A tissue injury sensing and repair pathway distinct from host pathogen defense.

Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces cytokines/chemokines to activate resistance mechanisms. Here, we show that, in contrast to most pathogen-induced cytokines, interleukin-24 (IL-24) is predominately induced by barrier epithelial progenitors after tissue injury and is independent of microbiome or adaptive immunity. Moreover, Il24 ablation in mice impedes not only epidermal proliferation and re-epithelialization but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic IL-24 induction in the homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, Il24 expression depends upon both epithelial IL24-receptor/STAT3 signaling and hypoxia-stabilized HIF1α, which converge following injury to trigger autocrine and paracrine signaling involving IL-24-mediated receptor signaling and metabolic regulation. Thus, parallel to innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL-24-mediated tissue repair.

Decoupling expression and editing preferences of ADAR1 p150 and p110 isoforms.

Human adenosine deaminase acting on RNA 1 (ADAR1) catalyzes adenosine-to-inosine deamination reactions on double-stranded RNA molecules to regulate cellular responses to endogenous and exogenous RNA. Defective ADAR1 editing leads to disorders such as Aicardi-Goutières syndrome, an autoinflammatory disease that manifests in the brain and skin, and dyschromatosis symmetrica hereditaria, a skin pigmentation disorder. Two ADAR1 protein isoforms, p150 (150 kDa) and p110 (110 kDa), are expressed and can edit RNA, but the contribution of each isoform to the editing landscape remains unclear, largely because of the challenges in expressing p150 without p110. In this study, we demonstrate that p110 is coexpressed with p150 from the canonical p150-encoding mRNA due to leaky ribosome scanning downstream of the p150 start codon. The presence of a strong Kozak consensus context surrounding the p110 start codon suggests the p150 mRNA is optimized to leak p110 alongside expression of p150. To reduce leaky scanning and translation initiation at the p110 start codon, we introduced synonymous mutations in the coding region between the p150 and p110 start codons. Cells expressing p150 constructs with these mutations produced significantly reduced levels of p110. Editing analysis of total RNA from ADAR1 knockout cells reconstituted separately with modified p150 and p110 revealed that more than half of the A-to-I edit sites are selectively edited by p150, and the other half are edited by either p150 or p110. This method of isoform-selective editing analysis, making use of the modified p150, has the potential to be adapted for other cellular contexts.

Translation from unconventional 5' start sites drives tumour initiation.

We are just beginning to understand how translational control affects tumour initiation and malignancy. Here we use an epidermis-specific, in vivo ribosome profiling strategy to investigate the translational landscape during the transition from normal homeostasis to malignancy. Using a mouse model of inducible SOX2, which is broadly expressed in oncogenic RAS-associated cancers, we show that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared. During tumour initiation, the translational apparatus is redirected towards unconventional upstream initiation sites, enhancing the translational efficiency of oncogenic mRNAs. An in vivo RNA interference screen of translational regulators revealed that depletion of conventional eIF2 complexes has adverse effects on normal but not oncogenic growth. Conversely, the alternative initiation factor eIF2A is essential for cancer progression, during which it mediates initiation at these upstream sites, differentially skewing translation and protein expression. Our findings unveil a role for the translation of 5' untranslated regions in cancer, and expose new targets for therapeutic intervention.

Narrative constructs in modern clinical case reporting.

Modern clinical case reporting takes the form of problem-solution narratives that redescribe symptoms in terms of disease categories. Authored almost always by those who have played a part in the medical assessment of the patient, reports historicise the salient details of an individual's illness as a complex effect of identifiable antecedent causes. Candidate hypotheses linking illness to pathological mechanisms are suggested by the patient's experience, and by data that emerge from clinical examination and investigation. Observational and interpretive statements from these considerations are fitted into a temporally inflected account of the patient's medical condition, configured from the vantage point of hindsight. Drawing on established forms of deferred telling, readers are invited to follow a story that drip-feeds a mixture of contingent and non-incidental information into the account, which engenders and frustrates curiosity, creates expectations, and challenges powers of reasoning and pattern recognition. Whereas case reporting once favoured memoir, the sentimental tale and eccentric biography as the means by which its historical narrative was cast, the preferred genres of contemporary case reporting include detective fiction, and puzzle and riddle narratives, formats that conceptualise the medical consultation in narrow problem-solution terms.

Medical humanities and medical alterity in fiction and in life.

A widely accepted component of any answer to the question 'What is it to do good medical ethics?' is the commitment to benefit people's health, in principlist terminology, 'beneficence'. This paper addresses deliberate maleficence and the cultural otherness with which it is associated, focusing on the activities of the serial killer Dr Harold Shipman. It finds an uncanny 'fit' between the normal operation of healthcare services and this sort of alterity which has attracted little attention from bioethicists but has been addressed by novelists. To the extent that the medical humanities offers useful insights into hard moral problems, its capacities rest on taking account of both the fictional and the real.

Medical humanities: lineage, excursionary sketch and rationale.

Medical Humanities the journal started life in 2000 as a special edition of the JME. However, the intellectual taproots of the medical humanities as a field of enquiry can be traced to two developments: calls made in the 1920s for the development of multidisciplinary perspectives on the sciences that shed historical light on their assumptions, methods and practices; refusals to assimilate all medical phenomena to a biomedical worldview. Medical humanities the term stems from a desire to situate the significance of medicine as a product of culture. But despite growing usage over half a century the term defies a unifying encapsulation and continues to conjure up a multitude of discourse communities, including scholars working at the interfaces of health and humanities, arts and health, and medical education and bioethics. The field is intellectually capacious and polymorphous, forming and reforming around critical new research questions and teaching tasks spanning disciplines.

Antibiotics versus placebo for acute bacterial conjunctivitis.

BACKGROUND: Acute bacterial conjunctivitis is an infection of the conjunctiva. Both the palpebral and the bulbar ocular conjunctival surfaces are usually affected and typically become red and inflamed. Antibiotic therapy is widely used for the treatment of acute bacterial conjunctivitis. This Cochrane Review was first published in The Cochrane Library in 1999; updated in 2006 and again in 2012. OBJECTIVES: To assess the benefits and harms of antibiotic therapy in the management of acute bacterial conjunctivitis. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 7), MEDLINE (January 1950 to July 2012), EMBASE (January 1980 to July 2012), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 18 July 2012. SELECTION CRITERIA: We included double-masked randomised controlled trials (RCTs) in which any form of antibiotic treatment had been compared with placebo/vehicle in the management of acute bacterial conjunctivitis. This included topical, systemic and combination (for example, antibiotics and steroids) antibiotic treatments. DATA COLLECTION AND ANALYSIS: Two authors (UN and SM) independently checked and reviewed the titles and abstracts of identified studies. We assessed the full text of all potentially relevant studies. We graded the included RCTs for methodological quality using Cochrane methodology. We performed data extraction in a standardised manner. We performed random-effects meta-analyses using RevMan. MAIN RESULTS: We identified 11 eligible RCTs which randomised a total of 3673 participants. One further trial, which was published in abstract form in 1990 but has yet to be reported fully, is currently 'awaiting assessment'. Six of the 11 included studies have been included for the first time in this latest (2012) update. The trials were heterogeneous in terms of their inclusion and exclusion criteria, the nature of the intervention, and the outcome measures assessed. We judged two of the trials to be of high quality and graded the remainder as poor quality.Meta-analyses of data on clinical and microbiological remission rates revealed that topical antibiotics were of benefit in improving 'early' (days two to five) clinical (risk ratio (RR) 1.36, 95% confidence interval (CI) 1.15 to 1.61) and microbiological (RR 1.55, 95% CI 1.37 to 1.76) remission rates. At the 'late' time point (days six to 10), antibiotics were found to still confer modest benefits in clinical remission (RR 1.21, 95% CI 1.10 to 1.33) and microbiological cure rates (RR 1.37, 95% CI 1.24 to 1.52). By days six to 10, 41% (95% CI 38 to 43) of cases had resolved in those receiving placebo. We found no data on the cost-effectiveness of antibiotics. No serious outcomes were reported in either the active or placebo arms of these trials, suggesting that important sight-threatening complications are an infrequent occurrence. AUTHORS' CONCLUSIONS: Although acute bacterial conjunctivitis is frequently self limiting, the findings from this updated systematic review suggest that the use of antibiotic eye drops is associated with modestly improved rates of clinical and microbiological remission in comparison to the use of placebo. Use of antibiotic eye drops should therefore be considered in order to speed the resolution of symptoms and infection.

The integrated stress response remodels the microtubule-organizing center to clear unfolded proteins following proteotoxic stress.

Cells encountering stressful situations activate the integrated stress response (ISR) pathway to limit protein synthesis and redirect translation to better cope. The ISR has also been implicated in cancers, but redundancies in the stress-sensing kinases that trigger the ISR have posed hurdles to dissecting physiological relevance. To overcome this challenge, we targeted the regulatory node of these kinases, namely, the S51 phosphorylation site of eukaryotic translation initiation factor eIF2α and genetically replaced eIF2α with eIF2α-S51A in mouse squamous cell carcinoma (SCC) stem cells of skin. While inconsequential under normal growth conditions, the vulnerability of this ISR-null state was unveiled when SCC stem cells experienced proteotoxic stress. Seeking mechanistic insights into the protective roles of the ISR, we combined ribosome profiling and functional approaches to identify and probe the functional importance of translational differences between ISR-competent and ISR-null SCC stem cells when exposed to proteotoxic stress. In doing so, we learned that the ISR redirects translation to centrosomal proteins that orchestrate the microtubule dynamics needed to efficiently concentrate unfolded proteins at the microtubule-organizing center so that they can be cleared by the perinuclear degradation machinery. Thus, rather than merely maintaining survival during proteotoxic stress, the ISR also functions in promoting cellular recovery once the stress has subsided. Remarkably, this molecular program is unique to transformed skin stem cells, hence exposing a vulnerability in cancer that could be exploited therapeutically.

Tracking shame and humiliation in Accident and Emergency.

In this paper, we reflect upon shame and humiliation as threats to personal and professional integrity and moral agency within contemporary health care. A personal narrative, written by a nurse about a particular shift in a British National Health Service Accident and Emergency Department, is provided as a case study. This is critically reflected and commented upon in dialogue with insights into the nature of shame and humiliation. It is suggested that Accident and Emergency is a locus that is latently prone to dynamics of shame and humiliation, a potential exacerbated within a culture subject to externally-determined time targets that are enforced by a top-down system of surveillance and management. The result is that nurses may lose their sense of professional competence and responsibility, moral agency, and integrity, to their own personal detriment, as well as to the detriment of patients with whom they work. Insofar as examining a small part of a whole may suggest insights into the operation and ethos of a very large system, this very particular case study narrative/reflection has some important implications and lessons for the wider organization and provision of health care in Britain and beyond.

House dust mite avoidance measures for perennial allergic rhinitis.

BACKGROUND: This is an update of a Cochrane Review first published in The Cochrane Library in Issue 4, 2001 and previously updated in 2003 and 2007.It is estimated that in developed countries approximately 30% of the general population suffer from one or more allergic disorders, of which allergic rhinitis is particularly common. Perennial rhinitis is most often due to allergy to the house dust mite. In such patients house dust mite avoidance is logical, but there is considerable uncertainty regarding the efficacy and effectiveness of interventions designed to reduce dust mite exposure. OBJECTIVES: To assess the benefit (and harm) of measures designed to reduce house dust mite exposure in the management of house dust mite sensitive allergic rhinitis. SEARCH STRATEGY: Our search included the Cochrane Ear, Nose and Throat Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials Register (CENTRAL) (The Cochrane Library Issue 4, 2009), MEDLINE and EMBASE. The date of the last search was 31 December 2009. SELECTION CRITERIA: Randomised controlled trials, with or without blinding, in which house dust mite control measures have been evaluated in comparison with placebo or other dust mite avoidance measures, in patients with clinician-diagnosed allergic rhinitis and confirmed allergy to dust mite. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles and abstracts, graded methodological quality using the Cochrane approach and extracted data. Meta-analysis was neither possible nor appropriate due to heterogeneity of the patient groups studied. MAIN RESULTS: Nine trials involving 501 participants satisfied the inclusion criteria. Only two studies investigating the effectiveness of mite impermeable bedding covers were of good quality; the remaining seven studies were small and of poor quality. Two trials investigated the efficacy of acaricides, another two trials investigated the role of high-efficiency particulate air (HEPA) filters. One trial, using a factorial design, investigated the efficacy of both acaricide and house dust mite impermeable bedding covers in isolation and combination; the remaining four trials investigated the efficacy of bedroom environmental control programmes involving use of house dust mite impermeable bedding covers. Seven of the nine trials reported that, when compared with control, the interventions studied resulted in significant reductions in house dust mite load. Of the interventions studied to date, acaricides appear to be the most promising type of intervention, although the findings from these studies need to be interpreted with care because of their methodological limitations. House dust mite impermeable bedding as an isolated intervention is unlikely to offer clinical benefit. No serious adverse effects were reported from any of the interventions. AUTHORS' CONCLUSIONS: Trials to date have on the whole been small and of poor methodological quality, making it difficult to offer any definitive recommendations on the role, if any, of house dust mite avoidance measures in the management of house dust mite sensitive perennial allergic rhinitis. The results of these studies suggest that use of acaricides and extensive bedroom-based environmental control programmes may be of some benefit in reducing rhinitis symptoms and, if considered appropriate, these should be the interventions of choice. Isolated use of house dust mite impermeable bedding is unlikely to prove effective.

Author Correction: Extracellular serine controls epidermal stem cell fate and tumour initiation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Extracellular serine controls epidermal stem cell fate and tumour initiation.

Tissue stem cells are the cell of origin for many malignancies. Metabolites regulate the balance between self-renewal and differentiation, but whether endogenous metabolic pathways or nutrient availability predispose stem cells towards transformation remains unknown. Here, we address this question in epidermal stem cells (EpdSCs), which are a cell of origin for squamous cell carcinoma. We find that oncogenic EpdSCs are serine auxotrophs whose growth and self-renewal require abundant exogenous serine. When extracellular serine is limited, EpdSCs activate de novo serine synthesis, which in turn stimulates α-ketoglutarate-dependent dioxygenases that remove the repressive histone modification H3K27me3 and activate differentiation programmes. Accordingly, serine starvation or enforced α-ketoglutarate production antagonizes squamous cell carcinoma growth. Conversely, blocking serine synthesis or repressing α-ketoglutarate-driven demethylation facilitates malignant progression. Together, these findings reveal that extracellular serine is a critical determinant of EpdSC fate and provide insight into how nutrient availability is integrated with stem cell fate decisions during tumour initiation.

Oncolytic HSV-Infected Glioma Cells Activate NOTCH in Adjacent Tumor Cells Sensitizing Tumors to Gamma Secretase Inhibition.

PURPOSE: To examine the effect of oncolytic herpes simplex virus (oHSV) on NOTCH signaling in central nervous system tumors. EXPERIMENTAL DESIGN: Bioluminescence imaging, reverse phase protein array proteomics, fluorescence microscopy, reporter assays, and molecular biology approaches were used to evaluate NOTCH signaling. Orthotopic glioma-mouse models were utilized to evaluate effects in vivo. RESULTS: We have identified that herpes simplex virus-1 (HSV-1; oncolytic and wild-type)-infected glioma cells induce NOTCH signaling, from inside of infected cells into adjacent tumor cells (inside out signaling). This was canonical NOTCH signaling, which resulted in activation of RBPJ-dependent transcriptional activity that could be rescued with dnMAML. High-throughput screening of HSV-1-encoded cDNA and miRNA libraries further uncovered that HSV-1 miR-H16 induced NOTCH signaling. We further identified that factor inhibiting HIF-1 (FIH-1) is a direct target of miR-H16, and that FIH-1 downregulation by virus encoded miR-H16 induces NOTCH activity. FIH-1 binding to Mib1 has been reported, but this is the first report that shows FIH-1 sequester Mib1 to suppress NOTCH activation. We observed that FIH-1 degradation induced NOTCH ligand ubiquitination and NOTCH activity. REMBRANDT and The Cancer Genome Atlas data analysis also uncovered a significant negative regulation between FIH-1 and NOTCH. Furthermore, combination of oHSV with NOTCH-blocking gamma secretase inhibitor (GSI) had a therapeutic advantage in two different intracranial glioma models treated with oncolytic HSV, without affecting safety profile of the virus in vivo. CONCLUSIONS: To our knowledge this is the first report to identify impact of HSV-1 on NOTCH signaling and highlights the significance of combining oHSV and GSI for glioblastoma therapy.

Pyruvate kinase M2 regulates homologous recombination-mediated DNA double-strand break repair.

Resistance to genotoxic therapies is a primary cause of treatment failure and tumor recurrence. The underlying mechanisms that activate the DNA damage response (DDR) and allow cancer cells to escape the lethal effects of genotoxic therapies remain unclear. Here, we uncover an unexpected mechanism through which pyruvate kinase M2 (PKM2), the highly expressed PK isoform in cancer cells and a master regulator of cancer metabolic reprogramming, integrates with the DDR to directly promote DNA double-strand break (DSB) repair. In response to ionizing radiation and oxidative stress, ATM phosphorylates PKM2 at T328 resulting in its nuclear accumulation. pT328-PKM2 is required and sufficient to promote homologous recombination (HR)-mediated DNA DSB repair through phosphorylation of CtBP-interacting protein (CtIP) on T126 to increase CtIP's recruitment at DSBs and resection of DNA ends. Disruption of the ATM-PKM2-CtIP axis sensitizes cancer cells to a variety of DNA-damaging agents and PARP1 inhibition. Furthermore, increased nuclear pT328-PKM2 level is associated with significantly worse survival in glioblastoma patients. Combined, these data advocate the use of PKM2-targeting strategies as a means to not only disrupt cancer metabolism but also inhibit an important mechanism of resistance to genotoxic therapies.

Lineages of language and the diagnosis of asthma.

Asthma, wheeze and cough are words with profoundly differing histories, etymologies and meanings. Yet their medical usage today is clustered around the diagnosis and management of a single disease. Hitherto, asthma has been a clinical diagnosis but wheeze, cough and asthma now are key terms in cross-cultural questionnaire surveys which seek information on asthma prevalence. In this essay, we examine differences in the linguistic properties of terms likely to be relevant to interpreting large-scale variations in asthma prevalence uncovered by questionnaires. We show how etymologically distinct each term is: while asthma and cough each share semantic congruencies across six European languages, albeit for different reasons, there is less congruence across these languages for the term wheeze. The medical meanings of all three terms contrast with meanings revealed by the non-medical usage of all three terms, which are highly figurative. Linguistic considerations indicate that interpretation of international questionnaires that phrase questions in terms of cough, asthma and their derivatives are likely to be more reliable for the purposes of comparing prevalence than those which deploy questions phrased in terms of wheeze.

The Status of "Nonmotor" Features of the Malady in an Essay on the Shaking Palsy (1817).

This chapter examines the status James Parkinson accorded "nonmotor" features of the malady set out in his 1817 Essay. In reading the Essay through the lens of this recently developed dichotomy I use "nonmotor" to mean the application of a late 20th-century category to a 200 year old account, whereas nonmotor designates application of the concept to contemporary understanding. While Parkinson granted "motor" components of the malady high definitional visibility, the Essay shows he was also attentive to patients' overall well-being and noticed some "nonmotor" aspects of the malady, in particular, constipation, interrupted speech, and difficulties with saliva and swallowing. He appears to have granted these features more than incidental status, especially in assessing variant pictures of the Shaking Palsy.