Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP).

Acquired aplastic anemia (AA) is a rare heterogeneous disorder characterized by pancytopenia and hypoplastic bone marrow. The incidence is 2-3 per million population per year in the Western world, but 3 times higher in East Asia. Survival in severe aplastic anemia (SAA) has improved significantly due to advances in hematopoietic stem cell transplantation (HSCT), immunosuppressive therapy, biologic agents, and supportive care. In SAA, HSCT from a matched sibling donor (MSD) is the first-line treatment. If a MSD is not available, options include immunosuppressive therapy (IST), matched unrelated donor, or haploidentical HSCT. The purpose of this guideline is to provide health care professionals with clear guidance on the diagnosis and management of pediatric patients with AA. A preliminary evidence-based document prepared by a group of pediatric hematologists of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Hemato-Oncology (AIEOP) was discussed, modified and approved during a series of consensus conferences that started online during COVID 19 and continued in the following years, according to procedures previously validated by the AIEOP Board of Directors.

Association between oral and fecal microbiome dysbiosis and treatment complications in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation.

The oral and gastrointestinal mucosae represent the main targets of the toxic effect of chemo and/or radiotherapy administered during the conditioning regimen before hematopoietic stem cell transplant (HSCT). These harmful consequences and the immunological complications that may occur after the transplant (such as Graft versus Host Disease, GvHD) are responsible for the clinical symptoms associated with mucositis during the aplasia phase, like pain, nausea, vomiting, and diarrhea. These toxicities could play a critical role in the oral and gastrointestinal microbiomes during the post-transplant phase, and the degree of microbial dysbiosis and dysregulation among different bacterial species could also be crucial in intestinal mucosa homeostasis, altering the host's innate and adaptive immune responses and favoring abnormal immune responses responsible for the occurrence of GvHD. This prospective pediatric study aims to analyze longitudinally oral and gut microbiomes in 17 pediatric patients who received allogeneic HSCT for malignant and non-malignant diseases. The oral mucositis was mainly associated with an increased relative abundance of Fusobacteria, and Prevotella species, while Streptococcus descendants showed a negative correlation. The fecal microbiome of subjects affected by cutaneous acute GvHD (aGvHD) correlated with Proteobacteria. Oral mucosal microbiota undergoes changes after HSCT, Fusobacteria, and Prevotella represent bacterial species associated with mucositis and they could be the target for future therapeutic approaches, while fecal microbiome in patients with acute GvHD (aGvHD) revealed an increase of different class of Proteobacteria (Alphaproteobacteria and Deltaproteobacteria) and a negative correlation with the class of Gammaproteobacteria.

The insemination status and social context influences quail laying and social behavior: A novel experimental set up.

Japanese quails in wild life live in small groups with females being even solitary during the laying period. Although it is a poultry species widely used for egg production, information regarding laying behavior motivations or influencing variables is scarce. Our study focuses on evaluating along 7 d the quail laying behavior in a novel environmental set up. This set up allows the female to choose between remaining separated from a conspecific in one side of the apparatus or to voluntarily enter their space (box-mate side) and interact with it. We evaluated whether the female insemination status prior to enter the environmental set up, and the presence of a female or a male partner in the box-mate side can influence their laying and social behavior. Thus, 4 experimental groups were established. Females spent a higher (P < 0.05) percentage of time in the box-mate side than in their separated sector in all groups. In 3 of the 4 experimental groups (non-inseminated females interacting with a female or a male box-mate, and inseminated females interacting with a male box-mate) females also laid a greater percentage (≥65%, P < 0.05, in all cases) of eggs in the box-mate sector than in their separated sector. However, the group of inseminated females that interacted with a female box-mate shifted their egg distribution and laid equally between both sides of the apparatus. Aggressive social interactions were reduced (P < 0.05) throughout the testing days but this was depending upon the female insemination status and the sex of their box-mate. Findings suggest that females can change their laying side choice when they are inseminated but depending on the sex identity of their box-mate partners. Thus, providing quail female breeders with the option of laying their eggs in separated enclosures from conspecifics could be key to favor their well-being.

Anti-D4GDI antibodies activate platelets in vitro: a possible link with thrombocytopenia in primary antiphospholipid syndrome.

BACKGROUND: Thrombocytopenia is a manifestation associated with primary antiphospholipid syndrome (PAPS), and many studies have stressed the leading role played by platelets in the pathogenesis of antiphospholipid syndrome (APS). Platelets are highly specialized cells, and their activation involves a series of rapid rearrangements of the actin cytoskeleton. Recently, we described the presence of autoantibodies against D4GDI (Rho GDP dissociation inhibitor beta, ARHGDIB) in the serum of a large subset of SLE patients, and we observed that anti-D4GDI antibodies activated the cytoskeleton remodeling of lymphocytes by inhibiting D4GDI and allowing the upregulation of Rho GTPases, such as Rac1. Proteomic and transcriptomic studies indicate that D4GDI is very abundant in platelets, and small GTPases of the RHO family are critical regulators of actin dynamics in platelets. METHODS: We enrolled 38 PAPS patients, 15 patients carrying only antiphospholipid antibodies without clinical criteria of APS (aPL carriers) and 20 normal healthy subjects. Sera were stored at - 20 °C to perform an ELISA test to evaluate the presence of anti-D4GDI antibodies. Then, we purified autoantibodies anti-D4GDI from patient sera. These antibodies were used to conduct in vitro studies on platelet activation. RESULTS: We identified anti-D4GDI antibodies in sera from 18/38 (47%) patients with PAPS, in sera from 2/15(13%) aPL carriers, but in no sera from normal healthy subjects. Our in vitro results showed a significant 30% increase in the activation of integrin αIIbß3 upon stimulation of platelets from healthy donors preincubated with the antibody anti-D4GDI purified from the serum of APS patients. CONCLUSIONS: In conclusion, we show here that antibodies anti-D4GDI are present in the sera of PAPS patients and can prime platelet activation, explaining, at least in part, the pro-thrombotic state and the thrombocytopenia of PAPS patients. These findings may lead to improved diagnosis and treatment of APS.

Long-time behavior of the momentum distribution during the sudden expansion of a spin-imbalanced Fermi gas in one dimension.

We study the sudden expansion of spin-imbalanced ultracold lattice fermions with attractive interactions in one dimension after turning off the longitudinal confining potential. We show that the momentum distribution functions of majority and minority fermions quickly approach stationary values due to a quantum distillation mechanism that results in a spatial separation of pairs and majority fermions. As a consequence, Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) correlations are lost during the expansion. Furthermore, we argue that the shape of the stationary momentum distribution functions can be understood by relating them to the integrals of motion in this integrable quantum system. We discuss our results in the context of proposals to observe FFLO correlations, related to recent experiments by Liao et al., Nature (London) 467, 567 (2010).

Landau-Zener sweeps and sudden quenches in coupled Bose-Hubbard chains.

We simulate numerically the dynamics of strongly correlated bosons in a two-leg ladder subject to a time-dependent energy bias between the two chains. When all atoms are initially in the leg with higher energy, we find a drastic reduction of the interchain particle transfer for slow linear sweeps, in quantitative agreement with recent experiments. This effect is preceded by a rapid broadening of the quasimomentum distribution of atoms, signaling the presence of a bath of low-energy excitations in the chains. We further investigate the scenario of quantum quenches to fixed values of the energy bias. We find that for a large enough density the momentum distribution relaxes to that of an equilibrium thermal state with the same energy.

Attractive Fermi gases with unequal spin populations in highly elongated traps.

We investigate two-component attractive Fermi gases with imbalanced spin populations in trapped one-dimensional configurations. The ground state properties are determined with the local density approximation, starting from the exact Bethe-ansatz equations for the homogeneous case. We predict that the atoms are distributed according to a two-shell structure: a partially polarized phase in the center of the trap and either a fully paired or a fully polarized phase in the wings. The partially polarized core is expected to be a superfluid of the Fulde-Ferrell-Larkin-Ovchinnikov type. The size of the cloud as well as the critical spin polarization needed to suppress the fully paired shell are calculated as a function of the coupling strength.

BCS-BEC crossover in a random external potential.

We investigate the ground state properties of a disordered superfluid Fermi gas across the BCS-BEC (Bose-Einstein condensate) crossover. We show that, for weak disorder, both the depletion of the condensate fraction of pairs and the normal fluid density exhibit a nonmonotonic behavior as a function of the interaction parameter 1/k{F}a, reaching their minimum value near unitarity. We find that, moving away from the weak-coupling BCS regime, Anderson's theorem ceases to apply and the superfluid order parameter is more and more affected by the random potential.

Quantum fluctuations and collective oscillations of a Bose-Einstein condensate in a 2D optical lattice.

We use Bogoliubov theory to calculate the beyond mean field correction to the equation of state of a weakly interacting Bose gas in the presence of a tight 2D optical lattice. We show that the lattice induces a characteristic 3D to 1D crossover in the behavior of quantum fluctuations. Using the hydrodynamic theory of superfluids, we calculate the corresponding shift of the collective frequencies of a harmonically trapped gas. We find that this correction can be of the order of a few percent and hence easily measurable in current experiments. The behavior of the quantum depletion of the condensate is also discussed.

Formation of molecules near a Feshbach resonance in a 1D optical lattice.

We study the molecular behavior of two atoms interacting near a Feshbach resonance in the presence of a 1D periodic potential. The critical value of the scattering length needed to produce a molecule and the binding energy at resonance are calculated as a function of the intensity of the periodic potential. Because of the non-separability of the center of mass and relative motion, the binding energy depends on the quasimomentum of the molecule. This has dramatic consequences on the molecular tunneling properties, which become strongly dependent on the scattering length.

Superfluid fermi gas in a 1D optical lattice.

We calculate the superfluid transition temperature for a two-component 3D Fermi gas in a 1D tight optical lattice and discuss a dimensional crossover from the 3D to quasi-2D regime. For the geometry of finite size discs in the 1D lattice, we find that even for a large number of atoms per disc the critical effective tunneling rate for a quantum transition to the Mott insulator state can be large compared to the loss rate caused by three-body recombination. This allows the observation of the Mott transition, in contrast to the case of Bose-condensed gases in the same geometry.

Umklapp collisions and center-of-mass oscillations of a trapped Fermi gas.

Starting from the Boltzmann equation, we study the center-of-mass oscillation of a harmonically trapped normal Fermi gas in the presence of a one-dimensional periodic potential. We show that for values of the Fermi energy above the first Bloch band the center of mass motion is overdamped in the collisional regime due to umklapp processes. This should be contrasted with the behavior of a superfluid where one instead expects the occurrence of persistent Josephson-like oscillations.

[Ticks and the pediatrician]. / Le zecche ed il pediatra.

The match between ticks and pediatricians in Italy is usually a seasonal event related to the spring and summer trips and to the increasing of outdoor activity that sun and warm weather allow, both for children and ticks. So cared parents reach emergencies asking for tick removal but more often after the tick has yet been removed by empirical manoeuvres and after the killing and the destruction of the "enemy". We have scheduled, in the years 2002-2003, the 167 children that reached our unit for a tick bite; they where 92 males (mean age four years) and 75 females (mean age five years). Two of them had only a questionable tick bite but one had erythema on the lateral side of the left ankle, fever of obscure origin and weakness with generalised malaise. She was six years old and she lived with a dog on which, in more instances, ticks where found, but she never noticed ticks on her body. The dog had positive levels of anti rickettsial and anti borrelia antibodies but no evidence of conclamate illness. In this girl we found high titers of anti borrelia antibodies that WB testing confirmed to be anti B. burgdoferi. We diagnosed Lyme disease and treated the girl with amoxicillin (50 mg/kg/day) for three weeks achieving the complete relief of symptomatology till today. Three children with conclamate tick bite had positive levels of anti Rickettsia conorii antibodies with increasing levels at a twenty days control; two (aged four and five years) of them had a full symptomatology (tache noire, satellite lymphadenopathy, fever, and maculopapular erythema) for Meditarranean spotted fever; the latter (three years old) had an atypical form with the complete absence of maculopapular erythema. The therapy was clarithromycin (15 mg/kg/day) for three weeks. In Campania, in the years 2002/2003 on 167 children with tick bite that reached our unit, we found only four pathological correlable events; so are our ticks not infected? But we don't know how many children where tick bited and if there were other children with Lyme disease or Rickettsial disease because of the lack of a pediatric reference centre for "tick bite diseases" and the incomplete and late diffusion of knowledge on these diseases. Other Italian regions and such as Trentino Alto Adige, Veneto, and Friuli Venezia Giulia had a remarkable officially notified number of cases of Lyme disease and in Sicilia, Sardegna and Lazio there were numerous officially notified Rickettsial diseases. So we hope that Campania may be an happy island but we also think that a more effective cooperation between pediatricians and veterinarians and the creation of regional reference centres for tick bite diseases may arise a surveillance net to prevent the diffusion of these world wide emerging diseases and so that parents can achieve an univoque and useful information, the only way to defeat the fear of ignorance.

Interferon: a meta-analysis of published studies in pediatric chronic hepatitis B.

Perinatally infected Asian children respond poorly to interferon (IFN) therapy. In contrast, IFN therapy seems to be more effective in Caucasian children who presumably acquired HBV infection later in life. We reviewed seven controlled studies of IFN treatment in children with chronic hepatitis B living in western countries (216 treated, and 200 untreated children). Before treatment all patients were HBeAg and HBV-DNA +ve, with a biopsy proven chronic hepatitis B. Ages ranged 1 to 16 years (mean age 7 years). Most patients were Caucasian. Protocols which have been adopted may schematically be divided into protocols which have used high doses of IFN (7.5 to 10 MU/sqm/TIW), and protocols which have used low doses of IFN (3 to 6 MU/sqm/TIW), with a short (3 to 6 months) or a long duration of treatment (12 months). The percentage of treated patients who, at the end of treatment, lost HBV-DNA (that in most studies corresponded also to HBeAg serum conversion) averages 20 to 58% (mean 35.5%) that is much higher than that observed in controls (range 8-17%; mean 11.4%). A better trend is probably observed only in patients who received the treatment for a longer period of time. At the end of treatment, low percentages of patients lost BsAg (range 0-4%; mean 1.1%): again higher doses tend to be more effective than lower doses. In some studies IFN has been shown to significantly accelerate the termination of viral replication. Data on longer term outcome of IFN treatment in Caucasian children are scarce and confirm results obtained at short and at medium-term FU either in horizontally either in perinatally infected children. Results from few randomized controlled trials of interferon therapy with prednisone priming in Chinese and Caucasian children were comparable to results obtained without prednisone. In one study steroid priming did not potentiate the effect of IFN, however it existed a tendency of prednisone to improve HBeAg clearance in patients with normal aspartate aminotransferase, and alanine aminotransferase activity lesser than 100 u/l. In most studies, factors positively influencing response rates of IFN treatment are represented by severe inflammation in the basal liver biopsy, high basal levels of serum transaminase, low basal levels of serum HBV-DNA. Vertical transmission may be considered a factor adversely affecting the response to IFN treatment both in Chinese and Caucasian population. In general in most controlled studies, the majority of responders have shown a significant reduction in hepatic inflammation and transaminase normalization. Children have a low risk of developing severe IFN-induced side effects. Adverse reactions and worsening of health-related quality of life were tolerable and did not seem to be a limiting factor for IFN therapy in young candidates.

Persistent hyperaminotransferasemia resolving after weight reduction in obese children.

Nine obese children were referred to our liver disease unit because of asymptomatic, long-standing (range, 4 to 49 months) hyperaminotransferasemia of unknown origin. Ultrasonography showed a "bright" liver in most patients. A hypocaloric diet was prescribed, and the hepatic abnormalities of the complaint patients showed a prompt and persistent improvement that paralleled the loss of excess weight.

Inefficacy of immunosuppressive treatment in HBSAg-positive, delta-negative, moderate chronic active hepatitis in children.

The efficacy of immunosuppressive treatment was evaluated in a group of 15 children (aged 2-10 years) affected by clinically asymptomatic, biochemically mild, HBSAg-positive, delta-antibody-negative, histologically moderate, chronic active hepatitis (CAH). Clinical, biochemical, serological, and histological features of chronic hepatitis B virus (HBV) infection were studied during a follow-up of 2 years. Eight of 15 patients received immunosuppressive treatment (prednisone plus azathioprine); seven received a placebo. No significant differences were found among treated and untreated patients, an overall improvement of nearly all parameters of disease (aminotransferases, albumin, prothrombin time, immunoglobulins, bromsulphalein at 45 min, and bile acid serum levels) being found in both groups. Treated patients showed an improvement in aminotransferase levels only at the first 3-month checkup. This finding, however, was not statistically significant in our study and disappeared at subsequent follow-up examinations. A high incidence of HBeAg was noted at entry into the study (10 of 15 patients checked). HBeAg seroconversion was observed in two of the six HBeAg-positive treated patients and in two of the four HBeAg-positive untreated patients. Finally, the histological picture showed similar patterns in both groups of patients studied. Our data suggest that no benefit from immunosuppressive therapy can be proven at this time in asymptomatic, moderately active, HBsAg-positive, delta-negative CAH in children.

[Problems in perfusion and preservation of the rat kidney isolated for the purpose of transplantation]. / Problemi di perfusione e conservazione di rene di ratto isolato a scopo di trapianto.

AA. performed an experimental trial on rats in order to demonstrate damages derived from organ perfusion (kidney) with endo- and extracellular electrolitic solutions. M/E values of structural alterations of the cells allowed the standardisation of renal perfusion methods for transplantation.