Management of heart failure in Piedmont Region

emerging problem in industrialized countries: it continues to be diagnosed at high rates and has an decreased survival time, raising new problems, such as the need of an adequate medical service organization and resource expenditure. Aim of this analysis was a quantitative evaluation of diagnostic and therapeutic resource use for CHF in outpatient departments in Piedmont, Italy. Methods. We performed a cross-sectional observational study, based on a two-month data collection in 12 outpatient departments dedicated to congestive heart failure. Information was obtained on each patient using a specific anonymous data collection form. Results. We obtained and analyzed for the study 547 forms. Mean patient age was 66.1 years, mean ejection fraction was 36.6%. Coronary artery disease accounted for 34.6% of congestive heart failure cases, followed by idiopathic etiology (26.4%). Main comorbidities were diabetes (22.3%) and chronic obstructive pulmonary disease (17.7%). Sixty-nine% of patients received a medical treatment with angiotensin-converting enzyme (ACE) inhibitors, 72.6% with β-blockers, 48.8% with aldosterone antagonists. As far as diagnostic resource use during a six-month period preceeding observation, 46.8% of patients underwent echocardiographic examination, 9.9% Holter ECG, 6.0% coronary angiography. Therapy was more often increased in patients who underwent an instrumental evaluation during the preceeding six-month period. Conclusions. Data suggests that in Piedmont outpatients with chronic heart failure receive a high drug prescription level and a small number of instrumental evaluations, as suggested in main international guidelines

A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease

Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration

Cellular communication and cancer therapy: targeting Ca2+and NO signalling within the tumour microenvironment

Cell death and bystander effect are crucial for both the efficacy of cancer therapy and the modulation of anti-tumour immune response. The ‘bystander effect’ refers to a process whereby untreated cells exhibit either the deleterious or beneficial indirect effects as a result of signals received from nearby targeted cells. Various molecular players and pathways have been suggested to mediate the bystander effects, nevertheless to date it is not known which are the key molecules and cellular mechanisms underpinning cell death signal propagation. Several reports suggest the involvement of both nitric oxide (NO) and reactive nitrogen species (RNS) in mediating the bystander effect. Nevertheless their role in the process has not been totally defined since these molecules can either inhibit or sustain tumour progression. Additionally, the methods conventionally applied for NO tracking do neither necessarily reflect real-time NO production nor allow studies into intact three-dimensional tumour mass. The primary aim of this study was to investigate and characterize cell signals responsible for the bystander effect within the tumour microenvironment, paying particular attention to NO. To this purpose, we exploited intravital microscopy by taking advantage of the novel fluorecent probe for NO (CuFL) and the dorsal skinfold chamber model on living tumour-bearing mice subjected to photodynamic therapy (PDT). Notably, the PDT-triggered bystander effect was associated to the generation of very fast NO and Ca2+ waves within the whole tumour mass, supported the hypothesis that constitutive NOS activity might be crucial for the beneficial spread of bystander response and death signals propagation. Additionally, we demonstrated that PDT triggered apoptosis in bystander cells, through gap junction intercellular communication. Finally, our results, provide the first direct evidence of NO involvement in bystander responses within a three-dimensional tumour mass, and strikingly corroborate the notion that connexin gap junction are instrumental for mediating bystander death signals propagation.La morte cellulare e l’effetto bystander rappresentano degli elementi decisivi per l’efficacia della terapia antitumorale nonchè per la modulazione della risposta immunitaria contro il cancro. Per “effetto bystander” si intende il processo per il quale le cellule non soggette a determinati trattamenti farmacologici subiscono indirettamente gli effetti terapeutici, siano essi positivi o negativi, risultanti dal trattamento esclusivo delle cellule vicine. Nonostante siano state proposte diverse molecole e vie di segnalazione coinvolte nell’effetto bystander, i messaggeri molecolari essenziali ed i meccanismi che sottendono alla propagazione dei segnali di morte non sono ancora noti. Diversi studi suggeriscono un coinvolgimento dell’ossido nitrico (NO) e delle specie reattive dell’azoto (RNS) nell’effetto bystander tuttavia, il loro ruolo nel processo non è tuttora totalmente chiaro, considerato che essi possono sia inibire che sostenere la progressione del tumore. Inoltre, i metodi tradizionalmente usati per lo studio dell’ossido nitrico non riflettono necessariamente la produzione di NO in tempo reale nè consentono studi su complesse masse tumorali tridimensionali. L’obiettivo principale di questo studio è stato quello di individuare e caratterizzare i segnali cellulari responsabili dell’effetto bystander all’interno del microambiente tumorale, rivolgendo particolare attenzione all’NO. A questo scopo, abbiamo utilizzato delle tecniche di microscopia intravitale, avvalendoci di una nuova sonda fluorescente per l’NO (CuFL) e del modello sperimentale delle camerette dorsali impiantate su topi affetti da tumore e sottoposti a terapia fotodinamica (PDT). Da questo studio è emerso che l’effetto bystander indotto dalla terapia fotodinamica è associato alla generazione all’interno della massa neoplastica di onde molto rapide di segnali di NO e di Ca2+. Questi eventi avallano l’ipotesi che l’attività delle isoforme costitutive dell’enzima NOS possa esercitare un ruolo cruciale nella diffusione delle risposte bystander e nella trasmissione dei segnali di morte. Questo lavoro inoltre ci ha consentito di dimostrare che la terapia fotodinamica è in grado di indurre l’apoptosi delle cellule vicine non trattate (bystander) attraverso i meccanismi di comunicazione intercellulare mediati dalle giunzioni comunicanti. Infine, i risultati ottenuti hanno fornito la prima evidenza diretta della partecipazione dell’NO all’effetto bystander all’interno di una massa tumorale tridimensionale e corroborano efficacemente l’ipotesi che le giunzioni comunicanti formate da connesine siano essenziali per garantire la propagazione dei segnali di morte osservati nell’effetto bystander

Cellular communication and cancer therapy: targeting Ca2+and NO signalling within the tumour microenvironment

Cell death and bystander effect are crucial for both the efficacy of cancer therapy and the modulation of anti-tumour immune response. The ‘bystander effect’ refers to a process whereby untreated cells exhibit either the deleterious or beneficial indirect effects as a result of signals received from nearby targeted cells. Various molecular players and pathways have been suggested to mediate the bystander effects, nevertheless to date it is not known which are the key molecules and cellular mechanisms underpinning cell death signal propagation. Several reports suggest the involvement of both nitric oxide (NO) and reactive nitrogen species (RNS) in mediating the bystander effect. Nevertheless their role in the process has not been totally defined since these molecules can either inhibit or sustain tumour progression. Additionally, the methods conventionally applied for NO tracking do neither necessarily reflect real-time NO production nor allow studies into intact three-dimensional tumour mass. The primary aim of this study was to investigate and characterize cell signals responsible for the bystander effect within the tumour microenvironment, paying particular attention to NO. To this purpose, we exploited intravital microscopy by taking advantage of the novel fluorecent probe for NO (CuFL) and the dorsal skinfold chamber model on living tumour-bearing mice subjected to photodynamic therapy (PDT). Notably, the PDT-triggered bystander effect was associated to the generation of very fast NO and Ca2+ waves within the whole tumour mass, supported the hypothesis that constitutive NOS activity might be crucial for the beneficial spread of bystander response and death signals propagation. Additionally, we demonstrated that PDT triggered apoptosis in bystander cells, through gap junction intercellular communication. Finally, our results, provide the first direct evidence of NO involvement in bystander responses within a three-dimensional tumour mass, and strikingly corroborate the notion that connexin gap junction are instrumental for mediating bystander death signals propagation.La morte cellulare e l’effetto bystander rappresentano degli elementi decisivi per l’efficacia della terapia antitumorale nonchè per la modulazione della risposta immunitaria contro il cancro. Per “effetto bystander” si intende il processo per il quale le cellule non soggette a determinati trattamenti farmacologici subiscono indirettamente gli effetti terapeutici, siano essi positivi o negativi, risultanti dal trattamento esclusivo delle cellule vicine. Nonostante siano state proposte diverse molecole e vie di segnalazione coinvolte nell’effetto bystander, i messaggeri molecolari essenziali ed i meccanismi che sottendono alla propagazione dei segnali di morte non sono ancora noti. Diversi studi suggeriscono un coinvolgimento dell’ossido nitrico (NO) e delle specie reattive dell’azoto (RNS) nell’effetto bystander tuttavia, il loro ruolo nel processo non è tuttora totalmente chiaro, considerato che essi possono sia inibire che sostenere la progressione del tumore. Inoltre, i metodi tradizionalmente usati per lo studio dell’ossido nitrico non riflettono necessariamente la produzione di NO in tempo reale nè consentono studi su complesse masse tumorali tridimensionali. L’obiettivo principale di questo studio è stato quello di individuare e caratterizzare i segnali cellulari responsabili dell’effetto bystander all’interno del microambiente tumorale, rivolgendo particolare attenzione all’NO. A questo scopo, abbiamo utilizzato delle tecniche di microscopia intravitale, avvalendoci di una nuova sonda fluorescente per l’NO (CuFL) e del modello sperimentale delle camerette dorsali impiantate su topi affetti da tumore e sottoposti a terapia fotodinamica (PDT). Da questo studio è emerso che l’effetto bystander indotto dalla terapia fotodinamica è associato alla generazione all’interno della massa neoplastica di onde molto rapide di segnali di NO e di Ca2+. Questi eventi avallano l’ipotesi che l’attività delle isoforme costitutive dell’enzima NOS possa esercitare un ruolo cruciale nella diffusione delle risposte bystander e nella trasmissione dei segnali di morte. Questo lavoro inoltre ci ha consentito di dimostrare che la terapia fotodinamica è in grado di indurre l’apoptosi delle cellule vicine non trattate (bystander) attraverso i meccanismi di comunicazione intercellulare mediati dalle giunzioni comunicanti. Infine, i risultati ottenuti hanno fornito la prima evidenza diretta della partecipazione dell’NO all’effetto bystander all’interno di una massa tumorale tridimensionale e corroborano efficacemente l’ipotesi che le giunzioni comunicanti formate da connesine siano essenziali per garantire la propagazione dei segnali di morte osservati nell’effetto bystander

Correction: Marcuzzi, E., et al. Chemokines and Chemokine Receptors: Orchestrating Tumor Metastasization. <i>Int. J. Mol. Sci.</i> 2019, <i>20</i>, 96

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Enterobius Vermicularis infestation of the appendix mimicking acute appendicitis in a young Italian boy. Case report

Enterobius Vermicularis (EV) is the most commonly identified heminth incidentally found within the appendix of a clinically diagnosed appendicitis. This simple presence of EV may cause appendicular colic, primarily affecting children, it is an important cause of negative appendicectomy. We report a case of a young male who presented with clinical features of acute appendicitis. Laparoscopic appendicectomy was uneventful and pathologic examination revealed the presence of an EV infestation originating from the lumen of his vermiform appendix

Chemokines and chemokine receptors: Orchestrating tumor metastasization

Metastasis still represents the primary cause of cancer morbidity and mortality worldwide. Chemokine signalling contributes to the overall process of cancer growth and metastasis, and their expression in both primary tumors and metastatic lesions correlate with prognosis. Chemokines promote tumor metastasization by directly supporting cancer cell survival and invasion, angiogenesis, and by indirectly shaping the pre-metastatic niches and antitumor immunity. Here, we will focus on the relevant chemokine/chemokine receptor axes that have been described to drive the metastatic process. We elaborate on their role in the regulation of tumor angiogenesis and immune cell recruitment at both the primary tumor lesions and the pre-metastatic foci. Furthermore, we also discuss the advantages and limits of current pharmacological strategies developed to target chemokine networks for cancer therapy

Role and clinical importance of Helicobacter pylori infection in hemodialysis patients

Dyspepsia is an extrarenal symptom frequently found in hemodialysed patients; it is due to chronic renal failure, and uremic gastritis is a specific associated condition in chronic renal failure (CRF). On the other hand, in the general population, Helicobacter pylori infection is an important dyspepsia-related risk factor; its close connections with gastro-duodenal pathology are already known, above all the peptic disease in a really exclusive way. By observation of a dyalitic group of patients, opportunely matched with a no CRF group, we evaluated CRF-associated uremia and Helicobacter pylori infection which could eventually interact causing symptoms and lesions. A statistical analysis of obtained data allowed us to conclude that, although there is not, from an epidemiological view-point, a larger diffusion of Helicobacter pylori among dyalitic patients compared to general population, moreover the infection is uremia-synergic in causing gastro-duodenal symptoms and lesions. These findings, therefore, suggest systematically investigation a possible Helicobacter pylori infection in CRF patients and its relation to gastritis grading, and searching for probable active peptic lesions