Respiratory assistance devices bypass essential host defenses and allow these pathogens direct access to the lower respiratory tract and hinder these defense systems to effectively clear respiratory pathogens (1). Mechanical ventilation in the presence of dental plaque with respiratory pathogens has the potential to lead to ventilator-associated pneumonia (VAP). Ventilator-associated pneumonia is the leading cause of morbidity and mortality in intensive care units. VAP influences increasing need for medical treatment and hospital length of stay (LOS) (2-4). Lower respiratory tract infections (LRTI) have been found to be the most expensive site per infection with 13% of all infections accounting for 29% of the total recorded cost (5). The purpose of this systematic review is to perform a comprehensive literature search to identify published randomized clinical trials relating to the efficacy of chlorhexidine gluconate (CHX) oral rinse in preventing VAP. CHX has been identified as the "gold standard" to reduce the number of microorganisms. This review also addresses the importance of oral health and the increased risk of respiratory infections from colonization by harmful pathogens within the oral mucosa. Clinical trials relating to the hypothesis in question were evaluated using Consolidated Standards of Reporting Trials (CONSORT) checklist for validity. Quality and strength of each randomized clinical trial were evaluated based on the requirements of the Agency for Healthcare Research and Quality (AHRQ). Nine bibliographic databases, from 1965-2012 were used to conduct the literature inquiry. Ten studies included populations greater than or equal to 18 years of age and admitted to the intensive care unit receiving mechanical ventilation. The patients were, ventilated due to either trauma, undergoing elective cardiothoracic surgery, or from some other form of surgery, at risk for VAP. In one study, CHX oral rinse decreased microbial colonization of the respiratory tract and hospital-acquired pneumonia (HAP) in patients who underwent open-heart surgery and were intubated less than 24 hours. Yet the difference was not significant in patients intubated more than 24 hours who had a higher amount of bacterial colonization (6). Modulation of oropharyngeal colonization by the use of oral chlorhexidine has reduced the number of ICU-acquired HAP in selected patient populations such as those undergoing coronary bypass grafting, but its routine use is not recommended until more data become available (7). Findings from several studies suggest a significant decrease in the incidence of total nosocomial respiratory infections and systemic antibiotic use in patients who underwent open heart and used a CHX oral rinse as compared with ventilator patients who did not use the rinse; there was also a 65% decrease (13% vs. 4%) in the overall nosocomial infection rate in the chlorhexidine group (7,8,9). Using 2% chlorhexidine solution presents the strongest evidence for decreasing VAP (10,11). From Scannapieco and colleagues' study we can conclude that twice daily is not necessarily better than once daily, but maybe a four times daily regimen with 2% instead of 0.12% CHX does make a difference in reducing the incidence of VAP (12).

According to the Centers for Disease Control, cancer is one of the leading causes of death in the United States. Characterized as a disease that develops as a result of an unstable genome, cancer is known to arise from numerous spontaneous mutations in the DNA of cells. Recent evidence shows that cancer cells within tumors are not self-reliant; rather, they progress along with other cells in their surrounding environment. Tumor cells recruit neighboring cells that, like the cancer cells, also become deregulated, forming the tumor stroma that aids in tumor progression. Within the stroma, cancer-associated fibroblasts (CAFs) play a vital role in the progression of cancer. Recent studies have found an important link between increased matrix stiffness surrounding the tumor and the invasion of the tumor. Thus, it is proposed that as the matrix stiffens, the tumor takes on more aggressive phenotypes. The transcriptional regulators YAP and TAZ (YAP/TAZ), key effectors of the Hippo pathway, are known to respond and influence matrix stiffening. In stiff matrix environments YAP/TAZ accumulate in the nucleus, and can drive transcriptional events. CAF's from late stage breast cancers have been found to exhibit increased YAP expression and increased ability to remodel and stiffen the extracellular matrix. Whether YAP or TAZ in these CAFs influences the metastatic properties of tumor cells is unclear. The present study aims to establish a link between YAP/TAZ activity in CAFs and cancer migration and invasion. We hypothesized that high nuclear activity of YAP/TAZ in fibroblasts would lead to non-autonomous signals that increase epithelial migration, and conversely that signals originating from epithelial cells affect YAP regulation in fibroblasts. We obtained CAFs from oral squamous cell carcinomas (OSCC) at various stages, and interestingly found that when CAFs obtained from stage III and stage IV tumors were co-cultured with OSCC cells they had the ability to cause OSCC cell migration. This CAF-induced migration was dependent on YAP/TAZ in the CAFs, as YAP/TAZ knockdown repressed this crosstalk. To gain insight into the mechanisms driving this process, transwell migration assays were conducted using NIH-3T3 fibroblasts engineered to overexpress YAP, or mutants of YAP, in doxycycline-inducible manner. We found that expression of YAP in NIH-3T3 cells, particularly a nuclear-localized YAP mutant, promoted the ability for OSCC cells to migrate in co-culture experiments. Media conditioned from these cells was sufficient to recapitulate this phenotype, suggesting that secreted factors from these fibroblasts may act as a signal that promotes migration. This activity of YAP was dependent on the ability for YAP to bind to the TEAD transcription factors, a major mediator of YAP transcriptional activity. Together these results indicate that nuclear YAP activity in fibroblasts can modulate the migration of neighboring cancer cells, suggesting that YAP plays a key role in stroma-cancer crosstalk during cancer progression.

Title: Whiplash syndrome-evaluation of the therapy effect through various physiotherapeutic approaches Objectives: The aim of this diploma thesis is to find out which treatment method is the best suited for the reduction of the convalescence period in an acute whiplash syndrome and how the treatment can the most effectively affect chronic whiplash syndrome. This thesis also summarizes the most recent knowledge regarding this issue. Methods: The diploma thesis is processed in the form of a literary review, it has an analytic descriptive character. The thesis is divided into two parts, the first part deals with the theoretical point of view and the second part deals with the thesis methodology together with results. The theoretical part is dedicated to the problematic itself and physiotherapeutic methods used in the treatment of whiplash syndrome in the form of passive and active approaches. The second part describes a criteria methodology for studies which are included in the thesis. Conclusions of the studies are discussed together with their effects. Results: A total of 23 studies have been selected for this thesis. The recommended threatment for the acute whiplash syndrome is a form of the active approach. From the physiotherapeutical methods perspective - The McKenzie Method and therapeutic...

Povrch buněk je bohatě pokryt oligosacharidy, které jsou v plazmalemě ukotvené pomocí proteinů a lipidů. Oligosacharidy zprostředkují vzájemnou vazbu mezi buňkami nebo vazbu buněk k složkám extracelulární matrix. Galektiny jsou živočišné lektinů které mají afinitu k oligosacharidům obsahujícím β-galaktózu. Jsou to multifaktoriální proteiny, které se účastňují řady reakcí v organizmu, jako jsou mezibuněčné interakce, interakce buněk s mezibuněčnou hmotou, proliferace i apoptóza a sestřih pre-mRNA. Proteiny po translaci procházejí různými strukturálnimy úpravami, které mají vliv na jejich funkci. Galektin-3 je možný prognostický ukazatel u nádorů vycházejících z vrstevnatých dlaždicových epitelů je fosforylován na N-konci. Prokázali jsme, že tato posttranslační modifikace nemá vliv na jeho vazebnou reaktivitu. Jiný endogenní lektin, galektin-1 je charakteristickou molekulou nádorového stromatu a granulační tkáně hojícího se poranění. Zjistili jsme, že galektin-1 indukuje na TGF-β nezávislý in vitro přechod normálních fibroblastů na myofibroblasty včetně produkce sítě extracelulární matrix bohaté fibronektinem a galektinem-1. Tento poznatek je využitelný v terapii hojení ran a v tkáňovém inženýrství. Dnes je jasné, že nádorové stroma ovlivňuje i biologické vlastnosti nádoru (lokální agresivita,...

Esta pesquisa apresenta um estudo de caso cujo objetivo é descrever os saberes produzidos no processo de auto-organização de grupos de mulheres da Rede Xique-Xique de Comercialização Solidária, nos municípios de Mossoró, Upanema, Governador Dix-Sept Rosado, Baraúna, Grossos, Tibau e Apodi, no estado do Rio Grande do Norte. Trata-se de uma análise sócio histórica e econômica das categorias discursivas de termos como \'mulheres\', \'trabalho, \'família\' e \'história\', assim como da capacidade de transformação social que estes saberes apresentam. A pesquisa de campo foi guiada essencialmente pelo método da observação participante, com procedimentos aplicados pelo método biográfico, mais especificamente pela história de vida. Sobre a coleta dos dados, foram realizadas 11 entrevistas individuais com as mulheres dos grupos auto-organizados; uma entrevista com a coordenadora do CF8 e uma entrevista coletiva, na qual estavam presentes mulheres participantes de seis grupos da região. Além das entrevistas, foram realizadas visitas aos grupos produtivos, participação em reuniões e seminários promovidos pela Rede Xique-Xique ou instituições parceiras. Para analisar todos os dados registrados, as entrevistas foram transcritas e categorizadas. A análise foi realizada a partir do objetivo apresentado e da referenciação das categorias supracitadas, com o auxílio do Software NVivo10. Nesse sentido, foi possível descrever e apreender que o processo de auto-organização dessas mulheres permite a construção de um ato comunicativo entre estas, que por sua vez possibilita a produção de saberes. Esse ato comunicativo torna-se emancipatório na medida em que se caracteriza como uma prática constante de autorreflexão a respeito dos efeitos da organização produtiva autogerida e contribui assim com a transformação de vida dessas mulheres. Sobre a estrutura textual do presente trabalho, a dissertação está dividida em três capítulos. O primeiro capítulo trata da descrição dos aspectos sócio históricos do estado do Rio Grande do Norte e sua relação constitutiva com a ação atual da Rede Xique-Xique. O capítulo dois descreve a estrutura de princípios ou pilares que sustentam a prática da Rede: agroecologia, economia solidária e feminismo. No capítulo três, com base nas categorias discursivas propostas, analiso as histórias de vidas das mulheres entrevistadas durante o trabalho de campo. Por fim, as considerações finais são apresentadas. / This research presents a case study which aims to describe the knowledge produced in the process of self-organizing groups of women Xique-Xique Network Marketing Partnership located in Mossoró, Upanema, Governador Dix-Sept Rosado, Baraúna, Grossos, Tibau e Apodi in the state of Rio Grande do Norte. It is a historical and socioeconomic analysis of the discursive categories of terms such as \'women\', \'work\', \'family\' and \'history\', as well as the ability to social transformation this knowledge presents. The field research was guided essentially by the method of participant observation with procedures applied by the biographical method, more specifically the history of life. On data collection, 11 individual interviews with women of self-organized groups were conducted; interview with the coordinator of the CF8 and a press conference, in which women from six groups in the region were present. Besides the interviews, visits to productive groups, participation in meetings and seminars sponsored by Xique-Xique Network or partner institutions were conducted. To analyze all the recorded data, the interviews were transcribed and using NVivo10, categorized. The analysis was based on the discursive and historical referencing of the above categories. Thus, it was possible to describe and understand that the process of self-organization of these women allows the construction of a communicative act between them, which in turn enables the production of knowledge. This communicative act becomes emancipatory in that it is characterized as a constant practice of self-reflection about the effects of self-managed productive organization and thus contributes to the transformation of these women\'s lives. On the textual structure of the present paper, it is divided into three chapters. The first chapter presents the description of the historical and social aspects of the state of Rio Grande do Norte and its constitutive relationship with the Xique-Xique Network current action. Chapter two describes the structure of principles that support the practice of the group: agroecology, economic solidarity and feminism. In chapter three, based on the discursive categories proposed, I analyze the life histories of the women interviewed during the field work. Finally, the concluding remarks are presented.

The mechanism by which prostate cancer progresses from androgen dependence (AD) to androgen independence/castration resistance (AI/CR) is currently a major focus of prostate cancer-related research. Prostate cancers that progress to a state of AI/CR are typically resistant to most standard types of treatments. Due to its primary role in driving normal prostate cell growth and proliferation, the androgen receptor (AR) is believed to play a key role in progression. Coregulators, or any proteins which may either enhance or abrogate AR activity, are considered to be one of the potential mechanisms by which AR function may become impaired. Cyclin G-associated kinase (GAK) was initially identified as a potential coregulator of AR in a Tup 1 repressed transactivation system. A LNCaP cDNA library was screened for proteins which interacted with the NH2-terminus of AR. GAK was isolated from three independent library clones using two different AR baits (AR 1-549 and AR 1-646). This interaction was confirmed via GST pulldown and coimmunoprecipitation experiments, and preliminary luciferase assays suggested that GAK activates AR in a hormone dependent manner. In this study, my objectives were to validate GAK’s role as a coregulator of AR and to determine if overexpressing GAK affects progression to AI. In vitro luciferase assays whereby GAK was either overexpressed or knocked down in both LNCaP and PC3 cells did not significantly affect AR activity. Xenograft experiments utilizing a doxycycline (DOX) inducible lentiviral LNCaP-GAK overexpressing stable cell line demonstrated that while GAK may not play a significant role in modulating AR activity, it may adopt a more subtle role enhancing tumour take and tumour volume growth rate in vivo. While these results could not confirm GAK to be a direct coregulator of AR, it is entirely possible that GAK may influence prostate cancer progression, albeit indirectly. Recent publications report a growing amount of evidence suggesting GAK’s involvement in the critical cellular process of clathrin coated vesicle endocytosis, the dysregulation of which could potentially indirectly affect AR regulated genes. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Spinal muscular atrophy is caused by mutation of the SMN1 gene resulting in the selective loss of spinal cord motor neurons. HuD has been shown to interact with SMN and to localize to RNA granules along axons. In conditions where SMN is decreased, like in SMA, HuD’s localization to RNA granules affected. Overexpression of HuD in an SMA cell culture model was shown to rescue SMA-like axonal defects. Here, existence of a signaling pathway downstream of PKC leading to the activation of HuD was investigated in MN-1 cells. Stimulation of this pathway using a pharmacological agonist of PKC increased HuD levels and enhanced its binding to GAP-43 and Tau mRNAs. An scAAV9 viral expression system to overexpress HuD in vivo was established, laying the foundation for the next phase of the study. Overall, modulating HuD expression and activity would be beneficial and could constitute an attractive therapeutic approach for SMA.

Abstract The function of the nervous system is based on the targeted transmission of electrical impulses assuring the coordinated function of tissues and organs. Myelination of the neuronal axons allows the fast saltatory conduction by producing repetitive sites where sodium channels cluster on the axolemma. In the peripheral nervous system (PNS), myelin is formed by differentiation of the Schwann cell plasma membrane. The cells form myelin by first wrapping consecutive layers of the plasma membrane around the axons and then excluding almost all of the cytoplasm from the structure, forming compacted and non-compacted membrane compartments. The myelin-associated glycoprotein (MAG) is located in all of the non-compacted regions of the PNS myelin sheath. Its two isoforms, L-MAG and S-MAG, differ only by the carboxy-terminal tails of their respective cytoplasmic domains. Both of the MAG isoforms are found in PNS myelin. They are differentially expressed during development and, until now, it has been thought that L-MAG is not present in the mature PNS myelin sheaths of murines. This study shows that both MAG isoforms can be found in different non-compacted membrane compartments in the mature PNS myelin sheaths in dorsal root ganglia (DRG)/Schwann cell cocultures. Early myelin development and myelin maturation were analyzed by means of a study of the expression of two early myelin markers, MAG and galactosyl cerebrosides (Gal-CB), believed to play roles in both myelin formation and maintenance. In order to allow the exploitation of the full potential of the DRG/Schwann cell coculture model through the use of mouse mutants, a coculture method was developed in which mouse DRGs and Schwann cells are able, for the first time, to produce significant amounts of myelin. To further explore the role of MAG in myelin maintenance and stability, the stability of purified MAG was studied through extensive degradation experiments.

Class of 2014 Abstract / Specific Aims: Clostridium difficile associated diarrhea (CDAD) frequently occurs in patients exposed to broad-spectrum antibiotics which can result in a life threatening illness. The role of probiotics in the prevention of CDAD is not well established and many medical centers across the United States are opting to remove probiotics from common CDAD prophylaxis. We aim to evaluate the efficacy of lactobacillus probiotics during the use of broad-spectrum antibiotic therapy in the acute care setting for the prophylaxis of CDAD at Kindred Hospital. Methods: We performed a single center, retrospective data analysis efficacy trial of inpatients receiving beta-lactam, fluoroquinolone or clindamycin antibiotics from the Kindred Hospital database. Two study groups will be compared: patients who received lactobacillus probiotic therapy based on protocol since May 2011 and patients who did not receive probiotic therapy. The presence or absence of CDAD will be used to evaluate probiotic efficacy. Main Results: Of the ### patients screened, ## were assigned to the treatment group and ## were assigned to the non-treatment group, a total of ## patients were analyzed for the primary endpoint. CDAD occurred in ## patients (xx%) receiving probiotic therapy while CDAD occurred in ## patients (xx%) not receiving probiotic therapy (relative risk [RR]: xx.x; p=0.xxx). Conclusion: [Anticipated] We identified no statistically significant evidence that the use of lactobacillus was effective in the prevention of CDAD. Further knowledge of the pathophysiology of CDAD and proper antibiotic use is needed for future studies.

Class of 2012 Abstract / Specific Aims: To identify the number of Clostridium difficile-associated disease (CDAD) cases in hospitalized oncology patients between 2005 and 2009. To identify the occurrence of mortality, comorbidities, and the amount of hospital charges in this patient population. Predictive variables for mortality and hospital charges were also identified. Methods: Data retrieved from the Nationwide Inpatient Sample were used to retrospectively identify the number of CDAD cases in hospitalized oncology patients, the occurrence of mortality and comorbidities, and the amount of hospital charges incurred between 2005 and 2009. Multivariate logistic regression was used to identify predictors of mortality and a lognormal regression was used to identify predictors of inpatient charges. Main Results: From 2005 to 2009, we identified 210,449 cases of CDAD in hospitalized adult patients with cancer. Total inpatient charges for all CDAD cases over the five-year period exceeded 18 billion dollars. The percentage of cases that resulted in death was 13%. Variables that were found to be predictors of mortality included increased age (OR 1.019, CI 1.018-1.020), chronic pulmonary disease (OR 1.231, CI 1.191-1.272), coagulopathy (OR 2.085, CI 2.011-2.162), liver disease (OR 1.159, CI 1.072-1.253), fluid and electrolyte disorders (OR 1.561, CI 1.518-1.605), renal failure (OR 1.405, CI 1.349-1.462), and weight loss (OR 1.408, CI 1.362-1.456)(all p<.001). Conclusions: This study identified a large number of CDAD cases in hospitalized adult cancer patients. Several factors that appeared to be predictive of mortality and inpatient charges were also identified, which may be useful knowledge for clinicians who need to identify at-risk patients.