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1.
Artigo em Inglês | MEDLINE | ID: mdl-32779079

RESUMO

Although optical coherence tomography (OCT) proved to be able to identify macrophage clusters, there are no available data on the possibility to obtain reproducible measurements of their circumferential extension and location. The purpose of the present post-hoc analysis of the CLIMA study was to revise the clinical and demographic variables of patients having coronary plaques with macrophages and to investigate the reproducibility of their quantitative assessment. A total of 577 patients out of 1003 undergoing OCT showed macrophage accumulation. Three groups were identified; group 1 (426 patients) without macrophages, group 2 (296) patients with low macrophage content (less than median value [67°] of circumferential arc) and group 3 (281) with high macrophage content arc [> 67°]. Patients with macrophages (groups 2 and 3) showed a higher prevalence of family history for coronary artery disease and hypercholesterolemia and had a significantly larger body mass index. Furthermore, group 3 had more commonly triple vessel disease and higher value of LDL cholesterol levels compared to the two other groups. The inter-observer agreement for macrophage interpretation was good: R values were 0.97 for the circumferential arc extension, 0.95 for the minimum distance and 0.98 for the mean distance. A non-significant correlation between circumferential extension of macrophages and hsCRP values was found (R = 0.013). Quantitative assessment of macrophage accumulations can be obtained with high reproducibility by OCT. The presence and amount of macrophages are poorly correlated with hsCRP and identify patients with more advanced atherosclerosis and higher LDL cholesterol levels.

2.
Sci Rep ; 10(1): 10964, 2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620902

RESUMO

Surgical mortality is the most significant measure of outcome in surgical healthcare. The objective was to assess surgical 30 days mortality and improve the identification of predictors for personalized risk stratification of patients undergoing elective and emergency surgery. The study was conducted as a single-center cohort retrospective observational study, based on the analysis of data collected from patients surgically treated from 2002 to 2014 in a multi-disciplinary research and care referral hospital with global case mix of 1.27. The overall in-hospital mortality rate was 1.89% (95% CI 1.82-1.95). In the univariable analysis, numerous predictors were significantly associated with in-hospital death following surgery. In the multivariable model, age, BMI (Body Mass Index), ASA score, department, planned surgical complexity, surgical priority, previous surgeries in the same hospitalization, cardiovascular, pulmonary, hepato-renal comorbidities, drug intolerance, cancer and AIDS were independently associated with mortality after surgery. At logistic regression, the computed SMATT score (graded 0-100), generated on the basis of multivariate analysis, demonstrated a good discrimination (10-fold cross-validated AUC-ROC 0.945, 95%CI 0.941-0.948) and correctly classified 98.5% of those admissions with a probability of death >50%. The novel SMATT score, based on individual preoperative and surgical factors, accurately predicts mortality and provides dynamic information of the risk in redo/reoperative surgery.

3.
G Ital Dermatol Venereol ; 155(3): 349-354, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32635709

RESUMO

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by severe cutaneous and ocular sensitivity to sunlight, leading to skin cancer. Most XP patients belong to the XP complementation groups (XP-A to XP-G), due to mutations in genes involved in nucleotide excision repair (NER). On the other hand, the XP Variant type (XP-V, OMIM#278750), which accounts for about 20% of all XP patients, is associated with normal NER function. The disease gene is POLH, which encodes polymerase η (pol η) allowing translesion synthesis in regions of DNA damage. We observed an Italian family presenting with photosensitivity, freckling since childhood and multiple skin cancers. Complete sequence analysis of XPA, XPC, XPD/ERCC2 genes and exons 1-9 and 11 of POLH gene did not reveal pathological mutations. No PCR product was observed for exon 10 in POLH gene. By RT-PCR analysis followed by POLH exon 10 sequencing, all affected members were found to harbor a homozygous 170-nucleotide deletion. The same deletion was previously described in 3 XP-V families, one of southern Italian descent and two from Algeria, suggesting a possible founder mutation. The deletion determines a severe protein truncation and defective pol η activity. Immunohistochemical study showed markedly reduced pol η expression in skin lesions of the affected siblings compared to the normal control skin.

4.
Orphanet J Rare Dis ; 15(1): 156, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32571412

RESUMO

In both classic and late-onset AFD, mutations of the GLA gene cause deficient activity of the alpha-galactosidase enzyme resulting in intracellular accumulation of the undigested substrate. Gastrointestinal symptoms (GI) are common but non-specific and imputed to the AFD, irrespective of the demonstration of substrate accumulation in GI cells. We demonstrate substrate accumulation in gastric epithelial, vascular, and nerve cells of patients with classic AFD and, vice versa, absence of accumulation in late-onset AFD and controls.

5.
J Mol Cell Cardiol ; 145: 74-83, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32535041

RESUMO

Despite recent progress in the understanding of cardiac ion channel function and its role in inherited forms of ventricular arrhythmias, the molecular basis of cardiac conduction disorders often remains unresolved. We aimed to elucidate the genetic background of familial atrioventricular block (AVB) using a whole exome sequencing (WES) approach. In monozygotic twins with a third-degree AVB and in another, unrelated family with first-degree AVB, we identified a heterozygous nonsense mutation in the POPDC2 gene causing a premature stop at position 188 (POPDC2W188⁎), deleting parts of its cAMP binding-domain. Popeye-domain containing (POPDC) proteins are predominantly expressed in the skeletal muscle and the heart, with particularly high expression of POPDC2 in the sinoatrial node of the mouse. We now show by quantitative PCR experiments that in the human heart the POPDC-modulated two-pore domain potassium (K2P) channel TREK-1 is preferentially expressed in the atrioventricular node. Co-expression studies in Xenopus oocytes revealed that POPDC2W188⁎ causes a loss-of-function with impaired TREK-1 modulation. Consistent with the high expression level of POPDC2 in the murine sinoatrial node, POPDC2W188⁎ knock-in mice displayed stress-induced sinus bradycardia and pauses, a phenotype that was previously also reported for POPDC2 and TREK-1 knock-out mice. We propose that the POPDC2W188⁎ loss-of-function mutation contributes to AVB pathogenesis by an aberrant modulation of TREK-1, highlighting that POPDC2 represents a novel arrhythmia gene for cardiac conduction disorders.

6.
Cells ; 9(5)2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32443613

RESUMO

Adaptation of glioblastoma to caloric restriction induces compensatory changes in tumor metabolism that are incompletely known. Here we show that in human glioblastoma cells maintained in exhausted medium, SHC adaptor protein 3 (SHC3) increases due to down-regulation of SHC3 protein degradation. This effect is reversed by glucose addition and is not present in normal astrocytes. Increased SHC3 levels are associated to increased glucose uptake mediated by changes in membrane trafficking of glucose transporters of the solute carrier 2A superfamily (GLUT/SLC2A). We found that the effects on vesicle trafficking are mediated by SHC3 interactions with adaptor protein complex 1 and 2 (AP), BMP-2-inducible protein kinase and a fraction of poly ADP-ribose polymerase 1 (PARP1) associated to vesicles containing GLUT/SLC2As. In glioblastoma cells, PARP1 inhibitor veliparib mimics glucose starvation in enhancing glucose uptake. Furthermore, cytosol extracted from glioblastoma cells inhibits PARP1 enzymatic activity in vitro while immunodepletion of SHC3 from the cytosol significantly relieves this inhibition. The identification of a new pathway controlling glucose uptake in high grade gliomas represents an opportunity for repositioning existing drugs and designing new ones.

7.
Eur J Heart Fail ; 22(5): 911-915, 2020 05.
Artigo em Inglês | MEDLINE | ID: covidwho-46118

RESUMO

We describe the first case of acute cardiac injury directly linked to myocardial localization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a 69-year-old patient with flu-like symptoms rapidly degenerating into respiratory distress, hypotension, and cardiogenic shock. The patient was successfully treated with venous-arterial extracorporeal membrane oxygenation (ECMO) and mechanical ventilation. Cardiac function fully recovered in 5 days and ECMO was removed. Endomyocardial biopsy demonstrated low-grade myocardial inflammation and viral particles in the myocardium suggesting either a viraemic phase or, alternatively, infected macrophage migration from the lung.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Coração/virologia , Miocardite/virologia , Pneumonia Viral/complicações , Choque Cardiogênico/terapia , Choque Cardiogênico/virologia , Idoso , Biópsia , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Oxigenação por Membrana Extracorpórea , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/virologia , Humanos , Masculino , Miocardite/patologia , Miocárdio/patologia , Pandemias , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Respiração Artificial , Choque Cardiogênico/etiologia , Choque Cardiogênico/patologia
8.
EuroIntervention ; 16(5): 380-386, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32310133

RESUMO

AIMS: The goal of the present post hoc analysis of the CLIMA registry was to establish the relationship between calcified nodules (CNs) with (CND) or without (CNWD) disruption of the superficial intimal fibrous layer and one-year occurrence of target lesion myocardial infarction (MI) and/or cardiac death. METHODS AND RESULTS: CND and CNWD were identified based on the presence or absence of superficial irregularities indicative of disruption of the intimal fibrous layer, with possible overlying local thrombus. In total, 222 CNs were found in the 1,776 non-culprit LAD plaques. CND had larger maximum calcific arc and smaller lumen area. Cardiac death and MI occurred in 20% of patients in the CND group versus 2.7% in the CNWD group and 3.3% in the group without CN (p<0.001). This figure was mainly due to the 13.3% incidence of cardiac death in the CND group versus 2.0% in the CNWD group and versus 2.2% in the group without CN (p<0.001). The presence of CND was confirmed as an independent predictor of events (HR 6.58, 95% CI: 2.7-15.8, p<0.001). CONCLUSIONS: The presence of CND was associated with a high one-year incidence of cardiac death and/or target lesion MI.


Assuntos
Infarto do Miocárdio/epidemiologia , Placa Aterosclerótica/diagnóstico por imagem , Angiografia Coronária , Humanos , Incidência , Tomografia de Coerência Óptica
9.
Eur J Heart Fail ; 22(5): 911-915, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32275347

RESUMO

We describe the first case of acute cardiac injury directly linked to myocardial localization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a 69-year-old patient with flu-like symptoms rapidly degenerating into respiratory distress, hypotension, and cardiogenic shock. The patient was successfully treated with venous-arterial extracorporeal membrane oxygenation (ECMO) and mechanical ventilation. Cardiac function fully recovered in 5 days and ECMO was removed. Endomyocardial biopsy demonstrated low-grade myocardial inflammation and viral particles in the myocardium suggesting either a viraemic phase or, alternatively, infected macrophage migration from the lung.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Coração/virologia , Miocardite/virologia , Pneumonia Viral/complicações , Choque Cardiogênico/terapia , Choque Cardiogênico/virologia , Idoso , Biópsia , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Oxigenação por Membrana Extracorpórea , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/virologia , Humanos , Masculino , Miocardite/patologia , Miocárdio/patologia , Pandemias , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Respiração Artificial , Choque Cardiogênico/etiologia , Choque Cardiogênico/patologia
13.
Heart ; 106(3): 196-202, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31350276

RESUMO

OBJECTIVES: N-terminal probrain natriuretic peptide (NT-proBNP) predicts mortality and the development of heart failure in hypertrophic cardiomyopathy (HCM). Mid-regional proatrial natriuretic peptide (MR-proANP) is a stable by-product of production of atrial natriuretic peptide. We sought to compare the prognostic value of MR-proANP and NT-proBNP in HCM. METHODS: We prospectively enrolled a cohort of patients with HCM from different European centres and followed them. All patients had clinical, ECG and echocardiographic evaluation and measurement of MR-proANP and NT-proBNP at inclusion. RESULTS: Of 357 patients enrolled, the median age was 52 (IQR: 36-65) years. MR-proANP and NT-proBNP were both independently associated with age, weight, New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), wall thickness and left atrial dimension. During a median follow-up of 23 months, 32 patients had a primary end point defined as death (n=6), heart transplantation (n=8), left ventricular assist device implantation (n=1) or heart failure hospitalisation (n=17). Both NT-proBNP and MR-proANP (p<10-4) were strongly associated with the primary endpoint, and the areas under the receiver operating characteristic (ROC) curves for both peptides were not significantly different. However, in a multiple stepwise regression analysis, the best model for predicting outcome was NYHA 1-2 vs 3-4 (HR=0.35, 95% CI 0.16 to 0.77, p<0.01), LVEF (HR=0.96, 95% CI 0.94 to 0.98, p=0.0005) and MR-proANP (HR=3.77, 95% CI 2.01 to 7.08, p<0.0001). CONCLUSIONS: MR-proANP emerges as a valuable biomarker for the prediction of death and heart failure related events in patients with HCM.

14.
J Hum Hypertens ; 34(3): 214-222, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31435004

RESUMO

Interaction between arterial stiffness and hypertension plays an important role in the development of cardiovascular disease. Accordingly, assessment of arterial stiffness may provide a tool for estimating cardiovascular risk and monitoring therapy in hypertensive patients. Radiofrequency-based vascular ultrasound allows accurate noninvasive assessment of local mechanical properties of large arteries, but for its use in clinical practice, reference values according to age and sex are mandatory for each vascular site. To provide reference values for common carotid artery stiffness as assessed by an echo-tracking imaging system Hitachi-Aloka, we pooled measurements collected in 1847 healthy subjects aged 3-74 years (1008 males and 839 females) recruited in 14 European centers in the E-tracking International Collaboration (ETIC). Statistical models were developed to describe relationships of different stiffness indices with age and to calculate median values and Z-scores corresponding to ± 1 and ± 2 standard deviations. In our apparently healthy population, age accounted for 53% of variability in the elastic modulus (epsilon), 39% in arterial compliance, 47% in stiffness index (ß), and 56% in local pulse wave velocity; on average, blood pressure accounted for a further 7.5% of variability. Dependence on age was not linear; changes in mean values increased at older ages, especially for epsilon and ß. There was an interaction between age and gender for arterial compliance, which was higher in males. We present nomograms and a software that can be used for the automated calculation of Z-scores for local carotid stiffness in individual patients. These tools can be used to establish prognostic indicators or surrogate targets for treatment monitoring.

15.
Eur J Surg Oncol ; 46(1): 15-23, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31445768

RESUMO

The surgical approach to the axilla in breast cancer has been a controversial issue for more than three decades. Data from recently published trials have provided practice-changing recommendations in this scenario. However, further controversies have been triggered in the surgical community, resulting in heterogeneous diffusion of these recommendations. The development of clinical guidelines for the management of the axilla in patients with breast cancer is a work in progress. A multidisciplinary team discussion was held at the research hospital Policlinico San Matteo from the Università degli Studi di Pavia with the aim to update recommendations for the management of the axilla in patients with breast cancer. An evidence-based approach is presented. Our multidisciplinary panel determined that axillary dissection after a positive sentinel lymph node biopsy may be avoided in cN0 patients with micro/macrometastasis to ≤2 sentinel nodes, with age ≥40y, lesions ≤3 cm, who have not received neoadjuvant chemotherapy and have planned breast conservation (BCS) with whole breast radiotherapy (WBRT). Cases with gross (>2 mm) ECE in SLNs are evaluated on individual basis for completion ALND, axillary radiotherapy or omission of both. Patients fulfilling the criteria listed above who undergo mastectomy, may also avoid axillary dissection after multidisciplinary discussion of individual cases for consideration of axillary irradiation. Women 70 years or older with hormone receptors positive invasive lesions ≤3 cm, clinically negative nodes, and serious or multiple comorbidities who undergo BCS with WBRT, may forgo axillary staging/surgery (if mastectomy or larger tumor, comorbidities and life expectancy are taken into account).

16.
Eur Heart J ; 41(3): 383-391, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31504405

RESUMO

AIMS: The CLIMA study, on the relationship between coronary plaque morphology of the left anterior descending artery and twelve months clinical outcome, was designed to explore the predictive value of multiple high-risk plaque features in the same coronary lesion [minimum lumen area (MLA), fibrous cap thickness (FCT), lipid arc circumferential extension, and presence of optical coherence tomography (OCT)-defined macrophages] as detected by OCT. Composite of cardiac death and target segment myocardial infarction was the primary clinical endpoint. METHODS AND RESULTS: From January 2013 to December 2016, 1003 patients undergoing OCT evaluation of the untreated proximal left anterior descending coronary artery in the context of clinically indicated coronary angiogram were prospectively enrolled at 11 independent centres (clinicaltrial.gov identifier NCT02883088). At 1-year, the primary clinical endpoint was observed in 37 patients (3.7%). In a total of 1776 lipid plaques, presence of MLA <3.5 mm2 [hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.1-4.0], FCT <75 µm (HR 4.7, 95% CI 2.4-9.0), lipid arc circumferential extension >180° (HR 2.4, 95% CI 1.2-4.8), and OCT-defined macrophages (HR 2.7, 95% CI 1.2-6.1) were all associated with increased risk of the primary endpoint. The pre-specified combination of plaque features (simultaneous presence of the four OCT criteria in the same plaque) was observed in 18.9% of patients experiencing the primary endpoint and was an independent predictor of events (HR 7.54, 95% CI 3.1-18.6). CONCLUSION: The simultaneous presence of four high-risk OCT plaque features was found to be associated with a higher risk of major coronary events.

17.
Acta Myol ; 38(3): 159-162, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31788659

RESUMO

In a five-generation family carrying a novel frameshift LMNA variant (c.1434dupG, p.Leu479AlafsX72), imaging-augmented segregation analysis supports its association with lamin heart disease. Affected members exhibit conduction abnormalities, supraventricular and ventricular arrythmias, dilated cardiomyopathy with non-infarct pattern midwall septal fibrosis, heart failure and thromboembolic complications.


Assuntos
Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/genética , Lamina Tipo A/genética , Imagem por Ressonância Magnética , Morte Súbita Cardíaca , Feminino , Mutação da Fase de Leitura , Humanos , Masculino , Linhagem , Fenótipo
18.
Orphanet J Rare Dis ; 14(1): 264, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752940

RESUMO

The ACTA2 gene encodes for smooth muscle specific α-actin, a critical component of the contractile apparatus of the vascular smooth muscle cell. Pathogenic variants in the ACTA2 gene are the most frequently encountered genetic cause of non-syndromic hereditary thoracic aortic disease (HTAD). Although thoracic aortic aneurysm and/or dissection is the main clinical manifestation, a variety of occlusive vascular disease and extravascular manifestations occur in ACTA2-related vasculopathy. Current data suggest possible mutation-specific manifestations of vascular and extra-aortic traits.Despite its relatively high prevalence, comprehensive recommendations on the care of patients and families with pathogenic variants in ACTA2 have not yet been established. We aimed to develop a consensus document to provide medical guidance for health care professionals involved in the diagnosis and treatment of patients and relatives with pathogenic variants in ACTA2.The HTAD Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN) convened to review current literature and discuss expert opinions on clinical management of ACTA2 related vasculopathy. This consensus statement summarizes our recommendations on diagnosis, monitoring, treatment, pregnancy, genetic counselling and testing in patients with ACTA2-related vasculopathy. However, there is a clear need for additional prospective multicenter studies to further define proper guidelines.

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