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Arrhythmogenic cardiomyopathy (ACM) is hallmarked by ventricular fibro‐adipogenic alterations, contributing to cardiac dysfunctions and arrhythmias. Although genetically determined (e.g., PKP2 mutations), ACM phenotypes are highly variable. More data on phenotype modulators, clinical prognosticators, and etiological therapies are awaited. We hypothesized that oxidized low‐density lipoprotein (oxLDL)‐dependent activation of PPARγ, a recognized effector of ACM adipogenesis, contributes to disease pathogenesis. ACM patients showing high plasma concentration of oxLDL display severe clinical phenotypes in terms of fat infiltration, ventricular dysfunction, and major arrhythmic event risk. In ACM patient‐derived cardiac cells, we demonstrated that oxLDLs are major cofactors of adipogenesis. Mechanistically, the increased lipid accumulation is mediated by oxLDL cell internalization through CD36, ultimately resulting in PPARγ upregulation. By boosting oxLDL in a Pkp2 heterozygous knock‐out mice through high‐fat diet feeding, we confirmed in vivo the oxidized lipid dependency of cardiac adipogenesis and right ventricle systolic impairment, which are counteracted by atorvastatin treatment. The modulatory role of oxidized lipids on ACM adipogenesis, demonstrated at cellular, mouse, and patient levels, represents a novel risk stratification tool and a target for ACM pharmacological strategies. Synopsis ACM mutations are necessary but not sufficient for disease penetrance. The contribution of oxidised lipids as novel pharmacologically targetable cofactors was demonstrated by a multi‐layer approach (patients – in vitro – in vivo ), leading to an advancement in the knowledge of ACM pathogenesis. ACM patients show high oxLDL plasma levels, which stratify ACM phenotype severity. oxLDL worsen adipogenic differentiation of ACM cells by altering the CD36/13HODE/PPARγ axis. By increasing oxLDL in an ACM mouse model with low penetrance, ACM‐specific tissue remodelling, functional and electrical impairments are unveiled. NAC and Atorvastatin can prevent ACM phenotypes in vitro / in vivo . Graphical Abstract ACM mutations are necessary but not sufficient for disease penetrance. The contribution of oxidised lipids as novel pharmacologically targetable cofactors was demonstrated by a multi‐layer approach (patients – in vitro – in vivo ), leading to an advancement in the knowledge of ACM pathogenesis.

In hypertrophic cardiomyopathy (HCM), the presence of pathogenic/likely pathogenic (P/LP) disease-causing genetic variants may indicate a worse prognosis. Few data exist on the effects of these genetic variants on cardiopulmonary exercise test (CPET) performance in HCM patients. We analysed asymptomatic and slightly symptomatic HCM patients (NYHA I-II) whose genetic analysis and CPET were available; at baseline, left ventricular function was normal and severe left ventricular outflow trait obstruction was excluded. Out of 120 HCM patients, we excluded 13 carrying variants of uncertain significance; of the remaining 107 patients, 54 were genotype negative [gene (−)], and 53 had a P/LP variant in sarcomeric genes [gene (+)]. Patients in the two groups had similar NYHA class, cardiovascular risk factors and echocardiographic characteristics. Gene (+) patients showed a lower peak VO2% and O2 pulse % (p < 0.05). Moreover, among gene (+), patients with P/LP variants in the so called “thin-filament” genes (TNNT2, TPM1 and MYL3) had the poorest CPET results. In asymptomatic or slightly symptomatic HCM patients with similar echocardiographic characteristics, exercise tolerance is affected by the genetic background. Indeed, exercise capacity is poorer in gene (+) compared to gene (−) patients and those carrying P/LP variants in “thin-filament” genes show the worst performance.

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited disorder, whose genetic cause is elusive in about 50–70% of cases. ACM presents a variable disease course which could be influenced by genetics. We performed next-generation sequencing on a panel of 174 genes associated with inherited cardiovascular diseases on 82 ACM probands (i) to describe and classify the pathogenicity of rare variants according to the American College of Medical Genetics and Genomics both for ACM-associated genes and for genes linked to other cardiovascular genetic conditions; (ii) to assess, for the first time, the impact of common variants on the ACM clinical disease severity by genotype-phenotype correlation and survival analysis. We identified 15 (likely) pathogenic variants and 66 variants of uncertain significance in ACM-genes and 4 high-impact variants in genes never associated with ACM (ABCC9, APOB, DPP6, MIB1), which deserve future consideration. In addition, we found 69 significant genotype-phenotype associations between common variants and clinical parameters. Arrhythmia-associated polymorphisms resulted in an increased risk of arrhythmic events during patients’ follow-up. The description of the genetic framework of our population and the observed genotype-phenotype correlation constitutes the starting point to address the current lack of knowledge in the genetics of ACM.

Primary myelofibrosis (PMF) is an acquired clonal disease of the hematopoietic stem cell compartment, characterized by bone marrow fibrosis, anemia, splenomegaly and extramedullary hematopoiesis. About 60% of patients with PMF harbor a somatic mutation of the JAK2 gene (JAK2-V617F) in their hematopoietic lineage. Recently, a splicing isoform of JAK2, lacking exon 14 (JAK2Δ14) was described in patients affected by myeloproliferative diseases. By using a specific RT-qPCR method, we measured the ratio between the splicing isoform and the JAK2 full-length transcript (JAK2+14) in granulocytes, isolated from peripheral blood, of forty-four patients with PMF and nine healthy donors. We found that JAK2Δ14 was only slightly increased in patients and, at variance with published data, the splicing isoform was also detectable in healthy controls. We also found that, in patients bearing the JAK2-V617F mutation, the percentage of mutated alleles correlated with the observed increase in JAK2Δ14. Homozygosity for the mutation was also associated with a higher level of JAK2+14. Bioinformatic analysis indicates the possibility that the G>T transversion may interfere with the correct splicing of exon 14 by modifying a splicing regulatory sequence. Increased levels of JAK2 full-length transcript and a small but significant increase in JAK2 exon 14 skipping, are associated with the JAK2-V617F allele burden in PMF granulocytes. Our data do not confirm a previous claim that the production of the JAK2Δ14 isoform is related to the pathogenesis of PMF.

Constrictive pericarditis is an uncommon complication of idiopathic pericarditis long thought to be irreversible, often requiring pericardiectomy to ensure recovery. Recently, transient constriction has been described in the setting of long-standing pericarditis with active inflammation. We report the case of a 16-year-old male with an idiopathic relapsing-remitting pericarditis, refractory to non-steroidal anti-inflammatory drugs (NSAIDs), who developed constrictive physiology. Despite proper tapering, the patient developed five relapses during steroid treatment, which led to IL-1 receptor antagonist starting. After a long treatment with anakinra, constrictive physiology resolved. Disappointingly, discontinuation of interleukin-1 receptor (IL-1R) treatment was followed by a relapse of pericarditis, in the absence of signs of constriction. Our case sustains that constrictive physiology may be a transient phenomenon, when the inflammation is still active and fibrotic transition has not been completed. When NSAIDs and steroid prove to be ineffective, IL-1R antagonist may represent a potential treatment for constrictive pericarditis, although there remains little evidence on de-escalation of IL-1R antagonist treatment in pericarditis.

A distinct set of channels and transporters regulates the ion fluxes across the lysosomal membrane. Malfunctioning of these transport proteins and the resulting ionic imbalance is involved in various human diseases, such as lysosomal storage disorders, cancer, as well as metabolic and neurodegenerative diseases. As a consequence, these proteins have stimulated strong interest for their suitability as possible drug targets. A detailed functional characterization of many lysosomal channels and transporters is lacking, mainly due to technical difficulties in applying the standard patch-clamp technique to these small intracellular compartments. In this review, we focus on current methods used to unravel the functional properties of lysosomal ion channels and transporters, stressing their advantages and disadvantages and evaluating their fields of applicability.

Carbon Monoxide (CO) intoxication is still a leading cause of mortality and morbidity in many countries. Due to the problematic detection in the environment and subtle symptoms, CO intoxication usually goes unrecognized, and both normobaric and hyperbaric oxygen (HBO) treatments are frequently administered with delay. Current knowledge is mainly focused on acute intoxication, while Delayed Neurological Sequelae (DNS) are neglected, especially their treatment. This work details the cases of two patients presenting a few weeks after CO intoxication with severe neurological impairment and a characteristic diffused demyelination at the brain magnetic resonance imaging, posing the diagnosis of DNS. After prolonged treatment with hyperbaric oxygen, combined with intravenous corticosteroids and rehabilitation, the clinical and radiological features of DNS disappeared, and the patients’ neurological status returned to normal. Such rare cases should reinforce a thorough clinical follow-up for CO intoxication victims and promote high-quality studies.

Abstract Introduction Recent randomised trials have questioned the benefit of endovascular therapy (EVT) for MeVO stroke, but data from clinical practice are limited. This study aimed to assess the effectiveness and safety of EVT, with or without intravenous thrombolysis (IVT), vs IVT alone in MeVO stroke using registry-based real-world data. Patients and methods This retrospective multicentre study included patients from 82 Italian centres in the Safe Implementation of Treatments in Stroke (SITS) registry (January 2020–December 2023). Adults with acute ischaemic stroke due to MeVO (ACA A1/A2, MCA M2/M3 or more distal or PCA P1/P2), treated with IVT or EVT ± IVT, and with available 90-day mRS scores were included. Patients with tandem occlusions were excluded. Propensity score matching (1:1) was used to balance baseline variables. Primary outcome was functional independence (mRS 0–2) at 90 days. Secondary outcomes included in-hospital mortality, intracranial haemorrhage incidence and recanalisation status. Results Among 1375 total patients, 780 were included and matched (390 per group) by propensity score. Baseline characteristics were balanced. Functional independence at 90 days was achieved in 60.6% of EVT ± IVT patients vs 60.9% in the IVT-only group (odds ratio [OR] 0.99; 95% CI, 0.73–1.34; P = .939). When restricted to patients with baseline mRS < 2, functional independence rates remained comparable between groups, confirming the primary findings. In-hospital mortality was non-significantly lower in the EVT ± IVT group (5.4% vs 8.7%, P = .069). Symptomatic intracranial haemorrhage rates were comparable between groups, although overall haemorrhagic complications were higher with EVT (18.4% vs 11.2%, P < .0001). Stratified analyses by stroke severity and treatment timing showed consistent lack of benefit across all subgroups (all interaction P-values > .05). Discussion The absence of functional benefit from EVT observed in this real-world cohort is consistent with the results of the ESCAPE-MeVO and DISTAL randomized trials. Notably, the higher rate of any intracranial haemorrhage in the EVT group (18.4% vs 11.2%), driven primarily by minor haemorrhagic events, represents a clinically meaningful safety concern that must be weighed against the lack of demonstrated efficacy. A hypothesis-generating signal was observed in patients treated within 180 minutes (OR 2.16, 95% CI 1.06–4.38), warranting prospective investigation. The retrospective design and the limitations inherent to registry-based data, including incomplete procedural data and anatomical heterogeneity in MeVO classification, should be considered when interpreting these findings. Conclusions Endovascular therapy did not improve long-term functional outcomes compared to IVT alone in MeVO stroke but was associated with higher haemorrhagic risk. These findings support a cautious approach to EVT in this setting, in line with recent trial evidence. Graphical Abstract Graphical Abstract

Background Use of information campaigns and educational interventions directed to citizens and supported by physicians, aimed at promoting the appropriate use of medicines, have been evaluated by several studies with conflicting results. These interventions are potentially relevant, favouring the reduction of unnecessary use of medicines and related risks. Several studies have specifically evaluated the promotion of the appropriate use of antibiotics in adults and children, with variable results. A controlled study is proposed to evaluate the feasibility and effectiveness of a multifaceted intervention aimed at reducing antibiotic prescription by increasing awareness on risks of their unnecessary use. Methods/design Information will be provided to citizens through several media (posters, local TV, radio and newspapers, video terminals, websites of Local Health Authorities). Brochures with information on expected benefits and risks of antibiotics will be also available, either with direct access in waiting rooms and pharmacies or handed out and mediated by doctors. Physicians and pharmacists will get specific data on local antibiotic resistance. A small group of representative doctors have also actively participated in defining the campaign key messages. A sample of general practitioners and paediatricians will be trained in patient counselling strategies. The information campaign will be implemented in two Provinces of Emilia-Romagna during the fall-winter season (November 2011-February 2012). Change in the overall prescribing rate of antibiotics (expressed as DDD per 1000 inhabitants/day) in the intervention area will be compared versus other areas in the same Region. Knowledge and attitudes of the general population will be evaluated through a phone and internet survey on a representative sample. Discussion While the campaign messages will be mainly directed to the general population, doctors' prescribing will be assessed. The main rationale for this apparent discrepancy lies in the influence patients may have on physicians' prescribing behaviour (directly or indirectly) and in physicians' endorsement of the campaign goals, considering their participation in its design. This study could observe a reduction lower than 5% in the prescribing rate of antibiotics. Such a reduction would be of public health relevance and would determine average savings of almost twice as much as the campaign costs.