplantation. The control population (group 2; n = 65) consisted of all patients who underwent transplantation at either center in the calendar year 1997 who were ventilator independent. The 1-year survival rates in each group were calculated by the Kaplan-Meier method. The number of days required for extubation in each group were compared by the nonparametric Wilcoxon rank sum test. The FEV(1) value at 1 year was reported in each group. RESULTS: The 1-year survival rates were 78% and 83% in group 1 and group 2, respectively. The mean number of days required until extubation were 41 days in group 1 and 9 days in group 2 (p < 0.01). The allograft function was comparable in the two groups at 1 year. CONCLUSIONS: In a select population of ventilator-dependent patients, the 1-year survival rate is comparable to the standard lung transplant population. However, these ventilator-dependent patients require a significantly longer time until extubation than other transplant recipients.

Adolescent↗
PubMed2001

Influenza pneumonia in lung transplant recipients: clinical features and association with bronchiolitis obliterans syndrome.

Influenza infection is increasingly recognized to cause significant morbidity and mortality in the community, especially in pediatric patients and elderly persons. Influenza infection, however, has not been well described among thoracic organ transplant recipients. We provide the first detailed clinical, radiographic, and histologic description of influenza pneumonia among three lung transplant recipients. The presentation varied considerably among the three patients and, in some cases, was atypical for influenza. Despite treatment, a persistent decline in pulmonary function occurred in all three patients after the acute illness. Interestingly, on follow-up biopsy specimens, each patient had histologic evidence of acute rejection and/or obliterative bronchiolitis. Additional research, therefore, is needed to clarify the relationship between influenza infection, acute rejection, and obliterative bronchiolitis.

Biopsy, Needle↗
PubMed2000

Ca(2+) influx stimulated phospholipase C activity in bovine adrenal chromaffin cells: responses to K(+) depolarization and histamine.

The role of Ca(2+) influx in activating phospholipase C in bovine adrenal chromaffin cells has been investigated. Phospholipase C activity in response to K(+) depolarization (56 mM) was blocked by the L-type Ca(2+) channel antagonist nifedipine and partially inhibited by the omega-conotoxins GVIA and MVIIC. In contrast, phospholipase C activity in response to histamine receptor activation was unaffected by omega-conotoxin GVIA and partially inhibited by omega-conotoxin MVIIC or nifedipine. This response was however markedly inhibited by the non-selective Ca(2+) channel antagonists La(3+) or 1-[beta-[3-(4-Methoxyphenyl)propoxy]-4-methoyphenethyl]-H-imidazol e (SKF-96365). Despite this Ca(2+) dependence phospholipase C activity was not increased during periods of "capacitative" Ca(2+) inflow generated by histamine-, caffeine- or thapsigargin-mediated depletion of internal Ca(2+) stores. Thus, while Ca(2+) influx in response to K(+) depolarization or G-protein receptor activation can increase phospholipase C activity in these cells, in the latter case it appears to be ineffective unless there is concurrent agonist occupation of the receptor.

Adrenal Glands↗
PubMed2000

Significance of blood stream infection after lung transplantation: analysis in 176 consecutive patients.

BACKGROUND: Although infection is a leading cause of death after lung transplantation, very little is known about the incidence, epidemiology, and clinical significance of bloodstream infections in lung transplant recipients. METHODS: All blood cultures were reviewed in 176 consecutive lung transplant recipients over a 6-year period. Data were obtained from a prospectively collected microbiological database. RESULTS: Bloodstream infection (BSI) occurred in 25% (44/176) of all lung transplant recipients over the 6-year study period. Staphylococcus aureus, Pseudomonas aeruginosa, and Candida species were the most common bloodstream isolates after lung transplantation. The epidemiology of posttransplant BSI, however, varied considerably between early and late posttransplant time periods and also differed between cystic fibrosis (CF) and non-CF patients. BSI infection after transplantation was associated with significantly worse survival by Kaplan-Meir analysis (P value log rank test=0.0001). In a multivariable logistic regression model, posttransplant BSI was a significant predictor of posttransplant death (odds ratio 5.62, CI 2.41-13.11, P=0.001), independent of other pre- and posttransplant factors. CONCLUSIONS: Bloodstream infection represents a serious complication after lung transplantation, occurring more frequently than previously recognized, and independently contributing to posttransplant mortality.

Adolescent↗
PubMed2000

Histamine-stimulated phospholipase C activity in bovine adrenal medullary chromaffin cells: the effect of chloride-channel antagonists and low extracellular chloride concentrations.

Histamine activates phospholipase C (PLC) in a number of cell-types including those of neuronal and neuroendocrine origin. We report here that Cl(-)-channel antagonists of the niflumic acid-, but not stilbene disulphonic acid-class, produced a concentration-dependent inhibition of histamine-stimulated PLC activity in bovine adrenal medullary chromaffin cells. Low extracellular [Cl-] (10 mM) produced a similar degree of inhibition. While the mechanism(s) responsible for this inhibition are not resolved it may be significant that low extracellular Cl- also reduced the magnitude of the histamine-induced Ca2+ signal. Thus, PLC inhibition may be secondary to a reduction in Ca2+-inflow, a conclusion consistent with the known actions of niflumic acid-type compounds and the previously reported importance of Ca2+-influx in supporting histamine-stimulated PLC activity.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2000

Influence of panel-reactive antibodies on posttransplant outcomes in lung transplant recipients.

BACKGROUND: Panel-reactive antibody (PRA) is used to estimate the degree of humoral sensitization in the recipient before transplantation. Although pretransplant sensitization is associated with increased complications in other solid organ transplant recipients, less is known about the outcome of sensitized lung transplant recipients. Therefore, we sought to determine the impact of elevated pretransplant PRA on clinical outcomes after lung transplantation. METHODS: The records of the first 200 lung transplant operations performed at Duke University Medical Center were reviewed. The outcomes of sensitized patients, PRA greater than 10% before transplantation (n = 18), were compared with the outcomes of nonsensitized patients. RESULTS: Sensitized patients experienced a significantly greater number of median ventilator days posttransplant (9 +/- 8) as compared with nonsensitized recipients (1 +/- 11; p = 0.0008). There were no significant differences between the number of episodes of acute rejection; however, there was a significantly increased incidence of bronchiolitis obliterans syndrome occurring in untreated sensitized recipients (56%) versus nonsensitized (23%; p = 0.044). In addition, there was a trend towards decreased survival in the sensitized recipients, with a 2-year survival of 58% in sensitized recipients as compared with 73% in the nonsensitized patients (p = 0.31). CONCLUSIONS: Sensitized lung transplant recipients experience more acute and chronic complications after transplantation. These patients probably warrant alternative management strategies.

Adolescent↗
PubMed2000

Gastroesophageal reflux as a reversible cause of allograft dysfunction after lung transplantation.

Gastroesophageal reflux (GER) is increasingly recognized as contributing to a number of pulmonary disorders. The relationship of GER to pulmonary allograft dysfunction after lung transplantation is unknown. In this report, we describe a lung transplant recipient who developed an acute decline in pulmonary function several months after a retransplantation for chronic rejection. A pulmonary workup at that time, including bronchoscopy with biopsy, revealed bronchial inflammation with no allograft rejection or infection. Because of increasing GI symptoms after retransplantation, the patient also underwent additional testing, which revealed severe acid reflux. The treatment of this patient's acid reflux with Nissen fundoplication surgery resulted in a prompt and sustained improvement in his pulmonary function. We suggest that GER should be considered among the potential causes of allograft dysfunction after lung transplantation.

Adult↗