Alternative polyadenylation (APA) regulates mRNA translation, stability, and protein localization. However, it is unclear to what extent APA regulates these processes uniquely in specific cell types. ...Using a new technique, cTag-PAPERCLIP, we discovered significant differences in APA between the principal types of mouse cerebellar neurons, the Purkinje and granule cells, as well as between proliferating and differentiated granule cells. Transcripts that differed in APA in these comparisons were enriched in key neuronal functions and many differed in coding sequence in addition to 3'UTR length. We characterize
, a transcript that shifted from expressing a short 3'UTR isoform to a longer one during granule cell differentiation. We show that
regulates granule cell precursor proliferation and that its long 3'UTR isoform is targeted by miR-124, contributing to its downregulation during development. Our findings provide insight into roles for APA in specific cell types and establish a platform for further functional studies.
For approval, a proposed generic drug product must demonstrate it is bioequivalent (BE) to the reference listed drug product. For locally acting drug products, conventional BE approaches may not be ...feasible because measurements in local tissues at the sites of action are often impractical, unethical, or cost‐prohibitive. Mechanistic modeling approaches, such as physiologically‐based pharmacokinetic (PBPK) modeling, may integrate information from drug product properties and human physiology to predict drug concentrations in these local tissues. This may allow clinical relevance determination of critical drug product attributes for BE assessment during the development of generic drug products. In this regard, the Office of Generic Drugs of the US Food and Drug Administration has recently established scientific research programs to accelerate the development and assessment of generic products by utilizing model‐integrated alternative BE approaches. This report summarizes the presentations and panel discussion from a public workshop that provided research updates and information on the current state of the use of PBPK modeling approaches to support generic product development for ophthalmic, injectable, nasal, and implant drug products.
BackgroundMusculoskeletal ultrasound is an established diagnostic technique for the assessment of tendon injuries. The purpose of the present study was to determine whether ultrasound is effective ...for evaluating peroneal tendon injuries, with surgical findings used as the standard of reference.MethodsFifty-eight patients with a suspected peroneal tendon injury were prospectively evaluated with use of dynamic ultrasound. Twenty-five patients were found to have peroneal tendon tears and were managed operatively. Five patients with normal peroneal tendons on ultrasound examination also were managed operatively for other reasons and are included in the series as the peroneal tendons were inspected at the time of the procedure. Ultrasound and surgical criteria were used to grade the peroneal tendons on a scale from grade 0 (normal tendon) to grade III (tendon rupture).ResultsOf the sixty tendons that were evaluated operatively, twenty-five were found to be torn. The sensitivity, specificity, and accuracy of ultrasonography were 100%, 85%, and 90%, respectively.ConclusionsThe use of dynamic ultrasound is effective for determining the presence or absence of a peroneal tendon tear and should be considered a first-line diagnostic tool.Level of EvidenceDiagnostic Level III. See Instructions to Authors for a complete description of levels of evidence.
An increase in the incidence of oropharyngeal squamous cell carcinoma (OPSCC) was observed in several population-based registries and has been attributed to human papillomavirus (HPV) infection. In ...the present study, we aimed to assess the contribution of HPV infection to the burden of mucosal head and neck squamous cell carcinoma (HNSCC) in Slovenia. For this purpose, data from the nationwide Cancer Registry of Slovenia for cases diagnosed between 1983 and 2009 were analyzed to determine time trends of age-adjusted incidence rates and survival in terms of annual percentage change (APC) for HNSCC in potentially HPV-related and HPV-unrelated sites. In addition, determination of p16 protein, HPV DNA and E6/E7 mRNA was performed in a cohort of OPSCC patients identified from the prospective database for the years 2007–2008. In total, 2,862 cases of HNSCC in potentially HPV-related sites and 7,006 cases in potentially HPV-unrelated sites were identified with decreased incidence observed over the time period in both groups (−0.58; 95 % CI −1.28 to −0.13 and −0.90; 95 % CI −1.23 to −0.57). Regardless of the group, incidence trends for both genders showed a significant decrease in men and increase in women. In a cohort of 99 OPSCC patients diagnosed between 2007 and 2008, 20 (20.2 %) patients had HPV positive tumors and exhibited a superior outcome compared to HPV-negative patients. In conclusion, results of the epidemiologic and histopathologic study confirmed that HPV infection had no major impact on the incidence trends in the Slovenian patients with HNSCC and, specifically, OPSCC during the studied period.
Musculoskeletal ultrasound is an established diagnostic technique for the assessment of tendon injuries. The purpose of the present study was to determine whether ultrasound is effective for ...evaluating peroneal tendon injuries, with surgical findings used as the standard of reference.
Fifty-eight patients with a suspected peroneal tendon injury were prospectively evaluated with use of dynamic ultrasound. Twenty-five patients were found to have peroneal tendon tears and were managed operatively. Five patients with normal peroneal tendons on ultrasound examination also were managed operatively for other reasons and are included in the series as the peroneal tendons were inspected at the time of the procedure. Ultrasound and surgical criteria were used to grade the peroneal tendons on a scale from grade 0 (normal tendon) to grade III (tendon rupture).
Of the sixty tendons that were evaluated operatively, twenty-five were found to be torn. The sensitivity, specificity, and accuracy of ultrasonography were 100%, 85%, and 90%, respectively.
The use of dynamic ultrasound is effective for determining the presence or absence of a peroneal tendon tear and should be considered a first-line diagnostic tool.
Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), is spread from person to person by the airborne route. It can be transmitted extensively in congregate settings, making ...investigating exposures and treating infected contacts challenging. In December 2011, a student at a Colorado high school with 1,381 students and school personnel received a diagnosis of pulmonary TB disease. One of five household contacts had TB disease, and the other four had latent M. tuberculosis infection (LTBI). Screening of 1,249 school contacts (90%) found one person with pulmonary TB disease, who was fully treated, and 162 with LTBI, of whom 159 started an LTBI treatment regimen for preventing progression to TB disease and 153 completed a regimen. Only the index patient required inpatient care for TB, and TB caused no deaths. Use of short-course treatment regimens, either 12-dose weekly isoniazid and rifapentine directly observed at school or 4 months of self-supervised rifampin daily, facilitated treatment completion. State and county incident command structures led by county TB control authorities guided a response team from multiple jurisdictions. News media reports brought public scrutiny, but meetings with the community addressed the concerns and enhanced public participation. Two contacts of the index patient outside of the school had TB disease diagnosed after the school investigation. As of July 2013, no additional TB disease associated with in-school exposure had been found. An emergency plan for focusing widespread resources, an integral public communications strategy, and new, efficient interventions should be considered in other large TB contact investigations.
Antituberculosis Drugs and Hepatotoxicity Saukkonen, Jussi J.; Cohn, David L.; Jasmer, Robert M. ...
American journal of respiratory and critical care medicine,
04/2007, Letnik:
175, Številka:
8
Journal Article
To make robotics feasible for use in small and medium enterprises (SMEs) several issues have to be addressed. The most obvious is the ability to produce small batches of products with minimal ...changeover cost and time. In this paper an innovative flexible fixture based on a Gough-Stewart platform called the hexapod is proposed. The fixture is designed to be suitable for a whole family of automotive lights. The main characteristics of the hexapod is its passivity, i.e. the reconfiguration can be performed manually or by using an external mechanism e.g. a robot. Once a desirable configuration is reached a set of hydromechanical brakes is used to hold the mechanism in the desired pose. To show the effectiveness of the hexapods a set of automotive lights assembly in dedicated robot cell experiments were performed. Additionally, positioning repeatability and the locked system stiffness were measured. Finally, a robot cell for a complete light assembly has been implemented together with robot assisted fixture reconfiguration between different light models.
PDF
