Developmental defects in zebrafish for classification of EGF pathway inhibitors

One of the major challenges when testing drug candidates targeted at a specific pathway in whole animals is the discrimination between specific effects and unwanted, off-target effects. Here we used the zebrafish to define several developmental defects caused by impairment of Egf signaling, a major pathway of interest in tumor biology. We inactivated Egf signaling by genetically blocking Egf expression or using specific inhibitors of the Egf receptor function. We show that the combined occurrence of defects in cartilage formation, disturbance of blood flow in the trunk and a decrease of myelin basic protein expression represent good indicators for impairment of Egf signaling. Finally, we present a classification of known tyrosine kinase inhibitors according to their specificity for the Egf pathway.     

Autoimmune neutropenia in children: analysis of 116 cases

To cite this article: Audrain M, Martin J, Fromont P, Prié N, Thomas C, Muller J‐Y. Autoimmune neutropenia in children: analysis of 116 cases. Pediatr Allergy Immunol 2011; 22 : 494–496. Diagnosis of autoimmune neutropenia (AIN) in infants is important, because it allows the exclusion of more severe forms of neutropenia that have an increased risk for leukemia. AIN is characterized by chronic neutropenia, which spontaneously resolves within several months to a few years, and mild infections. Diagnosis is confirmed by the presence of antibodies directed against neutrophil antigens. The human neutrophil antigen (HNA) system is a polymorphic system, which includes five antigen groups with different polymorphisms. In AIN, antibodies are mostly directed against HNA‐1 (or against a specific allele of HNA‐1) and HNA‐4. Here, we present a series of 116 infants with AIN. We observed that anti‐neutrophil antibodies were present in 60% cases; directed against HNA‐1a in 73% of cases. In addition, we showed there was a bias in the HNA allele distribution in these infants because the frequency of the HNA‐1a allele was greater in comparison with controls.     

Guide to the Development of an Industrial Medical Records System

Biological parameters known to be affected in lead poisoning were measured in rats following ingestion of graded dosages of lead. Intranuclear inclusion bodies are formed in renal tubular lining cells with smaller doses of lead than produce other changes. Decreased body weight is the next most sensitive abnormality. This is followed by increased delta-aminolevulinic acid (ALA) excretion, reticulocytosis, renal edema, and aminoaciduria. Anemia only occurs at the highest lead dosage. Over a wide range of lead ingestion, urinary lead excretion remains constant, although renal lead content increases. Quantitative lead analyses of cell organelles show that lead is concentrated within the inclusion bodies. Relatively small amounts of lead are present in the cytoplasm and mitochondria. It is suggested that soft-tissue lead accumulates in the intranuclear inclusion body, thereby sparing toxic injury to cytoplasmic organelles.     

Herpesvirus entry mediator (HVEM) attenuates signals mediated by the lymphotoxin β receptor (LTβR) in human cells stimulated by the shared ligand LIGHT

Signals mediated by members of the tumor necrosis factor receptor superfamily modulate a network of diverse processes including initiation of inflammatory responses and altering cell fate between pathways favoring survival and death. Although such pathways have been well-described for the TNF-α receptor, less is known about signaling induced by the TNF superfamily member LIGHT and how it is differentially altered by expression of its two receptors LTβR and HVEM in the same cell. We used cell lines with different relative expression of HVEM and LTβR to show that LIGHT-induced signals mediated by these receptors were associated with altered TRAF2 stability and RelA nuclear translocation. Production of the inflammatory chemokine CXCL10 was primarily mediated by LTβR. Higher expression of HVEM was associated with cell survival, while unopposed LTβR signaling favored pathways leading to apoptosis. Importantly, restoring HVEM expression in cells with low endogenous expression recapitulated the phenotype of cells with higher endogenous expression. Together, our data provide evidence that relative expression of HVEM and LTβR modulates canonical NF-κB and pro-apoptotic signals stimulated by LIGHT.     

Slow Early Graft Function: A Neglected Entity after Renal Transplantation

Background: After renal transplantation, early graft function (EGF) can be divided into delayed graft function (DGF), slow graft function (SGF) and immediate graft function (IGF). DGF is well documented. However, when evaluating the long-term significance of early function, the literature shows conflicting definitions and inconsistent results. In addition, SGF, a new entity separate to DGF and IGF, is a recent and poorly understood development. Aim: To investigate the risk factors for and the impact of poor EGF (PEGF) on long-term outcome. Methods: This retrospective study reviewed the records of local adult patients who underwent renal transplantation at the Groote Schuur Hospital (Cape Town, South Africa) between 2004 and 2008. EGF was divided according to day 5 serum creatinine into IGF (serum creatinine <150 μmol/l), SGF (serum creatinine >150 but <450 μmol/l) and DGF (serum creatinine >450 μmol/l or dialysis in the first week). DGF and SGF together comprised PEGF, with IGF alone representing good EGF (GEGF). Results: A total of 121 patients (77 men, 44 women; mean age 39 years, range 14-67) were included in the study. Eighteen were excluded due to nephrectomy (n = 8), death (n = 6) or loss to follow-up (n = 4) within the first year. Analysis of cadaveric donors showed no significant risk factors for PEGF with the exception of cold ischaemic time, which differed significantly between the GEGF and PEGF groups, with means of 12 and 16 h, respectively (p = 0.013). Considering both living and cadaveric grafts, the 1-year estimated glomerular filtration rate (eGFR) was significantly different between IGF and DGF (p = 0.038) as well as between IGF and SGF (p = 0.028), with no significant difference between SGF and DGF (p > 0.05). A comparison of the PEGF and GEGF groups yielded significantly different 1-year eGFR values (60 and 50 ml/min, respectively; p = 0.07), with PEGF also associated with a longer hospital stay (20 vs. 14 days; p = 0.00005). Acute rejection was independently associated with a lower 1-year eGFR (p = 0.028), but in the absence of rejection, GEGF and PEGF remained significantly different with regards to 1-year eGFR (p = 0.024). Conclusions: SGF is not related to IGF but rather to DGF and should thus be regarded as a form of PEGF as opposed to GEGF. PEGF has a worse long-term outcome, and this indicates the need for increased efforts in its prevention and greater attention to its management.