A multicenter evaluation of dysthyroxinemia in a defined patient cohort.

BACKGROUND: In the region Limburg (The Netherlands) almost all of the five participating laboratories use a different immunoassay platform to determine thyroid stimulating hormone (TSH) and free thryoxine (FT4). With the frequent transfer of patients within the region, harmonization of test result interpretation is necessary. In this study, we investigated dysthyroxinemia classification between participating laboratories and developed procedures for improvement. METHODS: Two ring surveys with an interval of 2 years were performed. Four patient groups (n=100) with different dysthyroxinemia classification were based on biochemical results of the Autodelphia analyzer. Samples were tested in five participating laboratories. In each group the percentage of patients classified with dysthyroxinemia was calculated and differences were analyzed by the Fisher's exact test. RESULTS: After the first survey, the percentage of patients with hyperthyroxinemia was more than 20% lower in three laboratories compared to the other two. Bhattacharya analysis revealed that the upper reference limit of FT4 was 20%-30% too high in two laboratories. Adjustments of reference ranges appeared to be effective in the second survey. The third laboratory reported significantly lower percentages of patients with hyperthyroxinemia in the second survey. New FT4 reference ranges were determined for this laboratory, resulting in adequate classification of hyperthyroxinemia. CONCLUSIONS: This study illustrates the potential of a multicenter evaluation of dysthyroxinemia in a biochemical-defined patient cohort. In particular, classification of hyperthyroxinemia differed between laboratories. Adjustments of reference ranges resulted in better agreement of dysthyroxinemia classification. Even using internal and external quality assurance programs, application of multicenter ring surveys is advised to prevent inadequate reference ranges.

IVF culture medium affects human intrauterine growth as early as the second trimester of pregnancy.

STUDY QUESTION: When does a difference in human intrauterine growth of singletons conceived after IVF and embryo culture in two different culture media appear? SUMMARY ANSWER: Differences in fetal development after culture of embryos in one of two IVF media were apparent as early as the second trimester of pregnancy. WHAT IS KNOWN ALREADY: Abnormal fetal growth patterns are a major risk factor for the development of chronic diseases in adult life. Previously, we have shown that the medium used for culturing embryos during the first few days after fertilization significantly affects the birthweight of the resulting human singletons. The exact onset of this growth difference was unknown. STUDY DESIGN, SIZE AND DURATION: In this retrospective cohort study, all 294 singleton live births after fresh embryo transfer in the period July 2003 to December 2006 were included. These embryos originated from IVF treatments that were part of a previously described clinical trial. Embryos were allocated to culture in either Vitrolife or Cook commercially available sequential culture media. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analysed ultrasound examinations at 8 (n = 290), 12 (n = 83) and 20 weeks' (n = 206) gestation and used first-trimester serum markers [pregnancy-associated plasma protein-A (PAPP-A) and free ß-hCG]. Differences between study groups were tested by the Student's t-test, χ(2) test or Fisher's exact test, and linear multivariable regression analysis to adjust for possible confounders (for example, parity, gestational age at the time of ultrasound and fetal gender). MAIN RESULTS AND THE ROLE OF CHANCE: A total of 294 singleton pregnancies (Vitrolife group nVL = 168, Cook group: nC = 126) from 294 couples were included. At 8 weeks' gestation, there was no difference between crown-rump length-based and ovum retrieval-based gestational age (ΔGA) (nVL = 163, nC = 122, adjusted mean difference, -0.04 days, P = 0.84). A total of 83 women underwent first-trimester screening at 12 weeks' gestation (nVL = 45, nC = 38). ΔGA, nuchal translucency (multiples of median, MoM) and PAPP-A (MoM) did not differ between the study groups. Free ß-hCG (MoM) ± SEM differed significantly (1.55 ± 0.19 in Vitrolife versus 1.06 ± 0.10 in Cook; P = 0.031, Student's t-test). At 20 weeks' gestation, a more advanced GA, reflecting an increased fetal growth, was seen at ultrasound examination in the Vitrolife group (n = 115) when compared with the Cook group (n = 91). After adjustment for confounding factors, both the difference between GA based on three biparietal diameter dating formulas minus the actual (ovum retrieval based) GA (adjusted mean difference + 1.14 days (P = 0.04), +1.14 days (P = 0.04) and +1.36 days (P = 0.048)), as well as head circumference (HC) and trans-cerebellar diameter (TCD) were significantly higher in the Vitrolife group (HCvl 177.3 mm, HCc 175.9 mm, adjusted mean difference 1.8, P = 0.03; TCDvl 20.5 mm, TCDc 20.2 mm, adjusted mean difference 0.4, P = 0.008). LIMITATIONS, REASONS FOR CAUTION: A first trimester (12 weeks) fetal screening was not yet offered routinely during the study period, therefore only 28% of women in our study participated in this elective screening programme. Although all sonographers were experienced and specially trained to perform these ultrasound examinations and were unaware of the randomization procedure, we cannot totally rule out possible intra- and inter-observer variability. Despite being indispensable in daily practice, sonographic weight formulas have a limited accuracy. WIDER IMPLICATIONS OF THE FINDINGS: According to the fetal origins hypothesis, many adult diseases originate in utero owing to adaptations made by the fetus to the environment it encounters. This study indicates that the embryonic environment is already important for fetal development. Therefore, our study emphasizes the need to investigate fetal growth patterns after assisted reproduction technologies and long-term health outcomes of IVF children, especially in relation to the culture medium used during the first few days of preimplantation development. TRIAL REGISTRATION NUMBER: Not applicable.

Primary ovarian insufficiency in classic galactosemia: role of FSH dysfunction and timing of the lesion.

FSH inactivity due to secondary hypoglycosylation has been suggested as a potential mechanism for primary ovarian insufficiency in classic galactosemia. To investigate the role of FSH and to gain insight in the timing of the damage, ovarian stimulation tests were performed and data on ovarian imaging collected. Fifteen patients with primary ovarian insufficiency underwent ovarian stimulation with gonadotropins. Only one patient showed a normal increase in estradiol level, all the others had a low or no estradiol response. Anti-Müllerian hormone measurement in all girls and women showed levels below the detection limit of 0.10 µg/l. Ovarian volumes were evaluated by MRI in 14 patients and compared to age matched controls, prepubertal controls and postmenopausal controls. The ovarian volumes of the galactosemic girls were smaller than those of the age matched controls (p = 0.001) and the prepubertal ovaries (p = 0.008), and did not differ significantly from postmenopausal ovarian volumes (p = 0.161). In conclusion we found no evidence that FSH inactivity plays a role in primary ovarian insufficiency in classic galactosemia. Moreover, ovarian imaging results point to an early onset of ovarian failure in this disease.

High prevalence of morphometric vertebral deformities in patients with inflammatory bowel disease.

BACKGROUND: Earlier studies have documented that the prevalence of decreased bone mineral density (BMD) is elevated in patients with inflammatory bowel disease. The objective of this study was to investigate the prevalence of vertebral deformities in inflammatory bowel disease patients and their relation with BMD and bone turnover. METHODS: One hundred and nine patients with Crohn's disease (CD) and 72 with ulcerative colitis (UC) (age 44.5+/-14.2 years) were studied. BMD of the hip (by dual X-ray absorptiometry) was measured and a lateral single energy densitometry of the spine for assessment of vertebral deformities was performed. Serum markers of bone resorption (carboxy-terminal cross-linked telopeptide of type I collagen) and formation (procollagen type I amino-terminal propeptide) were measured, and determinants of prevalent vertebral deformities were assessed using logistic regression analysis. RESULTS: Vertebral deformities were found in 25% of both CD and UC patients. Comparing patients with and without vertebral deformities, no significant difference was found between Z-scores and T-scores of BMD, or levels of serum carboxy-terminal cross-linked telopeptide of type I collagen and serum procollagen type I amino-terminal propeptide. Using logistic regression analysis the only determinant of any morphometric vertebral deformity was sex. The presence of multiple vertebral deformities was associated with older age and glucocorticoid use. CONCLUSION: The prevalence of morphometric vertebral deformities is high in CD and UC. Male sex, but neither disease activity, bone turnover markers, clinical risk factors, nor BMD predicted their presence. The determinants for having more than one vertebral deformity were age and glucocorticoid use. This implies that in addition to screening for low BMD, morphometric assessment of vertebral deformities is warranted in CD and UC.

Bone turnover and hip bone mineral density in patients with sarcoidosis.

BACKGROUND AND AIM OF THE WORK: Sarcoidosis is a chronic inflammatory T-cell-driven disease that can also affect bone. We evaluated bone remodelling and bone mineral density (BMD) in patients with sarcoidosis and their dependency of disease-related and treatment-related factors. METHODS: In 124 patients BMD of the hip (DXA) and markers of bone resorption (ICTP) and formation (PINP) were evaluated. Furthermore a lateral DXA of the spine for morphometric assessment of vertebral deformities was performed in 87 patients. Potential predictors of bone markers, BMD and determinants of prevalent vertebral deformities were assessed using multiple and logistic regression analysis. RESULTS: The population studied comprised untreated patients (n=51), patients that previously used glucocorticoids (n=31) and patients currently using glucocorticoids (n=42). In all these groups the age- and gender corrected Z-scores of the hip were normal, except in untreated patients, which revealed an increased Z-score at the trochanter (p = 0.004). In all but the patients currently on glucocorticoids the Z-scores for PINP and ICTP were increased (p < 0.05). In patients currently on glucocorticoids the Z-ICTP was also increased (p < 0.05), but the Z-PINP decreased (p < 0.01 compared to untreated patients). In 20.6% of patients one or more morphometric vertebral deformities were found. CONCLUSIONS: Hip BMD is normal in patients with sarcoidosis, despite an increased bone turnover. This may imply that in sarcoidosis mechanisms are involved that compensate for the well-known effects of cytokines in inflammatory diseases on osteoclastogenesis and bone resorption. Nonetheless, vertebral deformities suggestive of fracture were found in a significant number of patients which indicates that patients with sarcoidosis still have a relevant fracture risk.

Contra-lateral bone loss at the distal radius in postmenopausal women after a distal radius fracture: A two-year follow-up HRpQCT study.

Opposite to the fracture side, bone mineral density (BMD) measured by DXA at the contra-lateral side does not change after a distal radius fracture. However, it is unknown if also bone micro-architecture and strength at the contralateral side are unaffected. Therefore, the aim of this study was to assess BMD, micro-architecture and bone mechanical properties at the contra-lateral side during two years follow-up after a distal radius fracture using high resolution peripheral quantitative computed tomography (HRpQCT). The contra-lateral distal radius of 15 postmenopausal women (mean age 64±8years) with a distal radius fracture treated by cast immobilization was scanned by HRpQCT at baseline, 3months and 2years post-fracture. BMD and cortical and trabecular micro-architecture were measured and biomechanical parameters were estimated using micro finite element analysis (µFEA). Additionally, markers of bone resorption and formation were measured at each visit. Bone parameters and turnover markers across the three visits were analysed using a linear mixed-effect model with Bonferroni correction. Two years post-fracture, a significant decrease from baseline was found in cortical BMD (-4.2%, p<0.001), failure load (-6.1%, p=0.001), stiffness in compression (-5.7%, p=0.003) and bending (-6.4%, p=0.008), and bone formation (-47.6%, p=0.010). No significant changes from baseline were observed in total and trabecular BMD, nor in cortical or trabecular micro-architecture and neither in bone resorption. Results were similar between patients with or without adequate anti-osteoporosis drug treatment. We found a significant decline in BMD in the cortical but not the trabecular region, and a reduction in bone strength and stiffness at the contra-lateral side two years after a distal radius fracture. These changes exceeded the changes that may be expected due to aging, even in the presence of adequate anti-osteoporosis treatment.

Effect of calcium, vitamins K1 and D3 on bone in galactosemia.

Classical galactosemia is an inherited disorder of galactose metabolism. Recently, diminished bone mineral content (BMC) in children and adolescents has been found. The aim of this study was to evaluate the effect of calcium, vitamins K(1) and D(3) supplementation on bone in children with galactosemia. A 2-year randomized, double-blind, placebo-controlled clinical trial was undertaken in which 40 children with classical galactosemia (13 males and 27 females, aged 3-17 years) were included to receive daily either 750 mg calcium, 1.0 mg vitamin K(1) and 10.0 microg vitamin D(3) or placebo. BMC of femoral neck, lumbar spine and total body and body composition data were determined by dual energy X-ray absorptiometry (DXA) at baseline and after 1 and 2 years. Diet was assessed using a food frequency questionnaire and a 3-day food diary. Biochemical measurements were determined at baseline and after 1 and 2 years. In the children receiving treatment, carboxylated osteocalcin (cOC) concentration significantly increased (P < 0.001) and undercarboxylated osteocalcin (ucOC) concentration significantly decreased (P = 0.001) when compared to the children receiving placebo. Furthermore, there was a statistically significant increase in BMC of lumbar spine (P = 0.001), lean tissue mass (LTM: P = 0.016) and fat mass (FM: P = 0.014) in the treatment group when compared to the placebo group. The significant increase in cOC and decrease in ucOC concentration in the treatment group were present in prepubertal (P < 0.001 and P = 0.006 respectively) and pubertal children (P = 0.004 and P = 0.042 respectively). The significant increase in BMC of lumbar spine in the treatment group was present only in the prepubertal children (P = 0.015). Supplementation of calcium, vitamins K(1) and D(3) given in this dose (750 mg, 1.0 mg and 10.0 mug respectively) is likely to have a role in the treatment of BMC abnormalities in galactosemia.

Co-ingestion of a protein hydrolysate and amino acid mixture with carbohydrate improves plasma glucose disposal in patients with type 2 diabetes.

BACKGROUND: Although insulin secretion after carbohydrate ingestion is severely impaired in patients with type 2 diabetes, amino acid and protein co-ingestion can substantially increase plasma insulin responses. OBJECTIVE: We investigated insulin responses and the subsequent plasma glucose disposal rates after the ingestion of carbohydrate alone (CHO) or with a protein hydrolysate and amino acid mixture (CHO+PRO) in patients with a long-term diagnosis of type 2 diabetes. DESIGN: Ten type 2 diabetic patients [mean (+/-SEM) age: 62 +/- 2 y; body mass index (kg/m(2)): 27 +/- 1] and 9 healthy control subjects (age: 58 +/- 1 y; body mass index: 27 +/- 1) participated in 2 trials in which the plasma insulin response was measured after the ingestion of 0.7 g carbohydrate . kg(-1) . h(-1) with or without 0.35 g . kg(-1) . h(-1) of a mixture that contained a protein hydrolysate, leucine, and phenylalanine. Continuous infusions with [6,6-(2)H(2)]glucose were then given to investigate plasma glucose disposal. RESULTS: Plasma insulin responses were higher by 299 +/- 64% and 132 +/- 63% in the CHO+PRO trial than in the CHO trial in the diabetic patients and the matched control subjects, respectively (P < 0.001). The subsequent plasma glucose responses were reduced by 28 +/- 6% and 33 +/- 3% in the CHO+PRO trial than in the CHO trial in the diabetic patients and the matched control subjects, respectively (P < 0.001). The reduced plasma glucose response in the diabetic patients was attributed to a 13 +/- 3% increase in glucose disposal (P < 0.01). CONCLUSIONS: The combined ingestion of carbohydrate with a protein hydrolysate and amino acid mixture significantly increases de novo insulin production in patients with a long-term diagnosis of type 2 diabetes. The increased insulin response stimulates plasma glucose disposal and reduces postprandial glucose concentrations.

Hip bone mineral density, bone turnover and risk of fracture in patients on long-term suppressive L-thyroxine therapy for differentiated thyroid carcinoma.

OBJECTIVE: Untreated hyperthyroidism and treatment with high doses of thyroid hormone are associated with osteoporosis. However, their effect on bone turnover, their contribution to bone mineral density (BMD) in the context of other clinical risk factors for osteoporosis and the prevalence of vertebral fractures is not well documented. DESIGN: Cross-sectional study. METHODS: We studied 59 patients receiving L-thyroxine suppressive therapy for differentiated thyroid carcinoma (DTC). BMD of the hip was measured by dual X-ray absorptiometry (DXA) and lateral DXA pictures of the lumbar and thoracic vertebrae were performed. Bone resorption was measured by C-telopeptides of type I collagen (ICTP) and bone formation by procollagen type I N-propeptide (PINP). Clinical risk factors for osteoporosis were evaluated using a questionnaire. RESULTS: Z-scores of BMD were similar as the NHANES (National Health and Nutrition Examination Survey) III reference group in women and men, also after long-term (> 10 years) suppression therapy. Patients in the lowest and highest quartile of BMD showed significant differences in the presence of clinical risk factors. ICTP levels were significantly higher than in age-matched controls, PINP levels were not different. We found four patients with a prevalent vertebral fracture. CONCLUSIONS: We conclude that patients with well-differentiated thyroid carcinoma are not at increased risk of developing low bone mass nor have a higher prevalence of vertebral fracture at least when treated with relatively low doses of L-thyroxine.

Amino acid ingestion strongly enhances insulin secretion in patients with long-term type 2 diabetes.

OBJECTIVE: Insulin secretion in response to carbohydrate intake is blunted in type 2 diabetic patients. However, it is not clear whether the insulin response to other stimuli, such as amino acids, is also diminished. Recently, we defined an optimal insulinoptropic mixture containing free leucine, phenylalanine, and a protein hydrolysate that substantially enhances the insulin response in healthy young subjects when coingested with carbohydrate. In this study, we aimed to investigate the insulinotropic capacity of this mixture in long-term type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Ten type 2 diabetic patients (aged 59.1 +/- 2.0 years, BMI 26.5 +/- 0.7 kg/m(2)) and 10 healthy control subjects (58.8 +/- 2.1 years, 26.5 +/- 0.7 kg/m(2)) visited our lab twice, during which insulin responses were determined following ingestion of carbohydrate only (CHO) or carbohydrate with the free amino acid/protein mixture (CHO+PRO). All subjects received 0.7 g x kg(-1) x h(-1) carbohydrate with or without 0.35 g x kg(-1) x h(-1) of the amino acid/protein mixture. RESULTS: Insulin responses were dramatically increased in the CHO+PRO trial in both the type 2 diabetic and control groups (189 and 114%, respectively) compared with the CHO trial (P < 0.01). Plasma glucose, glucagon, growth hormone, cortisol, IGF-I, and IGF binding protein 3 responses were not different between trials within the 2-h time frame. CONCLUSIONS: The insulin secretory capacity in long-term type 2 diabetic patients is substantially underestimated, as the insulin response following carbohydrate intake can be nearly tripled by coingestion of a free amino acid/protein mixture. Future research should be performed to investigate whether such nutritional interventions can improve postprandial glucose disposal.

Evidence for a Cystic Fibrosis Enteropathy.

BACKGROUND: Previous studies have suggested the existence of enteropathy in cystic fibrosis (CF), which may contribute to intestinal function impairment, a poor nutritional status and decline in lung function. This study evaluated enterocyte damage and intestinal inflammation in CF and studied its associations with nutritional status, CF-related morbidities such as impaired lung function and diabetes, and medication use. METHODS: Sixty-eight CF patients and 107 controls were studied. Levels of serum intestinal-fatty acid binding protein (I-FABP), a specific marker for enterocyte damage, were retrospectively determined. The faecal intestinal inflammation marker calprotectin was prospectively studied. Nutritional status, lung function (FEV1), exocrine pancreatic insufficiency (EPI), CF-related diabetes (CFRD) and use of proton pump inhibitors (PPI) were obtained from the medical charts. RESULTS: Serum I-FABP levels were elevated in CF patients as compared with controls (p<0.001), and correlated negatively with FEV1 predicted value in children (r-.734, p<0.05). Faecal calprotectin level was elevated in 93% of CF patients, and correlated negatively with FEV1 predicted value in adults (r-.484, p<0.05). No correlation was found between calprotectin levels in faeces and sputum. Faecal calprotectin level was significantly associated with the presence of CFRD, EPI, and PPI use. CONCLUSION: This study demonstrated enterocyte damage and intestinal inflammation in CF patients, and provides evidence for an inverse correlation between enteropathy and lung function. The presented associations of enteropathy with important CF-related morbidities further emphasize the clinical relevance.

Gamma-linolenic acid supplementation for prophylaxis of atopic dermatitis--a randomized controlled trial in infants at high familial risk.

BACKGROUND: Studies suggest that low concentrations of n-6 long-chain polyenes in early life are correlated to atopic disease in later life. OBJECTIVE: The purpose of the study was to investigate the possible preventive effect of gamma-linolenic acid (GLA) supplementation on the development of atopic dermatitis in infants at risk. DESIGN: In a double-blind, randomized, placebo-controlled trial, formula-fed infants (n = 118) with a maternal history of atopic disease received borage oil supplement (containing 100 mg GLA) or sunflower oil supplement as a placebo daily for the first 6 mo of life. Main outcome measures were the incidence of atopic dermatitis in the first year of life (by UK Working Party criteria), the severity of atopic dermatitis (SCORing Atopic Dermatitis; SCORAD), and the total serum immunoglobulin E (IgE) concentration at the age of 1 y. RESULTS: The intention-to-treat analysis showed a favorable trend for severity of atopic dermatitis associated with GLA supplementation ( x+/- SD SCORAD: 6.32 +/- 5.32) in the GLA-supplemented group as compared with 8.28 +/- 6.54 in the placebo group (P = 0.09; P = 0.06 after adjustment for total serum IgE at baseline, age 1 wk), but no significant effects on the other atopic outcomes. The increase in GLA concentrations in plasma phospholipids between baseline and 3 mo was negatively associated with the severity of atopic dermatitis at 1 y (Spearman's correlation coefficient = -0.233, P = 0.013). There was no significant effect on total serum IgE concentration. CONCLUSION: Early supplementation with GLA in children at high familial risk does not prevent the expression of atopy as reflected by total serum IgE, but it tends to alleviate the severity of atopic dermatitis in later infancy in these children.

Expectations of analgesia do not affect spinal nociceptive R-III reflex activity: an experimental study into the mechanism of placebo-induced analgesia.

The purpose of this study was to investigate whether placebo analgesia is mediated by the release of beta-endorphin. In addition to subjective pain reports, we included an objective physiological parameter of nociception reflected by the opioid sensitive nociceptive R-III reflex. Placebo consisted of strong suggestions of pain relief and an intravenous injection of saline. Forty minutes after placebo, either the opioid antagonist naloxone or saline was administered intravenously without subjects noticing (hidden). Sixty healthy males, aged 18-30 years, voluntarily participated in this study. Subjects were randomized into one of four groups: group 1 received placebo and hidden naloxone, group 2 received hidden naloxone only, group 3 received placebo and hidden saline and group 4 received hidden saline only. Pain was induced by electrical stimulation of the sural nerve and evaluated with a visual analogue scale (VAS). In addition, changes in the magnitude of the nociceptive R-III reflex activity were assessed. We determined to what extent R-III reflex activity and subjective pain reports were decreased by placebo and we investigated whether these placebo-induced changes in reflex activity and subjective pain reports were naloxone reversible. Furthermore, we measured the degree of association between pain relief as measured on VAS and changes in R-III reflex activity. Finally, the role of beta-endorphin was assessed by measuring plasma endorphin levels before and after the administration of placebo. This study could not demonstrate a placebo effect as measured on VAS and R-III responses. The administration of placebo did not appear to have an effect on the release of beta-endorphins. Consistently, the antagonizing effects of naloxone were negligible. A subgroup analysis of those who did show a placebo response as indicated on the VAS did not support the supposition that beta-endorphin is released due to placebo suggestion. It is suggested that intensified stimuli and a more effective procedure to induce placebo analgesia (e.g. conditioning) may produce a proper placebo effect.

The effect of pegylated human recombinant leptin (PEG-OB) on neuroendocrine adaptations to semi-starvation in overweight men.

OBJECTIVE: Starvation induces a complex neuroendocrine response in humans thought to have evolved to defend against reduced energy intake. The drop in leptin levels observed during fasting has been implicated as a factor that triggers this adaptive response. To explore this hypothesis, we executed a randomized, double-blind, placebo-controlled study to investigate whether elevated leptin levels using long-acting pegylated human recombinant leptin (PEG-OB) influenced the neuroendocrine responses to semi-starvation in human subjects. DESIGN: Twenty-four overweight male subjects (mean+/-s.e.m.; 34.8+/-1.3 yrs; 28.8+/-0.5 kg/m(2)) were prescribed a very low energy diet (2.1 MJ/day) to induce a state of semi-starvation for the next 46 days. In addition, all subjects received a weekly treatment of 80 mg PEG-OB or matching placebo. Hormone measurements were performed throughout the study period and included 5-h frequent hormone samplings and 24-h urine collections. RESULTS: Weekly subcutaneous administration of PEG-OB led to significant additional weight loss (2.8 kg) but it did not reverse the fasting-induced changes in the thyroid, corticotropic, somatotropic axes and sympathetic nervous system activity. However, after adjustment for weight loss, the drop in mean luteinizing hormone levels was attenuated in the PEG-OB group compared with the placebo group. CONCLUSIONS: These results suggest that a reduced level of leptin accompanying food restriction might be a component of the fasting-induced neuroendocrine inhibition of the human reproductive axis.

Neuroendocrine response to meta-chlorophenylpiperazine and ipsapirone in relation to anxiety and aggression.

The aim of this study was to establish the association of trait anxiety and anger with hormonal responses to acute challenges with two different 5-HT agonists in a mixed group of patients with depressed mood. Fifteen patients and 16 normal controls received single oral doses of 0.5 mg/kg meta-chlorophenylpiperazine (MCPP), a 5-HT(2C) agonist, and 10 mg of ipsapirone, a 5-HT(1A) agonist, according to a double-blind, placebo-controlled, cross-over design. Dutch-adapted versions of the Spielberger Trait-Anxiety Inventory and the Spielberger Trait-Anger Scale administered assessed at study entry. Hormonal responses, expressed as drug-placebo differences, to MCPP and ipsapirone (changes in cortisol, ACTH and prolactin) were measured. Blood levels of MCPP and ipsapirone were also measured. MCPP and ipsapirone elevated cortisol, ACTH and prolactin. In the patient group, there was a significant correlation between trait anxiety and the cortisol response to MCPP. No significant correlations between the ACTH and prolactin responses to MCPP and levels of anxiety/anger were observed in the patients. No significant correlations could be established between levels of anxiety/anger and hormonal responses to ipsapirone. This study provided evidence for an association between measures of anxiety/aggression and the hormonal response to MCPP. Thus, in subjects with depressed mood, high levels of anxiety suggest a higher probability of 5-HT(2C) disturbances.

Blood biomarkers are helpful in the prediction of response to chemoradiation in rectal cancer: a prospective, hypothesis driven study on patients with locally advanced rectal cancer.

PURPOSE/OBJECTIVE: Chemoradiation (CRT) has been shown to lead to downsizing of an important portion of rectal cancers. In order to tailor treatment at an earlier stage during treatment, predictive models are being developed. Adding blood biomarkers may be attractive for prediction, as they can be collected very easily and determined with excellent reproducibility in clinical practice. The hypothesis of this study was that blood biomarkers related to tumor load, hypoxia and inflammation can help to predict response to CRT in rectal cancer. MATERIAL/METHODS: 295 patients with locally advanced rectal cancer who were planned to undergo CRT were prospectively entered into a biobank protocol (NCT01067872). Blood samples were drawn before start of CRT. Nine biomarkers were selected, based on a previously defined hypothesis, and measured in a standardized way by a certified lab: CEA, CA19-9, LDH, CRP, IL-6, IL-8, CA IX, osteopontin and 25-OH-vitamin D. Outcome was analyzed in two ways: pCR vs. non-pCR and responders (defined as ypT0-2N0) vs. non-responders (all other ypTN stages). RESULTS: 276 patients could be analyzed. 20.7% developed a pCR and 47.1% were classified as responders. In univariate analysis CEA (p=0.001) and osteopontin (p=0.012) were significant predictors for pCR. Taking response as outcome CEA (p<0.001), IL-8 (p<0.001) and osteopontin (p=0.004) were significant predictors. In multivariate analysis CEA was the strongest predictor for pCR (OR 0.92, p=0.019) and CEA and IL-8 predicted for response (OR 0.97, p=0.029 and OR 0.94, p=0.036). The model based on biomarkers only had an AUC of 0.65 for pCR and 0.68 for response; the strongest model included clinical data, PET-data and biomarkers and had an AUC of 0.81 for pCR and 0.78 for response. CONCLUSION: CEA and IL-8 were identified as predictive biomarkers for tumor response and PCR after CRT in rectal cancer. Incorporation of these blood biomarkers leads to an additional accuracy of earlier developed prediction models using clinical variables and PET-information. The new model could help to an early adaptation of treatment in rectal cancer patients.