Vasculogenesi, anomalie di crescita vascolari della placenta e cardiopatie congenite: uno studio sperimentale, multidisciplinare e multicentrico volto ad individuare una correlazione ad oggi non nota

Introduzione: Le Cardiopatie Congenite (CC), sono le anomalie congenite pi\uf9 frequenti alla nascita, con un'incidenza di 1 su 100 nati vivi. La placenta \ue8 l'organo fetale pi\uf9 complesso, in grado di garantire lo sviluppo e la crescita fetale durante la gravidanza. Sebbene lo sviluppo della placenta e del cuore avvenga in parallelo, il rapporto tra questi due organi risulta sconosciuto e trattato solo di recente. Metodi: Abbiamo condotto uno studio osservazionale retrospettivo, includendo i pazienti nati esclusivamente presso l'ospedale G. Gaslini, tra gennaio 2014 e marzo 2018 con una diagnosi prenatale di CC e un\u2019analisi anatomopatologica della placenta, per un totale di 151 pazienti. I feti affetti da CC sono stati divisi in 5 categorie, basate sulla fisiologia cardiovascolare, come segue: (1) ventricolo singolo con ostruzione aortica, (2) ventricolo singolo con ostruzione polmonare, (3) due ventricoli emodinamicamente instabili, (4) trasposizione delle grandi arterie, (5) due ventricoli emodinamicamente stabili. Per ogni paziente, sono stati considerati i seguenti dati: peso placentare assoluto, alterazioni macroscopiche e vascolari del cordone ombelicale, indice di massa corporea materna (BMI), genere, restrizione di crescita intrauterina fetale e neonatale (IUGR), anomalie extracardiache, procedura chirurgica o percutanea nel periodo neonatale. Per l\u2019analisi statistica \ue8 stato utilizzato il test esatto di Fisher, con il quale abbiamo studiato il rapporto di dipendenza fra una specifica variabile e le CC; un p <0,05 \ue8 stato ritenuto significativo per la dipendenza. Risultati: Solo quattro variabili hanno mostrato una significativit\ue0 scientifica: l'intervento neonatale (p = 0,000008), le anomalie associate extracardiache (p = 0,012), l'edema del cordone ombelicale (p = 0,007) e il genere (p = 0,015). Nonostante avessimo riscontrato un'alta incidenza di inserimento anomalo del cordone ombelicale nelle placente di neonati cardiopatici, il risultato dell\u2019analisi di Fisher non ha dimostrato alcuna dipendenza tra i gruppi CC e questa variabile (p = 0,379). Conclusione: Dallo studio dei nostri risultati, non riteniamo che il peso della placenta possa predire la diagnosi di CC, come precedentemente riportato in letteratura. Sulla base della nostra esperienza, non possiamo considerare l'inserimento anormale del cordone come un fattore ad alto rischio per CC. Pertanto, non riteniamo necessario ampliare la metodica di screening ecografico mediante l\u2019analisi della modalit\ue0 di inserimento del cordone. Contrariamente, la presenza di edema del cordone ombelicale \ue8 risultata dipendente dalle CC quindi, potrebbe essere ritenuto un fattore di rischio per CC. Analogamente, anche il genere \ue8 risultato dipendente dalle CC, con una forte associazione fra il sesso maschile e le CC Mayor. Per il futuro, riteniamo necessario implementare lo studio con l\u2019inserimento di un gruppo di controllo e con l\u2019inclusione di altre variabili cliniche e strumentali del feto e della placenta.Introduction: Congenital heart diseases (CHD) are the most frequent congenital anomalies at birth, with an incidence of 1 in 100 live births. The placenta is the most complex fetal organ, responsible of fetal development and growth during pregnancy. Although the development of the placenta and heart occurs in parallel, the relationship between these two organs is unknown and only recently elucidated. Methods: We conducted a retrospective observational study, including patients born exclusively at the G. Gaslini hospital, between January 2014 and March 2018 with a prenatal diagnosis of CHD and an anatomopathological analysis of the placenta, for a total of 151 patients. Fetuses with CHD Mayor were divided into 5 categories, based on cardiovascular physiology, as follows: (1) single ventricle with aortic obstruction, (2) single ventricle with pulmonary obstruction, (3) two hemodynamically unstable ventricles, (4) transposition of the great arteries, (5) two hemodynamically stable ventricles. For each patient, the following data were considered: absolute placental weight, macroscopic and vascular alterations of the umbilical cord, maternal body mass index (BMI), gender, fetal and neonatal intrauterine growth restriction (IUGR), extracardiac anomalies, surgical procedure or percutaneous in the neonatal period. For statistical analysis, the Fisher test was used, with which we studied the dependency ratio between a specific variable and the CHD; a p <0.05 was considered significant. Results: Only four variables showed scientific significance: neonatal surgery (p = 0.000008), associated extracardiac anomalies (p = 0.012), umbilical cord edema (p = 0.007) and gender (p = 0.015). Although we had found a high incidence of abnormal insertion of the umbilical cord in the placentas of heart disease infants, the result of Fisher's analysis showed no dependence between the CHD groups and this variable (p = 0.379). Conclusion: From the analysis of our results, we do not believe that the weight of the placenta can predict the diagnosis of CHD, as previously reported in the literature. Based on our experience, we cannot consider abnormal cord insertion as a high risk factor for CHD. Therefore, we do not consider it necessary to expand the ultrasound screening method by analyzing the cord insertion method. Conversely, the presence of edema of the umbilical cord was found to be CHD dependent therefore, it could be considered a risk factor for CHD. Similarly, gender was also dependent on CHD, with a strong association between the male sex and CHD Mayor. For the future, we believe it is necessary to implement the study with the inclusion of a control group and with the inclusion of other clinical and instrumental variables of the fetus and placenta

Medico-legal considerations on "lotus Birth" in the Italian legislative framework

The term "Lotus Birth" identifies the practice of not cutting the umbilical cord and of leaving the placenta attached to the newborn after its expulsion until it detaches spontaneously, which generally occurs 3-10 days after birth. The first reported cases of Lotus Birth date back to 2004 in Australia. Supporters of such a procedure claim that the newborn is better perfused, endowed with a more robust immune system and "less stressed". However, it should be pointed out that histopathological study of the placenta is increasingly being requested in order to investigate problems of an infective nature or dysmaturity affecting the foetus, and situations of risk affecting the mother. Moreover, from the legal standpoint, there is no uniform position on the question of whether the placenta belongs to the mother or to the newborn. Lastly, a proper conservation of the embryonic adnexa is very difficult and includes problems of a hygiene/health, infectivological and medico-legal nature. The authors analyzed all these aspect in the Italian legislative framework, reaching the conclusion that Lotus Birth is inadvisable from both the scientific and logical/rational points of view

In vivo morphological alterations of TAMs during KCa3.1 inhibition—by using in vivo two-photon time-lapse technology

Tumor associated macrophages (TAMs) are the mostprevalent cells recruited in the tumor microenvironment (TME). Once recruited, TAMs acquire a pro-tumor phenotype characterized by a typical morphology: ameboid in the tumor core and with larger soma and thick branches in the tumor periphery. Targeting TAMs by reverting them to an anti-tumor phenotype is a promising strategy for cancer immunotherapy. Taking advantage of Cx3cr1GFP/WT heterozygous mice implanted with murine glioma GL261-RFP cells we investigated the role of Ca2+-activated K+ channel (KCa3.1) on the phenotypic shift of TAMs at the late stage of glioma growth through in vivo two-photon imaging. We demonstrated that TAMs respond promptly to KCa3.1 inhibition using a selective inhibitor of the channel (TRAM-34) in a time-dependent manner by boosting ramified projections attributable to a less hypertrophic phenotype in the tumor core. We also revealed a selective effect of drug treatment by reducing both glioma cells and TAMs in the tumor core with no interference with surrounding cells. Taken together, our data indicate a TRAM-34-dependent progressive morphological transformation of TAMs toward a ramified and anti-tumor phenotype, suggesting that the timing of KCa3.1 inhibition is a key point to allow beneficial effects on TAMs

Evolution of nonspecific duodenal lymphocytosis over 2 years of follow-up

AIM: To assess the evolution of duodenal lymphocytosis (DL), a condition characterized by increased intraepithelial lymphocytes (IELs), over 2 years of follow-up. METHODS: Consecutive patients undergoing upper endoscopy/histology for abdominal pain, diarrhea, weight loss, weakness or other extraintestinal features compatible with celiac disease (CD) were included. Evaluation of IELs infiltrate in duodenal biopsy samples was carried out by CD3-immunohistochemistry and expressed as number of positive cells/100 enterocytes. Diagnostic agreement on the IELs count was tested by calculating the weighted k coefficient. All patients underwent serological detection of autoantibodies associated with CD: IgG and IgA anti-tissue transglutaminase and endomysium. Each patient underwent further investigations to clarify the origin of DL at baseline and/or in the course of 2 years of follow-up every six months. Autoimmune thyroiditis, intestinal infections, parasitic diseases, bacterial intestinal overgrowth, hypolactasia and wheat allergy were detected. Colonoscopy and enteric magnetic resonance imaging were performed when necessary. Risk factors affecting the final diagnosis were detected by multinomial logistic regression and expressed as OR. RESULTS: Eighty-five patients (16 males, 69 females, aged 34.1 ± 12.5 years) were followed up for a mean period of 21.7 ± 11.7 mo. At baseline, endoscopy/duodenal biopsy, CD3 immunohistochemistry revealed: > 25 IELs/100 enterocytes in 22 subjects, 15-25 IELs in 37 and < 15 IELs in 26. They all had negative serum anti-transglutaminase and anti-endomysium, whilst 5 showed IgG anti-gliadin positivity. In the course of follow-up, 23 developed CD seropositivity and gluten sensitivity (GS) was identified in 19. Other diagnoses were: 5 Helicobacter pylori infections, 4 jejunal Crohn's disease, 1 lymphocytic colitis and 1 systemic sclerosis. The disease in the remaining 32 patients was classified as irritable bowel syndrome because of the lack of diagnostic evidence. At multivariate analysis, the evolution towards CD was associated with an IELs infiltrate > 25 (OR = 1640.4) or 15-25 (OR = 16.95), human leukocyte antigen (HLA) DQ2/8 (OR = 140.85) or DQA1∗0501 (OR = 15.36), diarrhea (OR = 5.56) and weakness (OR = 11.57). GS was associated with IELs 15-25 (OR = 28.59), autoimmune thyroiditis (OR = 87.63), folate deficiency (OR = 48.53) and diarrhea (OR = 54.87). CONCLUSION: DL may have a multifactorial origin but the IELs infiltrate and HLA are strong predictive factors for CD development and a clinical diagnosis of GS

High-frequency rTMS modulates emotional behaviors and structural plasticity in layers II/III and V of the mPFC

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique, and it has been increasingly used as a nonpharmacological intervention for the treatment of various neurological and neuropsychiatric diseases, including depression. In humans, rTMS over the prefrontal cortex is used to induce modulation of the neural circuitry that regulates emotions, cognition, and depressive symptoms. However, the underlying mechanisms are still unknown. In this study, we investigated the effects of a short (5-day) treatment with high-frequency (HF) rTMS (15 Hz) on emotional behavior and prefrontal cortex morphological plasticity in mice. Mice that had undergone HF-rTMS showed an anti-depressant-like activity as evidenced by decreased immobility time in both the Tail Suspension Test and the Forced Swim Test along with increased spine density in both layer II/III and layer V apical and basal dendrites. Furthermore, dendritic complexity assessed by Sholl analysis revealed increased arborization in the apical portions of both layers, but no modifications in the basal dendrites branching. Overall, these results indicate that the antidepressant-like activity of HF-rTMS is paralleled by structural remodeling in the medial prefrontal cortex

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

Chorea-Acanthocytosis (ChAc) is a devastating, little understood, and currently untreatable neurodegenerative disease caused by VPS13A mutations. Based on our recent demonstration that accumulation of activated Lyn tyrosine kinase is a key pathophysiological event in human ChAc cells, we took advantage of Vps13a-/- mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, \u3b3-synuclein and phospho-tau proteins in Vps13a-/- basal ganglia secondary to impaired autophagy leading to neuroinflammation. Mice double knockout Vps13a-/- Lyn-/- showed normalization of red cell morphology and improvement of autophagy in basal ganglia. We then in vivo tested pharmacologic inhibitors of Lyn: dasatinib and nilotinib. Dasatinib failed to cross the mouse brain blood barrier (BBB), but the more specific Lyn kinase inhibitor nilotinib, crosses the BBB. Nilotinib ameliorates both Vps13a-/- hematological and neurological phenotypes, improving autophagy and preventing neuroinflammation. Our data support the proposal to repurpose nilotinib as new therapeutic option for ChAc patients

The “Diabetes Comorbidome”: A Different Way for Health Professionals to Approach the Comorbidity Burden of Diabetes

(1) Background: The disease burden related to diabetes is increasing greatly, particularly in older subjects. A more comprehensive approach towards the assessment and management of diabetes’ comorbidities is necessary. The aim of this study was to implement our previous data identifying and representing the prevalence of the comorbidities, their association with mortality, and the strength of their relationship in hospitalized elderly patients with diabetes, developing, at the same time, a new graphic representation model of the comorbidome called “Diabetes Comorbidome”. (2) Methods: Data were collected from the RePoSi register. Comorbidities, socio-demographic data, severity and comorbidity indexes (Cumulative Illness rating Scale CIRS-SI and CIRS-CI), and functional status (Barthel Index), were recorded. Mortality rates were assessed in hospital and 3 and 12 months after discharge. (3) Results: Of the 4714 hospitalized elderly patients, 1378 had diabetes. The comorbidities distribution showed that arterial hypertension (57.1%), ischemic heart disease (31.4%), chronic renal failure (28.8%), atrial fibrillation (25.6%), and COPD (22.7%), were the more frequent in subjects with diabetes. The graphic comorbidome showed that the strongest predictors of death at in hospital and at the 3-month follow-up were dementia and cancer. At the 1-year follow-up, cancer was the first comorbidity independently associated with mortality. (4) Conclusions: The “Diabetes Comorbidome” represents the perfect instrument for determining the prevalence of comorbidities and the strength of their relationship with risk of death, as well as the need for an effective treatment for improving clinical outcomes

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Antidiabetic Drug Prescription Pattern in Hospitalized Older Patients with Diabetes

Objective: To describe the prescription pattern of antidiabetic and cardiovascular drugs in a cohort of hospitalized older patients with diabetes. Methods: Patients with diabetes aged 65 years or older hospitalized in internal medicine and/or geriatric wards throughout Italy and enrolled in the REPOSI (REgistro POliterapuie SIMI—Società Italiana di Medicina Interna) registry from 2010 to 2019 and discharged alive were included. Results: Among 1703 patients with diabetes, 1433 (84.2%) were on treatment with at least one antidiabetic drug at hospital admission, mainly prescribed as monotherapy with insulin (28.3%) or metformin (19.2%). The proportion of treated patients decreased at discharge (N = 1309, 76.9%), with a significant reduction over time. Among those prescribed, the proportion of those with insulin alone increased over time (p = 0.0066), while the proportion of those prescribed sulfonylureas decreased (p < 0.0001). Among patients receiving antidiabetic therapy at discharge, 1063 (81.2%) were also prescribed cardiovascular drugs, mainly with an antihypertensive drug alone or in combination (N = 777, 73.1%). Conclusion: The management of older patients with diabetes in a hospital setting is often sub-optimal, as shown by the increasing trend in insulin at discharge, even if an overall improvement has been highlighted by the prevalent decrease in sulfonylureas prescription

Beta-Blocker Use in Older Hospitalized Patients Affected by Heart Failure and Chronic Obstructive Pulmonary Disease: An Italian Survey From the REPOSI Register

Beta (β)-blockers (BB) are useful in reducing morbidity and mortality in patients with heart failure (HF) and concomitant chronic obstructive pulmonary disease (COPD). Nevertheless, the use of BBs could induce bronchoconstriction due to β2-blockade. For this reason, both the ESC and GOLD guidelines strongly suggest the use of selective β1-BB in patients with HF and COPD. However, low adherence to guidelines was observed in multiple clinical settings. The aim of the study was to investigate the BBs use in older patients affected by HF and COPD, recorded in the REPOSI register. Of 942 patients affected by HF, 47.1% were treated with BBs. The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge (admission, 36.9% vs. 51.3%; discharge, 38.0% vs. 51.7%). In addition, no further BB users were found at discharge. The probability to being treated with a BB was significantly lower in patients with HF also affected by COPD (adj. OR, 95% CI: 0.50, 0.37-0.67), while the diagnosis of COPD was not associated with the choice of selective β1-BB (adj. OR, 95% CI: 1.33, 0.76-2.34). Despite clear recommendations by clinical guidelines, a significant underuse of BBs was also observed after hospital discharge. In COPD affected patients, physicians unreasonably reject BBs use, rather than choosing a β1-BB. The expected improvement of the BB prescriptions after hospitalization was not observed. A multidisciplinary approach among hospital physicians, general practitioners, and pharmacologists should be carried out for better drug management and adherence to guideline recommendations