Association of circulating interleukin (IL)-12- and IL-10-producing dendritic cells with time posttransplant, dose of immunosuppression, and plasma cytokines in renal-transplant recipients

BACKGROUND: Interleukin (IL)-12-producing dendritic cells (IL-12+DC) polarize T helper (Th) differentiation toward Th1, whereas IL-10+DC induce Th differentiation toward Th2. We investigated DC and plasma cytokine patterns early and late after transplantation. METHODS: Twenty-five hospitalized renal-transplant recipients without acute rejection or infection early (<40 days) posttransplant, 32 symptom-free outpatients with long-term functioning transplants (2,762+/-2,423 days posttransplant), and 17 healthy controls were studied. The intracellular production of IL-12 and IL-10 in CD11c+ CD83+ CD40+ DC was measured in freshly obtained whole blood using four-color fluorescence flow cytometry. In addition, plasma cytokine levels were investigated. RESULTS: Early and late posttransplant patients had significantly lower proportions of IL-12+DC (early: P=0.001; late: P=0.034) and lower ratios of IL-12+/IL-10+DC (early: P=0.0001; late: P<0.0001) than healthy controls. IL-10+DC (P=0.0004) and IL-12+DC (P=0.002) increased with time posttransplant in association with dose reductions of cyclosporine (IL-10+DC: P=0.003; IL-12+DC: P=0.005), methylprednisolone (IL-10+DC: P<0.0001; IL-12+DC: P=0.001) and mycophenolate mofetil (IL-10+DC: P<0.0001; IL-12+DC: P=0.004). Both IL-10+DC and IL-12+DC were associated with low plasma IL-10 (IL-10+DC: P=0.010; IL-12+DC: P=0.011) and high plasma IL-6 (IL-10+DC: P=0.001; IL-12+DC: P=0.009). IL-10+DC were also associated with high plasma levels of IL-3 (P=0.003), interferon (IFN)-gamma (P=0.014), and IL-2 (P=0.058). CONCLUSION: IL-10+DC and IL-12+DC in peripheral blood are associated with time after transplantation and dosage of immunosuppression. IL-10+DC dominate late posttransplant in the presence of Th1 plasma cytokines (high IFN-gamma and IL-2), high IL-3, and low IL-10. These findings could be a reflection of immunoregulatory processes favoring long-term allograft acceptance.     

Effectivity of a T-cell-adapted induction therapy with anti-thymocyte globulin (Sangstat).

BACKGROUND: Cytolytic induction therapy with anti-thymocyte globulin (ATG) should induce effective immunosuppression, with a low rate of rejection in the initial phase after heart transplantation. Induction therapy with ATG allows post-operative renal recovery without the negative effects of highly nephrotoxic cyclosporine levels. An increased rate of infection is a common problem, however, and has been associated with "over-immunosuppression" early after transplantation. Therefore, we investigated whether reduced T-cell-adapted ATG induction therapy could be performed without increasing the risk of graft loss by rejection and whether reductions in infection rates and costs are possible. METHODS: Between March 1999 and December 2002, T-cell-adapted ATG induction therapy with ATG (Sangstat) (1.5 mg/kg) was given to 62 heart transplant recipients (study group) starting on post-operative Days 1 to 6. T-lymphocyte sub-populations were screened daily using flow cytometry. If total lymphocytes were <100/microl (reference 1,300 to 2,300/microl), T-helper lymphocytes (CD4+) <50/microl (reference >500/microl) and T-suppressor cells (CD8+) <50/microl (reference >300/microl), then no ATG was given. Further immunosuppression was continued with triple therapy consisting of methylprednisolone, azathioprine and cyclosporine. An historic group of heart transplant recipients given a full-dose ATG regimen for 8 days served as controls. These recipients were treated with ATG (Merieux 1.5 mg/kg) until reaching monoclonal cyclosporine levels of >300 mg/dl. Additional immunosuppressive treatment did not differ. Patients in both groups received systemic antibiotics (Imipenem) peri-operatively. Results of routine endomyocardial biopsies and rates of infections were examined. RESULTS: Study group patients were older (52 +/- 10 vs 49 +/- 14 years). In the study group, mean cumulative ATG dose was reduced significantly to 596 +/- 220 mg (p < 0.05) for 3.9 +/- 1.6 days compared with 1,159 +/- 376 mg for 6.9 +/- 1.1 days in the control group. The rate of cytomegalovirus (CMV) seroconversion was 23% in the study group compared with 13% in the control group. Rate of deep sternal infections was lower in the study group (1.6% vs 3.2%). The mean rejection rate in the first 3 months was 0.4 +/- 0.7 for the study patients (185 biopsies) vs 1.1 +/- 1.7 for controls (237 biopsies). All biopsies with ISHLT Grade >2 were treated successfully with 1,000 mg of methylprednisolone intravenously for 3 days. Both groups showed a similar 1-year survival rate (study 88%, control 89%). CONCLUSIONS: T-cell-adapted ATG induction therapy can be a helpful tool for individualized immunosuppression. It is not associated with an increased rate of rejection. Lower doses of immunosuppression help to minimize the rates of infection. In addition, cytolytic induction therapy combined with reduced ATG results in significant cost reduction.     

Stem cells and cardiovascular and renal disease: today and tomorrow

The traditional view that organs have only limited regenerative capacity has been challenged in recent years as adult bone marrow stem cells as well circulating progenitor cells have been identified to retain the plasticity to participate in neovascularization, a process so far believed not to be possible after birth. An organ that is damaged by ischemia causes the release of cytokines; these act via the flowing blood and stimulate the bone marrow, which then mobilizes progenitor cells to the blood and directs them to adhere to and migrate into the damaged organ. Thus, these progenitor cells most likely constitute a natural repair mechanism that counteracts degenerative or aging processes. On the basis of encouraging experimental data, first clinical trials have been established to demonstrate the safety and the feasibility of progenitor cell therapy in case of peripheral artery disease or myocardial infarction. Trials investigating injection of bone marrow or circulating progenitor cells into the coronary artery after an acute myocardial infarction not only demonstrates safety of the procedure but also gave hints toward efficacy. Nevertheless, these findings have to be validated by subsequent larger, prospective, randomized, controlled trials. There are also potential topics in nephrology, where modification of progenitor cell activity might be of benefit, such as renal ischemic disease, glomerular disease, and renal transplant vasculopathy. Finding a way to integrate the principle of progenitor cell action into therapeutic efforts might provide a completely new therapeutic strategy that not only attempts to retard disease progression but furthermore targets to regenerate damaged organs.     

Improved Performance of Hip DXA Using a Novel Region of Interest in the Upper Part of the Femoral Neck: In Vitro Study Using Bone Strength as a Standard of Reference

We tested the hypothesis that bone mineral density (BMD) and bone mineral content (BMC) in proximal human femur specimens in the upper neck region of interest (ROI) and femoral neck axis length (FNAL) provide a significantly better prediction of femoral bone strength than standard ROIs in vitro. BMD and BMC were measured in 110 proximal femur specimens using a standard dual-energy X-ray absorptiometry (DXA) scanner. The analysis included a new ROI in the upper neck as well as the standard ROIs. FNAL was obtained from the scan images. The specimens' failure-load was measured in a mechanical loading device, simulating a fall on the greater trochanter. For the standard ROIs, correlations between failure-load and BMD ranged from R2 = 0.64 (shaft ROI) to R2 = 0.70, p < 0.001 (femoral neck). Prediction of strength by BMD did not significantly differ from those of BMC (R2 ranging from 0.65 to 0.75, p < 0.001). In the upper neck ROI, for both BMD and BMC correlations with failure-load were higher (R2 = 0.76 and 0.81, respectively; p < 0.001). A lower, yet still significant, correlation was found between FNAL and bone strength (R2 = 0.23, p < 0.001). Normalization of failure-load with respect to FNAL did not significantly increase the correlations with densitometric measures. This study provides in vitro evidence indicating that among the ROIs of the proximal femur the newly defined upper neck ROI provides the best prediction of bone strength. Only a weak association was observed between failure load and FNAL.     

Endoscopic management of anastomotic hemorrhage from pancreatogastrostomy

Background  Hemorrhage from pancreatic-enteric anastomosis after pancreaticoduodenectomy (PD) is a critical condition due to its difficult accessibility and delicate condition, and therefore remains a major challenge for the surgeon in charge. Objective  This study analyzed presentation and management of pancreatogastrostomy hemorrhage (PGH) after PD to determine the respective roles of endoscopy and surgery. Patients and methods  Patients who underwent PD with pancreatogastrostomy between 1989 and January 2008 were identified from a pancreatic resection database and analyzed with regards to PGH, treatment strategy and outcome, and incidence of postoperative complications. Results  Out of 265 consecutive patients with PD, 10 patients (3.7%) experienced an episode of PGH, detected on average on postoperative day 5. No patient with PGH died during hospital stay as opposed to a mortality rate of 2.7% in patients without PGH. Morbidity rates were 50% versus 48% and length of hospital stay was 23 versus 21 days for patients with and without PGH, respectively, with no statistical differences between the groups. Endoscopic approach to control PGH was successful in nine patients. Pancreatogastrostomies were not compromised regarding procedure or air insufflations and no concomitant development of pancreatic fistula was observed. Open surgery was inevitable in one patient with recurrent PGH in order to achieve hemostasis, but resulted in pancreatic fistula and protracted hospital stay. Conclusions  The present study demonstrates a feasible endoscopic approach for the management of PGH with high success rate and no concomitant procedure-related morbidity. Medical illustrations: Lothar Knorn, Bonn.     

A health economic analysis of the use of rhBMP-2 in Gustilo–Anderson grade III open tibial fractures for the UK, Germany, and France

The purpose of this study was to determine the cost savings from a societal perspective for recombinant human Bone Morphogenetic Protein-2 (rhBMP-2) in grade III A and B open tibial fractures treated with a locked intramedullary nail and soft-tissue management in the UK, Germany, and France. Health care system costs (direct health care costs) and costs for productivity losses (indirect health care costs) were calculated using the raw data from the Bone Morphogenetic Protein Evaluation Group in Surgery for Tibial Trauma “BESTT study”. Return-to-work time for estimation of productivity losses was assumed to correspond with the time of fracture healing. For calculation of secondary interventions costs and productivity losses the respective 2007/2008 national tariffs for surgical procedures and average national wages for the UK, Germany, and France were used. For a 1 year perspective, overall treatment costs per patient after the initial surgery of the control vs. the rhBMP-2 group were €44,757 vs. €36,847 for the UK, €50,197 vs. €40,927 for Germany and €48,766 vs. €39,474 for France in favour of rhBMP-2 with overall savings overall savings per case of rhBMP-2 treatment of €7911 for the UK, €9270 for Germany, and €9291 for France which was mainly due to reduced productivity losses by significant faster fracture healing in the rhBMP-2 group (p = 0.01). These savings largely offset the upfront price of rhBMP-2 of €2266 (£1790) in the UK, €2970 in Germany, and €2950 in France. Total net savings can be estimated to be €9.6 million for the UK, €14.5 million for Germany, and €11.4 million for France. The results depend on the methodology used particularly for calculation of productivity losses and return-to-work time which was assumed to correspond with fracture healing time. In summary, despite the apparent high direct cost of rhBMP-2 in grade III A and B open tibial fractures, at a national level there are net cost savings from a societal perspective for all three countries.     

Multiple target aspiration technique for subacute stereotactic aspiration of hematomas within the basal ganglia

BACKGROUND: Stereotactic surgery for deep-seated intracerebral hematomas as a minimally invasive procedure has gained wide acceptance, but debate continues to be controversial concerning the issue of how to aspirate a sufficient proportion of the hematoma with minimized risk for the patient. The objective of this paper is to present a modified stereotactic aspiration technique which complies saliently with both demands. METHODS: The multiple target aspiration technique was used in a series of 64 consecutive patients with spontaneous hematomas within the basal ganglia. The results obtained with this technique were evaluated with particular regard to degree of aspiration and rate of recurrent hemorrhage and were compared with results achieved with stereotactic techniques utilizing physical fragmentation or chemical lysis of the clots. RESULTS: Using this technique, it was feasible in one single surgical procedure to aspirate more than 80% of the hematoma volume in 73.4% of the patients. Mean degree of aspiration was 88.8%, and rebleeding occurred only once (1.6%). These results compare favorably with those achieved with application of intricate stereotactic techniques. CONCLUSION: The multiple target aspiration technique performed in the subacute stage is a rapid and simple method for stereotactic removal of deep-seated hematomas and combines a high success rate with very low risk of recurrent hemorrhage.     

Improved survival in patients with type 1 diabetes mellitus after renal transplantation compared with hemodialysis: a case-control study

BACKGROUND: Diabetes mellitus is the leading cause of renal failure worldwide. The question of which treatment modality-hemodialysis versus renal transplantation-is associated with the lowest risk of cardiovascular morbidity and mortality in the diabetic end-stage renal disease (ESRD) population has not yet been investigated in a controlled trial. METHODS: We therefore conducted a case-control study of patients with ESRD caused by type 1 diabetes mellitus. The case patients were diabetics who received a renal graft between 1978 and 1997, whereas the controls were registered for renal transplantation but stayed on maintenance hemodialysis without ever undergoing transplantation. The groups were matched for age, sex, duration of diabetes, length of hemodialysis (up to the registration), and date of registration for renal transplantation. RESULTS: Kaplan-Meier life table analysis, based on 46 case patients and 46 controls, demonstrated a highly significant (P=0.0001) poorer survival in the control group compared with the case group. Logistic regression showed that hemodialysis was a significant risk factor for death (P=0.0002) and cardiovascular morbidity (P=0.0023). Patients with cardiovascular complications such as coronary artery and peripheral vascular events were significantly more frequent in the control group. Additionally tested risk factors for cardiovascular complications (serum cholesterol, arterial blood pressure, number of antihypertensive drugs, serum calcium, serum phosphate, and glucose control [hemoglobin A(1c)]) showed no significant correlation to survival or morbidity in either group by logistic regression. CONCLUSIONS: Renal transplantation is associated with a significantly improved survival compared with hemodialysis in patients with ESRD caused by type 1 diabetes mellitus. This seems to be a result of a reduced incidence of cardiovascular complications after renal transplantation.     

Effects of a suction laryngoscope in a model with simulated severe airway hemorrhage

In severe airway hemorrhage, simultaneous suction and laryngoscopy may render intubation difficult. We built a suction laryngoscope that consists of an adjustable stainless steel-guide tube fixed at the lingual surface of a standard Macintosh laryngoscope blade. Via this steel-guide tube, a large suction catheter can be inserted and positioned exactly to suction pharyngeal blood or vomitus, rendering simultaneous suctioning and laryngoscopy possible. In contrast to previous suction laryngoscopes, our suction catheter has a large lumen, which enables fast suctioning and exact placement by adjusting the steel-guide tube. To assess whether our suction laryngoscope could provide better intubation conditions in comparison to a standard Macintosh laryngoscope in a bleeding airway scenario, 44 medical students intubated a manikin with severe simulated airway hemorrhage using our suction laryngoscope and a standard Macintosh laryngoscope in random order. There was no significant difference in time needed for intubation when using the suction versus the Macintosh laryngoscope (mean +/- SD: 43 +/- 13 vs 52 +/- 31 s; P = 0.07), but the number of esophageal intubations was significantly lower when using the suction laryngoscope [6 of 44 (13.6%) vs 19 of 44 (43.2%); P = 0.004]. In conclusion, when compared with a standard Macintosh laryngoscope, using a suction laryngoscope did not result in more rapid intubation, but significantly decreased the likelihood of esophageal intubations.     

The DGAI CPR registry - the datasets "hospital care" and "long-term process"

After several years of preparation the German Society of Anaesthesiology and Intensive Care Medicine (Deutsche Gesellschaft für An?sthesiologie und Intensivmedizin--DGAI) has, during its annual conference 2007, officially launched the DGAI CPR registry. After implementation of the dataset "primary care" in 2004, the datasets "definite care" and "long-term process" have now been released. The completed, internet based database is open for any interested person or institution as a tool for quality management. Data may be recorded online, and basic analyses be performed immediately. Beyond that benchmarks with other institutions are possible, by including the well accepted Utstein style on international level too.