Increased Stem Cell Factor Release by Hemangioma-Derived Endothelial Cells

Background: Capillary hemangiomas, the most common tumors in young children, consist of proliferating capillary vessels and endothelial cells. These tumors also contain large numbers of mast cells, compared with the normal surrounding skin or tissue. We have recently shown that stem cell factor (SCF), the gene product of the murine steel locus, can act as a chemoattractant for mast cells. In this study, we investigated whether SCF might be involved in the recruitment and maintenance of mast cells in hemangiomas. Experimental Design: Cultured endothelial cells derived from a murine hemangioma were compared with normal vascular endothelial cells for the ability to produce and release SCF, a mitogen for mast cells. Results: Conditioned medium from hemangioma-derived endothelial cells stimulated the proliferation of cultured mast cells. This proliferative activity was potentiated by interleukin-3. The same conditioned medium was unable to stimulate proliferation of mast cells expressing a defective receptor for SCF. The medium was also unable to stimulate proliferation when it was preincubated with neutralizing antibodies specific for SCF. Immunoprecipitation and Western blot analysis of the conditioned media from hemangioma cells and normal endothelial cells demonstrated the 31,000 molecular weight SCF in hemangioma-conditioned medium only. In addition, proliferative activity for mast cells could not be demonstrated in the conditioned medium of the normal endothelial cells, although Northern blot analysis indicated that both normal and hemangioma-derived endothelial cells express SCF mRNA. Reverse transcriptase-polymerase chain reaction techniques were used to amplify the DNA sequence coding for the proteolytic cleavage site used for release of SCF. Results indicated that both normal and hemangioma-derived endothelial cells express the same transcript for SCF. Conclusions: Our data suggest that increased release of SCF is a property of hemangioma-derived endothelial cells that may account for the high numbers of mast cells observed in hemangioma tissue. This increased release of SCF is not due to alternate splicing of SCF transcripts by hemangioma cells

Mycobiome of the Bat White Nose Syndrome (WNS) Affected Caves and Mines reveals High Diversity of Fungi and Local Adaptation by the Fungal Pathogen Pseudogymnoascus (Geomyces) destructans

The investigations of the bat White Nose Syndrome (WNS) have yet to provide answers as to how the causative fungus Pseudogymnoascus (Geomyces) destructans (Pd) first appeared in the Northeast and how a single clone has spread rapidly in the US and Canada. We aimed to catalogue Pd and all other fungi (mycobiome) by the culture-dependent (CD) and culture-independent (CI) methods in four Mines and two Caves from the epicenter of WNS zoonotic. Six hundred sixty-five fungal isolates were obtained by CD method including the live recovery of Pd. Seven hundred three nucleotide sequences that met the definition of operational taxonomic units (OTUs) were recovered by CI methods. Most OTUs belonged to unidentified clones deposited in the databases as environmental nucleic acid sequences (ENAS). The core mycobiome of WNS affected sites comprised of 46 species of fungi from 31 genera recovered in culture, and 17 fungal genera and 31 ENAS identified from clone libraries. Fungi such as Arthroderma spp., Geomyces spp., Kernia spp., Mortierella spp., Penicillium spp., and Verticillium spp. were predominant in culture while Ganoderma spp., Geomyces spp., Mortierella spp., Penicillium spp. and Trichosporon spp. were abundant is clone libraries. Alpha diversity analyses from CI data revealed that fungal community structure was highly diverse. However, the true species diversity remains undetermined due to under sampling. The frequent recovery of Pd indicated that the pathogen has adapted to WNS-afflicted habitats. Further, this study supports the hypothesis that Pd is an introduced species. These findings underscore the need for integrated WNS control measures that target both bats and the fungal pathogen.Comment: 59 pages, 7figure

Maximum Power Efficiency and Criticality in Random Boolean Networks

Random Boolean networks are models of disordered causal systems that can occur in cells and the biosphere. These are open thermodynamic systems exhibiting a flow of energy that is dissipated at a finite rate. Life does work to acquire more energy, then uses the available energy it has gained to perform more work. It is plausible that natural selection has optimized many biological systems for power efficiency: useful power generated per unit fuel. In this letter we begin to investigate these questions for random Boolean networks using Landauer's erasure principle, which defines a minimum entropy cost for bit erasure. We show that critical Boolean networks maximize available power efficiency, which requires that the system have a finite displacement from equilibrium. Our initial results may extend to more realistic models for cells and ecosystems.Comment: 4 pages RevTeX, 1 figure in .eps format. Comments welcome, v2: minor clarifications added, conclusions unchanged. v3: paper rewritten to clarify it; conclusions unchange

Effect of dietary n‐3 PUFA supplementation on the muscle transcriptome in older adults

Dietary fish oil‐derived n‐3 PUFA supplementation can increase muscle mass, reduce oxygen demand during physical activity, and improve physical function (muscle strength and power, and endurance) in people. The results from several studies conducted in animals suggest that the anabolic and performance‐enhancing effects of n‐3 PUFA are at least in part transcriptionally regulated. The effect of n‐3 PUFA therapy on the muscle transcriptome in people is unknown. In this study, we used muscle biopsy samples collected during a recently completed randomized controlled trial that found that n‐3 PUFA therapy increased muscle mass and function in older adults to provide a comprehensive assessment of the effect of n‐3 PUFA therapy on the skeletal muscle gene expression profile in these people. Using the microarray technique, we found that several pathways involved in regulating mitochondrial function and extracellular matrix organization were increased and pathways related to calpain‐ and ubiquitin‐mediated proteolysis and inhibition of the key anabolic regulator mTOR were decreased by n‐3 PUFA therapy. However, the effect of n‐3 PUFA therapy on the expression of individual genes involved in regulating mitochondrial function and muscle growth, assessed by quantitative RT‐PCR, was very small. These data suggest that n‐3 PUFA therapy results in small but coordinated changes in the muscle transcriptome that may help explain the n‐3 PUFA‐induced improvements in muscle mass and function

A briefing for mental health professionals : why asking about abuse matters to service users (REVA project, briefing 3)

There are high prevalence rates of violent and abusive experience in both the childhoods and adult lives of mental health service users. Histories of childhood sexual and physical abuse amongst women service users are particularly well documented. Although many of the samples in studies are small, figures of over 50% are not unusual (Palmer et al, 1992; Bryer et al, 1987; Walker and James, 1992; Wurr and Partridge, 1996). In secure settings this figure is even higher (Bland et al, 1999). Studies of severe domestic violence among psychiatric in-patients report lifetime prevalence ranging from 30% to 60% (Golding, 1999; Howard et al. 2010). The REVA study, on which this briefing is based, has also found that people who suffer violence and abuse are much more likely to have a mental disorder, self-harm or attempt suicide than those with little or no experience of this kind (Scott et al, 2013). Given the prevalence of experiences of abuse among users of adult mental health services it is vitally important that these experiences are identified to ensure appropriate diagnosis, support and referral. Since 2003 it has been Department of Health policy that all adult service users should be asked about experiences of violence and abuse in mental health assessments. Yet actually disclosing experiences of violence and abuse can be very difficult. Survivors can feel a deep sense of shame and responsibility for the abuse they have experienced – feelings that are often strategically encouraged by their abusers (Clark and Quadara, 2010). These feelings can be compounded by unhelpful responses from professionals when they try to disclose (Imkaanetal, 2014). And survivors consistently say that disclosure has to be ‘at the right time for them’, which may be immediately or many years after the abuse (McNaughton Nicholls, 2012). In this briefing paper we present findings from research funded by the Department of Health Policy Research Programme on responding effectively to the needs of survivors of violence and abuse: the REVA study. The study included specifically asking survivors of violence and abuse about their views on routine enquiry, their experiences of disclosing abuse and their recommendations for how staff should ask clients about abuse

Guidance for Trust managers : implementing and sustaining routine enquiry about violence and abuse in mental health services (REVA project, briefing 2)

Since 2003 it has been Department of Health policy that all adult service users should be asked about experiences of violence and abuse in mental health assessments. However, by 2006 it was apparent that mental health provider trusts were not generally implementing the policy and a two-year initiative was launched to pilot an approach to introducing routine enquiry and embedding it in clinical practice. The pilot involved a total of 15 trusts and its evaluation identified key lessons for effective implementation of routine enquiry in all trusts. In 2012 the Department of Health funded follow-up research on responding effectively to the needs of survivors of violence and abuse to include case-studies of four of the original pilot trusts to implement routine enquiry (the REVA study). This guidance is based on findings from this study

A briefing for commissioners : what survivors of violence and abuse say about mental health services (REVA project, briefing 4)

The Department of Health publication, Commissioning services for women and children who have experienced violence or abuse – a guide for health commissioners, clearly acknowledges that ‘victims of violence or abuse tend to use health services more than average’ and that this is ‘despite often finding it hard to access services’ (Golding and Duggal, 2011: 22). The guidance goes on to state that it is precisely because of this that ‘it is in the NHS interest to identify these women and children, provide opportunities for them to disclose, and provide services [..] to help them improve their physical and mental health’ (ibid). The policy that has been implemented to support this process is known as ‘routine enquiry’ (RE). Since 2003 it has been Department of Health policy that all adult service users should be asked about experiences of violence and abuse in mental health assessments. However, asking about experiences of abuse and violence is not enough. To be effective the policy of routine enquiry has to be underpinned by the provision of appropriate and effective services for survivors of abuse. As the commissioning guidance notes, ‘commissioners should be aware of the importance of clear referral pathways, so that health professionals know where and how to refer women and children to local services’. For appropriate services to be available, commissioners also need to be aware of the type of services and care pathways that people who have experienced abuse feel are appropriate to meet their needs. In this briefing we present information drawn from interviews with mental health service users who have experienced domestic and/or sexual violence. This briefing focusses on the links between experience of abuse and mental health and the implications this has for commissioners to create an effective service landscape. The REVA research included the experience of both male and female service users. Useful guidance focussing on commissioning services specifically for women and girls who have survived violence is also available: see Woman’s Aid and Imkaan, 2014 ‘Successful commissioning: a guide to commissioning services that support women and children survivors of violence’, see www.womensaid.org.uk for details

Variants in the Mitochondrial Intermediate Peptidase (MIPEP) Gene are Associated with Gray Matter Density in the Alzheimer’s Disease Neuroimaging Initiative Cohort

poster abstractCancer and Alzheimer’s disease (AD) incidence is inversely correlated, but the genetic underpinnings of this relationship remain to be elucidated. Recent findings identified lower gray matter density in frontal regions of participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with cancer history compared to those without such history, across diagnostic groups (Nudelman et al., 2014). Pathways proposed to impact cancer and AD, including metabolism and survival, may play an important role in the observed difference. To test this hypothesis, a genome-wide association study (GWAS) using mean frontal gray matter cluster values was performed for all Caucasian participants in this cohort with neuroimaging and genetic data (n=1405). Analysis covaried for age, sex, AD, and cancer history. Of the two genes with the most significant SNPs (p<10-5), WD repeat domain 5B (WDR5B) and mitochondrial intermediate peptidase (MIPEP), MIPEP was selected for further analysis given the hypothesis focus on metabolism. ANOVA analysis of MIPEP top SNP rs8181878 with frontal gray matter cluster values in SPSS indicated that while this SNP is significantly associated with gray matter density (p=2x10-6), no interaction was observed with cancer history or AD diagnosis. Furthermore, whole brain gray matter voxel-wise analysis of this SNP using Statistical Parametric Mapping 8 software showed that minor allele(s) of this SNP were significantly (PFWE<0.05) associated with higher gray matter density. These results suggest that the minor allele of MIPEP SNP rs8181878 may be protective against gray matter density loss, highlighting the importance of metabolic processes in aging and disease

A briefing for service providers and commissioners : measuring outcomes for survivors of violence and abuse (REVA project, briefing 5)

The long-term consequences of violence and abuse can only be addressed if appropriate services for survivors are available. Many such services are located within the voluntary sector, and the fact that they are oversubscribed indicates a high level of demand, but there is limited robust evidence as to whether, how and why they work. Third sector organisations need to demonstrate their effectiveness, particularly in the context of competitive commissioning (Harlock, 2013). However, cuts to already under-resourced services in the violence against women and girls (VAWG) sector have made it difficult for many, especially smaller services, to develop meaningful measurement frameworks or to fully engage in commissioning processes (Callanan et al., 2012; Women’s Aid & Imkaan, 2014). The lack of standardised sector-specific outcome measures also means that services may be required to conduct multiple monitoring exercises for a variety of different funding streams, with none fully reflecting the reality of their work. To address these gaps, one strand of the REVA project has involved developing an outcomes framework to reflect the work of such services more accurately. In doing this, we built upon work underway in the specialist women’s voluntary sector by Women’s Aid, Imkaan, Rape Crisis England and Wales, and consulted with a range of individuals and organisations through the REVA Reference Network. We also drew on tools developed and used within the health and mental health sectors. Our aim was for the measures to be suitable for use in a range of types of services addressing various forms of violence and abuse located in both the voluntary and statutory sectors. The resulting outcomes tool was piloted in seven voluntary sector and NHS settings in 2013-14

Association of cancer history with Alzheimer's disease onset and structural brain changes

Epidemiological studies show a reciprocal inverse association between cancer and Alzheimer's disease (AD). The common mechanistic theory for this effect posits that cells have an innate tendency toward apoptotic or survival pathways, translating to increased risk for either neurodegeneration or cancer. However, it has been shown that cancer patients experience cognitive dysfunction pre- and post-treatment as well as alterations in cerebral gray matter density (GMD) on MRI. To further investigate these issues, we analyzed the association between cancer history (CA±) and age of AD onset, and the relationship between GMD and CA± status across diagnostic groups in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort study. Data was analyzed from 1609 participants with information on baseline cancer history and AD diagnosis, age of AD onset, and baseline MRI scans. Participants were CA+ (N = 503) and CA− (N = 1106) diagnosed with AD, mild cognitive impairment (MCI), significant memory concerns (SMC), and cognitively normal older adults. As in previous studies, CA+ was inversely associated with AD at baseline (P = 0.025); interestingly, this effect appears to be driven by non-melanoma skin cancer (NMSC), the largest cancer category in this study (P = 0.001). CA+ was also associated with later age of AD onset (P < 0.001), independent of apolipoprotein E (APOE) ε4 allele status, and individuals with two prior cancers had later mean age of AD onset than those with one or no prior cancer (P < 0.001), suggesting an additive effect. Voxel-based morphometric analysis of GMD showed CA+ had lower GMD in the right superior frontal gyrus compared to CA− across diagnostic groups (Pcrit < 0.001, uncorrected); this cluster of lower GMD appeared to be driven by history of invasive cancer types, rather than skin cancer. Thus, while cancer history is associated with a measurable delay in AD onset independent of APOE ε4, the underlying mechanism does not appear to be cancer-related preservation of GMD