Use of aspirin, other nonsteroidal anti-inflammatory drugs and acetaminophen and risk of endometrial cancer: the Epidemiology of Endometrial Cancer Consortium.

BACKGROUND: Regular use of aspirin has been associated with a reduced risk of cancer at several sites but the data for endometrial cancer are conflicting. Evidence regarding use of other analgesics is limited. PATIENTS AND METHODS: We pooled individual-level data from seven cohort and five case-control studies participating in the Epidemiology of Endometrial Cancer Consortium including 7120 women with endometrial cancer and 16 069 controls. For overall analyses, study-specific odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression and combined using random-effects meta-analysis; for stratified analyses, we used mixed-effects logistic regression with study as a random effect. RESULTS: At least weekly use of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an approximately 15% reduced risk of endometrial cancer among both overweight and obese women (OR = 0.86 [95% CI 0.76-0.98] and 0.86 [95% CI 0.76-0.97], respectively, for aspirin; 0.87 [95% CI 0.76-1.00] and 0.84 [0.74-0.96], respectively, for non-aspirin NSAIDs). There was no association among women of normal weight (body mass index < 25 kg/m2, Pheterogeneity = 0.04 for aspirin, Pheterogeneity = 0.003 for NSAIDs). Among overweight and obese women, the inverse association with aspirin was stronger for use 2-6 times/week (OR = 0.81, 95% CI 0.68-0.96) than for daily use (0.91, 0.80-1.03), possibly because a high proportion of daily users use low-dose formulations. There was no clear association with use of acetaminophen. CONCLUSION: Our pooled analysis provides further evidence that use of standard-dose aspirin or other NSAIDs may reduce risk of endometrial cancer among overweight and obese women.

Neuroprotection by anaesthetics in rodent models of traumatic brain injury: a systematic review and network meta-analysis.

BACKGROUND: Anaesthetic neuroprotection in the setting of traumatic brain injury (TBI) remains unproved and is based upon the results in preclinical experiments. Here, we sought to synthesise the results in rodent models of TBI, and to evaluate the effects of publication bias, experimental manipulation, and poor study quality on the effect estimates. METHODS: After a systematic review, we used pairwise meta-analysis to estimate the effect of anaesthetics, opioids, and sedative-hypnotics on neurological outcome, and network meta-analysis to compare their relative efficacy. We sought evidence of bias related to selective publication, experimental manipulation, and study quality. RESULTS: Sixteen studies, involving 32 comparisons, were included (546 animals). The treatment improved the neurological outcomes by 35%; 95% confidence interval: 26-44%; P<0.001. The statistical heterogeneity was small (12%), but the 95% prediction interval for the estimate was wide (15-56%). The statistical power was low: 61% (90% confidence interval: 22-86%). The small sample size in the studies was a serious shortcoming reducing the statistical heterogeneity and obscuring differences in outcome between drugs and between experimental conditions. CONCLUSIONS: Anaesthetics do provide neuroprotection in rodent models of TBI. The effect-size estimates do not appear to be exaggerated by selective publication, experimental manipulation, or study design. The main shortcoming of the included studies were small sample sizes leading to low power and imprecision, which precluded the network meta-analysis from providing a meaningful ranking for efficacy amongst the drugs. Reliable preclinical investigations of neuroprotection by anaesthetics will require larger sample sizes.

The First Record of Aedes (Hulecoeteomyia) japonicus (Diptera: Culicidae) and Its Establishment in Western Canada.

The potential disease-carrying mosquito, Aedes japonicus (Theobald) (Diptera: Culicidae), was identified among larvae collected in suburban Vancouver, BC, in July 2014, and over 200 were found at the same site in February 2015 where it presumably had overwintered in the egg stage. In late May 2015, a female was captured taking a bloodmeal 13 km east of the larval site. This population and those in the Washington and Oregon states are clearly disjunct from those in eastern North America, and their origin, probably from one or more different introductions from Asia, is discussed. Key characters of those in British Columbia are examined and match the description of subspecies japonicus, presumably like the others in North America.

Infertility and incident endometrial cancer risk: a pooled analysis from the epidemiology of endometrial cancer consortium (E2C2).

BACKGROUND: Nulliparity is an endometrial cancer risk factor, but whether or not this association is due to infertility is unclear. Although there are many underlying infertility causes, few studies have assessed risk relations by specific causes. METHODS: We conducted a pooled analysis of 8153 cases and 11 713 controls from 2 cohort and 12 case-control studies. All studies provided self-reported infertility and its causes, except for one study that relied on data from national registries. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Nulliparous women had an elevated endometrial cancer risk compared with parous women, even after adjusting for infertility (OR=1.76; 95% CI: 1.59-1.94). Women who reported infertility had an increased risk compared with those without infertility concerns, even after adjusting for nulliparity (OR=1.22; 95% CI: 1.13-1.33). Among women who reported infertility, none of the individual infertility causes were substantially related to endometrial cancer. CONCLUSIONS: Based on mainly self-reported infertility data that used study-specific definitions of infertility, nulliparity and infertility appeared to independently contribute to endometrial cancer risk. Understanding residual endometrial cancer risk related to infertility, its causes and its treatments may benefit from large studies involving detailed data on various infertility parameters.

Anaerobic Chemolithotrophic Growth of the Haloalkaliphilic Bacterium Strain MLMS-1 by Disproportionation of Monothioarsenate.

A novel chemolithotrophic metabolism based on a mixed arsenic-sulfur species has been discovered for the anaerobic deltaproteobacterium, strain MLMS-1, a haloalkaliphile isolated from Mono Lake, California, U.S. Strain MLMS-1 is the first reported obligate arsenate-respiring chemoautotroph which grows by coupling arsenate reduction to arsenite with the oxidation of sulfide to sulfate. In that pathway the formation of a mixed arsenic-sulfur species was reported. That species was assumed to be monothioarsenite ([H2As(III)S(-II)O2](-)), formed as an intermediate by abiotic reaction of arsenite with sulfide. We now report that this species is monothioarsenate ([HAs(V)S(-II)O3](2-)) as revealed by X-ray absorption spectroscopy. Monothioarsenate forms by abiotic reaction of arsenite with zerovalent sulfur. Monothioarsenate is kinetically stable under a wide range of pH and redox conditions. However, it was metabolized rapidly by strain MLMS-1 when incubated with arsenate. Incubations using monothioarsenate confirmed that strain MLMS-1 was able to grow (µ = 0.017 h(-1)) on this substrate via a disproportionation reaction by oxidizing the thio-group-sulfur (S(-II)) to zerovalent sulfur or sulfate while concurrently reducing the central arsenic atom (As(V)) to arsenite. Monothioarsenate disproportionation could be widespread in nature beyond the already studied arsenic and sulfide rich hot springs and soda lakes where it was discovered.

Does alcohol increase breast cancer risk in African-American women? Findings from a case-control study.

BACKGROUND: Alcohol is an important risk factor for breast cancer in Caucasian women, but the evidence in African-American (AA) women is limited and results are inconclusive. METHODS: Associations between recent and lifetime drinking and breast cancer risk were evaluated in a large sample of AA women from a case-control study in New York and New Jersey. Multivariable logistic regression models provided odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: There was no association between recent drinking and breast cancer risk, even when stratified by menopausal status or by hormone receptor status. A borderline decreased risk with increased lifetime consumption was found (OR=0.77; 95% CI: 0.58-1.03), which was stronger among women who drank when under 20 years of age (OR=0.65; 95% CI: 0.47-0.89), regardless of menopausal or hormone receptor status. CONCLUSION: Breast cancer risk associated with recent alcohol consumption was not apparent in AA women, while early age drinking seemed to decrease risk. This is the first investigation on recent and lifetime drinking in subgroups and drinking during different age periods in AA women. If findings are replicated, racial differences in biological pathways involving alcohol and its metabolites should be explored.

Characterization of the in vitro expressed autoimmune rippling muscle disease immunogenic domain of human titin encoded by TTN exons 248-249.

Autoimmune rippling muscle disease (ARMD) is an autoimmune neuromuscular disease associated with myasthenia gravis (MG). Past studies in our laboratory recognized a very high molecular weight skeletal muscle protein antigen identified by ARMD patient antisera as the titin isoform. These past studies used antisera from ARMD and MG patients as probes to screen a human skeletal muscle cDNA library and several pBluescript clones revealed supporting expression of immunoreactive peptides. This study characterizes the products of subcloning the titin immunoreactive domain into pGEX-3X and the subsequent fusion protein. Sequence analysis of the fusion gene indicates the cloned titin domain (GenBank ID: EU428784) is in frame and is derived from a sequence of N2-A spanning the exons 248-250 an area that encodes the fibronectin III domain. PCR and EcoR1 restriction mapping studies have demonstrated that the inserted cDNA is of a size that is predicted by bioinformatics analysis of the subclone. Expression of the fusion protein result in the isolation of a polypeptide of 52 kDa consistent with the predicted inferred amino acid sequence. Immunoblot experiments of the fusion protein, using rippling muscle/myasthenia gravis antisera, demonstrate that only the titin domain is immunoreactive.

Karyotype differentiation between two stickleback species (Gasterosteidae).

The stickleback family (Gasterosteidae) of fish is less than 40 million years old, yet stickleback species have diverged in both diploid chromosome number (2n) and morphology. We used comparative fluorescence in situ hybridization (FISH) on 2 stickleback species, Gasterosteus aculeatus (2n = 42) and Apeltes quadracus (2n = 46), to ascertain the types of chromosome rearrangements that differentiate these species. The A. quadracus karyotype contains more acrocentric and telocentric chromosomes than the G. aculeatus karyotype. By using bacterial artificial chromosome probes from G. aculeatus in our FISH screen, we found that 6 pericentric inversions and 2 chromosome fusions/fissions are responsible for the greater number of acrocentric and telocentric chromosomes in A. quadracus. While most populations of G. aculeatus have an XX/XY sex chromosome system, A. quadracus has a ZZ/ZW sex chromosome system, as previously reported. However, we discovered that a population of A. quadracus from Connecticut lacks heteromorphic sex chromosomes, providing evidence for unexpected sex chromosome diversity in this species.

Inducible nitric oxide synthase gene expression in the brain during systemic inflammation.

Inducible nitric oxide synthase (iNOS) is a transcriptionally regulated enzyme that synthesizes nitric oxide from L-arginine that has a key role in the pathophysiology of systemic inflammation and sepsis. Transgenic animals with a null mutation for the iNOS gene are resistant to hypotension and death caused by Escherichia coli lipopolysaccharide (LPS). The regulation of peripheral iNOS has been well studied in sepsis, but little is known about iNOS regulation in the brain during systemic inflammation or sepsis. We know that at baseline there is no detectable iNOS gene expression in the brain, but a detailed neuroanatomical study reveals that early in the course of systemic inflammation there is a profound induction of iNOS messenger RNA in vascular, glial and neuronal structures of the rat brain, accompanied by the production of nitric oxide (NO) metabolites in brain parenchyma and cerebrospinal fluid (CSF). We propose that the spillover of nitrite into the CSF has the potential to be a diagnostic marker for systemic inflammation and sepsis. Pharmacological interventions aimed at regulating iNOS function in the brain might represent a new treatment strategy in sepsis. Brain iNOS may be relevant to the pathophysiology, diagnosis and treatment of systemic inflammation and sepsis.

Induction of mating behavior in rats by luteinizing hormone-releasing factor.

Ovariectomized female rats treated with estrogen, in dosages too low to provoke mating, displayed this behavior when given subcutaneous injections of synthetic luteinizing hormone-releasing factor (LRF) 48 hours later. Two hours after the injection of LRF, components of female sexual behavior appeared. The lordosis reflex followed mounting by the male, and darting and hopping behavior was quite prevalent. On the other hand, treatment with estrogen followed by luteinizing hormone, follicle-stimulating hormone, or thyrotropin-releasing factor did not induce copulatory behavior. The results suggest that LRF may play a role in induction of mating behavior.

Arginine vasopressin as a thyrotropin-releasing hormone.

Although hypothyroidism (with concomitant increased levels of thyroid-stimulating hormone) has been associated with elevated plasma vasopressin, the role that vasopressin plays in controlling thyroid-stimulating hormone secretion from the adenohypophysis is not understood. In two in vitro pituitary cell systems, vasopressin caused a specific and dose-related release of thyroid-stimulating hormone from cells that was equal in potency to that elicited by thyrotropin-releasing hormone, the primary acknowledged regulator of thyroid-stimulating hormone release. When injected into the hypothalamus, however, vasopressin specifically inhibited the release of thyroid-stimulating hormone. Thus, vasopressin may exert differential regulatory effects on thyroid-stimulating hormone secretion in the hypothalamus and pituitary gland.

Paradoxical elevation of growth hormone by intraventricular somatostatin: possible ultrashort-loop feedback.

Somatostatin, the growth hormone-inhibiting factor, when microinjected into the third ventricle of the rat brain, paradoxically induced the release of growth hormone. A pituitary site of action having been ruled out, this result supports the concept that exogenous somatostatin within the hypothalamus acts either to suppress the release of somatostatin from somatostatin-containing neurons, possibly via an ultrashort-loop feedback mechanism, or to augment release of hypothalamic growth hormone-releasing factor, thereby inducing a release of growth hormone. Injection of somatostatin into the third ventricle also decreased plasma concentrations of luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone, probably by inhibiting the release of luteinizing hormone-releasing factor and thyrotropin-releasing factor.

Prostaglandin involvement in hypothalamic control of gonadotropin and prolactin release.

Prostaglandin E(2) (PGE(2)) injected into the third ventricle of ovariectomized rats increased plasma luteinizing hormone dramatically and follicle stimulating hormone slightly. PGE(1) elevated prolactin; PGF(1alpha) or PGF(2alpha) had no effect. PGE(2) or PGE(1) injected directly into the anterior pituitary were ineffective. These results suggest that specific prostaglandins act at the hypothalamus to control pituitary hormone release.

Successful outcome of patients with relapsed/refractor Hodgkin lymphoma treated with high dose chemotherapy at the National Adult Bone Marrow Transplant Unit at St. James's Hospital.

Patients with Hodgkin lymphoma who relapse or are refractory to first line multi-agent chemotherapy can be successfully salvaged with high dose therapy (HDT) and autologous stem cell transplant (ASCT). Twenty-six patients with relapsed or refractory Hodgkin lymphoma have been treated with HDT and ASCT at St James Hospital between 2000 and 2005. At day 100 post HDT-ASCT, 23 patients were in complete remission. This group included all 6 patients transplanted at first relapse, 8 of 9 with advanced disease and 9 of 11 with primary refractory disease. Patients treated in first relapse had the best outcome with an overall and progression free survival of 100% (median, 37 months). Patients with primary refractory disease had the poorest outcome with an overall survival of 76% (median, 28 months). All patients with primary refractory disease responsive to salvage chemotherapy were in remission at a median of 28 months. The presence of chemosensitive disease prior to transplantation was the most important determinant of outcome. PET-CT imaging is useful to assess chemosensititvity prior to HDT and thus predict which patients will do well post HDT-ASCT. No patient died of treatment related toxicity. The outcome of this patient series compares favourably with international figures.

Using multimedia technology to help combat the negative effects of protective isolation on patients: the Open Window project--an engineering challenge.

The Open Window project was established with the aim of creating a "virtual window" for each patient who is confined to protective isolation due to treatment for illness. This virtual window as developed provides a range of media or experiences. This paper describes the approach taken to the system design and discusses initial experiences with implementing such a system in a critical care setting. The system design was predicated on two guiding principles. Firstly it should be intuitive to use and the technology used to create the virtual window hidden from patient view. Secondly the system must be able to be installed at the point of care in a way that delivers the experience under the patient's control, without compromising the function or safety of the clinical environment. Patient acceptance of the system is being measured as part of an on-going trial and at this interim phase of data analysis 100% (n=55) of participants in the intervention group have reported that the technology was easy to use. We conclude that the system as designed and installed is an effective, robust and reliable system upon which to base a multimedia interventions in a critical care room.

Protocol for a systematic review and meta-analysis of data from preclinical studies employing forced swimming test: an update.

OBJECTIVE: Forced swimming test (FST) in rodents is a widely used behavioural test for screening antidepressants in preclinical research. Translational value of preclinical studies may be improved by appraisal of the quality of experimental design and risk of biases, which remains to be addressed for FST. The present protocol of a systematic review with meta-analysis aims to investigate the quality of preclinical studies employing FST to identify risks of bias in future publications. In addition, this protocol will help to determine the effect sizes (ES) for primary and secondary outcomes according to several aspects of the FST study design. SEARCH STRATEGY SCREENING ANNOTATION DATA MANAGEMENT: Publications reporting studies testing different classes of antidepressants in FST will be collected from Medline, SCOPUS and Web of Science databases. A broad list of inclusion criteria will be applied excluding those studies whereby FST is used as a stressor or studies reporting data from co-treatments. For assessing the quality of the included publications, the quality checklist adapted by Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies will be used. If the meta-analysis seems feasible, the ES and the 95% CI will be analysed. The heterogeneity between studies will be assessed by using the χ2statistic with n-1 degrees of freedom. Subgroup meta-analysis (meta-regression, and if necessary, stratified regression) will be performed when possible according to characteristics of study design and study quality to assess their impact on efficacy of the treatments. In addition, funnel plotting, Egger regression, and 'trim and fill' will be used to assess the risk of publication bias. Results of this protocol will help to create rational methodological guidelines for application of FST in rodents and improve the quality and translational value of preclinical research on antidepressant discovery. REPORTING: A preliminary version of the present protocol has been preregistered with Systematic Review Facility (http://syrf.org.uk/). A preprint version of the current protocol has been registered with Open Science Framework (https://osf.io/9kxm4/). Results will be communicated in scientific meetings and peer-reviewed journals. We plan to conduct an anonymous and online survey within the scientific community to ask researchers about their perception of risk of bias and their experience with the publication of negative results.

The influence of cyclosporin alone, or cyclosporin and methotrexate, on the incidence of mixed haematopoietic chimaerism following allogeneic sibling bone marrow transplantation for severe aplastic anaemia.

We previously reported a randomized trial comparing Cyclosporin-A (CsA) and short-term methotrexate versus CsA alone for graft-versus-host disease (GvHD) prophylaxis in 71 patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) from a human leucocyte antigen-identical sibling for severe aplastic anaemia (SAA). We found a better survival in the group receiving the two-drug prophylaxis regimen with no significant difference in the probability of developing GvHD between the two groups. The present study details chimaeric analysis and its influence on survival and GvHD occurrence in 45 of the original 71 patients in whom serial samples were available. Analysis was carried out in a blinded prospective manner. Seventy-two per cent achieved complete donor chimaerism (DC), 11% stable mixed chimaerism (SMC) and 17% progressive mixed chimaerism (PMC). The overall 5-year survival probability was 82% (+/-11%) with a significant survival advantage (P = 0.0009) in DC or SMC compared to those with PMC. Chronic GvHD was more frequent in DC patients, whereas no patient with SMC developed chronic GvHD. Graft failure occurred in 50% of the PMC group. This study demonstrates the relevance of chimaerism analysis in patients receiving HSCT for SAA and confirms the occurrence of mixed chimaerism in a significant proportion of recipients.

Myb-related Schizosaccharomyces pombe cdc5p is structurally and functionally conserved in eukaryotes.

Schizosaccharomyces pombe cdc5p is a Myb-related protein that is essential for G2/M progression. To explore the structural and functional conservation of Cdc5 throughout evolution, we isolated Cdc5-related genes and cDNAs from Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and Homo sapiens. Supporting the notion that these Cdc5 gene family members are functionally homologous to S. pombe cdc5(+), human and fly Cdc5 cDNAs are capable of complementing the temperature-sensitive lethality of the S. pombe cdc5-120 mutant. Furthermore, S. cerevisiae CEF1 (S. cerevisiae homolog of cdc5(+)), like S. pombe cdc5(+), is essential during G2/M. The location of the cdc5-120 mutation, as well as mutational analyses of Cef1p, indicate that the Myb repeats of cdc5p and Cef1p are important for their function in vivo. However, we found that unlike in c-Myb, single residue substitutions of glycines for hydrophobic residues within the Myb repeats of Cef1p, which are essential for maintaining structure of the Myb domain, did not impair Cef1p function in vivo. Rather, multiple W-to-G substitutions were required to inactivate Cef1p, and many of the substitution mutants were found to confer temperature sensitivity. Although it is possible that Cef1p acts as a transcriptional activator, we have demonstrated that Cef1p is not involved in transcriptional activation of a class of G2/M-regulated genes typified by SWI5. Collectively, these results suggest that Cdc5 family members participate in a novel pathway to regulate G2/M progression.

Wilms' tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia: a wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring.

Wilms' tumor gene 1 (WT1) is overexpressed in the majority (70-90%) of acute leukemias and has been identified as an independent adverse prognostic factor, a convenient minimal residual disease (MRD) marker and potential therapeutic target in acute leukemia. We examined WT1 expression patterns in childhood acute lymphoblastic leukemia (ALL), where its clinical implication remains unclear. Using a real-time quantitative PCR designed according to Europe Against Cancer Program recommendations, we evaluated WT1 expression in 125 consecutively enrolled patients with childhood ALL (106 BCP-ALL, 19 T-ALL) and compared it with physiologic WT1 expression in normal and regenerating bone marrow (BM). In childhood B-cell precursor (BCP)-ALL, we detected a wide range of WT1 levels (5 logs) with a median WT1 expression close to that of normal BM. WT1 expression in childhood T-ALL was significantly higher than in BCP-ALL (P<0.001). Patients with MLL-AF4 translocation showed high WT1 overexpression (P<0.01) compared to patients with other or no chromosomal aberrations. Older children (> or =10 years) expressed higher WT1 levels than children under 10 years of age (P<0.001), while there was no difference in WT1 expression in patients with peripheral blood leukocyte count (WBC) > or =50 x 10(9)/l and lower. Analysis of relapsed cases (14/125) indicated that an abnormal increase or decrease in WT1 expression was associated with a significantly increased risk of relapse (P=0.0006), and this prognostic impact of WT1 was independent of other main risk factors (P=0.0012). In summary, our study suggests that WT1 expression in childhood ALL is very variable and much lower than in AML or adult ALL. WT1, thus, will not be a useful marker for MRD detection in childhood ALL, however, it does represent a potential independent risk factor in childhood ALL. Interestingly, a proportion of childhood ALL patients express WT1 at levels below the normal physiological BM WT1 expression, and this reduced WT1 expression appears to be associated with a higher risk of relapse.

The role of toll-like receptors in the immune-adrenal crosstalk.

Sepsis and septic shock remain major health concerns worldwide, and rapid activation of adrenal steroid release is a key event in the organism's first line of defense during this form of severe illness. Toll-like receptors (TLRs) are critical in the early immune response upon bacterial infection, and recent data from our lab demonstrate a novel link between the innate immune system and the adrenal stress response mediated by TLRs. Glucocorticoids and TLRs regulate each other in a bidirectional way. Bacterial toxins acting through TLRs directly activate adrenocortical steroid release. TLR-2 and TLR-4 are expressed in human and mice adrenals and TLR-2 deficiency is associated with an impaired glucocorticoid response. Furthermore, TLR-2 deficiency in mice is associated with marked cellular alterations in adrenocortical tissue. TLR-2-deficient mice have an impaired adrenal corticosterone release following inflammatory stress induced by bacterial cell wall compounds. This defect appears to be associated with a decrease in systemic and intraadrenal cytokine expression. In conclusion, TLRs play a crucial role in the immune-adrenal crosstalk. This close functional relationship needs to be considered in the treatment of inflammatory diseases requiring an intact adrenal stress response.