STUDIO DEL VENTRICOLO DESTRO CON ECOCARDIOGRAFIA SPECKLE-TRACKING IN PAZIENTI CON IPERTENSIONE ARTERIOSA POLMONARE ASSOCIATA A SCLERODERMIA

L’ipertensione arteriosa polmonare associata a Sclerosi Sistemica (IAP-ScS) è caratterizzata da una mortalità più elevata rispetto all’IAP idiopatica. Ciò è attribuibile almeno in parte allo sviluppo di insufficienza ventricolare destra. Ad oggi, gli effetti benefici della terapia iniziale di combinazione con vasodilatatori polmonari sulla funzione ventricolare destra in pazienti affetti da IAP-ScS sono stati poco studiati. L’ecocardiografia speckle-tracking è una metodica non invasiva utile per indentificare la disfunzione ventricolare tramite lo studio della contrattilità regionale e globale e può essere applicata anche per lo studio del ventricolo destro. Lo scopo del presente studio si articola in due punti: valutare le possibili differenze in termini di parametri ecocardiografici convenzionali ed innovativi derivati dall’analisi speckle-tracking della funzione ventricolare destra (in particolare, lo strain longitudinale regionale e globale del ventricolo destro) in pazienti con IAP-ScS e IAP idiopatica, ed esplorare i possibili effetti benefici su tali parametri della terapia iniziale di combinazione con ambrisentan e tadalafil in pazienti affetti da ScS con nuova diagnosi di IAP. In relazione al primo punto, sono stati valutati 55 pazienti affetti da IAP (23 IAP idiopatica e 32 IAP-ScS) arruolati nel “Pulmonary Hypertension Program” della Johns Hopkins University. In relazione al secondo punto, sono stati analizzati gli ecocardiogrammi effettuati all’arruolamento e dopo 36 settimane di terapia iniziale di combinazione con ambrisentan e tadalafil di 23 pazienti affetti da IAP-ScS arruolati nello studio prospettivo multicentrico ATPAHSS (Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension associated with Systemic Sclerosis). Attraverso i risultati di questo studio è stato dimostrato che l’analisi dello strain longitudinale del ventricolo destro è in grado di rivelare differenze nella funzione ventricolare destra tra pazienti con IAP idiopatica e IAP-ScS, che sono indipendenti dall’entità dell’impegno vascolare polmonare, e che valori più patologici di strain longitudinale si associano ad una peggiore prognosi. Inoltre, è stato dimostrato che in pazienti con IAP-ScS la terapia iniziale di combinazione con ambrisentan e tadalafil ha effetti benefici sulla funzione sistolica ventricolare destra

IPICT - An Explanatory Scheme About The Innovation Phenomena Towards Integrated Care Enhanced By Digital Technologies

The introduction of innovative models of care, especially in the management of chronic diseases and other long-term conditions, responds to an urgent need of economic sustainability of the health and social system, while maintaining or increasing the level of quality of the system. In this context it is crucial to assure the proper co-evolution of organizational models and technological solutions. This paper presents an explanatory scheme about Innovation Phenomena towards Integrated Care enhanced by digital Technologies (IPICT), developed in the context of the European project STOPandGO: organisational and informational integration may be achieved both vertically among care settings and horizontally between healthcare and social care. Full integration may be the final goal of a long process made by a progressive local deployment of several initiatives, possibly coherent with regional or national plans. Within each initiative, innovation has not to be necessarily present in each individual activity or in each technological component, but it may be triggered by the appropriate combination of activities and technologies according a suitable model of care. The proposed scheme identifies six layers, ranging from a technological approach on enabling infrastructures in Layers L1 and L2, to a perspective on organizational models co-designed with technological solutions in Layers L3 and L4, up to the comprehensive vision of the overall (regional) strategies on Integrated Care in Layers L5 and L6. In particular, Layer L4 regards the measures able to “reify the innovation” in the models of care deployed within the initiatives of Layer L5. The list of L4 measures worked out by STOPandGO project was tested on the production of a coherent set of local tenders to improve the health and well-being of citizens across hetero-geneous organisational/clinical circumstances

Detenzione parentale e comportamenti delinquenziali nella prole: quale possibile intervento*?

Research on the health of children after one of their parent’s imprisonment is relatively poor despite studies that link adverse experiences of childhood to a series of physical and mental health conditions. In this review, several clinical trials have been examined to examine the risks of child exposure to an unstable and dysfunctional family structure due to detention of one or both parents. Among the aspects related to detention, the one most concerning for prisoners is the separation from the family, and in particular from the children. From the offspring point of view, the detention of one parent translates to a loss of a stable reference point, which over the years leads to them taking less advisable choices that in turn make detention more likely. Studies have shown that, over the years, minor children of detainees develop acceptance towards parental detention, with normalization of event up to ignoring the socially shared concept of “detention” which morphs into the idea of what delinquency represents in micro and macro criminality contexts. It becomes important to foster relationships with children and with the prisoner’s family, but it becomes even more important that the prisoner embarks on a path that leads them to regain the parenting role, which allows them to feel like a person with resources to protect and with relationships to cultivate

Selected amino acid mutations in HIV-1 B subtype gp41 are Associated with Specific gp120V3 signatures in the regulation of Co-Receptor usage

<p>Abstract</p> <p>Background</p> <p>The third variable loop (V3) of the HIV-1 gp120 surface protein is a major determinant of cellular co-receptor binding. However, HIV-1 can also modulate its tropism through other regions in gp120, such as V1, V2 and C4 regions, as well as in the gp41 protein. Moreover, specific changes in gp41 are likely to be responsible for of damage in gp120-CCR5 interactions, resulting in potential resistance to CCR5 inhibitors.</p> <p>In order to genetically characterize the two envelope viral proteins in terms of co-receptor usage, we have analyzed 526 full-length <it>env </it>sequences derived from HIV-1 subtype-B infected individuals, from our and public (Los Alamos) databases. The co-receptor usage was predicted by the analysis of V3 sequences using Geno2Pheno (G2P) algorithm. The binomial correlation phi coefficient was used to assess covariation among gp120_V3and gp41 mutations; subsequently the average linkage hierarchical agglomerative clustering was performed.</p> <p>Results</p> <p>According to G2P false positive rate (FPR) values, among 526 env-sequences analyzed, we further characterized 196 sequences: 105 with FPR <5% and 91 with FPR >70%, for X4-using and R5-using viruses, respectively.</p> <p>Beyond the classical signatures at 11/25 V3 positions (S11S and E25D, R5-tropic viruses; S11KR and E25KRQ, X4-tropic viruses), other specific V3 and gp41 mutations were found statistically associated with the co-receptor usage. Almost all of these specific gp41 positions are exposed on the surface of the glycoprotein. By the covariation analysis, we found several statistically significant associations between V3 and gp41 mutations, especially in the context of CXCR4 viruses. The topology of the dendrogram showed the existence of a cluster associated with R5-usage involving E25D_V3, S11S_V3, T22A_V3, S129DQ_gp41and A96N_gp41signatures (bootstrap = 0.88). Conversely, a large cluster was found associated with X4-usage involving T8I_V3, S11KR_V3, F20IVY_V3, G24EKR_V3, E25KR_V3, Q32KR_V3, A30T_gp41, A189S_gp41, N195K_gp41and L210P_gp41mutations (bootstrap = 0.84).</p> <p>Conclusions</p> <p>Our results show that gp120_V3and several specific amino acid changes in gp41 are associated together with CXCR4 and/or CCR5 usage. These findings implement previous observations that determinants of tropism may reside outside the V3-loop, even in the gp41. Further studies will be needed to confirm the degree to which these gp41 mutations contribute directly to co-receptor use.</p

Cardiac sympathetic dysfunction in pulmonary arterial hypertension: Lesson from left-sided heart failure

Sympathetic nervous system hyperactivity has a well-recognized role in the pathophysiology of heart failure with reduced left ventricular ejection fraction. Alterations in sympathetic nervous system have been related to the pathophysiology of pulmonary arterial hypertension, but it is unclear whether cardiac sympathetic nervous system is impaired and how sympathetic dysfunction correlates with hemodynamics and clinical status in pulmonary arterial hypertension patients. The aim of this study was to evaluate the cardiac sympathetic nervous system activity by means of 123Iodine-metaiodobenzylguanidine nuclear imaging in pulmonary arterial hypertension patients and to explore its possible correlation with markers of disease severity. Twelve consecutive pulmonary arterial hypertension patients (nine women, median age 56.5 (17.8), eight idiopathic and four connective tissue-associated pulmonary arterial hypertension) underwent cardiac 123Iodine-metaiodobenzylguanidine scintigraphy. The results were compared with those of 12 subjects with a negative history of cardiovascular or pulmonary disease who underwent the same nuclear imaging test because of a suspected paraganglioma or pheochromocytoma, with a negative result (controls), and 12 patients with heart failure with reduced left ventricular ejection fraction. Hemodynamics, echocardiography, six-minute walking distance, cardiopulmonary exercise testing, and N-terminal pro brain natriuretic peptide were collected in pulmonary arterial hypertension patients within one week from 123Iodine-metaiodobenzylguanidine scintigraphy. Cardiac 123Iodine-metaiodobenzylguanidine uptake, assessed as early and late heart-to-mediastinum ratio, was significantly lower in pulmonary arterial hypertension compared to controls (p = 0.001), but similar to heart failure with reduced left ventricular ejection fraction. Myocardial 123Iodine-metaiodobenzylguanidine turnover, expressed as washout rate, was similar in pulmonary arterial hypertension and heart failure with reduced left ventricular ejection fraction and significantly higher compared to controls (p = 0.016). In the pulmonary arterial hypertension group, both early and late heart-to-mediastinum ratios and washout rate correlated with parameters of pulmonary arterial hypertension severity including pulmonary vascular resistance, right atrial pressure, tricuspid annular plane systolic excursion, N-terminal pro brain natriuretic peptide, and peak VO2. Although we evaluated a small number of subjects, our study showed a significant impairment in cardiac sympathetic nervous system in pulmonary arterial hypertension, similarly to that observed in heart failure with reduced left ventricular ejection fraction. This impairment correlated with indices of pulmonary arterial hypertension severity. Cardiac sympathetic dysfunction may be a contributing factor to the development of right-sided heart failure in pulmonary arterial hypertension

Biochemical Characterization of p16INK4- and p18-containing Complexes in Human Cell Lines

The regulation of the D-type cyclin-dependent kinase (CDK4 and CDK6) activity appears to be the key step in the progression of eukaryotic cells through the G1 cell cycle phase. One of the mechanisms involved in this process is the binding of some small proteic inhibitors, with a molecular mass ranging between 14 and 20 kDa, to these CDKs. We have evaluated the amount of two such inhibitors, namely p16INK4 and p18, in normal and transformed cells, as well as the biochemical features of the macromolecular complexes containing these proteins. The results obtained indicated that (i) p18 gene expression, unlike p16INK4 gene, is not regulated by pRb status, (ii) no evident relationship exists between the expression of p16INK4 and p18 genes, (iii) significant amounts of the two proteins are not bound to CDKs but occur as free molecules, (iv) each inhibitor forms a complex with the CDK protein with a 1:1 stoichiometry, and (v) a competition exists between cyclin D and the inhibitor protein toward the CDK protein resulting in the absence of detectable cellular free kinase. Moreover, employing the human native partially purified p16INK4 or the pure recombinant protein, we have been able to demonstrate in vitro the dissociation of CDK4-cyclin D1 complex and the formation of CDK4-p16INK4 bimolecular complex. Our findings suggest that during the cell division cycle the members of the p16INK4 protein family and cyclin Ds compete for binding to CDK4/CDK6 and that their quantitative ratio is essential for G1→ S transition

Right ventricular failure in left heart disease: from pathophysiology to clinical manifestations and prognosis

Right heart failure (RHF) is a clinical syndrome in which symptoms and signs are caused by dysfunction and/or overload of the right heart structures, predominantly the right ventricle (RV), resulting in systemic venous hypertension, peripheral oedema and finally, the impaired ability of the right heart to provide tissue perfusion. Pathogenesis of RHF includes the incompetence of the right heart to maintain systemic venous pressure sufficiently low to guarantee an optimal venous return and to preserve renal function. Virtually, all myocardial diseases involving the left heart may be responsible for RHF. This may result from coronary artery disease, hypertension, valvular heart disease, cardiomyopathies and myocarditis. The most prominent clinical signs of RHF comprise swelling of the neck veins with an elevation of jugular venous pressure and ankle oedema. As the situation worsens, fluid accumulation becomes generalised with extensive oedema of the legs, congestive hepatomegaly and eventually ascites. Diagnosis of RHF requires the presence of signs of elevated right atrial and venous pressures, including dilation of neck veins, with at least one of the following criteria: (1) compromised RV function; (2) pulmonary hypertension; (3) peripheral oedema and congestive hepatomegaly. Early recognition of RHF and identifying the underlying aetiology as well as triggering factors are crucial to treating patients and possibly reversing the clinical manifestations effectively and improving prognosis