68 research outputs found
Integrated Care for Heart Failure in Primary Care
Chronic heart failure (CHF or simply HF) is a complex clinical syndrome that involves more than 2% of the general population and over 10% of the older people. For people with reduced ventricular function (the classical HFrEF phenotype), the guideline-directed medical therapy (GDMT) (e.g., Ace-inhibitors, beta-blockers, diuretics, rehabilitation or implantable ventricular devices) demonstrated to be efficacious in reducing hospitalisations and prolonging survival. Vice-versa, the HF with preserved ejection fraction (diastolic HF or HFpEF phenotype) is a much more complex syndrome, in which co-morbidities (such as COPD, depression, anemia, and diabetes, CAD) play a significant role in the decompensation episodes
Population genetics and forensic DNA for conservation management of the Cypriot mouflon (Ovis orientalis ophion)
The mouflon (Ovis orientalis ophion) is the largest wild terrestrial mammal of Cyprus. Considered as the flagship species of the island, its population (c. 3000 head) has a distribution range limited to the mountainous Paphos Forest and adjacent areas including parts of Troodos National Forest (> 700 Km2). The species is protected by a rigorous national legislation supported since 1996 by management plans carried out by the Game and Fauna Service, and, together with its habitat, by the National Law 152 (I)/2003 for the Protection & Management of Wild Birds and Game Species. The species is listed in the Annexes II and IV of 92/43 Habitats Directive, in the Appendix I of CITES, and classified as “vulnerable” by the IUCN. Poaching, habitat loss, road network building and livestock intrusion (i.e., increased risk of pathogen infection) represent the main threatening factors. We aimed at elucidating the systematic placement of the Cypriot mouflon to enforce its protection within an adaptive conservation framework. Therefore, we attempted to determine its genetic structure and relationships with either historically preserved (Corsica, Sardinia) or recently introduced (central Italy) populations including also GenBank entries from the historical range of the species (Near East). The Game and Fauna Service in collaboration with the Cyprus Veterinary Service collected 63 blood samples: 53 were from mouflons captured in the Paphos forest, eight from captive individuals and two of unknown origin. We also sampled 20 mouflons in Sardinia either in the wild (16) or in captivity (4), and collected scats of both Corsican (19) and central Italy (23: Tuscan Archipelago National Park, 13; Tuscan-Emilian Apennines National Park, 6; Apuan Alps Regional Park, 4) mouflon populations in order to increase geographical scope. We genotyped each sample at the entire mitochondrial DNA Cytochrome-b codifying gene (Cyt-b, 1140 bp) and up to 12 microsatellite DNA markers (Short Tandem Repeats, STR) isolated from goat, sheep and cattle genomes. We found that the Cypriot mouflon strongly diverged from western Mediterranean conspecifics, while North West Iran appeared as the most credited geographic region as the source for its ancient introduction to Cyprus. Although we disclosed much lower mitochondrial and nuclear DNA diversity in the Cypriot than in other island populations, neither evidence of genetic bottleneck nor significant low level of both average pairwise relatedness and inbreeding coefficient was detected. Overall, present mitochondrial and STR dataset worked reliably as crime-fighting tool to tackle illegal mouflon killing in Cyprus. Between 2008 and 2013, the Police and the Game and Fauna Service, in collaboration with the Cyprus Veterinary Services, confiscated 29 samples (meat, hairs, bloodstains) dealing with nine episodes of supposed poaching against the Cypriot mouflon. In all cases, we identified the species in point by sequencing the mtDNA Cyt-b gene. In one case, we were specifically requested to establish if there was a link between three dead mouflons recovered at a roadside and 12 bloodstains collected in the car of suspected poachers at the crime scene. With reference to this case, we were able to match nine bloodstains to two out of the three carcasses (seven with very strong support: Likelihood Ratio >3000 and Random Match Probability <10-3), overall assigning 22 out of 29 samples to the Cypriot mouflon and the remaining ones to wild boar, cow, domestic goat, horse and hare. These results included the first genetic reference for the Cypriot mouflon and the first published material of forensic wildlife investigations in Cyprus
Ajulemic acid exerts potent anti-fibrotic effect during the fibrogenic phase of bleomycin lung
Background: Ajulemic acid (AjA) is a synthetic analogue of tetrahydrocannabinol that can prevent and limit progression of skin fibrosis in experimental systemic sclerosis. In this study we investigated whether AjA also prevents and modulates lung fibrosis induced by bleomycin (BLM) when administered in mice during the inflammatory or the fibrogenic phase of the model. Methods: The anti-inflammatory and antifibrotic efficacy of AjA was evaluated in DBA/2 mice treated orally once a day starting either at day 0 (preventive treatment) or at day 8 (therapeutic treatment) after a single intratracheal instillation of BLM. AjA was given at a dose of 1 mg/kg or 5 mg/kg. Mice were sacrificed at day 8, 14 and 21 after BLM and lungs were processed for histology and morphometry, and examined for HO-proline content and for the expression of transforming growth factor beta 1 (TGF-β1), phosphorylated Smad2/3 (pSMAD2/3), connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA) and peroxisome proliferator-activated receptor-gamma (PPAR-γ). Results: In the 1st week after BLM challenge, an acute inflammation characterized by neutrophil and macrophage accumulation was the main change present in lung parenchyma. The "switch" between inflammation and fibrosis occurs between day 8 and 14 after BLM instillation and involves the bronchi and vasculature. In the subsequent week (at day 21 after BLM instillation) bronchiolocentric fibrosis with significant increase of tissue collagen develops. The fibrotic response evaluated by morphometry and quantified as HO-proline in lung tissue at day 21 after BLM treatment was significantly reduced in mice receiving either AjA in the inflammatory or in early fibrogenic phase. AjA induces marked change in the expression pattern of products implicated in fibrogenesis, such as TGF-β1, pSMAD2/3, CTGF and α-SMA. In addition, AjA increases significantly the number of PPAR-γ positive cells and its nuclear localization. Conclusions: AjA treatment, starting either at day 0 or at day 8 after BLM challenge, counteracts the progression of pulmonary fibrosis. The anti-fibrotic effectiveness of AjA is irrespective of timing of compound administration. Further clinical studies are necessary to establish whether AjA may represent a new therapeutic option for treating fibrotic lung diseases
Sex-related differences in risk factors, type of treatment received and outcomes in patients with atrial fibrillation and acute stroke: Results from the RAF-study (Early Recurrence and Cerebral Bleeding in Patients with Acute Ischemic Stroke and Atrial Fibrillation)
Introduction: Atrial fibrillation is an independent risk factor of thromboembolism. Women with atrial fibrillation are at a higher overall risk for stroke compared to men with atrial fibrillation. The aim of this study was to evaluate for sex differences in patients with acute stroke and atrial fibrillation, regarding risk factors, treatments received and outcomes.
Methods Data were analyzed from the “Recurrence and Cerebral Bleeding in Patients with Acute Ischemic Stroke and Atrial Fibrillation” (RAF-study), a prospective, multicenter, international study including only patients with acute stroke and atrial fibrillation. Patients were followed up for 90 days. Disability was measured by the modified Rankin Scale (0–2 favorable outcome, 3–6 unfavorable outcome).
Results: Of the 1029 patients enrolled, 561 were women (54.5%) (p < 0.001) and younger (p < 0.001) compared to men. In patients with known atrial fibrillation, women were less likely to receive oral anticoagulants before index stroke (p = 0.026) and were less likely to receive anticoagulants after stroke (71.3% versus 78.4%, p = 0.01). There was no observed sex difference regarding the time of starting anticoagulant therapy between the two groups (6.4 ± 11.7 days for men versus 6.5 ± 12.4 days for women, p = 0.902). Men presented with more severe strokes at onset (mean NIHSS 9.2 ± 6.9 versus 8.1 ± 7.5, p < 0.001). Within 90 days, 46 (8.2%) recurrent ischemic events (stroke/TIA/systemic embolism) and 19 (3.4%) symptomatic cerebral bleedings were found in women compared to 30 (6.4%) and 18 (3.8%) in men (p = 0.28 and p = 0.74). At 90 days, 57.7% of women were disabled or deceased, compared to 41.1% of the men (p < 0.001). Multivariate analysis did not confirm this significance.
Conclusions: Women with atrial fibrillation were less likely to receive oral anticoagulants prior to and after stroke compared to men with atrial fibrillation, and when stroke occurred, regardless of the fact that in our study women were younger and with less severe stroke, outcomes did not differ between the sexes
The cannabinoid WIN55, 212-2 abrogates dermal fibrosis in scleroderma bleomycin model
Objectives: There is increasing evidence that the endocannabinoid system may be involved in pathological fibrosis, and that its modulation might limit fibrotic responses. The aim of this study was to examine the capacity of a synthetic cannabinoid receptor agonist to modify skin fibrosis in the bleomycin mouse model of scleroderma.
Methods: Skin fibrosis was induced by local injections of bleomycin in two groups of DBA/2J mice. One group was cotreated with the synthetic cannabinoid WIN55,212-2 at 1 mg/kg/day. Skin fibrosis was evaluated by histology and skin thickness and hydroxyproline content were quantified. Markers of fibroblast activation, including α smooth muscle actin and the profibrotic cytokines transforming growth factor (TGF)β, connective tissue growth factor (CTGF) and platelet-derived growth factor (PDGF)-BB, were examined. Levels of PSMAD2/3, which are crucial in extracellular matrix overproduction, were analysed.
Results: Bleomycin treatment induced typical skin fibrosis. Upon WIN55,212-2 treatment dermal fibrosis was completely prevented. Subcutaneous inflammatory cell infiltration, dermal thickness and collagen content resulted similar to those of the control group. The synthetic cannabinoid prevented fibroblasts activation induced by bleomycin, paralleled by a strong inhibition of TGFβ, CTGF and PDGF-BB expression. Phosphorylation of SMAD2/3 was significantly downregulated after WIN55,212-2 exposure.
Conclusions: Taken together, the results indicate that the synthetic cannabinoid WIN55,212-2 is capable of preventing skin fibrosis in a mouse model of scleroderma
Prediction of early recurrent thromboembolic event and major bleeding in patients with acute stroke and atrial fibrillation by a risk stratification schema: the ALESSA score study
Background and Purposes—This study was designed to derive and validate a score to predict early ischemic events and major bleedings after an acute ischemic stroke in patients with atrial fibrillation.
Methods—The derivation cohort consisted of 854 patients with acute ischemic stroke and atrial fibrillation included in prospective series between January 2012 and March 2014. Older age (hazard ratio 1.06 for each additional year; 95% confidence interval, 1.00–1.11) and severe atrial enlargement (hazard ratio, 2.05; 95% confidence interval, 1.08–2.87) were predictors for ischemic outcome events (stroke, transient ischemic attack, and systemic embolism) at 90 days from acute stroke. Small lesions (≤1.5 cm) were inversely correlated with both major bleeding (hazard ratio, 0.39; P=0.03) and ischemic outcome events (hazard ratio, 0.55; 95% confidence interval, 0.30–1.00). We assigned to age ≥80 years 2 points and between 70 and 79 years 1 point; ischemic index lesion >1.5 cm, 1 point; severe atrial enlargement, 1 point (ALESSA score). A logistic regression with the receiver-operating characteristic graph procedure (C statistic) showed an area under the curve of 0.697 (0.632–0.763; P=0.0001) for ischemic outcome events and 0.585 (0.493–0.678; P=0.10) for major bleedings.
Results—The validation cohort consisted of 994 patients included in prospective series between April 2014 and June 2016. Logistic regression with the receiver-operating characteristic graph procedure showed an area under the curve of 0.646 (0.529–0.763; P=0.009) for ischemic outcome events and 0.407 (0.275–0.540; P=0.14) for hemorrhagic outcome events.
Conclusions—In acute stroke patients with atrial fibrillation, high ALESSA scores were associated with a high risk of ischemic events but not of major bleedings
Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis
Background: Cannabinoids modulate fibrogenesis in scleroderma. Ajulemic acid (AjA) is a non-psychoactive synthetic analogue of tetrahydrocannabinol that can bind the peroxisome proliferator-activated receptor-γ (PPAR-γ). Recent evidence suggests a key role for PPAR-γ in fibrogenesis.
Objective: To determine whether AjA can modulate fibrogenesis in murine models of scleroderma.
Material and methods: Bleomycin-induced experimental fibrosis was used to assess the antifibrotic effects of AjA in vivo. In addition, the efficacy of AjA in pre-established fibrosis was analysed in a modified model of bleomycin-induced dermal fibrosis and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor I. Skin fibrosis was evaluated by quantification of skin thickness and hydroxyproline content. As a marker of fibroblast activation, α-smooth muscle actin was examined. To study the direct effect of AjA in collagen neosynthesis, skin fibroblasts from patients with scleroderma were treated with increasing concentrations of AjA. Protein expression of PPAR-γ, and its endogenous ligand 15d-PGJ2, and TGFβ were assessed before and after AjA treatment.
Results: AjA significantly prevented experimental bleomycin-induced dermal fibrosis and modestly reduced its progression when started 3 weeks into the disease. AjA strongly reduced collagen neosynthesis by scleroderma fibroblasts in vitro, an action which was reversed completely by co-treatment with a selective PPAR-γ antagonist.
Conclusions: AjA prevents progression of fibrosis in vivo and inhibits fibrogenesis in vitro by stimulating PPAR-γ signalling. Since therapeutic doses of AjA are well tolerated in humans, it is suggested that AjA as an interesting molecule targeting fibrosis in patients with scleroderma
Molecular DNA identity of the mouflon of Cyprus (Ovis orientalis ophion, Bovidae): Near Eastern origin and divergence from Western Mediterranean conspecific populations
The mouflon population of Cyprus (Ovis orientalis ophion) comprises historically preserved feral descendants of sheep
domesticated during the Neolithic. We determined genetic identity of this taxon in order to elucidate its systematic
placement and enforce its protection. We used 12 loci of microsatellite DNA to infer genetic relationships between the
Cypriot mouflon and either long-time isolated (Corsica, Sardinia) or recently introduced (central Italy) European mouflons
(O. o. musimon). We also sequenced the mitochondrial DNA (mtDNA) Cytochrome-b gene to infer the origin of the
Cypriot mouflon including many National Centre for Biotechnology Information (NCBI) entries of European and Near
Eastern conspecifics. Microsatellites disclosed net divergence between Western Mediterranean and Cypriot mouflon. The
latter was included in the highly heterogeneous Near Eastern O. orientalis mtDNA group, Iran representing the most
credited region as the source for its ancient introduction to Cyprus. Both international and national legislation protect the
mouflon of Cyprus as a wild taxon (O. o. ophion). However, the IUCN Red List of Threatened Species and NCBI include
the Cypriot mouflon as subspecies of its respective domestic species, the sheep (O. aries). Unfortunately, people charged
with crime against protected mouflon may benefit from such taxonomic inconsistency between legislation and databases, as
the latter can frustrate molecular DNA forensic outcomes. Until a definitive light can be shed on Near Eastern O. orientalis
systematics, we suggest that the Cypriot mouflon should be unvaryingly referred to as O. o. ophion in order not to impair
conservation in the country where it resides
APOLLO 11 Project, Consortium in Advanced Lung Cancer Patients Treated With Innovative Therapies: Integration of Real-World Data and Translational Research
Introduction: Despite several therapeutic efforts, lung cancer remains a highly lethal disease. Novel therapeutic approaches encompass immune-checkpoint inhibitors, targeted therapeutics and antibody-drug conjugates, with different results. Several studies have been aimed at identifying biomarkers able to predict benefit from these therapies and create a prediction model of response, despite this there is a lack of information to help clinicians in the choice of therapy for lung cancer patients with advanced disease. This is primarily due to the complexity of lung cancer biology, where a single or few biomarkers are not sufficient to provide enough predictive capability to explain biologic differences; other reasons include the paucity of data collected by single studies performed in heterogeneous unmatched cohorts and the methodology of analysis. In fact, classical statistical methods are unable to analyze and integrate the magnitude of information from multiple biological and clinical sources (eg, genomics, transcriptomics, and radiomics). Methods and objectives: APOLLO11 is an Italian multicentre, observational study involving patients with a diagnosis of advanced lung cancer (NSCLC and SCLC) treated with innovative therapies. Retrospective and prospective collection of multiomic data, such as tissue- (eg, for genomic, transcriptomic analysis) and blood-based biologic material (eg, ctDNA, PBMC), in addition to clinical and radiological data (eg, for radiomic analysis) will be collected. The overall aim of the project is to build a consortium integrating different datasets and a virtual biobank from participating Italian lung cancer centers. To face with the large amount of data provided, AI and ML techniques will be applied will be applied to manage this large dataset in an effort to build an R-Model, integrating retrospective and prospective population-based data. The ultimate goal is to create a tool able to help physicians and patients to make treatment decisions. Conclusion: APOLLO11 aims to propose a breakthrough approach in lung cancer research, replacing the old, monocentric viewpoint towards a multicomprehensive, multiomic, multicenter model. Multicenter cancer datasets incorporating common virtual biobank and new methodologic approaches including artificial intelligence, machine learning up to deep learning is the road to the future in oncology launched by this project
Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations
Background: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. Objective: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. Methods: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-kappa B) signaling. Results: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-kappa B1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. Conclusions: We present a comprehensive clinical overview of the NF-kappa B1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-kappa B1 pathway-targeted therapeutic strategies should be considered in the future.Peer reviewe
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