Remodelling of microRNAs in colorectal cancer by hypoxia alters metabolism profiles and 5-fluorouracil resistance

AN, HT and AP are Constance Travis post-graduate fellows. NS is a Barts and The London post-doctoral fellow. SMD is a Bowel & Cancer Research post-doctoral fellow. TS is supported by a Grant-in-Aid for scientific research on Innovative Areas, Japan (No. 22134007 to T.S.), and the Yamagata Prefectural Government and City of Tsuruoka

First aid in acute stroke: Introducing a concept of first action to laypersons

OBJECTIVE: First aid training is well established to teach the public how to recognize a medical emergency and take appropriate action. Though it is now handled as a high priority emergency stroke is not among the main topics of first aid. We investigated if first aid training may be useful for enhancing stroke awareness. METHODS: We developed a 15–20 minute teaching session about stroke as an emergency including signs and symptoms and first hands-on measures. The session was integrated in standard first aid training of the St John Ambulance of Germany and participants were asked to fill out a questionnaire regarding their knowledge about stroke. Subjects were questioned before the stroke lesson and again at the end of the training. RESULTS: 532 participants of the training responded to the questionnaire (mean age 28.6 years, 53.6% male). There was a significant increase in proportion of subjects correctly defining what stroke is (28.4% vs. 69.9%, p < 0,001) and in the mean number of stroke symptoms listed (1.52 vs. 3.35, p < 0,001) by the participants. The number of participants unable to list at least 1 symptom decreased significantly (12.8 vs. 3.6%, p<0.001). CONCLUSIONS: In our study a teaching lesson integrated in first aid training was effective in improving stroke knowledge of participants. First aid training should be used for stroke information complementary to other activities like mass media campaigns as it is effective, could reach younger people that are not primarily interested in stroke and provides connections to other health topics

Circulating microRNAs Reveal Time Course of Organ Injury in a Porcine Model of Acetaminophen-Induced Acute Liver Failure

Acute liver failure is a rare but catastrophic condition which can progress rapidly to multi-organ failure. Studies investigating the onset of individual organ injury such as the liver, kidneys and brain during the evolution of acute liver failure, are lacking. MicroRNAs are short, non-coding strands of RNA that are released into the circulation following tissue injury. In this study, we have characterised the release of both global microRNA and specific microRNA species into the plasma using a porcine model of acetaminophen-induced acute liver failure. Pigs were induced to acute liver failure with oral acetaminophen over 19h±2h and death occurred 13h±3h thereafter. Global microRNA concentrations increased 4h prior to acute liver failure in plasma (P<0.0001) but not in isolated exosomes, and were associated with increasing plasma levels of the damage-associated molecular pattern molecule, genomic DNA (P<0.0001). MiR122 increased around the time of onset of acute liver failure (P<0.0001) and was associated with increasing international normalised ratio (P<0.0001). MiR192 increased 8h after acute liver failure (P<0.0001) and was associated with increasing creatinine (P<0.0001). The increase in miR124-1 occurred concurrent with the pre-terminal increase in intracranial pressure (P<0.0001) and was associated with decreasing cerebral perfusion pressure (P<0.002)

Epigenetic and metabolic reprogramming of fibroblasts in Crohn's disease strictures reveals histone deacetylases as therapeutic targets.

BACKGROUND & AIMS: No effective therapeutic intervention exists for intestinal fibrosis in Crohn's disease [CD]. We characterised fibroblast subtypes, epigenetic and metabolic changes, and signalling pathways in CD fibrosis to inform future therapeutic strategies. METHODS: We undertook immunohistochemistry, metabolic, signalling pathway and Epigenetic [Transposase-Accessible Chromatin using sequencing] analyses associated with collagen production in CCD-18Co intestinal fibroblasts and primary fibroblasts isolated from stricturing [SCD] and non-stricturing [NSCD] CD small intestine. SCD/ NSCD fibroblasts were cultured with TGFβ and valproic acid [VPA]. RESULTS: Stricturing CD was characterised by distinct histone deacetylase [HDAC] expression profiles, particularly HDAC1, HDAC2, and HDAC7. As a proxy for HDAC activity, reduced numbers of H3K27ac+ cells were found in SCD compared to NSCD sections. Primary fibroblasts had increased extracellular lactate [increased glycolytic activity] and intracellular hydroxyproline [increased collagen production] in SCD compared to NSCD cultures. The metabolic effect of TGFβ-stimulation was reversed by the HDAC inhibitor VPA. SCD fibroblasts appear "metabolically primed" and responded more strongly to both TGFβ and VPA. Treatment with VPA revealed TGFβ-dependent and independent Collagen-I production in CCD-18Co cells and primary fibroblasts. VPA altered the epigenetic landscape with reduced chromatin accessibility at the COL1A1 and COL1A2 promoters. CONCLUSIONS: Increased HDAC expression profiles, H3K27ac hypoacetylation, a significant glycolytic phenotype, and metabolic priming, characterise SCD-derived as compared to NSCD fibroblasts. Our results reveal a novel epigenetic component to Collagen-I regulation and TGFβ-mediated CD fibrosis. HDAC inhibitor therapy may 'reset' the epigenetic changes associated with fibrosis

Femoral nerve compression secondary to a ganglion cyst arising from a hip joint: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Femoral nerve compression due to a cystic lesion around the hip joint is rare and only a few cases have been described in the literature. Among these, true ganglion cysts are even more rare.</p> <p>Case presentation</p> <p>We report the case of a 57-year-old woman with femoral nerve compression caused by a true ganglion cyst of the hip joint.</p> <p>Conclusion</p> <p>A high index of suspicion is required to predict a non-palpable cystic lesion around the hip joint as it may mimic different disorders and should be kept in mind in the differential diagnosis of unusual groin pain, radicular pain and peripheral vascular disorders.</p

Using dissolved H₂O in rhyolitic glasses to estimate palaeo-ice thickness during a subglacial eruption at Bláhnúkur(Torfajökull, Iceland)

The last decade has seen the refinement of a technique for reconstructing palaeo-ice thicknesses based on using the retained H2O and CO2 content in glassy eruptive deposits to infer quenching pressures and therefore ice thicknesses. The method is here applied to Bláhnúkur, a subglacially erupted rhyolitic edifice in Iceland. A decrease in water content from ~0.7 wt.% at the base to ~0.3 wt.% at the top of the edifice suggests that the ice was 400 m thick at the time of the eruption. As Bláhnúkur rises 350 m above the surrounding terrain, this implies that the eruption occurred entirely within ice, which corroborates evidence obtained from earlier lithofacies studies. This paper presents the largest data set (40 samples) so far obtained for the retained volatile contents of deposits from a subglacial eruption. An important consequence is that it enables subtle but significant variations in water content to become evident. In particular, there are anomalous samples which are either water-rich (up to 1 wt.%) or water-poor (~0.2 wt.%), with the former being interpreted as forming intrusively within hyaloclastite and the latter representing batches of magma that were volatile-poor prior to eruption. The large data set also provides further insights into the strengths and weaknesses of using volatiles to infer palaeo-ice thicknesses and highlights many of the uncertainties involved. By using examples from Bláhnúkur, the quantitative use of this technique is evaluated. However, the relative pressure conditions which have shed light on Bláhnúkur’s eruption mechanisms and syn-eruptive glacier response show that, despite uncertainties in absolute values, the volatile approach can provide useful insight into the mechanisms of subglacial rhyolitic eruptions, which have never been observed

Assessment of normal tricuspid valve anatomy in adults by real-time three-dimensional echocardiography

Background: The tricuspid valve (TV) is a complex structure. Unlike the aortic and mitral valve it is not possible to visualize all TV leaflets simultaneously in one cross-sectional view by standard two-dimensional echocardiography (2DE) either transthoracic or transesophageal due to the position of TV in the far field. Aim: Quantitative and qualitative assessment of the normal TV using real-time 3-dimensional echocardiography (RT3DE). Methods: RT3DE was performed for 100 normal adults (mean age 30 ± 9 years, 65% males). RT3DE visualization was evaluated by 4-point score (1: not visualized, 2: inadequate, 3: sufficient, and 4: excellent). Measurements included TV annulus diameters (TAD), TV area (TVA), and commissural width. Results: In 90% of patients with good 2DE image quality, it was possible to analyse TV anatomy by RT3DE. A detailed anatomical structure including unique description and measurement of tricuspid annulus shape and size, TV leaflets shape, and mobility, and TV commissural width were obtained in majority of patients. Identification of each TV leaflet as seen in the routine 2DE views was obtained. Conclusion: RT3DE of the TVis feasible in a large number of patients. RT3DE may add to functional 2DE data in description of TV anatomy and providing highly reproducible and actual reality (anatomical and functional) measurements

Alveolar hypoxia, alveolar macrophages, and systemic inflammation

Diseases featuring abnormally low alveolar PO2 are frequently accompanied by systemic effects. The common presence of an underlying inflammatory component suggests that inflammation may contribute to the pathogenesis of the systemic effects of alveolar hypoxia. While the role of alveolar macrophages in the immune and defense functions of the lung has been long known, recent evidence indicates that activation of alveolar macrophages causes inflammatory disturbances in the systemic microcirculation. The purpose of this review is to describe observations in experimental animals showing that alveolar macrophages initiate a systemic inflammatory response to alveolar hypoxia. Evidence obtained in intact animals and in primary cell cultures indicate that alveolar macrophages activated by hypoxia release a mediator(s) into the circulation. This mediator activates perivascular mast cells and initiates a widespread systemic inflammation. The inflammatory cascade includes activation of the local renin-angiotensin system and results in increased leukocyte-endothelial interactions in post-capillary venules, increased microvascular levels of reactive O2 species; and extravasation of albumin. Given the known extrapulmonary responses elicited by activation of alveolar macrophages, this novel phenomenon could contribute to some of the systemic effects of conditions featuring low alveolar PO2