Physiotherapists' training in oncology rehabilitation from entry-level to advanced education: A qualitative study.

BACKGROUND AND PURPOSE: Physiotherapy is gaining a central role in oncology. However, the training and competencies needed by physiotherapists in oncology rehabilitation are still unclear. This study aims to articulate the training trajectory of physiotherapists in oncology rehabilitation from entry-level education to advanced education degrees. METHODS: Qualitative focus group study following a 'Reflexive Thematic Analysis' for data analysis. Participants were Italian physiotherapists with expertise in Oncology Rehabilitation (either clinically or academically) and Physiotherapy Bachelor of Science (BSc) course leaders, selected through purposive sampling. RESULTS: Two focus groups were conducted with 14 participants. Six themes were developed: 1. 'Entry-Level Education in Oncology Rehabilitation: Let's Have a Taste', as the BSc introduces oncology rehabilitation. 2. 'Basic Knowledge: Building up the Library' as students acquire basic knowledge on oncology rehabilitation during their BSc; 3. 'Learning by Experience: The Relevance of the Placement' to answer the question "Is this the right road for me?"; 4. 'Clinical Reasoning and Competencies in Oncology Rehabilitation Embedded in Uncertainty' because oncology physiotherapists need to deal with the uncertainty of their patients' status; 5. 'Advanced Education Degree Skills: from Appetiser to the Main Course', as advanced education degree courses allow for becoming an expert in the field; 6. 'A Call to Action for Physiotherapists: Prevention-Diagnosis-Survivorship & End of Life', to realise their critical role in all the phases of the oncology path. CONCLUSIONS: The BSc in Physiotherapy provides a foundation for future physiotherapists to understand oncology rehabilitation, but advanced education is necessary for expertise. The findings of this study have important implications for creating a shared physiotherapy curriculum in oncology rehabilitation. IMPLICATION FOR PHYSIOTHERAPY PRACTICE: This study has significant implications for improving physiotherapy curricula in oncology rehabilitation, positively impacting the skills and competencies of practitioners in this paramount field.

Aberrant L-Fucose Accumulation and Increased Core Fucosylation Are Metabolic Liabilities in Mesenchymal Glioblastoma.

Glioblastoma (GBM) is a common and deadly form of brain tumor in adults. Dysregulated metabolism in GBM offers an opportunity to deploy metabolic interventions as precise therapeutic strategies. To identify the molecular drivers and the modalities by which different molecular subgroups of GBM exploit metabolic rewiring to sustain tumor progression, we interrogated the transcriptome, the metabolome, and the glycoproteome of human subgroup-specific GBM sphere-forming cells (GSC). L-fucose abundance and core fucosylation activation were elevated in mesenchymal (MES) compared with proneural GSCs; this pattern was retained in subgroup-specific xenografts and in subgroup-affiliated human patient samples. Genetic and pharmacological inhibition of core fucosylation significantly reduced tumor growth in MES GBM preclinical models. Liquid chromatography-mass spectrometry (LC-MS)-based glycoproteomic screening indicated that most MES-restricted core-fucosylated proteins are involved in therapeutically relevant GBM pathological processes, such as extracellular matrix interaction, cell adhesion, and integrin-mediated signaling. Selective L-fucose accumulation in MES GBMs was observed using preclinical minimally invasive PET, implicating this metabolite as a potential subgroup-restricted biomarker.Overall, these findings indicate that L-fucose pathway activation in MES GBM is a subgroup-specific dependency that could provide diagnostic markers and actionable therapeutic targets. SIGNIFICANCE: Metabolic characterization of subgroup-specific glioblastoma (GBM) sphere-forming cells identifies the L-fucose pathway as a vulnerability restricted to mesenchymal GBM, disclosing a potential precision medicine strategy for targeting cancer metabolism.

mTORC1 promotes malignant large cell/anaplastic histology and is a targetable vulnerability in SHH-TP53 mutant medulloblastoma.

Medulloblastoma (MB), one of the most malignant brain tumors of childhood, comprises distinct molecular subgroups, with p53 mutant sonic hedgehog-activated (SHH-activated) MB patients having a very severe outcome that is associated with unfavorable histological large cell/anaplastic (LC/A) features. To identify the molecular underpinnings of this phenotype, we analyzed a large cohort of MB developing in p53-deficient Ptch+/- SHH mice that, unexpectedly, showed LC/A traits that correlated with mTORC1 hyperactivation. Mechanistically, mTORC1 hyperactivation was mediated by a decrease in the p53-dependent expression of mTORC1 negative regulator Tsc2. Ectopic mTORC1 activation in mouse MB cancer stem cells (CSCs) promoted the in vivo acquisition of LC/A features and increased malignancy; accordingly, mTORC1 inhibition in p53-mutant Ptch+/- SHH MB and CSC-derived MB resulted in reduced tumor burden and aggressiveness. Most remarkably, mTORC1 hyperactivation was detected only in p53-mutant SHH MB patient samples, and treatment with rapamycin of a human preclinical model phenocopying this subgroup decreased tumor growth and malignancy. Thus, mTORC1 may act as a specific druggable target for this subset of SHH MB, resulting in the implementation of a stringent risk stratification and in the potentially rapid translation of this precision medicine approach into the clinical setting.

Technological Progress and Health Convergence: The Case of Penicillin in Postwar Italy.

Throughout history, technological progress has transformed population health, but the distributional effects of these gains are unclear. New substitutes for older, more expensive health technologies can produce convergence in population health outcomes but may also be prone to elite capture and thus divergence. We study the case of penicillin using detailed historical mortality statistics and exploiting its abruptly timed introduction in Italy after WWII. We find that penicillin reduced both the mean and standard deviation of infectious disease mortality, leading to substantial convergence across disparate regions of Italy. Our results do not appear to be driven by competing risks or confounded by mortality patterns associated with WWII.

Molecular testing on bronchial washings for the diagnosis and predictive assessment of lung cancer.

Cytopathological analyses of bronchial washings (BWs) collected during fibre-optic bronchoscopy are often inconclusive for lung cancer diagnosis. To address this issue, we assessed the suitability of conducting molecular analyses on BWs, with the aim to improve the diagnosis and outcome prediction of lung cancer. The methylation status of RASSF1A, CDH1, DLC1 and PRPH was analysed in BW samples from 91 lung cancer patients and 31 controls, using a novel two-colour droplet digital methylation-specific PCR (ddMSP) technique. Mutations in ALK, BRAF, EGFR, ERBB2, KRAS, MAP2K1, MET, NRAS, PIK3CA, ROS1 and TP53 and gene fusions of ALK, RET and ROS1 were also investigated, using next-generation sequencing on 73 lung cancer patients and 14 tumour-free individuals. Our four-gene methylation panel had significant diagnostic power, with 97% sensitivity and 74% specificity (relative risk, 7.3; odds ratio, 6.1; 95% confidence interval, 12.7-127). In contrast, gene mutation analysis had a remarkable value for predictive, but not for diagnostic, purposes. Actionable mutations in EGFR, HER2 and ROS1 as well as in other cancer genes (KRAS, PIK3CA and TP53) were detected. Concordance with gene mutations uncovered in tumour biopsies was higher than 90%. In addition, bronchial-washing analyses permitted complete patient coverage and the detection of additional actionable mutations. In conclusion, BWs are a useful material on which to perform molecular tests based on gene panels: aberrant gene methylation and mutation analyses could be performed as approaches accompanying current diagnostic and predictive assays during the initial workup phase. This study establishes the grounds for further prospective investigation.

Airway inflammatory profile is correlated with symptoms in stable COPD: A longitudinal proof-of-concept cohort study.

BACKGROUND AND OBJECTIVE: Symptoms negatively impact the quality of life and long-term prognosis of patients with chronic obstructive pulmonary disease (COPD). Little is known about the relationship linking airway inflammation and symptoms in stable COPD. In this study, we evaluated whether respiratory symptoms in COPD are related to sputum inflammatory cellular profile and whether symptom changes are associated with changes in airway inflammation. METHODS: A total of 40 patients with stable COPD with moderate-to-severe airflow obstruction were enrolled. Patients were visited weekly over 4 weeks. At each visit, patients underwent clinical assessments, lung function tests and sputum induction. Patients recorded daily dyspnoea, sputum and cough scores. RESULTS: The changes between two consecutive visits in the percent of sputum neutrophils and eosinophils were related to the changes in the cough (P < 0.001; r = 0.63) and dyspnoea scores (P < 0.001; r = 0.58) of the prior week. Furthermore, using regression analyses, we were able to demonstrate that changes in the cough score were specifically associated to the change in neutrophils, while changes in the dyspnoea score and use of rescue medications were associated with changes in eosinophils numbers. CONCLUSION: Our study showed an association between symptoms and the sputum inflammatory profile. In particular, changes in symptoms (cough and dyspnoea) were correlated with changes in the specific sputum inflammatory cell components of airway inflammation (neutrophils and eosinophils, respectively), providing novel information on the mechanisms of disease manifestation.

A pacemaker lead in the left ventricle: An "unexpected" finding?

Inadvertent malposition of a pacemaker lead in the left ventricle is uncommon, but it should not be misdiagnosed. We report the case of a 68-year-old woman with symptomatic sick-sinus syndrome requiring pacemaker implantation. Shortly afterwards the lead was extracted and a new pacemaker was contralaterally implanted due to pocket hematoma and suspected lead fracture. Three months later, she was referred to our echocardiography laboratory complaining of asthenia. At transthoracic echocardiography an echo-bright linear structure was recognized in left atrium, passing through the mitral valve and leaning against the posterior left ventricular wall. In short-axis and apical views, the lead apparently crossed the interatrial septum through patent foramen ovale. The QRS-paced electrocardiogram showed right bundle branch block morphology. The lead was apparently well positioned, examining the chest X-ray postero-anterior view. On the contrary, by latero-lateral view and left-anterior oblique view, lead curvature was consistent with misplacement into the left ventricle. Malposition was confirmed by transesophageal echocardiography. Given the relatively recent implant, system revision with lead extraction was scheduled and completed without complications. This case report is intended to improve our awareness in the prevention and in the prompt detection of misplaced pacemaker leads in order to manage an immediate correction. .

High mobility group box 1 orchestrates tissue regeneration via CXCR4.

Inflammation and tissue regeneration follow tissue damage, but little is known about how these processes are coordinated. High Mobility Group Box 1 (HMGB1) is a nuclear protein that, when released on injury, triggers inflammation. We previously showed that HMGB1 with reduced cysteines is a chemoattractant, whereas a disulfide bond makes it a proinflammatory cytokine. Here we report that fully reduced HMGB1 orchestrates muscle and liver regeneration via CXCR4, whereas disulfide HMGB1 and its receptors TLR4/MD-2 and RAGE (receptor for advanced glycation end products) are not involved. Injection of HMGB1 accelerates tissue repair by acting on resident muscle stem cells, hepatocytes, and infiltrating cells. The nonoxidizable HMGB1 mutant 3S, in which serines replace cysteines, promotes muscle and liver regeneration more efficiently than the wild-type protein and without exacerbating inflammation by selectively interacting with CXCR4. Overall, our results show that the reduced form of HMGB1 coordinates tissue regeneration and suggest that 3S may be used to safely accelerate healing after injury in diverse clinical contexts.

Comparison of multiple techniques for endobronchial ultrasound-transbronchial needle aspiration specimen preparation in a single institution experience.

BACKGROUND: The optimal method for specimen preparation of endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) is still controversial. This study aims to compare several techniques available for EBUS-TBNA specimen acquisition and processing, in order to identify the best performing technique. METHODS: We retrospectively reviewed the data of 199 consecutive patients [male, 73%; median age, 64 years (IQR: 52-74 years)] undergoing EBUS-TBNA at our institution from 2012 through 2014 for diagnosis of hilar-mediastinal lymph node enlargement suspect of neoplastic (n=139) or granulomatous (n=60) disease. All procedures were performed by two experienced bronchoscopists, under conscious sedation and local anaesthesia, using 21/22-Gauge (G) needle, without rapid on-site evaluation (ROSE). Five specimen-processing techniques were used: cytology slides in 42 cases (21%); cell-block in 25 (13%); core-tissue in 60 (30%); combination of cytology slides and core-tissue in 51 (26%); combination of cytology slides and cell-block in 21 (10%). To assess the diagnostic accuracy of each tissue-processing technique we compared the EBUS-TBNA results to those obtained with surgical lymphadenectomy, or 1-year follow-up in non-operated patients. RESULTS: Diagnostic yield, accuracy and area under the curve (AUC) were as follows. Cytology slides: 81%, 80%, 0.90; cell-block: 48%, 33%, 0.67; core-tissue: 87%, 99%, 0.96; cytology slides + core-tissue: 80%, 100%, 1.00; cytology slides + cell-block: 86%, 100%, 1.00. Cytology slides and core-tissue method showed non-significantly different diagnostic yield (P=0.435) and AUC (P=0.152). CONCLUSIONS: In our single-institution experience, cytology slides and core-tissue preparations demonstrated high and similar diagnostic performance. Cytology slides combination with core-tissue or cell-block showed the highest performance, however these combination methods were more resource-consuming.

Nitric Oxide Donor Molsidomine Positively Modulates Myogenic Differentiation of Embryonic Endothelial Progenitors.

Embryonic VE-Cadherin-expressing progenitors (eVE-Cad+), including hemogenic endothelium, have been shown to generate hematopoietic stem cells and a variety of other progenitors, including mesoangioblasts, or MABs. MABs are vessel-associated progenitors with multilineage mesodermal differentiation potential that can physiologically contribute to skeletal muscle development and regeneration, and have been used in an ex vivo cell therapy setting for the treatment of muscular dystrophy. There is currently a therapeutic need for molecules that could improve the efficacy of cell therapy protocols; one such good candidate is nitric oxide. Several studies in animal models of muscle dystrophy have demonstrated that nitric oxide donors provide several beneficial effects, including modulation of the activity of endogenous cell populations involved in muscle repair and the delay of muscle degeneration. Here we used a genetic lineage tracing approach to investigate whether the therapeutic effect of nitric oxide in muscle repair could derive from an improvement in the myogenic differentiation of eVE-Cad+ progenitors during embryogenesis. We show that early in vivo treatment with the nitric oxide donor molsidomine enhances eVE-Cad+ contribution to embryonic and fetal myogenesis, and that this effect could originate from a modulation of the properties of yolk sac hemogenic endothelium.

Comparison between IEGM-based approach and echocardiography in AV/PV and VV delay optimization in CRT-D recipients (Quicksept study).

BACKGROUND: AtrioVentricular (AV) and InterVentricular (VV) delay optimization can improve ventricular function in Cardiac Resynchronization Therapy (CRT) and is usually performed by means of echocardiography. St Jude Medical has developed an automated algorhythm which calculates the optimal AV and VV delays (QuickOpt™) based on Intracardiac ElectroGrams, (IEGM), within 2 min. So far, the efficacy of the algorhythm has been tested acutely with standard lead position at right ventricular (RV) apex. Aim of this project is to evaluate the algorhythm performance in the mid- and long-term with RV lead located in mid-septum. METHODS: AV and VV delays optimization data were collected in 13 centers using both echocardiographic and QuickOpt™ guidance in CRTD implanted patients provided with this algorhythm. Measurements of the aortic Velocity Time Integral (aVTI) were performed with both methods in a random order at pre-discharge, 6-month and 12-month follow-up. RESULTS: Fifty-three patients were studied (46 males; age 68 ± 10y; EF 28 ± 7%). Maximum aVTI obtained by echocardiography at different AV delays, were compared with aVTI acquired at AV delays suggested by QuickOpt. The AV Pearson correlations were 0.96 at pre-discharge, 0.95 and 0,98 at 6- and 12- month follow-up respectively. After programming optimal AV, the same approach was used to compare echocardiographic aVTI with aVTI corresponding to the VV values provided by QuickOpt. The VV Pearson Correlation were 0,92 at pre-discharge, 0,88 and 0.90 at 6-month and 12- month follow-up respectively. CONCLUSIONS: IEGM-based optimization provides comparable results with echocardiographic method (maximum aVTI) used as reference with mid-septum RV lead location.

Efficacy and safety of surgical lung biopsy for interstitial disease. Experience of 161 consecutive patients from a single institution in Italy.

BACKGROUND: The role of surgical biopsy for interstitial lung disease (ILD) is controversial, because of possible postoperative morbidity and mortality. We aimed to assess the efficacy and safety of surgical biopsy for ILD. METHODS: We retrospectively analysed the diagnostic performance and the postoperative complications of 161 consecutive surgical lung biopsy procedures carried out in suspected ILD cases that were undefined after multidisciplinary clinico-radiological evaluation. In 151 cases (93.8%) the biopsy was performed by video-assisted thoracoscopic surgery (VATS), in 6.2% by limited thoracotomy. RESULTS: A specific histological diagnosis was obtained in 154 (95.7%) of the surgically biopsied patients, while 4.3% remained histologically unclassified. The predominant histological patterns were sarcoidosis (29.8 %), usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) (24.2%), cryptogenic organizing pneumonia (18.6%) and nonspecific interstitial pneumonia (8.1%). The postoperative course was uneventful in 142 cases. In 19 patients (11.8%) we observed postoperative complications, predominantly prolonged air leakage (5.0% of all cases). Thirty-day postoperative mortality was 3.1%, mostly due to acute exacerbation of respiratory insufficiency. Postoperative mortality independently correlated with preoperative need of oxygen therapy (OR, 5.21; 95% CI, 1.19-22.95) and with UIP/IPF histology (OR, 5.67; 95% CI, 1.27-25.25). CONCLUSIONS: Lung biopsy was performed mostly by VATS, with limited morbidity, and was effective in yielding a specific histologic diagnosis in the vast majority of undefined ILD cases. To optimize the outcome of surgical biopsy for specific diagnosis of ILD, this procedure should be performed only exceptionally in patients with critical respiratory illness as postoperative mortality risk in these subjects is exceedingly high.

Intravenous immunoglobulin replacement induces an in vivo reduction of inflammatory monocytes and retains the monocyte ability to respond to bacterial stimulation in patients with common variable immunodeficiencies.

Intravenous IgG administration induces significant modifications in the innate and adaptive compartment of the immune system including the monocyte/macrophage system. We analyzed the in vivo effect of IgG administered at replacement dosages on the frequency of monocytes subsets, on the modulation of CD11b and sialic acid-binding immunoglobulin-like lectin receptor (Siglec 9) expression and on monocytes production of reactive oxygen species. We showed that patients with Common Variable Immune Deficiency have an increased frequency pro-inflammatory intermediate CD14(++)CD16(+) monocytes and an increased expression of CD11b and Siglec 9 on monocytes. IgG administered at replacement dosages exerted an in vivo anti-inflammatory effect as shown by a reduction of circulating monocytes, of intermediate pro-inflammatory monocytes, of CD11b and Siglec 9 expression and of ex vivo monocytes oxidative burst. Nevertheless, intravenous IgG administration did not affect the monocyte functional ability to respond to a bacterial stimulation in terms of CD11b and Siglec 9 expression and reactive oxygen species production.

MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms.

Rett syndrome (RTT) is an autism spectrum disorder mainly caused by mutations in the X-linked MECP2 gene and affecting roughly 1 out of 10.000 born girls. Symptoms range in severity and include stereotypical movement, lack of spoken language, seizures, ataxia and severe intellectual disability. Notably, muscle tone is generally abnormal in RTT girls and women and the Mecp2-null mouse model constitutively reflects this disease feature. We hypothesized that MeCP2 in muscle might physiologically contribute to its development and/or homeostasis, and conversely its defects in RTT might alter the tissue integrity or function. We show here that a disorganized architecture, with hypotrophic fibres and tissue fibrosis, characterizes skeletal muscles retrieved from Mecp2-null mice. Alterations of the IGF-1/Akt/mTOR pathway accompany the muscle phenotype. A conditional mouse model selectively depleted of Mecp2 in skeletal muscles is characterized by healthy muscles that are morphologically and molecularly indistinguishable from those of wild-type mice raising the possibility that hypotonia in RTT is mainly, if not exclusively, mediated by non-cell autonomous effects. Our results suggest that defects in paracrine/endocrine signaling and, in particular, in the GH/IGF axis appear as the major cause of the observed muscular defects. Remarkably, this is the first study describing the selective deletion of Mecp2 outside the brain. Similar future studies will permit to unambiguously define the direct impact of MeCP2 on tissue dysfunctions.

miR-135a Inhibits Cancer Stem Cell-Driven Medulloblastoma Development by Directly Repressing Arhgef6 Expression.

microRNAs (miRNAs) are short noncoding RNAs, which regulate gene expression post-transcriptionally and play crucial roles in relevant biological and pathological processes. Here, we investigated the putative role of miRNAs in modulating the tumor-initiating potential of mouse medulloblastoma (MB)-derived cancer stem cells (CSCs). We first subjected bona fide highly tumorigenic (HT) CSCs as well as lowly tumorigenic MB CSCs and normal neural stem cells to miRNA profiling, which identified a HT CSC-specific miRNA signature. Next, by cross-checking CSC mRNA/miRNA profiles, we pinpointed miR-135a as a potential tumor suppressor gene, which was strongly downregulated in HT CSCs as well as in the highly malignant experimental tumors derived from them. Remarkably, enforced expression of miR-135a in HT CSCs strongly inhibited tumorigenesis by repressing the miR-135a direct target gene Arhgef6. Considering the upregulation of Arhgef6 in human MBs and its involvement in mediating experimental medulloblastomagenesis, its efficient suppression by miR-135a might make available an effective therapeutic strategy to selectively impair the tumorigenic potential of MB CSCs. Stem Cells 2015;33:1377-1389.

The effect of age and time to death on primary care costs: the Italian experience.

A large body of literature shows that time to death (TTD) is by far a better predictor of health spending than age. In this paper, we investigate if this finding holds true also in presence of primary care costs (pharmaceuticals, diagnostic tests and specialist visits) in Italy, where they represent an important share (about 30%) of the total health care expenditure (HCE). Our analysis is based on a large sample of the Italian population (about 750,000 individuals), obtained from the Health Search-SiSSI database, which contains patient-level data collected routinely by General Practitioners in Italy since 2002. We study individuals aged 19 and older, over the period 2006-2009. By means of a two-part model which accounts for the presence of zero expenditure, our findings show that age represents the most important driver of primary care costs in Italy, although TTD remains a good predictor. These results suggest that age and TTD can have a different role in shaping health care costs according to the component of health expenditure examined. Therefore, our advice to policy makers is to use disaggregated models to better disentangle these contributions and to produce more reliable health spending forecasts.

Dysregulated extracellular signal-regulated kinase signaling associated with impaired B-cell receptor endocytosis in patients with common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by B-cell dysfunction and, in a subgroup, by expansion of CD21(low) B cells. The CD21(low) B cells display defects in early B-cell receptor (BCR) signaling resembling those of anergic B cells. OBJECTIVE: We sought to investigate whether B cells from patients with CVID, like anergic B cells, have defects in extracellular signal-regulated kinase (ERK) phosphorylation and in endocytic trafficking of the BCR. METHODS: Using flow cytometry, we evaluated phosphorylated ERK (pERK) expression and internalization of cross-linked BCR in B-cell subsets. The localization of internalized BCR to lysosome-associated membrane protein 1-positive late endosomes was evaluated with confocal microscopy. RESULTS: Constitutive pERK levels were increased in naive and IgM(+) memory B cells of patients with CVID compared with those of healthy donors, whereas the pERK increment induced by BCR cross-linking was relatively reduced. Intravenous immunoglobulin administration enhanced these anomalies, but they appeared to be intrinsic to B cells from patients with CVID. Cross-linking-induced BCR endocytosis was decreased in the IgM(+) memory B cells, especially in those with a CD21(low) phenotype, but not in the naive B cells of patients with CVID with CD21(low) expansion. Internalized BCR localized normally to late endosomes. Pharmacologic inhibition of ERK phosphorylation suppressed BCR endocytosis in B cells of healthy patients and those with CVID. CONCLUSIONS: The B cells of patients with CVID with CD21(low) B-cell expansion resemble anergic B cells based on high constitutive pERK expression. The IgM(+) memory B cells of these patients, especially those that are CD21(low), have a defect in BCR endocytosis seemingly caused by dysregulated ERK signaling.

Hemogenic endothelium generates mesoangioblasts that contribute to several mesodermal lineages in vivo.

The embryonic endothelium is a known source of hematopoietic stem cells. Moreover, vessel-associated progenitors/stem cells with multilineage mesodermal differentiation potential, such as the 'embryonic mesoangioblasts', originate in vitro from the endothelium. Using a genetic lineage tracing approach, we show that early extra-embryonic endothelium generates, in a narrow time-window and prior to the hemogenic endothelium in the major embryonic arteries, hematopoietic cells that migrate to the embryo proper, and are subsequently found within the mesenchyme. A subpopulation of these cells, distinct from embryonic macrophages, co-expresses mesenchymal and hematopoietic markers. In addition, hemogenic endothelium-derived cells contribute to skeletal and smooth muscle, and to other mesodermal cells in vivo, and display features of embryonic mesoangioblasts in vitro. Therefore, we provide new insights on the distinctive characteristics of the extra-embryonic and embryonic hemogenic endothelium, and we identify the putative in vivo counterpart of embryonic mesoangioblasts, suggesting their identity and developmental ontogeny.

Idiopathic non cirrhotic portal hypertension and spleno-portal axis abnormalities in patients with severe primary antibody deficiencies.

BACKGROUND AND AIM: Portal hypertension has been reported in association with acquired and primary immune deficiencies without a comprehensive description of associated spleno-portal axis abnormalities. Pathological mechanisms are poorly defined. METHODS: Observational, single centre study with the aim of assessing the prevalence of spleno-portal axis abnormalities in an unselected cohort of 123 patients with primary antibody deficiencies and without known causes of liver diseases regularly followed up for a mean time of 18 ± 14 years. A cumulative period of 1867 patients-year was analysed. Clinical and immunological data, abdominal ultrasounds, CT scans, and endoscopy features were included in the analysis. RESULTS: Twenty-five percent of patients with primary antibody deficiencies had signs of portal vein enlargement but only 4% of them had portal hypertension, with portal systemic collaterals. Liver biopsies showed liver sinusoids congestive dilatation, endothelization, and micronodularity fulfilling the criteria for noncirrhotic portal hypertension. Patients with portal vein enlargement had severe clinical and immunological phenotypes. CONCLUSIONS: In primary antibody deficient patients, infections, inflammations, splenomegaly, increased blood venous flow, and lymphocyte abnormalities contribute to establishment of liver damage possibly leading to noncirrhotic portal hypertension. Patients with primary antibody deficiency should be considered a good model to give insight into the pathological mechanisms underlying noncirrhotic portal hypertension.