The effects of hydroxycarbamide on the plasma proteome of children with sickle cell anaemia

We investigated changes in the plasma proteome of children with sickle cell anaemia (SCA) associated with hydroxycarbamide (HC) use, to further characterize the actions of HC. Fifty-one children with SCA consented to take part in this study. Eighteen were taking HC at a median dose of 22 mg/kg, and 33 were not on HC. Plasma was analysed using an unbiased proteomic approach and a panel of 92 neurological biomarkers. HC was associated with increased haemoglobin (Hb) (89·8 vs. 81·4 g/l, P = 0·007) and HbF (6·7 vs. 15·3%, P < 0·001). Seventeen proteins were decreased on HC compared to controls by a factor of <0·77, and six proteins showed >1·3 increased concentration. HC use was associated with reduced haemolysis (lower α, β, δ globin chains, haptoglobin-related protein, complement C9; higher haemopexin), reduced inflammation (lower α-1-acid glycoprotein, CD5 antigen-like protein, ceruloplasmin, factor XII, immunoglobulins, cysteine-rich secretory protein 3, vitamin D-binding protein) and decreased activation of coagulation (lower factor XII, carboxypeptidase B2, platelet basic protein). There was a significant correlation between the increase in HbF% on HC and haemopexin levels (r = 0·603, P = 0·023). This study demonstrated three ways in which HC may be beneficial in SCA, and identified novel proteins that may be useful to monitor therapeutic response.     

“Great Expectations”-Continued: Realistic Expectations: A Look at Childhood Asthma in the 1980s

Clinical features of adult-relapse asthma (group B, n = 15) were compared with those of child-onset asthma (group A, n = 18) and adult-onset asthma (group C, n = 34) in terms of allergic component and bronchial hypersensitivity. The percentage of patients with high levels of serum IgE (>300 U/ml) in groups A, B, and C was 83%, 73%, and 50%, respectively, and the percentage of patients with positive IgE RAST for house dust was 87.5%, 78.6%, and 46.7%, and that for mite was 93.3%, 92.9%, and 58.6% in groups A, B, and C, respectively. The histamine concentration of PC20 for the bronchial hypersensitivity test in groups A, B, and C was 196 µg/ml, 500 µg/ml, and 724 µg/ml, respectively. Thus, the adult-relapse asthma was closer to the child-onset asthma type in allergic state and closer to the adult-onset asthma type in bronchial hypersensitivity state. The classification employed here seemed to provide some merits in delineating the features of adulthood asthma.     

Higher anti-TNF serum levels are associated with perianal fistula closure in Crohn’s disease patients

Objectives: Anti-TNF agents are effective to treat perianal Crohn’s disease (CD). Evidence suggests that Crohn’s disease patients with perianal fistulas need higher infliximab (IFX) serum concentrations compared to patients without perianal CD to achieve complete disease control. Our aim was to compare anti-TNF serum concentrations between patients with actively draining and closed perianal fistulas.

Methods: A retrospective survey was performed in CD patients with perianal disease treated with IFX or adalimumab (ADL). Fistula closure was defined as absence of active drainage at gentle finger compression and/or fistula healing on magnetic resonance imaging.

Results: We identified 66?CD patients with a history of perianal fistulas treated with IFX (n?=?47) and ADL (n?=?19). Median IFX serum trough concentrations ([interquartile range]) were higher in patients with closed fistulas (n?=?32) compared to patients with actively draining fistulas (n?=?15): 6.0?µg/ml [5.4–6.9] versus 2.3?µg/ml [1.1–4.0], respectively (p?<?.001)). A similar difference was seen in patients treated with ADL: median serum concentrations were 7.4?µg/ml [6.5–10.8] in 13 patients with closed fistulas versus 4.8?µg/ml [1.7–6.2] in 6 patients with producing fistulas (p?=?.003). Serum concentrations of ≥5.0?µg/ml for IFX (area under the curve of 0.92; 95% CI: 0.82–1.00)) and 5.9?µg/ml for ADL (area under the curve of 0.89; 95% CI 0.71–1.00) were associated with fistula closure.

Conclusion: Cut-off serum concentrations ≥5.0?µg/ml for IFX and ≥5.9?µg/ml for ADL were associated with perianal fistula closure. Hence, patients with producing perianal fistulas may benefit from anti-TNF dose intensification to achieve fistula closure.     

The acute phase inflammatory response to maximal exercise testing in children and young adults with sickle cell anaemia

Although individuals with sickle cell anaemia (SCA) have elevated baseline inflammation and endothelial activation, the acute phase response to maximal exercise has not been evaluated among children with SCA. We measured the acute phase response to maximal exercise testing for soluble vascular cell adhesion molecule (sVCAM) as well as interleukin 6 (IL6), total white blood cell (WBC) count, C‐reactive protein (CRP) and D‐dimer in a cohort of children with SCA and matched controls at baseline, immediately after, and 30, 60 and 120 min following exercise. Despite higher baseline levels of all biomarkers except CRP, the acute phase response from baseline to immediately after exercise was significantly greater in subjects versus controls for CRP (2·1 vs. 0·2 mg/l, P = 0·02) and D‐dimer (160 vs. 10 μg/l, P < 0·01) only. Similar between‐group trends were observed over time for all biomarkers, including sVCAM, IL6, total WBC, CRP and D‐dimer. Lower fitness, defined by peak oxygen consumption (VO₂), was independently associated with greater acute phase responses to exercise for sVCAM. Our results suggest maximal exercise may not be associated with any greater escalation of endothelial activation or inflammation in SCA and provide preliminary biomarker evidence for the safety of brief, high‐intensity physical exertion in children with SCA.     

Bacteraemia in sickle cell anaemia is associated with low haemoglobin: a report of 890 admissions to a tertiary hospital in Tanzania

Bacteraemia is a leading cause of morbidity in sickle cell anaemia (SCA), but information from studies in Africa is limited. We evaluated 890 admissions from 648 SCA patients at a tertiary hospital in Tanzania. Bacteraemia was present in 43 admissions (4·8%); isolates included Staphylococcus aureus (12/43; 28%), non‐Typhi Salmonella (9/43; 21%), Streptococcus pneumoniae (3/43; 7%) and Salmonella Typhi (2/43; 5%). Compared to SCA patients without bacteraemia, SCA patients with bacteraemia had significantly lower haemoglobin [71 g/l vs. 62 g/l, odds ratio 0·72 (95% confidence interval 0·56–0·91), P < 0·01]. Further exploration is needed of the relationship between anaemia and bacterial infections in SCA in Africa.     

The impact of donor type and ABO incompatibility on transfusion requirements after nonmyeloablative haematopoietic cell transplantation

We retrospectively analyzed transfusion requirements within the first 100 d among allogeneic haematopoietic cell transplantation (HCT) recipients with haematological malignancies given either myeloablative (n = 1353) or nonmyeloablative conditioning (n = 503). We confirmed that myeloablative recipients required more platelet and red blood cell (RBC) transfusions than nonmyeloablative recipients (P < 0·0001 for both). Myeloablative patients given peripheral blood stem cells required less platelet transfusions (P < 0·0001) than those given marrow while RBC transfusion requirements did not differ significantly. Subsequent analyses were restricted to nonmyeloablative recipients. Platelet and RBC transfusions were less frequent among related compared to unrelated recipients (P < 0·0001 for both), with comparable median numbers of transfused units. Major/bidirectionally ABO‐mismatched recipients required more RBC transfusions than ABO‐matched recipients (P = 0·006). Rates of graft rejection/failure, grades II–IV acute and chronic graft‐versus‐host‐disease (GVHD), 2‐year relapse, 3‐year survivals and non‐relapse mortality were comparable among ABO‐matched, minor‐mismatched, and major/bidirectionally mismatched recipients (P = 0·93, 0·72, 0·57, 0·36, 0·17 and 0·79, respectively). Times to disappearance of anti‐donor IgG and IgM isohemagglutinins among major/bidirectionally ABO‐mismatched recipients were affected by magnitude of pre‐HCT titres (P < 0·001 for both) but not GVHD (P = 0·71 and 0·78, respectively). In conclusion, nonmyeloablative recipients required fewer platelet and RBC transfusions and among them, both unrelated and major/bidirectionally ABO‐mismatched recipients required more RBC transfusions. ABO incompatibility did not affect nonmyeloablative HCT outcomes.     

Monitoring disease activity using GH and IGF-I in the follow-up of 501 patients with acromegaly

Context The aims of treatment in patients with acromegaly are to achieve serum GH/IGF‐I concentrations associated with cure or normalization of mortality and alleviation of symptoms. Objective and methods Using the West Midlands Acromegaly database (n = 501) we investigated the reliability of basal fasting GH in predicting nadir or mean GH during oral glucose tolerance test (OGTT) or GH day curve (GHDC), respectively, the degree of discordance between disease activity measured by GH and IGF‐I values and the effect of radiotherapy on the above relationships. In total 773 OGTT and 507 GHDC were performed. Results Basal fasting GH was strongly correlated with nadir/mean GH on OGTT/GHDC (r = +0·87, P < 0·0001, r = +0·93, P < 0·0001, respectively). A basal GH < 2·5 µg/l was associated with a nadir/mean GH during OGTT/GHDC < 2·5 µg/l in 98·6% and 88·2% of cases, respectively. Elevated IGF‐I was seen in 32·4% and 46·4% of patients with GH nadir values during OGTT < 1 and < 2·5 µg/l, respectively, and in 21·2% and 45·9% of GHDC with mean GH < 1 and < 2·5 µg/l, respectively. Radiotherapy increased the discordance in GH and IGF‐I as markers of disease activity at GH < 2·5 µg/l (elevated IGF‐I‐values when OGTT nadir GH < 2·5 µg/l: radiotherapy 55·5%vs. no radiotherapy 36·9%, P = 0·002). Conclusions There is a close relationship between a basal fasting GH < 2·5 µg/l and nadir/mean GH < 2·5 µg/l during OGTT/GHDC. There is a large discordance between disease activity when assessed by GH and IGF‐I which is further increased by radiotherapy. These observations illustrate the challenge of defining appropriate biochemical end‐points to achieve control of disease and normalization of mortality in acromegaly.     

Urinary mRNA markers of epithelial-mesenchymal transition correlate with progression of diabetic nephropathy

Objective Epithelial–mesenchymal transition (EMT) plays an important role in the pathogenesis and progression of diabetic nephropathy (DN). Quantification of messenger RNA (mRNA) expression in urinary sediment is emerging as a noninvasive method of screening DN‐associated biomarkers. The aim of our study was to examine whether urinary mRNA profile of EMT‐associated genes may provide valuable clinical insight into the different stages of DN. Design and methods Diabetic nephropathy patients (n = 44) and healthy controls (n = 12) were enrolled in this study. DN patients were divided into three groups according to the levels of estimated glomerular filtration rate (eGFR): Group A (eGFR > 60 ml/min per 1·73 m², n = 27), Group B (45 < eGFR < 60 ml/min per 1·73 m², n = 9), and Group C (eGFR < 45 ml/min per 1·73 m², n = 8). Relative mRNA abundance of α‐smooth muscle actin (α‐SMA), fibronectin, FSP1 and matrix metalloproteinase‐9 (MMP‐9) were quantified, and correlations between target mRNAs and clinical parameters were examined. Results The urinary mRNA levels of α‐SMA, fibronectin and MMP‐9 were significantly higher in the DN group compared with controls (P < 0·05), and mRNA levels increased with DN progression. Urinary mRNA levels of all target genes positively correlated with both urinary albumin excretion (UAE) and blood urea nitrogen (BUN). Moreover, the expression of α‐SMA, fibronectin and MMP‐9 mRNA correlated with serum creatinine levels (r = 0·514, r = 0·53 and r = 0·469, all P < 0·001) and eGFR levels (r = ?0·374, r = ?0·392 and r = ?0·487, all P < 0·01). Conclusions Quantification of EMT‐associated genes in urinary sediment may be a novel approach for searching new biomarkers of DN.     

Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised,multicentre studies

Ravulizumab, a novel long-acting complement component 5 (C5) inhibitor administered every 8 weeks (q8w), was non-inferior to eculizumab for all efficacy outcomes in two randomised, open-label, phase 3 trials in C5 inhibitor-naïve (Study 301) and eculizumab-experienced (Study 302) adult patients with paroxysmal nocturnal haemoglobinuria (PNH). This pre-specified analysis characterised ravulizumab pharmacokinetics (PK), pharmacodynamics (PD; free C5 levels), and PD differences between medications (Study 301, n = 246; Study 302, n = 195). Ravulizumab PK parameters were determined using non-compartmental analysis. Serum free C5 was quantified with a Gyros-based fluorescence assay (ravulizumab) and an electrochemiluminescence ligand-binding assay (eculizumab). Ravulizumab PK parameters were numerically comparable in both studies; the median time to maximum concentrations ranged from 2·3 to 2·8 and 2·3 to 2·6 h in studies 301 and 302, respectively. Ravulizumab steady-state serum concentrations were achieved immediately after the first dose and sustained throughout treatment. For ravulizumab, the mean (SD) post hoc terminal elimination half-life was 49·7 (8·9) days. Serum free C5 concentrations <0·5 µg/ml were achieved after the first ravulizumab dose and sustained throughout treatment in both studies. In a minority of patients, free C5 concentrations <0·5 µg/ml were not consistently achieved with eculizumab in either study. Ravulizumab q8w was more consistent in providing immediate, complete, sustained C5 inhibition than eculizumab every-2-weeks in patients with PNH.     

Acute hyperinsulinaemia and hyperlipidaemia modify circulating adiponectin and its oligomers

Objective Obesity and insulin resistance are associated with low adiponectin levels, although adiponectin is exclusively expressed in white adipose tissue. The mechanism beyond that paradox is not entirely clear, although insulin itself may reduce circulating adiponectin levels. However, obesity is also associated with hyperlipidaemia and the effects of free fatty acids (FFAs) and triglycerides (TG) on circulating adiponectin levels have not yet been investigated. Materials and methods We analysed the effect of an acute and euglycaemic elevation of insulin on adiponectin oligomers in 23 healthy individuals. In a subgroup including 11 healthy men, FFAs and TG were acutely elevated by infusion of heparin/lipids over 120 min. Again the effect on circulating adiponectin and its oligomers was investigated. Adiponectin was determined by ELISA, oligomers were detected by nondenaturating Western blot. Results Acute hyperinsulinaemia resulted in a significant reduction of total adiponectin to 7·74 ± 0·98 µg/ml (P = 0·004). High molecular weight (HMW) adiponectin did not change (0·80 ± 0·12 to 0·81 ± 0·14 µg/ml; P = 0·887), whereas MMW adiponectin decreased from 4·30 ± 0·51 to 3·78 ± 0·48 µg/ml (P = 0·005) and LMW adiponectin from 3·63 ± 0·42 to 3·15 ± 0·46 µg/ml (P = 0·048). Interestingly, heparin/lipid infusion also reduced circulating adiponectin levels (P = 0·001), which was primarily the result of reduced MMW adiponectin (P = 0·004), whereas LMW and HMW were not significantly affected. Conclusions The presented data suggest that both, hyperinsulinaemia and hyperlipidaemia, may contribute to low adiponectin levels in states of obesity.     

Neurofilament light chain: A potential biomarker for cerebrovascular disease in children with sickle cell anaemia

Cerebrovascular injury frequently occurs in children with sickle cell anaemia (SCA). Limited access to magnetic resonance imaging and angiography (MRI-MRA) in sub-Saharan Africa impedes detection of clinically unapparent cerebrovascular injury. Blood-based brain biomarkers of cerebral infarcts have been identified in non-SCA adults. Using plasma samples from a well-characterized cross-sectional sample of Ugandan children with SCA, we explored relationships between biomarker levels and MRI-detected cerebral infarcts and transcranial Doppler (TCD) arterial velocity. Testing was performed using a 4-plex panel of brain injury biomarkers, including neurofilament light chain (NfL), a central nervous system neuron-specific protein. Mean biomarker levels from the SCA group (n = 81) were similar to those from non-SCA sibling controls (n = 54). Within the SCA group, NfL levels were significantly higher in those with MRI-detected infarcts compared to no infarcts, and higher with elevated TCD velocity versus normal velocity. Elevated NfL remained strongly associated with MRI-detected infarcts after adjusting for sex and age. All non-SCA controls and SCA participants lacking MRI-detected infarcts had low NfL levels. These data suggest potential utility of plasma-based NfL levels to identify children with SCA cerebrovascular injury. Replication and prospective studies are needed to confirm these novel findings and the clinical utility of NfL versus MRI imaging.     

Validation of keratan sulfate level in mucopolysaccharidosis type IVA by liquid chromatography–tandem mass spectrometry

Mucopolysaccharidosis type IVA (MPS IVA, Morquio A disease), a progressive lysosomal storage disease, causes skeletal chondrodysplasia through excessive storage of keratan sulfate (KS). KS is synthesized mainly in cartilage and released to the circulation. The excess storage of KS disrupts cartilage, consequently releasing more KS into circulation, which is a critical biomarker for MPS IVA. Thus, assessment of KS level provides a potential screening strategy and determines clinical course and efficacy of therapies. We have recently developed a tandem mass spectrometry liquid chromatography [LC/MS/MS] method to assay KS levels in blood. Forty-nine blood specimens from patients with MPS IVA [severe (n?=?33), attenuated (n?=?11) and undefined (n?=?5)] were analyzed for comparison of blood KS concentration with that of healthy subjects and for correlation with clinical severity. Plasma samples were digested by keratanase II to obtain disaccharides of KS. Digested samples were assayed by LC/MS/MS. We found that blood KS levels (0.4–26 µg/ml) in MPS IVA patients were significantly higher than those in age-matched controls (0.67–4.6 µg/ml; P?<?0.0001). It was found that blood KS level varied with age and clinical severity in the patients. Blood KS levels in MPS IVA peaked between 2 years and 5 years of age (mean 11.4 µg/ml). Blood KS levels in severe MPS IVA (mean 7.3 µg/ml) were higher than in the attenuated form (mean 2.1 µg/ml) (P?=?0.012). We also found elevated blood KS levels in other types of MPS. These findings indicate that the new KS assay for blood is suitable for early diagnosis and longitudinal assessment of disease severity in MPS IVA.     

Biological determinants of bleeding in patients with heterozygous factor XI deficiency

Bleeding risk is not predictable in patients with factor XI (FXI; F11) deficiency. In this prospective study, our objectives were to determine the biological determinants for bleeding risk in patients with heterozygous FXI deficiency. Patients were classified as either bleeding patients or non‐bleeding patients by calculating the bleeding score (BS) described for von Willebrand disease. Primary haemostasis, thrombin generation, thromboelastometry, procoagulant proteins, inhibitors, fibrinolysis, and F11 gene mutations were compared between bleeding and non‐bleeding patients. Thirty‐nine patients were included. BS significantly correlated with clinical assessment (P = 0·001), and a score over 3 discriminated between bleeding (n = 15) and non‐bleeding (n = 24) patients (P = 0·034). Despite normal values, von Willebrand factor (VWF) and thrombomodulin (TM) plasma levels were significantly lower in bleeding patients than non‐bleeding patients [ristocetin cofactor activity (VWF:RCo) = 80·6 ± 29·7 iu/dl and 101·8 ± 29·5 iu/dl respectively, P = 0·043; and VWF antigen (VWF:Ag) = 84·0 ± 28·0 iu/dl and 106·3 ± 36·1 iu/dl respectively, P = 0·035; and TM = 17·7 ± 11·7 ng/ml and 23·6 ± 9·7 ng/ml respectively, P = 0·043]. When considering BS as a continuous variable, only VWF:RCo remained significant (P = 0·042), which accounted for 11% of the variability in BS.     

Prospective quality control study of a novel gravity‐driven whole blood separation system suitable for humanitarian crises

Centrifugation‐based whole blood (WB) separation represents the worldwide standard but it depends on electricity and infrastructure. We have prospectively evaluated a novel hollow‐fibre WB separation system that does not require manual priming or blood flow regulation (n = 29). RBC units contained sufficient Hb (50·4 g ± 4·3), low leucocytes (90 000 ± 0·008), exhibited low haemolysis (0·57% ± 0·49) and robust ATP content (51·47% ± 8·2) after 43 days storage. Plasma units contained low leucocytes and mean coagulation factor activities for FV, FVIII and FXI were 47%, 90% and 68%, respectively. RBC met quality specifications but plasma units exhibited reduced FV and FXI activity.     

Serum concentrations of leptin, adiponectin and resistin, and their relationship with cardiovascular disease in patients with end-stage renal disease

Background and Objective High levels of some adipocytokines have been reported in patients with chronic renal failure, but little information is available on adipocytokine concentrations in uraemic patients under different modalities of therapy. Our aims were (1) to quantify the serum concentrations of leptin, adiponectin and resistin in uraemic patients on peritoneal dialysis (PD) and haemodialysis (HD), in comparison with patients on conservative management, and (2) to study the relationships between adipocytokine levels and previous atherosclerotic vascular disease. Patients and Measurements We studied 82 dialysis patients treated by PD (n = 44, 23 males and 21 females, mean age 54·4 ± 1·8 years) or HD (n = 38, 22 males and 16 females, age 60·8 ± 1·6 years). A group of 19 uraemic patients on conservative management served as the control. Serum concentrations of leptin, adiponectin and resistin were measured in all subjects. Information on vascular disease (cerebral vascular, peripheral vascular and heart disease) was obtained from a detailed medical history. Results PD patients showed significantly higher serum leptin concentrations [median (interquartile range), 28·7 (13·0–71·9) µg/l] than those found in patients on HD [9·7 (4·7–31·9) µg/l, P < 0·01] or in conservative management [5·9 (4·3–38·6) µg/l, P < 0·05]. Adiponectin concentrations were similar in the three groups of patients (mean ± SEM, 48·0 ± 4·5 mg/l in PD, 57·7 ± 4·4 mg/l in HD, and 44·4 ± 7·0 mg/l in controls, NS). Patients treated by both PD and HD exhibited resistin concentrations significantly higher than those found in controls (26·3 ± 0·99 and 27·5 ± 1·4 µg/l, respectively, vs. 17·3 ± 1·0 µg/l, P < 0·001). Leptin concentrations were positively correlated with body mass index (BMI) (r = 0·287, P < 0·01) and adiponectin levels were negatively related to BMI (r = ?0·416, P < 0·001) and the homeostatic model assessment (HOMA‐R) index (r =?0·216, P < 0·05). Leptin, adiponectin and resistin levels in patients with previous vascular events were similar to those found in patients without these complications. Logistic regression analysis did not demonstrate any relationship between serum adipocytokine concentrations and the presence of vascular disease of any type. A significant relationship between resistin and heart disease [odds ratio (OR) 1·80 (1·03–3·15), P = 0·039] was found when analysing subgroups of patients. Conclusions These data suggest that leptin levels are higher in PD patients, and resistin levels are higher in PD and HD patients in relation to patients on conservative management, whereas adiponectin concentrations are similar in the three groups. These results do not support the presence of a clinically relevant relationship between adipocytokines and previous episodes of vascular disease in the whole population or in patients classified in subgroups, with the only exception of a relationship between resistin levels and heart disease.     

Recombinant human prolactin for the treatment of lactation insufficiency

Context Lactation insufficiency has many aetiologies including complete or relative prolactin deficiency. Exogenous prolactin may increase breast milk volume in this subset. We hypothesized that recombinant human prolactin (r‐hPRL) would increase milk volume in mothers with prolactin deficiency and mothers of preterm infants with lactation insufficiency. Design Study 1: R‐hPRL was administered in an open‐label trial to mothers with prolactin deficiency. Study 2: R‐hPRL was administered in a randomized, double‐blind, placebo‐controlled trial to mothers with lactation insufficiency that developed while pumping breast milk for their preterm infants. Patients Study 1: Mothers with prolactin deficiency (n = 5). Study 2: Mothers of premature infants exclusively pumping breast milk (n = 11). Design Study 1: R‐hPRL (60 μg/kg) was administered subcutaneously every 12 h for 28 days. Study 2: Mothers of preterm infants were randomized to receive r‐hPRL (60 μg/kg), placebo or r‐hPRL alternating with placebo every 12 h for 7 days. Measurements Change in milk volume. Results Study 1: Peak prolactin (27·9 ± 17·3 to 194·6 ± 19·5 μg/l; P < 0·003) and milk volume (3·4 ± 1·6 to 66·1 ± 8·3 ml/day; P < 0·001) increased with r‐hPRL administration. Study 2: Peak prolactin increased in mothers treated with r‐hPRL every 12 h (n = 3; 79·3 ± 55·4 to 271·3 ± 36·7 μg/l; P < 0·05) and daily (101·4 ± 61·5 vs 178·9 ± 45·9 μg/l; P < 0·04), but milk volume increased only in the group treated with r‐hPRL every 12 h (53·5 ± 48·5 to 235·0 ± 135·7 ml/day; P < 0·02). Conclusion Twice daily r‐hPRL increases milk volume in mothers with prolactin deficiency and in preterm mothers with lactation insufficiency.     

Use of a GH receptor antagonist (GHRA) to explore the relationship between GH and IGF-I in adults with severe GH deficiency (GHD)

Objective At diagnosis, approximately 50% of adults with severe GH deficiency (GHD) have an IGF‐I within the reference range. It is unclear whether in such patients serum IGF‐I levels are regulated by factors other than GH. Design and patients We performed a double‐blind, randomized, placebo‐controlled, cross‐over study to investigate the effect of the GH receptor antagonist – pegvisomant (20 mg daily for 14 days) on GH and IGF‐I levels in three cohorts: patients with GHD and a normal IGF‐I (NORMS); patients with GHD and a low IGF‐I (LOWS) and healthy volunteers (CONS). Results Pegvisomant decreased IGF‐I in CONS and NORMS [158·5 (101–206) vs. 103 (77–125) µg/l, P < 0·01; 124 (81–136) vs. 95 (51–113) µg/l, P < 0·01 respectively], but not in LOWS [31 (< 31–32) vs. 34·5 (< 31–38) µg/l], and this was associated with an increase in mean 24 h GH in CONS [0·49 (0·12–0·89) to 1·38 (0·22–2·45) µg/l (P = 0·03)] and in NORMS [69 (0–320)% from 0·1 (< 0·1–0·13) to 0·17 (0·11–0·42) µg/l (P = 0·03)], but not in the LOWS. The peak GH response to arginine was increased by pegvisomant in CONS and NORMS [6·1 (0·8–9) vs. 20·4 (13·1–28·8) µg/l, P = 0·03; 0·4 (0·1–0·5) vs. 0·5 (0·3–0·6) µg/l, respectively], but not in LOWS. Conclusions These data indicate that patients with severe GHD with a normal IGF‐I are able to increase GH secretion in response to a pegvisomant‐induced fall in IGF‐I, whereas those with low IGF‐I levels are unable to increase GH secretion. Therefore circulating IGF‐I appears to be GH‐independent in GHD patients with a low IGF‐I, but remains partially GH‐dependant in GHD patients with a normal IGF‐I.     

Hydroxycarbamide treatment in sickle cell disease: estimates of possible leukaemia risk and of hospitalization survival benefit

Using health insurance claims databases we compared the frequency/incidence of acute myeloid leukaemia (AML) and inpatient mortality in sickle cell disease (SCD) subjects taking (n = 1051), or not taking (n = 9203) hydroxycarbamide (HC). Patients taking HC were older (median 19 vs. 17 years of age), had a higher proportion of males (53% vs. 38%), and their median hospitalizations per year was five times greater than in SCD patients not on HC (all P < 0·001). No new AML cases occurred in HC‐treated paediatric SCD patients. For adults, the new AML incidence with HC exposure was 10·7/10 000 patient years, vs. 4·0/10 000 patient years in subjects not on HC (P = 0·2), a possible AML risk ratio of 3·18. Adjustment for a probable database bias for AML diagnosis/ascertainment lowered the risk ratio to 0·94 (95% confidence interval = 0·16–5·47). Despite their greater disease severity, the inpatient mortality in SCD adults prescribed HC (0·29%) was lower than that of patients not taking the drug (0·42%, P = 0·032). In this SCD population we find no increased risk for AML with HC treatment. If such a risk is eventually proven, it will probably be lower than that for drugs with known AML association. By contrast, HC treatment appears to confer a survival benefit.     

Characterization of haematological parameters with bortezomib-melphalan-prednisone versus melphalan-prednisone in newly diagnosed myeloma, with evaluation of long-term outcomes and risk of thromboembolic events with use of erythropoiesis-stimulating agents: analysis of the VISTA trial

Although haematological toxicities, such as anaemia, are common in multiple myeloma (MM), no clear consensus exists on the use and impact of erythropoiesis‐stimulating agents (ESA) on outcomes in MM. This analysis characterizes haematological toxicities and associated interventions in the phase III VISTA (Velcade^® as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) study of bortezomib plus melphalan/prednisone (VMP, n = 344) versus MP (n = 338) in previously untreated MM patients ineligible for high‐dose therapy, and evaluates the impact of ESA use or red‐blood‐cell (RBC) transfusions on outcomes and thromboembolic risk. Incidence of haematological toxicities was similar with VMP and MP; similar rates of interventions and associated complications (e.g. bleeding, febrile neutropenia) were observed. Two hundred thirty three patients received ESA; 204 had RBC transfusions. Frequency of thromboembolic events was low and not affected by ESA use. Median time‐to progression (TTP) was similar between ESA/non‐ESA [hazard ratio: 1·03 (95% confidence interval 0·76–1·39); P = 0·8478] in both arms (VMP: 19·9/not reached; MP: 15·0/17·5 months). Three‐year overall survival (OS) rates were similar between ESA/non‐ESA in each arm. Patients receiving RBC transfusions had significantly shorter OS (P < 0·0001) versus non‐RBC‐transfusion patients. In conclusion, bortezomib did not add to melphalan haematological toxicity. Concomitant ESA use with VMP/MP in previously untreated MM patients did not adversely affect TTP or OS, or increase thromboembolic risk. However, RBC transfusion was associated with significantly shorter survival.     

Increased prevalence of potential right‐to‐left shunting in children with sickle cell anaemia and stroke

‘Paradoxical’ embolization via intracardiac or intrapulmonary right‐to‐left shunts (RLS ) is an established cause of stroke. Hypercoagulable states and increased right heart pressure, which both occur in sickle cell anaemia (SCA ), predispose to paradoxical embolization. We hypothesized that children with SCA and overt stroke (SCA  + stroke) have an increased prevalence of potential RLS . We performed contrasted transthoracic echocardiograms on 147 children (aged 2–19 years) with SCA  + stroke) mean age 12·7 ± 4·8 years, 54·4% male) and a control group without SCA or stroke (n  = 123; mean age 12·1 ± 4·9 years, 53·3% male). RLS was defined as any potential RLS detected by any method, including intrapulmonary shunting. Echocardiograms were masked and adjudicated centrally. The prevalence of potential RLS was significantly higher in the SCA +stroke group than controls (45·6% vs. 23·6%, P  < 0·001). The odds ratio for potential RLS in the SCA  + stroke group was 2·7 (95% confidence interval: 1·6–4·6) vs controls. In post hoc analyses, the SCA  + stroke group had a higher prevalence of intrapulmonary (23·8% vs. 5·7%, P  < 0·001) but not intracardiac shunting (21·8% vs. 18·7%, P  = 0·533). SCA patients with potential RLS were more likely to report headache at stroke onset than those without. Intrapulmonary and intracardiac shunting may be an overlooked, independent and potentially modifiable risk factor for stroke in SCA .