Non‐D Rh antibodies appearing after apheresis platelet transfusion: stimulation by red cells or microparticles?

Background Apheresis platelets (APs) have gained favour over whole blood‐derived platelets on the presumption that they are less likely to provoke alloimmunization to red‐blood‐cell antigens. Case Reports Non‐D Rh antibodies appeared in three patients after apheresis platelet transfusion. Anti‐C and anti‐E arose in two female patients with previous antigen exposure. Both anti‐c and anti‐E arose in a male recipient with no prior transfusion history. Materials and Methods Fifty APs were analysed for residual RBCs and RBC‐derived microparticles, using samples obtained from a local blood centre. Cells and microparticles were quantified with a flow cytometry gating scheme, using PE‐labelled anti‐CD235a (glycophorin A) and FITC‐labelled anti‐CD41a (platelet gp IIb/IIIa) to distinguish lineage. Results Apheresis platelets were found to contain a mean of 7·5 × 10⁶ (95% C.I. [6·3–8·5 × 10⁶]) RBCs on one manufacturer’s device and 5·2 × 10⁶ (95% C.I. [4·0–6·3 × 10⁶]) RBCs on another’s. RBC‐derived microparticles averaged 210·7 × 10⁶ (95% C.I. [166·2–254·2 × 10⁶]) on one manufacturer’s device and 232·3 × 10⁶ (95% C.I. [194·3–272·9 × 10⁶]) on another’s. These counts all correspond to volumes of < 1 μl. Conclusion Despite RBC contamination of APs below commonly accepted thresholds for Rh immunogenicity, AP transfusion can provoke non‐D Rh antibody formation. RBC‐derived microparticles, smaller but more numerous than RBCs, are volumetrically comparable and may be a hitherto underappreciated antibody stimulus. Further microparticle research will guide considerations of extended phenotypic matching of platelet components.     

Bone demineralization in adult thalassaemic patients: contribution of GH and IGF-I at different skeletal sites

Background and objective GH and IGF‐I exert an important role in the control of bone formation, as shown by decreased bone mineral density and increased fracture risk in adult hypopituitary patients untreated for GH deficiency (GHD). Different degrees of bone demineralization are frequently reported in patients affected by β‐thalassaemia. Considering the high prevalence of GHD recently observed by our group among adult thalassaemic patients, we elected to study the possible role of GH–IGF‐I abnormalities in the pathogenesis of the osteopenia/osteoporosis of this disease. Design Sixty‐four adult thalassaemic patients (49 with thalassaemia major and 15 with thalassaemia intermedia, 23 men and 41 women, aged 31·4 ± 6·8 years) were studied. Methods Bone mineral density was assessed by dual energy X‐ray absorptiometry at lumbar spine in 62 patients and at proximal femur in 58. All patients underwent GHRH (1 µg/kg as an i.v. bolus) plus arginine (0·5 g/kg as a 30‐min i.v. infusion) testing. Severe GHD was defined by GH peaks < 9 µg/l, whereas partial GHD was defined by GH peaks ranging from 9 to 16·5 µg/l. Blood samples for IGF‐I measurement were collected. Results Lumbar osteoporosis and osteopenia were demonstrated in 46/62 (74·1%) and 14/62 (22·5%) patients, respectively. Femoral osteoporosis and osteopenia were documented in 22/58 (37·9%) and 32/58 (55·1%) patients, respectively. Severe GHD was demonstrated in 16/64 patients (25%), while 11 additional patients (17·1%) displayed partial GHD. IGF‐I standard deviation score (SDS) was low, that is, below –1·88, in the majority (54·6%) of patients. Lumbar T‐score values were not correlated with either GH peaks or IGF‐I SDS values. Femoral T‐score values were positively correlated with GH peaks (r = 0·38, P < 0·005) and IGF‐I SDS values (r = 0·39, P < 0·005). Multiple regression analysis pointed to both GH peak and IGF‐I SDS as predictors of femoral T‐score. Furthermore, mean femoral T‐score was significantly lower in patients with severe GHD than in those with normal GH secretion (–2·94 ± 0·25 vs.–2·15 ± 0·12, P < 0·01). Conclusion This study, while confirming the high prevalence of both osteopenia/osteoporosis and somatotropin–somatomedin deficiency in adult thalassaemic patients, indicates that defective GH secretion and diminished serum IGF‐I levels may contribute to femoral demineralization in these patients. Further studies are worth carrying out to evaluate the efficacy of biosynthetic GH administration on bone abnormalities of GH‐deficient thalassaemic adults.     

Venous thromboembolism and hypercoagulability in splenectomized patients with thalassaemia intermedia

Thromboembolic phenomena have been described in patients with thalassaemia intermedia and major, although there are relatively few epidemiological data on the overall frequency of these complications. To obtain more insight into the risk and mechanism of venous thromboembolism in thalassaemia, the aims of this study were: (i) to establish retrospectively the prevalence of thromboembolic events in a large group of adults with thalassaemia intermedia and major during a follow up period of 10 years; (ii) to measure in subgroups of these patients sensitive markers of activation of coagulation and fibrinolysis enzymes; and (iii) to look for possible procoagulant mechanisms. A high prevalence of thromboembolic events was found, particularly in splenectomized patients with thalassaemia intermedia (29%). These patients had high plasma levels of markers of coagulation and fibrinolysis activation. Furthermore, thalassaemic red cells and erythroid precursors from splenectomized patients with thalassaemia intermedia had an enhanced capacity to generate thrombin. To evaluate the role of splenectomy per se on procoagulant activity, we evaluated the capacity to form thrombin in healthy individuals who had been splenectomized for trauma. They produced the same amount of thrombin as non-splenectomized controls. In conclusion, the results of this study show the existence of a hypercoagulable state in splenectomized patients with thalassaemia intermedia and that their red and erythroid cells are capable of acting as activated platelets in thrombin generation.     

Insulin sensitivity assessment with euglycemic insulin clamp in adult beta-thalassaemia major patients

Objective: To assess insulin sensitivity in young adult normoglycemic β‐thalassaemia major patients. Methods: We measured insulin sensitivity with the euglycemic insulin clamp in 10 young adult (mean age 24.85 ± 2.45 yrs) normoglycemic β‐thalassaemia major patients and 10 sex‐ & age‐ matched controls. Liver iron accumulation was assessed by magnetic resonance imaging (MRI). Results: Glucose infusion rate (M) required to maintain euglycemia was significantly reduced in thalassaemic patients compared to controls (261.5 ± 63.5 mg/m²·min vs. 355.6 ± 35.3 mg/m²·min, P = 0.008). Consequently, significantly reduced in the thalassaemic group were also tissue sensitivity to insulin (M/I_s‐s) and glucose metabolic clearance rate (M/G_s‐s). There was significant negative correlation between ferritin levels and glucose infusion rate (r = ?0.918 P = 0.004). No significant correlations were observed between age, body mass index, daily transfusional iron accumulation, liver iron content and any of the euglycemic clamp parameters. Fasting insulin levels were significantly increased in patients with β‐thalassaemia major compared to controls (P = 0.01), and had significant negative correlation to MRI‐derived liver iron content (r = ?0.733, P = 0.03). Conclusions: Our data indicate that reduced insulin sensitivity resulting in hyperinsulinaemia precedes the manifestation of glucose intolerance in patients with β‐thalassaemia major. Insulin resistance seems to correlate with increased serum ferritin levels.     

Phospholipid transfer protein activity is determined by type 2 diabetes mellitus and metabolic syndrome, and is positively associated with serum transaminases

Background The extent to which plasma phospholipid transfer protein (PLTP) activity is affected by type 2 diabetes mellitus (DM) and metabolic syndrome (MetS) is still unknown. PLTP is synthesized in the liver, and elevated serum transaminases are considered to predict nonalcoholic fatty liver disease (NAFLD). In this study, we examined the relationship between plasma PLTP activity and liver enzymes in subjects with and without DM and MetS. Design Plasma PLTP activity, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured in 71 subjects without DM or MetS, 21 without DM but with MetS, 26 with DM but without MetS and 55 with DM and MetS (WHO and NCEP‐ATP III criteria). Results After controlling for age, sex and alcohol intake, PLTP activity was positively related to both MetS (P < 0·001) and DM (P = 0·001). Serum ALT (P = 0·006) and AST (P = 0·04) were both associated with MetS, but only ALT was associated with DM (P < 0·001). In multiple linear regression models, serum ALT and AST were positively and independently associated with PLTP activity (P < 0·01 for all), even when the presence of MetS and DM was taken into account, as well as after controlling for glycated haemoglobin (HbA_1c), insulin resistance, triglycerides, free fatty acids (FFA), C‐reactive protein (CRP), leptin and adiponectin. Conclusions Plasma PLTP activity is determined by MetS and by diabetes per se. Serum transaminases are independently associated with PLTP activity. We suggest that this lipid transfer protein may be a marker for NAFLD.     

Flow cytometric assessment of circulating platelet and erythrocytes microparticles in young thalassemia major patients: relation to pulmonary hypertension and aortic wall stiffness

Heart disease is the leading cause of mortality and morbidity in β‐thalassemia major (β‐TM). Aggregability of abnormal red cells and membrane‐derived microparticles (MPs) stemming from activated platelets and erythrocytes are responsible for thrombotic risk. We measured platelet and erythrocyte MPs (PMPs and ErMPs) in 60 young β‐TM patients compared with 40 age‐ and sex‐matched healthy controls and assessed their relation to clinicopathological characteristics and aortic elastic properties. Patients were studied stressing on transfusion history, splenectomy, thrombotic events, chelation therapy, hematological and coagulation profiles, flow cytometric measurement of PMPs (CD41b⁺) and ErMPs (glycophorin A⁺) as well as echocardiographic assessment of aortic elastic properties. Aortic stiffness index and pulmonary artery pressure were significantly higher, whereas aortic strain and distensibility were lower in TM patients than controls (P < 0.001). Both PMPs and ErMPs were significantly elevated in TM patients compared with controls, particularly patients with risk of pulmonary hypertension, history of thrombosis, splenectomy or serum ferritin >2500 μg/L (P < 0.001). Compliant patients on chelation therapy had lower MPs levels than non‐compliant patients (P < 0.001). PMPs and ErMPs were positively correlated to markers of hemolysis, serum ferritin, D‐dimer, vWF Ag, and aortic stiffness, whereas negatively correlated to hemoglobin level and aortic distensibility (P < 0.05). We suggest that increased MPs may be implicated in vascular dysfunction, pulmonary hypertension risk, and aortic wall stiffness observed in thalassemia patients. Their quantification could provide utility for early detection of cardiovascular abnormalities and monitoring the biological efficacy of chelation therapy.     

Inflammatory markers and visceral fat are inversely associated with maximal oxygen consumption in women with polycystic ovary syndrome (PCOS)

Background We investigated whether several different inflammatory markers including C‐reactive protein (CRP) and fibrinogen and white blood cells (WBCs) count, are associated with maximal oxygen consumption (VO_2max) in women with polycystic ovary syndrome (PCOS). Methods In PCOS women (n = 124, 24·1 ± 4·5 year‐old) VO_2max was measured during symptom‐limited cardiopulmonary exercise test. Abdominal fat distribution was determined by ultrasound. Physical activity level was assessed by a standardized questionnaire. CRP was measured by immunoassays, fibrinogen by the Clauss method, and WBCs count with a Coulter counter. Results Pearson's analysis showed a significant correlation between VO_2max and logCRP (r = –0·437, P < 0·001), fibrinogen (r = –0·479, P < 0·001), and WBCs count (r = –0·438, P < 0·001). Multivariable logistic regression model showed that age (β = –0·127, P = 0·005), AUC_INS (β = –0·335, P < 0·001), HDL‐C (β = 0·390, P < 0·001), physical activity score (β = 0·238, P = 0·002), visceral fat (β =–0·184), P = 0·023), FAI (β = –0·291, P = 0·028); CRP (β = –0·216, P = 0·011), fibrinogen (β = –0·113, P = 0·008) and WBCs count (β = –0·177, P < 0·001) were significantly associated with VO_2max. Conclusions Acute‐phase reactants, such as CRP and fibrinogen, and WBCs count were independently and inversely associated with a direct measure of cardiorespiratory fitness (VO_2max) in women with PCOS, even after adjustment for physical activity level and other potential confounding factors. These findings add to the growing body of evidence linking inflammation to cardiorespiratory fitness in PCOS women.     

Blood transfusion requirements and independent predictors of increased transfusion requirements among adult patients on extracorporeal membrane oxygenation – a single centre experience

Background/Objectives More adults undergo extracorporeal membrane oxygenation (ECMO) now. They have high transfusion requirements. This study described transfusion requirements of adults during ECMO in a single institution, and determined factors associated with high transfusion requirements. Materials/Methods Retrospective analysis was done on the amount of blood products received by adults during ECMO. Predictors of increased average daily transfusion requirements during ECMO and increased ECMO duration (which correlated positively with total transfusion requirements) were determined. Results Forty‐one patients (median age 50 years) underwent 42 ECMO sessions for respiratory failure (16·7%), cardiogenic shock (76·2%) or massive pulmonary embolism (7·1%). They received 569 red blood cells, 852 platelets, 126 fresh‐frozen plasma (FFP) and 220 cryoprecipitate in total during median ECMO duration of 5 (1–15) days. On multivariate analysis, average daily red blood cell transfusion increased with nadir haemoglobin (Hb) during ECMO (Hb_nadir) of < 7·5 g/dl (P < 0·001). Average daily platelet transfusion increased with recent antiplatelet agents (P = 0·015) and maximum Hb decline of > 5·5 g/dl during ECMO (P = 0·011). Average daily platelet transfusion > 3 units was also associated with increased ECMO duration (P = 0·024). Average daily FFP transfusion was increased in patients with hypertension (P = 0·007) and Hb_nadir < 7·5 g/dl (P = 0·050). Patients with sepsis (P = 0·009) or without surgery (P = 0·009) had increased ECMO duration, which correlated positively with total transfusion requirements during the entire ECMO session. ECMO improved mortality of patients with fulminant myocarditis, respiratory failure and massive pulmonary embolism. Conclusion Adult ECMO patients with lower Hb_nadir require more daily red blood cell and FFP. Hypertension increases daily FFP requirements. Recent antiplatelet agents, larger Hb decline and longer ECMO duration increase daily platelet requirements. Patients with sepsis or on ECMO for medical reasons have longer ECMO duration, which is associated with total transfusion requirements. Some of these factors may be identified early to optimize blood product support.     

Pre-gravid physical activity and reduced risk of glucose intolerance in pregnancy: the role of insulin sensitivity

Objective Pre‐gravid physical activity has been associated with a reduced risk of gestational diabetes mellitus (GDM), although neither the types of exercise nor the physiologic mechanisms underlying this protective effect have been well‐studied. Thus, we sought to study the relationships between types of pre‐gravid physical activity and metabolic parameters in pregnancy, including glucose tolerance, insulin sensitivity and β‐cell function. Design/patients/measurements A total of 851 women underwent a glucose challenge test (GCT) and a 3‐h oral glucose tolerance test (OGTT) in late pregnancy, yielding four glucose tolerance groups: (i) GDM; (ii) gestational impaired glucose tolerance (GIGT); (iii) abnormal GCT with normal glucose tolerance on OGTT (abnormal GCT NGT); and (iv) normal GCT with NGT on OGTT (normal GCT NGT). Pre‐gravid physical activity was assessed using the Baecke questionnaire, which measures (i) total physical activity and (ii) its three component domains: work, nonsport leisure‐time, and vigorous/sports activity. Results Glucose tolerance status improved across increasing quartiles of pre‐gravid total physical activity (P = 0·0244). Whereas neither work nor nonsport leisure‐time activity differed between glucose tolerance groups, pre‐gravid vigorous/sports activity was significantly higher in women with normal GCT NGT compared to women with (i) abnormal GCT NGT (P = 0·0018) (ii) GIGT (P = 0·0025), and (iii) GDM (P = 0·0044). In particular, vigorous/sports activity correlated with insulin sensitivity (measured by IS_OGTT) (r = 0·21, P < 0·0001). Furthermore, on multiple linear regression analysis, pre‐gravid vigorous/sports activity emerged as a significant independent predictor of IS_OGTT in pregnancy (t = 4·97, P < 0·0001). Conclusions Pre‐gravid vigorous/sports activity is associated with a reduced risk of glucose intolerance in pregnancy, an effect likely mediated by enhanced insulin sensitivity.     

Biomodulatory metronomic therapy induces PET‐negative remission in chemo‐ and brentuximab‐refractory Hodgkin lymphoma

There are limited reports that baseline peripheral absolute neutrophil count (ANC), absolute monocyte count (AMC), absolute lymphocyte count (ALC) and serum β2‐microglobulin level independently predict survival in patients with diffuse large B‐cell lymphoma (DLBCL). To confirm these findings, we analysed these parameters together with components of the International Prognostic Index (IPI) in patients with newly‐diagnosed DLBCL. We evaluated baseline clinical features for their ability to predict survival in 817 newly diagnosed, previously untreated patients with DLBCL who received frontline treatments between October 2001 and December 2011. The median age at diagnosis was 58 years. Multivariate analysis identified elevated baseline ANC (P = 0·036), AMC (P = 0·028) and serum β2‐microglobulin level (P < 0·001), poor performance status (P < 0·001) and high number of extranodal disease sites (P = 0·0497) as independent unfavourable predictors of OS; serum β2‐microglobulin level was the strongest predictor of survival outcomes among all the parameters. High baseline serum β2‐microglobulin, ANC and AMC levels are independent prognostic factors for short overall survival in patients with newly diagnosed DLBCL. Our new model, based on the above five parameters, better stratifies patients into various risk categories than the IPI for newly diagnosed DLBCL.     

High plasma C-reactive protein (CRP) is related to low paraoxonase-I (PON-I) activity independently of high leptin and low adiponectin in type 2 diabetes mellitus

Objectives In type 2 diabetes mellitus, circulating C‐reactive protein (CRP) is increased, whereas the high density lipoprotein (HDL)‐associated, anti‐oxidative and anti‐inflammatory enzyme, paraoxonase‐I, is decreased. Both high CRP and low paraoxonase‐I activity may predict cardiovascular disease. It is unknown whether lower paraoxonase‐I activity contributes to higher CRP levels in diabetes. In type 2 diabetic and control subjects, we determined the relationship of CRP with paraoxonase‐I when taking account of plasma levels of pro‐ and anti‐inflammatory adipokines. Design and patients In 81 type 2 diabetic patients and 89 control subjects, plasma high‐sensitive CRP, serum paraoxonase‐I activity (arylesterase activity, assayed as the rate of hydrolysis of phenyl acetate into phenol), plasma leptin, adiponectin, resistin and lipids were determined. Results Body mass index (BMI), waist, insulin resistance, triglycerides, CRP, leptin and resistin levels were higher (P < 0·05 to P < 0·001), whereas HDL cholesterol, paraoxonase‐I activity and adiponectin levels were lower (P = 0·02 to P < 0·001) in diabetic compared to control subjects. Multiple linear regression analysis demonstrated that, after controlling for age and gender, CRP was inversely related to paraoxonase‐I activity (β = –0·15, P = 0·028) and adiponectin (β = –0·18, P = 0·009), and positively to leptin (β = 0·33, P < 0·001) and BMI (β = 0·22, P = 0·007), independently of the diabetic state (or of fasting glucose or HbA1c), insulin resistance and lipids (P > 0·20 for all). Conclusions low paraoxonase‐I activity is related to higher CRP, independently of adipokines, as well as of obesity and lipids. Low paraoxonase‐I activity in type 2 diabetes mellitus may contribute to increased cardiovascular risk via an effect on enhanced systemic low‐grade inflammation.     

Metformin increases fasting plasma peptide tyrosine tyrosine (PYY) in women with polycystic ovarian syndrome (PCOS)

Objective The beneficial effects of metformin in patients with type 2 diabetes mellitus (T2DM) and polycystic ovarian syndrome (PCOS) are thought to be in part due to weight reduction. However, the mechanisms by which metformin causes weight loss are unclear. We sought to determine whether circulating levels of the anorectic gut hormone peptide tyrosine tyrosine (PYY) show any correlation with metformin‐induced weight loss. Design and patients We examined the acute effects of orally administrated metformin on fasting PYY levels in eight healthy normal‐weight female subjects. Subsequently, we evaluated the effects of 6 months metformin treatment on fasting PYY levels and anthropometric measurements in 20 women with PCOS. Results In normal‐weight females 10 days’ metformin treatment increased fasting PYY levels (P < 0·01). Similarly, in PCOS subjects metformin treatment increased fasting PYY concentrations (P < 0·05). In both groups a marked variation in PYY increase in response to metformin was observed. Long‐term metformin treatment was associated with improvements in weight (P < 0·05), BMI (P < 0·05), fasting glucose (P < 0·05) and menstrual frequency (P < 0·01). Interestingly, change in PYY levels were correlated with change in waist circumference (r = 0·55, P < 0·05). Conclusions Acute and chronic oral metformin administration increase fasting PYY levels and may contribute to metformin's weight loss effect. Further studies are now required to clarify whether changes in circulating PYY levels in response to metformin treatment can be used to predict which patients will subsequently lose weight long‐term and gain cycle restoration.     

Obestatin and ghrelin levels in obese children and adolescents before and after reduction of overweight

Objectives Obestatin and ghrelin, which are derived from the same gene, are observed to have opposite effects on weight status. The aims of this study were to compare obestatin concentrations in obese and normal‐weight children and to analyse the effect of weight loss on obestatin and ghrelin levels. Methods We examined anthropometrical markers and fasting serum obestatin, ghrelin, leptin, glucose and insulin concentrations in 44 obese children (mean age 11·2 years) before and after participating in a 1‐year outpatient obesity intervention programme based on a high‐carbohydrate, fat‐reduced diet and increased physical activity. Additionally, total ghrelin, obestatin and leptin levels were determined in 22 normal‐weight healthy children of similar age, gender and pubertal stage. Results Obestatin and leptin concentrations were significantly (P < 0·001) higher and ghrelin concentrations were significantly (P < 0·001) lower in obese children compared to nonobese children. In contrast to the 13 children without weight loss, substantial weight loss in 31 children led to a significant (P = 0·007) increase in obestatin and to a significant (P < 0·05) decrease in leptin and insulin concentrations, while ghrelin concentrations did not change significantly. Children with substantial weight loss demonstrated significantly (P = 0·009) lower obestatin and a tendency (P = 0·064) to higher ghrelin concentrations at baseline. Changes in insulin were not related to changes in ghrelin or obestatin. Conclusion The increase in obestatin and the decrease in ghrelin in obese children point towards an adaptation process of weight status. Weight reduction due to a long‐term lifestyle intervention resulted in an increase in obestatin levels.     

Serum resistin is positively correlated with the accumulation of metabolic syndrome factors in type 2 diabetes

Objective Resistin, secreted from adipocytes, causes insulin resistance in rodents. We reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at ?420 increases type 2 diabetes (T2DM) susceptibility by enhancing promoter activity. We also showed that serum resistin was positively correlated with G at SNP‐420, the duration of T2DM, and HbA1c in T2DM. The aim of this study was to determine the relation between serum resistin and factors related to the metabolic syndrome (MetS) in T2DM. Design, patients and measurements We analysed 238 Japanese T2DM subjects (124 males and 114 females, age 60·2 ± 11·3 years, body mass index (BMI) 24·1 ± 3·9) whose overnight fasting sera were available. Serum resistin was measured using ELISA. Results Serum resistin was higher in subjects with either obesity (P = 0·041), low HDL (P = 0·004), high triglycerides (TG) (P = 0·019), hypertension (HT) (P = 0·001) or atherosclerosis (P = 0·012). Simple regression analysis revealed that serum resistin was correlated with lower HDL, TG and high‐sensitivity C‐reactive protein (hsCRP). Multiple regression analysis (or logistic regression analysis for HT), adjusted for age, gender, BMI and the duration of T2DM, revealed that serum resistin was correlated with lower HDL (P = 0·008), TG (P = 0·041), HT (P = 0·031) and hsCRP (P = 0·004). Serum resistin was positively correlated with the number of MetS factors, independent of age, gender and the duration of T2DM (P < 0·001). Adjustment by either thiazolidinedione (TZD) treatment or hsCRP had no effects on these findings. Conclusions Serum resistin was positively correlated with the accumulation of MetS factors in T2DM.     

Poor correlations between measurements of bone quality by quantitative ultrasound sonography and dual energy X-ray absorptiometry in patients with beta-thalassaemia major

Objectives: Osteopenia/osteoporosis is a major component of morbidity even in young patients with β‐thalassaemia major. Dual energy X‐ray absorptiometry (DXA) is the reference method for determining bone mineral density (BMD). Quantitative ultrasound sonography (QUS) for bone measurement is a relatively new, inexpensive and radiation‐free method that could serve as an alternative to DXA. Our aim was to assess bone status in thalassaemic patients both with QUS and DXA and, consequently, to investigate the degree of correlation between the two methods. Methods: Thirty‐three patients (15 male and 18 female) with β‐thalassaemia major, regularly transfused and systematically iron‐chelated, participated in the study. Mean age was 22.0 ± 8.0 yr (range: 6.5–41.0 yr). All patients were evaluated with QUS at radius and tibia and had DXA scan at lumbar spine vertebrae (L2–L4), whereas 20 patients were additionally assessed with DXA at the left hip (femoral neck, trochanter region and Ward’s triangle). Results: Results were expressed as Z‐scores compared with sex‐ and age‐matched population. Lowest mean Z‐scores measured with DXA were recorded at lumbar spine and Ward’s triangle (?1.1 ± 1.13 and ?0.95 ± 1.07, respectively). Lowest mean QUS‐derived Z‐scores were measured at radius, statistically significant compared with Z‐scores measured at tibia (?0.6 ± 1.1 vs. 0.4 ± 1.1, P < 0.001). QUS measurements at radius were significantly correlated to QUS measurements at tibia (r = 0.51, P = 0.002). The latter were correlated to BMD measured at lumbar spine (r = 0.516, P = 0.002) and at trochanter region (r = 0.646, P = 0.003). All BMD measurements at hip were significantly correlated to each other. Lumbar spine BMD was correlated to BMD at femoral neck (r = 0.607, P = 0.003) and to BMD at Ward’s triangle (r = 0.438, P = 0.027). Finally, no agreement was recorded between the two methods in identifying thalassaemic patients at risk for osteoporosis (κ = 0.203, P = 0.04). Conclusion: Quantitative ultrasound sonography could not serve as an alternate to DXA.     

The clinical impact of IKZF1 deletions in paediatric B‐cell precursor acute lymphoblastic leukaemia is independent of minimal residual disease stratification in Nordic Society for Paediatric Haematology and Oncology treatment protocols used between 1992 and 2013

Paediatric B‐cell precursor acute lymphoblastic leukaemias (BCP ALL) with IKZF1 deletions (?IKZF1) are associated with a poor outcome. However, there are conflicting data as to whether ?IKZF1 is an independent risk factor if minimal residual disease (MRD) and other copy number alterations also are taken into account. We investigated 334 paediatric BCP ALL, diagnosed 1992–2013 and treated according to Nordic Society for Paediatric Haematology and Oncology ALL protocols, with known IKZF1 status based on either single nucleotide polymorphism array (N = 218) or multiplex ligation‐dependent probe amplification (N = 116) analyses. ?IKZF1, found in 15%, was associated with inferior 10‐year probabilities of event‐free (60% vs. 83%; P < 0·001) and overall survival (pOS; 73% vs. 89%; P = 0·001). Adjusting for known risk factors, including white blood cell (WBC) count and MRD, ?IKZF1 was the strongest independent factor for relapse and death. ?IKZF1 was present in 27% of cases with non‐informative cytogenetics (‘BCP‐other’) and a poor 10‐year pOS was particularly pronounced in this group (58% vs. 90%; P < 0·001). Importantly, neither MRD nor WBC count predicted events in the ?IKZF1‐positive cases. Co‐occurrence of pseudoautosomal region 1 (PAR1) deletions in Xp22.33/Yp11.32 (P2RY8‐CRLF2) and ?IKZF1 increased the risk of relapse (75% vs. 30% for cases with only ?IKZF1; P = 0·045), indicating that BCP‐other ALL with both P2RY8‐CRLF2 and ?IKZF1 constitutes a particularly high‐risk group.     

Effects of T4 replacement therapy on glucose metabolism in subjects with subclinical (SH) and overt hypothyroidism (OH)

Objective To evaluate β‐cell function and insulin sensitivity in subjects with overt (OH) and subclinical hypothyroidism (SH) before and after T4 replacement therapy. Background Disturbances in glucose metabolism have been observed in hypothyroid states. However, the clinical significance and potential reversibility of these alterations by T4 replacement therapy remain to be elucidated especially in patients with SH. Design and patients Parameters of glucose metabolism have been investigated in subjects with OH (n = 12) and SH (n = 11). Insulin sensitivity has been assessed by the euglycaemic–hyperinsulinaemic clamp technique and β‐cell function by mathematical modelling of data derived from an oral glucose tolerance test. Results Fasting and dynamic glycaemia as assessed by the AUC_Glucose remained unaltered following substitution therapy (P > 0·05). Insulin sensitivity significantly improved only in subjects with OH (P < 0·05). Fasting insulin and proinsulin concentrations increased proportionally in both groups (P < 0·05) with the proinsulin : insulin ratio remaining unchanged (P > 0·05). Total insulin secretion was higher in OH before initiation of therapy (P < 0·05). In both groups, dynamic parameters including total insulin secretion, hepatic insulin extraction and the adaptation index were significantly attenuated (P < 0·05) after restoration of thyroid function, whereas the disposition index and the basal insulin secretion rate remained unaltered (P > 0·05). Conclusion In summary, SH and OH are characterized by attenuated basal plasma insulin levels and increased glucose‐induced insulin secretion. T4 replacement therapy partially ameliorates the insulin secretion profile and reduces the demand on pancreatic β‐cells after glucose challenge to an extent that exceeds any effect attributable to the improvement in insulin sensitivity.     

Staged diabetes management according to individual patient insulin resistance and beta-cell function ameliorates glycaemic control in type 2 diabetes mellitus

Objective The current consensus algorithm for management of type 2 diabetes is based on the fasting glucose concentration and glycated haemoglobin A_1c (HbA_1c) level. We applied a new therapeutic strategy by assessing insulin secretion and insulin resistance, in addition to glucose concentrations in individual patients. Design and patients We enrolled 193 patients with type 2 diabetes. The patients were assigned to one of six groups according to insulin secretion measured by the serum fasting C‐peptide concentration and insulin resistance measured by an insulin tolerance test (ITT). The two groups were treated differently: 108 patients were treated using a new staged diabetes management (SDM) strategy and 85 patients continued with conventional therapy. Measurements We compared metabolic variables in the two groups at baseline and 12 months after enrolment. Results In patients treated with the SDM strategy, fasting glucose concentration decreased from 9·8 ± 2·1 to 8·2 ± 1·7 mmol/l (P < 0·001). Postprandial 2‐h glucose concentration decreased from 14·19 ± 3·34 to 12·27 ± 3·24 mmol/l (P < 0·001). HbA_1c level decreased from 8·37 ± 1·42% to 7·72 ± 1·39% (P < 0·001). About 43% of the new SDM group achieved an HbA_1c of < 7·0% compared with 25% of patients in the conventional treatment group. Conclusions The new SDM strategy, based on individual data on insulin resistance and insulin secretion, may provide valuable clinical benefits in non‐obese Korean patients with type 2 diabetes.     

Concentrations of the acute phase reactants high-sensitive C-reactive protein and YKL-40 and of interleukin-6 before and after treatment in patients with acromegaly and growth hormone deficiency

Background Acromegaly is accompanied by increased cardiovascular mortality and a cluster of proatherogenic risk factors. In the general population, ischaemic heart disease (IHD) is associated with elevated levels of inflammatory markers. The acute phase reactant (APR) C‐reactive protein (CRP) has been reported to be reduced in acromegaly and increase after treatment, suggesting that excess of GH/IGF‐I could have anti‐inflammatory effects. This is in accordance with results obtained in patients with growth hormone deficiency (GHD), where increased levels of CRP have been reported. Objective To investigate the hypothesis that the GH/IGF‐I system is a suppressive regulator of inflammatory processes. Subjects and methods Twenty‐one acromegalic patients and 19 GH‐deficient patients were studied. The two APRs CRP and YKL‐40 and the proinflammatory cytokine interleukin‐6 (IL‐6) were measured before and after treatment and in healthy matched controls. Results In acromegalic patients, serum concentrations of high‐sensitive CRP (hsCRP) and YKL‐40 were reduced compared to controls (P < 0·001) and increased (P < 0·001) after treatment, together with IL‐6 (P = 0·021), to levels comparable with controls. Pretreatment serum YKL‐40 and IL‐6 showed a significant inverse correlation with IGF‐I and GH. In GH‐deficient patients, hsCRP and YKL‐40 were elevated compared to controls (P = 0·001 and P = 0·048). During treatment, levels of both APRs showed a trend towards a decrease (P = 0·087 and P = 0·060), and after treatment, levels of YKL‐40 no longer differed from that of controls. Serum IL‐6 was not different from controls and did not change during GH treatment. Conclusion The results point to the possibility of a relationship between GH disturbances and inflammatory processes.