Retinol-binding protein in nonobese women with polycystic ovary syndrome

Objective Although polycystic ovary syndrome (PCOS) is frequently associated with insulin resistance, cardiovascular disease and various metabolic diseases, the mechanisms linking PCOS to metabolic changes are not fully understood. Retinol‐binding protein (RBP) was recently reported as an adipocytokine that may link insulin resistance and lipid metabolism. The aim of this study was to investigate the potential role of RBP in women with PCOS. Research design and methods Fifty women with PCOS and 40 healthy women, all of whom were age‐ and weight‐matched, were studied. Blood was obtained to determine RBP levels as well as metabolic and hormonal parameters, and the homeostasis model assessment of insulin resistance (HOMA‐IR) was calculated for each subject. Results The RBP levels were higher (P < 0·01) in women with PCOS after adjusting for age, body mass index (BMI), mean blood pressure, triglyceride (TG), high density lipoprotein (HDL)‐cholesterol, low density lipoprotein (LDL)‐cholesterol, fasting glucose, fasting insulin, estimated glomerular filtration rate (GFR), LH/FSH, total testosterone and SHBG levels. PCOS status was the strongest predictor of elevated RBP levels. In both the PCOS and control groups, RBP levels were significantly correlated with HOMA‐IR (P = 0·03 in the PCOS group; P = 0·01 in controls). In addition, RBP levels were significantly correlated with total cholesterol, LDL‐cholesterol and TG levels in PCOS (P < 0·01, P < 0·01 and P = 0·01, respectively). Conclusions Higher RBP levels in the PCOS group, when compared to the non‐PCOS group, were observed, and this difference may play a role in the pathophysiology found in women with PCOS. Further studies are needed to clarify the role of RBP in these women.     

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.     

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.     

Frequency and characteristics of TBII-seronegative patients in a population with untreated Graves' hyperthyroidism: a prospective study

Objective It is claimed that second generation thyrotropin‐binding inhibitory immunoglobulin (TBII) assays have a very high sensitivity for the diagnosis of Graves’ hyperthyroidism (GH). However, studies evaluating the accuracy of TBII have been retrospective in nature and/or GH had not been diagnosed independently of TBII. The aim of the present study, therefore, was to prospectively evaluate the frequency and characteristics of TBII‐seronegative patients in a population of untreated GH diagnosed independent of serum TBII. Design Prospective multicentre observational study. Patients A total of 259 consecutive untreated patients with a first episode of GH, diagnosed independent of serum TBII. TBII levels were measured by second generation assay and correlated to thyroid function, clinical characteristics and exposure to environmental factors. Results Serum TBII was positive in 245 (94·6%) patients and negative (< 2 IU/l) in 14 (5·4%) patients. TBII‐seronegative patients had lower fT4 (median 42·5 vs. 53·9 pmol/l, P = 0·02), T3 (median 3·55 vs. 4·90 nmol/l, P < 0·01) and fT3‐index (median 4·30 vs. 6·27, P < 0·01) compared to TBII‐seropositive patients. None of the TBII‐seronegative patients had TSH‐receptor activating mutations, Graves’ orbitopathy or pretibial myxedema. Serum TBII was positively correlated to free T3 (fT3)‐index and free T4 (fT4)‐index (P < 0·01), goitre size (P < 0·01) and the prevalence of Graves’ orbitopathy (P < 0·01). There were no significant differences between TBII‐seropositive and TBII‐seronegative patients in environmental factors. Conclusion The prevalence of TBII‐seronegativity in untreated patients with GH is 5·4% using a second generation assay. TBII‐seronegative patients have biochemically less severe thyrotoxicosis and no Graves’ orbitopathy. TBII‐seronegative and TBII‐seropositive patients apparently belong to the same population of GH, albeit the severity of the autoimmune attack is less in TBII‐seronegative patients.     

Clinicopathological correlations of Bcl-xL and Bax expression in differentiated thyroid carcinoma

Objective The Bcl‐2 family proteins are essential mediators in the apoptotic process. Our aim was to investigate whether anti‐apoptotic Bcl‐xL and pro‐apoptotic Bax were over‐expressed in a large series of differentiated thyroid carcinomas (DTC) and to study their association with tumour presentation at diagnosis and prognosis. Design and Patients We examined the immunohistochemical expression of Bcl‐xL and Bax in benign nodular thyroid disease (BNTD) and DTC and their association with clinicopathological parameters. Thyroid tissue samples were collected from an unselected series of patients undergoing surgical resection for DTC (n = 74) or BNTD (n = 15). Results Among DTC cases, expression of Bcl‐xL was found to be high in 43·2% and low or absent in 56·8%. Expression of Bax was high in 75·7% and low or absent in 24·3%. Non‐neoplastic thyroid tissue was largely unstained for both proteins. Among BNTD cases, expression of Bcl‐xL was high in 13·3% and low or absent in 86·6%. Expression of Bax was high in 14·3% and low or absent in 86·6%. A significant association was found between Bcl‐xL expression and the presence of high‐risk histological subtype (P < 0·05), and regional lymph node (P < 0·01) and distant metastases (P < 0·01). The association between high Bcl‐xL expression levels and a longer time of persistent disease after radioiodine ablation was also significant (P < 0·01). Bcl‐xL expression was confirmed as an independent prognostic factor for persistent disease in DTC (relative risk, 2·5; 95% confidence interval, 1·1–5·9; P < 0·05). Conclusions Immunohistochemical expression of Bcl‐xL might be a valuable tool in the prediction of tumour aggressiveness in DTC.     

Relation between plasma fibroblast growth factor-23, serum fetuin-A levels and coronary artery calcification evaluated by multislice computed tomography in patients with normal kidney function

Objective To examine the correlation of plasma fibroblast growth factor (FGF)‐23 and serum fetuin A levels with the coronary artery calcification score (CACS) in patients with normal kidney function. Background Vascular calcification is an active process that may be aggravated by hyperphosphataemia and hypercalcaemia. FGF‐23 and human fetuin‐A have been associated with calcifying arteriosclerosis in renal failure. Plasma FGF‐23 was identified as an independent factor negatively associated with peripheral vascular calcification. Fetuin‐A acts as a systemic inhibitor of ectopic calcification in dialysis patients and can be correlated to the survival of these patients. Very few data exists on the role of FGF‐23 and fetuin‐A in coronary calcification of patients without impaired kidney function. Materials and methods Sixty‐four patients, 21 females and 43 males, were subjected to 64‐slice coronary computed tomography (CT) to evaluate coronary artery calcification (CAC). Plasma intact FGF‐23 was determined by ELISA. Serum fetuin‐A concentration were evaluated nephelometrically. Results Mean plasma FGF‐23 level was 20·4 ± 9·1 pg/ml and serum fetuin‐A was 0·46 ± 0·09 g/l. There was no correlation between FGF‐23 (P = 0·777) and fetuin‐A (P = 0·767) levels and the CACS. No correlation was found between the presence of noncalcified plaques and coronary artery stenosis (CAS) ≥  50%, and FGF‐23 (P = 0·313 and P = 0·775) and fetuin‐A levels (P = 0·601 and P = 0·659). Conclusion Plasma intact FGF‐23 and serum fetuin‐A concentration do not correlate with the CACS, the grade of stenosis or presence of noncalcified plaques of the coronary arteries in patients with normal kidney function.     

The antioxidant alpha-lipoic acid improves endothelial dysfunction induced by acute hyperglycaemia during OGTT in impaired glucose tolerance

Objective Impaired glucose tolerance (IGT) is considered a transitional phase in the development of type 2 diabetes, and is also independently associated with the occurrence of cardiovascular disease. Endothelial dysfunction (ED) represents a very early step in the development of atherosclerosis. The aim of the present study was to examine ED in the fasting state and after a glucose challenge as well as after administration of an antioxidant agent. Patients and methods The study subjects included 42 IGT patients and 26 healthy individuals (control group). The IGT patients were randomly divided into two groups, 21 in each group (the alpha‐lipoic acid group and the placebo group). In the alpha‐lipoic acid group, 300 mg of alpha‐lipoic acid was administrated before an oral glucose tolerance test (OGTT); in the placebo group, 250 ml of 0·9% sodium chloride was administrated before the OGTT. In addition, 250 ml of 0·9% sodium chloride was also administrated to the control subjects before the OGTT (control group), and then vascular function was examined in the fasting state and repeated 1 and 2 h after the glucose load. High‐resolution ultrasound was used to measure flow‐mediated endothelium‐dependent arterial dilation (FMD) and glyceryltrinitrate (GTN)‐induced endothelium‐independent arterial dilation. Results In the fasting state, and at 60 and 120 min, FMD in both the placebo and alpha‐lipoic acid groups was significantly lower than in the controls (P < 0·01). In the control group, FMD tended to decrease at 60 min after glucose loading and returned to the baseline levels at 120 min (P > 0·05). In the placebo group, FMD decreased significantly at 60 min after glucose loading (P < 0·01) and increased markedly from 60 to 120 min (P < 0·01). The alpha‐lipoic acid‐treated patients showed FMD values intermediate between the control subjects and the IGT patients treated with placebo, at both 60 and 120 min, and the differences were significant (P < 0·01). In multiple regression analysis, FMD was significantly correlated to fasting blood glucose (FBG), low density lipoprotein cholesterol (LDL‐C), lipoprotein (a) [Lp(a)], C‐reactive protein (CRP), thiobarbituric acid reactive substances (TBARS) and age in IGT patients at baseline (P < 0·01). Spearman's analysis showed a significant negative correlation between FMD and plasma glucose levels, and between FMD and TBARS during the OGTT in IGT patients (placebo group) (P < 0·01). There was also a significant correlation between FMD and plasma glucose levels, and between FMD and TBARS during the OGTT in IGT patients treated with alpha‐lipoic acid (P < 0·05), although the power of association decreased. Conclusion In subjects with IGT, FMD was impaired both in the fasting state and after a glucose challenge, probably through increased production of oxygen‐derived free radicals. The ED observed after a glucose challenge is related to the extent of hyperglycaemia and TBARS, and an antioxidant agent can improve the impairment of endothelial function induced by acute hyperglycaemia.     

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.     

Serum fasting cortisol in relation to bone, and the role of genetic variations in the glucocorticoid receptor

Objective To examine the relationship between endogenous cortisol and bone, and the role of genetic variations in the glucocorticoid receptor (GR). Design and patients The Longitudinal Ageing Study Amsterdam (LASA), a population‐based cohort study in older men and women. Measurements Serum fasting cortisol was assessed by competitive immunoassay (n = 1214); bone mineral density (BMD) by dual X‐ray absorptiometry (DXA) (n = 502); broadband ultrasound attenuation (BUA) by ultrasound (n = 1209); fractures by self‐report (n = 1211); and GR gene polymorphisms (ER22/23EK, N363S, 9beta, BclI) were genotyped by Taqman (n = 858). Results Higher serum fasting cortisol was significantly associated with lower BMD at all sites and BUA at the heel in women, although most relationships were attenuated by age and body mass index (BMI). The effect on femoral neck BMD remained statistically significant in the fully adjusted model (r = –0·135, P = 0·04). No significant associations in men were found. Female 9beta G‐allele carriers had 50·2 nmol/l lower cortisol and 1·2 lower free cortisol levels than AA homozygotes [P = 0·01 for (free) cortisol]. Furthermore, female BclI GG homozygotes had 54·8 nmol/l higher cortisol levels than C‐carriers (P = 0·03). In the total population, BclI GG homozygotes had 0·05 g/cm² lower trochanteric region BMD (P = 0·03). For the other GR gene polymorphisms, no significant associations were found. Conclusions Higher cortisol levels are associated with lower femoral neck BMD in elderly women. The G allele of the 9beta polymorphism was associated with lower serum cortisol levels in women. Female BclI GG homozygotes had higher serum cortisol levels, and BclI GG homozygotes had lower trochanteric region BMD in the total population.     

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.     

Vitamin D insufficiency prior to bariatric surgery: risk factors and a pilot treatment study

Objective To assess vitamin D status and the influences of race, sun exposure and dietary vitamin D intake on vitamin D levels, and to evaluate two vitamin D repletion regimens in extremely obese patients awaiting bariatric surgery. Methods A cross‐sectional analysis of dietary vitamin D, sun exposure, PTH [intact (iPTH) and PTH(1‐84)] and 25‐hydroxyvitamin D (25OHD; differentiated 25OHD2 and 25OHD3) in 56 obese [body mass index (BMI) > 35 kg/m²] men and women (age 20–64 years). In a pilot clinical trial, 27 subjects with 25OHD levels < 62 nmol/l were randomized to receive ergocalciferol or cholecalciferol for 8 weeks. Results Serum 25OHD was low (mean 45 ± 22 nmol/l) and was inversely associated with BMI (r = ?0·36, P < 0·01). Each BMI increase of 1 kg/m² was associated with a 1·3 nmol/l decrease in 25OHD (P < 0·01). BMI, sun exposure, African American race and PTH predicted 40% of the variance in 25OHD (P < 0·0001). Serum 25OHD significantly increased at 4 and 8 weeks in both treatment groups (P < 0·001), whereas PTH(1‐84) declined significantly in subjects treated with cholecalciferol (P < 0·007) and tended to decrease following ergocalciferol (P < 0·09). Conclusions In severely obese individuals, those who are African American, have higher BMI and limited sunlight exposure are at greatest risk for vitamin D insufficiency. These demographic factors can help to identify at‐risk patients who require vitamin D repletion prior to bariatric surgery. Commonly prescribed doses of ergocalciferol and cholecalciferol are effective in raising 25OHD. Further investigation is needed to evaluate whether these regimens have differential effects on PTH, and to determine the optimal regimen for vitamin D repletion in the extremely obese patient.     

Bone mineral density and bone turnover in Romanian children and young adults with classical 21-hydroxylase deficiency are influenced by glucocorticoid replacement therapy

Objective It remains controversial if glucocorticoid replacement therapy impairs bone mineral density (BMD) in young patients with 21‐hydroxylase deficiency. We aimed to analyze the impact of treatment variables, phenotype and genotype on BMD and bone metabolism in these patients. Design Cross‐sectional study. Measurements Twenty‐eight Caucasian patients with classical 21‐hydroxylase deficiency (5–39 years). Clinical parameters, hormonal status, osteocalcin (OC), C‐terminal telopeptide of type I collagen (CTX), genotype and lumbar BMD (Z‐scores) were assessed. Cumulative and mean hydrocortisone equivalent doses were calculated for the entire treatment period. Results Patients with severely reduced BMD Z‐scores (≤–2·5 SD) had significantly higher mean/cumulative glucocorticoid doses compared to patients with moderately reduced (P = 0·003/P = 0·026) and normal Z‐scores (> –1 SD) (P = 0·005/P = 0·011). Mean hydrocortisone equivalent doses > 20 mg/m²/day led to significantly lower lumbar BMD Z‐scores (–2·16 ± 1·4 SD) vs. doses ≤ 20 mg/m²/day (–0·59 ± 1·25 SD) (P = 0·008). BMD correlated negatively with mean/cumulative glucocorticoid doses and treatment duration. OC (86·45 ± 37·45 ng/ml) and CTX (1·45 ± 0·43 ng/ml) were significantly increased compared to an age‐ and sex‐matched control group in patients with active growth; only CTX was slightly increased in patients who completed growth. Conclusions High cumulative and mean glucocorticoid doses negatively impact on BMD in children and young adults with classical 21‐hydroxylase deficiency. Substitution therapy should be adapted particularly at this life period to prevent bone loss.     

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.     

GH and IGF-I deficiency are associated with reduced loss of fat mass after laparoscopic-adjustable silicone gastric banding

Context GH secretion is reduced in obese subjects and increases after body weight loss. It is still unclear if changes in the GH/IGF‐I axis after laparoscopic‐adjustable silicone gastric banding (LASGB) are associated with changes of body composition. Objective To analyse the relationships between changes in the GH/IGF‐I axis and those of body weight and composition before and after LASGB. Design Observational, prospective. Setting University ‘Federico II’ of Naples (Italy). Patients Seventy‐two severely obese females (BMI: 44·9 ± 4·68; mean age: 33·1 ± 11·34 years) were studied. Main outcome measures GH peak after GHRH plus arginine test, IGF‐I, IGFBP‐3 and ALS levels, fat mass (FM) and free fat mass (FFM) (by Bioelectrical Impedance Analysis) at baseline and 6 months after LASGB. The change in percentage of individual variables was calculated as well as that of excess of body weight loss (EBWL%). The FM%, FFM% and EBWL% were correlated with peak GH and IGF‐I levels changes. Results At baseline, GH deficiency (GHD) (GH peak = 4·1 µg/l) was found in 22 patients (31%), 16 of them also had IGF‐I deficiency (< –2SDS). IGF‐I levels were inversely correlated with waist circumference (r = –0·72, P < 0·001) and FM% (r = –0·75, P < 0·001). Post‐LASGB the patients were classified as follows: group (1) GH and IGF‐I sufficient (n = 44; 61·1%); group (2) GH and IGF‐I deficient (n = 14; 19·4%) and group (3) GH sufficient and IGF‐I deficient (n = 14; 19·4%). The percentage changes of EWBL (P < 0·05, P = 0·051, respectively) and FM (P < 0·001, P < 0·01, respectively) were lower in groups (2) and (3) than in group (1). At the stepwise linear regression analysis, postoperative IGF‐I levels were the strongest determinant of percent changes of FM (P < 0·0001), of FFM (P = 0·009) and of EBWL (P < 0·0001). Conclusions IGF‐I levels is the most sensitive to unfavourable changes in body composition 6 months after LASGB making investigation of the somatotropic axis useful in the evaluation of bariatric surgery outcomes.     

Alteration of ghrelin-neuropeptide Y network in obese patients with polycystic ovary syndrome: role of hyperinsulinism

Objective Insulin, ghrelin, neuropeptide Y (NPY) and leptin interact in the regulation of energy homeostasis. Most of these signals are altered in polycystic ovary syndrome (PCOS), which is characterized by a high prevalence of obesity. The present study was conducted to evaluate ghrelin–NPY and ghrelin–leptin interplays in relation to insulin secretion in obese PCOS subjects. Design Pilot prospective study. Patients Seven obese PCOS women and seven age–weight matched controls. Measurements Hormonal measurements, oral glucose tolerance test (OGTT) and a ghrelin test (1 µg/kg i.v. bolus). PCOS patients repeated the clinical work‐up after 4 months of metformin treatment (1500 mg/day orally). Results At baseline, PCOS women showed a significantly higher insulinaemic response to the OGTT compared to controls (P < 0·05). In basal conditions, PCOS women exhibited lower NPY levels than controls (P < 0·01). Ghrelin injection markedly increased NPY in controls (P < 0·01), whereas PCOS women showed a deeply blunted NPY response to the stimulus (area under the curve – AUC–NPY: P < 0·01 vs. controls.). Metformin treatment induced a significant decrease in insulin levels (P < 0·01) and the concomitant recovery of NPY secretory capacity in response to ghrelin (AUC–NPY: P < 0·05 vs. baseline) in PCOS women. Leptin levels, which were similar in the two groups, were not modified by ghrelin injection; metformin did not affect this pattern. Conclusion Hyperinsulinaemia seems to play a pivotal role in the alteration of NPY response to ghrelin in obese PCOS women. This derangement could be implicated in the physiopatology of obesity in these patients.     

Association of race, body fat and season with vitamin D status among young women: a cross-sectional study

Objective The purpose of this study was to provide an estimate of vitamin D status in young women residing in south‐east Texas and to determine factors that predict 25‐hydroxyvitamin D (25‐OHD) concentration. Design A cross‐sectional study was conducted on 800 non‐Hispanic white, non‐Hispanic black, and Hispanic women 16–33 years of age, who were seen in an outpatient clinic. Measurements Information was obtained on race, smoking, exercise and dietary intake of vitamin D. Percentage total body fat (%TBF) was assessed using dual‐energy X‐ray absorptiometry (DXA). Exposure to sunlight was estimated by examining national records of temperature, hours of daylight and UV index for the latitude of the study site. To determine the relationship between 25‐OHD and %TBF, season, race, body mass index (BMI), dietary vitamin D, age and smoking in a multivariate context, stepwise linear regression analysis was performed. Results Serum 25‐OHD levels differed among the racial groups (all pairwise differences P < 0·001), with the lowest value among non‐Hispanic blacks (37·7 nmol/l) and the highest value among non‐Hispanic whites (71·8 nmol/l). Among Hispanics, mean serum 25‐OHD was 47·9 nmol/l. Serum 25‐OHD was negatively associated with %TBF (r = –0·28), BMF (r = –0·36) and TBF (r = –0·33), all P < 0·001, and positively associated with dietary vitamin D (r = 0·10) and pack years of smoking (r = 0·11), both P < 0·01. In the summer months, serum 25‐OHD values were higher (55·4 nmol/l) than in the winter months (48·1 nmol/l), P < 0·001. The final regression model predicting serum 25‐OHD levels included race, %TBF and season (all P < 0·05) and explained 36% of the variance in 25‐OHD. Conclusions Favourable environmental conditions do not result in sufficient vitamin D status for young women, especially non‐Hispanic blacks, Hispanics and the obese.     

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.     

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.     

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.