Negative regulatory effect of histamine in DNFB-induced contact hypersensitivity

Histamine plays an important role in the regulation of various immunological functions. To evaluate the role of histamine in contact hypersensitivity, contact dermatitis was induced with dinitrofluorobenzene (DNFB) in histidine decarboxylase knockout (HDC-/-) histamine-deficient and wild-type mice. The DNFB-induced increase of the ear thickness was significantly higher in HDC-/- mice than in wild-type mice. Using flow cytometry, significantly lower percentages of CD4+ Th and CD8+ Tc cells, and significantly higher percentages of CD45R+ B cells were observed in the regional lymph nodes in HDC-/- mice than in wild-type mice. In the ear specimens of both groups, the majority of the infiltrating cells were neutrophils and macrophages at 24 and 48 h after challenge. Using immunohistochemistry, we observed significantly more CD45+ leukocytes in HDC-/- mice than in wild-type mice. The expression of Th1 (IL-2, IFN-gamma, TNF-alpha) and Th2 (IL-4) mRNAs was examined by quantitative real time RT-PCR in the ear samples. The levels of Th1 cytokine mRNAs both at 24 and 48 h after challenge and IL-4 mRNA at 48 h showed a significantly higher increase in HDC-/- mice than in wild-type mice. These results suggest that histamine plays a negative immunoregulatory role in DNFB-induced contact hypersensitivity.     

Long-term results of a randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia.

PURPOSE: Between September 1991 and May 1997, within the International Berlin-Frankfurt-Muenster Study Group (I-BFM-SG), a randomized study was performed aimed at assessing the efficacy of prolonged use of high-dose l-asparaginase (HD-l-ASP) during continuation therapy in children with standard risk (SR) acute lymphoblastic leukemia (ALL), treated with a reduced BFM-type chemotherapy. PATIENTS AND METHODS: The Italian, Dutch, and Hungarian groups participated in this study denominated IDH-ALL-91, and 494 children were enrolled. Treatment consisted of a BFM-type modified backbone with omission of the IB part in induction and elimination of two doses of anthracyclines during reinduction in both arms at the beginning of continuation therapy. Patients were randomly assigned to receive (YES-ASP) or not (NO-ASP) 20 weekly HD-l-ASP (25,000 IU/m2). RESULTS: The event-free-survival and overall survival probabilities at 10 years for the entire group were 82.5% (1.8) and 90.3% (1.3), respectively. Of the 490 patients eligible for random assignment, 355 (72.4%) were randomly assigned (178 YES-ASP and 177 NO-ASP). After a median follow-up of 9 years, the probability of disease-free survival at 10 years was 87.5% (SE, 2.5) for YES-ASP arm versus 78.7% (SE, 3.3) for NO-ASP arm (P = .03). In multivariate analysis, NO-ASP arm (P = .03), male sex (P = .004), and age older than 10 years (P = .0003) had a significantly adverse impact on outcome. CONCLUSION: In this subset of patients, selected with criteria not including monitoring of minimal residual disease, application of extended HD-l-ASP may improve prognosis, compensating reduced leukemia control that results from adoption of a reduced-intensity BFM-backbone for treatment of children with SR ALL.     

Imatinib accelerates progenitor cell‐mediated liver regeneration in choline‐deficient ethionine‐supplemented diet‐fed mice

Severe chronic hepatic injury can induce complex reparative processes. Ductular reaction and the appearance of small hepatocytes are standard components of this response, which is thought to have both adverse (e.g. fibrosis, carcinogenesis) and beneficial (regeneration) consequences. This complex tissue reaction is regulated by orchestrated cytokine action. We have investigated the influence of the tyrosine kinase inhibitor imatinib on a regenerative process. Ductular reaction was induced in mice by the widely used choline‐deficient ethionine‐supplemented diet (CDE). Test animals were treated daily with imatinib. After 6 weeks of treatment, imatinib successfully reduced the extent of ductular reaction and fibrosis in the CDE model. Furthermore, the number of small hepatocytes increased, and these cells had high proliferative activity, were positive for hepatocyte nuclear factor 4 and expressed high levels of albumin and peroxisome proliferator‐activated receptor alpha. The overall functional zonality of the hepatic parenchyma (cytochrome P450 2E1 and glucose 6 phosphatase activity; endogenous biotin content) was maintained. The expression of platelet‐derived growth factor receptor beta, which is the major target of imatinib, was downregulated. The anti‐fibrotic activity of imatinib has already been reported in several experimental models. Additionally, in the CDE model imatinib was able to enhance regeneration and preserve the functional arrangement of hepatic lobules. These results suggest that imatinib might promote the recovery of the liver following parenchymal injury through the inhibition of platelet‐derived growth factor receptor beta.     

Piezosurgical management of sealer extrusion‐associated mental nerve anaesthesia: A case report

The present report describes a case where sealer extrusion (Sealapex) occurred during root canal obturation of a left lower second premolar tooth, and the patient experienced sudden pain and followed by complete anaesthesia of the lower lip. After 3 weeks of conservative therapy and an unaltered anaesthesia period, piezosurgical removal of the extruded sealer and root‐end resection was performed despite the direct contact with the mental neurovascular bundle. At suture removal, 1 week after surgery, there was no improvement in sensation. Two weeks after the operation, the patient reported some changes, including a short paraesthesia period alternating with anaesthesia. At the fourth post‐operative week, neurosensory function recovered completely. This case represents successful use of the piezoelectric technique for mental nerve decompression and periapical surgery of a lower second premolar with close contact of the mental nerve.     

Network remodeling of intramural coronary resistance arteries in the aged rat: A statistical analysis of geometry

AimsTo identify the geometrical alterations in the age-remodeled rat coronary artery network and to develop a useful technique to analyze network properties in the rat heart.Methods and resultsWe analyzed the networks of the left anterior descendent coronary arteries on in situ perfused hearts of young (3 months) and old (18 months) male rats. All segments and branching over >80 μm diameter were analyzed using 50 μm long cylindrical ring units of the networks. Arterial widening and paucity, increased tortuosity were typical features in the old network. In addition, axis angles deviated more from the mother branches in the old, whereas the diameters of daughter branches fit the Murray law in both groups. The detected changes in the old network resulted in a longer blood flow route for the same direct distance.ConclusionWe developed a useful method to investigate arterial network property changes in the rat heart. Ageing resulted in longer, more tortuous flow route in the LAD network that might be hemodynamically disadvantageous.     

The BAFF Receptor Transduces Survival Signals by Co-opting the B Cell Receptor Signaling Pathway

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Highlights? Inducible loss of the Syk tyrosine kinase results in death of follicular B cells ? Syk transduces survival signals from BAFFR to the ERK and PI3 kinase-PDK1 pathways ? BAFFR signaling results in phosphorylation of Igα and Syk ? BAFFR transduces signals via the BCR to activation of Syk     

Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery

One of the promises of nanoparticle (NP) carriers is the reformulation of promising therapeutics that have failed clinical development due to pharmacologic challenges. However, current nanomedicine research has been focused on the delivery of established and novel therapeutics. Here we demonstrate proof of the principle of using NPs to revive the clinical potential of abandoned compounds using wortmannin (Wtmn) as a model drug. Wtmn is a potent inhibitor of phosphatidylinositol 3' kinase-related kinases but failed clinical translation due to drug-delivery challenges. We engineered a NP formulation of Wtmn and demonstrated that NP Wtmn has higher solubility and lower toxicity compared with Wtmn. To establish the clinical translation potential of NP Wtmn, we evaluated the therapeutic as a radiosensitizer in vitro and in vivo. NP Wtmn was found to be a potent radiosensitizer and was significantly more effective than the commonly used radiosensitizer cisplatin in vitro in three cancer cell lines. The mechanism of action of NP Wtmn radiosensitization was found to be through the inhibition of DNA-dependent protein kinase phosphorylation. Finally, NP Wtmn was shown to be an effective radiosensitizer in vivo using two murine xenograft models of cancer. Our results demonstrate that NP drug-delivery systems can promote the readoption of abandoned drugs such as Wtmn by overcoming drug-delivery challenges.     

CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development

The C-type lectin receptor CLEC-2 signals through a pathway that is critically dependent on the tyrosine kinase Syk. We show that homozygous loss of either protein results in defects in brain vascular and lymphatic development, lung inflation, and perinatal lethality. Furthermore, we find that conditional deletion of Syk in the hematopoietic lineage, or conditional deletion of CLEC-2 or Syk in the megakaryocyte/platelet lineage, also causes defects in brain vascular and lymphatic development, although the mice are viable. In contrast, conditional deletion of Syk in other hematopoietic lineages had no effect on viability or brain vasculature and lymphatic development. We show that platelets, but not platelet releasate, modulate the migration and intercellular adhesion of lymphatic endothelial cells through a pathway that depends on CLEC-2 and Syk. These studies found that megakaryocyte/platelet expression of CLEC-2 and Syk is required for normal brain vasculature and lymphatic development and that platelet CLEC-2 and Syk directly modulate lymphatic endothelial cell behavior in vitro.     

Coexistence of folie communiquée and folie simultanée

Objective. The authors report a case during which they observed serious subtypes of induced delusional psychosis (folie communiquée and folie simultanée) without any common genetic background or premorbid psychosis in the case of the secondary patient. Method. The clinical phenomenology of the case is described. Results. Mild intellectual disability and environmental–psychological factors (social isolation and the symbiotic-like interpersonal relatedness) play an essential aetiological role in the case of the secondary recipient patient. Conclusion. The authors emphasize the importance of subclassification of induced delusional psychosis for further aetiological and clinical research.