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In the last years, abstract argumentation has met with great success in AI, since it has served to capture several non-monotonic logics for AI. Relations between argumentation framework (AF) semantics and logic programming ones are investigating more and more. In particular, great attention has been given to the well-known stable extensions of an AF, that are closely related to the answer sets of a logic program. However, if a framework admits a small incoherent part, no stable extension can be provided. To overcome this shortcoming, two semantics generalizing stable extensions have been studied, namely semi-stable and stage. In this paper, we show that another perspective is possible on incoherent AFs, called paracoherent extensions, as they have a counterpart in paracoherent answer set semantics. We compare this perspective with semi-stable and stage semantics, by showing that computational costs remain unchanged, and moreover an interesting symmetric behaviour is maintained. Under consideration for acceptance in TPLP., Paper presented at the 35th International Conference on Logic Programming (ICLP 2019), Las Cruces, New Mexico, USA, 20-25 September 2019, 16 pages

solvers are a method to formally analyze algorithms that have been profitably used for describing, comparing and composing solving techniques in various fields such as Propositional Satisfiability (SAT), Quantified SAT, Satisfiability Modulo Theories, Answer Set Programming (ASP), and Constraint ASP. In this paper, we design, implement and test novel abstract solutions for cautious reasoning tasks in ASP. We show how to improve the current abstract solvers for cautious reasoning in ASP with new techniques borrowed from backbone computation in SAT, in order to design new solving algorithms. By doing so, we also formally show that the algorithms for solving cautious reasoning tasks in ASP are strongly related to those for computing backbones of Boolean formulas. We implement some of the new solutions in the ASP solver WASP and show that their performance are comparable to state-of-the-art solutions on the benchmark problems from the past ASP Competitions. Under consideration for acceptance in TPLP., Comment: Paper presented at the 35th International Conference on Logic Programming (ICLP 2019), Las Cruces, New Mexico, USA, 20-25 September 2019, 20 pages

Answer Set Programming (ASP) is a logic programming paradigm featuring a purely declarative language with comparatively high modeling capabilities. Indeed, ASP can model problems in NP in a compact and elegant way. However, modeling problems beyond NP with ASP is known to be complicated, on the one hand, and limited to problems in {\Sigma}^P_2 on the other. Inspired by the way Quantified Boolean Formulas extend SAT formulas to model problems beyond NP, we propose an extension of ASP that introduces quantifiers over stable models of programs. We name the new language ASP with Quantifiers (ASP(Q)). In the paper we identify computational properties of ASP(Q); we highlight its modeling capabilities by reporting natural encodings of several complex problems with applications in artificial intelligence and number theory; and we compare ASP(Q) with related languages. Arguably, ASP(Q) allows one to model problems in the Polynomial Hierarchy in a direct way, providing an elegant expansion of ASP beyond the class NP. Under consideration for acceptance in TPLP., Comment: Paper presented at the 35th International Conference on Logic Programming (ICLP 2019), Las Cruces, New Mexico, USA, 20-25 September 2019, 16 pages

Background In the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, variable phenotypic expression may delay diagnosis. Panleukopenia, malignancy, and chronic lung disease all affect morbidity and mortality risks. Routinely used treatments include immunoglobulins, granulocyte-colony stimulating factor (G-CSF), and antibiotics; recent trials with a target C-X-C chemokine receptor type 4 (CXCR4) antagonist show promising results. Objective We sought to characterize the largest cohort of patients with WHIM and evaluate their diagnostic and therapeutic management. Methods Data were collected from an international cohort of 18 patients with CXCR4 mutations. Results The clinical features manifested at 2.2 ± 2.6 years of age, whereas the disease diagnosis was delayed until 12.5 ± 10.4 years of age. Patients with WHIM commonly presented with a severe bacterial infection (78%). Pneumonia recurrence was observed in 61% of patients and was complicated with bronchiectasis in 27%. Skin warts were observed in 61% of patients at a mean age of 11 years, whereas human papilloma virus (HPV)-related malignancies manifested in 16% of patients. All the patients had severe neutropenia (195 ± 102 cells/mm3 at onset), whereas lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients, respectively. Approximately 50% of patients received antibiotic prophylaxis, whereas G-CSF and immunoglobulin treatments were used in 72% and 55% of patients, respectively. Conclusions The WHIM syndrome onsets early in life and should be suspected in patients with chronic neutropenia. Patients with WHIM need careful monitoring and timely intervention for complications, mainly lung disease and HPV-related malignancies. We suggest that immunoglobulin therapy should be promptly considered to control the frequency of bacterial infections and prevent chronic lung damage.

The issue of describing in a formal way solving algorithms in various fields such as Propositional Satisfiability (SAT), Quantified SAT, Satisfiability Modulo Theories, Answer Set Programming (ASP), and Constraint ASP, has been relatively recently solved employing abstract solvers. In this paper we deal with cautious reasoning tasks in ASP, and design, implement and test novel abstract solutions, borrowed from backbone computation in SAT. By employing abstract solvers, we also formally show that the algorithms for solving cautious reasoning tasks in ASP are strongly related to those for computing backbones of Boolean formulas. Some of the new solutions have been implemented in the ASP solver WASP, and tested.

Coalitional games are mathematical models suited to study payoff distribution problems in cooperative scenarios. In abstract terms, a coalitional game can be specified by explicitly listing all possible—in fact, exponentially many—coalitions with their associated distributions. This naive representation, however, quickly becomes infeasible over games involving many agents, thereby calling for suitable compact representations, that is, encoding mechanisms that (on some specific classes of games of interest) take an amount of space that grows polynomially with the number of agents. To date, a plethora of compact encodings have been already introduced and analyzed from the algorithm and computational viewpoints. Despite their specific technical differences, these encodings typically share the assumption that the utility associated with a coalition can be freely transferred among agents. Indeed, designing encoding mechanisms for the non-transferable utility (NTU) setting is a research issue that has been largely unexplored so far. The paper addresses this issue by proposing a compact encoding for representing and reasoning about the outcomes of NTU coalitional games founding on answer set programming. By exploiting the expressiveness of this well-known knowledge representation formalism, it is shown that the proposed representation can succinctly encode several games of interest within a wide range of application domains. Computational issues arising in the setting have been studied too, by addressing questions related to certain payoff distributions enjoying desirable stability properties. Eventually, a prototype system supporting the proposed framework has been implemented by leveraging a state-of-the-art answer set engine, and results of a thorough experimental activity conducted on top of it have been discussed.

Answer Set Programming (ASP) is a well-established paradigm for declarative programming and nonmonotonic reasoning. ASP allows for flexible modeling using rules. ASP rules induce a set of intended models called answer sets. Incoherence, the non-existence of answer sets, is therefore a feature of ASP, indicating that the rules admit no intended models. However, this feature can also be problematic in certain circumstances: errors that cause incoherence are notoriously difficult to debug, and query answering will not provide any meaningful answers for incoherent programs. Paracoherent semantics have been suggested as a remedy. They extend the classical notion of answer sets to draw meaningful conclusions also from incoherent programs. However, paracoherent semantics have essentially been inapplicable in practice, due to the lack of efficient algorithms and implementations. In this paper, this lack is addressed, and several different algorithms to compute semi-stable and semi-equilibrium models are proposed and implemented within an answer set solving framework. A key role in the framework is played by syntactic program transformations that allow for characterizing paracoherent semantics in terms of the answer sets of transformed programs. Apart from existing transformations from the literature, a novel transformation is also proposed, which provides an alternative characterization of paracoherent semantics in terms of (extended) externally supported models. Notably, the new transformation is more compact than the existing ones, and brings performance benefits. An extensive empirical performance comparison among the algorithms on benchmarks from ASP competitions and a real-world use case is given as well. It shows not only that the methods developed in this paper lead to practically effective systems, but also show a clear advantage of the methods that rely on (extended) externally supported models.

Recent cases of swordfish attacks on harpoon fishing vessels of the Sicilian fleet were examined and the particular behavior adopted by this fish during the approach to fishermen was described.The information was collected in the period between 1999 and 2014 in Sicilian waters (Mediterranean Sea) through interviews with harpoon fishermen and through direct observations during research activities. Additional cases of the attacks from the previous years are also reported. Overall, 29 cases of swordfish aggressive behavior against fishing boats were documented. Swordfish usually attacked when provoked or when wanted to defend its mate and in several cases, it tried to pierce the boat by the bill. Some attacks culminated with a damage to the target, whereas no injuries to humans were recorded.

Sommario: In questo articolo, analizzeremo da una prospettiva esistenzialista-soteriologica tre dei capolavori cinematografici di Ingmar Bergman, che si collocano tra la fine degli anni Cinquanta e l'inizio degli anni Sessanta del secolo scorso: Il posto delle fragole (1957), Come in uno specchio (1961) e Luci d'inverno (1963). La nostra riflessione sarà accompagnata da alcune domande fondamentali. È possibile rinvenire, a partire dall'angoscia esistenziale dei protagonisti di questi film, delle attese o, perlomeno, una nostalgia di salvezza? Il loro senso di nausea verso una vita che sembra sprofondare nell'oblio più angosciante lascia ancora aperto uno spiraglio verso una qualche luce che può penetrare per ridare speranza? È possibile ravvisare un bisogno di salvezza dalla morte e oltre la morte stessa? Cercheremo di mostrare come la richiesta di salvezza si declini innanzitutto come salvezza in questa vita attraverso la ricerca di relazioni interpersonali, nella prospettiva del vivere per gli altri e nella possibilità di amare gratuitamente, in una costante lotta di fronte all'angoscia esistenziale che sembra continuare a incombere e potrebbe ancora avere la meglio. Infine, quando la salvezza viene intesa come stabilità in una vita in balia delle onde del reale, essa viene riconosciuta nella presenza di Dio come garante dell'autenticità di ogni atto e desiderio di amore. Abstract: In this article, we will analyze from an existentialist-soteriological perspective three of Ingmar Bergman's cinematographic masterpieces, which are placed between the late fifties and the early sixties of the last century: Wild Strawberries (1957), Through a Glass Darkly (1961) and Winter Light (1963). Our reflection will be accompanied by some fundamental questions. Is it possible to find expectations, or at least a nostalgia for salvation, starting from the existential anxiety of the protagonists of these films? Does their sense of nausea towards a life that seems to sink into the most distressing oblivion still leave a glimmer towards some light that can penetrate to restore hope? Is it possible to recognize a need for salvation from death and beyond death itself? We will try to show how the request for salvation declines first and foremost as salvation in this life through the search for interpersonal relationships, in the perspective of living for others and in the possibility of loving for free, in a constant struggle in the face of existential anxiety that seems to continue to loom and could still have the upper hand. Finally, when salvation is understood as stability in a life at the mercy of the waves of reality, it is recognized in the presence of God as warrant of the authenticity of every act and desire for love.

Answer Set Programming (ASP) is a well-established formalism for logic programming. Problem solving in ASP requires to write an ASP program whose answers sets correspond to solutions. Albeit the non-existence of answer sets for some ASP programs can be considered as a modeling feature, it turns out to be a weakness in many other cases, and especially for query answering. Paracoherent answer set semantics extend the classical semantics of ASP to draw meaningful conclusions also from incoherent programs, with the result of increasing the range of applications of ASP. State of the art implementations of paracoherent ASP adopt the semi-equilibrium semantics, but cannot be lifted straightforwardly to compute efficiently the (better) split semi-equilibrium semantics that discards undesirable semi-equilibrium models. In this paper an efficient evaluation technique for computing a split semi-equilibrium model is presented. An experiment on hard benchmarks shows that better paracoherent answer sets can be computed consuming less computational resources than existing methods. Under consideration for acceptance in TPLP., Comment: Paper presented at the 35th International Conference on Logic Programming (ICLP 2019), Las Cruces, New Mexico, USA, 20-25 September 2019, 15 pages

Multi-factorial causes jeopardize brain integrity in β-thalassaemia. Intracranial parenchymal and vascular changes have been reported among young β-thalassaemia patients but conventional magnetic resonance imaging (MRI) findings are contradictory making early MRI and magnetic resonance angiography (MRA)/venography monitoring a matter of debate. This study prospectively investigated 75 neurologically asymptomatic β-thalassaemia patients (mean-age 35·2±10·7years; 52/75 transfusion-dependent; 41/75 splenectomised) using a 3T magnetic resonance scanner; clinical, laboratory and treatment data were also collected. White matter ischaemic-like abnormalities, intracranial artery stenoses, aneurysms and sinus venous thrombosis were compared between patients and 56 healthy controls (mean-age 33·9±10·8years). No patient or control showed silent territorial or lacunar strokes, intracranial artery stenoses or signs of sinus thrombosis. White matter lesions were found both in patients (35/75, 46·7%) and controls (28/56, 50·0%), without differences in terms of number (4·0±10·6 vs. 4·6±9·1, P=0·63), size and Fazekas' Score. Intracranial aneurysms did not differ between patients and controls for incidence rate (7/75, 9·3% vs. 5/56, 8·9%), size and site. Vascular and parenchymal abnormality rate did not differ according to treatments or clinical phenotype. According to this study, asymptomatic β-thalassaemia patients treated according to current guidelines do not seem to carry an increased risk of brain and intracranial vascular changes, thus weakening recommendations for regular brain MRI monitoring.

Answer Set Programming (ASP) is a well-established formalism for nonmonotonic reasoning.While incoherence, the non-existence of answer sets for some programs, is an important feature of ASP, it has frequently been criticised and indeed has some disadvantages, especially for query answering.Paracoherent semantics have been suggested as a remedy, which extend the classical notion of answer sets to draw meaningful conclusions also from incoherent programs. In this paper we present an alternative characterization of the two major paracoherent semantics in terms of (extended) externally supported models. This definition uses a transformation of ASP programs that is more parsimonious than the classic epistemic transformation used in recent implementations.A performance comparison carried out on benchmarks from ASP competitions shows that the usage of the new transformation brings about performance improvements that are independent of the underlying algorithms.

We propose two models of random quantified boolean formulas and their natural random disjunctive logic program counterparts. The models extend the standard models of random k-CNF formulas and the Chen-Interian model of random 2QBFs. The first model controls the generation of programs and QSAT formulas by imposing a specific structure on rules and clauses, respectively. The second model is based on a family of QSAT formulas in a non-clausal form. We provide theoretical bounds for the phase transition region in our models, and show experimentally the presence of the easy-hard-easy pattern and its alignment with the location of the phase transition. We show that boolean formulas and logic programs from our models are significantly harder than those obtained from the standard k-CNF and Chen-Interian models, and that their combination yields formulas and programs that are "super-hard" to evaluate. We also provide evidence suggesting that formulas from one of our models are well suited for assessing solvers tuned to real-world instances. Finally, it is noteworthy that, to the best of our knowledge, our models and results on random disjunctive logic programs are the first of their kind., Comment: 37 pages, 24 figures

Sommario: Cercheremo di mostrare come l'approccio da Enrico Chiavacci possa offrire un'utile prospettiva sulla morale sessuale e come questa sia coerente con l'attuale magistero di papa Francesco. Metteremo in luce la convergenza con le indicazioni di Amoris Laetitia, per orientare riflessioni future. Per rifondare la morale sessuale introdurremo le principali idee alla base della morale fondamentale di Chiavacci, in particolare l'attenzione al relativismo culturale, le acquisizioni scientifiche e la concezione della legge morale naturale. Porremo sotto esame alcuni elementi del rapporto tra sessualità e procreazione, mettendo in luce il cambiamento di paradigma operato dalla Gaudium et spes e la sua ripresa nella Humanae vitae, dove la reciproca donazione diviene centrale per una comprensione teologica ed antropologica della sessualità umana. Nonostante ciò, mostreremo come il paradigma precedente non sia totalmente superato ed evidenzieremo situazioni paradossali che richiedono un ascolto più attento delle acquisizioni scientifiche, filosofiche e teologiche. Abstract: We will try to show how Chiavacci's approach offers a useful perspective on sexual moral theology consistent with the current teaching of Pope Francis. We will highlight the convergence with the indications in Amoris Laetitia, to guide future reflections. To refound sexual morality, we will introduce the main ideas of Chiavacci's fundamental moral theology, giving particular attention to the cultural relativism; scientific knowledge; and the notion of the natural moral law. We will put under review some elements of the relationship between sexuality and procreation, highlighting the council synthesis of Gaudium et Spes and its recovery in Humanae Vitae, where the mutual gift becomes central to the theological and anthropological meaning of human sexuality. Nevertheless, we will show how the previous paradigm is not completely overcome and highlight paradoxical situations, which require a more careful listening to the scientific, philosophical and theological acquisitions.

Answer Set Programming (ASP) is a well-established formalism for nonmonotonic reasoning. An ASP program can have no answer set due to cyclic default negation. In this case, it is not possible to draw any conclusion, even if this is not intended. Recently, several paracoherent semantics have been proposed that address this issue,and several potential applications for these semantics have been identified. However, paracoherent semantics have essentially been inapplicable in practice, due to the lack of efficient algorithms and implementations. In this paper, this lack is addressed, and several different algorithms to compute semi-stable and semi-equilibrium models are proposed and implemented into an answer set solving framework. An empirical performance comparison among the new algorithms on benchmarks from ASP competitions is given as well.

Ontology-based query answering (OBQA) asks whether a Boolean conjunctive query is satisfied by all models of a logical theory consisting of a relational database paired with an ontology. The introduction of existential rules (i.e., Datalog rules extended with existential quantifiers in rule-heads) as a means to specify the ontology gave birth to Datalog+/-, a framework that has received increasing attention in the last decade, with focus also on decidability and finite controllability to support effective reasoning. Five basic decidable fragments have been singled out: linear, weakly-acyclic, guarded, sticky, and shy. Moreover, for all these fragments, except shy, the important property of finite controllability has been proved, ensuring that a query is satisfied by all models of the theory iff it is satisfied by all its finite models. In this paper we complete the picture by demonstrating that finite controllability of OBQA holds also for shy ontologies, and it therefore applies to all basic decidable Datalog+/- classes. To make the demonstration, we devise a general technique to facilitate the process of (dis)proving finite controllability of an arbitrary ontological fragment. This paper is under consideration for acceptance in TPLP., Paper presented at the 33nd International Conference on Logic Programming (ICLP 2017), Melbourne, Australia, August 28 to September 1, 2017 16 pages, LaTeX, 3 PDF figures

Fuzzy Answer Set Programming (FASP) combines the non-monotonic reasoning typical of Answer Set Programming with the capability of Fuzzy Logic to deal with imprecise information and paraconsistent reasoning. In the context of paraconsistent reasoning, the fundamental principle of minimal undefinedness states that truth degrees close to 0 and 1 should be preferred to those close to 0.5, to minimize the ambiguity of the scenario. The aim of this paper is to enforce such a principle in FASP through the minimization of a measure of undefinedness. Algorithms that minimize undefinedness of fuzzy answer sets are presented, and implemented.

Iron overload in β-thalassemia major (TM) typically results in iron-induced cardiomyopathy, liver disease, and endocrine complications. We examined the incidence and progression of endocrine disorders (hypothyroidism, diabetes, hypoparathyroidism, hypogonadism), growth and pubertal delay, and bone metabolism disease during long-term deferasirox chelation therapy in a real clinical practice setting. We report a multicenter retrospective cohort study of 86 transfusion-dependent patients with TM treated with once daily deferasirox for a median duration of 6.5 years, up to 10 years. No deaths or new cases of hypothyroidism or diabetes occurred. The incidence of new endocrine complications was 7% (P = 0.338, for change of prevalence from baseline to end of study) and included hypogonadism (n = 5) and hypoparathyroidism (n = 1). Among patients with hypothyroidism or diabetes at baseline, no significant change in thyroid parameters or insulin requirements were observed, respectively. Mean lumbar spine bone mineral density increased significantly (P

Among the tasks to be carried out by conference organizers is the one of assigning reviewers to papers. That problem is known in the literature as the Conference Paper Assignment Problem (CPAP). In this paper we approach the solution of a reasonably rich variant of the CPAP by means of Answer Set Programming (ASP). ASP is an established logic-based programming paradigm which has been successfully applied for solving complex problems arising in Artificial Intelligence. We show how the CPAP can be elegantly encoded by means of an ASP program, and we analyze the results of an experiment, conducted on real-world data, that outlines the viability of our solution.

The answer set semantics may assign a logic program to model, due to logical contradiction or unstable negation, which is caused by cyclic dependency of an atom on its negation. While logical contradictions can be handled with traditional techniques from paraconsistent reasoning, instability requires other methods. We consider resorting to a paracoherent semantics, in which 3-valued interpretations are used where a third truth value besides true and false expresses that an atom is believed true. This is at the basis of the semi-stable model semantics, which was defined using a program transformation. In this paper, we give a model-theoretic characterization of semi-stable models, which makes the semantics more accessible. Motivated by some anomalies of semi-stable model semantics with respect to basic epistemic properties, we propose an amendment that satisfies these properties. The latter has both a transformational and a model-theoretic characterization that reveals it as a relaxation of equilibrium logic, the logical reconstruction of answer set semantics, and is thus called the semi-equilibrium model semantics. We consider refinements of this semantics to respect modularity in the rules, based on splitting sets, the major tool for modularity in modeling and evaluating answer set programs. In that, we single out classes of canonical models that are amenable for customary bottom-up evaluation of answer set programs, with an option to switch to a paracoherent mode when lack of an answer set is detected. A complexity analysis of major reasoning tasks shows that semi-equilibrium models are harder than answer sets (i.e., equilibrium models), due to a global minimization step for keeping the gap between true and believed true atoms as small as possible. Our results contribute to the logical foundations of paracoherent answer set programming, which gains increasing importance in inconsistency management, and at the same time provide a basis for algorithm development and integration into answer set solvers.

Impaired switching from fetal haemoglobin (HbF) to adult globin gene expression leads to hereditary persistence of fetal haemoglobin (HPFH) in adult life. This is of prime interest because elevated HbF levels ameliorate β-thalassaemia and sickle cell anaemia. Fetal haemoglobin levels are regulated by complex mechanisms involving factors linked or not to the β-globin gene (HBB) locus. To search for factors putatively involved in the expression of the γ-globin genes (HBG1, HBG2), we examined the reticulocyte transcriptome of three siblings who had different HbF levels and different degrees of β-thalassaemia severity although they had the same ΗBA- and ΗΒB cluster genotypes. By mRNA differential display we isolated the cDNA coding for the cold shock domain protein A (CSDA), also known as dbpA, previously reported to interact in vitro with the HBG2 promoter. Expression studies performed in K562 and in primary erythroid cells showed an inverse relationship between HBG and CSDA expression levels. Functional studies performed by Chromatin Immunoprecipitation and reporter gene assays in K562 cells demonstrated that CSDA is able to bind the HBG2 promoter and suppress its expression. Therefore, our study demonstrated that CSDA is a trans-acting repressor factor of HBG expression and modulates the HPFH phenotype.

There is great interest in mesenchymal stromal cells (MSCs) for cell-therapy and tissue engineering approaches. MSCs are currently expanded in vitro in the presence of fetal calf serum (FCS); however, FCS raises concerns when used in clinical grade preparations. The aim of this study was to evaluate whether MSCs expanded in medium supplemented with platelet-lysate (PL), already shown to promote MSC growth, are endowed with biological properties appropriate for cell-therapy approaches. We confirm previously published data showing that MSCs expanded in either FCS or PL display comparable morphology, phenotype, and differentiation capacity, while PL-MSCs were superior in terms of clonogenic efficiency and proliferative capacity. We further extended these data by investigating the immune-regulatory effect of MSCs on the alloantigen-specific immune response in mixed lymphocyte culture (MLC). We found that MSCs-PL are comparable to MSCs-FCS in their capacity to: (i) decrease alloantigen-induced cytotoxic activity; (ii) favor differentiation of CD4+ T-cell subsets expressing a Treg phenotype; (iii) increase early secretion of IL-10 in MLC supernatant, as well as induce a striking augmentation of IL-6 production. As compared with MSCs-PL, MSCs-FCS were more efficient in suppressing alloantigen-induced lymphocyte subset proliferation and reducing early IFN-γ-secretion. Resistance to spontaneous transformation into tumor cells of expanded MSCs was demonstrated by molecular karyotyping and maintenance of normal morphology/phenotype after prolonged in vitro culture. Our data support the immunological functional plasticity of MSCs and suggest that MSCs-PL can be used as an alternative to MSCs-FCS, although these latter cells might be more suitable for preventing/treating alloreactivity-related immune complications. © 2006 Wiley-Liss, Inc.

Objective: Effector phase of acute graft-versus-host disease (a-GVHD) is mainly mediated by donor-derived, anti-host cytotoxic T cells. T-cell homing into gut-associated lymphoid tissues is ascribed to the α4β7 integrin. We reasoned that development of intestinal a-GVHD might be triggered by recruitment in the intestinal mucosa of circulating, alloreactive, α4β7+ donor T cells. Therefore, we evaluated the correlation existing between circulating β7+ T-lymphocyte subsets early after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and occurrence of a-GVHD. Patients and Methods: Surface expression of β7 integrin on T cells was evaluated by means of direct immunofluorescence, in three-color analysis. Sixty-five patients given allo-HSCT were evaluated: 13 of them experienced intestinal a-GVHD, 14 developed a-GVHD without intestinal involvement, and 38 did not develop a-GVHD. Patients were studied early after initial signs of hematologic reconstitution and before occurrence of a-GVHD. Results: We found a significantly higher absolute number of CD8+ and a significantly lower percentage of CD8+CD45RA+β7+ T cells in patients with intestinal a-GVHD than in patients with a-GVHD without intestinal involvement (p = 0.003 and p = 0.003, respectively) or not experiencing a-GVHD (p = 0.02 and p = 0.002, respectively). In particular, we found that intestinal a-GVHD occurred in over 70% of patients showing an absolute number of CD8+ T cells ≥ 60 × 106/L and a percentage of circulating CD8+CD45RA+β7+ T cells < 35%. Conclusion: Measuring the absolute number of CD8+ T cells and percentage of CD8+CD45RA+β7+ T cells at time of hematologic reconstitution may help identify patients at risk of developing intestinal a-GVHD who could benefit from strategies aimed at hampering alloreactive T-cell homing to intestinal mucosa. © 2006 International Society for Experimental Hematology.

The trisomy 8 found in malignancies may derive from a constitutional trisomy 8 mosaicism (CT8M), and in these cases the trisomy itself may be regarded as the first mutation in a multistep carcinogenetic process. To assess the frequency of CT8M in hematological dysplastic and neoplastic disorders with trisomy 8, an informative sample of 14 patients was collected. The data ascertained included chromosome analyses of fibroblast cultures and of PHA-stimulated blood cultures in patients with normal blood differential count, as well as possible CT8M clinical signs. One patient showed trisomy 8 in all cell types analyzed and undoubtedly has a CT8M; a second patient consistently showed trisomy 8 in PHA-stimulated blood cultures when no immature myeloid cells were present in blood and should be considered as having CT8M; a third patient, with Philadelphia-positive chronic myelocytic leukemia, was more difficult to interpret, but the possibility that she had CT8M is likely. A few clinical signs of CT8M were also present in these three patients. Our data indicate that the frequency of CT8M in hematological dysplastic and neoplastic disorders with trisomy 8 is approximately 15-20%.

This report represents an attempt to define the rate of beta-spectrin de novo mutations affecting mRNA accumulation in patients with hereditary spherocytosis (HS). 19 HS children with haematologically normal parents and varying degrees of spectrin deficiency were studied. 13 of the 19 cases who were heterozygous at the genomic level for polymorphisms in the beta-spectrin coding region were further studied. However, in an analysis of reverse-transcripted amplified cDNA from the regions of the polymorphisms, seven patients appeared to be homozygous, suggesting the occurrence of de novo mutational events affecting expression of one beta-spectrin allele. We conclude that in HS patients with isolated spectrin reduction and normal parents the apparently recessive pattern of inheritance may frequently be associated with de novo monoallelic expression of beta-spectrin.

Objective: To determine the efficacy of high-dose dexamethasone in chronic idiopathic thrombocytopenic purpura of childhood. Methods: Seventeen patients entered the protocol. Dexamethasone was to be given orally in two divided doses at a dosage of 20 mg/m 2 for 4 consecutive days every 28 days for six courses. Results: One month after the end of the sixth course, six patients (35%) had platelet values within the normal range. One year later, five patients (29%) still have normal platelet values. Five patients discontinued treatment before completion because of lack of response and in one case for important side effects. Duration of the disease before treatment was inversely correlated with response to dexamethasone: 5 of 10 patients who had had thrombocytopenia for 30 months or less went into remission, as opposed to none of the seven who had been sick for a longer period ( p = 0.04). Side effects included fatigue or irritability, anxiety, abdominal pain, striae, hirsutism, acne, and weight gain. Conclusions: Contrary to what is observed in adults, in our patients pulsed dexamethasone therapy did not prove to be uniformly effective. However, in view of its effectiveness in a third of the patients, acceptable side effects, and low cost, we believe that this treatment could be considered in patients with chronic idiopathic thrombocytopenic purpura who do not tolerate the disease well, especially if no more than 3 years have elapsed since diagnosis. Larger studies will be necessary to define which patients will respond to this type of therapy.

Background: The technology to recognize nucleated red blood cells (NRBC) automatically has only recently been developed. Modern hematology analyzers allow for rapid and accurate NRBC counts. The goal of our study was to evaluate NRBC counts and the concentrations of serum transferrin receptor (sTfR) in patients affected by different thalassemia syndromes and hereditary spherocytosis. We wished to gain a better understanding of the meaning of the presence of NRBC in peripheral blood and the relationship of the two parameters with effective and ineffective erythropoiesis in the different thalassemia syndromes. Methods: NRBC counts in peripheral blood were evaluated in a large group of patients with thalassemia (36 thalassemia major, 55 thalassemia intermedia and 61 Sβ-thalassemia patients) and compared with data from 29 patients with hereditary spherocytosis; in all the patients the concentration of sTfR was evaluated as an index of global erythropoiesis. Results: The NRBC count showed a good relationship with ineffective erythropoiesis: highest counts were observed in the thalassemia syndromes characterized by almost completely ineffective erythropoiesis. NRBCs were absent in patients affected by hereditary spherocitosis, a disease characterized by effective erythropoiesis. Conclusions: The NRBC count can be useful for better defining ineffective erythropoiesis in patients with thalassemia, and can help optimize transfusion therapy in severe thalassemia syndromes. Clin Chem Lab Med 2009;47:1539–42.

Objective Functional recovery of B lymphocytes after hematopoietic stem cell transplantation (HSCT) can take up to 2 years. HSCT recipients may obtain protective titers of pathogen-specific antibody through vaccination, but optimal timing of reimmunization remains to be defined. Patients and Methods In this study, we evaluated the reconstitution of B-cell number and activity in 139 children given HSCT, by B-cell subset phenotyping and in vitro immunoglobulin (Ig) production. Results Patients were longitudinally studied at 3, 6, 12, and 18 to 24 months after transplantation. At all time points, recipients displayed a significantly higher percentage of naive (IgD + CD27 − ) B cells and showed significantly lower production of stimulated in vitro Ig as compared to healthy controls. Moreover, during follow-up, we observed an increase in the proportion of patients who had CD27 + B subsets and who were able to mount in vitro Ig production greater than the 5th percentile. Conclusion Similar to what has been described in adults, most children lack memory B cells and produce low amounts of Ig. However, the number of B cells, as well as their function, gradually recovered over time and the spread of data we observed suggests that the reimmunization schedule should be individualized for each patient. It remains to be defined in a prospective clinical study the time point at which a patient should start reimmunization. A reasonable hypothesis to be explored is the time point at which a percentage of memory B cells greater than the 5th percentile of normal controls is reached.

SummaryThe increasing number of diagnosed cases of inherited thrombocytopenias, owing to the routine practice of including platelet counts in blood tests, suggests that this condition is not so rare as expected. In the majority of cases, the molecular basis of the disease is unknown, although the defect is likely to affect thrombocytopoiesis and regulation of the normal platelet count. Here we report a genomewide search in a large Italian family affected by autosomal dominant thrombocytopenia. Patients showed a moderate thrombocytopenia with minimal symptoms characterized by normocellular bone marrow, normal medium platelet volume, and positive aggregation tests. Microsatellite analysis demonstrated that the disease locus (THC2) is linked to chromosome 10p11.1-12, within a candidate region of 6 cM between markers D10S586 and D19S1639. A maximum LOD score of 8.12 at recombination fraction .00 was obtained with the microsatellite D10S588. These data localized the first locus of an autosomal dominant thrombocytopenia, and the subsequent identification of the gene will provide new insight into the basic mechanism of megakaryocytopoiesis disorders.

The Dynamics of International Competitiveness. — This paper focuses on the determinants of international competitiveness over the seventies and eighties. The theoretical framework adopted here is based on a “technology-gap” account of trade flows. The econometric analysis relies on a dynamic model estimated by pooling time-series across countries. The short- and long-term impacts of both technical change and labour costs on trade performance are investigated. It is found that technological variables (patents and investments) play a major role in shaping dynamics of exportshares, while labour costs asymmetries among countries appear to affect trade performance only in the short term.

Abstract 2071 Impaired switching from fetal hemoglobin (HbF) to adult globin gene expression leads to hereditary persistence of fetal hemoglobin (HPFH) in adult life. This is of prime interest because elevated HbF levels ameliorate beta-thalassemia and sickle cell anemia. Fetal hemoglobin levels are regulated by complex mechanisms involving factors linked or not to the beta-globin gene locus. Recently, we reported an inverse relationship between Ggamma-globin gene (HBG2) and Cold Shock Domain Protein A (CSDA) expression levels. Based on mRNA differential display analysis, RNA interference and over-expression studies in K562 and primary erythroid cells we postulated that CSDA could contribute to regulate HBG2 expression. The putative mechanism by which CSDA modulates HBG2 expression was investigated in K562 cells by gene reporter assays on wild-type and mutant constructs of the HBG2 promoter region suspected to bind CSDA, providing experimental evidence that CSDA acts as repressor of HBG2 expression. Furthermore, chromatin immunoprecipitation (ChIP) analysis on K562 cells showed that CSDA interacts in vivo with this promoter region. In this way we were able to demonstrate that CSDA modulates HBG2 expression at least in part at the transcriptional level (Petruzzelli R et al, Br J Haematol 2010). The CSDA gene is located at position 12p13.1 and comprises 10 exons. The C-terminus (exons 6–9) is involved in protein-protein interactions. Alternative splicing of exon 6 results in two main isoforms, namely CSDA isoform a and isoform b, which show different C-terminal domains, potentially able to take part to specific protein complexes. We found that expression levels of CSDA isoform a were reduced in HPFH patients respect to isoform b. These findings suggested that isoform a could be much more involved in repression of HBG2 expression compared to isoform b. To identify putative CSDA interactors, we over-expressed these two FLAG-tagged CSDA isoforms in K562 cells. Western-blot analysis on proteins immunoprecipitated with a FLAG antibody revealed the presence of NF-kB p50 and p65 subunits and histone deacethylase 2 (HDAC2) only in samples co-immunoprecipitated with CSDA isoform a, but not with isoform b (Fig. 1). By ChIP assays with antibodies against p65, p50 and HDAC2, we demonstrated that both the NF-kB p50-p65 heterodimer and HDAC2 interact with the –200 bp region of the HBG2 promoter containing the CSDA binding site (Fig. 2). To examine the role of NF-kB and histone deacetylases on the transcriptional repression of HBG2 expression, we treated K562 cells with the proteasome inhibitor bortezomib which blocks the nuclear traslocation and transcriptional activity of the NF-kB p65-p50 complex or with the histone deacetylase inhibitor trichostatin A (TSA). Quantitative analysis by Real Time PCR showed that HBG2 expression increased following either bortezomib or TSA treatments. Furthermore, by ChIP analysis we were able to demonstrate that knock-down of CSDA abolished these interactions. To investigate if treatment with bortezomib or TSA affects the histone acetylation levels at the -200 bp region of the HBG2 promoter, we performed ChIP assays in K562 cells using an anti-acetyl-H3 antibody. Results indicated that both these drugs induces a considerable increase in H3 acetylation levels at the -200 bp region of the HBG2 promoter (Fig. 3). Taken altogether these data indicate that NF-kB and HDAC2 interact with CSDA to form a multiprotein complex which take part to the regulation of HBG2 expression by modulating local chromatin conformation. Furthermore, our study contributes to better define the role played by CSDA in fetal globin gene expression and shed novel light on the molecular mechanisms involved in globin gene switching. Disclosures: No relevant conflicts of interest to declare.

Abstract 4831 Introduction Previous studies showed that chromosomal and genomic aberrations leading to activation of oncogenes or haploisufficiency of tumor suppressor genes are well-known pathogenic mechanisms in cancer. Additional copies of chromosme 21 are frequently found in Myelodisplastic Syndrome (MDS) and in Acute Myeloid Leukemia (AML); the presence of these chromosomal abnormalities and the high incidence of acute leukemias in subjects with constitutional trisomy 21, suggest that genes on chromosome 21, including RUNX1/AML1, play a particular role in leukemogenesis and hematopoiesis. We describe a patient with syndromic trombocytopenia ( average platelet count= 70000/mm3), psychomothor delay, microcephaly and low stature, that developed a progressive anemia and became transfusion-dependent at seventeen years of age. Materials and methods Cytogenetic analysis was performed on bone marrow cells and on peripheral blood lymphocytes, with standard techniques and evaluated with Giemsa-trypsin-Giemsa banding according to International System for Human Cytogenetic Nomenclature (ISCN 2005). Fluorescent In Situ Hybridization (FISH) experiments was performed on bone marrow samples with LSI AML1/ETO Dual Color, Dual Fusion Translocation and, at the same time, the High-resolution oligo array-CGH (Agilent Human Genome CGH Microarray 44B) was performed on the DNA of the patient. Results The bone marrow cells showed marked dysplastic morphology and the following abnormal karyotype: 46,XX[14]/47,XX,+21[6]; the peripheral blood karyotype was normal. The High-resolution oligo array-CGH demonstrated a constitutional de novo microdeletion of one chromosome 21. The interstitial deletion was found to be approximately 4,4Mb (Megabases), extending from 32,29 Mb to 36,51 Mb on band 21q22.11-12, involving MRAP, IFNAR2, IFNGRR2, KCNE2, KCNE1 and RUNX1 genes. The FISH performed on bone marrow cells, revealed two orange signals representing normal copies of ETO and one green signal for AML1 in 60% interphase cells and two orange signals and two green signals in the remaining 40% cells. The first pattern of signals, for AML1, is related to cells with karyotype 46,XX, while the second pattern of signals is related to cells with karyotype 47,XX,+21. These results indicate that in the myelodisplastic clone the third chromosome 21 are not deleted on band 21q22. Conclusion Three cases were recently published of syndromic thrombocytopenia with 21q22 constitutional deletion, including RUNX1, and variable degree of dysmorphic features and mental delay. One of the three patients developed LMA at the age of six years. Our results further support the fundamental role, in the pathogenetic mechanism of syndromic trombocytopenia and MDS/AML, of the numerical abnormalities of chromosome 21 associated with submicroscopic rearrangement of RUNX1 and other dosage-sensitive unknown genes on chromosome 21. Disclosures No relevant conflicts of interest to declare.

Allogeneic cord blood transplantation (CBT) is increasingly used in children with beta-thalassemia major. Donor/recipient mixed chimerism (MC) is frequently observed in patients with beta-thalassemia major given bone marrow transplantation (BMT) in the early post-transplant period, due to the persistence of haematopoietic and immune cells of host origin. Previous clinical data reported on these patients demonstrated that the majority of them exhibiting MC convert to full donor chimerism (FDC), some maintain MC stable over time, while a non negligible number of patients develop graft failure, in particular when increasing proportions of cells of host origin are observed in serial monitoring. Aims of the present study were to retrospectively investigate the proportion of children with beta-thalassemia major experiencing either transient, or long-lasting persistence of hematopoietic cells of host origin after CBT, as compared to those given BMT, and to analyze the relationship existing between the evolution of MC over time and clinical outcome. One hundred and six consecutive patients, 27 given CBT from an HLA-identical related donor (RD) and 79 given BMT (42 from a RD and 37 from an HLA-compatible unrelated volunteer, UD), were enrolled in the study. Donor/recipient chimerism status was evaluated by PCR-based assay, analyzing selected polymorphic short tandem repeat (STR) loci. CBT and BMT recipients received similar preparative regimens. Anti-thymocyte globulin (ATG 10 mg/Kg on days −4, −3 and −2; Fresenius, Graefelfing, Germany) was used in all patients given an UD-BMT. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (Cs-A) alone in CBT recipients; either CsA alone (12 RD-BMT recipients) or CsA in combination with methotrexate (MTX) was given to BMT patients. All patients given CBT engrafted and displayed MC early after transplantation, 13/27 converted to FDC (6 within 1 month and 7 within 1 year after CBT), 14/27 maintained stable MC, and all of them are alive, transfusionin-dependent and free of any immune-suppressive drug, the follow-up ranging between 15 and 89 months (median value 42 months). In the group of children given BMT, 24/79 (12 transplanted from UD and 12 from RD) exhibited FDC at all time points examined, 4/79 (1 transplanted from UD and 3 from RD) did not engraft and 51/79 (23 from UD and 28 from RD) displayed MC at time of haematological reconstitution. Forty out of these 51 BMT recipients with MC status converted to FDC (17 from UD and 23 from RD; 29 within 1 month and 11 within 1 year after BMT), 3/51 maintained stable MC (1 undergoing UD- and 2 RD-BMT), while 8/51 (5 from UD and 3 from RD) progressively lost the graft, returning to be transfusion-dependent. The median follow-up time was 51 months (range: 15–110 months) and 48 months (range: 16–81 months) in the RD-BMT and UD-BMT group, respectively. None of the patients given CBT experienced either grade II-IV acute GVHD, which was, by contrast, diagnosed in 3 and 7 patients given RD- and UD-BMT, respectively. Chronic GVHD was diagnosed in 8 children (2 from RD- and 6 from UDBMT). Five out of 106 pediatric patients enrolled in the study, 2 included in the RD-BMT and 3 in the UD-BMT group, died of transplantation-related complications. These results indicate that MC is frequently observed in children with beta-thalassemia after RD-CBT, without, however, predicting an increased risk of treatment failure. CBT from an HLA-identical related donor is a successful option in beta-thalassemia major, possibly also due to the establishment of an effective state of immune tolerance between host and donor that decreases the risk of both graft rejection and GVHD.

The switch from fetal to adult globin gene expression occurs around birth when fetal hemoglobin (HbF) production gradually declines within a few months. Much effort is underway to clarify the molecular basis of this mechanism, since impaired hemoglobin switching leading to persistent expression of fetal globin genes in adults (HPFH) offers therapeutic potential for hemoglobinopathies (S.L. Thein. Br. J. Haematol2004; 124: 264–74). In order to identify and study regulatory factors putatively involved in γ-globin gene expression, we examined the reticulocyte mRNAs differently expressed in three siblings (one brother, 54 years-old and two sisters 35- and 37-years old, respectively). The eldest brother had been referred to Umberto I Hospital for evaluation of a severe condition of β-thalassemia intermedia on chronic transfusion therapy since 1990. Both of his sisters resulted clinically affected by a milder form of thalassemia intermedia, non-transfusion dependent, showing Hb values around 8.4 g/dL, Hb A2 levels from 6.0 to 7.9% and HbF ranging from 14.5 to 27.6%, values higher than those resulted in their brother (5.9% Hb A2 and 7.2% HbF). Molecular analysis was performed on DNA extracted from peripheral leucocytes and revealed the same β-globin gene cluster genotype for all these subjects who resulted homozygous for the β+ IVSI-6 (C→T) mutation associated to haplotype VI chromosomes. Different levels of HbF were thus presumably responsible of different clinical phenotypes. To investigate the possible causes of the variations in γ-globin gene expression, extensive sequence analysis was performed on putative regulatory regions within the β-globin gene cluster (Zhi-Hong Lu et al., Blood1996; 87: 1604–11). Results showed the same genetic background in all the siblings. It was thus supposed that genetic determinants external to the β-globin gene cluster were responsible of the different γ-globin gene expression. To explore this hypothesis, the reticulocyte transcriptome was analyzed by a differential mRNA display approach. Reticulocytes were isolated from peripheral blood and total RNA extracted for all family members. Our study revealed several bands differentially displayed in the sample from the more severely affected sibling respect to his sisters. Selected bands were cloned in a pGEM T-vector (Promega, WI) and sequenced. Comparative sequence searches were performed using the BLAST algorithm. Preliminary data gave, for two of the clones originated from bands with increased expression in the brother, a complete homology (greater than 95%) with the cDNA sequence of a cold shock domain protein, displaying features of a repressor factor for several hematopoietic genes (Horwitz M. et al. JBC1994; 269: 14130–39; P. Coles et al. Nucleic Acids Res1996; 12: 2311–17).

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare immunodeficiency disorder. We report three patients with WHIM syndrome who are affected by Tetralogy of Fallot (TOF). This observation suggests a possible increased risk of TOF in WHIM syndrome and that birth presentation of TOF and neutropenia should lead to suspect WHIM syndrome.

Reasoning with existential rules typically consists of checking whether a Boolean conjunctive query is satisfied by all models of a first-order sentence having the form of a conjunction of Datalog rules extended with existential quantifiers in rule-heads. To guarantee decidability, five basic decidable classes - linear, weakly-acyclic, guarded, sticky, and shy - have been singled out, together with several generalizations and combinations. For all basic classes, except shy, the important property of finite controllability has been proved, ensuring that a query is satisfied by all models of the sentence if, and only if, it is satisfied by all of its finite models. This paper takes two steps forward: (i) devise a general technique to facilitate the process of (dis)proving finite controllability of an arbitrary class of existential rules; and (ii) specialize the technique to complete the picture for the five mentioned classes, by showing that also shy is finitely controllable.

Inherited thrombocytopenias are a heterogenous group of disorders. Different criteria have been suggested to classify the forms, such as the inheritance mechanism and the platelet volume as well as the number and morphology of megakaryocytes. However, the classification is often descriptive, and the precise mechanism of thrombocytopenia still remains unknown. We describe the clinical, biologic, and molecular findings of an autosomal dominant thrombocytopenia in a large family. The 17 patients had normocellular bone marrow and normal platelet volume. Platelets also showed a normal aggregation test and normal response to ADP and thrombopoietin (TPO). In the affected subjects, the mean +/- SD levels of platelet count and plasma TPO were 62+/-25 and 258+/-151, respectively. Comparative analysis showed that the patients with platelet count

Existential rules generalize Datalog with existential quantification in the head. Natively, Datalog is interpreted under a closed-world semantics, while existential rules typically employ the open-world assumption. The interpretation domain in the latter case is enlarged by infinitely many "anonymous" individuals. Then, in any rule, each variable ranges over all individuals, even if not needed or required. In this paper, we enhance existential rules by closed-world variables to consciously reason on the properties of "known" (non-anonymous) and arbitrary individuals in different ways. Accordingly, we uniformly generalize the basic classes of existential rules that ensure decidability of ontology-based query answering. For them, after observing that decidability is preserved, we prove that a strict increase in expressiveness is gained, and in most cases the computational complexity is not altered.