[Allergic emergencies]. / Notfälle in der Allergologie.

Both anaphylactic reactions and angioedema in the head and neck area can be life-threatening and require emergency treatment. Therapy needed is primarily directed by the patient's symptoms. The first measures taken should consist of immediate disruption of the allergen contact, adequate positioning of the patient, the insertion of an intravenous catheter and an emergency call. In case of cardiovascular or respiratory involvement, intramuscular ± inhalative adrenalin is the treatment of choice. In case of cardiovascular involvement, volume substitution by intravenous catheter and oxygen administration are crucial and in lower airway obstruction, additionally short-acting beta mimetics should be inhaled. Intravenous H1-antihistamines and glucocorticoids are added. Allergic reaction confined to the skin and mucosal surfaces without respiratory involvement or to the gastrointestinal tract should also be treated with intravenous H1-antihistamines and glucocorticoids. Angioedema in the head and neck area can, however, also be associated with a life-threatening upper airway obstruction. Histamine-induced angioedema should be treated as anaphylaxis involving the upper respiratory tract. In hereditary angioedema, or in unclassified angioedema unresponsive to therapy, early airway maintenance and subcutaneous injection of bradykinin-receptor antagonist icatibant, intravenous injection of C1-inhibitor concentrate or fresh frozen plasma is recommended. The same approach should be taken for severe angiotensin converting enzyme inhibitor-induced angioedema with dyspnea. Intubation by skilled personal is indicated in inspiratory stridor and dyspnea at rest. In all cases of anaphylaxis or angioemdema, patients should be surveyed until a safe remission is achieved.

Effect of short-term scrotal hyperthermia on spermatological parameters, testicular blood flow and gonadal tissue in dogs.

The objective was to assess the effect of a short-term scrotal hyperthermia in dogs on quantitative and qualitative ejaculate parameters, testicular blood flow and testicular and epididymal histology. After a control period, the scrotum of seven normospermic adult beagle dogs was insulated with a self-made suspensory for 48 h. Nine weeks later, two animals were castrated, while in five animals, scrotal hyperthermia was repeated. Dogs were castrated either 10 or 40 days thereafter. In each phase of scrotal insulation, average scrotal surface temperature increased by 3.0°C. Semen was collected twice weekly throughout the experiment. Total sperm count did not change after the first hyperthermia, but it slightly decreased after the second (p < 0.05). Profiles of sperm morphology and velocity parameters (CASA) rather indicated subtle physiological variations in sperm quality than effects of a local heat stress. Chromatin stability of ejaculated spermatozoa as indicated by SCSA remained constant throughout the experiment. Perfusion characteristics of the gonads, that is, systolic peak velocity, pulsatility and resistance index at the marginal location of the testicular artery, did not change due to hyperthermia (p > 0.05). Histological examination of excised testes and epididymides for apoptotic (TUNEL and activated caspase-3) and proliferating cells (Ki-67 antigen) indicated only marginal effects of scrotal insulation on tissue morphology. In conclusion, a mild short-term scrotal hyperthermia in dogs does not cause substantial changes in sperm quantity and quality. In contrast to other species, canine testes and epididymides may have a higher competence to compensate such thermal stress.

[Computerization of hospital blood banks in France: what has been done and what remains to be done]. / Informatisation des dépôts de sang: ce qui est fait et ce qui reste à faire.

French regulation requires hospital blood banks to have data processing of their blood transfusion activities. In order to help them to achieve this goal, guidelines were published by an official working party. For their diffusion, a study was launched to assess current gaps between guidelines and reality. Analysis of the first forty responses shows: 1) computerization is already set up for main blood banks and is going well for the others; 2) most of guideline functionalities are now working in main blood banks; but some points need specific developments; 3) taken as a whole, other blood banks are further from guideline requirements, even if some have already reached the goal; 4) guidelines are able to point out to all hospital blood banks what remains to be done.

Saliva/pathogen biomarker signatures and periodontal disease progression.

The purpose of this study was to determine the role of saliva-derived biomarkers and periodontal pathogens during periodontal disease progression (PDP). One hundred human participants were recruited into a 12-month investigation. They were seen bi-monthly for saliva and clinical measures and bi-annually for subtraction radiography, serum and plaque biofilm assessments. Saliva and serum were analyzed with protein arrays for 14 pro-inflammatory and bone turnover markers, while qPCR was used for detection of biofilm. A hierarchical clustering algorithm was used to group study participants based on clinical, microbiological, salivary/serum biomarkers, and PDP. Eighty-three individuals completed the six-month monitoring phase, with 39 [corrected] exhibiting PDP, while 44 [corrected] demonstrated stability. Participants assembled into three clusters based on periodontal pathogens, serum and salivary biomarkers. Cluster 1 members displayed high salivary biomarkers and biofilm; 71% [corrected] of these individuals were undergoing PDP. Cluster 2 members displayed low biofilm and biomarker levels; 76% [corrected] of these individuals were stable. Cluster 3 members were not discriminated by PDP status; however, cluster stratification followed groups 1 and 2 based on thresholds of salivary biomarkers and biofilm pathogens. The association of cluster membership to PDP was highly significant (p < 0.0007). [corrected] The use of salivary and biofilm biomarkers offers potential for the identification of PDP or stability (ClinicalTrials.gov number, CT00277745).

Leupaxin acts as a mediator in prostate carcinoma progression through deregulation of p120catenin expression.

Recently, we could show that the focal adhesion protein leupaxin (LPXN) is expressed in human prostate carcinomas (PCa) and induces invasiveness of androgen-independent PCa cells. In this study we show that LPXN enhanced the progression of existing PCa in vivo by breeding transgenic mice with prostate-specific LPXN expression and TRAMP mice (transgenic adenocarcinoma of mouse prostate). Double transgenic LPXN/TRAMP mice showed a significant increase in poorly differentiated PCa and distant metastases as compared with control TRAMP mice. Additional studies on primary PCa cells generated from both transgenic backgrounds confirmed the connection regarding LPXN overexpression and increased motility and invasiveness of PCa cells. One mediator of LPXN-induced invasion was found to be the cell-cell adhesion protein p120catenin (p120CTN). Both in vitro and in vivo experiments revealed that p120CTN expression negatively correlates with LPXN expression, followed by a redistribution of beta-catenin. Downregulation of LPXN using small interfering RNAs (siRNAs) resulted in a membranous localization of beta-catenin, whereas strong nuclear accumulation of beta-catenin was observed in p120CTN knockdown cells leading to enhanced transcription of the beta-catenin target gene matrix metalloprotease-7. In conclusion, the present results indicate that LPXN enhances the progression of PCa through downregulation of p120CTN expression and that LPXN could function as a marker for aggressive PCa in the future.

KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia.

Donor killer cell immunoglobulin-like receptor (KIR)-ligand incompatibility is associated with decreased relapse incidence (RI) and improved leukemia-free survival (LFS) after haploidentical and HLA-mismatched unrelated hematopoietic stem cell transplantation. We assessed outcomes of 218 patients with acute myeloid leukemia (AML n=94) or acute lymphoblastic leukemia (n=124) in complete remission (CR) who had received a single-unit unrelated cord blood transplant (UCBT) from a KIR-ligand-compatible or -incompatible donor. Grafts were HLA-A, -B or -DRB1 matched (n=21) or mismatched (n=197). Patients and donors were categorized according to their degree of KIR-ligand compatibility in the graft-versus-host direction by determining whether or not they expressed HLA-C group 1 or 2, HLA-Bw4 or HLA-A3/-A11. Both HLA-C/-B KIR-ligand- and HLA-A-A3/-A11 KIR-ligand-incompatible UCBT showed a trend to improved LFS (P=0.09 and P=0.13, respectively). Sixty-nine donor-patient pairs were HLA-A, -B or -C KIR-ligand incompatible and 149 compatible. KIR-ligand-incompatible UCBT showed improved LFS (hazards ratio=2.05, P=0.0016) and overall survival (OS) (hazards ratio=2.0, P=0.004) and decreased RI (hazards ratio=0.53, P=0.05). These results were more evident for AML transplant recipients (2-year LFS and RI with or without KIR-ligand incompatibility 73 versus 38% (P=0.012), and 5 versus 36% (P=0.005), respectively). UCBT for acute leukemia in CR from KIR-ligand-incompatible donors is associated with decreased RI and improved LFS and OS.

Triple-negative high-risk breast cancer derives particular benefit from dose intensification of adjuvant chemotherapy: results of WSG AM-01 trial.

BACKGROUND: This paper evaluates the prognostic and predictive impact of protein expression of various molecular markers in high-risk breast cancer (HRBC) patients with >9 involved lymph nodes, who received different chemotherapy dose-intensification strategies within a prospective randomized WSG AM-01 trial. MATERIALS AND METHODS: Paraffin-embedded tumors from 236 patients, who were randomly assigned to dose-dense conventional chemotherapy with four cycles of E(90)C(600) followed by three cycles of C(600)M(40)F(600) every 2 weeks (DD) or a rapidly cycled tandem high-dose regimen with two cycles of E(90)C(600) every 2 weeks followed by two cycles of E(90)C(3000)Thiotepa(400) every 3 weeks (HD), were available for retrospective central pathological review (116 HD/120 DD). Expression of estrogen receptor (ER), progesterone receptor (PR), MIB-1, epidermal growth factor receptor, and Her-2/neu was evaluated immunohistochemically using tissue microarrays. Results were correlated with follow-up data and treatment effects by proportional hazard Cox regression models (including interaction analysis). RESULTS: After a median follow-up of 61.7 months, 5-year event-free survival (EFS) as well as overall survival (OS) rates for the 236 patients were significantly better in the HD arm: EFS: 62% versus 41% [hazard ratio (HR) = 0.60, 95% CI 0.43-0.85, P = 0.004]; OS: 76% versus 61% (HR = 0.58, 95% CI 0.39-0.87, P = 0.007). In multivariate analysis, HD, tumor size <3 cm, positive PR, negative MIB-1 staining, and grade 1/2 were associated with favorable outcome. Interaction analysis showed that regarding predictive effects, triple negative (ER/PR/Her-2/neu) and G3 tumors derived most benefit from HD. CONCLUSION: Tandem HD improves both EFS and OS in HRBC. This therapy effect may be partly attributable to superior efficacy in the subgroup of triple-negative tumors and/or G3 with their poor prognostic marker profile.

Analyzing effects of photodynamic therapy with 5-aminolevulinic acid (ALA) induced protoporphyrin IX (PPIX) in urothelial cells using reverse phase protein arrays.

Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PPIX) is clinically established approach for a number of defined applications. However, in order to optimize the therapeutic benefits of PDT, the specific mode of cell destruction should be better defined. Apoptosis is favored over necrosis for clinical practice as the latter causes more side-effects. In the present study, we analyse PDT-induced cell death and its correlation to various PDT parameters (different doses applied, time after PDT treatment) in vitro using reverse phase protein arrays. Human urothelial cell lines with varying degrees of differentiation (UROtsa, RT4, RT112, J82) were subjected to in vitro-PDT using increasing doses of irradiation. In addition, positive controls for apoptosis, necrosis and un-/specific cellular damage were included. Cells were harvested over a specified time course, lysed and arrayed onto nitrocellulose-covered glass slides. The arrays were analyzed for expression of apoptosis-related proteins by immunohistochemistry. Analysis of caspase-3 and -9 expression, the activation of HIF-1alpha, Bcl2, Cox2 and the phosphorylation of AKT reveals signal activation due to a PDT-stimulus in correlation with the positive controls. Data were analyzed by unsupervised hierarchical clustering and depicted as a heat map revealing cell-specific patterns of pathway stimulation. Higher differentiated phenotypes showed a more distinct signal response in general and a higher apoptotic response in detail. Lower differentiated cell lines lost pathway regulation capabilities according to their state of dedifferentiation. Reverse phase protein arrays are a promising technique for signal pathway profiling: they exceed the range of traditional western blots by sensitivity, high-throughput capability, minimal sample consumption and easy quantification of results obtained.

Assessment of uncertainty in Great Barrier Reef catchment models.

This paper addresses uncertainty in socio-economic and sediment-nutrient models that are being developed for the assessment of change in the Great Barrier Reef (GBR) area. The catchments draining into the GBR lagoon are sources of pollutants. The Reef Water Quality Management Plan of the Queensland Government identified sediments and nutrients transported to the GBR lagoon as the major long-term threats to the reef and inshore ecosystems and the wellbeing of the human communities. The plan clearly indicates that changes in land management are required by 2013 to reduce pollutant inputs and, at the same time, maintain or enhance the benefits from using the inland waters. Science that provides decision tools for natural resource management and improves socio-economic and biophysical understanding is required to enable managers to make better decisions. A major research activity (the Water for a Healthy Country Flagship) aims to address social, economic and biophysical outcomes of land management change in the GBR. It contains research activities that provide information for integrated model development. Currently, however, these models lack the ability to estimate the uncertainty associated with prediction. This project aims to provide statistical methods for assessing uncertainty in models of sediment transportation to the GBR. Furthermore, it provides a link between the models and the decision-making process that allows assessment of uncertainty, a step pertinent to the risk analysis of policy options. This paper describes current and ongoing approaches for assessing uncertainty using a sediment modelling example and provides a way forward for the integration of applied socio-economic and biophysical models used in the decision-making process.

HLA-identical sibling allogeneic peripheral blood stem cell transplantation with reduced intensity conditioning compared to autologous peripheral blood stem cell transplantation for elderly patients with de novo acute myeloid leukemia.

We conducted a retrospective registry-based analysis to compare the outcome of 361 allogeneic human leukocyte antigen (HLA)-identical peripheral blood stem cell transplants (PBSCT) with reduced intensity conditioning (RIC) to that of 1369 autologous (auto) PBSCT in patients aged 50 years or older with de novo acute myeloid leukemia (AML), performed from 1997 until 2003 and reported to the European Group for Blood and Marrow Transplantation. Median age was 58 and 57 years in the RIC and auto groups, respectively. RIC patients had more advanced disease at the time of transplant. At a median follow-up of 24 months for RIC and 16 months for auto, multivariate analysis showed a lower risk for relapse (RR 0.77, P=0.013) without increased non-relapse mortality (NRM) in RIC patients (RR 1.26, P=0.28). Moreover, leukemia-free survival (RR 1.22, P=0.02) and overall survival (OS) (RR 1.32, P=0.005) were superior in the RIC group. In patients in 1st (CR), fewer relapses were counterbalanced by significantly increased NRM. Therefore, there was no survival advantage in this subgroup. In patients in 2nd or subsequent CR, LFS and OS were superior in the RIC group. RIC transplants show encouraging results in this older patient population with de novo AML.

[Prognostic and predictive impact of protein expression profiling in high risk breast cancer patients treated with high-dose chemotherapy]. / Prognostische und prädiktive Bedeutung von Proteinexpressions-Profilen in einer Hochrisiko-Mammakarzinomsubgruppe aus der WSG AM01 phase III-Studie (Hochdosis-Chemotherapie versus konventionelle dosis-dichte Chemotherapie).

The prognostic and predictive impact of protein expression profiles was analyzed in high-risk breast cancer patients who had previously been shown to benefit from high-dose chemotherapy (HDCT) in comparison to dose-dense chemotherapy (DDCT). Using tissue microarrays, the expression of 34 protein markers was evaluated in 236 patients who had received either HDCT or DDCT (in the WSG AM01 trial). 1) 24 protein markers of the initial panel of 34 markers were sufficient to identify five profile clusters by K-means clustering: luminal A (27%), luminal B (12%), HER-2 (21%), basal-like (13%) cluster and a so called 'multiple marker negative'=MMN cluster (27%) characterized by the absence of specifying markers. 2) After DDCT, HER-2 and basal-like groups had significantly worse event-free survival (EFS) (HR 3.6 (95% CI, 1.65-8.18; p = 0.001) and HR 3.7 (95% CI, 1.68-8.48); p < 0.0001), respectively) when compared to both luminal groups. 3) After HDCT, the hazard ratio was 1.5 (95% CI, 0.76-3.05) for EFS in the HER-2 subgroups and 1.1 (95% CI, 0.37-3.32) in the basal-like subgroups which indicates a better outcome for patients in the HER-2 and basal-like subgroups who received HDCT. Protein expression profiling in high-risk breast cancers identified 5 subtypes, which differed with respect to survival and response to chemotherapy: In contrast to luminal A and B subtypes, HER-2 and basal-like subgroups had a significant predictive benefit from HDCT when compared to DDCT.

Artificial intelligence and bladder cancer arrays.

Non-muscle invasive bladder cancer is a heterogenous disease whose management is dependent upon the risk of progression to muscle invasion. Although the recurrence rate is high, the majority of tumors are indolent and can be managed by endoscopic means alone. The prognosis of muscle invasion is poor and radical treatment is required if cure is to be obtained. Progression risk in non-invasive tumors is hard to determine at tumor diagnosis using current clinicopathological means. To improve the accuracy of progression prediction various biomarkers have been evaluated. To discover novel biomarkers several authors have used gene expression microarrays. Various statistical methods have been described to interpret array data, but to date no biomarkers have entered clinical practice. Here, we describe a new method of microarray analysis using neurofuzzy modeling (NFM), a form of artificial intelligence, and integrate it with artificial neural networks (ANN) to investigate non-muscle invasive bladder cancer array data (n=66 tumors). We develop a predictive panel of 11 genes, from 2800 expressed genes, that can significantly identify tumor progression (average Logrank p = 0.0288) in the analyzed cancers. In comparison, this panel appears superior to those genes chosen using traditional analyses (average Logrank p = 0.3455) and tumor grade (Logrank, p = 0.2475) in this non-muscle invasive cohort. We then analyze panel members in a new non-muscle invasive bladder cancer cohort (n=199) using immunohistochemistry with six commercially available antibodies. The combination of 6 genes (LIG3, TNFRSF6, KRT18, ICAM1, DSG2 and BRCA2) significantly stratifies tumor progression (Logrank p = 0.0096) in the new cohort. We discuss the benefits of the transparent NFM approach with respect to other reported methods.

Structural insights into antibody-mediated mucosal immunity.

The mucosal regions of the body are responsible for defense against environmental pathogens. Particularly in the lumen of the gut, antibody-mediated immune responses are critical for preventing invasion by pathogens. In this chapter, we review structural studies that have illuminated various aspects of mucosal immunity. Crystal structures of IgA1-Fc and IgA-binding fragments of the polymeric immunoglobulin receptor and Fc alphaRI, combined with models of intact IgA and IgM from solution scattering studies, reveal potential mechanisms for immune exclusion and induction of inflammatory responses. Other recent structures yield insights into bacterial mechanisms for evasion of the host immune response.

C-kit expression in high-risk breast cancer subgroup treated with high-dose or conventional dose-dense chemotherapy.

The proto-oncogene c-kit is known to be expressed in poorly differentiated breast cancer. In this study, we retrospectively evaluated the prognostic and predictive impact of c-kit in a high risk subgroup of breast cancer patients (>9 axillary node metastases) who received high-dose (HDCT) or dose-dense (DDCT) conventional chemotherapy and correlated these findings with the expression of the basal-type markers CK5 and CK 17, estrogen (ER) and progesterone (PR) receptor, Her-2/neu and MIB 1. C-kit, CK5, CK17, ER, PR, Her-2/neu and MIBI expression was evaluated immunohistochemically using tissue microarrays containing breast cancer samples from 236 patients who were randomized to the WSG AM01 trial (median follow-up of 60 months). There was a significant overall survival (OS) benefit for patients receiving HDCT compared to DDCT (p = 0.027). C-KIT expression was found in 12 % of all breast cancers and correlated with a poorer OS in multivariate analysis (p = 0.051). Furthermore, c-kit correlated with high grade (p = 0.019), CK5- and CK17-positivity (p <0.0001 and p = 0.001, respectively) and ER- and PR-negativity (p = 0.04 and p = 0.008, respectively). In contrast to CK5 and CK17, patients with c-kit positive breast cancers revealed no benefit from high-dose chemotherapy. These findings underline that c-kit expression represents an independent negative prognostic marker in high-risk breast cancer. Correlation with CK5 +/CK17+ and ER-/PR-suggests that c-kit positive carcinomas are at least partly of basal-type.

Early lymphocyte recovery following autologous peripheral stem cell transplantation is associated with better survival in younger patients with lymphoproliferative disorders.

Early absolute lymphocyte count (ALC) has become an important end point for engraftment in patients undergoing autologous peripheral stem cell transplantation (APSCT). In this retrospective study, we evaluate the prognostic significance of early recovery of ALC ( > or = 0.5 cells x 10(9)/l on or before day 15) following APSCT in predicting transplant outcome in 72 patients with lymphoproliferative disorders, including non-Hodgkin's lymphoma (n = 30), Hodgkin's lymphoma (n = 8) and multiple myeloma (n = 34). The median quantities of CD34+ stem cells and lymphocytes infused were 4.97 x 10(6)/kg (range 0.64-11.7) and 11.3 x 10(7)/kg (range 1.11-110) respectively. After a median follow-up of 18 months (range 2-68), 28 patients had experienced a relapse and 16 had died. Of the 72 patients, 27 (37%) demonstrated early recovery of ALC. Early recovery of ALC was strongly associated with long-term overall and disease-free survival in patients aged less than 50 years (P < 0.001). In both univariate and multivariate survival analyses, a shorter time from diagnosis to APSCT was associated with early recovery of ALC (P = 0.03). These findings indicate that early recovery of ALC may contribute to longer survival in younger patients with lymphoproliferative disorders. A shorter time from diagnosis to APSCT may favor recovery of ALC independent of the infused stem cell or lymphocyte doses.

Granulocyte colony-stimulating factor for poor graft function after allogeneic stem cell transplantation: 3 days of G-CSF identifies long-term responders.

Poor graft function (PGF) is a frequent cause of morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). To study the value of granulocyte colony-stimulating factor (G-CSF) in PGF, we retrospectively analyzed 81 episodes of PGF in 66 patients transplanted from 01/94 to 01/99 from an HLA-identical sibling (n = 45) or an unrelated (n = 21) donor. Median age was 29 years, 55 patients had malignancies. A total of 11 patients received a CD34+ selected graft. Viral infections (25%), myelotoxic drug (33%), fungal/bacterial infections (14%), and GVHD (31%) were present before PGF diagnosis. Median time from allo-HSCT to PGF was 75 (25-474) days. All patients were treated with G-CSF. In 77/81 episodes, there was a response that was sustained in 57. A total of 27 patients presented an increase of white cell count (WBC) >0.1 x 10(9)/l after 3 days of G-CSF. The 5-year survival was 37% and was significantly better in patients with increased WBC > 0.1 x 10(9)/l after 3 days of G-CSF (65 vs 18%, P < 0.0001). In multivariate analysis, increased WBC > 0.1 x 10(9)/l after 3 days of G-CSF (P = 0.002) was associated with better survival, while BuCy-based conditioning (P = 0.02) and GVHD (P = 0.005) were associated with higher risk of death. In conclusion, hematological response after 3 days with G-CSF predicted a better survival for patients with PGF after allo-SCT.