Clinical relevance of circulating tumour cells in the bone marrow of patients with SCCHN

Background: Clinical outcome of patients with head and neck squamous cell carcinoma (SCCHN) depends on several risk factors like the presence of locoregional lymph node or distant metastases, stage, localisation and histologic differentiation of the tumour. Circulating tumour cells in the bone marrow indicate a poor prognosis for patients with various kinds of malignoma. The present study examines the clinical relevance of occult tumour cells in patients suffering from SCCHN. Patients and Methods: Bone marrow aspirates of 176 patients suffering from SCCHN were obtained prior to surgery and stained for the presence of disseminated tumour cells. Antibodies for cytokeratin 19 were used for immunohistochemical detection with APAAP on cytospin slides. Within a clinical follow-up protocol over a period of 60 months, the prognostic relevance of several clinicopathological parameters and occult tumour cells was evaluated. Results: Single CK19-expressing tumour cells could be detected in the bone marrow of 30.7% of the patients. There is a significant correlation between occult tumour cells in the bone marrow and relapse. Uni- and multivariate analysis of all clinical data showed the metastases in the locoregional lymph system and detection of disseminated tumour cells in the bone marrow to be statistically highly significant for clinical prognosis. Conclusion: The detection of minimal residual disease underlines the understanding of SCCHN as a systemic disease. Further examination of such cells will lead to a better understanding of the tumour biology, as well as to improvement of diagnostic and therapeutic strategies

Robustness of H2 and H∞ Design Techniques in the Design of a Guided Missile Controller

This work follows Capt. R.L. Riddle\u27s 1989 thesis (ADA216147) which compared conventional, H2 and H∞ controlled guided missiles in simulated flyouts against an airborne target. The simulation results did not clearly demonstrate the H2 and H∞ controller advantages. In this study the missile model and simulation were refined. In addition to simulation runs, performance, noise attenuation, and μ (structural singular value) robustness analyses were conducted. Results showed areas where improvement was needed in the H2 and H∞ controllers used in the study. An H2 and H∞ controller redesign is recommended using the μ synthesis design technique. Additional simulation runs are also recommended to examine whether the improved controllers reduce miss distances

As relações de ensino e aprendizagem no processo de formação humana na Escola Municipal Professor Jurandir Liberino de Mesquita - Sinop-MT

Este artigo expõe uma análise sobre as relações humanas que perpassam o processo de ensino e aprendizagem na Escola Municipal de Educação Básica Professor Jurandir Liberino de Mesquita, localizada na cidade de Sinop, Mato Grosso, e que atende à modalidade de Educação de Jovens e Adultos no período noturno. Para a coleta de dados, foram utilizados o procedimento de observação e entrevistas com perguntas do tipo semiestruturadas. A análise dos dados obtidos no campo de pesquisa revela que as práticas de ensino e aprendizagem, em função da divisão social do trabalho capitalista e das determinações de mercado, são condicionadas por uma escola utilitarista. Palavras-chave: Ensino e aprendizagem; educação de jovens e adultos; escola utilitarista; Paulo Freire

The Importance of Bone Mineral Density in Hip Arthroplasty: Results of a Survey Asking Orthopaedic Surgeons about Their Opinions and Attitudes Concerning Osteoporosis and Hip Arthroplasty

Objective. In patients scheduled to undergo total joint arthroplasty of the hip, the bone quality around the joint affects the safety of prosthetic implantation. Bone strength is clinically assessed by measuring bone mineral density (BMD); therefore we asked if BMD is important to orthopaedic surgeons performing hip arthroplasty. Methods. In a 14-question survey, we asked about treatment patterns with respect to BMD, osteoporosis work-up, and treatment for patients with low BMD scheduled to undergo hip arthroplasty. Results. 72% of all asked orthopaedics reported to use cementless implants as a standard in hip arthroplasty. Over 60% reported that low BMD is a reason to reconsider operation strategies, but only 4% performed BMD measurement preoperatively. 26% would change their treatment strategy in case of a BMD (T-Score) between −1.5 and −2 and 40% in case of a T-score between −2 and −2.5, and 29% would change their intraoperative strategy if a T-score smaller than −2.5 was measured. Conclusion. The majority of orthopaedic surgeons who responded to the survey reported that they do not perform routine measurement of BMD before arthroplasty. However, most surgeons commented that low bone mineral density will influence their surgical plan and the implant design

Widespread expression of erythropoietin receptor in brain and its induction by injury

Erythropoietin (EPO) exerts potent neuroprotective, neuroregenerative and procognitive functions. However, unequivocal demonstration of erythropoietin receptor (EPOR) expression in brain cells has remained difficult since previously available anti-EPOR antibodies (EPOR-AB) were unspecific. We report here a new, highly specific, polyclonal rabbit EPOR-AB directed against different epitopes in the cytoplasmic tail of human and murine EPOR and its characterization by mass spectrometric analysis of immuno-precipitated endogenous EPOR, Western blotting, immunostaining and flow cytometry. Among others, we applied genetic strategies including overexpression, Lentivirus-mediated conditional knockout of EpoR and tagged proteins, both on cultured cells and tissue sections, as well as intracortical implantation of EPOR-transduced cells to verify specificity. We show examples of EPOR expression in neurons, oligodendroglia, astrocytes and microglia. Employing this new EPOR-AB with double-labeling strategies, we demonstrate membrane expression of EPOR as well as its localization in intracellular compartments such as the Golgi apparatus. Moreover, we show injury-induced expression of EPOR. In mice, a stereotactically applied stab wound to the motor cortex leads to distinct EpoR expression by reactive GFAP-expressing cells in the lesion vicinity. In a patient suffering from epilepsy, neurons and oligodendrocytes of the hippocampus strongly express EPOR. To conclude, this new analytical tool will allow neuroscientists to pinpoint EPOR expression in cells of the nervous system and to better understand its role in healthy conditions, including brain development, as well as under pathological circumstances, such as upregulation upon distress and injury

Zur Wirkung von Methylnaltrexon und Naloxon auf eine experimentelle Loperamid-induzierte Obstipation bei gesunden Probanden

Die bisherige pharmakologische Therapie von Opioid-induzierter Obstipation in der Schmerztherapie ist limitiert. Opioidrezeptorantagonisten könnten hier Abhilfe schaffen, in dem sie kausal in die Problematik eingreifen und somit zu einer besseren Lebensqualität bei vielen schmerzgeplagten Patienten führen. In klinischen Studien konnte eine Reduktion von intestinalen Transitzeiten nach subkutaner Methylnaltrexon-Gabe (MNTX) beobachtet werden. Auch orale Applikationsformen sowohl von MNTX als auch von Naloxon (NLX) stellten sich teilweise als wirksam dar. Daher war es das Ziel dieser Dissertation die Wirksamkeit hinsichtlich der Prävention einer Opioid-induzierten Obstipation von subkutaner und oraler Applikation von MNTX nach einmaliger Gabe miteinander zu vergleichen, sowie nach wiederholten Gaben die daraus resultierende effektivste Darreichungsform dem retardiert-freisetzenden NLX gegenüberzustellen. Dazu führten wir zwei kontrollierte, randomisierte, doppelblinde klinische Studien in gesunden Probanden durch. Die Obstipation wurde mit Loperamid (LOP) induziert. Die orozökale Transitzeit (OCT) und die Kolon-Transitzeit (CTT) wurden mit Hilfe von Sulfasalazin/ Sulfapyridin und röntgendichten Markern gemessen. Durch die LC-MS/MS-Methode konnten die Wirkstoffe bzw. deren Metaboliten in den Körperflüssigkeiten ermittelt werden und nachfolgend pharmakokinetische Parameter erhoben werden. In der single-dose-Studie konnten wir zeigen, dass retardiert freisetzendes MNTX (MNTX-ER) signifikant die LOP-induzierte Verzögerung im Intestinaltrakt antagonisiert. Subkutanes Methylnaltrexon (MNTX-SC) und schnell freisetzendes Methylnaltrexon (MNTX-IR) hatten keinen signifikanten Einfluss auf die OCT, CTT oder Gesamt-Darm-Transitzeit (WGT). (Publikation 1) Nach der mehrmaligen Applikation von MNTX-ER bzw. NLX-ER in der multiple-dose-Studie Studie konnte NLX-ER eine signifikante Reduktion der durch LOP verlängerten WGT herbeiführen, während MNTX-ER keinen nennenswerten Effekt erzielte. LOP verursachte nur kurzzeitig eine Erhöhung der Darmtransitzeiten. Es erfolgte nach der zweiten Applikation ein Gewöhnungseffekt. (Publikation 2) Aus diesem Grund erscheint LOP nicht geeignet eine anhaltende Obstipation zu induzieren. Die Toleranzentwicklung und auch die Entstehung der Obstipation bei Opioidtherapie lassen noch viele Fragen offen. Weitere Studien sowohl auf zellulärer Ebene als auch in der klinischen Anwendung werden folgen müssen um in diese komplexe Thematik mehr Licht zu bringen.Opioids are potent analgetics. However, serious side effects like constipation often limit the use of opioids. One approach is the use of opioid receptor antagonists like methylnaltrexone (MNTX) and naloxone (NLX). MNTX is a quaternary ammonium compound which does not cross the blood–brain barrier and therefore does not antagonize opioid-induced analgesia in the central nervous system. NLX is a central opioid receptor antagonist which exerts due to a high hepatic first-pass effect only a low bioavailability after oral administration. Prior clinical studies reported that the application of subcutaneous methylnaltrexone (MNTX-SC) results in a reduction of intestinal transit time. Indeed, an oral formulation of MNTX as well as NLX seems to be effective. Limitations of these former studies were firstly, the use of lactulose which exerts an own laxative effect and secondly, the missing determination of the colon transit time (CTT) which might be affected predominantly by the constipation. Therefore, we initiated a controlled, randomized, double-blind clinical study in 15 healthy subjects. We measured the pharmacokinetics of MNTX after single-dose oral administration of immediate-release (MNTX-IR) and an extended-release (MNTX-ER) dosage form in comparison with MNTX-SC and evaluated the antagonistic effects on the loperamide-induced delay of orocecal transit time (OCT) and the CTT which were measured using the sulfasalazine/sulfapyridine method and a radio-opaque marker procedure, respectively. In 12 of 15 subjects loperamide induced a prolongation of the whole gut transit time. In these subjects MNTX-ER significantly antagonized the loperamide effects. MNTX-ER reduced the OCT and CTT significantly, baseline levels could not be reached. MNTX-SC and MNTX-IR were without significant effects on the OCT and CTT. MNTX-ER was nearly not absorbed in the intestine. Probably, the antagonism of MNTX-ER results from local effects on the µ-opioid receptors in the colon. In a second controlled, randomized, double-blind multiple-dose clinical study in 16 healthy subjects we compared the efficacy of MNTX-ER with NLX in healthy subjects. Only NLX reduced the whole gut transit time while MNTX-ER was without significant effect on the intestinal transit time. However, the efficacy of MNTX as well as NLX might be underestimated because of a development of tolerance of loperamide after second application. Thus, the peripheral opioid receptor agonist loperamide is not an appropriate substance to induce constipation

The Influence of Coordinative Skills on the Oral Health of Children and Adolescents in Permanent Dentition

Removing dental plaque by using a toothbrush is the most important measure for oral hygiene. The aim of the present study was to estimate the impact of the coordination skills of children and adolescents on their oral health (plaque level, DMF/T: decayed, missing, filled teeth). Within a prospective cohort study, 996 children (10 to 18 years) were examined. The results of three coordination tests from the Motorik Modul (MoMo) were included to evaluate the coordination skills. Other parameters taken into account were age, sex, orthodontic treatment and socioeconomic status (SES). Univariate and various multivariate analyses were performed to evaluate relationships. Better results in precision coordination tests were significantly related to a better oral hygiene (backward balancing: logistic regression OR 0.86, 95%CI: 0.73–0.99, p = 0.051, proportional odds model OR 0.86, 95%CI: 0.75–0.99, p = 0.037; one-leg-stand: logistic regression OR 0.78, 95%CI: 0.63–0.96, p = 0.018, proportional odds model OR 0.77, 95%CI: 0.64–0.92, p = 0.003). Higher scores on one-leg-stand were significantly related to a lower caries prevalence (logistic regression OR 0.81, 95%CI: 0.66–0.99, p = 0.037; Poisson regression exp(ß) 0.82, 95%CI: 0.74–0.91, p < 0.001). Coordination test under a time constraint (jumping side-to-side) showed no significant relation. Oral hygiene was poorer in younger children, boys and low SES. Caries prevalence increased with low SES and increasing age. The present results suggest that oral health is influenced by coordinative skills