Miracle-dz/UniFAR-FTUs huggingface dataset:
Paraoxonase-2 regulates coagulation activation through endothelial tissue factor.

Oxidative stress and inflammation of the vessel wall contribute to prothrombotic states. The antioxidative protein paraoxonase-2 (PON2) shows reduced expression in human atherosclerotic plaques and endothelial cells in particular. Supporting a direct role for PON2 in cardiovascular diseases, Pon2 deficiency in mice promotes atherogenesis through incompletely understood mechanisms. Here, we show that deregulated redox regulation in Pon2 deficiency causes vascular inflammation and abnormalities in blood coagulation. In unchallenged Pon2-/- mice, we find increased oxidative stress and endothelial dysfunction. Bone marrow transplantation experiments and studies with endothelial cells provide evidence that increased inflammation, indicated by circulating interleukin-6 levels, originates from Pon2 deficiency in the vasculature. Isolated endothelial cells from Pon2-/- mice display increased tissue factor (TF) activity in vitro. Coagulation times were shortened and platelet procoagulant activity increased in Pon2-/- mice relative to wild-type controls. Coagulation abnormalities of Pon2-/- mice were normalized by anti-TF treatment, demonstrating directly that TF increases coagulation. PON2 reexpression in endothelial cells by conditional reversal of the knockout Pon2 cassette, restoration in the vessel wall using bone marrow chimeras, or treatment with the antioxidant N-acetylcysteine normalized the procoagulant state. These experiments delineate a PON2 redox-dependent mechanism that regulates endothelial cell TF activity and prevents systemic coagulation activation and inflammation.
Perioperative glucocorticoids in hip and knee surgery – benefit vs. harm? A review of randomized clinical trials

Glucocorticoids are frequently used to prevent post‐operative nausea and vomiting (PONV), and may be part of multimodal analgesic regimes. The objective of this review was to evaluate the overall benefit vs. harm of perioperative glucocorticoids in patients undergoing hip or knee surgery. A wide search was performed in PubMed, Embase, and Cochrane Central to identify relevant randomized clinical trials. A systematic approach was used, starting from the PRISMA recommendations. The Cochrane Collaboration's tool was used for risk of bias assessment. Studies were divided into three groups: systemic glucocorticoid administration analogous to > 10 mg or ≤ 10 mg dexamethasone, and local glucocorticoid administration. Seventeen studies with data from 1081 patients were included in the final qualitative synthesis. Benefit (of any kind) with glucocorticoid vs. placebo was reported in 15 studies. PONV was reduced with systemic glucocorticoid. Pain was reduced with high‐dose systemic and local glucocorticoid, but not with low‐dose systemic glucocorticoid. Systemic inflammatory markers were reduced with low‐dose and high‐dose systemic glucocorticoid, and with local glucocorticoid. Functional recovery was improved with local glucocorticoid. All studies were small‐sized and none sufficiently powered to meaningfully evaluate uncommon adverse events. Most of the local administration studies had poor scientific quality (high risk of bias). Due to clinical heterogeneity and poor scientific quality, no meta‐analysis was performed.
Biology of nitrogen oxides in the gastrointestinal tract

Throughout the human gastrointestinal tract a variety of reactive nitrogen oxides are continuously formed as a result of a complex interplay between the host, commensal bacteria and dietary factors. These compounds include nitric oxide, nitrite, nitrate, peroxynitrite, S-nitrosothiols, nitrated fatty acids and N-nitrosamines, all of which are bioactive with the potential to affect physiological and pathological processes locally in the gut as well as systemically after absorption. Historically, the literature has been dominated by studies on the formation of potentially carcinogenic nitrosamines, but the focus was shifted in the 1980s with the seminal discovery of the L-arginine-nitric oxide pathway and its profound impact on normal physiological functions. More recently, a nitrate-nitrite-nitric oxide pathway has been discovered, with implications for local host defence and gut mucosal integrity and, intriguingly, also for systemic regulation of cardiovascular and metabolic function. This review discusses recent advances in the understanding of the formation, biochemistry, physiology and pathophysiology of reactive nitrogen oxides in the gastrointestinal tract. In addition, opportunities for nitric oxide-based pharmacological or dietary interventions are highlighted.
The organisation of dementia care by families in Malta: The experiences of family caregivers

This paper discusses the experiences of dementia family caregivers in Malta. The study design was essentially exploratory as this is the first funded social research on dementia in the island of Malta. In-depth semi-structured interviews were conducted in October 2008 with 17 caregivers. Identification of caregivers was through their relatives’ attendance at a hospital based outpatient memory clinic. Interviews were recorded, transcribed and when required, phrases were translated from Maltese to English. A thematic analysis was guided by the questions; What are the experiences of family caregiving in Malta? And what impact does caregiving have for individual/family life? Three key findings are discussed, namely: the organization of family care in Malta; the use of formal services; and the dislocation of dementia caregiving experiences from wider community life. This paper raises questions about support mechanisms currently available in Malta while presenting cross-national learning opportunities to apply established knowledge to the Maltese context.
Vascular disease in West Indian and white diabetics in Britain and Jamaica

Cardiovascular complication rates among matched groups of black and white diabetics in England were compared with those among black diabetics in Kingston, Jamaica. Raised or uncontrolled blood pressure (≥ 160/95 mmHg) was common in all groups but diastolic hypertension was more severe in black patients. Despite this, clinical evidence of myocardial ischaemia was significantly more common in whites when compared with blacks in both centres but no such differences were found in peripheral vascular disease. Cataracts were much more frequent, and background retinopathy was slightly although not significantly commoner, in black patients. Complication rates were not correlated with cigarette smoking which was greatest in black men in Birmingham. The diagnosis and continuous control of hypertension remains a major goal in diabetes.
The gut microbiota elicits a profound metabolic reorientation in the mouse jejunal mucosa during conventionalisation

Objective Proper interactions between the intestinal mucosa, gut microbiota and nutrient flow are required to establish homoeostasis of the host. Since the proximal part of the small intestine is the first region where these interactions occur, and since most of the nutrient absorption occurs in the jejunum, it is important to understand the dynamics of metabolic responses of the mucosa in this intestinal region. Design Germ-free mice aged 8–10 weeks were conventionalised with faecal microbiota, and responses of the jejunal mucosa to bacterial colonisation were followed over a 30-day time course. Combined transcriptome, histology, 1H NMR metabonomics and microbiota phylogenetic profiling analyses were used. Results The jejunal mucosa showed a two-phase response to the colonising microbiota. The acute-phase response, which had already started 1 day after conventionalisation, involved repression of the cell cycle and parts of the basal metabolism. The secondary-phase response, which was consolidated during conventionalisation (days 4–30), was characterised by a metabolic shift from an oxidative energy supply to anabolic metabolism, as inferred from the tissue transcriptome and metabonome changes. Detailed transcriptome analysis identified tissue transcriptional signatures for the dynamic control of the metabolic reorientation in the jejunum. The molecular components identified in the response signatures have known roles in human metabolic disorders, including insulin sensitivity and type 2 diabetes mellitus. Conclusion This study elucidates the dynamic jejunal response to the microbiota and supports a prominent role for the jejunum in metabolic control, including glucose and energy homoeostasis. The molecular signatures of this process may help to find risk markers in the declining insulin sensitivity seen in human type 2 diabetes mellitus, for instance.
Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis

Objective Entecavir (ETV) is a potent inhibitor of viral replication in chronic hepatitis B and prolonged treatment may result in regression of fibrosis. The aim of this study was to investigate the effect of ETV on disease progression. Design In a multicentre cohort study, 372 ETV-treated patients were investigated. Clinical events were defined as development of hepatocellular carcinoma (HCC), hepatic decompensation or death. Virological response (VR) was defined as HBV DNA <80 IU/ml. Results Patients were classified as having chronic hepatitis B without cirrhosis (n=274), compensated cirrhosis (n=89) and decompensated cirrhosis (n=9). The probability of VR was not influenced by severity of liver disease (p=0.62). During a median follow-up of 20 months (IQR 11–32), the probability of developing clinical events was higher for patients with cirrhosis (HR 15.41 (95% CI 3.42 to 69.54), p<0.001). VR was associated with a lower probability of disease progression (HR 0.29 (95% CI 0.08 to 1.00), p=0.05) which remained after correction for established risk factors such as age. The benefit of VR was only significant in patients with cirrhosis (HR 0.22 (95% CI 0.05 to 0.99), p=0.04) and remained after excluding decompensated patients (HR 0.15 (95% CI 0.03 to 0.81), p=0.03). A higher HBV DNA threshold of 2000 IU/ml was not associated with the probability of disease progression (HR 0.20 (95% CI 0.03 to 1.10), p=0.10). Conclusion VR to ETV is associated with a lower probability of disease progression in patients with cirrhosis, even after correction for possible baseline confounders. When using a threshold of 2000 IU/ml, the association between viral replication and disease progression was reduced, suggesting that complete viral suppression is essential for nucleoside/nucleotide analogue treatment, especially in patients with cirrhosis.
Clinical implications of cancer gene mutations in patients with chronic lymphocytic leukemia treated with lenalidomide.

Lenalidomide is clinically active in chronic lymphocytic leukemia (CLL), but its effectiveness in the context of the CLL mutational landscape is unknown. We performed targeted capture sequencing of 295 cancer genes in specimens from 102 CLL patients with treatment-naïve disease (TN patients) and 186 CLL patients with relapsed/refractory disease (R/R patients) who received lenalidomide-based therapy at our institution. The most frequently mutated gene was SF3B1 (15%), followed by NOTCH1 (14%) and TP53 (14%), with R/R patients having significantly more TP53 mutations than did TN patients. Among all lenalidomide-treated patients, del(17p) (P ≤ .001), del(11q) (P = .032), and complex karyotype (P = .022), along with mutations in TP53 (P ≤ .001), KRAS (P = .034), and DDX3X (P ≤ .001), were associated with worse overall response (OR). R/R patients with SF3B1 and MGA mutations had significantly worse OR (P = .025 and .035, respectively). TN and R/R patients with del(17p) and TP53 mutations had worse overall survival (OS) and progression-free survival (PFS). In R/R patients, complex karyotype and SF3B1 mutations were associated with worse OS and PFS; DDX3X mutations were associated with worse PFS only. Weibull regression multivariate analysis revealed that TP53 aberrations (del(17p), TP53 mutation, or both), along with complex karyotype and SF3B1 mutations, were associated with worse OS in the R/R cohort. Taken together, cancer gene mutations in CLL contribute to the already comprehensive risk stratification and add to prognosis and response to treatment. The related trials were registered at www.clinicaltrials. gov as #NCT00267059, #NCT00535873, #NCT00759603, #NCT01446133, and #NCT01002755.
New perspectives in the therapy of chronic hepatitis B

Since approval of the first nucleos(t)ide analogue (NUC) in 1998, remarkable advances have been made in antiviral treatment of chronic hepatitis B virus (HBV) infection. Both interferon-based therapy and treatment with NUCs have evolved to the stage that pegylated interferon (Peg-IFN) has replaced conventional IFN, and entecavir (ETV) and tenofovir disoproxil fumarate (TDF) have become the first-line oral treatments.1–3 As the therapeutic outcomes are still far from satisfactory, many attempts have been made to optimise antiviral therapy of chronic HBV infection. Along with the evolution of drug therapy, quantitation of hepatitis B surface antigen (HBsAg) has gained popularity as a clinically useful seromarker for assessing the natural course and response to therapy of chronic HBV infection. In addition, the discovery of IL28B polymorphism, which has shed new light on the treatment of hepatic C virus (HCV) infection, has been applied in the study of the response of patients with HBV to IFN regimens. These recent developments are reviewed in this article, focusing on the following topics: IL28B and response to IFN or Peg-IFN therapy; response-guided therapy of Peg-IFN treatment; ETV and TDF in field practice naive patients. ### IL28B as a baseline host factor in the response to IFN- or Peg-IFN-based therapy Peg-IFN treatment remains an attractive anti-HBV strategy because it provides higher rates of off-therapy immune control (normal alanine aminotransferase (ALT) levels coupled with HBV DNA <2000 IU/ml and anti-HBe positivity) compared with NUCs.1–3 These benefits, however, are restricted to a subgroup of patients, ∼30%, and the tolerability, although significantly improved compared with standard IFN, is suboptimal, and also there are significant costs. There have been many attempts to identify pretreatment predictors of a response, resulting in the identification of high ALT levels, low HBV DNA, and virus genotype as significant predictors.1–3 However, these factors have limited applicability in clinical practice, the most important …
Enteroglial-derived S100B protein integrates bacteria-induced Toll-like receptor signalling in human enteric glial cells

Objective Enteric glial cells (EGC) have been suggested to participate in host–bacteria cross-talk, playing a protective role within the gut. The way EGC interact with microorganisms is still poorly understood. We aimed to evaluate whether: EGC participate in host–bacteria interaction; S100B and Toll-like receptor (TLR) signalling converge in a common pathway leading to nitric oxide (NO) production. Design Primary cultures of human EGC were exposed to pathogenic (enteroinvasive Escherichia coli; EIEC) and probiotic (Lactobacillus paracasei F19) bacteria. Cell activation was assessed by evaluating the expression of cFos and major histocompatibility complex (MHC) class II molecules. TLR expression in EGC was evaluated at both baseline and after exposure to bacteria by real-time PCR, fluorescence microscopy and western blot analysis. S100B expression and NO release from EGC, following exposure to bacteria, were measured in the presence or absence of specific TLR and S100B pathway inhibitors. Results EIEC activated EGC by inducing the expression of cFos and MHC II. EGC expressed TLR at baseline. Pathogens and probiotics differentially modulated TLR expression in EGC. Pathogens, but not probiotics, significantly induced S100B protein overexpression and NO release from EGC. Pretreatment with specific inhibitors of TLR and S100B pathways abolished bacterial-induced NO release from EGC. Conclusions Human EGC interact with bacteria and discriminate between pathogens and probiotics via a different TLR expression and NO production. In EGC, NO release is impaired in the presence of specific inhibitors of the TLR and S100B pathways, suggesting the presence of a novel common pathway involving both TLR stimulation and S100B protein upregulation.
Bcor insufficiency promotes initiation and progression of myelodysplastic syndrome.

BCOR, encoding BCL-6 corepressor (BCOR), is X-linked and targeted by somatic mutations in various hematological malignancies including myelodysplastic syndrome (MDS). We previously reported that mice lacking Bcor exon 4 (Bcor ΔE4/y ) in the hematopoietic compartment developed NOTCH-dependent acute T-cell lymphoblastic leukemia (T-ALL). Here, we analyzed mice lacking Bcor exons 9 and 10 (Bcor ΔE9-10/y ), which express a carboxyl-terminal truncated BCOR that fails to interact with core effector components of polycomb repressive complex 1.1. Bcor ΔE9-10/y mice developed lethal T-ALL in a similar manner to Bcor ΔE4/y mice, whereas Bcor ΔE9-10/y hematopoietic cells showed a growth advantage in the myeloid compartment that was further enhanced by the concurrent deletion of Tet2 Tet2 Δ/Δ Bcor ΔE9-10/y mice developed lethal MDS with progressive anemia and leukocytopenia, inefficient hematopoiesis, and the morphological dysplasia of blood cells. Tet2 Δ/Δ Bcor ΔE9-10/y MDS cells reproduced MDS or evolved into lethal MDS/myeloproliferative neoplasms in secondary recipients. Transcriptional profiling revealed the derepression of myeloid regulator genes of the Cebp family and Hoxa cluster genes in Bcor ΔE9-10/y progenitor cells and the activation of p53 target genes specifically in MDS erythroblasts where massive apoptosis occurred. Our results reveal a tumor suppressor function of BCOR in myeloid malignancies and highlight the impact of Bcor insufficiency on the initiation and progression of MDS.
Prevalence and predictors of persistent post‐surgical pain 12 months after thoracotomy

Persistent post‐surgical pain is recognised as a major problem. Prevalence after different surgical procedures has been reported to range from 5% up to 85%. Limb amputation and thoracotomy have the highest reported prevalence. Prediction of persistent post‐surgical pain has over the last decade caught attention. Several factors have been investigated, but in‐depth knowledge is still scarce. The purpose of this study was to investigate the prevalence of persistent post‐surgical pain, and predictive factors for persistent post‐surgical pain 12 months after thoracotomy.
Recurrent STAT3-JAK2 fusions in indolent T-cell lymphoproliferative disorder of the gastrointestinal tract.

TO THE EDITOR: Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract (GI TLPD) is a newly recognized entity in the World Health Organization (WHO) classification of lymphoid neoplasms. [1][1] GI TLPD is defined as a clonal T-cell proliferation occurring in the GI tract, most
Whole blood glutathione status and ICU morbidity in critically ill children

A high reduced glutathione ratio is associated with high mortality in adult ICU patients. Whole blood glutathione status in critically ill children is less well characterized. In this study, whole blood glutathione status in pediatric intensive care (PICU) patients was determined and the relation between the redox status of whole blood glutathione and morbidity was investigated.
Lung stress and strain calculations in mechanically ventilated patients in the intensive care unit

Stress and strain are parameters to describe respiratory mechanics during mechanical ventilation. Calculations of stress require invasive and difficult to perform esophageal pressure measurements. The hypothesis of the present study was: Can lung stress be reliably calculated based on non‐invasive lung volume measurements, during a decremental Positive end‐expiratory pressure (PEEP) trial in mechanically ventilated patients with different diseases?
A fellowship of Ring1 maintains AML stem cells.

Polycomb repressive complex 1 (PRC1) and PRC2 are transcriptional repressors that function as key regulators of the self-renewal and differentiation (cell lineage specification) pathways in stem cells. In this issue of Blood, Shima et al1 report that 2 ubiquitin ligases (Ring1A and Ring1B), which are key components of PRC1 complexes, are essential for the establishment and maintenance of acute myeloid leukemia (AML) in mouse models.
Hypothesis-free analysis of ATG16L1 demonstrates gene-wide extent of association with Crohn's disease susceptibility

We read with interest the recent paper by Plantinga et al showing a role for the threonine to alanine (T300A)-variant of ATG16L1 in regulating the expression of ATG16L1 and cytokine production in response to a NOD2-ligand.1 ATG16L1 , notably T300A (rs2241880) in exon 9, was first implicated in Crohn's disease (CD) susceptibility in a non-synonymous single nucleotide polymorphism (SNP) study, followed by a tagging SNP study and regression analysis.2 These authors were unable to demonstrate differences in ATG16L1 expression based on T300A-genotype or intestinal inflammation. ATG16L1 consists of a N-terminal Atg5-interacting domain, a coiled-coil domain (involved in self-dimerisation, containing the T300A variant) and seven WD-domains (putatively interacting with NOD2) at the C-terminus. In ATG16L1-deficient and hypomorphic mice, canonical and bacteria-induced autophagy, Paneth-cell homeostasis and interleukin-1β secretion were dependent on ATG16L1.3 ,4 By contrast, studies focusing on T300A have shown conflicting results.1 , …
Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by Caesarean section

Objective The early intestinal microbiota exerts important stimuli for immune development, and a reduced microbial exposure as well as caesarean section (CS) has been associated with the development of allergic disease. Here we address how microbiota development in infants is affected by mode of delivery, and relate differences in colonisation patterns to the maturation of a balanced Th1/Th2 immune response. Design The postnatal intestinal colonisation pattern was investigated in 24 infants, born vaginally (15) or by CS (nine). The intestinal microbiota were characterised using pyrosequencing of 16S rRNA genes at 1 week and 1, 3, 6, 12 and 24 months after birth. Venous blood levels of Th1- and Th2-associated chemokines were measured at 6, 12 and 24 months. Results Infants born through CS had lower total microbiota diversity during the first 2 years of life. CS delivered infants also had a lower abundance and diversity of the Bacteroidetes phylum and were less often colonised with the Bacteroidetes phylum. Infants born through CS had significantly lower levels of the Th1-associated chemokines CXCL10 and CXCL11 in blood. Conclusions CS was associated with a lower total microbial diversity, delayed colonisation of the Bacteroidetes phylum and reduced Th1 responses during the first 2 years of life.