Evaluation of the chronic toxicity and oncogenicity of N,N-diethyl-m- toluamide (DEET)

Chronic toxicity and/or oncogenicity studies were conducted in rats, mice, and dogs with the insect repellent DEET. DEET was mixed in the diet and administered to CD rats for two years at concentrations that corresponded to dosage levels of 10, 30 or 100 mg/kg/day for males and 30, 100, or 400 mg/kg/day for females; to CD-1 mice for 18 months at dosage levels of 250, 500, or 1000 mg/kg/day; and to dogs for one year, via gelatin capsules, at dosage levels of 30, 100, or 400 mg/kg/day. In the rodent studies, each group consisted of 60 animals of each sex, and two concurrent independent control groups, each containing 60 animals/sex were included in each study. Each group in the dog study consisted of four male and four female dogs and one control group was included in the study. Treatment-related effects were observed at the highest dose level in all three studies. For rats, the effects included decreases in body weight and food consumption and an increase in serum cholesterol in females only. In mice, the effects observed were decreases in body weight and food consumption in both sexes. The effects observed in dogs included increased incidences of emesis and ptyalism, and levels of transient reduction in hemoglobin and hematocrit, increased alkaline phosphatase (males only), decreased cholesterol, and increased potassium. One male dog in the high-dose group also exhibited ataxia, tremors, abnormal head movements, and/or convulsions on several occasions during the study. The highest no- observed-effect levels (NO-ELs) for rats, mice and dogs were determined to be 100, 500, and 100 mg/kg/day, respectively. No specific target organ toxicity or oncogenicity was observed in any of the studies.      

Vascular responses to radiotherapy and androgen-deprivation therapy in experimental prostate cancer

Background

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in tumor cells and promotes tumor cell survival after radiation-induced DNA damage. Because the pathway may not be completely inhibited after blockade of PI3K itself, due to feedback through mammalian target of rapamycin (mTOR), more effective inhibition might be expected by targeting both PI3K and mTOR inhibition.

Materials and methods

We investigated the effect of two dual PI3K/mTOR (both mTORC1 and mTORC2) inhibitors, NVP-BEZ235 and NVP-BGT226, on SQ20B laryngeal and FaDu hypopharyngeal cancer cells characterised by EGFR overexpression, on T24 bladder tumor cell lines with H-Ras mutation and on endothelial cells. Analysis of target protein phosphorylation, clonogenic survival, number of residual ??H2AX foci, cell cycle and apoptosis after radiation was performed in both tumor and endothelial cells. In vitro angiogenesis assays were conducted as well.

Results

Both compounds effectively inhibited phosphorylation of Akt, mTOR and S6 target proteins and reduced clonogenic survival in irradiated tumor cells. Persistence of DNA damage, as evidenced by increased number of ??H2AX foci, was detected after irradiation in the presence of PI3K/mTOR inhibition, together with enhanced G2 cell cycle delay. Treatment with one of the inhibitors, NVP-BEZ235, also resulted in decreased clonogenicity after irradiation of tumor cells under hypoxic conditions. In addition, NVP-BEZ235 blocked VEGF- and IR-induced Akt phosphorylation and increased radiation killing in human umbilical venous endothelial cells (HUVEC) and human dermal microvascular dermal cells (HDMVC). NVP-BEZ235 inhibited VEGF-induced cell migration and capillary tube formation in vitro and enhanced the antivascular effect of irradiation. Treatment with NVP-BEZ235 moderately increased apoptosis in SQ20B and HUVEC cells but not in FaDu cells, and increased necrosis in both tumor and endothelial all cells tumor.

Conclusions

The results of this study demonstrate that PI3K/mTOR inhibitors can enhance radiation-induced killing in tumor and endothelial cells and may be of benefit when combined with radiotherapy.     

hs-CRP is a potential predictor of no-reflow in patients with AMI after emergency PCI

The paper aims to determine whether the inflammation,a powerful risk factor that has been demonstrated for the development of coronary artery disease,plays a role in no-reflow phenomenon in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI).Methods We prospectively analyzed 656 patients with AMI after primary PCI.Based on post-PCI angiography data,patients were divided into two groups:the no-reflow group (TIMI=2,n =60) and the reflow group (TIMI=3,n =596).Results Our results showed that the inflammatory factors including leukocyte count (×109/L) (10.90±4.04 vs.9.12±2.98 P =0.002),hs-CRP (5.04±0.71 vs.4.70±0.75 P =0.001) and other factor platelet count (×109/L) (210.96±33.42 vs.196.41±46.06 P =0.033) in no-reflow group are significantly higher than those in reflow group,major adverse cardiac events happened in the patients with no-reflow are higher than in reflow patients no matter in hospital or at the end of follow-up.We also found the left ventricular ejection fraction (LVEF) dramatically decreased (58.65±9.34 vs.51.29±11.38,P＜0.001) and left ventricular end-diastolic dimension (LVEDD) significantly increased (49.94±6.75 mm vs.54.66±6.68mm,P＜0.001) in no-reflow patients at the end of follow-up.Conclusions Our results suggest that inflammation factors function in no-reflow phenomenon,and no-reflow is a serious complication after primary PCI which predicts poor left ventricular systolic functional recovery and mortality in patients with AMI.(J Geriatr Cardiol 2008;5:217-222)     

Ist die geschlossene Rhinoplastik überholt?

Closed rhinoplasty has been performed for over 50 years. Advantages over the open approach lie in the avoidance of unnecessary skin retraction and damage, as well as a better overview during surgery. In addition, transplantations are less frequently required. The present article describes the closed approach to rhinoplasty, including septum correction, hump removal, nasal bridge augmentation and nasal tip reshaping. Additionally, the use of a mastoid composite bone graft in nasal corrections is recommended and described for the first time. By using similar bone types and autologous tissue, particularly natural and well-tolerated results can be achieved.     

Die Schnittmethode bei der Otoplastik

As an alternative to the commonly used techniques of scratching, partial incision and sutures to correct protruding ears, a method based solely on incisions is explained here. The described method offers the surgeon more options with one technique to deal with a multitude of auricular malformations.     

Gerät zur Spracherkennung bei gleichzeitigem Lärmschutz

Summary A device consisting of a hearing protector headset and a modified hearing aid is used as a protective hearing aid for normal hearing subjects. Understanding of sufficiently redundant speech is remarkably improved, especially for a noise level of about 20 dB above speech level. Tests have been made with the Freiburger Zahlentest and amplified party noise up to noise levels of 105 dB_SPL. As an example: the above mentioned device enables the wearer to understand speech of 85 dB within 105 dB loud speech similar background noise while still the ears are charged with no more than 90 dB at all.Application for hyperacusis and recruitment patients is discussed.

Vorgetragen auf der 47. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Halschirurgie, Basel 1976     

Die Situation der onkologischen Chirurgie in Deutschland 1998: Aktuelle Umfrageergebnisse

The situation of oncological surgery in Germany was evaluated by sending a questionnaire in January 1998 to 1979 registered surgical clinics. A total of 938 responded and stated that they are involved in that field. In 72% of the departments oncological surgery adds up to 10-30% of their overall work. The proportion of oncological surgery correlated to hospital size and is highest in university clinics. Colorectal surgery is 93% and is the leading topographical field in oncological surgery. 73% of the hospitals regularly perform gastric tumor surgery. The proportion of hospitals with breast surgery is surprisingly high (45%). Many hospitals (54.6%) report neoadjuvant treatment regimens. Together with adjuvant therapy this rate amounts to 85.2%. The diagnostic spectrum of the hospitals involved in the inquiry is satisfactory. However, the modern possibilities of network and telecommunication are not sufficiently used. A second opinion is required predominantly in their own department or clinic, but not between centers. The surgeon's position concerning the speciality "surgical oncology" is ambivalent: only 35.3% of the department chiefs support this speciality--and over 90% of the departments reject the structural independence of "surgical oncology" from "visceral surgery".     

Characterization of murine JAK2V617F-positive myeloproliferative disease

The JAK2(V617F) mutation is present in almost all patients with polycythemia vera (PV), large proportions of patients with essential thrombocythemia and idiopathic myelofibrosis, and less frequently in atypical myeloproliferative disorders (MPD). We show that transplantation of JAK2(V617F)-transduced bone marrow into BALB/c mice induces MPD reminiscent of human PV, characterized by erythrocytosis, granulocytosis, extramedullary hematopoiesis, and bone marrow fibrosis, but not thrombocytosis. Fluorescence-activated cell sorting of bone marrow and spleen showed proportional expansion of common myeloid progenitors, granulocyte-monocyte and megakaryocyte-erythrocyte progenitors. Megakaryocyte and late erythroid progenitors were dramatically increased, with only modest expansion of early erythroid progenitors. Erythropoietin (Epo) receptor expression was reduced on early, but normal on late erythroblasts. Serum levels of Epo and granulocyte colony-stimulating factor, but not granulocyte macrophage colony-stimulating factor, were reduced, whereas tumor necrosis factor-alpha was increased, possibly exerting a negative effect on JAK2(V617F)-negative hematopoiesis. These data suggest that erythrocytosis and granulocytosis in JAK2(V617F) mice are the net result of a complex interplay between cell intrinsic and extrinsic factors. There were no thromboembolic events and no animals succumbed to their disease, implicating additional factors in the manifestation of human disease. The disease was not transplantable and prolonged observation showed normalization of blood counts in most JAK2(V617F) mice, suggesting that the mutation may not confer self-renewal capacity.     

Dopa-responsive dystonia in British patients: new mutations of the GTP- cyclohydrolase I gene and evidence for genetic heterogeneity

Dopa-responsive dystonia (DRD) was originally described in a series of Japanese patients, but is now increasingly recognized in other countries. Recently the GTP cyclohydrolase I (GTPCH) gene was isolated as the first causative gene for dopa-responsive dystonia (DRD). Mutations were identified in three Japanese families with autosomal dominantly inherited DRD and in one sporadic Japanese patient. Characterisation of the exon-intron boundaries of this gene has now allowed the analysis of mutations at the level of genomic DNA. Amplifying all six exons, we analyzed the GTPCH gene in nine British families with 33 affected family members and in three sporadic cases and found six new mutations. Only point mutations were found, causing a stop codon in one family and an amino acid change in highly conserved regions of the gene in a further four families and in one sporadic case. None of these mutations were detected more than once and none of the mutations previously described were found in our patients. No mutations were identified in four families and in two sporadic cases.