Inhibition of Tendon Cell Proliferation and Matrix Glycosaminoglycan Synthesis by Non-Steroidal Anti-Inflammatory Drugs in vitro

The purpose of this study was to investigate the effects of some commonly used non-steroidal anti-inflammatory drugs (NSAIDs) on human tendon. Explants of human digital flexor and patella tendons were cultured in medium containing pharmacological concentrations of NSAIDs. Cell proliferation was measured by incorporation of 3H-thymidine and glycosaminoglycan synthesis was measured by incorporation of 35S-Sulphate. Diclofenac and aceclofenac had no significant effect either on tendon cell proliferation or glycosaminoglycan synthesis. Indomethacin and naproxen inhibited cell proliferation in patella tendons and inhibited glycosaminoglycan synthesis in both digital flexor and patella tendons. If applicable to the in vivo situation, these NSAIDs should be used with caution in the treatment of pain after tendon injury and surgery

Recurrence of Clostridium difficile infection in the Western Australian population

Clostridium difficile, the most common cause of hospital-associated diarrhoea in developed countries, presents major public health challenges. The high clinical and economic burden from C. difficile infection (CDI) relates to the high frequency of recurrent infections caused by either the same or different strains of C. difficile. An interval of 8 weeks after index infection is commonly used to classify recurrent CDI episodes. We assessed strains of C. difficile in a sample of patients with recurrent CDI in Western Australia from October 2011 to July 2017. The performance of different intervals between initial and subsequent episodes of CDI was investigated. Of 4612 patients with CDI, 1471 (32%) were identified with recurrence. PCR ribotyping data were available for initial and recurrent episodes for 551 patients. Relapse (recurrence with same ribotype (RT) as index episode) was found in 350 (64%) patients and reinfection (recurrence with new RT) in 201 (36%) patients. Our analysis indicates that 8- and 20-week intervals failed to adequately distinguish reinfection from relapse. In addition, living in a non-metropolitan area modified the effect of age on the risk of relapse. Where molecular epidemiological data are not available, we suggest that applying an 8-week interval to define recurrent CDI requires more consideration

Recent applications of a single quadrupole mass spectrometer in 11C, 18F and radiometal chemistry

Mass spectrometry (MS) has longstanding applications in radiochemistry laboratories, stemming from carbon-dating. However, research on the development of radiotracers for molecular imaging with either positron emission tomography (PET) or single photon emission computed tomography has yet to take full advantage of MS. This inertia has been attributed to the relatively low concentrations of radiopharmaceutical formulations and lack of access to the required MS equipment due to the high costs for purchase and maintenance of specialized MS systems. To date, single quadrupole (SQ)-MS coupled to liquid chromatography (LC) systems is the main form of MS that has been used in radiochemistry laboratories. These LC–MS systems are primarily used for assessing the chemical purity of radiolabeling precursor or standard molecules but also have applications in the determination of metabolites. Herein, we highlight personal experiences using a compact SQ-MS in our PET radiochemistry laboratories, to monitor the small amounts of carrier observed in most radiotracer preparations, even at high molar activities. The use of a SQ-MS in the observation of the low mass associated with non-radioactive species which are formed along with the radiotracer from the trace amounts of carrier found is demonstrated. Herein, we describe a pre-concentration system to detect dilute radiopharmaceutical formulations and metabolite analyses by SQ-MS. Selected examples where SQ-MS was critical for optimization of radiochemical reactions and for unequivocal characterization of radiotracers are showcased. We also illustrate examples where SQ-MS can be applied in identification of radiometal complexes and development of a new purification methodology for Pd-catalyzed radiofluorination reactions, shedding light on the identity of metal complexes present in the labelling solution

Rational inhibitor design for Pseudomonas aeruginosa salicylate adenylation enzyme PchD

Pseudomonas aeruginosa is an increasingly antibiotic-resistant pathogen that causes severe lung infections, burn wound infections, and diabetic foot infections. P. aeruginosa produces the siderophore pyochelin through the use of a non-ribosomal peptide synthetase (NRPS) biosynthetic pathway. Targeting members of siderophore NRPS proteins is one avenue currently under investigation for the development of new antibiotics against antibiotic-resistant organisms. Here, the crystal structure of the pyochelin adenylation domain PchD is reported. The structure was solved to 2.11 Å when co-crystallized with the adenylation inhibitor 5′-O-(N-salicylsulfamoyl)adenosine (salicyl-AMS) and to 1.69 Å with a modified version of salicyl-AMS designed to target an active site cysteine (4-cyano-salicyl-AMS). In the structures, PchD adopts the adenylation conformation, similar to that reported for AB3403 from Acinetobacter baumannii

From College To Jobs: Making Sense of Labor Market Returns To Higher Education

This report summarizes key findings from recent research on links between higher education and the workforce. Featuring eight brief papers from leading education and workforce experts from around the country, the report offers practical advice for institutional leaders, policymakers, students and their advisers about how to use the increasingly available information on the economic value of higher education. Specifically, the authors' papers and the opening summary explore what various audiences can learn from emerging evidence about: variations in labor market outcomes by program and institution; the value of degrees to jobs both in and out of fields studied; returns to the completion of certain course clusters that don't add up to a degree; and distortions that may result from examining returns to individual degrees rather than "stacked" degrees

External validation of clinical prediction models:simulation-based sample size calculations were more reliable than rules-of-thumb

INTRODUCTION: Sample size "rules-of-thumb" for external validation of clinical prediction models suggest at least 100 events and 100 non-events. Such blanket guidance is imprecise, and not specific to the model or validation setting. We investigate factors affecting precision of model performance estimates upon external validation, and propose a more tailored sample size approach.METHODS: Simulation of logistic regression prediction models to investigate factors associated with precision of performance estimates. Then, explanation and illustration of a simulation-based approach to calculate the minimum sample size required to precisely estimate a model's calibration, discrimination and clinical utility.RESULTS: Precision is affected by the model's linear predictor (LP) distribution, in addition to number of events and total sample size. Sample sizes of 100 (or even 200) events and non-events can give imprecise estimates, especially for calibration. The simulation-based calculation accounts for the LP distribution and (mis)calibration in the validation sample. Application identifies 2430 required participants (531 events) for external validation of a deep vein thrombosis diagnostic model.CONCLUSION: Where researchers can anticipate the distribution of the model's LP (eg, based on development sample, or a pilot study), a simulation-based approach for calculating sample size for external validation offers more flexibility and reliability than rules-of-thumb.</p

Growth Endocrine Axis and Bovine Chromosome 5: Association of SNP Genotypes and Reproductive Phenotypes in an Angus, Brahman and Romosinuano Diallele

The growth endocrine axis influences reproduction. A QTL associated with enhanced ovulation exists on chromosome 5 in cattle and there are 6 genes underlying this region involved in the mechanisms of GH action. Resequencing exons, 5’ and 3’ untranslated regions and conserved non-coding regions of these genes in a multibreed resource population revealed 75 SNP usable for genotype to phenotype association studies. In the current study, phenotypes included age at first calving, calving interval, days to calving, and pregnancy rate. Data were collected from developing heifers (n = 650) of a diallele composed of Angus, Brahman, and Romosinuano breeds. A SNP in the promoter of the signal transducer and activator of transcription (STAT)2 gene, which is a second messenger of GH, had minor allele frequency \u3e 10% across the three breeds. This SNP did not deviate from Hardy- Weinberg equilibrium (X2 = 1.00, P \u3e 0.31), so deemed useful for genotype to phenotype association analyses. Since the remaining SNP appeared to predict breed, they were used to correct for population stratification using STRUCTURE, which revealed three distinctive ancestral clusters. No significant association was detected between the STAT2 genotype and reproductive traits in mixed effects analyses using genotype as a fixed term, sire as a random term, and coefficient of ancestry as a covariate; however, the interaction of SNP genotype and ancestral cluster was associated with the traits days to calving (P \u3c 0.05) and calving interval (P \u3c 0.10). Interaction plots revealed a higher estimated effect of heterozygous genotype in cluster 1 (inferred primarily from Brahman) and lower estimates in clusters 2 and 3 (inferred primarily from Bos taurus). The heterozygous genotype extended these trait levels ~100 d. A SNP in the promoter of the STAT2 gene was associated with fertility trait levels in admixed cows of the breeds Angus, Brahman, and Romosinuano. The effect appeared to be a non-additive genetic relationship as heterozygous genotype extended levels of traits indicative of postpartum rebreeding

Criteria for the diagnosis of corticobasal degeneration

Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed