Default-Mode Network Connectivity Changes Correlate with Attention Deficits in ALL Long-Term Survivors Treated with Radio- and/or Chemotherapy.

Whether chemotherapy (ChT) and radiotherapy (RT) determine neurocognitive impairment in acute lymphoblastic leukemia long-term survivors (ALL LTSs) through similar mechanisms affecting the same brain regions is still unknown. We compared neurocognitive alterations, regional brain tissue volumes (by voxel-based morphometry), and functional connectivity of the main default-mode network hubs (by seed-based analysis of resting state functional MRI data), in 13 ALL LTSs treated with RT and ChT (Group A) and 13 treated with ChT only (Group B). Group A performed significantly worse than Group B at the digit span and digit symbol tests (p = 0.023 and 0.013, respectively). Increased connectivity between the medial prefrontal cortex (the main anterior hub of the default-mode network) and the rolandic operculi was present in Group A compared to Group B, along with the absence of significant differences in regional brain tissue volumes. In these regions, the functional connectivity correlated inversely with the speed of processing scores, independent of treatment group. These results suggest that similar mechanisms may be involved in the neurocognitive deficits in ALL LTS patients, regardless of the treatment group. Further studies are needed to clarify whether these changes represent a direct expression of the mechanisms underlying the cognitive deficits or ineffective compensatory phenomena.

Steroid treatment in Ataxia-Telangiectasia induces alterations of functional magnetic resonance imaging during prono-supination task.

BACKGROUND: Ataxia-Teleangiectasia (A-T) is a rare neurodegenerative disorder characterized by progressive cerebellar degeneration. Till few years ago only supportive care was available to improve the neurological function in A-T patients. Even though A-T remains an incurable disease, we recently demonstrated a drug dependent amelioration of neurological signs in A-T patients during a short-term treatment with oral betamethasone. AIMS: The aim of this study is to evaluate whether the steroid induced motor performance changes in A-T are associated with functional magnetic resonance imaging (fMRI) modifications. This represents a preliminary pilot study, which requires a validation on a larger cohort of patients. METHODS: Six A-T patients received a 10-days cycle of oral betamethasone at 0.03 mg/kg/day. fMRI studies were carried out at T0 and at the end of the cycle. The neurological evaluation was performed through the Scale for the Assessment and Rating of Ataxia (SARA) quantification. The fMRI protocol was a block design with alternating epochs of rest and prono-supination of the dominant (right) hand. RESULTS: The voxel-based comparison showed a remarkable increase in the number of activated voxels within the motor cortex under the on-therapy condition as compared with the cortical activity under baseline condition in the 2 patients who completed the study protocol. CONCLUSIONS: Changes in motor performance in A-T patients treated with betamethasone are coupled with an increase in the activation in relevant cortical areas, thus suggesting that in A-T patients steroid treatment could improve motor performance facilitating cortical compensatory mechanisms.

Severe combined immunodeficiences: new and old scenarios.

Severe combined immunodeficiencies (SCIDs) represent a group of distinct congenital disorders affecting either cell-mediated or humoral immunity, which lead invariably to severe and life-threatening infections. The different forms of SCID are currently classified according to the presence or absence of T, B, and NK cells. This greatly helps define the site of the blockage during the differentiation process. Even though SCID patients share common clinical features, such as opportunistic infections and failure to thrive, irrespective of the underlying pathogenetic mechanism, the discovery of new causative gene alterations led to identify novel complex clinical phenotypes, sometimes associated to extrahematopoietic manifestations. In a few cases, the presenting signs may be peculiar to that specific form and physicians should be alerted in recognizing such complex phenotypes, in order to avoid delay in the diagnostic procedures. The aim of this review is to alert care-givers to take into account also the less frequent clinical features and novel pathogenic mechanisms to direct the functional and molecular studies toward a certain genetic alteration.

Magnetic resonance imaging is an accurate and reliable method to evaluate non-cystic fibrosis paediatric lung disease.

BACKGROUND AND OBJECTIVE: Chest MRI is increasingly used to assess pulmonary diseases, but its utility compared with high-resolution computed tomography (HRCT) has never been evaluated in children using specific performance outcomes. The aim of this study was to assess the accuracy and reliability of MRI compared with HRCT in children with non-cystic fibrosis (CF) chronic lung disease. METHODS: Fifty subjects aged 5.9-20 years, with primary ciliary dyskinesia (n = 17), primary immunodeficiency (n = 17) or recurrent pneumonia (n = 16), underwent chest HRCT and MRI. The prevalence of lung abnormalities on HRCT was evaluated, and sensitivity, specificity, accuracy and positive and negative likelihood ratios for MRI versus HRCT were calculated. MRI and HRCT scans were also assessed using a modified Helbich score. RESULTS: Bronchiectasis, mucous plugging, peribronchial wall thickening, consolidation, bullae, abscesses and emphysema were detected by HRCT in 72, 68, 66, 60, 10, 8 and 8% of subjects, respectively. Sensitivity, specificity, accuracy and positive and negative likelihood ratios for MRI were good or excellent for most of the changes that were assessed. Median total Helbich scores for HRCT and MRI were 10 (range 0-20) and 10 (range 0-18), respectively. There was good-to-excellent agreement between the two techniques for all scores (r ≥ 0.8). A Bland-Altman plot confirmed this agreement between total scores (bias value: 0.2 ± 1.18; 95% limits of agreement of mean difference: -2.12-2.52). CONCLUSIONS: Chest MRI was equivalent to HRCT to determine the extent of lung disease in children with non-CF lung disease. The findings support the use of chest MRI as an alternative to HRCT in diagnostic pathways for paediatric chronic lung disorders.

Iron chelation therapy in thalassemia major: a systematic review with meta-analyses of 1520 patients included on randomized clinical trials.

The effectiveness of deferoxamine (DFO), deferiprone (DFP), or deferasirox (DFX) in thalassemia major was assessed. Outcomes were reported as means±SD, mean differences with 95% CI, or standardized mean differences. Statistical heterogeneity was tested using χ2 (Q) and I2. Sources of bias and Grading of Recommendations Assessment, Development and Evaluation system (GRADE) were considered. Overall, 1520 patients were included. Only 7.4% of trials were free of bias. Overall measurements suggest low trial quality (GRADE). The meta-analysis suggests lower final liver iron concentrations during associated versus monotherapy treatment (p<0.0001), increases in serum ferritin levels during DFX 5, 10, and 20 mg/kg versus DFO-treated groups (p<0.00001, p<0.00001, and p=0.002, respectively), but no statistically significant difference during DFX 30 mg/kg versus DFO (p=0.70), no statistically significant variations in heart T2* signal during associated or sequential versus mono-therapy treatment (p=0.46 and p=0.14, respectively), increases in urinary iron excretion during associated or sequential versus monotherapy treatment (p=0.008 and p=0.02, respectively), and improved ejection fraction during associated or sequential versus monotherapy treatment (p=0.01 and p<0.00001, respectively). These findings do not support any specific chelation treatment. The literature shows risks of bias, and additional larger and longer trials are needed.

Intergenerational anticipation of disease onset in people with multiple autoimmune syndrome.

We compared the intergenerational variations of the clinical phenotype between 30 patients affected with multiple autoimmune syndrome (MAS) and their affected first- and second-degree relatives. Mean age at onset was always significantly higher in the previous generation than in probands for all the considered diseases.

γ Chain transducing element: a shared pathway between endocrine and immune system.

Several molecules, involved in the intracellular communication network, have been identified as the cause of primary immunodeficiencies. In most cases, these molecules are exclusively expressed in hematopoietic cells, being involved in cell development and/or functionality of terminal differentiated cells of immune system. In the case of γc, the abundance of the protein suggests a potential pleiotropic effect of the molecule. Immune and endocrine systems participate to an integrated network of soluble mediators that communicate and coordinate responsive cells to achieve effector functions in an appropriate fashion. It has been demonstrated a novel dependence of GH signaling on the common cytokines receptor γc in certain cell types, supporting the hypothesis of an interplay between endocrine and immune system. The evidence that different receptors share a few molecules may certainly lead to a better knowledge on the mechanism of coordination and integration of several pathways implicated in the control of cell growth and proliferation under physiological or pathogenic conditions. This review focuses on the γc as a common transducing element shared between several cytokines and growth hormone receptors, indicating a further functional link between endocrine and immune system.

Eosinophilia and thrombosis in parasitic diseases: an overview.

It is known that peripheral blood eosinophilia (PBE) is a normal hematopoietic response to several parasitic diseases, but it is less known that PBE promotes a hypercoagulable state that may favor thrombosis. Scope of this article is to explore which parasitic infestations are most likely to be complicated by thrombosis and to highlight the pathogenetic contribution of PBE to vascular occlusions in this setting. A review of the world literature revealed 18 cases in which PBE was associated with vascular occlusion though no specific surveys were dedicated to this topic. The eosinophil exerts its thrombogenic potential by inhibition of the natural anticoagulant pathways and release of tissue factor with enhanced coagulation activation leading to vascular occlusion. It is hoped that this review contributes to the awareness of the link between PBE and thrombosis in parasitic disorders to foster research in this area.

Altered signaling through IL-12 receptor in children with very high serum IgE levels.

An alteration of Th1/Th2 homeostasis may lead to diseases in humans. In this study, we investigated whether an impaired IL-12R signaling occurred in children with elevated serum IgE levels divided on the basis of the IgE levels (group A: >2000kU/l; group B: <2000kU/l). We evaluated the integrity of the IL-12R signaling through the analysis of phosphorylation/activation of STAT4, and mRNA expression and membrane assembly of the receptor chains. At a functional level, a proliferative defect of lymphocytes from group A patients was observed. In these patients, an abnormal IL-12R signaling was documented, and this finding was associated with abnormal expression of the IL-12Rbeta2 chain. Our data indicate that in patients with very high IgE levels the generation of Th1 response is impaired, and that this abnormality associates with abnormal IL-12R signaling.