S100A4 Elevation Empowers Expression of Metastasis Effector Molecules in Human Breast Cancer.

Many human glandular cancers metastasize along nerve tracts, but the mechanisms involved are generally poorly understood. The calcium-binding protein S100A4 is expressed at elevated levels in human cancers, where it has been linked to increased invasion and metastasis. Here we report genetic studies in a Drosophila model to define S100A4 effector functions that mediate metastatic dissemination of mutant Ras-induced tumors in the developing nervous system. In flies overexpressing mutant RasVal12 and S100A4, there was a significant increase in activation of the stress kinase JNK and production of the matrix metalloproteinase MMP1. Genetic or chemical blockades of JNK and MMP1 suppressed metastatic dissemination associated with S100A4 elevation, defining required signaling pathway(s) for S100A4 in this setting. In clinical specimens of human breast cancer, elevated levels of the mammalian paralogs MMP2, MMP9, and MMP13 are associated with a 4- to 9-fold relative decrease in patient survival. In individual tumors, levels of MMP2 and MMP13 correlated more closely with levels of S100A4, whereas MMP9 levels correlated more closely with the S100 family member S100P. Overall, our results suggest the existence of evolutionarily conserved pathways used by S100A4 to promote metastatic dissemination, with potential prognostic and therapeutic implications for metastasis by cancers that preferentially exploit nerve tract migration routes. Cancer Res; 77(3); 1-10. ©2016 AACR

Lessons learned from England's Health Checks Programme : Using qualitative research to identify and share best practice

Background: This study aimed to explore the challenges and barriers faced by staff involved in the delivery of the National Health Service (NHS) Health Check, a systematic cardiovascular disease (CVD) risk assessment and management program in primary care. Methods: Data have been derived from three qualitative evaluations that were conducted in 25 General Practices and involved in depth interviews with 58 staff involved all levels of the delivery of the Health Checks. Analysis of the data was undertaken using the framework approach and findings are reported within the context of research and practice considerations. Results: Findings indicated that there is no ‘one size fits all’ blueprint for maximising uptake although success factors were identified: evolution of the programme over time in response to local needs to suit the particular characteristics of the patient population; individual staff characteristics such as being proactive, enthusiastic and having specific responsibility; a supportive team. Training was clearly identified as an area that needed addressing and practitioners would benefit from CVD specific baseline training and refresher courses to keep them up to date with recent developments in the area. However there were other external factors that impinged on an individual’s ability to provide an effective service, some of these were outside the control of individuals and included cutbacks in referral services, insufficient space to run clinics or general awareness of the Health Checks amongst patients. Conclusions: The everyday experiences of practitioners who participated in this study suggest that overall, Health Check is perceived as a worthwhile exercise. But, organisational and structural barriers need to be addressed. We also recommend that clear referral pathways be in place so staff can refer patients to appropriate services (healthy eating sessions, smoking cessation, and exercise referrals). Local authorities need to support initiatives that enable data sharing and linkage so that GP Practices are informed when patients take up services such as smoking cessation or alcohol harm reduction programmes run by social services

Mapping of Mycobacterium tuberculosis Complex Genetic Diversity Profiles in Tanzania and Other African Countries

The aim of this study was to assess and characterize Mycobacterium tuberculosis complex (MTBC) genotypic diversity in Tanzania, as well as in neighbouring East and other several African countries. We used spoligotyping to identify a total of 293 M. tuberculosis clinical isolates (one isolate per patient) collected in the Bunda, Dar es Salaam, Ngorongoro and Serengeti areas in Tanzania. The results were compared with results in the SITVIT2 international database of the Pasteur Institute of Guadeloupe. Genotyping and phylogeographical analyses highlighted the predominance of the CAS, T, EAI, and LAM MTBC lineages in Tanzania. The three most frequent Spoligotype International Types (SITs) were: SIT21/CAS1-Kili (n = 76; 25.94%), SIT59/LAM11-ZWE (n = 22; 7.51%), and SIT126/EAI5 tentatively reclassified as EAI3-TZA (n = 18; 6.14%). Furthermore, three SITs were newly created in this study (SIT4056/EAI5 n = 2, SIT4057/T1 n = 1, and SIT4058/EAI5 n = 1). We noted that the East-African-Indian (EAI) lineage was more predominant in Bunda, the Manu lineage was more common among strains isolated in Ngorongoro, and the Central-Asian (CAS) lineage was more predominant in Dar es Salaam (p-value<0.0001). No statistically significant differences were noted when comparing HIV status of patients vs. major lineages (p-value = 0.103). However, when grouping lineages as Principal Genetic Groups (PGG), we noticed that PGG2/3 group (Haarlem, LAM, S, T, and X) was more associated with HIV-positive patients as compared to PGG1 group (Beijing, CAS, EAI, and Manu) (p-value = 0.03). This study provided mapping of MTBC genetic diversity in Tanzania (containing information on isolates from different cities) and neighbouring East African and other several African countries highlighting differences as regards to MTBC genotypic distribution between Tanzania and other African countries. This work also allowed underlining of spoligotyping patterns tentatively grouped within the newly designated EAI3-TZA lineage (remarkable by absence of spacers 2 and 3, and represented by SIT126) which seems to be specific to Tanzania. However, further genotyping information would be needed to confirm this specificity

Hospital and community isolates of uropathogens at a tertiary hospital in South Africa

Aim. To investigate the profile of common uropathogensisolated from urine specimens submitted to the diagnostic microbiology laboratory at a tertiary teaching hospital and assess their antimicrobial susceptibility patterns to commonly used antimicrobial agents.Methods. We conducted a retrospective analysis of laboratoryreports for all urine specimens submitted for investigations over a 1-year period. Isolates were tested by means of the Kirby-Bauer disc diffusion method for susceptibility to amoxicillin, ciprofloxacin, gentamicin, co-trimoxazole and nitrofurantoin, and for extended-spectrum beta-lactamase (ESBL) production.Results. Out of the total specimens (N=2 203) received over the 1-year study period, 51.1% (1 126) of the urine samples were culture-positive, the majority (65.4%) having come from females. The most common isolate was Escherichia coli (39.0%) followed by Klebsiella species (20.8%) and Enterococcus faecalis (8.2%). The  ram-negative isolates displayed a very high level of resistance to amoxicillin (range 43 - 100%) and co-trimoxazole (range 29 - 90%), whereas resistance to gentamicin (range 0 - 50%) and ciprofloxacin (range 0 - 33%)was lower. E. coli isolates were susceptible to nitrofurantoin (94%), and ESBL production was significantly higher (p=0.01) in the hospital isolates, compared with those from the community referral sites.Conclusions. The culture-positive rate for uropathogens washigh, with a greater incidence among females. E. coli was the most common aetiological agent identified, and remained susceptible to nitrofurantoin. Resistance levels to amoxicillin and co-trimoxazole were very high for all Gram-negative isolates, and it is recommended that these antibiotics should not be used for the empiric treatment of urinary tract infections

Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study

Background Diagnosing drug-resistance remains an obstacle to the elimination of tuberculosis. Phenotypic drug-susceptibility testing is slow and expensive, and commercial genotypic assays screen only common resistance-determining mutations. We used whole-genome sequencing to characterise common and rare mutations predicting drug resistance, or consistency with susceptibility, for all first-line and second-line drugs for tuberculosis. Methods Between Sept 1, 2010, and Dec 1, 2013, we sequenced a training set of 2099 Mycobacterium tuberculosis genomes. For 23 candidate genes identified from the drug-resistance scientific literature, we algorithmically characterised genetic mutations as not conferring resistance (benign), resistance determinants, or uncharacterised. We then assessed the ability of these characterisations to predict phenotypic drug-susceptibility testing for an independent validation set of 1552 genomes. We sought mutations under similar selection pressure to those characterised as resistance determinants outside candidate genes to account for residual phenotypic resistance. Findings We characterised 120 training-set mutations as resistance determining, and 772 as benign. With these mutations, we could predict 89·2% of the validation-set phenotypes with a mean 92·3% sensitivity (95% CI 90·7–93·7) and 98·4% specificity (98·1–98·7). 10·8% of validation-set phenotypes could not be predicted because uncharacterised mutations were present. With an in-silico comparison, characterised resistance determinants had higher sensitivity than the mutations from three line-probe assays (85·1% vs 81·6%). No additional resistance determinants were identified among mutations under selection pressure in non-candidate genes. Interpretation A broad catalogue of genetic mutations enable data from whole-genome sequencing to be used clinically to predict drug resistance, drug susceptibility, or to identify drug phenotypes that cannot yet be genetically predicted. This approach could be integrated into routine diagnostic workflows, phasing out phenotypic drug-susceptibility testing while reporting drug resistance early

Can sleep and resting behaviours be used as indicators of welfare in shelter dogs (Canis lupusfamiliaris)?

Previous research on humans and animals suggests that the analysis of sleep patterns may reliably inform us about welfare status, but little research of this kind has been carried out for non-human animals in an applied context. This study explored the use of sleep and resting behaviour as indicators of welfare by describing the activity patterns of dogs (Canis lupus familiaris) housed in rescue shelters, and comparing their sleep patterns to other behavioural and cognitive measures of welfare. Sleep and activity patterns were observed over five non-consecutive days in a population of 15 dogs. Subsequently, the characteristics of sleep and resting behaviour were described and the impact of activity on patterns of sleep and resting behaviour analysed. Shelter dogs slept for 2.8% of the day, 14.3% less than previously reported and experienced less sleep fragmentation at night (32 sleep bouts). There were no statistically significant relationships between behaviours exhibited during the day and sleep behaviour. A higher proportion of daytime resting behaviour was significantly associated with a positive judgement bias, less repetitive behaviour and increased time spent coded as ‘relaxed’ across days by shelter staff. These results suggest that, in the context of a busy shelter environment, the ability to rest more during the day could be a sign of improved welfare. Considering the non-linear relationship between sleep and welfare in humans, the relationship between sleep and behavioural indicators of welfare, including judgement bias, in shelter dogs may be more complex than this study could detect

Potential Drug-Drug Interactions in Psychiatric Ward of a Tertiary Care Hospital: Prevalence, Levels and Association with Risk Factors

Purpose: To identify the prevalence of potential drug-drug interactions (pDDIs) in a psychiatric ward, their levels and association with risk factors.Methods: This study was conducted in the psychiatric ward of Ayub Teaching Hospital, Abbottabad, Pakistan. Medical records of 415 patients were retrospectively reviewed for pDDIs using Micromedex Drug-Reax software. Logistic regression was applied to determine association of pDDIs with age, gender, hospital stay and number of drugs.Results: In our study, we identified total number of 825 pDDIs of 126 types, with median number of 1 pDDIs per patient. Overall 64.8 % of the patients had at least one pDDI; 27.2 % at least one major pDDI; and 58.5 % patients at least one moderate pDDI. Among 825 identified pDDIs, most were of moderate (75.6 %) or major (20.8 %) severity, good (66.4 %) or fair (29 %) type of scientific evidence; and delayed onset (71 %). The most frequent major and moderate pDDIs included haloperidol + procyclidine (127 cases), haloperidol + olanzapine (49), haloperidol + promethazine (47), haloperidol + fluphenazine (41), diazepam + divalproex sodium (40), haloperidol + trihexyphenidyl (37), lorazepam + divalproex sodium (34), fluphenazine + procyclidine (33) and olanzapine + divalproex sodium (32). There was significant association of occurrence of pDDIs with hospital stay of 7 days or longer (p = 0.005) and taking 7 or more drugs (p &lt; 0.001).&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Conclusion: A high prevalence of pDDIs in the psychiatric ward was recorded, a majority of which were of moderate severity. Patients with long hospital stay and increased number of drugs were more exposed to pDDIs.Keywords: Drug-drug interactions, Potential drug-drug interaction, Prescriptions screening, Drug-related problems, Clinical pharmacy

Random-phase approximation and its applications in computational chemistry and materials science

The random-phase approximation (RPA) as an approach for computing the electronic correlation energy is reviewed. After a brief account of its basic concept and historical development, the paper is devoted to the theoretical formulations of RPA, and its applications to realistic systems. With several illustrating applications, we discuss the implications of RPA for computational chemistry and materials science. The computational cost of RPA is also addressed which is critical for its widespread use in future applications. In addition, current correction schemes going beyond RPA and directions of further development will be discussed.Comment: 25 pages, 11 figures, published online in J. Mater. Sci. (2012

EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice

Background We have previously shown that EphrinA1/EphA expression profile changes in response to myocardial infarction (MI), exogenous EphrinA1-Fc administration following MI positively influences wound healing, and that deletion of the EphA2 Receptor (EphA2-R) exacerbates injury and remodeling. To determine whether or not ephrinA1-Fc would be of therapeutic value in the hyperglycemic infarcted heart, it is critical to evaluate how ephrinA1/EphA signaling changes in the hyperglycemic myocardium in response to MI. Methods Streptozotocin (STZ)-induced hyperglycemia in wild type (WT) and EphA2-receptor mutant (EphA2-R-M) mice was initiated by an intraperitoneal injection of STZ (150 mg/kg) 10 days before surgery. MI was induced by permanent ligation of the left anterior descending coronary artery and analyses were performed at 4 days post-MI. ANOVAs with Student-Newman Keuls multiple comparison post-hoc analysis illustrated which groups were significantly different, with significance of at least p < 0.05. Results Both WT and EphA2-R-M mice responded adversely to STZ, but only hyperglycemic EphA2-R-M mice had lower ejection fraction (EF) and fractional shortening (FS). At 4 days post-MI, we observed greater post-MI mortality in EphA2-R-M mice compared with WT and this was greater still in the EphA2-R-M hyperglycemic mice. Although infarct size was greater in hyperglycemic WT mice vs normoglycemic mice, there was no difference between hyperglycemic EphA2-R-M mice and normoglycemic EphA2-R-M mice. The hypertrophic response that normally occurs in viable myocardium remote to the infarct was noticeably absent in epicardial cardiomyocytes and cardiac dysfunction worsened in hyperglycemic EphA2-R-M hearts post-MI. The characteristic interstitial fibrotic response in the compensating myocardium remote to the infarct also did not occur in hyperglycemic EphA2-R-M mouse hearts to the same extent as that observed in the hyperglycemic WT mouse hearts. Differences in neutrophil and pan-leukocyte infiltration and serum cytokines implicate EphA2-R in modulation of injury and the differences in ephrinA1 and EphA6-R expression in governing this are discussed. Conclusions We conclude that EphA2-mutant mice are more prone to hyperglycemia-induced increased injury, decreased survival, and worsened LV remodeling due to impaired wound healing