Ioannis Papassotiriou

Magnetic resonance imaging in the evaluation of iron overload in patients with beta thalassaemia and sickle cell disease

Magnetic resonance imaging (MRI) appears to be useful for monitoring iron overload in thalassaemia. We studied 106 patients with beta‐thalassaemia: 80 with thalassaemia major (TM) and 26 with thalassaemia intermedia (TI). Thirty‐five patients with sickle cell disease (SCD) were also evaluated. Serum ferritin, liver and myocardial T2‐relaxation time and liver iron concentration (LIC) were measured. LIC values, based on biopsies from 29 patients, showed a close inverse correlation with the respective liver T2‐values, along with a strong positive correlation with ferritin levels in all patients. Heart T2‐values correlated with left ventricular ejection fraction in TM and SCD, but not in TI patients. Both liver and heart T2‐values were significantly lower in TM patients than those of TI, and SCD patients. Ferritin levels showed a strong correlation with liver T2‐values in all three groups of patients. Similarly, a negative correlation was found between serum ferritin levels and heart T2‐values in TM, but not in TI and SCD patients. Heart and liver T2‐values showed a significant correlation only in TM patients. These results suggest that the MRI technique (T2 relaxation time) used in our study, is a reliable, safe and non‐invasive method for the assessment of the deposition of iron in the liver; results for the heart become reliable only when there is heavy iron deposition.

Elevated morning serum interleukin (IL)-6 or evening salivary cortisol concentrations predict posttraumatic stress disorder in children and adolescents six months after a motor vehicle accident.

BACKGROUND This study examined prospectively the activity of the hypothalamic-pituitary-adrenal axis, the sympathetic nervous system and inflammatory factors in children shortly after a motor vehicle accident (MVA) in relation to later posttraumatic stress disorder (PTSD) development. PATIENTS AND METHODS Fifty six children, aged 7-18, were studied after an MVA and 1 and 6 months later; 40 subjects served as controls. Morning serum cortisol and interleukin (IL)-6 and plasma catecholamine concentrations were measured within 24h after the event. Salivary cortisol was measured 5 times at defined time points during the same day. PTSD diagnoses 1 and 6 months later were based on K-SADS interview. RESULTS Morning serum IL-6 concentrations, measured within the first 24h after the accident, were higher in children that developed PTSD 6 months later than those who did not and those of the control group. Longitudinal IL-6 measurements revealed normalization of IL-6 in the PTSD group, while no differences between the three groups were detected 1 and 6 months later. Evening salivary cortisol and morning serum IL-6 after the accident were positively inter-related (r=0.54, p<0.001) and in separate regression analyses both predicted PTSD development 6 months later. In contrast, morning serum IL-6 did nor correlate with morning serum or salivary cortisol concentrations. CONCLUSIONS Immediate posttraumatic alterations in neuroendocrine or inflammatory factors-increased evening salivary cortisol and/or increased morning serum IL-6 concentrations-are involved in subsequent PTSD development in children and adolescents.

Unstable and Thalassemic α Chain Hemoglobin Variants: A Cause of Hb H Disease and Thalassemia Intermedia

We report an update of the α-globin gene point mutations resulting in structural modification associated with an α-thalassemia (α-thal) phenotype. These variants, barely symptomatic in the heterozygous state, are either unstable due to folding defects and/or defects in binding to α-hemoglobin stabilizing protein (AHSP). This is predicted to result in precipitation of the unstable α chains or Hb variant, a concomitant decrease in the overall quantity of normal α-globin in the red cells and a potential degree of anemia and possibly, hemolysis. Genotype/phenotype correlation and potential genetic risk in combination with common or less common α-thal defects are discussed.

The natural history of neuroendocrine changes in pediatric posttraumatic stress disorder (PTSD) after motor vehicle accidents: progressive divergence of noradrenaline and cortisol concentrations over time.

BACKGROUND The hypothalamic-pituitary-adrenal axis and the catecholaminergic system are involved in the pathophysiology of post-traumatic stress disorder (PTSD). This was a prospective and longitudinal study of neuroendocrine physiology in children with PTSD following a motor vehicle accident (MVA). METHODS Sixty children aged 7-18 were studied immediately after an MVA and 1 and 6 months later. Fasting morning plasma catecholamine and serum cortisol concentrations were measured. Salivary cortisol concentrations were measured serially five times daily to examine circadian variation in all three assessments. Values were compared between those who did (PTSD) or did not develop PTSD (non-PTSD) after the trauma and a control group at months 1 and 6. RESULTS Twenty-three of the children had PTSD at the 1-month and 9 children at the 6-month evaluations. 1) Plasma noradrenaline concentrations were higher in the PTSD group than in the other two groups at both months 1 and 6 (p = .001 and p = .001, respectively). Additionally, the PTSD patients presented with significantly higher salivary cortisol concentrations at 18.00 (p = .03) and 21.00 (p = .04) at month 1.2) Eight children suffering from PTSD at both months 1 and 6 had significantly elevated plasma noradrenaline concentrations at month 6 compared with those at month 1 and at baseline and to the other two groups (within subjects: p < .001; between subjects: p = .005). The initially elevated evening salivary cortisol concentrations in this group normalized at month 6. CONCLUSIONS This progressive divergence of noradrenaline and cortisol concentrations over time might underlie the natural history and pathophysiology of PTSD.

Absence of insulin resistance and low-grade inflammation despite early metabolic syndrome manifestations in children born after in vitro fertilization

OBJECTIVE To investigate the metabolic profile, traditional adipokines, and indices of insulin resistance and low-grade inflammation in children born as a result of IVF compared with spontaneously conceived controls. DESIGN Cross-sectional, case-control study. SETTING IVF Section of the First Department of Obstetrics and Gynecology and the First Department of Pediatrics of the University of Athens. PATIENT(S) One hundred six children conceived after classic IVF and 68 age-matched spontaneously conceived controls, aged 4-14 years. INTERVENTION(S) Children underwent physical examination and morning fasting samples were collected. MAIN OUTCOME MEASURE(S) Lipid profile, circulating fasting glucose, insulin, leptin, adiponectin, high-sensitivity interleukin-6, and high-sensitivity C-reactive protein were determined and the fasting glucose-to-insulin ratio was calculated. RESULT(S) Children born as a result of classic IVF had significantly higher systolic and diastolic blood pressures (BP) and triglycerides than controls. These BP differences remained significant even after correction for birth size and multiple births. No significant differences in biochemical indices of insulin resistance, circulating adipokines, and inflammatory markers were detected before or after these same corrections. CONCLUSION(S) Despite an increase of BP, children born as a result of IVF have no biochemical evidence of insulin resistance, including fasting glucose-to-insulin ratio and circulating adipokines, or low-grade chronic inflammation. However, the long-term impact of periconceptual manipulations should be closely monitored.

Phenotypic and molecular diversity of haemoglobin H disease: a Greek experience

Haemoglobin H (Hb H) disease is the severest form of α‐thalassaemia compatible with post‐natal life and occurs when α‐thalassaemia mutations interact to reduce α‐globin synthesis to levels approximately equivalent to the output of a single α‐globin gene. Hb H disease has variable clinical expression, mainly related to underlying genotypes. The spectrum of α‐thalassaemia determinants in Greece appears greater than in any other population studied and, in 75 Greek Hb H disease patients, we found 12 α‐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 α‐thalassaemia mutations had more severe clinical expression. Additionally, we found that all patients with the most severe phenotypes had α‐thalassaemic globin variants. Phenotypic severity was not simply related to the degree of α‐globin deficiency: high Hb H levels were found to exacerbate anaemia by negatively influencing tissue oxygenation, and both Hb H and α‐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.

Circulating levels of matrix metalloproteinase-9 (MMP-9), neutrophil gelatinase-associated lipocalin (NGAL) and their complex MMP-9/NGAL in breast cancer disease

BackgroundRecent evidence suggests that neutrophil gelatinase-associated lipocalin (NGAL) expression is induced in many types of human cancer, while detection of its complex with matrix metalloproteinase-9 (MMP-9) is correlated with cancer disease status. We aim to evaluate the serum expression of MMP-9, NGAL and their complex (MMP-9/NGAL) during the diagnostic work-up of women with breast abnormalities and investigate their correlation with disease severity.MethodsThe study included 113 women with non-palpable breast lesions undergoing vacuum-assisted breast biopsy for histological diagnosis, and 30 healthy women, which served as controls. Expression levels of MMP-9, NGAL and their complex MMP-9/NGAL were determined in peripheral blood samples with immunoenzymatic assays.ResultsWomen with invasive ductal carcinoma exhibited significantly increased levels of MMP-9, NGAL and MMP-9/NGAL compared to healthy controls (MMP-9: p < 0.003, NGAL: p < 0.008 MMP-9/NGAL: p < 0.01). Significant correlations were observed between MMP-9 and NGAL serum levels and breast disease severity score (r = 0.229, p < 0.006 and r = 0.206, p < 0.01, respectively), whereas a non-significant correlation was found for their complex. MMP-9, NGAL and their complex MMP-9/NGAL levels were not correlated with either Body Mass Index (BMI) or age of patients.ConclusionThese findings suggest that the serum measurement of MMP-9 and NGAL may be useful in non-invasively monitoring breast cancer progression, while supporting their potential role as early biomarkers of breast disease status.

Thiol-based antioxidant supplementation alters human skeletal muscle signaling and attenuates its inflammatory response and recovery after intense eccentric exercise

BACKGROUND The major thiol-disulfide couple of reduced glutathione (GSH) and oxidized glutathione is a key regulator of major transcriptional pathways regulating aseptic inflammation and recovery of skeletal muscle after aseptic injury. Antioxidant supplementation may hamper exercise-induced cellular adaptations. OBJECTIVE The objective was to examine how thiol-based antioxidant supplementation affects skeletal muscles performance and redox-sensitive signaling during the inflammatory and repair phases associated with exercise-induced microtrauma. DESIGN In a double-blind, crossover design, 10 men received placebo or N-acetylcysteine (NAC; 20 mg · kg(-1) · d(-1)) after muscle-damaging exercise (300 eccentric contractions). In each trial, muscle performance was measured at baseline, after exercise, 2 h after exercise, and daily for 8 consecutive days. Muscle biopsy samples from vastus lateralis and blood samples were collected before exercise and 2 h, 2 d, and 8 d after exercise. RESULTS NAC attenuated the elevation of inflammatory markers of muscle damage (creatine kinase activity, C-reactive protein, proinflammatory cytokines), nuclear factor κB phosphorylation, and the decrease in strength during the first 2 d of recovery. NAC also blunted the increase in phosphorylation of protein kinase B, mammalian target of rapamycin, p70 ribosomal S6 kinase, ribosomal protein S6, and mitogen activated protein kinase p38 at 2 and 8 d after exercise. NAC also abolished the increase in myogenic determination factor and reduced tumor necrosis factor-α 8 d after exercise. Performance was completely recovered only in the placebo group. CONCLUSION Although thiol-based antioxidant supplementation enhances GSH availability in skeletal muscle, it disrupts the skeletal muscle inflammatory response and repair capability, potentially because of a blunted activation of redox-sensitive signaling pathways. This trial was registered at clinicaltrials.gov as NCT01778309.

Leptin and adiponectin concentrations in intrauterine growth restricted and appropriate for gestational age fetuses, neonates, and their mothers.

OBJECTIVE Leptin and adiponectin are two adipocytokines that play a critical role in the control of energy balance and metabolism as well as in conditions, such as insulin resistance, inflammation, and the development of the metabolic syndrome in adult life. Leptin has been associated with asymmetric intrauterine growth restriction (IUGR). The aim of this study was to investigate the perinatal implication of leptin and adiponectin in IUGR. Design Leptin and adiponectin were measured in the plasma of 40 mothers, in the umbilical cord (UC) blood of their 20 appropriate for gestational age (AGA) and 20 IUGR singleton, full-term fetuses, and neonates on day 1 (d1) and day 4 (d4) of life postnatally. METHODS Serum leptin and adiponectin levels were measured by RIA. Serum cortisol levels were measured with an electrochemiluminescence immunoassay. RESULTS Leptin and adiponectin serum levels were higher and lower respectively in IUGR (mean+/-s.e.m., 32.5+/-3.8 and 5.4+/-0.9 mug/l respectively) compared with AGA (20.4+/-2.1 and 11.8+/-1.3 mug/l respectively) mothers (P<0.05), although body mass index did not differ between these two groups. Leptin levels positively correlated with adiponectin levels in the AGA (r=0.547, P<0.05) but not in the IUGR mothers. UC, d1, and d4 leptin and adiponectin levels did not differ between IUGR and AGA groups. UC were significantly higher than d1 leptin levels (P<0.05) in the IUGR group but not in the AGA group. CONCLUSIONS The increased UC leptin levels compared with d1 in IUGR fetuses might be directly and/or indirectly related to the subsequent development of insulin resistance in these neonates. This pathologic situation seems to be related to a specific profile of increased leptin and decreased adiponectin levels in IUGR mothers indicating a genetic predisposition for the development of insulin resistance.

Early indicators of dysmetabolic syndrome in young survivors of acute lymphoblastic leukemia in childhood as a target for preventing disease.

Purpose To investigate the presence of early indicators of the dysmetabolic syndrome (DS) in young survivors with acute lymphoblastic leukemia (ALL) in childhood. Patients and Methods We enrolled 80 patients with ALL (50 males, median age 13.9 y, median interval since completion of chemotherapy 6.3 y). Sixty-two patients (group A) received chemotherapy only, whereas 18 patients (group B) received chemotherapy and cranial irradiation (18 Gy). Results Frank obesity [25%; confidence interval (CI) 95%, 16.7%-35.6%], increased blood pressure (21%; CI 95%, 13.6%-31.5%), increased serum triglycerides (21%; CI 95%, 13.6%-31.5%), reduced serum high-density lipoprotein cholesterol (12%; CI 95%, 6.7%-21.7%), increased fasting insulin (8%; CI 95%, 3.2%-15.7%), and osteopenia (71%; CI 95%, 60.5%-80.1%) were detected in groups A and B. Reduced IGF-1 (15%; CI 95%, 8.6%-24.6%) and thyroid hormone abnormalities (11%; CI 95%, 5.8%-20.2%) were detected only in group B. In group B, there was a statistically significant increase in the prevalence of obesity (P=0.024), hyperinsulinemia (P=0.004), and the full DS (22%; CI 95%, 8.6%-45.9% vs. 8%; CI 95%, 3.1%-18.0%; P=0.017) compared with group A. Conclusions Young survivors of childhood ALL, especially those treated with cranial irradiation, are at risk for obesity, dyslipidemia, insulin resistance, hypertension, and the full DS early after the completion of therapy.