A 'large and valuable' Siwalik fossil collection in the archives of the Oxford University Museum of Natural History

This article describes results from a review of South Asian fossils in the Oxford University Museum of Natural History. These materials include two early 19th century collections of fossils from the Siwalik Hills in India. While this assemblage was summarised in 1837 by William Buckland as ‘large and valuable collections of fossil bones’, it has remained largely unstudied and unpublished in any detail since collection. Here, as a precursor to a comprehensive re-evaluation, we establish a chronological and geographical context of one collection event, provide details of its donor, and outline its history after arrival in Oxford. We then describe select taxa in the collection, including a well-preserved maxilla and toothrow of the large extinct giraffid, Sivatherium giganteum, as a basis to justify our current understanding of the biostratigraphic affinity of the assemblage. Conservatively, the collection is a ‘classic’ Upper Siwalik Plio-Pleistocene fauna, possibly the first to be transported to the UK. While further analyses will realise the scientific potential of the fossils, the narrative of their journey from India to Oxford remains incomplete. Further investigation of the hidden history of the collection is warranted

Potential Savings of Harmonising Hospital and Community Formularies for Chronic Disease Medications Initiated in Hospital

Hospitals in Canada manage their formularies independently, yet many inpatients are discharged on medications which will be purchased through publicly-funded programs. We sought to determine how much public money could be saved on chronic medications if hospitals promoted the initiation of agents with the lowest outpatient formulary prices.We used administrative databases for the province of Ontario to identify patients initiated on a proton pump inhibitor (PPI), angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) following hospital admission from April 1(st) 2008-March 31(st) 2009. We assessed the cost to the Ontario Drug Benefit Program (ODB) over the year following initiation and determined the cost savings if prescriptions were substituted with the least expensive agent in each class.The cost for filling all PPI, ACE inhibitor and ARB prescriptions was $2.48 million,$968 thousand and $325 thousand respectively. Substituting the least expensive agent could have saved$1.16 million (47%) for PPIs, $162 thousand (17$14 thousand (4%) for ARBs over the year following discharge.In a setting where outpatient prescriptions are publicly funded, harmonising outpatient formularies with inpatient therapeutic substitution resulted in modest cost savings and may be one way to control rising pharmaceutical costs

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

Healthcare professionals' perceptions of pain in infants at risk for neurological impairment

BACKGROUND: To determine whether healthcare professionals perceive the pain of infants differently due to their understanding of that infant's level of risk for neurological impairment. METHOD: Neonatal Intensive Care Units (NICU's) at two tertiary pediatric centers. Ninety-five healthcare professionals who practice in the NICU (50 nurses, 19 physicians, 17 respiratory therapists, 9 other) participated. They rated the pain (0–10 scale and 0–6 Faces Pain Scale), distress (0–10), effectiveness of cuddling to relieve pain (0–10) and time to calm without intervention (seconds) for nine video clips of neonates receiving a heel stick. Prior to each rating, they were provided with descriptions that suggested the infant had mild, moderate or severe risk for neurological impairment. Ratings were examined as a function of the level of risk described. RESULTS: Professionals' ratings of pain, distress, and time to calm did not vary significantly with level of risk, but ratings of the effectiveness of cuddling were significantly lower as risk increased [F (2,93) = 4.4, p = .02]. No differences in ratings were found due to participants' age, gender or site of study. Physicians' ratings were significantly lower than nurses' across ratings. CONCLUSION: Professionals provided with visual information regarding an infants' pain during a procedure did not display the belief that infants' level of risk for neurological impairment affected their pain experience. Professionals' estimates of the effectiveness of a nonpharmacological intervention did differ due to level of risk

Use of DNA–Damaging Agents and RNA Pooling to Assess Expression Profiles Associated with BRCA1 and BRCA2 Mutation Status in Familial Breast Cancer Patients

A large number of rare sequence variants of unknown clinical significance have been identified in the breast cancer susceptibility genes, BRCA1 and BRCA2. Laboratory-based methods that can distinguish between carriers of pathogenic mutations and non-carriers are likely to have utility for the classification of these sequence variants. To identify predictors of pathogenic mutation status in familial breast cancer patients, we explored the use of gene expression arrays to assess the effect of two DNA–damaging agents (irradiation and mitomycin C) on cellular response in relation to BRCA1 and BRCA2 mutation status. A range of regimes was used to treat 27 lymphoblastoid cell-lines (LCLs) derived from affected women in high-risk breast cancer families (nine BRCA1, nine BRCA2, and nine non-BRCA1/2 or BRCAX individuals) and nine LCLs from healthy individuals. Using an RNA–pooling strategy, we found that treating LCLs with 1.2 µM mitomycin C and measuring the gene expression profiles 1 hour post-treatment had the greatest potential to discriminate BRCA1, BRCA2, and BRCAX mutation status. A classifier was built using the expression profile of nine QRT–PCR validated genes that were associated with BRCA1, BRCA2, and BRCAX status in RNA pools. These nine genes could distinguish BRCA1 from BRCA2 carriers with 83% accuracy in individual samples, but three-way analysis for BRCA1, BRCA2, and BRCAX had a maximum of 59% prediction accuracy. Our results suggest that, compared to BRCA1 and BRCA2 mutation carriers, non-BRCA1/2 (BRCAX) individuals are genetically heterogeneous. This study also demonstrates the effectiveness of RNA pools to compare the expression profiles of cell-lines from BRCA1, BRCA2, and BRCAX cases after treatment with irradiation and mitomycin C as a method to prioritize treatment regimes for detailed downstream expression analysis

BACH1 Ser919Pro variant and breast cancer risk

BACKGROUND: BACH1 (BRCA1-associated C-terminal helicase 1; also known as BRCA1-interacting protein 1, BRIP1) is a helicase protein that interacts in vivo with BRCA1, the protein product of one of the major genes for hereditary predisposition to breast cancer. Previously, two BACH1 germ line missense mutations have been identified in early-onset breast cancer patients with and without family history of breast and ovarian cancer. In this study, we aimed to evaluate whether there are BACH1 genetic variants that contribute to breast cancer risk in Finland. METHODS: The BACH1 gene was screened for germ line alterations among probands from 43 Finnish BRCA1/2 negative breast cancer families. Recently, one of the observed common variants, Ser-allele of the Ser919Pro polymorphism, was suggested to associate with an increased breast cancer risk, and was here evaluated in an independent, large series of 888 unselected breast cancer patients and in 736 healthy controls. RESULTS: Six BACH1 germ line alterations were observed in the mutation analysis, but none of these were found to associate with the cancer phenotype. The Val193Ile variant that was seen in only one family was further screened in an independent series of 346 familial breast cancer cases and 183 healthy controls, but no additional carriers were observed. Individuals with the BACH1 Ser919-allele were not found to have an increased breast cancer risk when the Pro/Ser heterozygotes (OR 0.90; 95% CI 0.70–1.16; p = 0.427) or Ser/Ser homozygotes (OR 1.02; 95% CI 0.76–1.35; p = 0.91) were compared to Pro/Pro homozygotes, and there was no association of the variant with any breast tumor characteristics, age at cancer diagnosis, family history of cancer, or survival. CONCLUSION: Our results suggest that the BACH1 Ser919 is not a breast cancer predisposition allele in the Finnish study population. Together with previous studies, our results also indicate that although some rare germ line variants in BACH1 may contribute to breast cancer development, the contribution of BACH1 germline alterations to familial breast cancer seems marginal

<em>Enterococcus faecalis</em> Infection Causes Inflammation, Intracellular Oxphos-Independent ROS Production, and DNA Damage in Human Gastric Cancer Cells

Background: Achlorhydria caused by e.g. atrophic gastritis allows for bacterial overgrowth, which induces chronic inflammation and damage to the mucosal cells of infected individuals driving gastric malignancies and cancer. Enterococcus faecalis (E. faecalis) can colonize achlohydric stomachs and we therefore wanted to study the impact of E. faecalis infection on inflammatory response, reactive oxygen species (ROS) formation, mitochondrial respiration, and mitochondrial genetic stability in gastric mucosal cells. Methods: To separate the changes induced by bacteria from those of the inflammatory cells we established an in vitro E. faecalis infection model system using the gastric carcinoma cell line MKN74. Total ROS and superoxide was measured by fluorescence microscopy. Cellular oxygen consumption was characterized non-invasively using XF24 microplate based respirometry. Gene expression was examined by microarray, and response pathways were identified by Gene Set Analysis (GSA). Selected gene transcripts were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Mitochondrial mutations were determined by sequencing. Results: Infection of MKN74 cells with E. faecalis induced intracellular ROS production through a pathway independent of oxidative phosphorylation (oxphos). Furthermore, E. faecalis infection induced mitochondrial DNA instability. Following infection, genes coding for inflammatory response proteins were transcriptionally up-regulated while DNA damage repair and cell cycle control genes were down-regulated. Cell growth slowed down when infected with viable E. faecalis and responded in a dose dependent manner to E. faecalis lysate. Conclusions: Infection by E. faecalis induced an oxphos-independent intracellular ROS response and damaged the mitochondrial genome in gastric cell culture. Finally the bacteria induced an NF-kappa B inflammatory response as well as impaired DNA damage response and cell cycle control gene expression

Understanding the (non-)Use of Societal Wellbeing Indicators in National Policy Development : What Can We Learn from Civil Servants? A UK Case Study

Gross Domestic Product is often used as a proxy for societal well-being in the context of policy development. Its shortcomings in this context are, however, well documented, and numerous alternative indicator sets have been developed. Despite this, there is limited evidence of widespread use of these alternative indicator sets by people working in policy areas relevant to societal wellbeing. Civil servants are an important group of indicator end-users. Better understanding their views concerning measuring societal wellbeing can support wider discussions about what factors determine indicator use and influence in policy decision-making. Taking the UK as a case study, we ask what views exist among civil servants in the UK about measuring societal well-being? To answer this question, we used a bootstrapped Q methodology, interviewing 20 civil servants to elicit their views about measuring societal well-being. Three distinct discourses emerged from our analysis: one that was concerned about the consequences of ignoring natural, social and human capital in decision making; one that emphasised opportunity and autonomy as key determinants of well-being; and one that focused on the technical aspects of measuring societal well-being. Each of these discourses has direct implications for the way that we integrate societal wellbeing into policy making and highlights the potential benefits of including end-users in indicator development and strategy

Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.

Cigarette smoke induces genetic instability in airway epithelial cells by suppressing FANCD2 expression

Chromosomal abnormalities are commonly found in bronchogenic carcinoma cells, but the molecular causes of chromosomal instability (CIN) and their relationship to cigarette smoke has not been defined. Because the Fanconi anaemia (FA)/BRCA pathway is essential for maintenance of chromosomal stability, we tested the hypothesis that cigarette smoke suppresses that activity of this pathway. Here, we show that cigarette smoke condensate (CSC) inhibited translation of FANCD2 mRNA (but not FANCC or FANCG) in normal airway epithelial cells and that this suppression of FANCD2 expression was sufficient to induce both genetic instability and programmed cell death in the exposed cell population. Cigarette smoke condensate also suppressed FANCD2 function and induced CIN in bronchogenic carcinoma cells, but these cells were resistant to CSC-induced apoptosis relative to normal airway epithelial cells. We, therefore, suggest that CSC exerts pressure on airway epithelial cells that results in selection and emergence of genetically unstable somatic mutant clones that may have lost the capacity to effectively execute an apoptotic programme. Carcinogen-mediated suppression of FANCD2 gene expression provides a plausible molecular mechanism for CIN in bronchogenic carcinogenesis