In vitro synergy and enhanced murine brain penetration of saquinavir coadministered with mefloquine.

Highly active antiretroviral therapy has substantially improved prognosis in human immunodeficiency virus (HIV). However, the integration of proviral DNA, development of viral resistance, and lack of permeability of drugs into sanctuary sites (e.g., brain and lymphocyte) are major limitations to current regimens. Previous studies have indicated that the antimalarial drug chloroquine (CQ) has antiviral efficacy and a synergism with HIV protease inhibitors. We have screened a panel of antimalarial compounds for activity against HIV-1 in vitro. A limited efficacy was observed for CQ, mefloquine (MQ), and mepacrine (MC). However, marked synergy was observed between MQ and saquinavir (SQV), but not CQ in U937 cells. Furthermore, enhancement of the antiviral activity of SQV and four other protease inhibitors (PIs) by MQ was observed in MT4 cells, indicating a class specific rather than a drug-specific phenomenon. We demonstrate that these observations are a result of inhibition of multiple drug efflux proteins by MQ and that MQ also displaces SQV from orosomucoid in vitro. Finally, coadministration of MQ and SQV in CD-1 mice dramatically altered the tissue distribution of SQV, resulting in a >3-fold and >2-fold increase in the tissue/blood ratio for brain and testis, respectively. This pharmacological enhancement of in vitro antiviral activity of PIs by MQ now warrants further examination in vivo

Endoscopic laser-ablation for the treatment of orthotopic and ectopic ureteroceles in dogs: 13 cases (2008-2017).

BACKGROUND: Ureteroceles are a rare condition in dogs in which conventional treatments can result in substantial morbidity. Cystoscopic and fluoroscopic-guided laser ablation (CLA) of ureteroceles can successfully relieve obstruction. OBJECTIVES: To describe the technique and outcomes of attempting CLA for treatment of ureteroceles in dogs. ANIMALS: Thirteen client-owned dogs that underwent CLA for treatment of ureteroceles. METHODS: Retrospective multicentered study. Medical records were reviewed in all dogs that underwent CLA for ureterocele(s). A laser was used to extend the opening of the ureteral orifice (UO) unless surgical conversion was necessary. Data collected included signalment, clinicopathologic data, imaging, procedural findings, complications, and short- and long-term outcome. RESULTS: Thirteen dogs with 13 ureteroceles associated with 14 UOs resulting in ureteral obstruction were included. One ureterocele extended bilaterally. Treatment was initiated via retrograde cystoscopy (7 females), percutaneous perineal urethrocystoscopy (4 males), or percutaneous antegrade cystoscopy (2 males). Surgical conversion was necessary in 2 males. Ten of 14 (71%) UOs associated with the ureteroceles were ectopic. Thirteen of 14 had stenotic or imperforate UOs. No postoperative complications were noted. Preoperative incontinence or pollakiuria was present in 9 of 13 and 3 of 13 dogs and resolved in 8 of 9 and 3 of 3 dogs, respectively. Follow-up imaging showed resolution of all ureteroceles and improved ureteral/renal pelvic dilatation. Median follow-up time was 27 months (range, 3-96 months). CONCLUSIONS AND CLINICAL IMPORTANCE: Cystoscopic-guided laser ablation was effective for the treatment of ureteroceles(s) in 11 of 13 dogs

A cross sectional study of water quality from dental unit water lines in dental practices in the West of Scotland

OBJECTIVE: To determine the microbiological quality of water from dental units in a general practice setting and current practice for disinfection of units. DESIGN: A cross-sectional study of the water quality from 40 dental units in 39 general practices and a questionnaire of the disinfection protocols used in those practices. SETTING: NHS practices in primarydental care. SUBJECTS: Thirty-nine general practices from the West of Scotland. METHODS: Water samples were collected on two separate occasions from dental units and analysed for microbiological quality by the total viable count (TVC) method. Water specimens were collected from the triple syringe, high speed outlet, cup filler and surgery tap. Each participating practitioner was asked to complete a questionnaire. Results Microbial contamination was highest from the high speed outlet followed by the triple syringe and cup filler. On average, the TVC counts from the high speed water lines at 37 degrees C and for the high speed lines, triple syringe and cup filler at 22 degrees C were significantly higher than that from the control tap water specimens. The study included units from 11 different manufacturers with ages ranging from under one year to over eight years. The age of the dental unit analysed did not appear to influence the level of microbial contamination. Five of the practices surveyed used disinfectants to clean the dental units but these had no significant effect on the microbiological quality of the water. The majority of dental units (25 out of 40) were never flushed with water between patients. A number of different non-sterile irrigants were used for surgical procedures. CONCLUSION: The microbiological quality of water from dental units in general dental practice is poor compared with that from drinking water sources. Suitable sterile irrigants should be used for surgical procedures in dental practice. Further work is required for pragmatic decontamination regimens of dental unit water lines in a general dental practice setting

Using the Gene Ontology to Annotate Key Players in Parkinson's Disease

The Gene Ontology (GO) is widely recognised as the gold standard bioinformatics resource for summarizing functional knowledge of gene products in a consistent and computable, information-rich language. GO describes cellular and organismal processes across all species, yet until now there has been a considerable gene annotation deficit within the neurological and immunological domains, both of which are relevant to Parkinson's disease. Here we introduce the Parkinson's disease GO Annotation Project, funded by Parkinson's UK and supported by the GO Consortium, which is addressing this deficit by providing GO annotation to Parkinson's-relevant human gene products, principally through expert literature curation. We discuss the steps taken to prioritise proteins, publications and cellular processes for annotation, examples of how GO annotations capture Parkinson's-relevant information, and the advantages that a topic-focused annotation approach offers to users. Building on the existing GO resource, this project collates a vast amount of Parkinson's-relevant literature into a set of high-quality annotations to be utilized by the research community

Evaluating Maintainability Prejudices with a Large-Scale Study of Open-Source Projects

Exaggeration or context changes can render maintainability experience into prejudice. For example, JavaScript is often seen as least elegant language and hence of lowest maintainability. Such prejudice should not guide decisions without prior empirical validation. We formulated 10 hypotheses about maintainability based on prejudices and test them in a large set of open-source projects (6,897 GitHub repositories, 402 million lines, 5 programming languages). We operationalize maintainability with five static analysis metrics. We found that JavaScript code is not worse than other code, Java code shows higher maintainability than C# code and C code has longer methods than other code. The quality of interface documentation is better in Java code than in other code. Code developed by teams is not of higher and large code bases not of lower maintainability. Projects with high maintainability are not more popular or more often forked. Overall, most hypotheses are not supported by open-source data.Comment: 20 page

Predictive feedback control and Fitts' law

Fitts’ law is a well established empirical formula, known for encapsulating the “speed-accuracy trade-off”. For discrete, manual movements from a starting location to a target, Fitts’ law relates movement duration to the distance moved and target size. The widespread empirical success of the formula is suggestive of underlying principles of human movement control. There have been previous attempts to relate Fitts’ law to engineering-type control hypotheses and it has been shown that the law is exactly consistent with the closed-loop step-response of a time-delayed, first-order system. Assuming only the operation of closed-loop feedback, either continuous or intermittent, this paper asks whether such feedback should be predictive or not predictive to be consistent with Fitts law. Since Fitts’ law is equivalent to a time delay separated from a first-order system, known control theory implies that the controller must be predictive. A predictive controller moves the time-delay outside the feedback loop such that the closed-loop response can be separated into a time delay and rational function whereas a non- predictive controller retains a state delay within feedback loop which is not consistent with Fitts’ law. Using sufficient parameters, a high-order non-predictive controller could approximately reproduce Fitts’ law. However, such high-order, “non-parametric” controllers are essentially empirical in nature, without physical meaning, and therefore are conceptually inferior to the predictive controller. It is a new insight that using closed-loop feedback, prediction is required to physically explain Fitts’ law. The implication is that prediction is an inherent part of the “speed-accuracy trade-off”

REI:An integrated measure for software reusability

To capitalize upon the benefits of software reuse, an efficient selection among candidate reusable assets should be performed in terms of functional fitness and adaptability. The reusability of assets is usually measured through reusability indices. However, these do not capture all facets of reusability, such as structural characteristics, external quality attributes, and documentation. In this paper, we propose a reusability index (REI) as a synthesis of various software metrics and evaluate its ability to quantify reuse, based on IEEE Standard on Software Metrics Validity. The proposed index is compared with existing ones through a case study on 80 reusable open-source assets. To illustrate the applicability of the proposed index, we performed a pilot study, where real-world reuse decisions have been compared with decisions imposed by the use of metrics (including REI). The results of the study suggest that the proposed index presents the highest predictive and discriminative power; it is the most consistent in ranking reusable assets and the most strongly correlated to their levels of reuse. The findings of the paper are discussed to understand the most important aspects in reusability assessment (interpretation of results), and interesting implications for research and practice are provided