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The Corfu δ0β+ thalassemic allele is a unique thalassemic allele consisting of the simultaneous presence in cis of a deletion of the δ-globin (Hemoglobin Subunit Delta, HBD) and a single nucleotide variant in the β-globin gene (Hemoglobin Subunit Beta, HBB). The allele has, so far, been described in individuals of Greek origin. The objectives of the study are to ascertain the prevalence of the Corfu δ0β+ allele in comparison to other β-thalassemia variants encountered in Greece using our in-house data repository of 2558 β-thalassemia heterozygotes, and to evaluate the hematological phenotype of Corfu δ0β+ heterozygotes in comparison to heterozygotes with the most common β+-and deletion α0-thalassemia variants in Greece. The results of the study showed a relative incidence of heterozygotes with Corfu δ0β+ at 1.56% of all β-thalassemic alleles, and a distinct hematological phenotype of the heterozygotes characterized by microcytic, hypochromic anemia with normal levels of HbA2 (Hemoglobin A2) and elevated HbF (Hemoglobin F) levels. The application of a specific methodology for the identification of the Corfu δ0β+ allele is important for precise prenatal and antenatal diagnosis programs in Greece. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Objective: The management of prediabetes and hyperglycemia is an increasingly important aspect of care in patients with thalassemia. In light of the limited evidence about the management of GD (glucose dysregulation) with glucose-lowering agents (GLAs), we have conducted a retrospective survey in TDT and NTDT patients with diabetes mellitus to collect more detailed information on GLA use in order to make preliminary recommendations. Study design and method: A questionnaire was prepared and distributed to the tertiary thalassemia care Centers of ICET-A Network. Results: Eight thalassemia care Centers [Bulgaria, Greece, Iran, Italy (4 Centers) and Qatar], following 1.554 with transfusion-dependent thalassemia (TDT), 132 (8.4%) with diabetes and 687 with non-transfusion-dependent thalassemia (NTDT), 27 (3.9%) with diabetes, participated in the retrospective survey. The records of 117 TDT patients and 9 NTDT patients with diabetes treated with GLAs were analyzed. Metformin, a biguanide, was the most frequently used drug (47.6 %), followed by alpha-glucosidase inhibitors (5.5 %), incretins (4.7%) and insulin secretagogues (3.1%). In 68 (61.2) patients GLAs was prescribed as monotherapy, while the remaining 49 (38.8%), who had inadequate glucose control with metformin, were treated with combination treatment. Fifty-one patients of 126 (40.4%) initially treated with oral GLA, for a mean duration of 61.0 ± 35.6 months (range: 12-120 months), required insulin therapy for better metabolic control. Conclusion: This retrospective study covers an unexplored area of research in patients with thalassemia and GD. Oral GLAs appear to be safe and effective for the treatment of diabetes mellitus in patients with thalassemia, and can achieve adequate glycemic control for a substantial period of time. (www.actabiomedica.it). © 2022, Mattioli 1885. All rights reserved.

Objective: To study the endocrine pancreas' function in transfusion-dependent β-thalassemia (β-TDT) patients with a normal glucose tolerance test (NGT) and hypoinsulinemia. In addition, the prospective long-term follow-up using an annual oral glucose tolerance test (OGTT) to detect any abnormality of glucose metabolism. Patients and methods: Seven β-TDT patients (mean age 22.4 ± 4.2 years) with NGT and inadequate insulin response (hypoinsulinemia) to OGTT were referred for a second opinion to an Italian Centre. Results: The first-phase insulin response (FPIR), expressed as the sum of 1 and 3 minutes insulin, to intravenous glucose tolerance test (IVGTT), was between the 1st and 3rd percentile in two patients and between the 3rd and 10th percentile in five. The results were not associated with β-cell autoimmunity. After 43 ± 26 months (range 11 - 80 months) of follow-up, two patients developed impaired glucose tolerance (IGT), three both IGT and impaired fasting glucose (IFG) and two overt diabetes mellitus (DM). Interestingly, the patients who developed DM had, at baseline, the lowest value of the insulinogenic index (IGI: 0.08 and 0.25), defined as the ratio of the increment of plasma insulin to plasma glucose during the first 30 minutes after OGTT. Moreover, a significant correlation was found between the IGI at baseline and at follow-up in the patients who developed IGT with or without IFG (R= 0.927; P: 0.023). A significant reduction of Matsuda insulin sensitivity index (ISIM) and Insulin Secretion-Sensitivity Index-2 (ISSI-2) was documented in the study cohort at the diagnosis of IFG, IGT, and DM. There was a significant inverse correlation between ISSI-2 and area under the curve plasma glucose (AUC-PG). Conclusions: These data demonstrated, for the first time, progressive deterioration in glucose homeostasis in β-TDT subjects with NGT and hypoinsulinemia and that the ISSI-2 index may be a valuable parameter to identify patients at high risk for developing glucose dysregulation. © 2021 Universita Cattolica del Sacro Cuore. All rights reserved.

Background: Patients with transfusion dependent β-thalassemia (TDT) are at high risk for developing, over the time, a form of diabetes distinct from type 1 and type 2 diabetes, but with similarities to both. Aims of study: The aim of this study is to describe the clinical and laboratory data, and the insulin secretion and sensitivity, in TDT patients recently diagnosed with diabetes mellitus (DM). Materials and Methods: The medical records of 25 TDT patients with DM, diagnosed by standardized oral glucose tolerance test (OGTT) and insulin secretion, were analysed; data were compared to TDT patients without diabetes and to a group of healthy subjects. Natural history of glucometabolic status before the diagnosis of DM was also reviewed. Results: On average, the TDT patients with DM were younger compared to TDT patients without diabetes. The mean age at diagnosis of DM in female and male TDT patients was 24.0 ± 7.1 years and 31.9 ± 5.6 years, respectively (P: 0.007). Serum alanine aminotransferase values, basal insulin levels and prevalence of hypogonadism were consistently higher in TDT patients with DM compared to those without diabetes. Decreased insulin secretion and increased insulin resistance was observed in patients with DM. Conclusion: The natural history of glucometabolic status in TDT patients is characterized by a deterioration of glucose tolerance over time. Iron overload and liver dysfuction are the main factors responsible for glucose disturbances (GD) in TDT patients. The therapeutic approach must be individualized and followed by a multidisciplinary team. (www.actabiomedica.it). © Mattioli 1885.

Objective: Subjects with normal glucose tolerance (NGT) but 1-hour post-load plasma glucose (1-h OGTT) ≥ 155 mg/dl (8.6 mmol/L; H-NGT) have an increased risk for developing Type 2 diabetes mellitus (T2DM), determining a new risk factor category with deeper metabolic impairment. The aim of this study was to evaluate the H-NGT as a diagnostic predictor of future dysglycemia in β-transfusion dependent thalassemia (β-TDT). Indices of insulin secretion and insulin sensitivity derived at baseline from OGTTs, were also reviewed. Study design and methods: OGTT and indices of insulin secretion and insulin sensitivity, derived at baseline during OGTT, in 17 β-TDT with H-NGT and 29 β-TDT with normal OGTT (NGT) and without H-NGT followed for 12 years were studied. Results: H-NGT was associated with decreased insulin sensitivity and progressive deterioration of glucose tolerance. At baseline, serum ferritin and serum alanine aminotransferase (ALT) levels were higher in patients with H-NGT compared to patients with NGT. A strong correlation was observed between ALT and 1-hour plasma glucose value during OGTT in the total group of 36 patients . Compliance to iron chelation therapy was poor in β-TDT patients with H-NGT. An inverse correlation was found between 1-hour plasma glucose value during OGTT and insulin secretion-sen-sitivity index-2 (ISSI-2) (r:-0.3298; p: 0.025), between ISSI-2 and ALT (r:-0.3262; p: 0.027), and between 1-hour plasma glucose value and ISSI-2 (r:-0.537; p: 0.005) in the whole group of β-TDT patients enrolled in our study. Conclusions: It is of paramount importance to screen early β-TDT patients at increased risk for glucose dysregulation. This retrospective study displayed that finding an isolated high 1-hour post-load glucose level (≥155 mg/dL; H-NGT) during the OGTT may serve as a simple biomarker to detect high-risk patients, with chronic liver disease and/or iron overload, who need periodic glycemic surveillance. Measuring the ISSI 2 represented another valuable predictive marker in the assessment of glycemia in these patients. © Mattioli 1885.

Background and aim: Dysregulation of glucose metabolism is a common complication of transfusions in Transfusion Dependent Thalassemia (TDT) patients. For early diagnosis of glucose disturbances, screening is recommended. The age of starting and the type of screening vary; the more common methods are assessment of RPG, FPG, 2h PG and 2 hours OGTT. The combined assessment of glucose tolerance and insulin response during OGTT is rarely recommended. The main objective of the study is the evaluation of simultaneous assessment of Glucose Tolerance (GT) and Insulin Response (IR) during OGTT in patients with TDT. Methods: 43 TDT patients aged 12-28years, without clinical evidence of glucose disturbances, were randomly selected for the study. The 2-hour OGTT in 30 minutes intervals was applied. Plasma glucose and insulin were assessed in all samples using routine laboratory methods. Results: Of 43 patients 31(72%) had Normal GT; of them 9 (29%) had normal insulin response (NIR), 14 (45%) high IR and 8(26%) delayed peak IR. Delayed peak IR was found in 8 of the 9 patients with Impaired GT and in 2 of the 3 with diabetic GT. Deficient IR (hypoinsulinemia) was found in two patients. Conclusions: Simultaneous assessment of GT and IR during OGTT in TDT patients, seems to be a most sensitive and creditable screening test for early diagnosis of glucose disturbances. High IR and delayed peak IR in normoglycemic patients are valuable indices for diagnosis of the pre-diabetic state that precede the development of glucose disturbances in TDT patients and start proper follow and management. (www.actabiomedica.it). © Mattioli 1885.

Background: Data on the prevalence and type of endocrine disorders in β-thalassemia intermedia (β-TI) patients are scarce. This multicenter study was designed to determine the prevalence of endocrine complications and the associated risk factors in a large group of β-TI patients. Methods: In this cross-sectional multicenter study, 726 β-TI patients, aged 2.5–80 years, registered at 12 thalassemic centers, from nine countries, were enrolled during 2017. In a subgroup of 522 patients (mean age 30.8 ± 12.1; range: 2.5–80 years) from Qatar, Iran, Oman, Cyprus, and Jordan detailed data were available. Results: Overall, the most prevalent complications were osteopenia/osteoporosis (22.3%), hypogonadism (10.1%), and primary hypothyroidism (5.3%). In the subgroup multivariate analysis, older age was a risk factor for osteoporosis (Odds ratio: 7.870, 95% CI: 4.729–13.099, P < 0.001), hypogonadism (Odds ratio: 6.310, 95% CI: 2.944–13.521, P < 0.001), and non-insulin-dependent diabetes mellitus (NIDDM; Odds ratio: 17.67, 95% CI: 2.217–140.968, P = 0.007). Splenectomy was a risk factor for osteoporosis (Odds ratio: 1.736, 95% CI: 1.012–2.977, P = 0.045). Hydroxyurea was identified as a “protective factor” for NIDDM (Odds ratio: 0.259, 95% CI: 0.074–0.902, P = 0.034). Conclusions: To the best of our knowledge, this is the largest cohort of β-TI patients with endocrine disorders evaluated in extremely heterogenic thalassemic populations for age, clinical, hematological, and molecular composition. The study demonstrates that endocrine complications are less common in patients with β-TI compared with β-TM patients. However, regular monitoring with timely diagnosis and proper management is crucial to prevent endocrine complications in β-TI patients. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

A review of the literature on COVID-19 pandemic in patients with thalassemias is presented. Globally, the prevalence of COVID-19 among β-thalassemia patients seems to be lower than in general population; associated co-morbidities aggravated the severity of COVID-19, leading to a poorer prognosis, irrespective of age. A multicenter registry will enhance the understanding of COVID-19 in these patients and will lead to more evidence-based management recommendations. (www.actabiomedica.it). © 2020, Mattioli 1885. All rights reserved.

At present, assessment of haemoglobin A1c (HbA1c) is widely used for the diagnosis and monitoring of treatment in diabetes mellitus (DM). However, the HbA1c level is affected by many factors such as those influencing the lifespan of red blood cells and the structure, function and amount of normal HbA. Therefore, the clinical significance of HbA1c assessment in thalassemia patients needs careful consideration, especially in transfusion dependent thalassemia patients (TDT) in whom circulating Hb is that of blood donors. Preliminary reports have documented that HbA1c estimation in efficiently transfused patients seems valuable in diagnosis and monitoring of treatment in DM and other glucose disturbances in TDT patients. Herein, a short review of HbA1c measurement in anemias, blood transfusions and hemoglobinopathies, and the debate of the credibility of Hb A1c assessment in TDT patients is reported. Copyright© of YS Medical Media ltd.

Summary. The current outbreak of infections with SARS-CoV-2 is defined as Coronavirus Disease 2019 (COVID-19). The clinical symptoms of COVID-19 include fever, fatigue, cough, breathing difficulty that may lead to respiratory distress; a small population of patients may have diarrhea, nausea or vomiting. The highest infection rate occurs in adults; however, neonates, children, and adolescents can also be infected. As the outbreak continues to spread worldwide, attention has switched toward determinants of clinical manifestations and disease severity. The situation surrounding the outbreak is rapidly evolving and the information and recommendations are changing as new information becomes available. This paper summarises the current findings (April 3,2020) from a systematic literature review on the current knowledge of COVID-19 in adolescents (10-19 years according to the WHO definition) and reports the preliminary epidemiological data stated by the Italian National Institute of Health. (www.actabiomedica.it). © Mattioli 1885.

Self-medication (SM) is an important worldwide public health issue affecting children and adolescents. The pattern of SM varies in different communities, affected by factors such as age, sex, income, expense, self-care orientation, educational level and medical knowledge. It is a fairly common practice: for minor health problems, it often provides cheap, rapid, and convenient solutions, outside of the health care system of many countries. Painkillers, antipyretics, cough medicines, cold preparations, dermatological products, nutritional supplements and antibiotics are the drugs most frequently used. Potential risks include incorrect self-diagnosis, improper dosage, inappropriate choice of therapy, masking of severe disease and drug interactions. Lack of awareness of warnings and precautions, storage conditions, the recommended shelf-life and adverse reactions increase the risk of side effects. Little is known about the SM of dysmenorrhea by adolescent girls. Attitudes towards treatment are influenced by cultural, ethnic, and religious factors. Some girls discuss dysmenorrhea with family and friends, and the majority may not seek medical advice. As dysmenorrhea is a common problem for adolescents, it is essential that these girls be aware of the normal and abnormal symptoms of menstruation. In the light of these findings, the roles of family, school, health professionals and health authorities are of utmost importance for the implementation of measures to approach this health problem in a more efficient way. (www.actabiomedica.it). © Mattioli 1885.

Background: More than five decades ago, thalassemia major (TDT) was fatal in the first decade of life. Survival and quality of life have improved progressively thanks to the implementation of a significant advance in diagnostic and therapeutic methods, consisting mainly of a frequent transfusion program combined with intensive chelation therapy. Improvement also includes imaging methods used to measure liver and cardiac iron overload. Improved survival has led to a growing number of adults requiring specialised care and counselling for specific life events, such as sexual maturity and acquisition of a family. Aims of the study: The main aim is to present the results of a survey on the marital and paternity status in a large population of adult males with TDT and NTDT living in countries with a high prevalence of thalassemia and a review of current literature using a systematic search for published studies. Results: Ten out of 16 Thalassemia Centres (62.5%) of the ICET-A Network, treating a total of 966 male patients, aged above 18 years with β- thalassemias (738 TDT and 228 NTDT), participated in the study. Of the 966 patients, 240 (24.8%) were married or lived with partners, and 726 (75.2%) unmarried. The mean age at marriage was 29.7 ± 0.3 years. Of 240 patients, 184 (76.6%) had children within the first two years of marriage (2.1 ± 0.1 years, median 2 years, range 1.8 - 2.3 years). The average number of children was 1.32 ± 0.06 (1.27 ± 0.07 in TDT patients and 1.47 ± 0.15 in NTDT patients; p: >0.05). Whatever the modality of conception, 184 patients (76.6%) had one or two children and 1 NTDT patient had 6 children. Nine (4.8%) births were twins. Of 184 patients, 150 (81.5%) had natural conception, 23 (12.5%) required induction of spermatogenesis with gonadotropins (hCG and hMG), 8 (4.3%) needed intracytoplasmic sperm injection (ICSI) and 3 adopted a child. 39 patients with TDT and NTDT asked for medical help as they were unable to father naturally: 7 TDT patients (17.9%) were azoospermic, 17 (37.7%) [13 with TDT and 4 with NTDT] had dysspermia and 15 (33.3%) [13 with TDT and 2 with NTDT] had other “general medical and non-medical conditions”. Conclusions: Our study provides detailed information in a novel area where there are few contemporary data. Understanding the aspects of male reproductive health is important for physicians involved in the care of men with thalassemias to convey the message that prospects for fatherhood are potentially good due to progressive improvements in treatment regimens and supportive care. © 2019, Mattioli 1885. All rights reserved.

Background: Transfusion-dependent β-thalassemia (TDT) is associated with several complications necessitating a multidisciplinary approach for diagnosis, treatment and follow-up. Hypogonadism in female TDT patients is one of the most common endocrine complications, requiring hormone replacement therapy (HRT) throughout reproductive life. Little is known about the balance of benefits versus risks of treatment with sex steroids. Aim: The aim of this manuscript is to review the action and the associated adverse effects of HRT in hypogonadal TDT females. Design: Retrospective medical database records from a single centre, over a period of 38 years (January 1980 to June 2018), were reviewed. Study population: Forty-two cases of hypogonadism in TDT females followed in a pediatric and adolescent outpatient clinics, were in included in the study. Methods: Auxological, clinical, laboratory, hormonal and imaging investigations were reviewed, as well as all adverse events registered during HRT. Main results: In general, HRT was safe for most patients. There were few minor side effects and a couple of rare but serious adverse events. Conclusions: The study provides a representative clinical profile of long-term effects of HRT in hypogonadal adolescents and young adult TDT women. Our results highlight also the need for further research in other areas for which HRT may have a role. We hope this will contribute to a wider understanding, and potential improvement, of patient safety and quality of life. (www.actabiomedica.it). © Mattioli 1885.

Changes in thyroid function and thyroid function tests occur in patients with β-thalassemia major (TM). The frequency of hypothyroidism in TM patients ranges from 4% to 29 % in different reports. The wide variation has been attributed to several factors such as patients' genotype, age, ethnic heterogeneity, treatment protocols of transfusions and chelation, and varying compliance to treatment. Hypothyroidism is the result of primary gland failure or insufficient thyroid gland stimulation by the hypothalamus or pituitary gland. The main laboratory parameters of thyroid function are the assessments of serum thyroid-stimulating hormone (TSH) and serum free thyroxine (FT4). It is of primary importance to interpret these measurements within the context of the laboratory-specific normative range for each test. An elevated serum TSH level with a standard range of serum FT4 level is consistent with subclinical hypothyroidism. A low serum FT4 level with a low, or inappropriately normal, serum TSH level is consistent with secondary hypothyroidism. Doctors caring for TM patients most commonly encounter subjects with subclinical primary hypothyroidism in the second decade of life. Several aspects remain to be elucidated as the frequency of thyroid cancer and the possible existence of a relationship between thyroid dysfunction, on one hand, cardiovascular diseases, components of metabolic syndrome (insulin resistance) and hypercoagulable state, on the other hand. Further studies are needed to explain these emerging issues. Following a brief description of thyroid hormone regulation, production and actions, this article is conceptually divided into two parts; the first reports the spectrum of thyroid disease occurring in patients with TM, and the second part focuses on the emerging issues and the open problems in TM patients with thyroid disorders. © 2019 Universita Cattolica del Sacro Cuore. All rights reserved.

In the last five decades an increasing number of studies and clinical reports demonstrated the importance of testicular volume assessment in pediatric and adolescent population. Reliable and accurate determination of testicular volume (TV) through infancy and adolescence is of great importance for assessing normal pubertal development to diagnose disturbances in development and to suspect certain genetic and endocrine diseases. Various approaches are available for the assessment of TV, including orchidometry, rulers, callipers, and ultrasonography (USG). Our report focuses on the importance of the evolution of TV from birth to adulthood and debates the main factors influencing the accuracy of different TV measurements. We endorse that any method for the evaluation of TV must satisfy certain criteria: a. be applicable to persons of all ages from pre-adolescence, through the pubertal spurt to full maturity, b. be simple to use, c. be free from observer error as possible, and d. have a high degree of correlation with other observable developmental characteristics. Copyright© of YS Medical Media ltd.

Summary. Juvenile fibromyalgia syndrome (JFMS) is a chronic condition characterized by symptoms of chronic diffuse musculoskeletal pain and multiple painful tender points on palpation. It is often accompanied by fatigue, disorders of sleep, chronic headaches, irritable bowel syndrome, and subjective soft tissue swelling. The complexity of the presenting clinical picture in JPFS has not been sufficiently defined in the literature. Similarities to adult fibromyalgia syndrome in JFMS are often difficult to compare, because many of the symptoms are “medically unexplained” and often overlap frequently with other medical conditions. However, a valid diagnosis of JFMS often decreases parents’ anxiety, reduces unnecessary further investigations, and provides a rational framework for a management plan. The diagnostic criteria proposed by Yunus and Masi in 1985 to define JFMS were never validated or critically analyzed. In most cases, the clinical diagnosis is based on the history, the physical examination that demonstrates general tenderness (muscle, joints, tendons), the absence of other pathological conditions that could explain pain and fatigue, and the normal basic laboratory tests. Research and clinical observations defined that JFMS may have a chronic course that impacts the functional status and the psychosocial development of children and adolescents. This paper briefly reviews the existing knowledge on JFMS focusing on the diagnosis, clinical and the epidemiological characteristics in children and adolescents for better understanding of this disorder. (www.actabiomedica.it). © Mattioli 1885.

The diagnosis of hypoparathyroidism(HPT)is readily made in the presence of hypocalcemia with markedly reduced or absent parathormone (PTH) levels. Currently available treatments for HPT include high dose vitamin D (ergocalciferol, D2 and cholecalciferol, D3) or, the active metabolite dihydroxy vitamin D (calcitriol), in addition to calcium supplements.This regimen, if not well monitored, can lead to hypercalciuria, as PTH deficiency impairs renal calcium reabsorption. Thus the goal of treatment, is to maintain serum calcium at the low end of the normal range. Undertreatment can cause symptomatic hypocalcemia, while overtreatment hypercalciuria, which may lead to nephrolithiasis, nephrocalcinosis, and renal insufficiency. At present, there is no consensus on the management of HPT in children and adolescents and only few studies are available on the long term outcome of patients with recombinant HPT treatment. The purpose of this article is to review, in a comprehensive manner, the major aspects of HPT management in children and adolescents waiting for authoritative guidelines for the treatment of HPT in this group of patients. Further research, addressing specific questions for this population are urgently needed to improve long-term safety of patients. Educational interventions are also needed for professionals, parents and patients to enable them to improve knowledge, quality of life and effective management care at home. (www.actabiomedica.it). © Mattioli 1885.

Bone disorders in patients with thalassemia major (TM) and intermedia (TI) constitute complex conditions that result from various factors affecting the growing skeleton. Although much progress has been made in our understanding of the natural history, pathogenesis and clinical manifestations of β- and δβ-thalassemia, bone manifestations remain a puzzle for the clinician. In this review, we outline the key points in the current literature on the pathogenesis and management of bone disease in patients with TM and TI who were conventionally treated in recent decades with frequent blood transfusions and iron chelation. Prevention, early recognition and treatment are the most effective strategies for the management of bone disease in these patients. However, further studies are required to maintain optimal bone health for both TM and TI patients. Studying bone disease in patients with non-transfusion dependent TI, which seems to worsen considerably with age, is important to delineate the effect of the disease itself on bone health without the intervening factors of transfusions, iron intoxication and chelation. © 2017 Elsevier Inc.

Management of hypoparathyroidism (hypoPT), depends on the etiology and the severity of hypocalcemia. Treatment goals include control of hypocalcemic symptoms preserving serum calcium in the low-normal range and phosphate in the high normal range. While correction of serum calcium to low-normal range does not fully correct mineral and bone metabolism it may be associated with increased risk of complications such as nephrolithiasis, nephrocalcinosis and soft tissue calcifications. Therefore, it is imperative to find out ways to individualize treatment of patients with hypoPT to achieve the best prognosis while minimizing complications. Replacement therapy with recombinant human PTH (rhPTH) was recently tested for optimizing treatment of hypoPT in a small number of patients. For children and adolescents, further studies are needed to evaluate the long-term effects and safety of rhPTH. In this short review we summarize current knowledge on the management of hypoPT and debate our gaps on the long-term management of children and adolescents with hypoPT. Copyright© of YS Medical Media ltd.

In adult thalassemia major (TM) patients, a number of occult and emerging endocrine complications, such as: central hypothyroidism (CH), thyroid cancer, latent hypocortisolism, and growth hormone deficiency (GHD) have emerged and been reported. As the early detection of these complications is essential for appropriate treatment and follow-up, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) promoted a survey on these complications in adult TM patients, among physicians (pediatricians, hematologists and endocrinologists) caring for TM patients in different countries. The data reported by 15 countries are presented.The commonest endocrine complications registered in 3.114 TM adults are CH and GHD (4.6 % and 3.0 %, respectively), followed by latent hypocortisolism (1.2%). In 13 patients (0.41%) a cytological papillary or follicular thyroid carcinoma was diagnosed in 11 and 2 patients, respectively, and a lobectomy or thyroidectomy was carried out. Of 202 TM patients below the age of 18 years, the reported endocrine complications were: GHD in 4.5%, latent hypocortisolism in 4.4% and central hypothyrodisim in 0.5%. Transition phase was an area of interest for many clinicians, especially as patients with complex chronic health conditions are responding to new treatments extending their lifespan beyond imagination.. In conclusion, our survey provides a better understanding of physicians’ current clinical practices and beliefs in the detection, prevention and treatment of some endocrine complications prevailing in adult TM patients. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are recommended. (www.actabiomedica.it). © Mattioli 1885.

Summary. Significant advances have been made over recent decades in the treatment of childhood malignancies. These advances had an incredible cost, as an increasing number of young survivors suffer subfertility or infertility, because of the high sensitivity of testicular cells, especially the rapidly dividing germ cells, to cyto-toxic drugs and irradiation. Therefore, the impact of treatment on future fertility is of significant concern, both to parents and patients. Assessment of fertility damage in childhood remains problematic. For post-pubertal males, semen analysis represents a good indicator of spermatogenesis and testicular function, and allows for sperm cryopreservation. The available method for prepubertal children is only gonadal tissue cryopreservation. This method is still experimental and raises ethical concerns. Ideally, a multidisciplinary team approach needs to be used in addressing the needs of fertility preservation for this population. Precise knowledge of these issues would help pediatric oncologists and endocrinologists to counsel their patients and inform them for factors and resources that may protect or preserve parenthood options in the future. (www.actabiomedica.it). © Mattioli 1885.

Background: Haemoglobinopathies constitute the commonest recessive monogenic disorders worldwide, and the treatment of affected individuals presents a substantial global disease burden. β -thalassaemia is characterised by the reduced synthesis (β+) or absence (βo) of the β-globin chains in the HbA molecule, resulting in accumulation of excess unbound a-globin chains that precipitate in erythroid precursors in the bone marrow and in the mature erythrocytes, leading to ineffective erythropoiesis and peripheral haemolysis. Approximately 1.5% of the global population are heterozygotes (carriers) of the β-thalassemias; there is a high incidence in populations from the Mediterranean basin, throughout the Middle East, the Indian subcontinent, Southeast Asia, and Melanesia to the Pacific Islands. Aim: The principal aim of this paper is to review, from a historical standpoint, our knowledge about an ancient disease, the β-thalassemias, and in particular, when, how and in what way β-thalassemia spread worldwide to reach such high incidences in certain populations. Results: Mutations involving the β-globin gene are the most common cause of genetic disorders in humans. To date, more than 350 β-thalassaemia mutations have been reported. Considering the current distribution of β- thalassemia, the wide diversity of mutations and the small number of specific mutations in individual populations, it seems unlikely that β-thalassemia originated in a single place and time. Conclusions: Various processes are known to determine the frequency of genetic disease in human populations. However, it is almost impossible to decide to what extent each process is responsible for the presence of a particular genetic disease. The wide spectrum of β-thalassemia mutations could well be explained by looking at their geographical distribution, the history of malaria, wars, invasions, mass migrations, consanguinity, and settlements. An analysis of the distribution of the molecular spectrum of haemoglobinopathies allows for the development and improvement of diagnostic tests and management of these disorders.

Introduction: Hypogonadism is the most frequently reported endocrine complication, affecting 40%–80% of thalassemia major (TM) patients. The prevalence and severity of hypogonadism in TM varies among studies, depending on patients’ age, genotype, transfusion frequency and starting age and efficiency of iron chelation. Areas covered: The diagnosis requires careful clinical assessment and appropriate laboratory testing. Its management is more complex compared to other ‘classical’ causes of hypogonadism because of multiple associated disorders (cardiac, hepatic and endocrine) and other contributing factors basically iron overload and iron toxicity. Expert commentary: Early recognition and treatment of hypogonadism in TM patients is most important to prevent late complications and to enhance the chances of parenthood. The goal of management is to restore deficient glandular function. If fertility is the issue and the testis is under-stimulated because of gonadotropin deficiency, it is possible to induce or restore spermatogenesis with exogenous gonadotropins in some patients. Assisted reproductive techniques may supplementary help to overcome previously untreatable causes of male infertility. These positive achievements should encourage health care providers to pay closer attention to the reproductive health of TM patients. This would involve the collaboration of clinicians caring for thalassemia with endocrinologists and specialists in assisted reproductive technologies. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Background: Multi-transfused thalassemia major (TM) patients frequently develop severe endocrine complications, mainly due to iron overload, anemia, and chronic liver disease, which require prompt diagnosis, treatment and follow-up by specialists. The most common endocrine complication documented is hypogonadotropic hypogonadism which increases with age and associated comorbidities. It is thus important for physicians to have a clear understanding of the pathophysiology and management of this disorder. Also to be aware of the side effects, contraindications and monitoring of sex steroid therapy. In this paper, practical ICET-A recommendations for the management of hypogonadism in adult females with TM are addressed. Methods: In March 2015, the Coordinator of the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) conducted a two-step survey to assess the attitudes and practices of doctors in the ICET-A network taking care of adult female TM patients with hypogonadism. They were clinically characterized by the absence of pubertal development or discontinuation or regression of the maturation of secondary sex characteristics, and biochemically by persistent low FSH, LH and estradiol levels. Recently a supplementary survey on adult female hypogonadism in TM was undertaken within the ICET-A network. Results: The completed questionnaires were returned by 16 of 27 specialists (59.2%) following 590 female TM patients over the age of 18 years; 315 patients (53.3%) had hypogonadism, and only 245 (74.6%) were on hormone replacement therapy (HRT). Contraceptive oral pills (COC) were the first treatment choice in 11 centers (68.7%). A wide range of COCs was used with different progestin contents. In general, the patients' compliance to treatment was reported as good in 81.2 % of centers. The frequency of required tests for follow-up HRT, in addition to the regular check-up for thalassemia, was variable in the participating centers. Conclusions: Doctors taking care of TM patients should have sound knowledge of the pathophysiology of hypogonadism in adult females with TM. They should know the potential effects of HRT including advantages and disadvantages of estrogen and progestins. Moreover, they should keep in consideration the emotional needs of these patients dreaming of attaining a full pubertal development.

Background: In March 2015, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) implemented a two-step survey on central adrenal insufficiency (CAI) assessment in TM patients and after analysis of the collected data, recommendations for the assessment of hypothalamic-pituitary- adrenal (HPA) axis in clinical practice were defined. Methods: To ascertain the current practice for assessment of CAI in thalassemia, the Coordinator of ICET-A sent two questionnaires by email: i) The first to evaluate the current interpretation of basal serum cortisol level (first step) and ii) The second to assess the current usage of ACTH test and the variability in practice" (second step). Based on the surveys the core ICET-A group prepared the recommendations for the assessment of suspected CAI in thalassemia (third step). Results: A total of 19 thalassemologists/endocrinologists have participated in the first survey and 35 specialists participated in the second step questionnaire. The study demonstrated a considerable variability in almost all aspects of relevant current criteria used for the diagnosis of CAI. An ROC analysis using peak value > 20 μg/dl (> 550 nmol/L), after ACTH stimulation test, was performed with the aim of identifying the optimal basal serum cortisol cut-off. The optimal threshold that maximizes sensitivity plus specificity for morning basal cortisol against peak post-ACTH value >20 μg/dl (>550 nmol/L) was 10 μg/dl (275 nmol/L). Furthermore, the values associated with the highest negative predictive value (NPV) and highest, positive predictive value (PPV) were 4.20 (115 nmol/L) and 18.45 μg/dl (510 nmol/L), respectively. Surprisingly, 20 specialists in thalassemia working in blood bank, thalassemia centres (day hospital), internal medicine, hematology and onco-hematology had poor knowledge and experience in testing for CAI and stopped filling the questionnaire after the second question. In contrast, 9 endocrinologists (8 pediatricians) and 6 hematologists working in collaboration with endocrinologists completed the questionnaire. Conclusions: While waiting for more extensive adequately powered and targeted studies, physicians should adopt an acceptable policy for accurate assessment of HPA in TM patients. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are also recommended. The ICET-A recommendations are reported in order to facilitate for interested physicians the approach to a successful assessment of adrenal function in thalassemia. © 2016.

In patients with TM, uncontrolled iron overload has serious clinical consequences with considerable morbidity and mortality. Complications include liver damage, cardiac disease and endocrine dysfunction. Diabetes is an important complication of TM. The mechanisms of abnormal glucose homeostasis are complex and multifactorial. This review updates the current knowledge about glycemic abnormalities in TM patients and directs the attention to an early diagnosis and proper management. © 2016 Taylor & Francis.

Aim: Chronic iron overload resulting from frequent transfusions, poor compliance to efficient chelation therapy and chronic liver disease is basically responsible for the most severe complications of thalassemia major (TM). Before conventional treatment, TM was entirely childhood disease with a very short survival. Today, survival improved to 40-50 years and becomes a prevalent disease of adulthood and in the near future it will be one of senility. Furthermore, clinical phenotype of TM is changing with age and appearance of severe complications from the heart and endocrine glands that require special health care from well-informed specialists. Objectives: The aims of our study were to: (1) Imprint the clinical profile of long-lived TM patients; (2) evaluate retrospectively the cumulative incidence of endocrine diseases; (3) identify potential risk factors; and (4) orient the physicians in the modified clinical phenotype and the relative patients' health needs. Design: A retrospective cross-sectional study followed from childhood to adulthood by the same physician in a tertiary thalassemia clinic. Participants: Forty-three long-lived TM patients (mean age: 50.3 ± 10.8 years; range: 45.8-59.5 years; 23 females) were studied. Patients and Methods: An extensive medical history, with detailed clinical and laboratory data, endocrine complications, and current treatments, was obtained. Results: The data indicate that 88.4% of adult TM patients suffered from at least one endocrine complication. The majority of patients developed endocrine complications in the second decade of life when serum ferritin level was very high (12/23 TM female and 8/20 TM male patients, the serum ferritin levels at the diagnosis were above 5.000 ng/ml). Conclusions: These data underline that endocrine and bone complications in adult TM patients are highly prevalent and necessitate close monitoring, treatment, and follow-up. Physicians' strategies to optimize chelation therapy include identifying patients who are at risk for developing organ damage, developing chelation plans, promoting compliance, and educating patients. Several clinical aspects remain to be elucidated such as growth and impairment of glucose tolerance in relation to hepatitis C virus infection. Furthermore, affordable worldwide-established long-term treatment protocols for hypogonadism and osteoporosis are needed.

Introduction. In males, acquired hypogonadotropic hypogonadism (AHH) includes all disorders that damage or alter the function of gonadotropin-releasing hormone (GnRH) neurons and/or pituitary gonadotroph cells. The clinical characteristics of AHH are androgen deficiency and lack, delay or halt of pubertal sexual maturation. AHH lead to decreased libido, impaired erectile function, and strength, a worsened sense of well-being and degraded quality of life (QOL). Patients and methods. We studied 11 adult men with thalassemia major (TM) aged between 26 to 54 years (mean ± SD: 34.3 ± 8.8 years) with AHH. Twelve age- and sex-matched TM patients with normal pubertal development were used as a control group. All patients were on regular transfusions and iron chelation therapy. Fasting venous blood samples were collected two weeks after transfusion to measure serum concentrations of IGF-1, free thyroxine (FT4), thyrotropin (TSH), cortisol, luteinizing hormone (LH), follicle stimulating hormone (FSH), total testosterone (TT), prolactin and estradiol (E2), glucose, urea, creatinine and electrolytes (including calcium and phosphate). Liver functions and screening for hepatitis C virus seropositivity (HCVab and HCV-RNA) were performed. Iron status was assessed by measuring serum ferritin levels, and evaluation of iron concentrations in the liver (LIC) and heart using MRI- T2*. Bone mineral density was measured at the lumbar spine (L1-L4) for all patients with AHH by dual energy X-ray absorptiometry (DXA) using Hologic QDR 4000 machine. Results. The mean basal serum LH and FSH concentrations in AHH patients were 2.4 ± 2.2 IU/L and 1.2 ± 0.9 IU/L respectively; these, values were significantly lower compared to the control group. Semen analysis in 5 patients with AHH showed azoospermia in 3 and oligoasthenozoospermia in 2. The percentage of patients with serum ferritin level >2000 ng/ml (severe iron load) was significantly higher in AHH patients compared to controls, 5/11 (45.4 %) versus1/12 (8.3%), p=0.043. Heart iron concentrations (T2* values) were significantly lower in AHH patients compared to controls (p=0.004). Magnetic resonance imaging in the 3 azoospermic patients revealed volume loss and reduction of pituitary signal intensity. Heart T2* values were significantly reduced in the AHH group vs. the controls (p=0.004). On the other hand, liver iron concentration (mg/g dry weight) was not different between the two groups of TM patients. Using DXA, 63.6 % (7/11) of patients with AHH were osteoporotic, and 36.3 % (4/11) were osteopenic. Conclusions. In this cohort of thalassemic patients iron overload and chronic liver disease appear to play a role in the development of AHH. Treatment of AHH in TM patients is a vital and dynamic field for improving their health and QOL. Early identification and management of AHH are very crucial to avoid long-term morbidity, including sexual dysfunction and infertility. Therapy aims to restore serum testosterone levels to the mid-normal range. Many exciting opportunities remain for further research and therapeutic development.

Rationale: Both insulin and IGF-1 have been implicated in the control of retinal endothelial cell growth, neovascularization and diabetic retinopathy. Recent findings have established an essential role for IGF-1 in angiogenesis and demonstrated a new target for control of retinopathy that explains why diabetic retinopathy initially increases with the onset of insulin treatment Objective: This cross-sectional study was designed to give insights into relationship between Insulin-Growth-Factor 1 (IGF-1) levels and diabetic retinopathy (DR) in a sample of thalassemia major (TM) patients with insulin dependent diabetes mellitus (IDDM). This relation was not previously evaluated, despite the fact that both diseases co-exist in the same patient. The study also describes the clinical and biochemical profile of the associated complications in TM patients with and without IDDM. Design: A population-based cross-sectional study. Participants: The study includes 19 consecutive TM patients with IDDM and 31 age- and sex-matched TM patients without IDDM who visited our out-patient clinics for an endocrine assessment Methods: An extensive medical history, with data on associated complications and current medications, was obtained. Blood samples were drawn in the morning after an overnight fast to measure the serum concentrations of IGF-1, glucose, fructosamine, free thyroxine (FT4), thyrotropin (TSH) and biochemical analysis. Serologic screening assays for hepatitis C virus seropositivity (HCVab and HCV-RNA) were also evaluated; applying routine laboratory methods. Plasma total IGF-1 was measured by a chemiluminescent immunometric assay (CLIA) method. Ophthalmology evaluation was done by the same researcher using stereoscopic fundus biomicroscopy through dilated pupils. DR was graded using the scale developed by the Global Diabetic Retinopathy Group. Iron stores were assessed by direct and indirect methods. Results: Eighteen TM patients with IDDM (94.7 %) and ten non-diabetic patients (32.2 %) had IGF-1 levels below the 2.5th percentile of the normal values for the Italian population. The mean serum IGF-1 concentrations were significantly lower in the diabetic versus the non-diabetic TM groups (p < 0.001). DR was present in 4 (21 %) of 19 TM patients with IDDM and was associated with the main classical risk factors, namely inefficient glycemic control and duration of the disease but not hypertension. Using the scale developed by the Global Diabetic Retinopathy Group, the DR in our patients was classified as non proliferative diabetic retinopathy (NPDR). Only a few numbers of microaneurysms [1-3] were detected. Our data also confirm the strong association of IDDM in TM patients with other endocrine and non-endocrine complications.

A randomised, double-blind trial was undertaken to investigate the efficacy and tolerability of formoterol Turbuhaler in children with mild to moderate asthma. After a two-week run-in, 248 children aged 6-17 years were randomised to receive formoterol 4.5 and 9 pmicro b.i.d. or placebo for 12 weeks. Morning PEF (primary variable), was significantly improved versus placebo only in the formoterol 9 pmicro b.i.d. group (13 l/min, 95% CCI 1.9, 24.2%; p = 0 .02). Both formoterol 4.5 and 9 pmicro significantly increased the pre-bronchodilator FEV1 by 5.2-6.7% (p0 .05) and reduced use of daytime relief medication versus placebo (p0 .05). Formoterol 9 pmicro significantly reduced night-time reliever use and awakenings due to asthma versus placebo (p0.05). Both doses of formoterol were as well tolerated as placebo. In conclusion, formoterol 4.5 and 9 micro b.i.d. is effective and well tolerated as maintenance therapy in children with mild to moderate asthma.

Objectives: Cardiac complications because of transfusional iron overload are the main cause of death in thalassaemia major. New chelators and iron monitoring methods such as cardiac magnetic resonance (CMR) became available after the year 2000. We evaluated the impact of these new management options on cardiac mortality and morbidity. Methods: The risk of cardiac death during 1990-1999 and 2000-2008 was compared. Furthermore, after 1999, morbidity, mortality and reversal of heart failure were evaluated according to chelation regime: desferrioxamine (DFO), deferiprone (DFP) and combination therapy of DFO and DFP. We also present preliminary results for deferasirox (DFX), a new oral chelator. Results: Three hundred and fifty-four patients were included in the de novo cardiac event evaluation, while 86 were included in the improvement component. The annual risk of cardiac death in patients aged between 20-30 and 30-40 reduced from 1.52% to 0.67% and 1.87% to 0.56%, respectively, before and after the year 2000. The risk for a de novo cardiac event for DFO was 9.1 times greater than that of DFP and 23.6 than with the combination of DFP and DFO. For DFX, there was one cardiac event over 269 patient-years. The risk of cardiac death was 9.5 per 1000 patient-years for DFO, 2.5 on DFP, 1.4 on combination. In the DFX group no cardiac deaths were recorded. The odds of improvement were 8.5 times greater with DFP and 6.1 with combination therapy compared to DFO. Conclusions: The new chelation regimes, together with CMR have contributed significantly to the reduction in cardiac morbidity and mortality in patients with thalassaemia major. © 2010 John Wiley & Sons A/S. Patients:The risk of cardiac death analysis: n=1124, 597 in 1990-1999 (only Desferal was available) and 527 in 2000-2008 (Desferal, DFP or combination of both were available). De novo cardiac event analysis: n=354; 343 were on Desferal (176 males and 167 females, mean age 21.2 years; 338 in 1999, 316 in 2000, 282 in 2001, 246 in 2002, 189 in 2003, 147 in 2004, 111 in 2005, 69 in 2006, 43 in 2007 and 33 in 2008), 97 DFP (46 males and 51 females, mean age 25.3 years; 2 in 2000, 16 in 2001, 18 in 2002, 42 in 2003, 63 in 2004, 58 in 2005, 50 in 2006, 35 in 2007 and 43 in 2008), and 166 Desferal/DFP combination (79 males and 87 females, mean age 26.7 years; 4 in 2000, 17 in 2001, 40 in 2002, 63 in 2003, 69 in 2004, 92 in 2005, 115 in 2006, 99 in 2007 and 98 in 2008). Improvement component analysis: n=86, 75 Desferal (51 males and 24 females, mean age 26.8 years; 39 in 2000, 42 in 2001, 32 in 2002, 21 in 2003, 19 in 2004, 11 in 2005, 7 in 2006, 5 in 2007 and 4 in 2008), DFP group (21 males and 14 females, mean age 31 years; 1 in 2000, 1 in 2001, 6 in 2002, 12 in 2003, 16 in 2004, 15 in 2005, 14 in 2006, 11 in 2007 and 9 in 2008) and 61 Desferal/DFP (36 males and 25 females, mean age 30.1 years; 1 in 2001, 14 in 2002, 24 in 2003, 24 in 2004, 34 in 2005, 38 in 2006, 36 in 2007 and 29 in 2008). Indications:An unspecified number of patients with transfusional iron overload and cardiac hemosiderosis (characterized by heart failure) and for the prevention of cardiac events. Coexisting disease was thalassemia in all patients. FreeText:All patients received blood transfusion. DFP was given at 75-100 mg/kg daily in 3 divided doses. An unspecified number of patients received DFP concomitantly. Combinations were given at similar doses as with monotherapy, 8-24 hourly infusions/3-7 times per week. Ferritin levels were evaluated. Cardiac (CMR) and hepatic magnetic resonance imaging (MRI) were used to evaluate the degree of cardiac and hepatic iron loading (liver iron concentration [LIC]). Cardiac function was assessed by symptomatology, clinical examination, chest X-rays, electrocardiograms (ECGs) and echocardiography. The risk of cardiac death between 1990-1999 and 2000-2008 was compared in all patients with thalassemia regardless of the chelation regime. The risk of cardiac death (CD) was evaluated in 2 age groups for each time period (20-30 years [yr] vs. 30-40 yr). The assessment of the incidence of de novo cardiac events (CEs) according to the chelation regime was conducted in patients with thalassemia older than 10 years. The development of a CE and the risk of CD in relation to the chelation regime were evaluated. The sum of patients in all groups was greater than the total number of patients in this study. DosageDuration:20-40 mg/kg per infusion with at least 3 (3-5) infusions per week. Duration: not stated. TypeofStudy:An open study evaluating the impact of chelation regimes (Desferal, deferiprone [DFP] and combination of both) on cardiac mortality and morbidity and reversal of heart failure in patients with thalassemia major from 1990-2008. An open, observational study from a large Greek Unit. ComparativeDrug:Deferiprone was given 75-100 mg/kg daily orally in 3 divided doses. Duration: not stated. Results:The risk of cardiac-related death during 1990-1999 vs. 2000-2008 for the 20-30 years (yr) old and 30-40 yr old were 15.2 and 18.7 vs. 6.7 and 5.6, respectively; the rate of death were 30 and 5 vs. 14 and 8, respectively. 63 de novo CEs were noted: 58 Desferal (16 in 1999, 8 in 2000, 13 in 2001, 7 in 2002, 5 in 2003, 6 in 2004, 1 in 2005, 2 in 2006, 1 in 2007 and 0 in 2008), 1 DFP (2003) and 1 Desferal/DFP (2006). Patients on DFP and Desferal/DFP had 9.1 times and 23.6 times, respectively, lower risk of de novo CE vs. Desferal. Patients on any DFP (DFP or Combination) showed 14 times lower risk vs. Desferal group. The odds ratio (OR) for the development of CEs of Desferal vs. DFP groups in patients with mild, moderate and severe hemosiderosis were 3, 3.2 and 10.3, respectively; in Desferal vs. Desferal/DFP groups, 8.9, 9.1 and 9.1, respectively. For Desferal/DFP, the effect was similar in all severities of iron load while for DFP the protective effect is more prominent in severe iron load. The rates of events were 3.3/100 person-years for Desferal (58 events median time on Desferal = 2.4 yr), 0.3/100 person-years for DFP (1 event in a patient after 4 yr on DFP), 0.6/100 person-years for Desferal/DFP (3 events in 3 patients who had been for 6 months, 73 and 35 days, respectively, on combination therapy). In all patients with cardiac improvement and those who have not been included as an improvement, the left ventricular ejection fraction normalized (>60%). Combined 9-yr data revealed that DFP patients were 8.5 times more likely to improve vs. Desferal patients, while those on combination had a 6.1 time greater likelihood. The patients on any DFP had a 6.7 times greater chance of improving vs. Desferal. Increasing level of hemosiderosis reduced the likelihood of improvement. The rates of improvement were 0.6/100 person-years for Desferal, 13.9/100 person-years for DFP, 6/100 person-years for Desferal/DFP. Overall, after 1999, 22 deaths occurred: 20 cardiac-related and 2 other causes (1 accident and 1 thromboembolic event). There were 18 CDs in the Desferal group over 1900 patient-years (risk = 9.5/1000 patients-years, median time of exposure = 2.6 yr), on the DFP group for 393 patient-years (risk = 2.5/1000 patients-years, the 1 death occurred in a patient after 1.3 yr on DFP) and 1 in the Desferal/DFP group over 709 patient-years (risk = 1.4/1000 patients-years, the 1 death occurred in a patient after 4.1 yr on combination therapy). When adjusted for sex and degree of hemosiderosis, the relative risks (RR) of experiencing CD were: Desferal 6.1 RR and 5.7 RR compared to DFP and combination, respectively (marginally non-significant). The RR for Desferal vs. DFP and Desferal/DFP was 5.2. AdverseEffects:No adverse events were mentioned. AuthorsConclusions:New chelation options in patients with thalassaemia have reduced cardiac morbidity and mortality. Cardiac deaths have reduced in many centres throughout the world since the year 2000. The newer chelation regimes demonstrate lower risk of cardiac events. In the past, the onset of cardiac failure in patients with thalassaemia usually progressed to death within a short period of time. This study clearly demonstrates that a significant proportion of patients who developed cardiac events, were able to regain normal cardiac function with appropriate therapy. The new regimes together with better non-invasive diagnostic facilities for identifying both hepatic and cardiac iron load are expected to improve survival even further and reduce incidence and severity of complications caused by haemosiderosis.

Journal URL: http://www.spandidos-publications.com/or/ Infections caused by Human Cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) are common in multiple transfused patients, such as patients with ßthalassaemia. The ability of the Polymerase Chain Reaction (PCR) to amplify HCMV and EBV DNA from blood and other samples makes this technique a valuable diagnostic tool for the detection of both viruses in the early stages of the infection. PCR was used for the amplification of a 435 bp region of the immediate early-1 (IE-1) gene of HCMV and a 375 bp sequence from the EcoRI Β fragment of EBV genome. Blood samples from 80 patients with ß-thalassaemia were examined. HCMV was found in 14 and EBV in 12 patients. The results obtained confirm the implications of HCMV and EBV in the diagnosis of viral infections in multiple transfused patients as well as the importance of PCR technique as a valuable diagnostic tool.

The simultaneous use of deferioxamine (DFO) and deferiprone (DFP) has an additive effect in iron excretion in transfusion-dependent thalassemic patients. In a prospective study, we evaluated the safety and effectiveness of combined therapy with these two chelators. Fifty patients with β-thalassemia were uniformly treated with DFP for 4 days per week and combined therapy with DFP and DFO for 3 days of the week. Efficacy was evaluated by ferritin and cardiac shortening fraction (SF). Hepatic hemosiderosis was also assessed by estimation of the T2 relaxation time by magnetic resonance in a subgroup of patients. Forty-three patients completed 1 year of therapy. Mean ferritin decreased from 3363.7±2144.5 μg/L to 2323.2±1740.8 μg/L (P

Iron-induced organ degeneration is the main factor of mortality in patients with thalassemia major. Since chelation therapy is at a turning point, from the laborious parenteral route to the use of new promising oral agents, we investigated the current status of survival of these patients to present reliable data that will be useful in future comparative studies. Survival probabilities were estimated by the Kaplan-Meier method, and results were compared by the log-rank test in a total of 647 thalassemic patients (pts) (52% males) born between 1/1/58 and 1/2/04. Terminal follow-up was 1/12/04. All transfusion-dependent pts monitored in our center, or in frequent contact if they had moved elsewhere, were strictly selected, excluding all rarely transfused or intermediate cases. Pts born before 1/1/75 were classified in group A (n = 366), while pts born later were included in group B (n = 281). According to the last 5 years' mean serum ferritin level, pis were divided into three hemosiderosis groups: (1) mild (4000 μg/L) 23%. Of the 647 pts, 115 died (mean age: 22.6 ± 6.2 years), most frequently by heart failure (71.3%) followed by sepsis (7.8%). Life expectancy in the entire population was up to 59% at 46 years. Survival was higher for pts born after 1975 than those before (P < .001). Statistically significantly different survival probabilities were found between groups with mild, moderate, or severe hemosiderosis (P < .001). Effective management with improved chelation therapy could lead to better results. © 2005 New York Academy of Sciences.

The 7.2 kilobase (kb) Corfu deltabeta thalassemia mutation is the smallest known deletion encompassing a region upstream of the human delta gene that has been suggested to account for the vastly different phenotypes in hereditary persistence of fetal hemoglobin (HPFH) versus beta thalassemia. Fetal hemoglobin (HbF) expression in Corfu heterozygotes and homozygotes is paradoxically dissimilar, suggesting conflicting theories as to the function of the region on globin gene regulation. Here, we measure gamma- and beta-globin gene transcription, steady-state mRNA, and hemoglobin expression levels in primary erythroid cells cultured from several patients with Corfu deltabeta thalassemia. We show through RNA fluorescence in situ hybridization that the Corfu deletion results in high-level transcription of the fetal gamma genes in cis with a concomitant reduction in transcription of the downstream beta gene. Surprisingly, we find that elevated gamma gene transcription does not always result in a corresponding accumulation of gamma mRNA or fetal hemoglobin, indicating a post-transcriptional regulation of gamma gene expression. The data suggest that efficient gamma mRNA accumulation and HbF expression are blocked until beta mRNA levels fall below a critical threshold. These results explain the Corfu paradox and show that the deleted region harbors a critical element that functions in the developmentally regulated transcription of the beta-globin genes. (C) 2005 by The American Society of Hematology

The authors studied the long-term clinical and hematological response to hydroxyurea (HU) therapy in young patients, with either S/beta-thalassemia (beta(thal) ) (8 patients) or SS (6 patients). All patients with S/beta(thal) responded well to treatment. Longitudinal evaluation of Hb, HbF, and MCV showed a significant increase compared to baseline levels, but the pattern of HbF changes varied among patients. Changes in HbF and Hb correlated well with baseline HbF. Favorable clinical responses, as documented by decline in hospitalization days for vasoocclusive crisis and transfused units of packed red blood cells, were also noted. During treatment, 1 patient was diagnosed with Hodgkin’s lymphoma and 2 patients developed bilateral avascular necrosis of the femoral head. HU seems to be effective in a high proportion of young patients with sickle cell disease and in particular with S/beta(thal) , but cannot eliminate occurrence of serious adverse events.

Background. A high incidence of Helicobacter pylori among family members of children with H. pylori gastritis has previously been documented on biopsy material. The main objective of this study was the genetic clarification of H. pylori strains involved in intrafamilial dispersion. Materials and Methods. Formalin-fixed, paraffin-embedded material of antral mucosa from 32 members of 11 families was studied for the presence of genetic homogeneity. To achieve this goal, the entire genome of H. pylori was studied by the polymerase chain reaction (PCR)-based random amplified polymorphic DNA (RAPD) fingerprinting method. Furthermore, the Urease A gene was analyzed using a multiplex PCR-assay and an alternative mutation detection method based on the Hydrolink(TM) analysis. Results. RAPD fingerprinting confirmed that closely related H. pylori strains were involved in the intrafamilial dispersion. Mutations and small deletions in Urease A gene were found in 22 out of 32 individuals. Conclusions. The homology of the H. pylori genome in members of the same family strongly supports the hypothesis of transmission of H. pylori from person-to-person or from a common source.

The elements conferring high-level gentamicin resistance in 64 clinical isolates of Enterococcusfaecalis were characterized by PCR and by restriction enzyme hybridization analysis of genomic and plasmid DNA. There was a strong association between gentamicin resistance and the aac(6′)-aph(2″) gene carried on IS256-based elements with different structures, locations, and transfer characteristics.

An open, randomised, multicentre trial was performed to assess the reactogenicity and safety profile of the administration of a candidate Haemophilus influenzae type b (Hib) conjugate vaccine with a quadrivalent diphtheria-tetanus-acellular pertussis-hepatitis B (DTPa-HBV) vaccine as a single injection (Group 1) versus the simultaneous administration of the latter vaccine (DTPa-HBV) and an available Hib conjugate vaccine (Group 2) in opposite thighs, as a primary vaccination course to healthy infants at 2, 4 and 6 months of age. Eight hundred and eighty five infants (9.3 ± 1.4 weeks old) were randomly allocated to Group 1 (n = 665) and Group 2 (n = 221). Oral polio vaccine was given concomitantly to all subjects. Blood samples (pre-vaccination and 1 month after the third dose) were obtained from a subset of infants (Group 1, 73; Group 2, 22) for serological determinations. Local and general symptoms were recorded by parents on diary cards. 2614 diary cards (Group 1, 1966; Group 2, 648) were collected. There were no statistically significant differences in the incidence of local and general symptoms between groups. Pain such that the infant cried when limb was moved was reported in 0.6 and 0.2% in groups 1 and 2, respectively. Redness and swelling ( > 20 mm in diameter) were recorded between 2.1 and 3% in both groups. Fussiness preventing normal activities was the most frequently reported general symptom in both groups (1.6 and 1.9% in groups 1 and 2, respectively). Fever (rectal temperature > 39.5°C) was reported in 0.4% (Group 1) and 0.3% (Group 2). All subjects included in the immunogenicity analysis had seroprotective or seropositive titres to the diphtheria, tetanus, hepatitis B and pertussis components of the vaccines. About 99 and 100% of infants had anti-PRP titres ≥ 0.15 mcg/ml in groups 1 and 2, respectively. This study indicates that DTPa-HBV vaccine given in a single injection with a candidate Hib conjugate vaccine has a similar reactogenicity profile to that of two commercially available vaccines (DTPa-HBV, Hib) given in two simultaneous injections to infants 2, 4 and 6 months of age. © 2001 Published by Elsevier Science Ltd.

We studied the changing pattern of the distribution of ferritin levels in 430 regularly-transfused patients with thalassemia in an attempt to evaluate compliance of chelation with deferoxamine. The study covered 15 years and was divided in three periods: 1981-1985, 1986-1990, and 1991-1995. The patients were stratified in age-groups. The mean ferritin levels of each period were calculated for each patient individually. The study showed that: (i) When all the patients were compared as a group, there was a significant decrease in mean ferritin between 1981-1985 and 1991-1995, despite a significant change in the patients’ mean age; (ii) When patients of same age were compared between periods, there was a decrease in mean ferritin between 1981-1985 and 1991-1995, as well as a decrease in the proportion of patients with ferritin > 4000 mug/L, with a parallel increase in the proportion of patients who had ferritin < 2000 mug/L; (ill) When the same patients were followed longitudinally, they showed a decrease in their ferritin levels in all age groups with the exception of the late adolescence period. The decrease in iron overload observed in patients on close follow up implies that compliance with chelation therapy has improved with time and therefore, a favourable influence in survival could be expected. (C) 2001 Wiley-Liss, Inc.

Hb F levels in beta-thalassemia heterozygotes are usually less than 2%, but amongst 1,059 patients studied, 73 (7%) had Hb F levels above 2.5% (2.614,0%), To investigate factors that may influence the increase of Hb F levels in these heterozygotes, we characterized the beta-thalassemia mutations and their chromosomal background, gamma-globin gene promoter variations, and gamma-globin genotypes, All 73 beta-thalassemia heterozygotes carried beta-thalassemia point mutations previously observed in the Greek population; gene mapping excluded b gene cluster deletions; only two cases had an additional gamma-globin gene(gamma gamma gamma/gamma gamma). Five alpha-globin genes (alpha alpha alpha/alpha alpha) were detected in 17/73 cases (23%) as compared to a carrier rate of 1.76% in the general population. Molecular, hematological, and biosynthetic findings in these compound heterozygotes indicated that the raised Hb F levels were caused by cell selection due to ineffective erythropoiesis. In the remaining 56 simple beta-thalassemia heterozygotes, 11 beta-thalassemia mutations were observed, each on the expected haplotype(s), and analysis of the y gene promoters revealed three known polymorphisms (in linkage disequilibrium), with minimal influence on gamma-globin levels. However, the overall distribution of beta-thalassemia mutations in the 56 simple beta-thalassemia heterozygotes was significantly different (P < 0.0002) compared to that in 986 simple beta-thalassemia heterozygotes with T), IVS-II-1 (G–>A), codon 6 (-A), and codon 8 (-AA), which accounted for 41/56 (73%) cases with >2.5% Hb F. In the remaining 15/56 (27%) cases, no common underlying globin genotypes could explain the raised Hb F levels. Overall, this study indicates that the control of Hb F levels in beta-thalassemia heterozygotes is heterogeneous and multi-factorial.

Haemoglobin H (Hb H) disease is the severest form of alpha -thalassaemia compatible with post-natal life and occurs when alpha -thalassaemia mutations interact to reduce alpha -globin synthesis to levels approximately equivalent to the output of a single alpha -globin gene. Hb H disease has variable clinical expression, mainly related to underlying genotypes. The spectrum of alpha -thalassaemia determinants in Greece appears greater than in any other population studied and, in 75 Greek Hb H disease patients, we found 12 alpha -thalassaemia mutations interacting to produce 15 Hb H disease genotypes. Evaluation of haematological, biochemical and clinical findings, and correlation with genotypes, defined genetic predictors of disease severity and factors involved in disease progression. In accordance with previous reports, patients with non-deletion alpha -thalassaemia mutations had more severe clinical expression. Additionally, we found that all patients with the most severe phenotypes had alpha -thalassaemic globin variants. Phenotypic severity was not simply related to the degree of alpha -globin deficiency: high Hb H levels were found to exacerbate anaemia by negatively influencing tissue oxygenation, and both Hb H and alpha -thalassaemic haemoglobin variants appear to reduce red cell survival within the bone marrow and circulation. Together with the long-term follow-up in many patients, this report provides comprehensive information for management of Hb H disease and appropriate family counselling.