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Increased decision latency in alcohol use disorder (AUD) has been generally explained in terms of psychomotor slowing. Recent results suggest that AUD patients’ slowed decision-making might rather reflect alterations in the neural circuitry underlying the engagement of controlled processing by salient stimuli. We addressed this hypothesis by testing a relationship between decision latency at the Cambridge Gambling Task (CGT) and intrinsic brain activity in 22 individuals with AUD and 19 matched controls. CGT deliberation time was related to two complementary facets of resting-state fMRI activity, i.e. coherence and intensity, representing early biomarkers of functional changes in the intrinsic brain architecture. For both metrics, we assessed a multiple regression (to test a relationship with deliberation time in the whole sample), and an interaction analysis (to test a significantly different relationship with decision latency across groups). AUD patients’ slowed deliberation time (p

A group of international experts, including hematopathologists, oncologists, and geneticists were recently summoned (September 2021, Chicago, IL, USA) to update the 2016/17 World Health Organization classification system for hematopoietic tumors. After careful deliberation, the group introduced the new International Consensus Classification (ICC) for Myeloid Neoplasms and Acute Leukemias. This current in-depth review focuses on the ICC-2022 category of JAK2 mutation-prevalent myeloproliferative neoplasms (MPNs): essential thrombocythemia, polycythemia vera, primary myelofibrosis, and MPN, unclassifiable. The ICC MPN subcommittee chose to preserve the primary role of bone marrow morphology in disease classification and diagnostics, while also acknowledging the complementary role of genetic markers for establishing clonality, facilitating MPN subtype designation, and disease prognostication.

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

Decreased punishment sensitivity in alcohol use disorder (AUD) might reflect a reduction in the typical human tendency to overweigh negative choice outcomes compared with equivalent positive ones, that is, 'loss aversion.' While this hypothesis is supported by previous reports of reduced loss aversion in AUD, it is still unknown whether such decreased sensitivity to prospective losses represents a specific facet of altered decision-making or a secondary effect of executive/working-memory impairments. We addressed this issue by assessing whether lower loss aversion in 22 AUD patients compared with 19 healthy controls is explained by their differential executive or working-memory performance and by investigating its neural basis in terms of grey matter density and cortical thickness via voxel- and surface-based morphometry, respectively. A significant decrease of loss aversion in patients, unrelated to their impaired executive/working-memory performance, reflected the reduction of posterior fronto-medial grey matter density and right frontopolar cortical thickness. Rather than their executive deficits, patients' reduced loss aversion reflects the structural damage of the posterior fronto-medial cortex previously associated with solving conflicts at the response level, where earlier functional magnetic resonance imaging (fMRI) studies have shown a 'neural loss aversion' pattern of steeper deactivation for losses than activation for gains, and of the frontopolar cortex in charge of managing competing goals. These findings highlight possible directions for addressing AUD patients' high relapse rate, for example, cognitive-behavioural rehabilitative interventions enhancing the awareness of the adverse outcomes of addiction or neurostimulation protocols targeting the regions processing their salience.

BACKGROUND: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense. OBJECTIVE: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2. METHODS: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI. RESULTS: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died. CONCLUSIONS: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:147 issue:2 pages:520-531 ispartof: location:United States status: published

The persistence of addictive behaviours despite their adverse consequences highlights decreased punishment sensitivity as a facet of decision-making impairments in Alcohol Use Disorder (AUD). This attitude departs from the typical loss aversion (LA) pattern, i.e. the stronger sensitivity to negative than positive outcomes, previously associated with striatal and limbic-somatosensory responsiveness in healthy individuals. Consistent evidence highlights decreased LA as a marker of disease severity in AUD, but its neural bases remain largely unexplored. AUD-specific modulations of frontolateral activity by LA were previously related to the higher executive demands of anticipating losses than gains, but the relationship between LA and executive/working-memory performance in AUD is debated. Building on previous evidence of overlapping neural bases of LA during decision-making and at rest, we investigated a possible neural signature of altered LA in AUDs, and its connections with executive skills, in terms of complementary facets of resting-state functioning. In patients, smaller LA than controls, unrelated to executive performance, reflected reduced connectivity within striatal and medial temporal networks, and altered connectivity from these regions to the insular-opercular cortex. AUD-specific loss-related modulations of intrinsic connectivity thus involved structures previously associated both with drug-seeking and with coding the trade-off between appetitive and aversive motivational drives. These findings fit the hypothesis that altered striatal coding of choice-related incentive value, and interoceptive responsiveness to prospective outcomes, enhance neural sensitivity to drug-related stimuli in addictions. LA and its neural bases might prove useful markers of AUD severity and effectiveness of rehabilitation strategies targeting the salience of negative choice outcomes.

We analyzed cytogenetic data at diagnosis in 395 primary myelofibrosis (PMF) patients to evaluate any possible association between karyotype and WHO 2017 classification and its impact on prognosis. All the cases were diagnosed and followed at five Italian Hematological Centers between November 1983 and December 2016. An abnormal karyotype (AK) was found in 69 patients and clustered differently according to bone marrow fibrosis grade as it was found in 31 (27.0%) cases with overt fibrotic and 38 (13.6%) with pre-fibrotic PMF (p = 0.001). Sex, anemia, thrombocytopenia, circulating blasts ≥1%, higher lactate dehydrogenase, and International Prognostic Scoring System risk classes were all significantly associated with karyotype. At a median follow-up of >6 years, 101 deaths were recorded. Survival was different between AK and normal karyotype (NK) patients with an estimated median overall survival (OS) of 11.6 and 25.7 years, respectively (p = 0.0148). In conclusion, in our cohort around 20% of patients had an AK, more frequently in subjects with an advanced bone marrow fibrosis grade and clinical-laboratory features indicative of a more aggressive disease. This study shows that an AK confers a more severe clinical phenotype and impacts adversely on OS, thus representing an additional parameter to be considered in the evaluation of PMF prognosis.

Kidneys retrieved from donors after cardiac death (DCD) pose significant challenges from a clinical and technical point of view, undergoing a variable degree of ischemia-reperfusion injury. At present, the utilization of kidneys is assessed according to the Karpinski score, which does not take into account the ischemic insult and does not predict the functional recovery of the organ once transplanted. Therefore, the correlation between biopsy results and post-transplant graft function is still debated. In this study we examined kidney biopsies from DCD donors; we calculated the Karpinski score and subsequently identified and quantified the ischemic lesions in the glomerular, interstitial, and tubular compartments. These same lesions were quantified in kidney biopsies from donors after brain death (DBD) in a case-control analysis. The collected data were correlated with the clinical data of the donors and the post-transplant follow-up. Proximal tubule alterations are crucial in ischemia-reperfusion damage, showing precise histological alterations, which are more frequent in DCD than in DBD donors and are statistically correlated with functional recovery of the organ. Quantification of ischemic tubular lesions in biopsies of kidneys from DCD donors is a useful tool for predicting post-transplant renal function and a valid parameter for assessing the quality of the graft.

The COVID-19 pandemic caused by SARS-CoV-2 has greatly modified outpatient follow-ups. The aim of this retrospective study was to evaluate the organizational modalities and clinical effects of rearrangements of pacemaker (PM) and implantable cardioverter-defibrillator (ICD) outpatient visits performed in our centers at Ravenna and Lugo Hospitals, Italy, during the pandemic outbreak in 2020.All scheduled in-person device follow-up visits in March-December 2020 have been considered. On the basis of documented past functioning of each device and of remote monitoring (RM) capabilities, in-person visits were either performed or postponed at variable times. The characteristics of the follow-ups and the device-related clinically relevant events were analyzed, the latter being further divided into serious malfunction and problems to be corrected by device reprogramming.Overall, 27% of in-person visits were postponed (n = 576) (36% of ICDs and 25% of PMs), peaking 62% in March-May 2020. RM compensated nearly all hold-ups in ICDs and just 63% of postponements in PMs. The postponement-caused delay between in-person visits was 5.6 ± 1.1 months for ICDs and 4.7 ± 1.2 months for PMs; in 24% of ICDs the time interval between in-person visits was ≥18 months. Clinically relevant events were 56 (18 [4.4%] in ICDs, 38 [2.1%] in PMs), with no deaths and 21 serious malfunctions (4 [1%] in ICDs, 15 [0.8%] in PMs). RM identified all ICD malfunctions, while it was not available in the affected PMs. In comparison with the year 2019, serious malfunctions increased, though the difference was not significant. Monthly RM transmissions increased by 2.3 fold.In our single-center experience during the COVID-19 pandemic, numerous in-person PM/ICD follow-up visits were postponed, and delays were well beyond the previously recommended time limits. However, device-related malfunctions did not increase, notably, when RM capabilities were used.

We tested the hypothesis that circulating CXCL10 and IL-6 in donor after brain death provide independent additional predictors of graft outcome. From January 1, 2010 to June 30, 2012 all donors after brain death managed by the NITp (n = 1100) were prospectively included in this study. CXCL10 and IL-6 were measured on serum collected for the crossmatch at the beginning of the observation period. Graft outcome in recipients who received kidney (n = 1325, follow-up 4.9 years), liver (n = 815, follow-up 4.3 years) and heart (n = 272, follow-up 5 years) was evaluated. Both CXCL-10 and IL-6 showed increased concentration in donors after brain death. The intensive care unit stay, the hemodynamic instability, the cause of death, the presence of risk factors for cardiovascular disease and the presence of ongoing infection resulted as significant determinants of IL-6 and CXCL10 donor concentrations. Both cytokines resulted as independent predictors of Immediate Graft Function. Donor IL-6 or CXCL10 were associated with graft failure after liver transplant, and acted as predictors of recipient survival after kidney, liver and heart transplantation. Serum donor IL-6 and CXCL10 concentration can provide independent incremental prediction of graft outcome among recipients followed according to standard clinical practice.

The COVID-19 pandemic and the measures to counteract it have highlighted the role of individual differences in evaluating and reacting to emergencies, and the challenges inherent in promoting precautionary behaviours. We aimed to explore the psychological and cognitive factors modulating behaviour and intentions during the national lockdown in Italy. We administered an online questionnaire (N = 244) that included tests for assessing personality traits (Temperament and Character Inventory; Locus of Control of Behaviour) and moral judgment (Moral Foundations Questionnaire), alongside behavioural economics tasks addressing different facets of risk attitude (loss aversion, risk aversion and delay discounting). We then assessed the extent to which individual variations in these dimensions modulated participants’ compliance with the lockdown norms. When assessing their joint contribution via multiple regressions, lockdown adherence was mostly predicted by internal locus of control, psycho-economic dimensions suggestive of long-sighted and loss-averse attitudes, as well as personality traits related to cautionary behaviour, such as harm avoidance, and the authority moral concern. These findings show that a multi-domain assessment of the factors underlying personal intentions, and thus driving compliance with government measures, can help predict individuals’ actions during health emergencies. This evidence points to factors that should be considered when developing interventions and communication strategies to promote precautionary behaviours.

Approximately one-fourth of patients with essential thrombocythemia or primary myelofibrosis carry a somatic mutation of the calreticulin gene (CALR), the gene encoding for calreticulin. A 52-bp deletion (type I mutation) and a 5-bp insertion (type II mutation) are the most frequent genetic lesions. The mechanism(s) by which a CALR mutation leads to a myeloproliferative phenotype has been clarified only in part. We studied the interaction between calreticulin and store-operated calcium (Ca2+) entry (SOCE) machinery in megakaryocytes (Mks) from healthy individuals and from patients with CALR-mutated myeloproliferative neoplasms (MPNs). In Mks from healthy subjects, binding of recombinant human thrombopoietin to c-Mpl induced the activation of signal transducer and activator of transcription 5, AKT, and extracellular signal-regulated kinase 1/2, determining inositol triphosphate–dependent Ca2+ release from the endoplasmic reticulum (ER). This resulted in the dissociation of the ER protein 57 (ERp57)-mediated complex between calreticulin and stromal interaction molecule 1 (STIM1), a protein of the SOCE machinery that leads to Ca2+ mobilization. In Mks from patients with CALR-mutated MPNs, defective interactions between mutant calreticulin, ERp57, and STIM1 activated SOCE and generated spontaneous cytosolic Ca2+ flows. In turn, this resulted in abnormal Mk proliferation that was reverted using a specific SOCE inhibitor. In summary, the abnormal SOCE regulation of Ca2+ flows in Mks contributes to the pathophysiology of CALR-mutated MPNs. In perspective, SOCE may represent a new therapeutic target to counteract Mk proliferation and its clinical consequences in MPNs.

Summary Background Medico-legal conflicts arise when it is difficult to prove the cause of nosocomial infections. Aim To report an outbreak of patient-to-patient transmission of hepatitis C virus (HCV) through the repeated use of a multi-dose saline flask during the rinsing of central venous catheters. Methods Blood samples were taken from each patient for the comparative analysis of their HCV RNA strains. No samples were available for one patient who died before the investigation started. Despite the known lability of HCV RNA, the body was exhumed four months after burial and postmortem samples were collected. HCV RNA was extracted successfully from liver and spleen samples. Genotyping of all the HCV strains was performed by sequence analysis of the 5′NC untranslated region, the E1 core conserved region and the E1/E2 hypervariable region. Findings Forensic investigators retraced the route used by two ward nurses, when saline catheter flushes were given to 14 patients with each nurse administering to seven patients. The comparative phylogenetic analysis of all case strains identified the deceased patient as the source of contamination to five patients. Conclusions This study highlights the value of sequence analysis as a tool for solving medico-legal conflicts. The High Court of Justice found that a health worker's re-use of a contaminated needle resulted in the nosocomial transmission of HCV.

The Action-sentence Compatibility Effect (ACE) is a well-known demonstration of the role of motor activity in the comprehension of language. Participants are asked to make sensibility judgments on sentences by producing movements toward the body or away from the body. The ACE is the finding that movements are faster when the direction of the movement (e.g., toward) matches the direction of the action in the to-be-judged sentence (e.g., Art gave you the pen describes action toward you). We report on a pre-registered, multi-lab replication of one version of the ACE. The results show that none of the 18 labs involved in the study observed a reliable ACE, and that the meta-analytic estimate of the size of the ACE was essentially zero. ispartof: Psychonomic Bulletin & Review vol:29 issue:2 pages:613-626 ispartof: location:United States status: published

Breast implant-associated anaplastic large cell lymphoma is a new provisional entity in the revised World Health Organization classification of lymphoid malignancies, the pathogenesis and cell of origin of which are still unknown. We performed gene expression profiling of microdissected breast implant-associated anaplastic large cell lymphoma samples and compared their transcriptional profiles with those previously obtained from normal T-cells and other peripheral T-cell lymphomas and validated expression of selected markers by immunohistochemistry. Our results indicate that most breast implant-associated anaplastic large cell lymphomas exhibit an activated CD4+ memory T-cell phenotype, which is associated with CD25 and FoxP3 expression. Gene ontology analyses revealed upregulation of genes involved in cell motility programs (e.g., CCR6, MET, HGF, CXCL14) in breast implant-associated anaplastic large cell lymphomas compared to normal CD4+ T-cells and upregulation of genes involved in myeloid cell differentiation (e.g., PPARg, JAK2, SPI-1, GAB2) and viral gene transcription (e.g., RPS10, RPL17, RPS29, RPL18A) compared to other types of peripheral T-cell lymphomas. Gene set enrichment analyses also revealed shared features between the molecular profiles of breast implant-associated anaplastic large cell lymphomas and other types of anaplastic large cell lymphomas, including downregulation of T-cell receptor signaling and STAT3 activation. Our findings provide novel insights into the biology of this rare disease and further evidence that breast implant-associated anaplastic large cell lymphoma represents a distinct peripheral T-cell lymphoma entity.

Multiple myeloma (MM) is a hematologic malignancy produced by a clonal expansion of plasma cells and characterized by abnormal production and secretion of monoclonal antibodies. This pathology exhibits an enormous heterogeneity resulting not only from genetic alterations but also from several epigenetic dysregulations. Here we provide evidence that Che-1/AATF (Che-1), an interactor of RNA polymerase II, promotes MM proliferation by affecting chromatin structure and sustaining global gene expression. We found that Che-1 depletion leads to a reduction of “active chromatin” by inducing a global decrease of histone acetylation. In this context, Che-1 directly interacts with histones and displaces histone deacetylase class I members from them. Strikingly, transgenic mice expressing human Che-1 in plasma cells develop MM with clinical features resembling those observed in the human disease. Finally, Che-1 downregulation decreases BRD4 chromatin accumulation to further sensitize MM cells to bromodomain and external domain inhibitors. These findings identify Che-1 as a promising target for MM therapy, alone or in combination with bromodomain and external domain inhibitors.

The possible uniqueness of social stimuli constitutes a key topic for cognitive neuroscience. Growing evidence highlights graded contributions to their semantic processing by the anterior temporal lobe (ATL), where the omni-category response displayed by its ventrolateral sector might reflect the integration of information relayed from other regions. Among these, the superior polar ATL was specifically associated with representing social concepts. However, most previous studies neglected the close relationship between social and emotional semantic features, which might confound interpreting the degree of overlap vs. specificity of social and emotional conceptual processing. We addressed this issue via two activation-likelihood-estimation meta-analyses of neuroimaging studies reporting brain structures associated with processing social or emotional concepts. Alongside a common involvement of the ventromedial prefrontal cortex, we found social and emotional concepts to be specifically associated with lateral temporal areas (including the superior polar ATL) and the amygdala, respectively. These results support the specialization of distinct sectors of the fronto-temporo-limbic circuitry for processing social vs. emotional concepts, and the integration of their output in medial prefrontal regions underlying the regulation of social behavior. These results pave the way for further studies addressing the neural bases of conceptual knowledge, its impairment after fronto-temporal brain damage, and the effect of rehabilitative interventions targeting its main functional modules.

Introduction: The first-line therapy for patients with low-risk myelodysplastic syndromes (MDSs) commonly consists of erythropoietin stimulating agents (ESAs), with a response rate ranging from 34 to 62%. For nonresponder patients, outside clinical trials, blood transfusions are the most frequent therapeutic option, with detrimental effect on the quality of life and with risks of iron-overload. Since no studies have been yet conducted on this topic, we investigated the potential predictive role of bone marrow (BM) histological evaluation in patients treated with ESAs. Materials and Methods: We performed a morphological and immunohistochemical retrospective analysis of BM biopsies of 96 patients with low-risk MDSs subsequently treated with ESAs. Results: In our series, substantial morphological overlap was found between responder and nonresponder patients. On the contrary, patients with a percentage of CD34-positive blasts >3% or with p53 protein expression Conclusions: Our study reinforces the role of BM biopsy as diagnostic tool in MDSs, being also able to supply information related to response to ESAs and to its loss over time.

The bone marrow is a preferential site for both reactive and neoplastic histiocytic proliferations. The differential diagnosis ranges from reactive histiocyte hyperplasia in systemic infections, vaccinations, storage diseases, post myeloablative therapy, due to increased cell turnover, and in hemophagocytic lymphohistiocytosis, through extranodal Rosai-Dorfman disease to neoplasms derived from histiocytes, including histiocytic sarcomas (HS), Langerhans cell histiocytoses (LCH), Erdheim-Chester disease (ECD), and disseminated juvenile xanthogranuloma (JXG). One of the most important recent developments in understanding the biology of histiocytic neoplasms and in contributing to diagnosis was the detection of recurrent mutations of genes of the Ras/Raf/MEK/ERK signaling pathway, in particular the BRAFV600E mutation, in LCH and ECD. Here, we summarize clinical and pathological findings of 17 histiocytic neoplasms that were presented during the bone marrow symposium and workshop of the 18th European Association for Haematopathology (EAHP) meeting held in Basel, Switzerland, in 2016. A substantial proportion of these histiocytic neoplasms was combined with clonally related lymphoid (n = 2) or myeloid diseases (n = 5, all ECD). Based on the latter observation, we suggest excluding co-existent myeloid neoplasms at initial staging of elderly ECD patients. The recurrent nature of Ras/Raf/MEK/ERK signaling pathway mutations in histiocytic neoplasms was confirmed in 6 of the 17 workshop cases, illustrating their diagnostic significance and suggesting apotential target for tailored treatments.

Introduction: Hypereosinophilic syndromes are a heterogeneous group of disorders that may be associated with life-threatening organ injury as a result of tissues infiltration by eosinophils. The main goal of therapy is to mitigate eosinophil-mediated organ damage. When possible, therapy should be directed at the underlying etiology. However, even in the absence of any known cause, when organ damage is present, hypereosinophilia must be treated promptly and aggressively to reduce potential morbidity and mortality.Areas covered: Conventional therapies, including corticosteroids, hydroxyurea (hydroxycarbamide) and interferon-alpha, have shown variable efficacy and a non-negligible toxicity emphasizing the need of new therapeutic strategies based on drugs with different mechanisms of action.Expert opinion: Tyrosine kinase inhibitors have a central role among targeted therapies of hypereosinophilic syndromes. Imatinib, initially empirically used based on its activity in chronic myeloid leukemia, achieved preliminary excellent results further confirmed in large series of patients. Third-generation tyrosine kinase inhibitors such as ponatinib, while active in vitro and in vivo in animals, still deserve confirmation in properly designed clinical trials. In addition, clinical investigation on monoclonal antibodies against interleukin-5, interleukin-5Rα, IgE, and CD52 represents a promising area of research.

Background Mitochondrial functions are exploited in cancer and provide a validated therapeutic target. However, how this process is regulated has remained mostly elusive and the identification of new pathways that control mitochondrial integrity in cancer is an urgent priority. Methods We studied clinically-annotated patient series of primary and metastatic prostate cancer, representative cases of multiple myeloma (MM) and publicly available genetic databases. Gene regulation studies involved chromatin immunoprecipitation, PCR amplification and Western blotting of conditional Myc-expressing cell lines. Transient or stable gene silencing was used to quantify mitochondrial functions in bioenergetics, outer membrane permeability, Ca2+ homeostasis, redox balance and cell death. Tumorigenicity was assessed by cell proliferation, colony formation and xenograft tumour growth. Findings We identified Mitochondrial Fission Factor (MFF) as a novel transcriptional target of oncogenic Myc overexpressed in primary and metastatic cancer, compared to normal tissues. Biochemically, MFF isoforms, MFF1 and MFF2 associate with the Voltage-Dependent Anion Channel-1 (VDAC1) at the mitochondrial outer membrane, in vivo. Disruption of this complex by MFF silencing induces general collapse of mitochondrial functions with increased outer membrane permeability, loss of inner membrane potential, Ca2+ unbalance, bioenergetics defects and activation of cell death pathways. In turn, this inhibits tumour cell proliferation, suppresses colony formation and reduces xenograft tumour growth in mice. Interpretation An MFF-VDAC1 complex is a novel regulator of mitochondrial integrity and actionable therapeutic target in cancer.

Contains fulltext : 219909.pdf (Publisher’s version ) (Open Access) Most cases of mastocytosis are indolent, usually cutaneous mastocytosis or indolent systemic mastocytosis (SM). Aggressive mast cell (MC) diseases are very rare and often fatal. They can develop de novo or due to progression of indolent forms and can present in different ways; either as MC sarcoma or as advanced SM which includes aggressive SM, MC leukemia, and SM with an associated hematological neoplasm. This review will describe these different aggressive forms of mastocytosis, illustrated by cases submitted to the workshop of the 18th Meeting of the European Association for Haematopathology, Basel 2016, organized by the European Bone Marrow Working Group. In addition, the diagnostic criteria for identifying myelomastocytic leukemia, an aggressive myeloid neoplasm with partial MC differentiation that falls short of the criteria for SM, and disease progression in patients with established mastocytosis are discussed.

Currently available prognostic scoring systems in primary myelofibrosis (PMF) do not integrate clinical, histological, and molecular data, or they also required information on "other" mutations that are available in the clinical practice only in a very limited number of laboratories. In the present multicenter study, including 401 PMF patients, an integrated International Prognostic Scoring System (I-IPSS) was developed by combining IPSS, grade of bone marrow fibrosis (GBMF), and driver mutations molecular status (MS) to define PMF prognosis at diagnosis. Four prognostic categories were identified: I-IPSS-low risk (113 patients), I-IPSS-intermediate-1 risk (56 patients), I-IPSS-intermediate-2 risk (154 patients), and I-IPSS-high risk (78 patients). Median overall survival was 26.7 years in I-IPSS-intermediate-1, 10.8 in I-IPSS-intermediate-2, and 6.4 in I-IPSS-high-risk patients (log-rank test

Lymphoplasmacytic lymphoma (LPL) is usually associated with a serum IgM paraprotein, corresponding to Waldenstrom's Macroglobulinemia (WM). Cases presenting with IgG or IgA, or without a monoclonal protein are extremely rare. We analyzed clinical characteristics, frontline treatment, and the outcome of 45 patients with non-IgM LPL, and compared them with a control group of WM patients. The median age was similar, with significantly higher prevalence of females in non-IgM LPL, than in WM patients (60% vs 39%, P = .016). Patients with non-IgM LPL more frequently presented with lymphadenopathies (53% vs 15%, P

In two experiments, we compared the dynamics of corticospinal excitability when processing visually or linguistically presented tool-oriented hand actions in native speakers and sequential bilinguals. In a third experiment we used the same procedure to test non-motor, low-level stimuli, i.e. scrambled images and pseudo-words. Stimuli were presented in sequence: pictures (tool + tool-oriented hand action or their scrambled counterpart) and words (tool noun + tool-action verb or pseudo-words). Experiment 1 presented German linguistic stimuli to native speakers, while Experiment 2 presented English stimuli to non-natives. Experiment 3 tested Italian native speakers. Single-pulse trascranial magnetic stimulation (spTMS) was applied to the left motor cortex at five different timings: baseline, 200 ms after tool/noun onset, 150, 350 and 500 ms after hand/verb onset with motor-evoked potentials (MEPs) recorded from the first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles. We report strong similarities in the dynamics of corticospinal excitability across the visual and linguistic modalities. MEPs’ suppression started as early as 150 ms and lasted for the duration of stimulus presentation (500 ms). Moreover, we show that this modulation is absent for stimuli with no motor content. Overall, our study supports the notion of a core, overarching system of action semantics shared by different modalities.

Myeloproliferative neoplasms represent a heterogenous group of disorders of the hematopoietic stem cell, with an intrinsic risk of evolution into acute myeloid leukemia. The frequency of leukemic evolution varies according to myeloproliferative neoplasms subtype. It is highest in primary myelofibrosis, where it is estimated to be approximately 10–20% at 10 years, following by polycythemia vera, with a risk of 2.3% at 10 years and 7.9% at 20 years. In essential thrombocythemia, however, transformation to acute myeloid leukemia is considered relatively uncommon. Different factors are associated with leukemic evolution in myeloproliferative neoplasms, but generally include advanced age, leukocytosis, exposure to myelosuppressive therapy, cytogenetic abnormalities, as well as increased number of mutations in genes associated with myeloid neoplasms. The prognosis of these patients is dismal, with a medium overall survival ranging from 2.6–7.0 months. Currently, there is no standard of care for managing the blast phase of these diseases, and no treatment to date has consistently led to prolonged survival and/or hematological remission apart from an allogeneic stem cell transplant. Nevertheless, new targeted agents are currently under development. In this review, we present the current evidence regarding risk factors, molecular characterization, and treatment options for this critical subset of myeloproliferative neoplasms patients.

This study, performed on behalf of the Italian Registry of Thrombocythaemias (Registro Italiano Trombocitemie), aimed to test the inter-observer reproducibility of the histological parameters proposed by the WHO classification for the diagnosis of the Philadelphia chromosome-negative myeloproliferative neoplasms. A series of 103 bone marrow biopsy samples of Philadelphia chromosome-negative myeloproliferative neoplasms consecutively collected in 2004 were classified according to the WHO criteria as follows: essential thrombocythaemia (n=34), primary myelofibrosis (n=44) and polycythaemia vera (n=25). Two independent groups of pathologists reviewed the bone marrow biopsies. The first group was asked to reach a collegial 'consensus' diagnosis. The second group reviewed individually all the cases to recognize the main morphological parameters indicated by the WHO classification and report their results in a database. They were subsequently instructed to individually build a 'personal' diagnosis of myeloproliferative neoplasms subtype just assembling the parameters collected in the database. Our results indicate that high levels of agreement (≥70%) have been reached for about all of the morphological features. Moreover, among the 18 evaluated histological features, 11 resulted statistically more useful for the differential diagnosis among the different Philadelphia chromosome-negative myeloproliferative neoplasms. Finally, we found a high percentage of agreement (76%) between the 'personal' and 'consensus' diagnosis (Cohen's kappa statistic >0.40). In conclusion, our results support the use of the histological criteria proposed by the WHO classification for the Philadelphia chromosome-negative myeloproliferative neoplasms to ensure a more precise and early diagnosis for these patients.

Morbidity and mortality of BCR-ABL1-negative myeloproliferative neoplasm (MPN) patients are influenced by disease-related hemostatic complications, mostly of thrombotic nature. The pathogenesis of thrombosis is multifactorial: in particular, it has been demonstrated that a deregulated expression of Mac1 (also known as surface receptor integrin CD18/CD11b) by leukocytes has a role in favoring platelets’ activation in MPN patients. Based on these data, we investigated the epigenetic status of CD18/CD11b in 78 primary myelofibrosis (PMF) patients to explore any possible association between the epigenetic profiles of these two genes and thrombotic risk. The percentage of CD18 methylation in the PMF samples ranged from hypomethylated to hypermethylated (range: 11–90 %, mean: 64 %), whereas in controls CD18 methylation status clustered in a more restricted interval (range: 24–68 %, mean: 45 %; cases vs. controls: p = 0.006). Furthermore, the results showed that CD18 hypermethylation (>76 % methylation) was correlated with thrombotic complications. On the contrary, CD11b promoter resulted unmethylated (1–5 %) in both cases and controls. Previous studies showed that older age, JAK2V617F mutation, and thrombophilia might play a role in MPN patients’ thrombotic risk. In our cases, the prognostic value of these variables was coherent, being thrombotic events significantly associated with age >65 years (p = 0.001), JAK2 mutation (p = 0.01), and positive thrombophilia tests (p = 0.04). However, multivariate analysis showed that only CD18 methylation and age >65 years were independent prognostic factors of thrombosis (p = 0.02 and p = 0.04, respectively). Taken together, our findings suggest a possible role of CD18 epigenetic regulation in the pathogenesis of the thrombotic complications in PMF patients.

Extracellular matrix (ECM) components initiate crucial biochemical and biomechanical cues that are required for bone marrow homeostasis. In our research, we prove that a peri-cellular matrix composed primarily of type III and type IV collagens, and fibronectin surrounds human megakaryocytes in the bone marrow. The data we collected support the hypothesis that bone marrow megakaryocytes possess a complete mechanism to synthesize the ECM components, and that thrombopoietin is a pivotal regulator of this new function inducing transforming growth factor-β1 (TGF-β1) release and consequent activation of the downstream pathways, both in vitro and in vivo. This activation results in a dose dependent increase of ECM component synthesis by megakaryocytes, which is reverted upon incubation with JAK and TGF-β1 receptor specific inhibitors. These data are pivotal for understanding the central role of megakaryocytes in creating their own regulatory niche within the bone marrow environment.

Dr Migone De Amicis and Dr FattizzoWe report the case of a 32-year-old man admitted to ourInternal Medicine Department for severe anemia andsplenomegaly. Four months before hospital admission, thepatient was admitted to the Emergency Department (ED) ofthe city where he lived, for a flu-like syndrome charac-terized by fever, diarrhea, profuse sweating and severebone pain in his ankles, knees and lumbosacral region. Thelaboratory tests excluded an infectious disease, but showeda severe unexplained microcytic anemia (Hb 5.2 g/dL,MCV 59 fL). The patient was known as beta-thalassemiacarrier, he denied health problems nor blood transfusion inthe past. He was discharged with diagnosis of ‘‘unex-plained anemia in beta thalassemia carrier,’’ and referred tothe Thalassemia Center of his city. The hematologicalwork-up was negative, and he was put on a regularhematological follow-up and a weekly blood transfusionregimen. In the next 3 months, he progressively developedsplenomegaly and motor ability impairment. Physical ex-amination revealed only diffuse cutaneous pallor and amild splenomegaly, confirmed at the abdomen US (spleenbipolar diameter 145 mm). Blood tests, although posttransfusion, documented persistent moderate microcyticanemia (Hb 8.7 g/dL, MCV 69 fL), undetectable hap-toglobin, increased serum ferritin (722 ng/mL) and ery-thropoietin value (414 U/L, n.v. 3.7–31.5). Betathalassemia trait was confirmed by increased HbA2 level(3.3 %) and normal fetal hemoglobin (0.9 %) at the he-moglobin HPLC test. Infections were excluded by commonserologic tests. A whole-body CT scan confirmed thesplenomegaly, and revealed a systemic lymphadenopathy(maximum diameter 25 mm in the neck, abdomen andinguinal regions) and widespread lytic bone lesions(homerus, femur, iliac wings, costal and sacral region, andall the dorsal vertebra), also confirmed by the scintigraphystudy. In the hypothesis of primary bone marrow (BM)disease, a marrow examination was performed. The aspi-rate demonstrated only a trilinear hypoplasia, while the BMhistology revealed the presence of numerous histiocyticlike aggregates. Erdheim–Chester disease was first hy-pothesized, but it was excluded since BRAF gene analysisdid not reveal any mutations [1, 2]. Thereafter, the patientwas discharged as affected by an ‘‘autoimmune diseasewith bone involvement,’’ and he continued to be regularlytransfused. The patient’s general condition progressivelyworsened, and he was therefore referred to our hospital.At admission, the patient complained of a draggingsensation in the abdomen, as a consequence of a massivesplenomegaly. On general physical examination, there wasmarked pallor and bilateral cervical lymphadenopathy(maximum diameter 20 mm). The heart and the lungs were

Contains fulltext : 170085.pdf (Publisher’s version ) (Open Access) BACKGROUND: Because the pattern of illnesses changes in an aging population and many people manage to live well with chronic diseases, a group of health care professionals recently proposed reformulating the static WHO definition of health towards a dynamic one based on the ability to physically, mentally and socially adapt and self-manage. This paper is the result of a collaborative action of the INTERDEM Social Health Taskforce to operationalize this new health concept for people with dementia, more specifically the social domain, and to formulate directions for research and practice to promote social health in dementia. METHOD: Based on the expertise of the Social Health Taskforce members (N = 54) three groups were formed that worked on operationalizing the three social health dimensions described by Huber et al.: (1) capacity to fulfil potential and obligations; (2) ability to manage life with some degree of independence; (3) participation in social activities. For each dimension also influencing factors, effective interventions and knowledge gaps were inventoried. After a consensus meeting, the operationalizations of the dimensions were reviewed by the European Working Group of People with Dementia (EWGPWD). RESULTS: The social health dimensions could be well operationalized for people with dementia and are assessed as very relevant according to the Social Health Taskforce and EWGPWD. Personal (e.g. sense of coherence, competencies), disease-related (e.g. severity of cognitive impairments, comorbidity), social (support from network, stigma) and environmental factors (e.g. enabling design, accessibility) that can influence the person with dementia's social health and many interventions promoting social health were identified. CONCLUSION: A consensus-based operationalization of social health in dementia is proposed, and factors that can influence, and interventions that improve, social health in dementia identified. Recommendations are made for research and practice.

We analyze the invisibility of fisheries and inadequacy of fishers' participation in the process of hydropower development in the Amazon, focusing on gaps between legally mandated and actual outcomes. Using Ostrom's institutional design principles for assessing common-pool resource management, we selected five case studies from Brazilian Amazonian watersheds to conduct an exploratory comparative case-study analysis. We identify similar problems across basins, including deficiencies in the dam licensing process; critical data gaps; inadequate stakeholder participation; violation of human rights; neglect of fishers' knowledge; lack of organization and representation by fishers' groups; and lack of governmental structure and capacity to manage dam construction activities or support fishers after dam construction. Fishers have generally been marginalized or excluded from decision-making regarding planning, construction, mitigation, compensation, and monitoring of the social-ecological impacts of hydroelectric dams. Addressing these deficiencies will require concerted investments and efforts by dam developers, government agencies and civil society, and the promotion of inter-sectorial dialogue and cross-scale participatory planning and decision-making that includes fishers and their associations.

The purpose of the study was to assess consensus and interobserver agreement among an international panel of six hematopathologists regarding characterization and reproducibility of bone marrow (BM) histologic features used to diagnose early stage myeloproliferative neoplasms, in particular differentiation of so-called masked/prodromal polycythemia vera (mPV) from JAK2-mutated essential thrombocythemia (ET). The six members of the hematopathology panel evaluated 98 BM specimens independently and in a blinded fashion without knowledge of clinical data. The specimens included 48 cases of mPV according to the originally published hemoglobin threshold values for this entity (male: 16.0-18.4 g/dL, female: 15.0-16.4 g/dL), 31 cases with overt PV according to the updated 2016 WHO criteria, and 19 control cases. The latter group included cases of JAK2-mutated ET, primary myelofibrosis, myelodysplastic syndrome, and various reactive conditions. Inter-rater agreement between the panelists was very high (overall agreement 92.6%, kappa 0.812), particularly with respect to separating mPV from ET. Virtually all cases of mPV were correctly classified as PV according to their BM morphology. In conclusion, a central blinded review of histology slides by six hematopathologists demonstrated that highly reproducible specific histological pattern characterize PV and confirmed the notion that there are no significant differences between mPV and overt PV in relation to BM morphology.

Background Acute myeloid leukemia (AML) accounts for more than two thirds of leukemia during pregnancy and has an incidence of 1 in 75,000 to 100,000. Its clinical management remains a challenging therapeutic task both for patient and medical team, given to the therapy-attributable risks for mother and fetus and the connected counseling regarding pregnancy continuation. Methods We provided a review of updated literature and a comprehensive description of five maternal/fetal outcomes of AML cases diagnosed concomitantly to pregnancy and treated at our Institution from 2006 to 2012. Results Median age at AML diagnosis was 32 years (31–39). One diagnosis was performed in first trimester and the patient asked for therapeutic abortion before starting chemotherapy. Three cases were diagnosed in second/third trimester; in one case leukemia was diagnosed concomitantly with intrauterine fetal death, while the remaining two patients continued pregnancy and delivered a healthy baby by cesarean section. In only one of these two cases chemotherapy was performed during pregnancy (at 24 + 5 weeks) and consisted of a combination of daunorubicine and cytarabine. Therapy was well tolerated and daily fetus monitoring was performed. After completion of 30 weeks of gestation a cesarean section was carried out; the newborn had an Apgar score of 5/1'-7/5'-9/10', oxygen therapy was temporarily given and peripheral counts displayed transient mild leukopenia. One patient had diagnosis of myelodysplastic syndrome rapidly progressed to AML after delivery. Four out of the 5 described women are currently alive and disease-free. Three children were born and long-term follow-up has shown normal growth and development. Conclusions The treatment of AML occurring during pregnancy is challenging and therapeutic decisions should be taken individually for each patient. Consideration must be given both to the immediate health of mother and fetus and to long-term infant health. Our series confirmed the literature data: fetal toxicity of cytostatic therapy clusters during the first trimester; while chemotherapy can be administered safely during second/third trimester and combination of daunorubicin and cytarabine is recommended for induction.

Aims to evaluate whether a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in bone marrow trephine biopsies (BMBs) of primary myelofibrosis (PMF) patients may have prognostic implications. Methods reticulin fibrosis, collagen deposition and osteosclerosis were graded from 0 to 3 in a series of 122 base-line BMBs. Then, we assigned to each case a comprehensive score (RCO score, ranging from 0 to 9) that allowed us to distinguish two groups of patients, with low-grade (RCO score 0-4) and high-grade (RCO score 5-9) stromal changes. Results and discussion of 122 patients, 88 displayed a low-grade and 34 a high-grade RCO score. The latter was more frequently associated with anemia, thrombocytopenia, peripheral blood blasts and increased lactate dehydrogenase levels. RCO score resulted strictly correlated with overall mortality (p=0.013) and International Prognostic Scoring System (IPSS) risk categories, and was able to discriminate the overall survival of both low- and high-grade patients (Log-Rank test: p

Background: It is not known whether antiretroviral therapy (ART) including lopinavir/r has a different effect on the lipid metabolism in HIV patients co-infected with HCV. This study investigated changes in lipid levels, comparing patients with HIV infection alone and those with HCV too, in the lopinavir/r cohort of the SCOLTA project. Methods: We analyzed the data for the lopinavir/r nationwide cohort from 25 Italian infectious disease departments, which comprises 743 HIV-infected patients followed prospectively, comparing subjects with HIV-HCV co-infection and those with single-infection. Results: At enrolment, co-infected patients had significantly lower mean cholesterol than HCV negative cases (162 ± 43 mg/dL vs. 185 ± 52 mg/dL, p = 0.0009). Total and non-HDL cholesterol and triglycerides rose significantly from baseline in HIV single-infection patients, but not in those with co-infection. The patients with dual HIV-HCV infection, treated with an ART regimen including lopinavir/r, have only limited increases in total and non-HDL cholesterol and triglycerides. Conclusions: Changes in serum lipids in co-infected patients differed significantly from those in patients without HCV. It remains to be seen whether this is associated with a lower risk of progression of atherosclerotic disease. © 2007 Elsevier Masson SAS. All rights reserved.

Background and Objectives This study explored variations in the clinical manifestations of intravascular lymphoma (IVL) on the bases of the association with hemophagocytosis and the country where the diagnosis was made. Design and Methods The clinical features of 50 Western patients with IVL were compared with those of 123 patients with IVL diagnosed in Eastern countries (87 diagnosed in Japan and 36 in other Asian countries), previously reported in English literature, and collected by an electronic bibliographic search. Results Hemophagocytosis was absent in Western patients, but reported in 38 (44%) Japanese patients ( p =0.00001) and in seven (19%) patients from other Asian countries ( p =0.002). No clinical differences were evident between patients with hemophagocytosis-negative IVL diagnosed in Western countries, Japan and other Asian Countries. Conversely, Japanese and non-Japanese patients with hemophagocytosis-related IVL more frequently had stage IV disease, fever, hepato-splenic involvement, marrow infiltration, dyspnea, anemia, and thrombocytopenia, and rarely exhibited cutaneous or central nervous system involvement. Lymph node and peripheral blood involvement was uncommon in all subgroups. In Western patients, anthracycline-based chemotherapy was associated with a 52% remission rate, and a 2-year overall survival of 46%. Interpretation and Conclusions The clinical features of IVL vary according to the association with hemophagocytosis, regardless of the country in which the diagnosis is made. Western, Japanese and other Asian patients with hemophagocytosis-negative IVL display similar clinical characteristics and should be considered as having classical IVL. Patients with hemophagocytosis-related IVL show significantly different clinical features. Both forms have a poor prognosis. Extensive molecular studies are needed to explore whether these clinical differences might reflect discordant biological entities within IVL.

Objective: Inflammatory bowel diseases are characterized by disorders of immunity, thrombosis of large vessels, and microthrombosis of mucosal vessels. The expression of endothelial protein C receptor (EPCR) and thrombomodulin-two receptors of the protein C pathway involved in thrombin scavenging and inflammation-was studied in intestinal resection specimens or mucosal biopsies from patients with inflammatory bowel disease and from controls. The soluble forms of the receptors in plasma were measured. Data Source: This study involved patients from two large university hospitals. After surgery or biopsy, tissue samples were either frozen or fixed in formalin and embedded in paraffin. Sections for immunohistochemistry examination were cut and tested with the specific antibodies to EPCR and thrombomodulin. RNA was extracted from frozen tissue for amplification via reverse-transcriptase polymerase chain reaction. Normal intestinal and diverticulitis tissue was used as a control. Resection samples from 36 patients with ulcerative colitis, 38 with Crohn's disease, 38 with colonic cancer, and 32 with diverticulitis were studied by immunohistochemistry, and frozen sections from the same patients were studied by immunofluorescence. Twelve biopsy specimens of adjacent intestinal areas from six patients with inflammatory bowel disease were included in the study for reverse-transcriptase polymerase chain reaction. Soluble receptors were measured in the plasma of 52 inflammatory bowel disease patients and 52 controls. Data Summary: EPCR and thrombomodulin were expressed on the mucosal endothelium of controls, and the intensity of the signal decreased in inflammatory bowel disease patients. EPCR was expressed by dendritic-like cells in controls, which also stained positive for CD21. The EPCR + /CD21 + dendritic-like cells were not as commonly observed in sections from ulcerative colitis patients as they were in sections from control patients (12.0 ± 3.6 cells per high-power field vs. 23.8 ± 10.4 cells per high-power field, p = .03), and this decrease was less evident in sections from Crohn's disease patients. Levels of messenger RNA for EPCR paralleled protein expression. Soluble thrombomodulin and EPCR levels were both higher in patients than in controls: 41.5 vs. 26.0 ng/mL (p