Late Organ Failure Research Articles

Sleeve Technique is Superior to End-to-End Anastomosis and Cuff Technology in Mouse Model of Graft Vascular Disease

Graft vascular disease (GVD) is the main reason of late transplanted organ failure, which limits the long-term survival of patients. Murine aortic transplant is widely used in the field to understand the mechanisms leading to GVD. Currently, 3 major techniques, end-to-end anastomosis, sleeve suture and cuff technology, have been used to study the mechanism of GVD. However, which method is more suitable in mouse model of GVD? Herein, we compared these 3 surgical techniques in a mouse allograft arteriosclerosis model to determine the technique with the most appreciable outcomes. Male C57Bl/6 (H-2b) and BALB/c (H-2d) mice were used for aorta transplantation with these 3 techniques. These 3 techniques were compared with regard to donor artery acquisition time, artery anastomosis time, overall surgical time, the amount of bleeding of each technique and the success rate of surgery. Hematoxylin and eosin (H&E) and Masson staining were used to examine the pathological changes of grafted vessels. The protein expression of phospho-NF-κb P65 and PCNA were determined to validate laminar flow and proliferative capacity of neointima obtained from different surgical and control groups. Sleeve suture had a shorter vascular anastomosis time and total operation time than end-to-end anastomosis and cuff technique. Sleeve suture and cuff technique had significantly fewer amount of bleeding from the site of vascular anastomosis than end-to-end anastomosis. Moreover, sleeve suture had the highest success rate among these 3 techniques. There was no difference in the degree of graft stenosis and collagen deposition between these 3 techniques. In addition, there was no significant difference in the expression of phospho-NF-κb P65and PCNA between the experimental group. Sleeve suture is superior to end-to-end anastomosis and cuff technique with regard to vascular grafting in the murine model.

Feasibility of Custom Made Fenestrated Devices Designed for Other Patients to Treat Ruptured TAAA And JRAAA

Introduction - Ruptured TAAA or JRAAA is a challenge for patients and surgeons. Although FEVAR provides good results for elective cases, its feasibility in an emergency setting is limited by manufacturing and delivering delays. The aim of this study was to assess the feasibility of using custom made fenestrated devices designed for other patients to treat urgent TAAA and JRAAA in an emergency setting. Methods - From 2006 to 2017, pre and post-operative data from patients with ruptured or symptomatic TAAA or JRAAA treated with fenestrated devices custom-made for other patients in two high volume aortic centers were reviewed retrospectively. Data was collected and imaging reviewed to determine the major adverse events and outcomes for patients undergoing these procedures. Results - Nine patients were included (5 women, mean age 78y +/-4) with a median follow up of 6 months {1-72}. All patients underwent fenestrated EVAR for ruptured TAAA or JRAAA (type 3 TAAA: n=1, type 4 TAAA: n=4, JRAAA: n=4). Anatomical compatibility with a locally available FEVAR was assessed pre operatively by the senior surgeon. Intra operative success of aortic branch catheterization through the graft fenestrations was achieved in 27 of the 31 targeted vessels (87%). Three in-hospital deaths were recorded. One patient died intra operatively, and two patients died from a late multi organ failure at 1 months and 3 months. A secondary intervention was necessary in 2 cases (1 retrograde SMA embolectomy after 7 days and a 1 renal artery stenting after 3 months). Conclusion - In our centres, perioperative outcomes of in stock FEVAR in emergency cases are encouraging, achieving good target vessel patency with acceptable mortality. Longer follow-up is required to assess the durability of this endovascular option.

An overview of T follicular cells in transplantation: spotlight on their clinical significance

ABSTRACTIntroduction: For late stage organ failure patients, transplantation is the best option to increase life expectancy with a superior quality of life. Unfortunately, after transplantation many patients are at risk of cellular and antibody-mediated rejection (ABMR). The latter is initiated by donor specific antibodies (DSA) which depend on the actions of B cells, T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells that are present in the germinal center of lymphoid organs.Areas covered: In this overview paper, we discuss the biology and function of Tfh and Tfr cells in lymphoid tissues, transplanted organs and their circulating counterparts. We report on their relevance to alloimmunity and on the effects of immunosuppressive drugs on these immunocompetent cell populations.Expert opinion: Growing knowledge about the actions of Tfh and Tfr allows for a better understanding of the immunological mechanisms of ABMR after organ transplantation. This understanding feeds the hypothesis that immunosuppressive drugs targeting the actions of Tfh cells have huge therapeutic potential. This new concept in the treatment of the humoral rejection response will improve graft and patient survival after organ transplantation.

Murine Cervical Aortic Transplantation Model using a Modified Non-Suture Cuff Technique

With the introduction of powerful immunosuppressive protocols, distinct advances are possible in the prevention and therapy of acute rejection episodes. However, only minor improvement in the long-term results of transplanted solid organs could be observed over the past decades. In this context, chronic allograft vasculopathy (CAV) still represents the leading cause of late organ failure in cardiac, renal and pulmonary transplantation. Thus far, the underlying pathogenesis of CAV development remains unclear, explaining why effective treatment strategies are presently missing and emphasizing a need for relevant experimental models in order to study the underlying pathophysiology leading to CAV formation. The following protocol describes a murine heterotopic cervical aortic transplantation model using a modified non-suture cuff technique. In this technique, a segment of the thoracic aorta is interpositioned in the right common carotid artery. With the use of the non-suture cuff technique, an easy to learn and reproducible model can be established, minimizing the possible heterogeneity of sutured vascular micro anastomoses.

Adenosine 2A Receptor Activation Attenuates Ischemia Reperfusion Injury During Extracorporeal Cardiopulmonary Resuscitation.

We tested the hypothesis that systemic administration of an A2AR agonist will reduce multiorgan IRI in a porcine model of ECPR. Advances in ECPR have decreased mortality after cardiac arrest; however, subsequent IRI contributes to late multisystem organ failure. Attenuation of IRI has been reported with the use of an A2AR agonist. Adult swine underwent 20 minutes of circulatory arrest, induced by ventricular fibrillation, followed by 6 hours of reperfusion with ECPR. Animals were randomized to vehicle control, low-dose A2AR agonist, or high-dose A2AR agonist. A perfusion specialist using a goal-directed resuscitation protocol managed all the animals during the reperfusion period. Hourly blood, urine, and tissue samples were collected. Biochemical and microarray analyses were performed to identify differential inflammatory markers and gene expression between groups. Both the treatment groups demonstrated significantly higher percent reduction from peak lactate after reperfusion compared with vehicle controls. Control animals required significantly more fluid, epinephrine, and higher final pump flow while having lower urine output than both the treatment groups. The treatment groups had lower urine NGAL, an early marker of kidney injury (P = 0.01), lower plasma aspartate aminotransferase, and reduced rate of troponin rise (P = 0.01). Pro-inflammatory cytokines were lower while anti-inflammatory cytokines were significantly higher in the treatment groups. Using a novel and clinically relevant porcine model of circulatory arrest and ECPR, we demonstrated that a selective A2AR agonist significantly attenuated systemic IRI and warrants clinical investigation.

Coagulopathy and Mortality in Combat Casualties: Do the Kidneys Play a Role?

Acute traumatic coagulopathy (ATC) is a common condition after traumatic injury and is known to be associated with an increase in morbidity and mortality in trauma patients. ATC has been implicated as a causative factor in both early hemorrhage and late organ failure in this population, yet the pathophysiology remains largely unknown. Additionally, acute kidney injury (AKI) is a common condition among critically injured trauma patients. AKI has been associated with an elevated International Normalized Ratio (INR) and warfarin use, but its development has not been well studied in the setting of ATC. We hypothesized that the presence of ATC influences the development of AKI and may mediate mortality in combat casualties. Data were obtained from the Department of Defense Trauma Registry, Medical Data Store and Composite Healthcare System, and the Armed Forces Medical Examiner System. A retrospective review was conducted of US service members injured in Iraq or Afghanistan between February 1, 2002 and February 1, 2011, who required ICU level care and survived evacuation out of theater. Exclusions were made for missing data. Cox proportional hazard regression was performed to determine the effect of ATC (a priori defined as first INR > 1.3) on the development of AKI. Further analysis was conducted to determine the influence of these variables on 30-d mortality, and multiple sensitivity analyses were performed to determine the effect of ATC on both AKI and mortality. A total of 1,288 patients were identified for analysis. ATC was a risk factor for subsequent AKI after adjustment (HR 1.67, 95% CI 1.28-2.18; p < 0.001). However, ATC was not a risk factor for mortality after adjustment in the full model (HR 1.87, 95% CI 0.95-3.65; p = 0.069). On sensitivity analyses exploring alternate definitions of ATC, an INR of 1.2 remained associated with AKI (HR 1.46, 95% CI 1.13-1.88; p = 0.004) and an INR of 1.5 became significant for mortality (HR 1.76, 95% CI 1.32-2.35; p < 0.001). ATC is independently associated with the development of AKI. Although ATC is associated with mortality in the unadjusted model, it is not significant after adjustment for AKI. This implies that the kidneys may play a role in the adverse outcomes observed after ATC. Increased awareness and monitoring for coagulopathy and the subsequent development of AKI in combat casualty patients may lead to earlier diagnosis and treatment of these conditions, possibly decreasing morbidity and mortality.

Primary and Secondary Organ Failures Cause Mortality Differentially in Acute Pancreatitis and Should be Distinguished.

The aim of this study was to study the development of early and late organ failure (OF) and their differential impact on mortality in patients with acute pancreatitis (AP). Consecutive patients (N = 805) with acute pancreatitis were included in an observational study. Organ failure was categorized as primary if it occurred early due to pancreatitis per se and secondary if it occurred late due to infected pancreatic necrosis (IPN). Primary outcome was a relative contribution of primary OF, secondary OF, and IPN to mortality. Of the 614 patients (mean age, 38.8; standard deviation, 14.6 years; 430 males) in a derivation cohort, 274 (44.6%) developed OF, with 177 having primary OF and 97 secondary OF due to sepsis. Primary OF caused early mortality in 15.8% and was a risk factor for IPN in 76% of patients. Mortality in patients with primary OF and IPN was 49.5% versus 36% in those with IPN and secondary OF (P = 0.06) and 4% in those with IPN but without OF (P < 0.001). The results of the 191 patients in the validation cohort confirmed the relative contribution of primary and secondary OF to mortality. Primary and secondary OF contributed to mortality independently and are distinct in their timing, window of opportunity for intervention, and prognosis.

A novel and effective method to generate human porcine-specific regulatory T cells with high expression of IL-10, TGF-\u03b21 and IL-35

Organ transplantation remains the most effective treatment for patients with late stage organ failure. Transgenic pigs provide an alternative organ donor source to the limited availability of human organs. However, cellular rejection still remains to be the obstacle for xenotransplantation. Superior to other methods, antigen-specific regulatory T cells (Treg) alleviate cellular rejection with fewer side effects. Here we demonstrate the use of a fast method to provide tolerogenic dendritic cells (tolDC) that can be used to generate effective porcine-specific Treg cells (PSTreg). TolDC were produced within three days from human monocytes in medium supplemented with anti-inflammatory cytokines. Treg were generated from naïve CD4+ T cells and induced to become PSTreg by cocultivation with porcine-antigen-loaded tolDC. Results showed that PSTreg exhibited the expected phenotype, CD4+CD25+CD127low/− Foxp3+, and a more activated phenotype. The specificity of PSTreg was demonstrated by suppression of effector T cell (Teff) activation markers of different stages and inhibition of Teff cell proliferation. TolDC and PSTreg exhibited high expression of IL-10 and TGF-β1 at both protein and RNA levels, and PSTreg also highly expressed IL-35 at RNA levels. Upon restimulation, PSTreg retained the activated phenotype and specificity. Taken together, the newly developed procedure allows efficient generation of highly suppressive PSTreg.

A simplified cuff technique for abdominal aortic transplantation in mice

BackgroundAllograft arteriopathy is still a leading cause of late organ failure. The aortic allograft model in mice has been used to study chronic rejection and has given useful information in the development of graft arteriosclerosis. However, the technical difficulties of small vessel anastomoses still continue to limit its widespread use. We introduce a new simple method for aortic transplantation in mice. MethodsThe descending aorta or infrarenal aorta from the donor mouse was anastomosed to the infrarenal aorta using a cuff technique. Aortic transplantation was performed in 30 mice, 10 isografts and 20 allografts. No immunosuppression was administered, and the recipients were sacrificed at day 28. The grafts were histologically analyzed. ResultsImplantation of grafts could be completed in an average of 23 min. There was no technical failure in all 60 anastomoses. The overall survival rate was 93.3%. Histology of aortas revealed typical aspects of chronic rejection in the allografts at day 28. No significant lesion was observed in isografts. ConclusionsWe have developed an innovative, stable, and simple aortic transplantation model in mice, which is useful for vascular research in transplantation and beyond.

P925 RECIPIENTS WITH NASH HAVE HIGHER PREVALENCE AND MORE SEVERE CORONARY ARTERY DISEASE COMPARED TO HCV-INFECTED PATIENTS

Background and Aims: The evaluation of potential liver donors for transplantation is based in the careful analysis of the clinical, biochemical and histological data. In our center, liver biopsy is performed systematically to minimize the risk of the recipient to receive a suboptimal organ. The aim is to evaluate the main histological findings responsible for the exclusion of livers that were previously selected. Methods: Retrospective study of histological findings in livers for transplantation excluded based on histological criteria. Demographics, laboratory data and the cause of death were collected. Results:We excluded 110 organs from donors, mean age of 46 years, mostly male (59%). Fatty liver disease was the major cause of exclusion, presented as isolated macrovesicular steatosis in 59 patients and steatohepatitis in 5. The Body Mass Index (BMI) was a poor marker for the presence of steatosis since 80% of patients excluded for this had BMI below 25 kg/m. Fibrosis was identified in 22 patients, of which 3 had cirrhosis. Degenerative processes associated with ischemia time excluded 10 livers. Lesions consistent with chronic hepatitis were found in 5 cases. The least common causes were the presence of hepatic granulomas (4patients), hydatid cysts (two cases) and one case of autoimmune hepatitis. Transaminases and cholestasis enzymes did not correlate with histological findings. Conclusions: Liver biopsy before transplantation represents an important complementary test for the success of liver transplantation. The realization of biopsy enables the exclusion of histological changes in patients considered potential donors, thereby decreasing the risk of early and late organ failure. P925 RECIPIENTS WITH NASH HAVE HIGHER PREVALENCE AND MORE SEVERE CORONARY ARTERY DISEASE COMPARED TO HCV-INFECTED PATIENTS S.K. Satapathy, A.C. Flowers, J.M. Vanatta, N. Dbouk, S.P. Nair, J. Eason. Methodist University Hospital, University of Tennessee Health Sciences Center, Internal Medicine, Methodist University Hospital, University of Tennessee Health Sciences Center, Memphis, TN, United States E-mail: aflowe11@uthsc.edu

Update on management options in the treatment of nosocomial and ventilator assisted pneumonia: review of actual guidelines and economic aspects of therapy

ObjectiveNosocomial or more exactly, hospital-acquired (HAP) and ventilator-associated pneumonia (VAP) are frequent conditions when treating intensive care unit (ICU) patients that are only exceeded by central line-associated bloodstream infections. In Germany, approximately 18,900 patients per year suffer from a VAP and another 4,200 from HAP. We therefore reviewed the current guidelines about HAP and VAP, from different sources, regarding the strategies to address individual patient risks and medication strategies for initial intravenous antibiotic treatment (IIAT).Material and methodsWe conducted an analysis of the recent guidelines for the treatment of HAP. The current guidelines of the American Thoracic Society, the treatment recommendations of the Paul-Ehrlich-Gesellschaft (PEG), the guidelines from the British Society for Antimicrobial Chemotherapy, the VAP guideline of the Canadian Critical Care trials group, as well as the new German S3-guideline for HAP were examined.ResultsAll guidelines are based on grading systems that assess the evidence underlying the recommendations. However, each guideline uses different grading systems. One common aspect of these guidelines is the risk assessment of the patients for decision making regarding IIAT. Most guidelines have different recommendations depending on the risk of the presence of multidrug resistant (MDR) bacteria. In guidelines using risk assessment, for low-risk patients (early onset, no MDR risk) aminopenicillins with beta-lactamase inhibitors (BLI), second or third generation cephalosporins, quinolones, or ertapenem are recommended. For patients with higher risk, imipenem, meropenem, fourth generation cephalosporins, ceftazidime or piperacillin/tazobactam are recommended. The PEG recommendations include a combination therapy in cases of very high risk (late onset, MDR risk, ICU, and organ failure) of either piperacillin/tazobactam, dori-, imi- or meropenem or cefepime or ceftazidime with ciprofloxacin, levofloxacin, fosfomycin or an aminoglycoside. For the treatment of HAP caused by methicillin-resistant Staphylococcus aureus (MRSA), either linezolid or vancomycin is recommended. With regard to the ZEPHyR-trial, linezolid has shown higher cure rates but, no difference in overall survival. Economic analyses show the relevance of guideline-adherent IIAT (GA-IIAT). Besides significantly better clinical outcomes, patients with GA-IIAT cause significantly lower costs (€28,033 versus (vs) €36,139) (P=0.006) and have a shorter length of stay in hospital (23.9 vs 28.3 days) (P=0.022).ConclusionWe conclude that most current treatment guidelines take into account the individual patient risk and that the correct choice of IIAT affects clinical as well as economical outcomes.

Biomarker-guided antibiotic therapy in adult critically ill patients: a critical review

Biomarkers of infection, namely C-reactive protein and procalcitonin (PCT), are potentially useful in the diagnosis of infection as well as in the assessment of its response to antibiotic therapy. C-reactive protein variations overtime appears to have a good performance for the diagnosis of infection. Procalcitonin shows a better correlation with clinical severity. In addition, to overcome the worldwide problem of antibiotic overuse as well as misuse, biomarker guidance of antibiotic stewardship represents a promising new approach. In several randomized, controlled trials, including adult critically ill patients, PCT guidance was repeatedly associated with a decrease in the duration of antibiotic therapy. However, these trials present several limitations, namely high rate of patients’ exclusion, high rate of algorithm overruling, long duration of antibiotic therapy in the control group, disregard the effect of renal failure on PCT level, and above all a possible higher mortality and higher late organ failure in the PCT arm. In addition, some infections (e.g., endocarditis) as well as frequent nosocomial bacteria (e.g., Pseudomonas aeruginosa) are not suitable to be assessed by PCT algorithms. Therefore, the true value of PCT-guided algorithm of antibiotic stewardship in assisting the clinical decision-making process at the bedside remains uncertain. Future studies should take into account the issues identified in the present review.

Molecular Imaging of Vascular Endothelial Growth Factor Receptors in Graft Arteriosclerosis

Vascular endothelial growth factor (VEGF) signaling plays a key role in the pathogenesis of vascular remodeling, including graft arteriosclerosis. Graft arteriosclerosis is the major cause of late organ failure in cardiac transplantation. We used molecular near-infrared fluorescent imaging with an engineered Cy5.5-labeled single-chain VEGF tracer (scVEGF/Cy) to detect VEGF receptors and vascular remodeling in human coronary artery grafts by molecular imaging. VEGF receptor specificity of probe uptake was shown by flow cytometry in endothelial cells. In severe combined immunodeficiency mice, transplantation of human coronary artery segments into the aorta followed by adoptive transfer of allogeneic human peripheral blood mononuclear cells led to significant neointima formation in the grafts over a period of 4 weeks. Near-infrared fluorescent imaging of transplant recipients at 4 weeks demonstrated focal uptake of scVEGF/Cy in remodeling artery grafts. Uptake specificity was demonstrated using an inactive homolog of scVEGF/Cy. scVEGF/Cy uptake predominantly localized in the neointima of remodeling coronary arteries and correlated with VEGF receptor-1 but not VEGF receptor-2 expression. There was a significant correlation between scVEGF/Cy uptake and transplanted artery neointima area. Molecular imaging of VEGF receptors may provide a noninvasive tool for detection of graft arteriosclerosis in solid organ transplantation.

Mathematical modeling of community-acquired pneumonia patients

Sepsis is defined by the systemic response to an infection, governed by dynamic interactions between the tissues, immune cells and inflammatory mediators. We used the Immunetrics platform to build a large-scale mathematical model that encompasses these biological components. The model incorporates a virtual clinician, an automated system to examine simulated patients' status at clinically relevant intervals and administer standard of care interventions as necessary, thereby altering the dynamics of the disease state. The model reproduces many characteristics of systemic response to an infection, including the time course of cytokines, coagulation factors, clinical markers, early and late organ failure, and early versus late deaths.

Incidence and prognosis of early hepatic dysfunction in critically ill patients—A prospective multicenter study

In critically ill patients, hepatic dysfunction is regarded as a late organ failure associated with poor prognosis. We investigated the incidence and prognostic implications of early hepatic dysfunction (serum bilirubin >2 mg/dL within 48 hrs of admission). Prospective, multicenter cohort study. Thirty-two medical, surgical, and mixed intensive care units. A total of 38,036 adult patients admitted consecutively over a period of 4 yrs. None. Excluding patients with preexisting cirrhosis (n = 691; 1.8%) and acute or acute-on-chronic hepatic failure (n = 108, 0.3%), we identified 4,146 patients (10.9%) with early hepatic dysfunction. These patients had different baseline characteristics, longer median intensive care unit stays (5 vs. 3 days; p < .001) and increased hospital mortality (30.4% vs. 16.4%; p < .001). Hepatic dysfunction was also associated with higher observed-to-expected mortality ratios (1.02 vs. 0.91; p < .001). Multiple logistic regression analysis showed an independent mortality risk of hepatic dysfunction (odds ratio, 1.86; 95% confidence interval, 1.71-2.03; p < .001), which exceeded the impact of all other organ dysfunctions. A case-control study further confirmed these results: Patients with early hepatic dysfunction exhibited significantly increased raw and risk-adjusted mortality compared with control subjects. Our results provide strong evidence that early hepatic dysfunction, occurring in 11% of critically ill patients, presents a specific and independent risk factor for poor prognosis.

Long-Term Outcome of Methotrexate-Free GVHD Prophylaxis Using Sirolimus and Tacrolimus in Matched Related (MRD) and Unrelated Donor (URD) Peripheral Blood Stem Cell Transplantation (PBSCT).

Methotrexate (Mtx) is an antiproliferative agent associated with toxicity and delayed engraftment after transplantation. Sirolimus is an immunosuppressive mTOR inhibitor that acts synergistically when administered with tacrolimus. We assessed the combination of sirolimus and tacrolimus without Mtx after MRD and URD PBSCT in concurrent trials. Methods Eligible subjects had HLA-A, B, C and DRβ1 matched MRD and URD donors. Conditioning consisted of cytoxan (1800 mg/m2 x 2 days) and TBI (14 Gy, 7 fractions with lung shielding). Tacrolimus (serum conc. 5–10 ng/mL) and sirolimus (serum conc. 3–12 ng/mL) were given as GVHD prophylaxis. No Mtx was given. G-CSF (5 μg/kg/day) was administered from day+12 until neutrophil engraftment as needed. PCP, VZV, and HSV prophylaxis was used, and CMV was treated pre-emptively. No routine anti-fungal prophylaxis was given. Results 53 MRD and 30 URD recipients were enrolled between 7/2002 and 8/2005. The median number of stem cells infused was lower in MRD recipients (7.6 x106 CD34+ cells/kg vs. 10.2 x106 CD34+ cells/kg, p<0.001). Neutrophil engraftment was similar in MRD and URD patients (14 vs. 13.5 days, p=0.2). Platelet engraftment to 20 x106/ml (12 vs. 12 days, p=0.13) and to 100 x106/ml (17.5 vs. 17 days, p=0.32) were similar in the two cohorts. The median time to hospital discharge was 19 days in both groups (p=0.95), with only 2 deaths prior to discharge. Acute lung injury (IPS/DAH) occurred in only 1 subject and was not fatal. 7 (8.4%) subjects developed hepatic veno-occlusive disease (VOD) and was the cause of death in 4. Thrombotic microangiopathy (TMA) was noted in 6 subjects (MRD 5, URD 1; combined incidence 7.3%) and resolved with the elimination of tacrolimus. Renal function recovered in all individuals and TMA did not contribute to the cause of death in any subject. The cumulative incidence of grade II–IV acute GVHD was 20.5%, and was not different between cohorts (18.9 vs. 23.3%, p=0.78). There were only 3 cases of grade III–IV acute GVHD (2 MRD, 1 URD). In a competing risk model (relapse/death as competing risk) the cumulative incidence of chronic GVHD was 52.4% and was not different between groups (50.9 vs. 53.3%, p=0.67). The median follow-up of all surviving patients is 29.5 months from transplantation. Non-relapse and relapse-related mortality at 30 days was 0%. At 100 days they were 4.8% and 1.2% respectively (overall 100 day mortality 6%), without differences in cohorts. Relapse-free survival for the entire group was 72.3% and 68.1% at 1 and 2 years (MRD 71.7% and 66.0%; URD 73.3% at both times points, log rank p=0.6). Overall survival at 1 and 2 years is 77.1% and 71.7% (MRD 77.4% and 69.8%; URD 76.7% at both time points, log-rank p=0.67). The causes of death (n=24) include relapse(13), VOD(4), late pulmonary disease(3), GVHD(2), infection and organ failure(2). Conclusions Sirolimus in lieu of Mtx in a tacrolimus-based GVHD prophylactic regimen is associated with lower transplant-related toxicity, lower rates of acute GVHD and excellent outcomes than would be expected with a Mtx-based regimen. Moreover, MRD and URD outcomes appear to be equivalent, suggesting that the historical disparity in outcomes between MRD and URD transplantation can be abrogated with effective GVHD prophylaxis. This regimen is worthy of further study and broader use in MRD and URD PBSCT.

Activation of the endothelium in cardiac allografts

Initial graft failure, especially in hearts from “marinal” or “expanded” donors, and cardiac allograft asculopathy (CAV), which develops in more than half f transplant recipients who survive beyond 3 to 5 ears, represent the major limitations for the recipients’ hortand long-term survival. The causes for both of hese pathophysiologic processes are largely undefined nd most likely multifactorial; however, activation of he allograft endothelium and the ensuing inflammatory eaction represent early events, serving as potential herapeutic targets (Figure 1). This article initially discusses the pathophysiology of ndothelial activation in cardiac allografts and then ocuses on possible therapeutic strategies to minimize he activation of the endothelium, thereby reducing the ncidence of early and late organ failure.

Circulating Inflammatory and Metabolic Parameters to Predict Organ Failure after Muliple Trauma

Background: Patients encountering severe trauma are at high risk of sequential organ complications. We studied the value of circulating inflammatory mediators and metabolic parameters to evaluate their predictive value with respect to the development of multiple organ failure (MOF). Patients and Methods: In 77 traumatized patients with a mean Injury Severity Score (ISS) of 28.8±1.1 points, C-reactive protein (CRP), polymorphonuclear (PMN) elastase, lactate, interleukin-6 (IL-6), IL-8, and soluble tumor necrosis factor receptors 1 and 2 (TNF-R1 and TNF-R2) were determined for a period of 11 days following multiple trauma. Results: Weak and moderate correlations were found between mean plasma concentrations of all parameters and mean MOF scores calculated from the whole observation period [range: lactate (r=0.31, p < 0.01) to TNF-R1 (r=0.53, p < 0.001)]. Daily TNF-R1 and lactate concentrations of the 1st week moderately correlated with mean MOF scores of the 2nd week (p < 0.01). ISS weakly correlated with all parameters exept lactate [range: IL-8 (r=0.27, p < 0.05) and PMN elastase (r=0.46, p < 0.001)]. Prediction of MOF could not be improved by inclusion of several or all investigated mediators into multiple regression models. Conclusion: Only early plasma TNF-R1 and blood lactate concentrations showed a moderate association with the development of late posttraumatic organ failure. Thus, the predictive role of inflammatory mediators with respect to the manifestation of organ dysfunction after severe trauma seems limited.

Sequential Changes in Mucosal Immunity after Hemorrhagic Shock

Immunoinflammatory responses after shock and major trauma are characterized by an early hyperinflammatory response and later by compensatory anti-inflammatory host mediator production. This late phase is associated with depressed immune function that has been causally linked with post-traumatic infectious complications and late organ failure. Gut barrier failure is noted in this setting and may be an important source of nosocomial infections and organ failure. Secretory immunoglobulin A (sIgA) is the predominant immunoglobin at mucosal surfaces and is difficult to quantify in luminal secretions. Attempts to normalize sIgA concentrations may not be accurate and/or may not be applicable in vivo. A method using mucosal immunization with cholera toxin (ChT) to normalize gut sIgA levels was used to assess serial changes in sIgA after hemorrhagic shock (HS) in rodents. Total and anti-ChT sIgA levels were highly variable in both HS and sham animals. However, when normalized using the specific anti-ChT/total sIgA ratio, differences were clearly evident. This ratio was depressed between 3 and 10 days post-HS. The specific anti-ChT/total sIgA ratio is a reliable index of secretory antibody at gut luminal surfaces. Impaired mucosal immune function occurred in a time frame consistent with development of late nosocomial infections. This may be important mechanistically in the development of these infectious complications.

Controlled delivery of inductive proteins, plasmid DNA and cells from tissue engineering matrices.

It has been estimated that half the annual health care budget in the United States is spent on patients suffering from tissue loss and late stage organ failure. Critical limitations inherent in traditional therapies call for novel tissue and organ replacement strategies. This paper discusses development of biomaterials for conductive, inductive and cell-based tissue replacement strategies. Biodegradable polymer scaffolds can be used as space-filling matrices for tissue development and barriers to migration of epithelial cells in tissue conductive approaches. Inductive approaches involve sustained delivery of bioactive factors, such as protein growth factors and DNA, to alter cell function in localized regions. Factors can be released from highly porous polymer scaffolds to allow factor delivery and tissue development to occur in concert. Cell-based approaches involve seeding of cells onto polymeric scaffolds in vitro and subsequent transplantation of the scaffold. New scaffold materials are being developed that address specific tissue engineering design requirements, and in some cases attempt to mimic natural extracellular matrices. These strategies together offer the possibility of predictably forming specific tissue structures, and may provide solutions to problems such as periodontal ligament detachment, alveolar bone resorption and furcation defects.