Citations

SummaryBackgroundChemokines contribute to the pathogenesis of autoimmune hepatitis by directing the migration and positioning of inflammatory and immune cells within the liver.AimDescribe the liver‐infiltrating effector cell populations in autoimmune hepatitis, indicate the chemokines that influence their migration, describe the role of chemokines in hepatic fibrosis and identify chemokine‐directed treatment opportunities.MethodsStudies cited in Pub Med from 1972 to 2014 for autoimmune hepatitis, chemokines in liver disease, pathogenesis of autoimmune hepatitis and chemokine therapy were selected.ResultsT helper type 17 lymphocytes expressing CXCR3 and CCR6 are attracted to the liver by the secretion of CXCL9, CXCL10 and CXCL11. These cells recruit pro‐inflammatory T helper type 1 lymphocytes expressing CXCR3 and CCR5 by secreting CXCL10. Resident natural killer T cells expressing CXCR6 migrate in response to the local secretion of CXCL16, and they modulate the inflammatory response. T helper type 2 lymphocytes expressing CCR4 are attracted by CCL17 and CCL22, and they dampen the expansion of pro‐inflammatory cells. Regulatory T cells expressing CXCR3 are attracted by the secretion of CXCL9, and they help dampen the pro‐inflammatory responses. CCL2, CCL3, CCL5, CXCL4, CXCL10 and CXCL16 promote fibrosis by activating or attracting hepatic stellate cells, and CX3CL1 may prevent fibrosis by affecting the apoptosis of monocytes.ConclusionsChemokines are requisites for mobilising, directing and positioning the effector cells in immune‐mediated liver disease. They are feasible therapeutic targets in autoimmune hepatitis, and the evaluation of monoclonal antibodies that neutralise the pro‐inflammatory ligands or designer peptides that block receptor activity are investigational opportunities.

ABSTRACTMutations in leucine‐rich repeat kinase 2 (LRRK2) are found in a significant proportion of late‐onset Parkinson's disease (PD) patients. Elucidating the neuroanatomical localization of LRRK2 will further define LRRK2 function and the molecular basis of PD. Here, we utilize recently characterized monoclonal antibodies to evaluate LRRK2 expression in rodent brain regions relevant to PD. In both mice and rats, LRRK2 is highly expressed in the cortex and striatum, particularly in pyramidal neurons of layer V and in medium spiny neurons within striosomes. Overall, rats have a more restricted distribution of LRRK2 compared with mice. Mice, but not rats, show high levels of LRRK2 expression in the substantia nigra pars compacta. Expression of the pathogenic LRRK2‐G2019S protein from mouse bacterial artificial chromosome (BAC) constructs closely mimics endogenous LRRK2 distribution in the mouse brain. However, LRRK2‐G2019S expression derived from human BAC constructs causes LRRK2 to be expressed in additional neuron subtypes in the rat such as striatal cholinergic interneurons and the substantia nigra pars compacta. The distribution of LRRK2 from human BAC constructs more closely resembles descriptions of LRRK2 in humans and nonhuman primates. Computational analyses of DNA regulatory elements in LRRK2 show a primate‐specific promoter sequence that does not exist in lower mammalian species. These noncoding regions may be involved in directing neuronal expression patterns. Together, these studies will aid in understanding the normal function of LRRK2 in the brain and will assist in model selection for future studies. J. Comp. Neurol. 522:2465–2480, 2014. © 2014 Wiley Periodicals, Inc.

Understanding the mechanisms that sustain pluripotency in human embryonic stem cells (hESCs) is an active area of research that may prove useful in regenerative medicine and will provide fundamental information relevant to development and cancer. hESCs and cancer cells share the unique ability to proliferate indefinitely and rapidly. Because the protein survivin is uniquely overexpressed in virtually all human cancers and in hESCs, we sought to investigate its role in supporting the distinctive capabilities of these cell types. Results presented here suggest that survivin contributes to the maintenance of pluripotency and that post‐transcriptional control of survivin isoform expression is selectively regulated by microRNAs. miR‐203 has been extensively studied in human tumors, but has not been characterized in hESCs. We show that miR‐203 expression and activity is consistent with the expression and subcellular localization of survivin isoforms that in turn modulate expression of the Oct4 and Nanog transcription factors to sustain pluripotency. This study contributes to understanding of the complex regulatory mechanisms that govern whether hESCs proliferate or commit to lineages. J. Cell. Physiol. 230: 63–70, 2015. © 2014 Wiley Periodicals, Inc.

BackgroundFew patients decline therapy of a cardiovascular implantable electronic device (CIED), and little is known about the characteristics or reasoning of those who do. Our objective was to describe the reasons why patients decline CIED implantation using qualitative methods.MethodsQualitative, engaging thematic analysis. Three patient focus groups led by two trained facilitators and one semi‐structured interview guide.ResultsOf the 13 patients, two were women and all were white (median age [range], 65 [44–88] years). Five themes emerged: (1) don't mess with a good thing; (2) my health is good enough; (3) independent decision making; (4) it's your job, but it's my choice; and (5) gaps in learning. Most patients who decline CIEDs are asymptomatic. Other reasons to decline included feeling well, enjoying life, acceptance of the future, desire to try to improve health through diet and exercise, hearing of negative CIED experiences, and unwillingness to take on associated risks of CIED implantation. A medical record review showed that clinicians understand patients’ reasons for declining CIED treatment. However, focus group data suggest that gaps in patients’ knowledge around the purpose and function of CIEDs exist and patients may benefit from targeted education.ConclusionsPatients decline implantation of CIEDs for various reasons. Most patients who decline therapy are asymptomatic at the time of their device consult. Focus group information show data suggestive that device consultations should be enhanced to address gaps in patient learning and confirm knowledge transfer. Clinicians should revisit treatment options iteratively.

AbstractIdeas about personalized medicine are underpinned in part by evolutionary biology's Modern Synthesis. In this essay we link personalized medicine to the efforts of the early statistical investigators who quantified the heritability of human phenotype and then attempted to reconcile their observations with Mendelian genetics. As information about the heritability of common diseases was obtained, similar efforts were directed at understanding the genetic basis of disease phenotypes. These ideas were part of the rationale driving the Human Genome Project and subsequently the personalized medicine movement. In this context, we discuss: (1) the current state of the genotype–phenotype relationship in humans, (2) the common‐disease–common‐variant hypothesis, (3) the current ability of ‘omic’ information to inform clinical decision making, (4) emerging ideas about the therapeutic insight available from rare genetic variants, and (5) the social and behavioural barriers to the wider potential success of personalized medicine. There are significant gaps in knowledge as well as conceptual, intellectual, and philosophical limitations in each of these five areas. We then provide specific recommendations to mitigate these limitations and close by asking if it is time for the biomedical research community to ‘stop chasing Mendel?’