DIR-visible grey matter lesions and atrophy in multiple sclerosis: partners in crime?

The extent and clinical relevance of grey matter (GM) pathology in multiple sclerosis (MS) are increasingly recognised. GM pathology may present as focal lesions, which can be visualised using double inversion recovery (DIR) MRI, or as diffuse pathology, which can manifest as atrophy. It is, however, unclear whether the diffuse atrophy centres on focal lesions. This study aimed to determine if GM lesions and GM atrophy colocalise, and to assess their independent relationship with motor and cognitive deficits in MS

Adherence to Highly Active Antiretroviral Treatment in HIV-Infected Rwandan Women

Scale-up of highly active antiretroviral treatment therapy (HAART) programs in Rwanda has been highly successful but data on adherence is limited. We examined HAART adherence in a large cohort of HIV+ Rwandan women.The Rwanda Women's Interassociation Study Assessment (RWISA) was a prospective cohort study that assessed effectiveness and toxicity of ART. We analyzed patient data 12±3 months after HAART initiation to determine adherence rates in HIV+ women who had initiated HAART.Of the 710 HIV+ women at baseline, 490 (87.2%) initiated HAART. Of these, 6 (1.2%) died within 12 months, 15 others (3.0%) discontinued the study and 80 others (19.0%) remained in RWISA but did not have a post-HAART initiation visit that fell within the 12±3 month time points leaving 389 subjects for analysis. Of these 389, 15 women stopped their medications without being advised to do so by their doctors. Of the remaining 374 persons who reported current HAART use 354 completed the adherence assessment. All women, 354/354, reported 100% adherence to HAART at the post-HAART visit. The high self-reported level of adherence is supported by changes in laboratory measures that are influenced by HAART. The median (interquartile range) CD4 cell count measured within 6 months prior to HAART initiation was 185 (128, 253) compared to 264 (182, 380) cells/mm(3) at the post-HAART visit. Similarly, the median (interquartile range) MCV within 6 months prior to HAART initiation was 88 (83, 93) fL compared to 104 (98, 110) fL at the 12±3 month visit.Self-reported adherence to antiretroviral treatment 12±3 months after initiating therapy was 100% in this cohort of HIV-infected Rwandan women. Future studies should explore country-specific factors that may be contributing to high levels of adherence to HAART in this population

The Formation of the First Massive Black Holes

Supermassive black holes (SMBHs) are common in local galactic nuclei, and SMBHs as massive as several billion solar masses already exist at redshift z=6. These earliest SMBHs may grow by the combination of radiation-pressure-limited accretion and mergers of stellar-mass seed BHs, left behind by the first generation of metal-free stars, or may be formed by more rapid direct collapse of gas in rare special environments where dense gas can accumulate without first fragmenting into stars. This chapter offers a review of these two competing scenarios, as well as some more exotic alternative ideas. It also briefly discusses how the different models may be distinguished in the future by observations with JWST, (e)LISA and other instruments.Comment: 47 pages with 306 references; this review is a chapter in "The First Galaxies - Theoretical Predictions and Observational Clues", Springer Astrophysics and Space Science Library, Eds. T. Wiklind, V. Bromm & B. Mobasher, in pres

Management and prevention of chronic obstructive pulmonary disease exacerbations: a state of the art review

Exacerbations of chronic obstructive pulmonary disease (COPD) are important events in the natural history of this prevalent and devastating condition. This review provides a concise, state of the art summary on prevention and management of exacerbations. Considerable new data underpins evidence in support of many preventative interventions, pharmacological and non-pharmacological, that are now available. Challenges remain in developing new approaches, and delivering those that already exist to the right patient at the right time. Management of an exacerbation remains stepwise according to clinical severity, but there is now additional focus on addressing comorbidities and taking the opportunity at acute events to optimise preventative strategies for the future. Ultimately, exacerbations are heterogeneous events in a heterogeneous disease, and an individualised approach is paramount

Therapeutic targets for bone metastases in breast cancer

Breast cancer is prone to metastasize to bone. Once metastatic cells are in the bone marrow, they do not, on their own, destroy bone. Instead, they alter the functions of bone-resorbing (osteoclasts) and bone-forming cells (osteoblasts), resulting in skeletal complications that cause pathological fractures and pain. In this review, we describe promising molecular bone-targeted therapies that have arisen from recent advances in our understanding of the pathogenesis of breast cancer bone metastases. These therapies target osteoclasts (receptor activator of nuclear factor kB ligand, integrin αvβ3, c-Src, cathepsin K), osteoblasts (dickkopf-1, activin A, endothelin A) and the bone marrow microenvironment (transforming growth factor β, bone morphogenetic proteins, chemokine CXCL-12 and its receptor CXCR4). The clinical exploitation of these bone-targeted agents will provide oncologists with novel therapeutic strategies for the treatment of skeletal lesions in breast cancer

Calcium Prevents Tumorigenesis in a Mouse Model of Colorectal Cancer

Calcium has been proposed as a mediator of the chemoprevention of colorectal cancer (CRC), but the comprehensive mechanism underlying this preventive effect is not yet clear. Hence, we conducted this study to evaluate the possible roles and mechanisms of calcium-mediated prevention of CRC induced by 1,2-dimethylhydrazine (DMH) in mice.For gene expression analysis, 6 non-tumor colorectal tissues of mice from the DMH + Calcium group and 3 samples each from the DMH and control groups were hybridized on a 4×44 K Agilent whole genome oligo microarray, and selected genes were validated by real-time polymerase chain reaction (PCR). Functional analysis of the microarray data was performed using KEGG and Gene Ontology (GO) analyses. Hub genes were identified using Pathway Studio software.The tumor incidence rates in the DMH and DMH + Calcium groups were 90% and 40%, respectively. Microarray gene expression analysis showed that S100a9, Defa20, Mmp10, Mmp7, Ptgs2, and Ang2 were among the most downregulated genes, whereas Per3, Tef, Rnf152, and Prdx6 were significantly upregulated in the DMH + Calcium group compared with the DMH group. Functional analysis showed that the Wnt, cell cycle, and arachidonic acid pathways were significantly downregulated in the DMH + Calcium group, and that the GO terms related to cell differentiation, cell cycle, proliferation, cell death, adhesion, and cell migration were significantly affected. Forkhead box M1 (FoxM1) and nuclear factor kappa-B (NF-κB) were considered as potent hub genes.In the DMH-induced CRC mouse model, comprehensive mechanisms were involved with complex gene expression alterations encompassing many altered pathways and GO terms. However, how calcium regulates these events remains to be studied

Sharing vocabularies: towards horizontal alignment of values-driven business functions

This paper highlights the emergence of different ‘vocabularies’ that describe various values-driven business functions within large organisations and argues for improved horizontal alignment between them. We investigate two established functions that have long-standing organisational histories: Ethics and Compliance (E&C) and Corporate Social Responsibility (CSR). By drawing upon research on organisational alignment, we explain both the need for and the potential benefit of greater alignment between these values-driven functions. We then examine the structural and socio-cultural dimensions of organisational systems through which E&C and CSR horizontal alignment can be coordinated to improve synergies, address tensions, and generate insight to inform future research and practice in the field of Business and Society. The paper concludes with research questions that can inform future scholarly research and a practical model to guide organizations’ efforts towards inter-functional, horizontal alignment of values-driven organizational practice

Sources of stakeholder salience in the responsible investment movement: why do investors sign the Principles for Responsible Investment?

Since its inception in 2006, the United Nations-backed Principles for Responsible Investment (PRI) have grown to over 1300 signatories representing over $45 trillion. This growth is not slowing down. In this paper, we argue that there is a set of attributes which make the PRI salient as a stakeholder and its claim to sign the six PRI important to institutional investors. We use Mitchell et al.’s (Acad Manag Rev 22:853–886, 1997) theoretical framework of stakeholder salience, as extended by Gifford (J Bus Eth 92:79–97, 2010). We use as evidence confidential data from the annual survey of signatories carried out by the PRI in a 5-year period between 2007 and 2011. The findings highlight pragmatic and organizational legitimacy, normative and utilitarian power, and management values as the attributes that contribute most to the salience of the PRI as a stakeholder