Visfatin, low-grade inflammation and body mass index (BMI)

Objective Visfatin is an adipokine with revealing roles in inflammatory mechanisms but its implication in inflammation related to excessive adiposity/obesity is not studied yet. Our aim was to investigate the relations of visfatin with inflammation markers and body mass index (BMI) in the peripheral blood mononuclear cells (PBMCs), a type of cells closely related to inflammatory mechanisms. Design Cross‐sectional study, quantification of visfatin, TNF‐α, IL‐6 mRNA in PBMCs. Patients Eighty‐three supposed healthy individuals from the STANISLAS cohort, belonging in three BMI categories: BMI < 25 kg/m² (lean), 25 kg/m² ≤ BMI < 30 kg/m² (overweight) or BMI ≥ 30 kg/m² (obese). Measurements We measured visfatin gene expression (by real‐time quantitative PCR), in relation to gene expression of the pro‐inflammatory cytokines TNF‐α, IL‐6 in PBMCs and to anthropometric parameters (weight, BMI, waist : hip ratio), blood pressure, lipid profile, glucose and inflammatory markers (C‐reactive protein, lymphocyte count). Results Visfatin expression in PBMCs was significantly associated with BMI in a negative way (r = –0·21, P = 0·05). Global anova analysis test for lean and over‐weight/obese individuals showed a negative significant association between visfatin expression in PBMCs and BMI both for men and women (P = 0·05 and P = 0·01, respectively) and these associations remained significant after separating subjects in three groups (lean, overweight, obese) for men and women (P = 0·02 and P = 0·05, respectively). Correlation analysis between levels of expression of visfatin and TNF‐α showed a significant positive linear association (r² = 0·27, P < 0·0001). Conclusion These findings reveal a probable new role of visfatin in inflammation reflected in PBMCs, in the context of obesity.     

Relationship between ghrelin and the metabolic syndrome in the elderly: a longitudinal population-based study

Context Ghrelin regulates energy homeostasis and may contribute to the development of the metabolic syndrome (MS) in the elderly. Objective To study the relationship between ghrelin and the MS, IGF‐I and life style factors over a 2‐year follow‐up. Design Longitudinal population‐based study, starting from 2002; 2 years follow‐up. Participants Three hundred and thirteen (153 men/160 women) individuals living independently older than 70 years. Results MS was found in 54·9% of men and 61% of women. In the 229 subjects available at follow‐up, ghrelin was higher in men than in women at basal (P = 0·002) and 2‐year follow‐up (P = 0·004). Ghrelin decreased over time in both genders (P < 0·01). Ghrelin was lower in individuals showing MS compared to non‐MS (P = 0·08), but this difference was more evident at 2‐year follow‐up (P = 0·016), mostly due to men with MS (P = 0·002) and even after adjustment for BMI, gender and age. Individuals with MS had an OR of 1·67 (95% CI: 1·0–2·78) for low ghrelin (< first tertile); when adjusting by BMI, gender and age, only high triglycerides with OR 1·8 (1·0–3·3), remained statistically significant among the MS components. IGF‐I showed a positive correlation with ghrelin only in individuals without MS (r_s 0·403, P < 0·001) with no gender differences; this relationship was not found in MS (r_s 0·120, P = 0·129). A positive association of ghrelin was found with academic level, alcohol consumption and smoking. Conclusions Ghrelin is higher in old men in comparison to women and decreases over time with a steeper decline in subjects with MS; moreover, in these subjects ghrelin/IGF‐I correlation is lost.     

High immunohistochemical expression of p‐AKT predicts inferior survival in patients with diffuse large B‐cell lymphoma treated with immunochemotherapy

Chemotherapy and rituximab (R) is current standard therapy in diffuse large B‐cell lymphoma (DLBCL), but a substantial proportion of patients still fail to reach sustained remission. In vitro studies have indicated that rituximab resistance could be accompanied by dysregulated apoptotic pathways, such as the phosphatidylinositol 3‐kinase (PI3K)/AKT signaling pathway, which can be constitutively activated in DLBCL. In this retrospective, immunohistochemical study on 106 patients treated with R‐CHO(E)P (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab [+etoposide]), we investigated the prognostic role of proteins involved in different apoptotic pathways; phosphorylated AKT (p‐AKT), bcl‐2, MCL1, bcl‐xL, Bax and Bak. High p‐AKT expression (>108 cells/mm², highest quartile, n = 27) predicted worse progression‐free (PFS) (P = 0·02) and overall (OS) (P = 0·01) survival, independent of International Prognostic Index and sex. Also bcl‐2+ (cut‐off 50%) predicted worse PFS (P = 0·005) and OS (P = 0·05) but after adjustment for clinical factors only the influence on PFS (P = 0·03) remained significant. The prognostic impact of p‐AKT overexpression was independent of bcl‐2 status. MCL1, bcl‐xL, Bax and Bak expression did not add any prognostic information. Our results suggest that high p‐AKT expression predicts worse outcome, possibly indicating that inhibition of the activated PI3K/AKT pathway could be of clinical interest in DLBCL patients. In addition, bcl‐2 status could have prognostic importance also in the era of immunochemotherapy.     

Influence of ethnicity on IGF-I and procollagen III peptide (P-III-P) in elite athletes and its effect on the ability to detect GH abuse

Context A method based on the two GH dependent markers, IGF‐I and procollagen III peptide (P‐III‐P) has been proposed to detect exogenously administered GH. As previous studies involved predominantly white European elite athletes, it is necessary to validate the method in other ethnic groups. Objective To examine serum IGF‐I and P‐III‐P in elite athletes of different ethnicities within 2 h of competing at national or international events. Design Cross‐sectional observational study. Setting National and International sporting events. Subjects 1085 elite athletes of different ethnicities. Intervention Serum IGF‐I and P‐III‐P were measured and GH‐2000 discriminant function score was calculated. Effect of ethnicity was assessed. Results In men, IGF‐I was 21·7 ± 2·6% lower in Afro‐Caribbeans than white Europeans (P < 0·0001) but there were no differences between other ethnic groups. In women, IGF‐I was 14·2 ± 5·1% lower in Afro‐Caribbeans (P = 0·005) and 15·6 ± 7·0% higher in Orientals (P = 0·02) compared with white Europeans. P‐III‐P was 15·2 ± 3·5%, 26·6 ± 6·6% and 19·3 ± 5·8% lower in Afro‐Caribbean (P < 0·0001), Indo‐Asian (P < 0·0001) and Oriental men (P = 0·001), respectively, compared with white European men. In women, P‐III‐P was 15·7 ± 4·7% lower in Afro‐Caribbeans compared to white Europeans (P =0·0009) but there were no differences between other ethnicities. Despite these differences, most observations were below the upper 99% prediction limits derived from white European athletes. All GH‐2000 scores lay below the cut‐off limit proposed for doping. Conclusions The GH‐2000 detection method based on IGF‐I and P‐III‐P would be valid in all ethnic groups.     

Significant inverse relationship between serum free T4 concentration and body mass index in euthyroid subjects: differences between smokers and nonsmokers

Objective There are conflicting data regarding the relationship between thyroid function and body mass index (BMI) in euthyroid subjects, and it is uncertain whether tobacco smoking modifies this relationship. The objective of this study was to examine the relationships between thyroid function, BMI and smoking in euthyroid subjects. Design Linear regression models were used to examine the relationships between serum free T4, serum TSH, BMI and smoking in a cross‐sectional, community‐based sample of 1853 euthyroid subjects in Busselton, Western Australia. Results There was a significant negative relationship between free T4 and BMI: after adjustment for age and sex, each 1 pmol/l increase in free T4 was associated with a decrease in BMI of 0·12 kg/m² (95% CI 0·06, 0·18; P < 0·001). The mean BMI ± SD of subjects in the highest quintile of free T4 concentration was 24·4 ± 3·5 kg/m², compared with 26·1 ± 3·8 kg/m² for the lowest quintile. The relationship between free T4 and BMI was statistically significant (adjusted for age and sex) in subjects who had never smoked (P = 0·001) and former smokers (P = 0·011), but not in current smokers (P = 0·77). There was no significant relationship between TSH and BMI: after adjustment for age and sex, each 1 mU/l increase in TSH was associated with an increase in BMI of 0·08 kg/m² (95% CI –0·16, 0·32; P = 0·53). Conclusions In euthyroid subjects, small differences in free T4 are associated with differences in BMI. This relationship is not present in current smokers. We speculate that this may be relevant to weight changes associated with smoking cessation.     

Molecular characteristics in papillary thyroid cancers (PTCs) with no 131I uptake

Objective Papillary thyroid cancers (PTCs) with no iodine uptake have an aggressive behaviour and a poor prognosis. The aim of our study was to characterize, at molecular level, a subset of PTC with no 131 iodine (¹³¹I) uptake. Design and methods Forty‐eight cancer tissues were divided into three groups: Group 1, 28 primary cancers; Group 2, 7 recurrences capable of trapping ¹³¹I; and Group 3, 13 recurrences incapable of trapping ¹³¹I. mRNA levels of thyroid genes (sodium/iodide symporter NIS, thyroglobulin, thyroperoxidase and pendrin) and glycolytic metabolism genes (GLUT‐1, hexokinase I and II) and BRAF mutations were evaluated in the different groups. Results Cancers with no ¹³¹I uptake had slightly reduced NIS, significantly reduced thyroglobulin (P < 0·01), thyroperoxidase (P = 0·01) and pendrin (P = 0·03) and significantly increased GLUT‐1 (P = 0·01) gene expression levels; and a high frequency of BRAF mutations (77%). BRAF^V600E mutation, in both primary and metastatic thyroid cancers, is associated with a marked drop in thyroperoxidase (29‐fold) and pendrin (20‐fold) expression and a considerable increase (five‐fold) in GLUT‐1 expression. Conclusions (1) The loss of ¹³¹I uptake in recurrences depends not only on a decrease in NIS gene, but possibly on a reduction in the molecules regulating its intracellular metabolism; (2) the high GLUT‐1 gene expression supports the use of positron emission tomography with specific tracers in clinical management of such cancers; and (3) BRAF^V600E point mutations may lead to less differentiated phenotypes, suggesting a worse prognosis.     

Does partial surgical tumour removal influence the response to octreotide‐LAR in acromegalic patients previously resistant to the somatostatin analogue?

Objective To compare the intrapatient response to the same dose of slow‐release octreotide (OCT‐LAR) before and after noncurative surgery in acromegalic patients who did not attain disease control after primary treatment with OCT‐LAR. Design Prospective clinical study. Patients Eleven acromegalic patients (eight men, aged 42·45 ± 11·15 years, 10 macroadenomas) received OCT‐LAR (20 mg, n = 1; 30 mg, n = 10) every 28 days as the primary treatment (1stOCT‐LAR) for 11·3 ± 4·2 months, without IGF‐I normalization. They were subsequently submitted to surgery without cure and were then treated with the same dose of OCT‐LAR for 8·0 ± 6·5 months (2ndOCT‐LAR). Measurements GH and IGF‐I serum concentrations were obtained under basal conditions as well as during treatment. Pituitary tumour volume was assessed by magnetic resonance imaging (MRI) of the sella. IGF‐I was also expressed as a percentage of the upper limit of the normal age‐ and sex‐matched range (%ULNR IGF‐I). Results After 1stOCT‐LAR, there was a decrease in GH levels (P = 0·003) and %ULNR IGF‐I (P = 0·009) compared to baseline (B), but no IGF‐I normalization. Tumour shrinkage was observed in eight of 10 patients with macroadenomas (median 63·7%, range 24·5–75·5%). After surgery, mean levels of GH and %ULNR IGF‐I were lower than those at baseline (P = 0·0004 and P = 0·003, respectively), but not when compared to values during 1stOCT‐LAR (P = 1·000 and P = 0·957, respectively). MRI confirmed surgical tumour removal (median 64%, range 4·9–96·6%) in eight of the 10 patients. Comparing the 2ndOCT‐LAR results with postsurgical results, there were no significant decrease in %ULNR IGF‐I (P = 0·061) and GH levels (P = 0·414). Nine patients (82%) achieved IGF‐I normalization. The degree of surgical tumour reduction did not correlate with IGF‐I normalization (P = 0·794). When comparing the results between 1stOCT‐LAR and 2ndOCT‐LAR, there was a decrease, albeit not statistically significant, in serum GH levels (P = 0·059) and a significant decrease in %ULNR IGF‐I (P = 0·011). Conclusions Using strict criteria (same patient, same drug, same dose) our results strongly suggest that the surgical reduction of tumour mass can improve the outcome of OCT‐LAR treatment in acromegalic patients resistant to primary therapy with SA.     

Epitope recognition patterns of thyroid peroxidase autoantibodies in healthy individuals and patients with Hashimoto's thyroiditis*

Objective Thyroid peroxidase antibodies (TPOAb) are markers of autoimmune thyroid disease (AITD), including Hashimoto's thyroiditis (HT), but naturally occurring TPOAb are also detectable in healthy, euthyroid individuals. In AITD, circulating TPOAb react mainly with two immunodominant regions (IDR), IDR‐A and IDR‐B. The present study was undertaken in order to compare the epitope recognition pattern of TPOAb in HT patients and healthy subjects. Design Sera from 21 out of 98 healthy controls were selected on the basis of high TPOAb values, required for determination of TPOAb recognition pattern; as were sera from 92 HT patients. Measurements Measurement of IDR‐reactivity was possible in 90 patients and 12 controls. IDR‐A‐, IDR‐B‐ and non‐IDR‐A/non‐IDR‐B‐Ab constituted 24 ± 11%, 50 ± 15% and 26 ± 12%, respectively, in the patients. The distribution in the controls was distinctly different, only 12 ± 13% being directed against IDR‐A (P < 0·002) and 66 ± 22% against IDR‐B (P < 0·002). Half of the healthy individuals, vs. none of the HT patients, lacked IDR‐A reactivity completely (P < 0·0001). In HT patients, IDR‐B‐Ab proportions increased slightly with increasing TPOAb levels (P < 0·05), while IDR‐B‐Ab of the controls showed a strong opposite trend (P < 0·0001). Accordingly, the proportion of non‐A/non‐B‐Ab correlated with TPOAb levels in the healthy controls (P < 0·008), and an inverse correlation was seen in HT patients (P < 0·02). Conclusion The data suggest that TPOAb do not differ only in quantity between HT patients and healthy individuals, but may also follow distinct qualitative patterns. Larger studies are required to confirm this, and to determine whether the propensity to produce antibodies to certain TPO epitopes, for example, IDR‐A, is of pathogenic relevance.     

Endothelial nitric oxide synthase Glu298Asp, 4b/a, and T-786C polymorphisms in type 2 diabetic retinopathy

Objective The possible association between the endothelial nitric oxide (eNOS) gene T‐786C (promoter region), 27‐bp repeat 4b/4a (intron 4), and Glu298Asp (exon 7) polymorphisms with diabetic retinopathy (DR) was investigated. Design A retrospective case‐control study. Patients A total of 872 type 2 diabetes (T2DM) patients were studied, of whom 383 presented with preproliferative/proliferative retinopathy (DR group), and 489 with absent/mild retinopathy (DWR group). Measurements Glu298Asp and T‐786C genotyping was carried out by PCR‐RFLP analysis, while 4b/4a was assessed by PCR. Genotype distribution was compared using the χ²‐test, and the contributions of the polymorphisms to DR were analysed by haplotype analysis and multivariate regression analysis. Results Lower prevalence of mutant 4a (P = 0·011), and heterozygous 4b/4a (P = 0·042) were seen in the DR compared to the DWR groups; the allele and genotype distribution of the Glu298Asp and T‐786C polymorphisms were comparable between DR and DWR groups. Three‐loci haplotype analysis demonstrated significant association between eNOS variants and DR, with protective [haplotype 122 (Glu298/4a/‐786C)], and susceptible haplotypes [haplotypes 112 (Glu298/4b/‐786C) and 222 (Asp298/4a/‐786C)] identified. Multivariate regression analysis confirmed the association between haplotypes 122 (P = 0·015); 112 (P = 0·027), and 222 (P = 0·048) and DR, after controlling for potential covariates (including age, sex, age of disease onset; HbA1c; hypertension, total cholesterol). Conclusions This study identifies genetic variation at the eNOS locus as genetic risk factor for diabetic retinopathy, which may serve as a useful marker of increased susceptibility to the risk of retinopathy.     

Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness

Background Critical illness results in activation of the hypothalamic–pituitary–adrenal (HPA) axis, which might be accompanied by a peripheral adaptation in glucocorticoid sensitivity. Tissue sensitivity is determined by the active glucocorticoid receptor GRα, of which two splice variants involving the hormone‐binding domain exist, GRβ and GR‐P. Objective To study tissue mRNA expression of the GR and its splice variants in fatal critical illness. Design and methods We assessed mRNA expression of the GRα, GRβ and GR‐P variants in liver (n = 58) and muscle (n = 65) of patients who had died after intensive care, and had been randomized for insulin treatment. We analysed whether GR mRNA expression was associated with insulin treatment, cortisol levels and glucocorticoid treatment. Results GRα and GR‐P mRNA constituted 87 ± 8% and 13 ± 2%, respectively, of total GR mRNA in liver. GRβ mRNA could only be amplified in five liver samples. All variants were present in most muscle samples (α = 96 ± 11%, P = 3·9 ± 0·4%, β = 0·010 ± 0·002%). GR expression was not associated with insulin therapy. A strong positive relationship was observed between the different GR variants in both liver and muscle (P < 0·001 for all). Serum cortisol levels were negatively associated with liver GRα and muscle GR‐P expression (P < 0·05). mRNA expression of both liver GRα and GR‐P, but not muscle GR, was substantially lower in patients who had received exogenous glucocorticoids (P < 0·01). Conclusion We demonstrate the presence of GRα and GR‐P mRNA in liver and of GRα, GRβ and GR‐P mRNA in muscle, with no evidence for altered splicing in critical illness. In contrast to muscle GR, liver GR expression was substantially lower in patients receiving exogenous glucocorticoids.     

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.     

Reduced thyroid volume and nodularity in dyslipidaemic patients on statin treatment

Background Little information is available concerning the possible antiproliferative effects of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors (statins) on the thyroid gland. We have hypothesized that the antiproliferative effects of statins observed in thyroid cell lines in vitro may have a clinical counterpart that could be detected by investigating the prevalence and size of thyroid nodules in patients on long‐term treatment with statins. Methods We retrospectively evaluated 135 dyslipidaemic patients receiving statin therapy continuously for at least 5 years, and 137 controls. All the subjects were submitted to ultrasound investigation of the thyroid gland, to establish prevalence, number and volume of thyroid nodules. Results Subjects treated with statins showed markedly lower prevalence of thyroid nodules (36·3%vs. 67·9%, P < 0·001), as well as reduced number and smaller total volume of lesions, as compared to the control group. A logistic regression analysis, taking into account age, sex, risk factors for the development of thyroid nodules and concomitant drug treatment, revealed that treatment with statins remained the only important predictor of the presence of thyroid nodules [odds ratio (OR) 0·312, 95% confidence interval (CI) 0·156–0·625, P < 0·001] besides risk factors. Conclusions Our data provide the first circumstantial evidence of an association between HMG‐CoA reductase inhibitor treatment and reduced prevalence, number and volume of thyroid nodules. This finding may be explained by an antiproliferative and/or pro‐apoptotic effect of long‐term statin treatment on thyroid cells, in vivo.     

Glucocorticoid replacement is associated with hypertriglyceridaemia, elevated glucose and higher non-HDL cholesterol and may diminish the association of HDL cholesterol with the -629C>A CETP promoter polymorphism in GH-receiving hypopituitary patients

Objectives The effect of glucocorticoid substitution on the prevalence of metabolic syndrome components (NCEP ATP III criteria) and serum lipid levels was determined in GH‐replaced hypopituitary patients. As glucocorticoid replacement is associated with a pronounced decrease in plasma cholesteryl ester transfer protein (CETP) activity, we also tested associations of HDL cholesterol with the –629C>A CETP promoter polymorphism in subjects with and without ACTH deficiency. Design and patients In a university setting, we retrieved protocolized clinical and laboratory data from 165 adult hypopituitary patients, who had received GH for 1 year. Results After adjustment for age, sex and smoking, non‐HDL cholesterol (P = 0·05) and triglycerides (P = 0·004) were higher, but HDL cholesterol was not decreased in 117 glucocorticoid (mainly cortisone acetate in two divided doses) receiving subjects compared to 48 ACTH‐sufficient subjects. The prevalence of elevated plasma glucose and/or diabetes (P = 0·04) and hypertriglyceridaemia (P = 0·005), but not of other metabolic syndrome components, was higher in glucocorticoid‐replaced subjects. HDL cholesterol was higher in –629 A allele carriers compared to –629CC homozygotes in ACTH‐sufficient subjects (P = 0·04), but not in glucocorticoid‐treated subjects (P = 0·13). Multiple linear regression analysis demonstrated that only in ACTH‐sufficient subjects, HDL cholesterol was independently related to this CETP gene variation (P = 0·03). Conclusions In GH‐ and glucocorticoid‐replaced hypopituitary patients, serum non‐HDL cholesterol and triglycerides are higher and the prevalence of hyperglycaemia is increased, but HDL cholesterol is not decreased. Conventional glucocorticoid replacement appears to diminish the association of HDL cholesterol with a common CETP gene variation.     

The serum levels of the EGF-like homeotic protein dlk1 correlate with different metabolic parameters in two hormonally different children populations in Spain

Background The Dlk1 gene encodes for dlk1, a transmembrane protein belonging to the EGF‐like repeat‐containing family. Dlk1 has been shown to act as a regulator of adipogenesis. Fc‐dlk1 transgenic mice show a decrease in adipose tissue and glucose tolerance, hypertriglyceridaemia and lower insulin sensitivity. Dlk1‐deficient mice show growth retardation, increased serum lipid metabolites and develop obesity. These data advocate for a role of dlk1 in the maintenance of lipid homeostasis, and suggest that dlk1 levels may influence the development of cardiovascular disease. Aim and methods In this study, we analysed whether dlk1 serum levels could be indicative of the different hormonal or metabolic status shown by two Spanish children populations (6–8 years‐old), Orense and Murcia. We determined dlk1 serum levels by ELISA assay, using an antibody raised against the recombinant protein, and performed a correlation analysis against measurements of several hormonal and biochemical parameters in samples from 494 subjects. Results We found a statistically significant positive correlation between serum levels of dlk1 and those of glucose (P < 0·05), total cholesterol (P < 0·01) and high‐density lipoprotein‐cholesterol (HDL‐C) (P < 0·01) in children from Murcia, but not from Orense's population, where dehydroepiandrosterone‐sulphate (DHEA‐S) levels were significantly higher (P < 0·01) and dlk1 correlated positively with insulin (P < 0·01), homeostasis model assessment (HOMA) (P < 0·01) and free fatty acids (FFA) (P < 0·05). Conclusions dlk1 serum levels appear related to the anabolic status of the children in association with changes in the levels of DHEA‐S, which have been associated with hyperinsulinaemia and diabetes. Monitoring dlk1 levels may be important to evaluate the metabolic and hormonal stage of child development.     

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.     

Substance P is increased in patients with sickle cell disease and associated with haemolysis and hydroxycarbamide use

Sickle cell disease (SCD) pain transitions from acute to chronic for unknown reasons. Chronic elevation of the pain neurotransmitter substance P (SP) sensitizes pain nociceptors. We evaluated SP levels in controls and SCD patients during baseline and acute pain and investigated associations between SP and age, gender, pain history, haemolysis and hydroxycarbamide (also termed hydroxyurea) use. Plasma SP levels were measured using enzyme‐linked immunosorbent assay. Independent samples t‐test compared SP levels between: (i) SCD baseline and controls, and (ii) SCD baseline and acute pain. Multivariate linear regression determined associations between SP and age, gender, pain history and hydroxycarbamide use. Spearman correlation determined an association between SP and haemolysis. We enrolled 35 African American controls, 25 SCD baseline and 12 SCD pain patients. SCD patients were 7‐19 years old. Mean ± standard deviation SP level (pg/ml) in SCD baseline was higher than controls (32·4 ± 11·6 vs. 22·9 ± 7·6, P = 0·0009). SP in SCD pain was higher than baseline (78·1 ± 43·4 vs. 32·4 ± 11·6, P = 0·004). Haemolysis correlated with increased SP: Hb (r = ?0·7, P = 0·0002), reticulocyte count (r = 0·61, P = 0·0016), bilirubin (r = 0·68, P = 0·0216), lactate dehydrogenase (r = 0·62, P = 0·0332), aspartate aminotransferase (r = 0·68, P = 0·003). Patients taking hydroxycarbamide had increased SP (β = 29·2, P = 0·007). SP could be a mediator of or marker for pain sensitization in SCD and a biomarker and/or target for novel pain treatment.     

Complex karyotype predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lymphocytic leukaemia

Complex karyotype (CK) on metaphase cytogenetics discriminates poor outcome in chronic lymphocytic leukaemia (CLL) patients undergoing salvage treatment; we hypothesized that it might provide prognostic information for patients undergoing allogeneic stem cell transplant. Fifty‐one CLL patients were analysed following transplant; 18‐month overall survival (OS), event‐free survival (EFS) and cumulative incidence of progression estimates were 35%, 14% and 63%, respectively, in patients with CK (n = 19) versus 83%, 68% and 29% in patients without (n = 32) (P ≤ 0·0001, P ≤ 0·0001, and P = 0·02). In patients with high‐risk interphase cytogenetics, CK remained predictive of worse OS (P = 0·02) and EFS (P = 0·009). These findings support further evaluation of metaphase karyotype in transplant risk assessment.