Saccharomyces cerevisiae supplemented diets mitigate the effects of waterborne cadmium toxicity on gilthead seabream (Sparus aurata L.): growth performance, haemato-biochemical, stress biomarkers, and histopathological investigations.

Yeast, Saccharomyces cerevisiae, has been utilized as a probiotic in aqua-feeds to promote growth and alleviate the stress in aquatic animals. On the other hand, cadmium (Cd) toxicity causes serious retardation of growth and welfare status of aquatic animals. The present study was conducted to evaluate the protective role of dietary yeast in mitigating the waterborne Cd toxicity effects on the growth, haemato-biochemical, stress biomarkers, and histopathological investigations of gilthead seabream (Sparus aurata L.). In a 3 × 3 factorial design, the acclimated fish (20-24 g) were randomly distributed into nine treatments in triplicates where they were fed on 0.0% (control), 0.5%, and 1.0% of yeast along with exposure to 0.0, 1.0, and 2.0 mg Cd/L for 60 days. All growth parameters and mRNA expressions of IGF-1 and GH genes as well as haematological parameters were markedly increased with the increase of dietary yeast levels; meanwhile these variables were significantly retarded with Cd exposure. Contradictory effects on the above-mentioned variables were observed with Cd toxicity. In contrast, blood cortisol, glucose, total cholesterol, and triglyceride, lactate dehydrogenase, alanine transaminase, aspartate transaminase, alkaline phosphatase, in addition to DNA fragments % were noticeably increased with Cd toxicity especially at the treatment of 2.0 mg Cd/L, while decreasing with increasing dietary yeast levels. Compared with the control fish group, Cd concentrations in the gill, liver, and muscle tissues of gilthead seabream were higher in Cd-exposed treatments, especially at the treatment of 2.0 mg Cd/L. Deposition of Cd in fish liver was higher than that in gill tissues but lowest Cd residue was observed in muscle tissues. No significant changes in Cd residues in fish organs were observed in yeast-fed fish with no Cd exposure. The Cd exposure negatively affected histological status of gill, liver, and kidney tissues of S. aurata; while feeding Cd-exposed fish on yeast diets lowered the Cd residues in fish organs and recovered the adverse effects of Cd toxicity. Hence, this study recommends the addition of bakery yeast (1.0%) to fish diets to improve the performance, overall welfare, and histopathological status of gilthead seabream, S. aurata.

A prospective guide for clinical implementation of selected OGTT- derived surrogate indices for the evaluation of ß- cell function and insulin sensitivity in patients with transfusion-dependent ß- thalassaemia.

The gold standard for the measurement of insulin secretion is the hyperglycemic clamp and for insulin sensitivity the hyperinsulinemic euglycemic clamp, respectively. A number of surrogate indices, derived from plasma glucose and insulin levels at a fasting state or after oral glucose load, have been proposed to estimate ß-cell response, and the ability of ß-cells to compensate for changes of insulin sensitivity by modulating insulin secretion (disposition index). Starting from the current recommendations for the annual screening of glucose dysregulation in patients with transfusion dependent ß-thalassemia (ß-TDT), this article summarizes the most frequently used indirect indices of insulin secretion and resistance derived from the oral glucose tolerance test (OGTT) and discusses the strengths and weaknesses of selected indices and the basic concepts underlying each method for the appropriate evaluation of glucose regulation. Basal indices for ß-cell function and insulin sensitivity, albeit simple and cheap, have limited usefulness due to a high coefficient variation and the lack of data about response to glucose load. Therefore, measurement of indices during an OGTT, despite being costly and time-consuming, is suggested since it can detect, even subtle, dynamic changes in insulin secretion and glucose handling. In patients with ß-TDT, the indices derived from OGTT may offer an additional factor to evaluate the efficiency of iron chelation therapy and detect patients who may need intensification of iron chelation therapy and/or pharmacological intervention.

A Multicenter ICET-A Study on Age at Menarche and Menstrual Cycles in Patients with Transfusion-Dependent Thalassemia (TDT) who Started Early Chelation Therapy with Different Chelating Agents.

Introduction: To evaluate the effect of early chelation therapy (≤ 3 years) with a variety of chelating agents on age at menarche and menstrual characteristics in patients with transfusion-dependent thalassemia (TDT). Design: A retrospective multicenter study promoted by the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A). Setting: Eight of 13 International Thalassemia Centers (61.5%) in the ICET-A Network participated. Patients: Fifty-seven female TDT patients, aged 11 to 26 years, and with early iron chelation therapy, were eligible for the present study. They were enrolled from one center from Iran (33 patients), 3 centers from Bulgaria (9), 1 from Greece (8), one from Oman (4), 1 from Cyprus (2), and 1 from Italy (1). Seven patients were excluded, four still prepubertal (age 12-14 years) and 3 with primary amenorrhea. Therefore 50 patients were finally enrolled. Results: All fifty TDT patients developed spontaneous menarche at a mean age of 14.2 ± 2.24 years (range 9 - 20). A significant positive correlation was observed between age at menarche and serum ferritin levels (r: 0. 41, p=0.005). Regular menstrual cycles were reported from 32 (64%) patients, of whom 28 (83.3%) get menarche at age ≤ 14 years. Complications were more frequent in patients older than 14 years at menarche and in those with secondary amenorrhea. Conclusions: Age at menarche greater than 14 years was a forerunner of menstrual irregularities and associated complications in 36% of patients despite precocious chelation therapy. The poor adherence to treatment, to be demonstrated in future studies, could explain the finding.

Retrospective study on long-term effects of hormone replacement therapy (HRT) and iron chelation therapy on glucose homeostasis and insulin secretion in female ß- thalassemia major (ß-TM) patients with acquired hypogonadotropic- hypogonadism (AHH).

BACKGROUND AND AIM: Hypogonadism and abnormalities of glucose homeostasis, resulting from iron-induced pituitary and pancreatic ß-cell dysfunction respectively, are the most frequently reported endocrine abnormalities in patients with ß-thalassemia major (ß-TM), also identified as transfusion-dependent thalassemia (TDT). STUDY DESIGN AND PATIENTS: The aim of the present retrospective study was to evaluate the long-term effects of hormone replacement therapy (HRT) on glucose metabolism and insulin secretion/sensitivity during 3-h oral glucose tolerance test (OGTT) in adolescent and young ß-TM women with acquired hypogonadototropic -hypogonadism (AHH).Twelve hypogonadal ß-TM females with AHH on HRT were followed for 8.26 ± 1.49 years. RESULTS: At baseline, 10 patients (83.3%) had normal OGTT, 1 patient presented with impaired glucose tolerance (IGT) and 1 patient had an isolated PG level of 165 mg/dL at 1-h during OGTT (H-NGT). At last evaluation, 7 patients (58.4 %) had normal OGTT, while 5 patients (41.6%) had abnormal OGTT. Reduced insulin sensitivity and impaired first-phase insulin secretion were also documented. Three of 4 ß-TM patients on treatment with estradiol hemihydrate MX 50 patches plus oral medroxyprogesterone acetate (MPA), associated with a very effective iron chelation therapy, maintained normal glucose tolerance from baseline to last evaluation. Significant adverse events due to HRT or additional endocrine complications were not documented in any cases during the follow-up. CONCLUSION: Deterioration of glycemia (dysglycemia) occurred in 45.4% (5/11) of thalassemic females on long-term HRT. Additional studies are needed to elucidate the validity of our preliminary observations.

Longitudinal study of ICET-A on glucose tolerance, insulin sensitivity and ß-cell secretion in eleven ß-thalassemia major patients with mild iron overload.

BACKGROUND: Iron chelation therapy (ICT) is the gold standard for treating patients with iron overload, though its long-term effects are still under evaluation. According to current recommendations regarding  transfusion-dependent  (TD)  ß-thalassemia major (ß-TM) patients, their serum ferritin (SF) levels should be maintained below 1,000 ng/mL and ICT should be discontinued when the levels are <500 ng/mL in two successive tests. Alternatively, the dose of chelator could be considerably reduced to maintain a balance between iron input and output of  frequent transfusions. STUDY DESIGN: Due to the paucity of information on long-term effects of ICT  in ß-TM with low SF levels on glucose homeostasis, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) promoted a retrospective and an ongoing prospective observational study with the primary aim to address the long-term effects of ICT on glucose tolerance and metabolism (ß-cell function and peripheral insulin sensitivity) in adult ß-TM patients with persistent SF level below 800 ng/mL. PATIENTS AND METHODS: 11 ß-TM patients (mean age: 35.5 ± 5.5 years; SF range: 345-777 ng/mL) with normal glucose tolerance test (OGTT) or abnormal glucose tolerance (AGT) for a median of 5.3(1.1-8.3) years. RESULTS: Abnormal glucose tolerance (AGT) was observed in 7 patients (63.6%) at first observation and ) persisted in 6 patients (54.5%) at last observation. None of them developed diabetes mellitus. AGT was reversed in two patients. One patient with NGT developed early glucose intolerance (1-h PG ≥155 and 2-h PG <140 mg/dL). Three out of  5 patients with isolated impaired glucose tolerance presented a variation of  ATG. Stabilization of low indices for ß-cell function and insulin sensitivity/resistance was observed. One patient developed hypogonadotrophic hypogonadism. Three out of 6 patients with SF below 500 ng/dL had hypercalciuria. CONCLUSION: Despite low SF level, the burden of endocrine complications remains a challenge in ß-TM patients. The ability to keep iron at near "normal" level with acceptable risks of toxicity remains to be established.

Glucose Homeostasis and Assessment of ß-Cell Function by 3-hour Oral Glucose Tolerance (OGTT) in Patients with ß-Thalassemia Major with Serum Ferritin below 1,000 ng/dL: Results from a Single ICET-A Centre.

Aims: The primary aim of this study was to evaluate retrospectively the glucose homeostasis and surrogate indices of insulin sensitivity and resistance, during a 3-hour oral glucose tolerance test (OGTT), in ß-thalassemia major patients (ß-TM) with serum ferritin (SF) below 1,000 ng/mL. Patients and methods: The retrospective cohort study evaluated the medical records of 24 ß-TM patients from 2010 to 2022. At the year of study the mean age of patients was 31.0 ± 4.1 (20-37.11) years; 13 (54.1%) were females. The most commonly used iron chelator was deferoxamine (DFO: 75%), followed by deferiprone (DFP:12.5%) and deferasirox (DFX: 12.5%). Insulin sensitivity and resistance indices were derived from OGTT. A liver iron concentration (LIC) < 3 mg/g d.w. and a global heart T2* value > 20 ms were considered as conservative cut-off values for insignificant iron overload (IOL). Results: The mean SF levels in the whole study cohort population at the age of evaluation was 549.6 ± 232.3 ng/mL. Based on the SF levels, two groups were identified: Group A (N = 14) < 500 ng/mL and Group B (N=10) 500-1,000 ng/mL. Normal glucose tolerance (NGT) during OGTT was observed in 4 patients of Group A (28.5 %) and in 5 patients of Group B (50%) (P: 0.29). The remaining 15/24 patients (62.5%) had glucose dysregulation (GD). The mean age at starting iron chelation therapy (ICT) and the mean SF peak in Group A versus Group B were significantly higher in group A. The GD was associated with significantly attenuated IGI (first phase of insulin response) and impaired oral disposition index (oDI). Hypogonadotropic hypogonadism (HH) was the most common associated endocrine complication in both groups of patients. Conclusions: This study showed that efficient iron chelation monotherapy in patients with ß-TM and SF < 1,000 ng/ml did not entirely prevent glucose metabolism disorders, abnormalities of insulin secretion and sensitivity, and development of acquired hypogonadism.

A Short Review on Growth and Endocrine Long-term Complications in Children and Adolescents with ß-Thalassemia Major: Conventional Treatment versus Hematopoietic Stem Cell Transplantation.

The conventional treatment of ß-thalassemia (ß-TM) patients is based on the correction of anemia through regular blood transfusions and iron chelation therapy. However, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only currently available technique that has curative potential. Variable frequency and severity of long-term growth and endocrine changes after conventional treatment as well as after HSCT have been reported by different centers. The goal of this mini-review is to summarize and update knowledge about long-term growth and endocrine changes after HSCT in patients with ß-TM in comparison to those occurring in ß-TM patients on conventional treatment. Regular surveillance, early diagnosis, treatment, and follow-up in a multi-disciplinary specialized setting are suggested to optimize the patient's quality of life (www.actabiomedica.it).

Blood transfusion and iron overload in patients with Sickle Cell Disease (SCD): Personal experience and a short update of diabetes mellitus occurrence.

The conventional treatment of ß-thalassemia (ß-TM) patients is based on the correction of anemia through regular blood transfusions and iron chelation therapy. However, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only currently available technique that has curative potential. Variable frequency and severity of long-term growth and endocrine changes after conventional treatment as well as after HSCT have been reported by different centers. The goal of this mini-review is to summarize and update knowledge about long-term growth and endocrine changes after HSCT in patients with ß-TM in comparison to those occurring in ß-TM patients on conventional treatment. Regular surveillance, early diagnosis, treatment, and follow-up in a multi-disciplinary specialized setting are suggested to optimize the patient's quality of life (www.actabiomedica.it).

Screening for glucose dysregulation in ß-thalassemia major (ß-TM): An update of current evidences and personal experience.

Glucose dysregulation (GD) in patients with ß-thalassemia major (ß-TM) usually develops gradually. Prediabetes consists of two abnormalities, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), the latter detected by a standardized oral glucose tolerance test (OGTT). Diagnosis of prediabetes is essential for an early identification of high-risk individuals who will benefit from intensive iron chelation therapy and lifestyle modification. Therefore, patients with ß-TM should undergo annual screening for glucose abnormalities, according to international recommendations, starting from the age of 10 years. OGTT remains the preferred screening method as it is more sensitive for GD than fasting plasma glucose (FPG), although it is poorly reproducible. The use of HbA1c measurement has limited use as it is generally considered unreliable in patients with thalassemia. Continuous glucose monitoring system (CGMS) is an accurate method to detect the variability of glucose fluctuations and offers the opportunity for better assessment of glucose homeostasis in a selected group of ß-TM patients. Pancreatic Magnetic Resonance Imaging (MRI) associated with insulin secretion-sensitivity index-2 (ISSI-2) could be a complementary test, minimizing the necessity for OGTT and identifying high-risk patients before irreversible pancreatic damage occurs. The aims of this short report are to give practical guidance for an early identification of GD in ß-TM patients, to summarise our experience, and to offer an impetus for further research in the field.

Impact of oral nutritional supplements (ONS) on growth outcomes and IGF-1 level in underweight older children and young adolescents (5-14 years) with short stature and no systemic disease: High versus normal calories density formula.

OBJECTIVES: This controlled trial investigated the effects of energy-dense pediatric oral nutritional supplements ONS versus standard ONS in pediatric patients requiring oral nutritional support for low body mass index (BMI) or weight gain per day (WGD) below the average for age and sex.  Patients and Methods: 34 children and adolescents (mean age 10.2 years) with faltering growth requiring ONS were randomized to cONS (n =22) or sONS (n = 12) for a year. We recorded their weight (WT), height (HT) and calculated height growth velocity (GV), Ht-SDS, BMI, WGD, every 3 months for a year.  Results: The WGD, height growth velocity (GV: cm/year), and Ht-SDS increased significantly, in both groups, during the year of ONS. The use of the cONS resulted in significantly greater mean total WGD and BMI-SDS after 6 months and 1 year, compared to the sONS group. The increase in IGF1-SDS was significantly higher in the cONS groups versus the sONS group. Moreover, the WGD was correlated significantly with the height GV during the year of ONS intake. CONCLUSIONS: ONS improved the growth of underweight old children and adolescents who had no systemic illness. There was a significantly higher WGD and BMI-SDS in the group on cONS compared to those on sONS. In both groups, long-term use of ONS significantly improved Ht-SDS.

A study of isolated hyperglycemia (blood glucose ≥155 mg/dL) at 1-hour of oral glucose tolerance test (OGTT) in patients with ß-transfusion dependent thalassemia (ß-TDT) followed for 12 years.

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 ß-transfusion dependent thalassemia (ß-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 ß-TDT with H-NGT and 29 ß-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 ß-TDT patients with H-NGT. An inverse correlation was found between 1-hour plasma glucose value during OGTT and insulin secretion-sensitivity 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 ß-TDT patients enrolled in our study. CONCLUSIONS: 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.

The Pancreatic changes affecting glucose homeostasis in transfusion dependent ß- thalassemia (TDT): a short review.

BACKGROUND: The natural history of the glycometabolic state in transfusion-dependent ß-thalassemia (TDT) patients is characterized by a deterioration of glucose tolerance over time. AIMS: This review depicts our current knowledges on the complex and multifacet pathophysiologic mechanisms implicated in the development of alteration of glucose homeostasis in patients with TDT. SEARCH STRATEGY: A systematic search was done on December 2020 including Web of Science (ISI), Scopus,  PubMed, Embase, and Scholar for papers published in the last 20 years. Moreover, we checked the reference lists of the relevant articles and previously performed reviews for additional pertinent studies. The personal experience on the care of patients with thalassemias is also reported. CONCLUSION: A regular packed red blood cells (PRBCs) transfusion program, optimization of chelation therapy, and prevention and treatment of liver infections are critical to achieve adequate glucometabolic control in TDT patients. Many exciting opportunities remain for further research and therapeutic development.

Iron-Induced Thrombocytopenia: A Mini-Review of the Literature and Suggested Mechanisms.

Anemia constitutes a major global health burden, and iron deficiency is the most common cause of it. Iron deficiency and replacement affect not only hemoglobin (Hb) levels but also other hematological parameters such as platelet count. In this mini-review, we explore thrombocytopenia as a side effect of iron replacement therapy. We searched for relevant articles published in English, and all case reports/series of iron-induced thrombocytopenia were collected and analyzed. A total of 11 case reports and one case series were found relating to very low Hb at a baseline level of 5.25 +/- 2.2 g/dl and variable platelet count at baseline that dropped in 9 +/-3 days to an average of 121 +/- 112 x 109/L, which in most of the cases was self-corrected. The parenteral route was more commonly reported to be associated with thrombocytopenia, and discontinuation of therapy was needed in two patients. The mechanisms, prevalence, and clinical significance of thrombocytopenia associated with iron replacement are unknown; several effects of iron on the primary hematopoietic cells and stromal cell lines have been proposed, such as influence on common progenitors, effects on cytokines, and thrombopoietic effect of erythropoietin, which is directly affected by iron levels. Iron replacement can lead to significant thrombocytopenia. Further research is needed to describe the exact incidence, mechanism, and clinical significance of thrombocytopenia associated with iron supplementation.

Short-Term Outcome and MRI Changes in Three Adult Patients with Sickle Cell Disease and Aseptic Osteonecrosis after Treatment with Hyperbaric Oxygen Therapy: A Preliminary Report.

BACKGROUND: Musculoskeletal manifestations are common in sickle cell disease (SCD). Vaso-occlusive crisis can manifest acutely as joint and bone pain, osteomyelitis and/or arthritis. It can also lead to chronic bone aches, bone deformities, degenerative arthritis, pathological fractures, and osteoporosis. Hyperbaric oxygen (HBO) therapy is a mode of treatment in which the patient is exposed to very high arterial and tissue oxygen pressure, during multiple sessions. It has been used as primary or adjunctive therapy for a variety of medical disorders, including necrotizing infection and sickle cell crisis. CASE REPORT: In this case series, 3 patients with SCD and avascular necrosis were treated with 15-40 sessions of HBO and were assessed 6-12 months by MRI after treatment. They showed different clinical outcomes and MRI changes. CONCLUSION: We concluded that HBO can result in some subjective improvement, especially in early stages. Further studies on severe cases are needed.

Prevalence, attitude and practice of self-medication among adolescents and the paradigm of dysmenorrhea self-care management in different countries.

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.

Marital status and paternity in patients with Transfusion- Dependent Thalassemia (TDT) and Non Transfusion-Dependent Thalassemia (NTDT): an ICET - A survey in different countries.

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 ß- 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.

Final Height and Endocrine Complications in Patients with ß-Thalassemia Intermedia: Our Experience in Non-Transfused Versus Infrequently Transfused Patients and Correlations with Liver Iron Content.

BACKGROUND: ß-thalassemia intermedia (TI) spans a wide spectrum of severity and carries higher morbidity than previously recognized, including extramedullary hematopoiesis, leg ulcers, gallstones, thrombosis, secondary heart failure, pulmonary hypertension, skeletal deformity, growth retardation and endocrine abnormalities, such as diabetes mellitus, hypothyroidism, osteoporosis, and hypogonadism. OBJECTIVES: To evaluate the final height and the endocrine complications encountered in young adult patients with TI followed at Hematology Section, Doha (Qatar) in relation to liver iron content in non-transfused versus infrequently transfused TI patients. PATIENTS AND METHODS: This retrospective cohort study was performed on 28 young adults with TI who were randomly selected from the Hematology Clinic of the Hematology Section, National Centre for Cancer Care and Research, Hamad Medical Corporation of Doha (Qatar).Eligibility criteria for this retrospective analysis included TI patients diagnosed by complete blood count, hemoglobin electrophoresis and young adult age ( ≥ 18 years).Group 1 included nine patients who did not receive any blood transfusion, and Group 2 included 19 patients who infrequently received blood transfusions.Data recorded from charts included demographic characteristics (gender, date of birth, ethnicity), disease and treatment characteristics (e.g., transfusion frequency, history of chelation therapy, and splenectomy), auxological and pubertal data [growth percentiles and pubertal stages, and body mass index (BMI)], laboratory data and target organ complications (including endocrinopathies and liver disease). Iron overload was assessed by direct (liver iron content; LIC) and indirect methods (SF), and bone mass index (BMA) by dual-energy X-ray absorptiometry (DXA). RESULTS: Short stature [Final Height (Ht) SDS < -2] occurred in 25% of patients with no difference between the two groups of patients. Insulin growth factor 1 (IGF-1) SDS was low in 35.7 % of patients with no statistical difference among the two groups. Impaired fasting blood glucose occurred in 17.8% of patients, diabetes mellitus in 25% and hypogonadotropic hypogonadism in 10.7% of them. Morning cortisol was low in one patient. No thyroid or hypo-parathyroid abnormalities were detected in any patient. Liver iron content (LIC) > 15 mg/g dry weight and SF > 2,000 ng/mL were detected in 75% of the patients. The values resulted significantly higher in the transfused group (Group 2). High liver enzyme level (ALT) was detected in 42.8 % of patients, and the values were significantly higher in the transfused group (Group 2). Total and fetal Hb was significantly higher in group 1 versus group 2. Osteopenia was diagnosed in 14.3% of patients. Females had significantly better final height SDS, higher IGF-1 SDS, lower LIC and fasting blood glucose level compared to males. Significant correlations were found between Ht-SDS and IGF-1 SDS; LIC and SF, level; ALT and LIC, SF levels. Total and fetal Hb did not correlate significantly with Ht-SDS or IGF-1 level. CONCLUSIONS: A significant number of TI patients have high LIC, short stature and endocrine disorders. Patients who require occasional transfusions have more liver iron overload and higher hepatic dysfunction. Females appear to attain a better final adult height and have higher IGF1-SDS versus males. Our data emphasize the need for long term surveillance for identification of organ-specific risk factors and early disease manifestations. We also recommend close monitoring of endocrine and other complications, according to the international guidelines.

Severe Liver Iron Concentrations (LIC) in 24 Patients with ß-Thalassemia Major: Correlations with Serum Ferritin, Liver Enzymes and Endocrine Complications.

INTRODUCTION: Chronic blood transfusion is the mainstay of care for individuals with ß-thalassemia major (BTM). However, it causes iron-overload that requires monitoring and management by long-term iron chelation therapy to prevent endocrinopathies and cardiomyopathies, which can be fatal. Hepatic R2 MRI method (FerriScan®) has been validated as the gold standard for evaluation and monitoring liver iron concentration (LIC) that reflects the total body iron-overload. Although adequate oral iron chelation therapy (OIC) is promising for the treatment of transfusional iron-overload, some patients are less compliant with it, and others suffer from long-term effects of iron overload. OBJECTIVE: The aim of our study was to evaluate the prevalence of endocrinopathies and liver dysfunction, in relation to LIC and serum ferritin level, in a selected group of adolescents and young adult BTM patients with severe hepatic iron overload (LIC from 15 to 43 mg Fe/g dry weight). PATIENTS AND METHODS: Twenty-four selected BTM patients with severe LIC, due to transfusion-related iron-overload, followed at the Haematology Section, National Centre for Cancer Care and Research, Hamad Medical Corporation of Doha (Qatar), from April 2015 to July 2017, were retrospectively evaluated. The prevalence of short stature, hypogonadism, hypothyroidism, hypoparathyroidism, impaired fasting glucose (IFG), diabetes, and adrenal insufficiency was defined and assessed according to the International Network of Clinicians for Endocrinopathies in Thalassemia (ICET) and American Diabetes Association criteria. RESULTS: Patients' most common transfusion frequency was every three weeks (70.8%). At the time of LIC measurements, their median age was 21.5 years with a mean age of 21.7 ± 8.0 years. Mean LIC was 32.05 ± 10.53 mg Fe/g dry weight (range: 15 to 43 mg Fe/g dry weight), and mean serum ferritin level was 4,488.6 ± 2,779 µg/L. LIC was correlated significantly with serum ferritin levels (r = 0.512; p = 0.011). The overall prevalence of short stature was 26.1% (6/23), IFG was 16.7% (4/24), sub-clinical hypothyroidism was 14.3% (3/21), hypogonadotropic hypogonadism was 14.3% (2/14), diabetes mellitus was 12.5% (3/24), and biochemical adrenal insufficiency was 6.7% (1/15). The prevalence of hepatitis C positivity was 20.8% (5/24). No case of clinical hypothyroidism, adrenal insufficiency or hypoparathyroidism was detected in this cohort of patients. The prevalence of IFG impaired fasting glucose was significantly higher in BTM patients with very high LIC (>30 mg Fe/g dry liver) versus those with lower LIC (p = 0.044). The prevalence of endocrinopathies was not significantly different between the two groups of patients with LIC above and below 15 mg Fe/g dry weight. CONCLUSIONS: A significant number of BTM patients, with high LIC and endocrine disorders, still exist despite the recent developments of new oral iron chelating agents. Therefore, physicians' strategies shall optimize early identification of those patients to optimise their chelation therapy and to avoid iron-induced organ damage. We believe that further studies are needed to evaluate if serial measurements of quantitative LIC may predict the risk for endocrine complications. Until these data are available, we recommend a close monitoring of endocrine and other complications, according to the international guidelines.

Jadenu® Substituting Exjade® in Iron Overloaded ß-Thalassemia Major (BTM) Patients: A Preliminary Report of the Effects on the Tolerability, Serum Ferritin Level, Liver Iron Concentration and Biochemical Profiles.

INTRODUCTION: Due to the chronic nature of chelation therapy and the adverse consequences of iron overload, patient adherence to therapy is an important issue. Jadenu ® is a new oral formulation of deferasirox (Exjade ®) tablets for oral suspension. While Exjade® is a dispersible tablet that must be mixed in liquid and taken on an empty stomach, Jadenu ® can be taken in a single step, with or without a light meal, simplifying administration for the treatment of patients with chronic iron overload. This may significantly improve the compliance to treatment of patients with ß-thalassemia major (BMT). The aim of this study was to evaluate the drug tolerability and the effects of chelation therapy on serum ferritin concentration, liver iron concentration (LIC) and biochemical profiles in patients with BMT and iron overload. PATIENTS AND METHODS: Twelve selected adult patients BMT (mean age: 29 years; range:15-34 years) were enrolled in the study. All patients were on monthly regular red cell transfusion therapy to keep their pre-transfusional hemoglobin (Hb) level not less than 9 g/dL. They were on Exjade® therapy (30 mg/kg per day) for two years or more before starting Jadenu® therapy (14-28 mg/kg/day). The reason for shifting from Deferasirox® to Jadenu® therapy was lack of tolerability, as described by patients, such as nausea, vomiting, diarrhea, stomach pain. Most of them also reported that Deferasirox® was not palatable. Lab investigations included monthly urine analysis and measurement of their serum concentrations of creatinine, fasting blood glucose (FBG), serum ferritin, alkaline phosphatase (ALP), alanine transferase (ALT), aspartate transferase (AST) and albumin concentrations. LIC was measured using FerriScan ®. Thyroid function, vitamin D and serum parathormone, before and one year after starting Jadenu ® therapy, were also assessed. RESULTS: Apart from some minor gastrointestinal complaints reported in 3 BMT patients that did not require discontinuation of therapy, other side effects were not registered during the treatment. Subjectively, patients reported an improvement in the palatability of Jadenu® compared to Exjade® therapy in 8 out of 12 BMT patients. A non-significant decrease in LIC measured by FerriScan® and serum ferritin levels was observed after one year of treatment with Jadenu®. A significant positive correlation was found between serum ferritin level and LIC measured by the FerriScan® method. LIC and serum ferritin level correlated significantly with ALT level (r = 0.31 and 0.45 respectively, p < 0.05). No significant correlation was detected between LIC and other biochemical or hormonal parameters. CONCLUSIONS: Our study shows that short-term treatment with Jadenu ® is safe but is associated with a non-significant decrease in LIC and serum ferritin levels. Therefore, there is an urgent need for adequately-powered and high-quality trials to assess the clinical efficacy and the longterm outcomes of new deferasirox formulation.

The effect of different forms of dysglycemia during pregnancy on maternal and fetal outcomes in treated women and comparison with large cohort studies.

AIMS OF THE STUDY: We describe the impact of different forms of dysglycemia on maternal and neonatal health. This research is a part of the PEARL-Peristat Maternal and newborn registry, funded by Qatar National Research Fund (QNRF) Doha, Qatar. METHODS: A population-based retrospective data analysis of 12,255 women with singleton pregnancies screened during the year 2016-2017, of which 3,027 women were identified with gestation diabetes mellitus (GDM) during pregnancy and 233 were diabetic before pregnancy. Data on maternal outcome was collected from the PEARL-Peristat Maternal and newborn registry. RESULTS: The prevalence of GDM and diabetes mellitus (DM) was 24.7 % and 1.9%, respectively. 55% of DM, 38% of GDM and 25.6% of controls were obese (p<0.001). 71% of pregnant women with DM and 57.8% of those with GDM were older than 30 years versus 44.2% of controls. Pregnant women with DM or GDM had higher prevalence of hypertension versus normal controls (9.9%, 5.5% and 3.5%, respectively; p<0.001). Among women with vaginal deliveries, the proportion of women with induction of labor was significantly higher in the DM and GDM compared to control subjects (33.9%, 26.5% and 12.4%, respectively; p<0.001). The number of women who underwent Cesarean section was significantly higher in the DM and GDM groups versus normal controls (51.9%, 36.8%, and 28.5%, respectively; p<0.001).  Preterm delivery was significantly higher in women with DM and GDM (13.7% and 9%, respectively versus normal women (6.4%); p<0.001). Babies of DM and GDM had significantly higher occurrence of respiratory distress (RDS) or transient tachypnea (TTS): 9% and 5.8 % versus normal controls (4.8%). Macrosomia was more prevalent in babies of DM (6.4%) and GDM (6.8%) compared to controls (5%) (p: <0.001). Significant hypoglycemic episodes occurred more frequently in babies of DM and GDM women (11.2% and 3%, respectively) versus controls (0.6%) (p: <0.001. Infants of DM and GDM mothers required more treatments of phototherapy (9.4% and 8.9%, respectively) versus those born to normal women (7.2%) (p: 0.006). The prevalence of congenital anomalies and neonatal death did not differ between the groups. CONCLUSIONS: Despite the improvement in the prenatal diagnosis and management of dysglycemia, there is still a higher prevalence of prematurity, macrosomia, and hypoglycemia in infants of mothers with DM and GDM. Measurements to reduce obesity and control dysglycemia in women during the childbearing period are highly required to prevent the still higher morbidity during pregnancy.