HLA-A, -B, -C, -DR, and -DQ Matching in Pancreas Transplantation: Effect on Graft Rejection and Survival.

To enhance selection of appropriate deceased donors for pancreas transplants, we sought to determine whether HLA matching improved posttransplantation outcomes. In this single-center study of 1219 pancreas transplants, we correlated posttransplantation outcomes with HLA-A, -B, -C, -DR, and -DQ matches and mismatches. Rejection was linearly correlated with the number of mismatches. The individual number of HLA mismatches reached significance at four or more with a 2.3- to 2.9-fold increase in rejection. The effect was most predominant with HLA-B (1.8-fold with one mismatch and 2.0-fold with two mismatches) and -DR (1.9-fold with two mismatches) loci, whereas HLA-A, -C, and -DQ matches or mismatches did not independently predict acute rejection. The affect was strongest in solitary pancreas transplants, with little impact for simultaneous pancreas and kidney (SPK). In contrast, HLA matching did not affect graft or patient survival rates but was associated with a reduced risk of opportunistic infection. Avoidance of acute rejection saved an estimated $32 000 for solitary pancreas recipients and $52 000 for SPK recipients in hospital costs. Our data do not support the use of HLA matching for predicting pancreas graft survival but do support its significance for the reduction of acute rejection, particularly for solitary pancreas recipients.

Dynorphins regulate the strength of social memory.

Emotionally arousing events like encounter with an unfamiliar con-species produce strong and vivid memories, whereby the hippocampus and amygdala play a crucial role. It is less understood, however, which neurotransmitter systems regulate the strength of social memories, which have a strong emotional component. It was shown previously that dynorphin signalling is involved in the formation and extinction of fear memories, therefore we asked if it influences social memories as well. Mice with a genetic deletion of the prodynorphin gene Pdyn (Pdyn(-/-)) showed a superior partner recognition ability, whereas their performance in the object recognition test was identical as in wild-type mice. Pharmacological blockade of kappa opioid receptors (KORs) led to an enhanced social memory in wild-type animals, whereas activation of KORs reduced the recognition ability of Pdyn(-/-) mice. Partner recognition test situation induced higher elevation in dynorphin A levels in the central and basolateral amygdala as well as in the hippocampus, and also higher dynorphin B levels in the hippocampus than the object recognition test situation. Our result suggests that dynorphin system activity is increased in emotionally arousing situation and it decreases the formation of social memories. Thus, dynorphin signalling is involved in the formation of social memories by diminishing the emotional component of the experience.

Smad-interacting protein 1 affects acute and tonic, but not chronic pain.

BACKGROUND: Smad-interacting protein 1 (also named Zeb2 and Zfhx1b) is a transcription factor that plays an important role in neuronal development and, when mutated, causes Mowat-Wilson syndrome (MWS). A corresponding mouse model carrying a heterozygous Zeb2 deletion was comprehensively analysed in the German Mouse Clinic. The most prominent phenotype was the reduced pain sensitivity. In this study, we investigated the role of Zeb2 in inflammatory and neuropathic pain. METHODS: For this, we tested mutant Zeb2 animals in different models of inflammatory pain like abdominal constriction, formalin and carrageenan test. Furthermore, we studied the pain reactivity of the mice after peripheral nerve ligation. To examine the nociceptive transmission of primary sensory dorsal root ganglia (DRG) neurons, we determined the neuronal activity in the spinal dorsal horn after the formalin test using staining of c-Fos. Next, we characterized the neuronal cell population in the DRGs and in the sciatic nerve to study the effect of the Zeb2 mutation on peripheral nerve morphology. RESULTS: The present data show that Zeb2 is involved in the development of primary sensory DRG neurons, especially of C- and Aδ fibres. These alterations contribute to a hypoalgesic phenotype in inflammatory but not in neuropathic pain in these Zeb2(+/-) mice. CONCLUSION: Our data suggest that the under-reaction to pain observed in MWS patients results from a reduced responsivity to nociceptive stimulation rather than an inability to communicate discomfort.

Management and outcomes after multiple corneal and solid organ transplantations from a donor infected with rabies virus.

BACKGROUND: This article describes multiple transmissions of rabies via transplanted solid organ from a single infected donor. The empirical Milwaukee treatment regimen was used in the recipients. METHODS: Symptomatic patients were treated by deep sedation (ketamine, midazolam, and phenobarbital), ribavirin, interferon, and active and passive vaccination. Viral loads and antibodies were continuously monitored. RESULTS: Recipients of both cornea and liver transplants developed no symptoms. The recipient of the liver transplant had been vaccinated approximately 20 years before transplantation. Two recipients of kidney and lung transplants developed rabies and died within days of symptomatic disease. Another kidney recipient was treated 7 weeks before he died. The cerebrospinal fluid viral load remained at constant low levels (<10,000 copies/mL) for approximately 5 weeks; it increased suddenly by almost 5 orders of magnitude thereafter. After death, no virus was found in peripheral compartments (nerve tissue, heart, liver, or the small intestine) in this patient, in contrast to in patients in the same cohort who died early. CONCLUSIONS: Our report includes, to our knowledge, the longest documented treatment course of symptomatic rabies and the first time that the virus concentration was measured over time and in different body compartments. The postmortem virus concentration in the periphery was low, but there was no evidence of a reduction of virus in the brain.

Organ recipients suffering from undifferentiated neuroendocrine small-cell carcinoma of donor origin: a case report.

BACKGROUND: Transmission of donor-derived cancer by organ transplantation is rare, but the risk has been increasing due to the aging donor pool. Undifferentiated neuroendocrine small-cell carcinoma is an aggressive tumor with the tendency to spread. Herein we have demonstrated different approaches to treat organ recipients with transmitted tumors. METHODS AND RESULTS: Grafts were retrieved from a decreased donor without any history of previous diseases. Autopsy was not performed after donation. The recipient of the liver graft presented with suspected nodules on routine abdominal ultrasound. After computed tomography (CT) scan, biopsy confirmed the diagnosis of a small-cell carcinoma. Donor origin was unequivocally identified by DNA fingerprinting. Despite chemotherapy the patient died 7 months after orthotopic liver transplantation (OLT). All involved transplantation centers were informed immediately following diagnosis. The male kidney recipient underwent detailed diagnostic work-up to exclude tumor transmission. One year after transplantation, liver metastases caused by a histologically proven small-cell carcinoma from the same donor were apparent. Chemotherapy was immediately started and the graft was removed. Despite continued treatment the tumor progressed and the patient died after repeated intestinal complications. The pathological examination of the explanted second kidney graft did not show any tumor infiltration. CONCLUSION: Therapeutic regimens in recipients suffering from donor-derived carcinoma differ depending on the transplanted organ. Graft removal of non-life-sustaining organs and discontinuation of immunosuppressive medication should result in complete tumor rejection. Minimizing the risk of tumor transmission, a CT scan might be advisable in donors of more advanced age.

Technical complications in organ procurement.

It is of crucial importance that harvested organs are not discarded because of lesions inflicted during the procurement operation. From January 2005 to January 2006, a total of 395 organs were procured: 266 kidneys, 102 livers, and 27 pancreas. Two kidneys were lost due to vascular lesions, and 1 liver could not be transplanted because of a severe parenchymal injury (0.75% total organ losses). In 33 of 198 cases (16.7%) despite lesions to renal vessels or to the ureter, the kidneys were transplanted after back-table repair procedures. Vascular lesions were observed in 10% of the evaluated livers (8 of 102) and in 3 of 18 pancreatic grafts. In the literature, a total organ loss of 0.75% because of technical problems demonstrates a high standard of visceral organ procurement in our region. Hence, reparable vascular and ureteral lesions in 10% to 16.4% indicated the need for better surgical training and standardization in procurement techniques. We believe that double-checking both the organ and quality reports and giving immediate feedback to the procurement surgeons in cases of technical problems are effective ways to perform quality control. It must be our goal to increase the response rate of the quality forms.

Intraoperative assessment of liver organ condition by the procurement surgeon.

UNLABELLED: Generally the transplanting surgeon accepts or declines the offer of a marginal organ in view of all available information. Hence, in some cases it is the procurement surgeon who decides about the suitability for potential further liver transplantation. METHODS: From January 1, 2003 to September 30, 2005, a total of 402 organ procurement operations were performed in our region. RESULTS: Due to infrastructural problems in nine cases intraoperative evaluation of liver biopsies was not achievable in time, and the decision to reject the organs was based on the procurement surgeon's clinical assessment. The main reason for liver rejection was alleged extreme steatosis, (6 of 9) or liver cirrhosis (3 of 9). Surprisingly, postoperative histological examinations only confirmed the clinical impression in one of nine cases. CONCLUSIONS: The clinical assessment of the explanting surgeon resulted in discarding eight of nine organs, potentially not contributing them to the donor pool of EUROTRANSPLANT. Further research is necessary to examine the accuracy of clinical evaluation of donor livers as well their correlation with histology.

Ventilation volumes with different self-inflating bags with reference to the ERC guidelines for airway management: comparison of two compression techniques.

The 1998 ERC-guidelines for airway-management recommend an tidal volume of 400-600 ml for adults undergoing CPR. As commercially available self-inflating bags were designed to meet former recommendations (800-1200 ml) we investigated how to meet the latest recommendations with these bags. We combined the head of a training manikin (Laerdal Medical) and a standard lung (VTTL; Michigan Instrument), adjusted to a physiological compliance and resistance. Volume was measured with a Wright spirometer (BOC). Seven self-inflating bags were investigated. Tests were carried out by ten people (five female and five male) for 5 min each using two different techniques. Technique 1: standard ventilation with one hand without compression of the self-inflating bag against the rescuers knee. Technique 2: modified open palm technique with total squeezing of the self-inflating bag by compression against the rescuers knee. The average tidal volumes for technique 1 ranged from 438 to 604 ml. Applying technique 2 the volumes ranged from 888 to 1192 ml. The latest recommendations were met using a single hand technique without compression against the rescuers knee for all seven bags tested. The modified open palm technique produced larger tidal volumes which were more in line with previous recommendations.

Brain tissue pO2 related to SjvO2, ICP, and CPP in severe brain injury.

The aim of this report is to present first experience in comparing the course of brain tissue oxygen pressure values (PtiO2) to changes in jugular vein oxygen saturation (SjvO2), intracranial pressure (ICP), and cerebral perfusion pressure (CPP) after severe brain injury. PtiO2 monitoring was done using a polarographic Clark type microcatheter (LICOX pO2 probe) (GMS, Kiel, Germany) with a diameter of 0.5 mm and a sensitive area 7.9 mm long inserted in a right frontal position. The microcatheter was connected to a LICOX pO2 device. A fiber-optic catheter was used to measure SjvO2 and placed into the right internal jugular vein. The ICP monitoring was performed with a fiber-optic intraparenchymal device (Camino Laboratories, San Diego, Calif.) inserted in a left frontal position. Consistent correlations could be noticed between reduced PtiO2 and higher ICP and lower CPP levels. However, the absolute value of a single SjvO2 data point seemed to be less relevant diagnostically than its trend over a period of time. Owing to their experience, the authors suppose that PtiO2 monitoring will be a very important and reliable tool in the treatment of brain injury in the future, especially in its correlation to ICP and CPP.

Alternative methods of mechanical cardiopulmonary resuscitation.

Due to the relative ineffectiveness of standard resuscitation techniques, alternative methods have been explored for many years. The aim of new methods is to improve haemodynamics and increase survival rates. In spite of some encouraging haemodynamic results, all but one study failed to show an increase in long-term survival rates with an alternative method in a convincingly large group of patients (hospital discharge without neurological damage, and 1-year survival). In this study active compression-decompression resuscitation (ACD-CPR) increased long-term survival compared to standard-CPR. The results from certain individual studies, which showed a significant increase in short-term survival rate, could not be reproduced in other trials. This may be attributed in part to the fact that the alternative methods are not significantly superior, but also due to logistical and statistical problems in the conduct of the studies and differences in application within and between the study sites. ACD-CPR has been the most studied method amongst the alternatives and can be recommended for patients with asystole in centres with special training and where outcome quality is regularly verified and evaluated.

Maintaining updated DNA-based HLA assignments in the National Marrow Donor Program Bone Marrow Registry.

The National Marrow Donor Program (NMDP) has instituted an approach to address the impact of new alleles on the DNA-based HLA assignments obtained during volunteer donor typing. This approach was applied to the DRB typing results from 371,187 donors received from 14 laboratories in 1999. Samples were tested with a standardized set of sequence specific oligonucleotide reagents and the positive and negative hybridization results transmitted electronically to the NMDP. A software program interpreted the primary data into HLA assignments and rejected assignments which did not produce a result at the specified level of resolution. Comparison of the HLA assignments derived by the NMDP software to the assignments made by the laboratories using several local software prograins showed 90.5% of the assignments to be identical. Differences in assignments were explained by varying levels of typing resolution, variation in the inclusion of the second expressed DRB loci, disparity arising when alternative assignments were summarized, and failure to submit correct information. When the primary data collected in 1999 were interpreted into HLA assignments using the set of alleles defined in July 2000, 74% of the HLA-DRB assignments were altered by the description of new alleles, justifying the development of this software.

Effect of active compression-decompression resuscitation (ACD-CPR) on survival: a combined analysis using individual patient data.

Active compression decompression resuscitation (ACD-CPR) has been developed as an alternative to standard cardiopulmonary resuscitation (S-CPR). To determine the effect of ACD-CPR on survival and neurologic outcome in patients with out-of-hospital cardiac arrest, this combined analysis involved individual patient data from 2866 patients from seven separate randomized prospective prehospital studies who had received ACD-CPR or S-CPR after out-of-hospital cardiac arrest in seven international sites. Significant improvement in 1-h survival (odds ratio (OR) = 0.83; confidence interval (CI): 0.695-0.99; P < 0.05) was found with ACD-CPR (n = 1410) versus S-CPR (n = 1456). The odds ratio for hospital discharge after ACD-CPR was similar (OR = 0.82; CI: 0.609-1.107, P = NS), but this finding was not statistically significant. Using the chi2-test for trend, there was a significant improvement in overall survival with ACD-CPR (P < 0.05) versus S-CPR. This improvement was largely due to the influence of results from one study site. Neurological outcome and complication rates were comparable between groups. Further study is needed to determine which emergency medical services systems may benefit from out-of-hospital use of ACD-CPR.

Attraction of Culex pipiens pipiens (Diptera: Culicidae) to flower volatiles.

Methylene chloride extracts of flowers from 4 plants (common milkweed, Asclepias syriaca L; ox-eye daisy, Leucanthemum vulgare Lamarck; Canada goldenrod, Solidago canadensis L.; and yarrow, Achillea millefolium L.) were tested in a dual-port olfactometer for attractiveness to female northern house mosquitoes, Culex pipiens pipiens L. Fifty milligrams of extract was used for each test, which was equivalent to the amount of extract from flowers of 0.58 common milkweed inflorescences, 1.75 ox-eye daisy flower heads, 0.33 Canada goldenrod plants, or 3.14 yarrow plants. Significantly more Cx. pipiens responded to the common milkweed flower extract than to a control. Ox-eye daisy, Canada goldenrod and yarrow flower extracts were not significantly attractive to this species. A headspace sample of the common milkweed extract was collected by solid phase microextraction and analyzed by gas chromatography-mass spectrometry. The most abundant compounds in the headspace sample were 2-phenylethanol and benzyl alcohol. Analysis of the common milkweed extract and standards of 2-phenylethanol and benzyl alcohol by gas chromatography-flame ionization detection confirmed that these compounds were present in the extract. Cx. pipiens did not respond to synthetic blends of these 2 compounds when tested in a dual-port olfactometer.

Carbon dioxide levels during pre-hospital active compression--decompression versus standard cardiopulmonary resuscitation.

In a prospective randomised study we investigated end-tidal carbon dioxide levels during standard versus active compression-decompression (ACD) cardiopulmonary resuscitation (CPR) assuming that the end-tital carbon dioxide reflects cardiac output during resuscitation. In each group 60 patients with out-of-hospital cardiac arrest were treated either with the standard or the ACD method. End-tidal CO2 (p(et)CO2, mmHg) was assessed with a side-stream capnometer following intubation and then every 2 min up to 10 min or restoration of spontaneous circulation (ROSC). There was no difference in p(et)CO2 between both patient groups. However, CO2 was significantly higher in patients who were admitted to hospital as compared to patients declared dead at the scene. All of the admitted patients had a p(et)CO2 of at least 15 mmHg no later than 2 min following intubation, none of the dead patients ever exceeded 15.5 mmHg. From these data we conclude that capnometry adds valuable information to the estimation of a patient's prognosis in the field (threshold, 15 mmHg), but we could not detect any difference in p(et)CO2 between ACD and standard CPR.

Allogeneic bone marrow transplantation with matched unrelated donors for patients with hematologic malignancies using a preparative regimen of high-dose cyclophosphamide and fractionated total body irradiation.

Allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling donor is effective therapy for patients with bone marrow failure states and those with hematologic malignancies. However, only a minority of them will have an HLA-identical sibling donor; unrelated donors, matched or partially mismatched, have been used successfully for patients lacking a related donor. Even though results with allogeneic transplants using unrelated donors are encouraging, the incidence of complications including graft-versus-host disease (GVHD) and graft rejection or late graft failure is increased compared to identical sibling transplants. The combination of cyclophosphamide and total body irradiation (TBI) has been used as an effective preparative regimen for allogeneic transplants, however, the total dosage and dosing schedule of both the cyclophosphamide and TBI has varied significantly among studies. To decrease the rate of graft rejection and late graft failure with volunteer donors, we evaluated a preparative regimen of high-dose cyclophosphamide (200 mg/kg over 4 consecutive days, days -8, -7, -6, -5) followed by fractionated TBI (1400 cGy administered in eight fractions over 4 days, days -4, -3, -2, -1). GVHD prophylaxis included FK506 and methotrexate. From July 1993 to January 1996, 43 adult patients, median age 38 years (range 18-58 years), were treated with this preparative regimen. Seventeen patients had low-risk disease and 26 had high-risk disease. Thirty-one donor/recipient pairs were matched for HLA-A, -B, and -DR by serology and molecular typing. Seven additional pairs were minor mismatched at the HLA-A or HLA-B loci. Four other donor/recipient pairs were HLA-A,-B, and -DR identical by serology but allele mismatched at either DRB1 or DQB. Forty patients were evaluable for myeloid engraftment. Engraftment occurred in all 40 patients at a median of 19 days. There were no cases of graft rejection or late graft failure. Nephrotoxicity was the primary adverse event with 26 patients (60%) experiencing a doubling of their creatinine. Hepatic veno-occlusive disease occurred in seven patients, six of whom had high-risk disease. All patients who had relapsed or refractory disease prior to BMT achieved a complete remission following BMT. Six patients transplanted for high-risk disease relapsed a median of 377 days post-BMT. None of the patients with low-risk disease have relapsed following transplant; the Kaplan-Meier survival for those patients with low-risk disease is 62% and 37% for those patients transplanted with high-risk disease (P = 0.0129). The median Karnofsky performance status is 100% (range 70-100%). Therefore, a preparative regimen of high-dose cyclophosphamide and fractionated TBI is an acceptable regimen for patients receiving an allograft from unrelated donors.

[Active compression-decompression resuscitation. Improved survival rate in an emergency medicine system with emergency physician assistance?]. / Aktive Kompressions-Dekompressions-Reanimation (ACD-CPR). Verbesserte Uberlebensraten in einem notarztgestützten Rettungssystem?

BACKGROUND: Improved cardiopulmonary circulation with active compression-decompression resuscitation (ACD-CPR) has been demonstrated in studies using different animal models and a small number of human in cardiac arrest (CA). However, prehospital studies have shown both positive and no extra benefit of ACD-CPR on survival rates and neurologic outcome. MATERIAL AND METHODS: The aim of our prospective study was to compare standard manual CPR (S-CPR) to ACD-CPR as the initial technique of resuscitating patients with out-of-hospital CA with respect to survival rates and neurological outcome in our two-tiered EMS system with physicians in the field. RESULTS: Patients with out-of-hospital CA treated by emergency medical services (EMS) personnel were randomly assigned to 1 of 2 groups (ACD-CPR versus S-CPR). The treatment groups were similar with respect to age, sex, time interval from collapse to CPR, defibrillation and first epinephrine medication. There was no difference between the ACD group and the standard CPR group in terms of survival rates and neurologic outcome. No differences occurred concerning complications of CPR. CONCLUSION: In our two-tiered EMS system with physician-staffed ambulances ACD-CPR neither improved nor impaired the survival rates and the neurological prognosis in patients with out-of-hospital cardiac arrest. Our results are in accordance with other studies carried out in EMS systems, with first tier call-response intervals between 4 and 6 min.

Active compression-decompression resuscitation: a prospective, randomized study in a two-tiered EMS system with physicians in the field.

Improved cardiopulmonary circulation with active compression-decompression cardiopulmonary resuscitation (ACD-CPR) has been demonstrated in studies using different animal models and a small number of humans in cardiac arrest (CA). However, prehospital studies have shown both positive and no extra benefit of ACD-CPR on return of spontaneous circulation (ROSC), hospital admission and discharge rates. The aim of our prospective study was to compare standard manual CPR (S-CPR) with ACD-CPR as the initial technique of resuscitating patients with out-of-hospital CA, with respect to survival rates and neurological outcome. Patients with out-of-hospital CA treated by emergency medical services (EMS) personnel were randomly assigned to one of two groups (ACD-CPR versus S-CPR). Time intervals to key measures were documented by means of on-line tape-recording. Neurological outcome was assessed using standard scoring systems (cerebral and overall performance categories (CPC and OPC)). A total of 220 patients (S-CPR, n = 114: ACD-CPR, n = 106) were included in the study in a random order. The treatment groups were similar with respect to age, sex, time interval from collapse to CPR, defibrillation and first adrenaline medication. There was no difference between the ACD group and the standard CPR group in terms of ROSC (50.9% vs. 59.6%), hospital admission (33% vs. 33.3%), hospital discharge (16% vs. 14%), or CPC and OPC (1.82 vs. 2.13 and 2.06 vs. 2.25, respectively). Concerning complications of CPR, there was no difference between the groups. In our two-tiered EMS system with physician-staffed ambulances, ACD-CPR neither improved nor impaired survival rates and neurological prognosis in patients with out-of-hospital cardiac arrest. The new CPR technique did not increase the complications associated with the resuscitation effort.

Factors that influence phoneme-grapheme correspondence learning.

The present study examined (a) the relative impact visual and phonetic factors have on learning phoneme-grapheme correspondences, and (b) the relationship between measures of visual and phonological processing and children's ability to learn novel phoneme-grapheme correspondence pairs. Participants were 20 children with reading disabilities (RD), 10 normally achieving children matched for mental age (MA), and 10 children matched for reading age (RA). The children ranged in age from 5 years 2 months to 9 years 3 months. All children completed a phoneme-grapheme learning task consisting of four novel correspondence pairs, a visual processing task, and five measures of phonological processing. The MA and RA groups learned the four correspondence pairs in significantly fewer trials than the RD group. The RD group had the least difficulty learning the correspondence pair with different phonemes and graphemes and the most difficulty learning the correspondence pair with similar phonemes and graphemes. Performance on the learning task was significantly correlated to performance on the visual processing task and the five measures of phonological processing. Performance on the phonological processing task of short-term memory was the best predictor of overall performance on the learning task. Although children with RD were able to learn the four novel correspondence pairs, their processing deficiencies affected how readily they learned each of the correspondence pairs.