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Purpose Beta-thalassemia major is a severe, congenital hematological disorder and, if untreated, leads to early mortality. Progress in therapeutical strategies improved clinical outcomes and life expectancy; however, increased survival led to the development of new disorders, including endocrinopathies. Little is known on the possible impairment of adrenocortical function, a potentially life-threatening condition, in long-term thalassaemic survivors. We therefore decided to assess adrenal reserve and the value of salivary cortisol during ACTH stimulation in the diagnosis of adrenocortical insufficiency in adult patients with β-thalassemia major. Methods Cross-sectional study including 72 adults with β-thalassemia major. Patients were tested with 1 µg ACTH for serum and salivary cortisol. Results Subnormal serum cortisol responses to ACTH stimulation (i.e.

The reported cumulative prevalence of hyponatremia (sodium135 mmol/L) in bronchiolitis is 28%. However, sodium level was never measured by direct potentiometry, the method recommended by the International Federation of Clinical Chemistry and Laboratory Medicine. Aim of this study was to assess the prevalence of hyponatremia, measured by direct potentiometry, in infants with moderate-severe bronchiolitis.A prospective cross-sectional study was conducted in infants ≥1month and ≤24months of age with bronchiolitis.160 consecutive infants were enrolled. Hyponatremia was observed in 91 (57%) patients and occurred more commonly in infants ≤6 months than in older infant (P 0.005).The first study on sodium level measured by the direct potentiometry in infants with bronchiolitis points out that the prevalence of hyponatremia is two-fold higher than so far reported.

Background Many biological and inflammatory markers have been proposed as having a prognostic value at diagnosis of Hodgkin lymphoma (HL), but very few have been validated in paediatric patients. We explored the significance of these markers in a large population of 769 affected children. Patients and methods By using the database of patients enrolled in A.I.E.O.P. (Associazione Italiana di Emato-Oncologia Pediatrica) trial LH2004 for paediatric HL, we identified 769 consecutive patients treated with curative intent from 1st June 2004 to 1st April 2014 with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), or hybrid COPP/ABV (cyclophosphamide, vincristine, prednisone, procarbazine, doxorubicin, bleomycin and vinblastine) regimens. Results On multivariate analysis with categorical forms, the 5-year freedom from progression survival was significantly lower in patients with stage IV or elevated value of platelets, eosinophils and ferritin at diagnosis. Furthermore, stage IV and eosinophils seem to maintain their predictive value independently of interim (after IV cycles of chemotherapy) positron emission tomography. Conclusion Using the combination of four simple markers such as stage IV and elevated levels of platelets, ferritin and eosinophils, it is possible to classify the patients into subgroups with very different outcomes.

Summary Background and objective GH and IGF-I exert an important role in the control of bone formation, as shown by decreased bone mineral density and increased fracture risk in adult hypopituitary patients untreated for GH deficiency (GHD). Different degrees of bone demineralization are frequently reported in patients affected by β-thalassaemia. Considering the high prevalence of GHD recently observed by our group among adult thalassaemic patients, we elected to study the possible role of GH–IGF-I abnormalities in the pathogenesis of the osteopenia/osteoporosis of this disease. Design Sixty-four adult thalassaemic patients (49 with thalassaemia major and 15 with thalassaemia intermedia, 23 men and 41 women, aged 31·4 ± 6·8 years) were studied. Methods Bone mineral density was assessed by dual energy X-ray absorptiometry at lumbar spine in 62 patients and at proximal femur in 58. All patients underwent GHRH (1 µg/kg as an i.v. bolus) plus arginine (0·5 g/kg as a 30-min i.v. infusion) testing. Severe GHD was defined by GH peaks

Previous evidence supports a role for growth hormone (GH)-insulin-like growth factor (IGF)-I deficiency in the pathophysiology of osteopenia/osteoporosis in adult thalassemia. Moreover, serum IGF-II has never been studied in this clinical condition. Thus, we elected to study the GH secretory status and the levels of circulating somatomedins, correlating these parameters with bone mineral density (BMD) and biochemical markers of bone turnover. A hundred and thirty-nine normal weight adult thalassemic patients (72 men and 67 women) were studied. Lumbar and femoral neck BMD were measured in 106/139 patients. Sixty-eight patients underwent growth hormone releasing hormone plus arginine testing. Measurement of baseline IGF-I and IGF-II was performed in all patients, while osteocalcin, C-terminal telopeptide of type I collagen (CTx), and urinary cross-linked N-telopeptides of type I collagen (NTx) were assayed in 95 of them. Femoral and lumbar osteoporosis/Z score below the expected range for age were documented in 61.3 and in 56.6 % of patients, respectively. Severe GH deficiency (GHD) was demonstrated in 27.9 % of cases, whereas IGF-I SDS was low in 86.3 %. No thalassemic patients displayed circulating levels of IGF-II below the reference range. GH peaks were positively correlated with femoral, but not lumbar, Z score. No correlations were found between GH peaks and osteocalcin, CTx and NTx. GH peaks were positively correlated with IGF-I values, which in their turn displayed a positive correlation with osteocalcin, CTx, and NTx. No correlations emerged between IGF-I values and either femoral or lumbar Z scores. No correlations were found between IGF-II and any of the following parameters: GH peaks, osteocalcin, CTx, NTx, femoral Z score, and lumbar Z score. Our study, besides providing for the first time evidence of a normal IGF-II production in thalassemia, contributes to a better understanding of the involvement of the somatotropin-somatomedin axis in the pathophysiology of bone demineralization in this disease. In particular, the contribution of GHD to femoral osteoporosis appears to be likely mediated by locally produced rather than circulating IGF-I.

Deferiprone (DFO) at the standard daily dose of 75 mg/kg was given to 13 transfusion-dependent patients with thalassemia in whom conventional desferrioxamine (DFX) therapy had proven ineffective and caused adverse side effects. In six patients, serum ferritin and alanine aminotransferase levels decreased significantly and urinary iron excretion increased. In seven patients in whom DFO administration alone was ineffectual, DFX was added at a daily dose of 40 to 50 mg/kg given subcutaneously for 7 to 10 days following transfusion. All patients exhibited a significant decrease in serum ferritin levels and an increase in urinary iron excretion, with alanine aminotransferase levels decreased in four patients. The combined DFX and DFO therapy could represent an effective alternative to conventional DFX therapy not only in nonresponding patients with thalassemia but also, by lowering to less than 25% the DFX dosage, in patients who exhibit important DFX-related side effects.

In order to evaluate the immunogenicity, safety, and tolerability of monovalent 2009 pandemic influenza A/H1N1 MF59-adjuvanted vaccine in patients with β-thalassemia major, 31 subjects (19 males; mean age 17.8 ± 8.7 years) with β-thalassemia major and 28 age- and gender-matched healthy controls were enrolled. Four weeks after vaccination, seroconversion rates were about 80% and seroprotection rates 100% in both groups. Three months after vaccination, most of the subjects remained seroconverted and the seroprotection rates were 93.5% among the patients and 100% among the controls. Safety and tolerability were also very good, with no differences between the groups.

ObjectiveWe previously described in young thalassaemic patients an altered cortisol and ACTH responsiveness suggesting an impaired adrenocortical reserve. Owing to iron overload, a worsening of adrenal function should be expected in adult patients.DesignIn 124 adults with β-thalassaemia, urinary free cortisol (UFC) and plasma ACTH levels were determined and compared with those measured in 150 controls. In 45 patients, cortisol was measured in response to: i) tetracosactide 1 μg as an i.v. bolus (low-dose test, LDT) and ii) tetracosactide 250 μg infused i.v. over 8 h (high-dose test, HDT).ResultsUFC and serum cortisol were within the reference range in all patients. Conversely, basal plasma ACTH values were above the upper limit of the normal range in 19 patients. There were no statistically significant differences in the mean values of UFC, basal serum cortisol and plasma ACTH between patients and controls. A subnormal cortisol response to the LDT was registered in 18 out of 56 patients. Three of these patients also displayed a subnormal response to the HDT, together with elevated baseline plasma ACTH levels. In the LDT, a positive correlation was found between basal and peak cortisol values (PPPConclusionsAdult thalassaemic patients often present a subtle impairment of adrenocortical function. This may become clinically relevant in case of major stressful events. Thus, we recommend an assessment of adrenocortical function in all adult thalassaemic patients.

Summary Background and objective Short stature and growth hormone deficiency (GHD) are frequent occurrences in thalassaemic children, while data on the prevalence of GHD in adult patients are lacking. Therefore, we elected to study the growth hormone and insulin-like growth factor-I (GH–IGF-I) axis in a large group of adult thalassaemic subjects. Design Cross-sectional study on the prevalence of GHD in 94 adult thalassaemic patients (69 with thalassaemia major and 25 with thalassaemia intermedia, 39 men and 55 women, aged 31·5 ± 6·8 years, on sex steroid replacement when necessary). Methods All patients underwent GHRH (1 µg/kg as an i.v. bolus) plus arginine (0·5 g/kg as a 30 min i.v. infusion) testing. Severe GHD was defined by GH peaks lower than 9 µg/l, whereas partial GHD was defined by GH peaks ranging from 9–16·5 µg/l. Blood samples for IGF-I, ferritin and pseudocholinesterase measurements were collected. Urinary free cortisol (UFC) levels were also assayed. Results Severe GHD was demonstrated in 21 of the 94 patients (22·3%), while 18 additional patients (19·1%) displayed partial GHD. GH peaks were positively correlated with IGF-I standard deviation score (SDS) (r = 0·22, P

The Gardos channel (KCNN4) is a Ca2+ sensitive, intermediate conductance, K+ selective channel abundant in several tissues including red blood cells (RBC) where it is involved in cell volume regulation (Hoffman et al. 2003, Cahalan et al. 2015). Hereditary dehydrate stomatocytosis (DHSt) is characterized by mild to moderate congenital hemolytic anemia with reticulocytosis and splenomegaly associated with RBC dehydration. Affected RBC are characterized by a nonspecific cation leak, reflected in elevated Na+ content, decreased K+, elevated MCHC and MCV, and decreased osmotic fragility. The definitive diagnosis of DHSt is made by osmotic gradient ektacytometry, which shows a leftward shift of the bell-shaped curve. Heterozygous mutations associated with delayed channel inactivation have been identified for PIEZO1 (Zarychanski et al. 2012), although there are patients lacking a mutation in this gene. Differential diagnosis in hereditary stomatocytosis is important because in DHSt patients, splenectomy is contraindicated due to increased risk of thromboembolic complications. We studied a 40 year-old Italian man, affected since infancy by chronic hemolyitc anemia (Hb 7-9 g/dL, reticulocytes 10%). The unrelated parents and three siblings were healthy with normal hematologic parameters. He was occasionally transfused until splenectomy, performed at the age of 11 years. After splenectomy Hb levels maintained around 10 g/dL, thrombotic events did not occur. Increased ferritin levels (>1000 ng/ml) and moderate iron overload required chelation therapy. Peripheral blood smear showed anysopoikilocytosis with stomatocytes (13%) echinocytes (7%) schistocytes (6%) ellyptocytes (5%) spherocytes (4%). Bone marrow evaluation revealed erythroid hyperplasia with some dyserytrhopoietc changes, in particular binucleated erythroblasts. Eosin 5 maleimide (EMA) binding test was negative; despite the high number of stomatocytes in peripheral blood, the osmotic gradient ektacytometry curve was not suggestive for hereditary xerocytosis. The proband's first daughter, born at term after an uneventful pregnancy, presented with severe anemia (Hb 6.1 g/dL) requiring RBC transfusion at birth and at 4 months; at the age of 1 year she displayed a clinical pattern similar to the one of the father, with median Hb levels of 9 g/dL and no need of transfusions. To uncover the underlying etiologies, all the family members underwent whole exome sequencing. Only one candidate gene, the KCNN4 could be identified: a heterozygous missense mutation (c.1055G>A, p.R352H) was detected as a de novo mutation in the proband, and dominantly transmitted to the daughter. The mutation falling in exon 7 involved in the calmodulin binding domain was predicted to be pathogenic by in silico analysis. Sanger sequencing confirmed the presence of the mutation. Very recently (July 2015), the same mutation in the KCNN4 gene was described by other groups (Rapetti-Mauss et al. 2015; Andolfo et al. 2015). In heterologous expression systems it could be shown that the Ca2+ sensitivity of the mutated Gardos channel was increased. We performed single cell experiments, including patch-clamp recordings in RBCs and precursor cells, Ca2+ fluorescence imaging as well as tracer flux experiments in RBCs of the above described patients and healthy controls to get a mechanistic link between the Gardos channel mutation and the cellular symptoms. Despite the presence of a single mutation in Gardos channel alone, pathological alterations in function of multiple ion transport systems were revealed during these studies. Our findings together with recent reports (Rapetti-Mauss et al. 2015; Andolfo et al. 2015; Glogowska et al. 2015) suggest that the prevalence of mutations in the Gardos channel is higher than previously thought. Therefore it is important to understand the mechanisms implicated by the mutation and to develop reliable diagnostic tools and treatment strategies. Disclosures No relevant conflicts of interest to declare.