Corticosteroids for the management of cancer-related pain in adults (Review)

Background: One of the most feared symptoms associated with cancer is pain. Opioids remain the mainstay of pain treatment but corticosteroids are often used concurrently as co- or adjuvant analgesics. Due to their anti-inflammatory mechanism of action, corticosteroids are said to provide effective analgesia for pain associated with inflammation and in the management of cancer-related complications such as brain metastasis and spinal cord compression. However, corticosteroids have a wide range of adverse effects that are dose and time dependent. Objectives: To evaluate the efficacy of corticosteroids in treating cancer-related pain in adults. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 4), MEDLINE (OVID) (1966 to 29 September 2014), EMBASE (OVID) (1970 to 29 September 2014), CINAHL (1982 to 29 September 2014), Science Citation Index (Web of Science) (1899 to 29 September 2014) and Conference Proceedings Citation Index - Science (Web of Science) (1990 to 29 September 2014). Selection criteria: Any randomised or prospective controlled trial that included patients over 18 years with cancer-related pain were eligible for the review. Corticosteroids were compared to placebo or usual treatment and/or supportive care. Data collection and analysis: All review authors independently assessed trial quality and extracted data. We used arithmetic means and standard deviations for each outcome to report the mean difference (MD) with 95% confidence interval (CI). Main results: Fifteen studies met the inclusion criteria, enrolling 1926 participants. The trial size varied from 20 to 598 patients. Most studies compared corticosteroids, particularly dexamethasone, to standard therapy. We included six studies with data at one week in the meta-analysis for pain intensity; no data were available at that time point for the remaining studies. Corticosteroid therapy resulted in less pain (measured on a scale of 0 to 10 with a lower score indicating less pain) compared to control at one week (MD 0.84 lower pain, 95% CI 1.38 to 0.30 lower; low quality evidence). Adverse events were poorly documented. Factors limiting statistical analysis included the lack of standardised measurements of pain and the use of different agents, dosages, comparisons and routes of drug delivery. Subgroup analysis according to type of cancer was not possible. The quality of this evidence was limited by the risk of bias of the studies and small sample size. The results were also compromised by attrition, with data missing for the enrolled patients. Authors' conclusions: The evidence for the efficacy of corticosteroids for pain control in cancer patients is weak. Significant pain relief was noted in some studies, albeit only for a short period of time. This could be important for patients with poor clinical status. Further trials, with increased numbers of participants, are needed to evaluate the safety and effectiveness of corticosteroids for the management cancer pain in adults, and to establish an ideal dose, duration of therapy and route of administration

Prepregnancy weight, gestational weight gain, and risk of growth affected neonates

BACKGROUND: In 2009, the Institute of Medicine published revised gestational weight gain (GWG) guidelines with changes notable for altered body mass index (BMI) categorization as per World Health Organization criteria and a stated range of recommended gain (11-20 pounds) for obese women. The goal of this study was to evaluate associations between maternal BMI-specific GWG adherence in the context of these new guidelines and risk of small for gestational age (SGA) and large for gestational age (LGA) neonates. METHODS: Subjects were a retrospective cohort of 11,203 live birth singletons delivered at 22-44 weeks at a Massachusetts tertiary care center between April 2006 and March 2010. Primary exposure was GWG adherence (inadequate, appropriate, or excessive) based on BMI-specific recommendations. SGA and LGA were defined as /=90th percentiles of U.S. population growth curves, respectively. The association between GWG adherence and SGA and LGA was examined in polytomous logistic regression models that estimated adjusted odds ratios (AOR) stratified by prepregnancy weight status, controlling for potential confounders. RESULTS: Before pregnancy, 3.8% of women were underweight, 50.9% were normal weight, 24.6% were overweight, and 20.6% were obese. Seventeen percent had inadequate GWG, and 57.2% had excessive GWG. Neonates were 9.6% SGA and 8.7% LGA. Inadequate GWG was associated with increased odds of SGA (AOR 2.51, 95% confidence interval [CI] 1.31-4.78 for underweight and AOR 1.78, 95% CI 1.42-2.24 for normal weight women) and decreased odds of LGA (AOR 0.5, 95% CI 0.47-0.73 for normal weight and AOR 0.56, 95% CI 0.34-0.90 for obese women). Excessive GWG was associated with decreased odds of SGA (AOR 0.59, 95% CI 0.47-0.73 for normal weight and AOR 0.64, 95% CI 0.47-0.89 for overweight women) and increased odds of LGA (AOR 1.76, 95% CI 1.38-2.24 for normal weight, AOR 2.99, 95% CI 1.92-4.65 for overweight, and AOR 1.55, 95% CI 1.10-2.19 for obese women). CONCLUSIONS: Efforts to optimize GWG are essential to reducing the proportion of SGA and LGA neonates, regardless of prepregnancy BMI

Policies, Political-Economy, and Swidden in Southeast Asia

For centuries swidden was an important farming practice found across the girth of Southeast Asia. Today, however, these systems are changing and sometimes disappearing at a pace never before experienced. In order to explain the demise or transitioning of swidden we need to understand the rapid and massive changes that have and are occurring in the political and economic environment in which these farmers operate. Swidden farming has always been characterized by change, but since the onset of modern independent nation states, governments and markets in Southeast Asia have transformed the terms of swiddeners’ everyday lives to a degree that is significantly different from that ever experienced before. In this paper we identified six factors that have contributed to the demise or transformation of swidden systems, and support these arguments with examples from China (Xishuangbanna), Laos, Thailand, Malaysia, and Indonesia. These trends include classifying swiddeners as ethnic minorities within nation-states, dividing the landscape into forest and permanent agriculture, expansion of forest departments and the rise of conservation, resettlement, privatization and commoditization of land and land-based production, and expansion of market infrastructure and the promotion of industrial agriculture. In addition we note a growing trend toward a transition from rural to urban livelihoods and expanding urban-labor markets

Mendelian adult-onset leukodystrophy genes in Alzheimer´s disease. Critical influence of CSF1R and NOTCH3

Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, Cerebral Autosomal Dominant and Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL and CARASIL), Cerebroretinal vasculopathy (CRV), Metachromatic leukodystrophy (MLD), Hereditary diffuse Leukoencephalopathy with spheroids (HDLS), Vanishing white matter disease (VWM) present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer’s disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis 1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10 and TAU), at 5 different developmental stages (Embryo [E15], 2 months, 4 months, 8 months and 18 months), 2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant and single-gene (c-alpha and SKAT tests) based genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (Log2FC>1, adj. p-val<0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ core dense plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H and p.H703Y) in our discovery and validation cohort, composed of 465 AD and MCI Caucasian patients from the UK. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-val = 0.01). Adult onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R and sporadic LOAD, that warrants further investigation

ABCA7 p.G215S as potential protective factor for Alzheimer’s disease

Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer’s disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyse the single independent and joint effect of rare and low frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low frequency coding variant (p.G215S, rs72973581, MAF=4.3%) conferring a modest but statistically significant protection against AD (p-value= 6x10-4, OR=0.57, 95% CI 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provide new insights that should address functional studies

The InterLACE study: design, data harmonization and characteristics across 20 studies on women's health

The International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) project is a global research collaboration that aims to advance understanding of women's reproductive health in relation to chronic disease risk by pooling individual participant data from several cohort and cross-sectional studies. The aim of this paper is to describe the characteristics of contributing studies and to present the distribution of demographic and reproductive factors and chronic disease outcomes in InterLACE

Sox2 Is Essential for Formation of Trophectoderm in the Preimplantation Embryo

In preimplantation mammalian development the transcription factor Sox2 (SRY-related HMG-box gene 2) forms a complex with Oct4 and functions in maintenance of self-renewal of the pluripotent inner cell mass (ICM). Previously it was shown that Sox2-/- embryos die soon after implantation. However, maternal Sox2 transcripts may mask an earlier phenotype. We investigated whether Sox2 is involved in controlling cell fate decisions at an earlier stage.We addressed the question of an earlier role for Sox2 using RNAi, which removes both maternal and embryonic Sox2 mRNA present during the preimplantation period. By depleting both maternal and embryonic Sox2 mRNA at the 2-cell stage and monitoring embryo development in vitro we show that, in the absence of Sox2, embryos arrest at the morula stage and fail to form trophectoderm (TE) or cavitate. Following knock-down of Sox2 via three different short interfering RNA (siRNA) constructs in 2-cell stage mouse embryos, we have shown that the majority of embryos (76%) arrest at the morula stage or slightly earlier and only 18.7-21% form blastocysts compared to 76.2-83% in control groups. In Sox2 siRNA-treated embryos expression of pluripotency associated markers Oct4 and Nanog remained unaffected, whereas TE associated markers Tead4, Yap, Cdx2, Eomes, Fgfr2, as well as Fgf4, were downregulated in the absence of Sox2. Apoptosis was also increased in Sox2 knock-down embryos. Rescue experiments using cell-permeant Sox2 protein resulted in increased blastocyst formation from 18.7% to 62.6% and restoration of Sox2, Oct4, Cdx2 and Yap protein levels in the rescued Sox2-siRNA blastocysts.We conclude that the first essential function of Sox2 in the preimplantation mouse embryo is to facilitate establishment of the trophectoderm lineage. Our findings provide a novel insight into the first differentiation event within the preimplantation embryo, namely the segregation of the ICM and TE lineages

Recommendations for the design of therapeutic trials for neonatal seizures

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from welldesigned clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics