Trichloroethanol alters action potentials in a subgroup of primary sensory neurones

We investigated the effects of 2,2,2-trichloroethanol (TCE), the active metabolite of chloral hydrate, on large-conductance calcium-activated K+ channels (BKCa channels) of dorsal root ganglion (DRG) neurones. In outside-out patches, 2 and 5 mM TCE increased the open probability of BKCa channels to 1.7-fold and 2.8-fold of control, respectively. In 50% of the cells investigated (group A) the action potential (AP) was shortened reversibly by TCE by 20% and the whole-cell outward-current was increased by 44%. Both effects could be antagonized by iberiotoxin. In a second group of neurone (group B), TCE prolonged the AP duration. The effects of TCE in group A, which was 20-fold more potent than ethanol on BKCa channels and AP might contribute to the described analgesic effect of chloral hydrate.     

Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells

A central role for polo-like kinases (PLK) in regulating several stages of mitotic progression has been born out in several species. Overexpression of PLK1 is observed in the majority of hitherto analysed human tumors. PLK1 overexpression is a negative prognostic factor in patients suffering from non-small cell lung cancer, head and neck tumors, esophageal carcinomas and melanomas. In order to define the role of PLK1 for mitotic progression of human cells and for neoplastic cell growth, phosphorothioate antisense oligonucleotides (ASOs) were tested to selectively downregulate PLK1 expression in MDA-MB-435 (breast cancer), HeLa S3 (cervical carcinoma) and A549 (non-small cell lung cancer) cells. ASOs were identified which suppress PLK1 mRNA and protein in a dose-dependent and sequence-specific manner. This approach also led to reduced PLK1 serine/threonine kinase activity. Downregulation of cellular PLK1 levels in cancer cells altered cell cycle progression moderately with an elevated percentage (20-30%) of cells in G(2)/M. Furthermore, cells with reduced PLK1 protein gained a rounded phenotype with multiple centrosomes. Moreover, ASO treatment resulted in potent antiproliferative effects in cell culture. Considerable antitumor activity was observed in vivo against A549 cells. This study suggests that antisense inhibitors targeted against PLK1 at well tolerated doses may be considered as a cancer therapeutic agent.     

Chemotherapy for metastatic breast cancer-report of a European expert panel

The anthracyclines doxorubicin and epirubicin, and the taxanes paclitaxel and docetaxel, are effective chemotherapeutic agents for the first-line and second-line treatment of metastatic breast cancer, and their clinical use is widespread. However, for women whose disease has progressed despite receiving these drugs, treatment options are limited. These women often have a good performance status, and may survive for many months or even years, so they should be given the opportunity to benefit from further chemotherapy. The goals of chemotherapy in these patients are to obtain maximum control of symptoms, prevent serious complications, and increase survival without diminishing quality of life. Several agents are used for this purpose, including fluorouracil, docetaxel (in patients who have already received paclitaxel), vinorelbine, and mitomycin c, but because data from controlled trials are limited, a standard regimen has not yet been established. Moreover, these agents may be inconvenient to administer and can be associated with adverse events requiring hospitalisation. Therefore, there is a clear need for additional therapeutic options for patients with metastatic breast cancer. Ideally, agents should have a convenient method of administration, eg, oral, and should be suitable for home-based rather than hospital-based therapy. Treatment should control disease in at least 20-30% of patients with an acceptable side-effect profile. Novel oral therapies have now been developed and are being used increasingly in patients whose disease has progressed following taxane therapy.     

Postmastectomy Electron-Beam-Rotation Irradiation in Locally Advanced Breast Cancer

BACKGROUND: Different radiotherapy techniques are used for postmastectomy irradiation. We review the results with the electron-beam-rotation technique in advanced breast cancer patients. Main endpoint was local tumor control. PATIENTS AND METHODS: From 1990 to 1998 119 patients with adverse pathology features (pT3 17% of patients, pT4 42%, multicentricity 36%, pN >/= 3 positive nodes and/or pN1biii 81%, close margins 30%) underwent electron-beam-rotation irradiation of the chest wall with daily fractions of 2.0-2.5 Gy per day to 50 Gy total dose after modified radical mastectomy and axillary lymph node dissection. A local boost of 10 Gy and/or irradiation of locoregional lymph nodes were applied depending on the completeness of resection and lymph node involvement. RESULTS: After a median follow-up of 73 months for patients at risk the 5-year local tumor control, local tumor control first event, disease-free, and overall survival were 82%, 92%, 57%, and 63% (Kaplen Meier analysis), respectively. Significant predictors of poor local tumor control were maximal tumor diameter >/= 5 cm (p = 0.01), "close margins" or residual tumor (p < 0.01), four or more involved axillary lymph nodes (p = 0.02), two or more involved lymph node levels (p = 0.04), negative estrogen receptor status (p = 0.03), and high-grade histopathology (GIIb-III, p < 0.01). The subgroup analysis showed a high local failure rate of 37% for high-grade (GIIb-III) and estrogen receptor negative tumors, whereas no local recurrence was found in low-grade (GI-Iia) and receptor positive tumors (p = 0.01). The multivariate analysis revealed maximal tumor diameter >/= 5 cm, four or more involved axillary lymph nodes and high-grade histopathology (GIIb-III) as independent predictors of poor local tumor control. CONCLUSION: In high-risk breast cancer patients postmastectomy irradiation with the electron-beam-rotation technique is an effective therapy, resulting in a 5-year local failure rate of 8%. Intensified local therapy needs further investigation in subgroups of patients with additional risk factors.     

Measurement of vocal fold collision forces during phonation: methods and preliminary data.

Forces applied to vocal fold tissue as the vocal folds collide may cause tissue injury that manifests as benign organic lesions. A novel method for measuring this quantity in humans in vivo uses a low-profile force sensor that extends along the length and depth of the glottis. Sensor design facilitates its placement and stabilization so that phonation can be initiated and maintained while it is in place, with minimal interference in vocal fold vibration. In 2 individuals with 1 vibrating vocal fold and 1 nonvibrating vocal fold, peak collision force correlates more strongly with voice intensity than pitch. Vocal fold collision forces in 1 individual with 2 vibrating vocal folds are of the same order of magnitude as in previous studies. Correlations among peak collision force, voice intensity, and pitch were indeterminate in this participant because of the small number of data points. Sensor modifications are proposed so that it can be used to reliably estimate collision force in individuals with 2 vibrating vocal folds and with changing vocal tract conformations.     

Feasibility and construct validity of a novel laparoscopic skills testing and training model

The apprentice–tutor model was useful for training surgeons for many years, but the complexity of surgical technology in the 21st century, especially endoscopic surgery, has exponentially increased the demands for surgical education. Therefore, more and more people now accept that endoscopic surgery, demanding as it requires specific skills, should also be taught outside the operating theatre. Although many systems, including animal models and simulators, have been proposed, an in-house structured and validated method for testing and training laparoscopic skills is missing in gynaecology. We have developed a laparoscopic skills testing and training (LASTT) model and performed two studies evaluating its feasibility and the construct validity of three different exercises (camera navigation, camera navigation and forceps handling, and forceps handling and bi-manual coordination), specifically selected to test and train laparoscopic psychomotor skills (LPS). In the first study, ten experts and 14 novices repeated each exercise between 20 and 30 times. The results demonstrated that the model is useful for testing and training laparoscopic skills. Clear learning curves were observed for both experts and novices, with better scores for the former at the beginning and the end of the study, proving the construct validity of the model. In the second study, 42 experts and 241 novices repeated each exercise three times during skill evaluation workshops organised by the European Academy of Gynaecological Surgery. The results confirmed the construct validity of the model. In conclusion, the LASTT model seems a cost-effective tool for providing an in-house program for continuous training and evaluation of LPS in all surgical disciplines in which laparoscopic procedures are, or might be, performed.