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1.  Plasma intact fibroblast growth factor 23 levels in women with anorexia nervosa 
Background
Fibroblast growth factor (FGF)23 is a novel phosphaturic factor associated with inorganic phosphate homeostasis. Previous human studies have shown that serum FGF23 levels increase in response to a high phosphate diet. For anorexia nervosa (AN) patients, inorganic phosphate homeostasis is important in the clinical course, such as in refeeding syndrome. The purpose of this study was to determine plasma levels of intact FGF23 (iFGF23) in restricting-type AN (AN-R) patients, binge-eating/purging-type AN (AN-BP) patients, and healthy controls.
Methods
The subjects consisted of 6 female AN-R patients, 6 female AN-BP patients, and 11 healthy female controls; both inpatients and outpatients were included. Plasma iFGF23, 1,25-dihydroxyvitamin D (1,25-(OH)2D), and 25-hydroxyvitamin D (25-OHD) levels were measured. Data are presented as the median and the range. A two-tailed Mann-Whitney U-test with Bonferroni correction was used to assess differences among the three groups, and a value of p < 0.017 was considered statistically significant.
Results
There were no differences between AN-R patients and controls in the iFGF23 and 1,25-(OH)2D levels. In AN-BP patients, the iFGF23 level (41.3 pg/ml; range, 6.1–155.5 pg/ml) was significantly higher than in controls (3.8 pg/ml; range, not detected-21.3 pg/ml; p = 0.001), and the 1,25-(OH)2D was significantly lower in AN-BP patients (7.0 pg/ml; range, 4.2–33.7 pg/ml) than in controls (39.7 pg/ml; range, 6.3–58.5 pg/ml; p = 0.015). No differences in plasma 25-OHD levels were observed among the groups.
Conclusion
This preliminary study is the first to show that plasma iFGF23 levels are increased in AN-BP patients, and that these elevated plasma FGF23 levels might be related to the decrease in plasma 1,25-(OH)2D levels.
doi:10.1186/1751-0759-2-10
PMCID: PMC2346464  PMID: 18412981
2.  Fibroblast growth factor 23 and parathyroid hormone after treatment with active vitamin D and sevelamer carbonate in patients with chronic kidney disease stage 3b, a randomized crossover trial 
BMC Nephrology  2012;13:49.
Background
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that is secreted from bone and serum level increases as renal function declines. Higher levels of FGF23 are associated with increased mortality in hemodialysis-patients and in patients with chronic kidney disease (CKD) stage 2-4. The use of active vitamin D and phosphate binders as recommended in international guidelines, may affect the level of FGF23 and thereby clinical outcome. We investigated the effects of a phosphate binder and active vitamin D on the serum levels of intact FGF23 (iFGF23) and intact parathyroid hormone (iPTH) in patients with CKD stage 3b (glomerular filtration rate (GFR) 30–44 ml/min/1.73 m2).
Methods
Seven women and 14 men were included, mean age 65.6 ± 12.2 years. They were randomized in a 1:1 ratio to receive one of two treatment sequences. Group-1 (the alphacalcidol-sevelamer carbonate group): alphacalcidol 0.25 μg once daily for two weeks followed by sevelamer carbonate 800 mg TID with meals for two weeks after a two-week washout period. Group-2 (the sevelamer carbonate-alphacalcidol group): vice versa. Nineteen patients completed the study. The 25-hydroxyvitamin D level at baseline was 97.6 ± 25.0 nmol/l.
Results
There were no treatment effects on the iFGF23 and iPTH levels overall. In group-1 the iFGF23 level was higher after treatment with alphacalcidol compared with sevelamer carbonate (mean 105.8 ± 41.6 vs. 79.1 ± 36.5 pg/ml, p = 0.047 (CI: 0.4-52.9), and the iPTH level was lower (median: 26.5, range: 14.6-55.2 vs. median 36.1, range 13.4-106.9 pg/ml, p = 0.011). In group-2 the iFGF23 level increased non-significantly after treatment with sevelamer carbonate and throughout the washout period.
Conclusions
In this crossover trial with alphacalcidol and sevelamer carbonate in patients with CKD stage 3b, the levels of iFGF23 were not significantly different after the two treatments. However, in the group of patients initiating therapy with sevelamer carbonate the iFGF23 levels seemed to increase while this response was mitigated in the group of patients given alphacalcidol followed by sevelamer carbonate. This may have therapeutic implications on choice of first line therapy. The number of patients is small and this conclusion is in part based on subgroup analysis. It is therefore important that these results are confirmed in larger studies.
Trial registration
Trial Registration Number: European Clinical Trial Database (EudraCT) 2010-020415-36 and Clinical Trials.gov NCT01231438
doi:10.1186/1471-2369-13-49
PMCID: PMC3462711  PMID: 22742720
Active vitamin D; Chronic kidney disease; Fibroblast growth factor 23; FGF23; Phosphate-binder; Parathyroid hormone; PTH; Sevelamer carbonate
3.  The Serum Level of Fibroblast Growth Factor-23 and Calcium-Phosphate Homeostasis in Obese Perimenopausal Women 
Plasma FGF-23 concentrations and its relationship with calcium-phosphate homeostasis were evaluated in 48 perimenopausal obese women and in 29 nonobese controls. Serum parathyroid hormone, 25-hydroxyvitamin D3, CTX1, osteocalcin, total calcium, phosphorus, creatinine, and plasma intact FGF-23 concentrations were assessed. DXA of lumbar spine and femoral neck was performed to determine bone mineral density (BMD). Plasma iFGF-23 concentration was significantly higher in obese patients (by 42%) and correlated with age and BMD of proximal femur (R = −0.346; R = 0.285, resp.) but not with markers of bone turnover. However, serum phosphorus level in obese subjects was significantly lower. iFGF-23 concentration correlated significantly with body mass index (R = 0.292) and fat content (R = 0.259) in all study subjects. Moreover, a significant correlation between iFGF-23 and iPTH (R = 0.254) was found. No correlation between serum phosphorus or eGFR and plasma iFGF-23 and between eGFR and serum phosphorus was found. Elevated serum iFGF-23 concentration may partially explain lower phosphorus levels in the obese and seems not to reflect bone turnover.
doi:10.1155/2011/707126
PMCID: PMC3227462  PMID: 22164160
4.  High dose intravenous iron, mineral homeostasis and intact FGF23 in normal and uremic rats 
BMC Nephrology  2013;14:281.
Background
High iron load might have a number of toxic effects in the organism. Recently intravenous (iv) iron has been proposed to induce elevation of fibroblast growth factor 23 (FGF23), hypophosphatemia and osteomalacia in iron deficient subjects. High levels of FGF23 are associated with increased mortality in the chronic kidney disease (CKD) population. CKD patients are often treated with iv iron therapy in order to maintain iron stores and erythropoietin responsiveness, also in the case of not being iron depleted. Therefore, the effect of a single high iv dose of two different iron preparations, iron isomaltoside 1000 (IIM) and ferric carboxymaltose (FCM), on plasma levels of FGF23 and phosphate was examined in normal and uremic iron repleted rats.
Methods
Iron was administered iv as a single high dose of 80 mg/kg bodyweight and the effects on plasma levels of iFGF23, phosphate, Ca2+, PTH, transferrin, ferritin and iron were examined in short and long term experiments (n = 99). Blood samples were obtained at time 0, 30, 60, 180 minutes, 24 and 48 hours and in a separate study after 1 week. Uremia was induced by 5/6-nephrectomy.
Results
Nephrectomized rats had significant uremia, hyperparathyroidism and elevated FGF23. Iron administration resulted in significant increases in plasma ferritin levels. No significant differences were seen in plasma levels of iFGF23, phosphate and PTH between the experimental groups at any time point within 48 hours or at 1 week after infusion of the iron compounds compared to vehicle.
Conclusions
In non-iron depleted normal and uremic rats a single high dose of either of two intravenous iron preparations, iron isomaltoside 1000, and ferric carboxymaltose, had no effect on plasma levels of iFGF23 and phosphate for up to seven days.
doi:10.1186/1471-2369-14-281
PMCID: PMC3877875  PMID: 24373521
Iron; FGF23; Phosphate; Chronic kidney disease
5.  Changes in fibroblast growth factor 23 levels in normophosphatemic patients with chronic kidney disease stage 3 treated with lanthanum carbonate: results of the PREFECT study, a phase 2a, double blind, randomized, placebo-controlled trial 
BMC Nephrology  2014;15:71.
Background
High levels of circulating fibroblast growth factor 23 (FGF23) are associated with chronic kidney disease (CKD) progression and high mortality. In the Phosphate Reduction Evaluation of FGF23 in Early CKD Treatment (PREFECT) study, we assessed the effect of reducing intestinal phosphate absorption using lanthanum carbonate on FGF23 levels in normophosphatemic patients with CKD stage 3.
Methods
Thirty-five individuals were randomized to lanthanum carbonate 3000 mg/day (n = 23) or placebo (n = 12) for 12 weeks. Levels of intact FGF23 (iFGF23), C-terminal FGF23, serum and urinary phosphate and calcium, intact parathyroid hormone and 1,25-dihydroxyvitamin D were assessed.
Results
The median age was 65 years in the lanthanum group and 73 years in the placebo group; 58.8% and 41.7% were men, respectively. No significant difference was seen in mean iFGF23 between groups at week 12. There was, however, a transient reduction from baseline in iFGF23 in the lanthanum group at week 1, from 70.5 pg/ml to 51.9 pg/ml, which was not seen in the placebo group; this between-group difference in percentage change from baseline was significant in post hoc analyses (p = 0.0102). Urinary phosphate decreased after 1 week of lanthanum treatment and remained low at week 12.
Conclusions
Reducing intestinal phosphate absorption with lanthanum carbonate did not lead to sustained reductions in iFGF23 in patients with CKD stage 3, although phosphaturia decreased. This suggests that factors other than phosphate burden may be responsible for driving increases in circulating FGF23 in patients with CKD.
Trial registration
ClinicalTrials.gov NCT01128179, 20 May 2010.
doi:10.1186/1471-2369-15-71
PMCID: PMC4107721  PMID: 24885942
CKD-MBD; FGF23; Parathyroid hormone; Phosphate binders; Phosphaturia; Lanthanum carbonate
6.  Iron and Obesity Status-Associated Insulin Resistance Influence Circulating Fibroblast-Growth Factor-23 Concentrations 
PLoS ONE  2013;8(3):e58961.
Fibroblast growth factor 23 (FGF-23) is known to be produced by the bone and linked to metabolic risk. We aimed to explore circulating FGF-23 in association with fatness and insulin sensitivity, atherosclerosis and bone mineral density (BMD). Circulating intact FGF-23 (iFGF-23) and C-terminal (CtFGF-23) concentrations (ELISA) were measured in 133 middle aged men from the general population in association with insulin sensitivity (Cohort 1); and in association with fat mass and bone mineral density (DEXA) and atherosclerosis (intima media thickness, IMT) in 78 subjects (52 women) with a wide range of adiposity (Cohort 2). Circulating iFGF-23 was also measured before and after weight loss. In all subjects as a whole, serum intact and C-terminal concentrations were linearly and positively associated with BMI. In cohort 1, both serum iFGF-23 and CtFGF-23 concentrations increased with insulin resistance. Serum creatinine contributed to iFGF-23 variance, while serum ferritin and insulin sensitivity (but not BMI, age or serum creatinine) contributed to 17% of CtFGF-23 variance. In cohort 2, CtFGF-23 levels were higher in women vs. men, and increased with BMI, fat mass, fasting and post-load serum glucose, insulin, HOMA-IR and PTH, being negatively associated with circulating vitamin D and ferritin levels. The associations of CtFGF-23 with bone density in the radius, lumbar spine and carotid IMT were no longer significant after controlling for BMI. Weight loss led to decreased iFGF-23 concentrations. In summary, the associations of circulating FGF-23 concentration with parameters of glucose metabolism, bone density and atherosclerosis are dependent on iron and obesity status-associated insulin resistance.
doi:10.1371/journal.pone.0058961
PMCID: PMC3605441  PMID: 23555610
7.  A comparison of calcium acetate/magnesium carbonate and sevelamer-hydrochloride effects on fibroblast growth factor-23 and bone markers: post hoc evaluation from a controlled, randomized study 
Nephrology Dialysis Transplantation  2013;28(9):2383-2392.
Background
Different phosphate binders exert differing effects on bone mineral metabolism and levels of regulating hormones. The objective of this post hoc evaluation of the CALcium acetate MAGnesium carbonate (CALMAG) study was to compare the effects of calcium acetate/magnesium carbonate (CaMg) and a calcium-free phosphate binder, sevelamer-hydrochloride (HCl), on serum levels of fibroblast growth factor-23 (FGF-23) and markers of bone turnover.
Methods
This secondary analysis of the controlled, randomized CALMAG study, comparing the effect of CaMg and sevelamer-HCl on serum phosphorus (P), aimed to investigate the parameters described above. The analysis included 204 patients who completed the initial study per protocol (CaMg, n = 105; sevelamer-HCl, n = 99).
Results
The study showed that serum levels of FGF-23 were significantly reduced with CaMg and sevelamer-HCl, with no difference between groups at Week 25 [analysis of covariance (ANCOVA); log-intact FGF-23 (iFGF-23), P = 0.1573]. FGF-23 levels strongly correlated with serum P levels at all time points in both groups. The bone turnover parameters alkaline phosphatase (AP), bone AP (BAP), procollagen type 1 amino-terminal propeptide 1 (P1NP), osteoprotegerin (OPG), beta-crosslaps (β-CTX) and tartrate-resistant acid phosphatase 5b (TRAP 5b) increased significantly in the sevelamer-HCl group; they remained almost unchanged in the CaMg group, after the initial phase of P lowering (ANCOVA, P < 0.0001 for all except OPG, P = 0.1718).
Conclusions
CaMg and sevelamer-HCl comparably lower serum levels of iFGF-23. Changes in bone parameters were dependent on characteristics of the phosphate binder; in contrast with sevelamer-HCl, CaMg had no influence on bone turnover markers.
doi:10.1093/ndt/gft203
PMCID: PMC3769980  PMID: 23787550
bone markers; calcium acetate; fibroblast growth factor-23; haemodialysis; magnesium carbonate; phosphate binder
8.  Effect of chitosan chewing gum on reducing serum phosphorus in hemodialysis patients: a multi-center, randomized, double-blind, placebo-controlled trial 
BMC Nephrology  2014;15:98.
Background
HS219 (40 mg chitosan-loaded chewing gum) is designed to bind salivary phosphorus as an add-on to available phosphorus binders. We performed a randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of HS219 in hemodialysis (HD) patients with hyperphosphatemia as an add-on to phosphorus binders.
Methods
Sixty-eight HD patients who were maintained on calcium carbonate (n = 33) or sevelamer hydrochloride (n = 35) were enrolled. The primary end point was a change in serum phosphorus levels. Secondary end points included changes in levels of salivary phosphorus, serum calcium, parathyroid hormone (PTH), and intact fibroblast growth factor (iFGF) 23.
Results
Sixty-three patients chewed either HS219 (n = 35) or placebo (n = 28) for 30 min, three times a day, for 3 weeks. HS219 was well tolerated and safe. However, HS219 was not superior to placebo with additional reduction of serum phosphorus with respect to phosphorus binders at the end of the chewing period. There were no significant effects of HS219 on reduction of salivary phosphorus, serum calcium, iPTH, or iFGF23 levels.
Conclusions
The chitosan-loaded chewing gum HS219 does not affect serum and salivary phosphorus levels in Japanese HD patients with hyperphosphatemia. Our findings do not support previous findings that 20 mg of chitosan-loaded chewing gum reduces serum and salivary phosphorus levels.
Trail registration
ClinicalTrials.gov NCT01039428, 24 December, 2009.
doi:10.1186/1471-2369-15-98
PMCID: PMC4080692  PMID: 24968790
Chewing gum; Chitosan; Clinical trial; Hemodialysis; Hyperphosphatemia; Phosphorus binders
9.  Serum Amylase in Bulimia Nervosa and Purging Disorder: Differentiating the Association with Binge Eating versus Purging Behavior 
Physiology & behavior  2011;104(5):684-686.
Objective
Elevated serum amylase levels in bulimia nervosa (BN), associated with increased salivary gland size and self-induced vomiting in some patients, provide a possible marker of symptom severity. The goal of this study was to assess whether serum hyperamylasemia in BN is more closely associated with binge eating episodes involving consumption of large amounts of food or with purging behavior.
Method
Participants included women with BN (n=26); women with “purging disorder” (PD), a subtype of EDNOS characterized by recurrent purging in the absence of objectively large binge eating episodes (n=14); and healthy non-eating disorder female controls (n=32). There were no significant differences in age or body mass index (BMI) across groups. The clinical groups reported similar frequency of self-induced vomiting behavior and were free of psychotropic medications. Serum samples were obtained after overnight fast and were assayed for alpha-amylase by enzymatic method.
Results
Serum amylase levels were significantly elevated in BN (60.7 ± 25.4 international units [IU]/liter, mean ± sd) in comparison to PD (44.7 ± 17.1 IU/L, p < 02) and to Controls (49.3 ± 15.8, p < .05).
Conclusion
These findings provide evidence to suggest that it is recurrent binge eating involving large amounts of food, rather than self-induced vomiting, which contributes to elevated serum amylase values in BN.
doi:10.1016/j.physbeh.2011.06.025
PMCID: PMC3204380  PMID: 21781981
bulimia nervosa; purging disorder; self-induced vomiting; binge eating; serum amylase; hyperamylasemia
10.  A higher response of plasma neuropeptide Y, growth hormone, leptin levels and extracellular glycerol levels in subcutaneous abdominal adipose tissue to Acipimox during exercise in patients with bulimia nervosa: single-blind, randomized, microdialysis study 
Background
Neuropeptide Y (NPY) is an important central orexigenic hormone predominantly produced by the hypothalamus, and recently found to be secreted in adipose tissue (AT). Acipimox (Aci) inhibits lipolysis in AT and reduces plasma glycerol and free fatty acid (FFA) levels. Exercise and Aci are enhancers of growth hormone (GH) and NPY secretion and exercise may alter leptin levels. We expect to find abnormal neuropeptidergic response in plasma and AT in patients with bulimia nervosa (BN). We hypothesize that Aci influences these peptides via a FFA-independent mechanism and that Aci inhibits lipolysis through a cyclic adenosine monophosphate (cAMP)-dependent pathway. Dysregulations of the AT-brain axis peptides might be involved in binge eating as is the case in BN.
Methods
The objective of this study was to determine the responses of plasma NPY, GH, leptin, FFA and glycerol levels to exercise in BN patients and healthy women (C) given the anti-lipolytic drug Aci or placebo. The secondary objective of this study was to compare the responses of extracellular glycerol levels and plasma glycerol levels to exercise alone or together with Aci administration in BN patients and C women. Extracellular glycerol was measured in vivo in subcutaneous (sc) abdominal AT using microdialysis. Eight BN and eight C women were recruited for this single-blind, randomized study. Aci or placebo was given 1 hour before the exercise (45 min, 2 W/kg of lean body mass [LBM]). NPY, GH, leptin, FFA, glycerol plasma and AT glycerol levels were measured using commercial kits.
Results
The primary outcome of this study was that the exercise with Aci administration resulted in plasma NPY and GH increase (after a 45-minute exercise) and leptin (after a 90-minute post-exercise recovering phase) increased more in BN patients. The secondary outcomes of this study were that the exercise with Aci administration induced a higher decrease of extracellular glycerol in BN patients compared to the C group, while the exercise induced a higher increase of glycerol concentrations in sc abdominal AT of BN patients. Plasma glycerol levels decreased more in BN patients and plasma FFA levels were depressed in both groups after the exercise with Aci administration. The exercise induced similar increases in plasma NPY, GH, FFA and glycerol levels, and a similar decrease in the plasma leptin level in both groups.
Conclusions
We confirm the results of a single-blind, randomized, microdialysis study, i.e. that the Aci-induced elevation in plasma NPY and GH levels during the exercise is higher in BN patients and that Aci increased plasma leptin levels in the post-exercise recovering phase (90-minute) more in BN patients. The post-exercise rise (45-minute) in AT glycerol is much more attenuated by acute Aci treatment in BN patients. Simultaneously, we found facilitated turnover of plasma glycerol after the exercise together with Aci administration in BN. Our results support the hypotheses that Aci exerts an effect on the FFA-independent and cAMP-dependent mechanism.
Trial Registration
Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12611000955910
doi:10.1186/1743-7075-8-81
PMCID: PMC3245450  PMID: 22093818
Neuropeptide Y; Growth hormone; Leptin; Bulimia nervosa; Acipimox; Exercise; Adipose tissue; Free fatty acids; Glycerol; Microdialysis
11.  Personality Dimensions in Bulimia Nervosa, Binge Eating Disorder, and Obesity 
Comprehensive psychiatry  2009;51(1):31-36.
Objective
The purpose of this investigation was to examine differences in personality dimensions among individuals with bulimia nervosa, binge eating disorder, non-binge eating obesity and a normal weight comparison group as well as to determine the extent to which these differences were independent of self-reported depressive symptoms.
Method
Personality dimensions were assessed using the Multidimensional Personality Questionnaire in 36 patients with bulimia nervosa, 54 patients with binge eating disorder, 30 obese individuals who did not binge eat, and 77 normal weight comparison participants.
Results
Participants with bulimia nervosa reported higher scores on measures of stress reaction and negative emotionality compared to the other three groups, and lower well-being scores compared to the normal weight comparison and the obese samples. Patients with binge eating disorder scored lower on well-being and higher on harm avoidance than the normal weight comparison group. In addition, the bulimia nervosa and binge eating disorder groups scored lower than the normal weight group on positive emotionality. When personality dimensions were re-analyzed using depression as a covariate, only stress reaction remained higher in the bulimia nervosa group compared to the other three groups and harm avoidance remained higher in the binge eating disorder than the normal weight comparison group.
Conclusions
The higher levels of stress reaction in the bulimia nervosa sample and harm avoidance in the binge eating disorder sample after controlling for depression indicate that these personality dimensions are potentially important in the etiology, maintenance, and treatment of these eating disorders. Although the extent to which observed group differences in well-being, positive emotionality and negative emotionality reflect personality traits, mood disorders, or both is unclear, these features clearly warrant further examination in understanding and treating bulimia nervosa and binge eating disorder.
doi:10.1016/j.comppsych.2009.03.003
PMCID: PMC2838502  PMID: 19932823
12.  Effect of eating rate on binge size in Bulimia Nervosa 
Physiology & behavior  2007;93(3):481-485.
Effect of eating rate on binge size in bulimia nervosa. Bulimia Nervosa (BN) is an eating disorder characterized by recurrent episodes of binge eating. During binge eating episodes, patients often describe the rapid consumption of food, and laboratory studies have shown that during binges patients with BN eat faster than normal controls (NC), but the hypothesis that a rapid rate of eating contributes to the excessive intake of binge meals has not yet been experimentally tested. The aim of this study was to assess the effect of eating rate on binge size in BN, in order to determine whether binge size is mediated, in part, by rate of eating. Thirteen BN and 14 NC subjects were asked to binge eat a yogurt shake that was served at a fast rate (140g/min) on one occasion and at a slow rate (70g/min) on another. NC subjects consumed 169 g more when eating at the fast rate than when eating at the slow rate. In contrast, consumption rates failed to influence binge size in patients with BN (fast: 1205 g; slow: 1195 g). Consequently, there was a significant group by rate interaction. As expected, patients with BN consumed more overall than NC subjects (1200 g vs. 740 g). When instructed to binge in the eating laboratory, patients with BN ate equally large amounts of food at a slow rate as at a fast rate. NC subjects ate less at a slow rate. These findings indicate that in a structured laboratory meal paradigm binge size is not affected by rate of eating.
doi:10.1016/j.physbeh.2007.10.007
PMCID: PMC2323454  PMID: 17996257
bulimia nervosa; eating laboratory; eating rate; binge eating; eating disorders
13.  Tumor Localization and Biochemical Response to Cure in Tumor-Induced Osteomalacia 
Tumor-induced osteomalacia (TIO) is a rare disorder of phosphate wasting due to fibroblast growth factor-23 (FGF23)-secreting tumors that are often difficult to locate. We present a systematic approach to tumor localization and post-operative biochemical changes in 31 subjects with TIO. All had failed either initial, or re-localization (in case of recurrence or metastases at outside institutions). Functional imaging with 111Indium-octreotide with single photon emission computed tomography (octreo-SPECT or SPECT/CT), and 18fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) were performed, followed by anatomic imaging (CT,MRI). Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern. Tumors were localized in 20/31 subjects (64.5%). Nineteen of 20 subjects underwent octreo-SPECT imaging, and 16/20 FDG-PET/CT imaging. Eighteen of 19 (95%) were positive on octreo-SPECT, and 14/16 (88%) on FDG-PET/CT. Twelve of 20 subjects underwent VS; 10/12 (83%) were positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were: sensitivity=0.95, specificity=0.64, PPV=0.82 and NPV=0.88 for octreo-SPECT; sensitivity=0.88, specificity=0.36, PPV=0.62 and NPV=0.50 for FDG-PET/CT. Fifteen subjects had their tumor resected at our institution, and were disease-free at last follow-up. Serum phosphorus returned to normal in all subjects within 1-5 days. In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days. C-terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio. Serum 1,25-dihydroxyvitamin D3 (1,25D) rose and exceeded the normal range. In this systematic approach to TIO tumor localization Octreo-SPECT was more sensitive and specific, but in many cases FDG-PET/CT was complementary. VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery. Sustained elevations in cFGF23 and 1,25D were observed, suggesting novel regulation of FGF23 processing and 1,25D generation.
doi:10.1002/jbmr.1881
PMCID: PMC3900247  PMID: 23362135
FGF23; hypophosphatemia; mineral metabolism; vitamin D
14.  Effectiveness of a web-based treatment program using intensive therapeutic support for female patients with bulimia nervosa, binge eating disorder and eating disorders not otherwise specified: study protocol of a randomized controlled trial 
BMC Psychiatry  2013;13:310.
Background
Disordered eating behavior and body dissatisfaction affect a large proportion of the Dutch population and account for severe psychological, physical and social morbidity. Yet, the threshold for seeking professional care is still high. In the Netherlands, only 7.5% of patients with bulimia nervosa and 33% of patients with anorexia nervosa are treated within the mental health care system. Easily accessible and low-threshold interventions, therefore, are needed urgently. The internet has great potential to offer such interventions. The aim of this study is to determine whether a web-based treatment program for patients with eating disorders can improve eating disorder psychopathology among female patients with bulimia nervosa, binge eating disorder and eating disorders not otherwise specified.
Methods/design
This randomized controlled trial will compare the outcomes of an experimental treatment group to a waiting list control group. In the web-based treatment program, participants will communicate personally and asynchronously with their therapists exclusively via the internet. The first part of the program will focus on analyzing eating attitudes and behaviors. In the second part of the program participants will learn how to change their attitudes and behaviors. Participants assigned to the waiting list control group will receive no-reply email messages once every two weeks during the waiting period of 15 weeks, after which they can start the program. The primary outcome measure is an improvement in eating disorder psychopathology as determined by the Eating Disorder Examination Questionnaire. Secondary outcomes include improvements in body image, physical and mental health, body weight, self-esteem, quality of life, and social contacts. In addition, the participants’ motivation for treatment and their acceptability of the program and the therapeutic alliance will be measured. The study will follow the recommendations in the CONSORT statement relating to designing and reporting on RCTs.
Discussion
This study protocol presents the design of a RCT for evaluating the effectiveness of a web-based treatment program using intensive therapeutic support for female patients with bulimia nervosa, binge eating disorder and eating disorders not otherwise specified.
Trial registration
The protocol for this study is registered with the Netherlands Trial Registry NTR2415.
doi:10.1186/1471-244X-13-310
PMCID: PMC3840645  PMID: 24238630
Eating disorders; Bulimia nervosa; Binge eating disorder; Eating disorders not otherwise specified; Randomized controlled trial; Web-based treatment program; e-health; Intensive therapeutic support; Asynchronous support
15.  FGF14 N-Terminal Splice Variants Differentially Modulate Nav1.2 and Nav1.6-Encoded Sodium Channels 
The Intracellular Fibroblast Growth Factor (iFGF) subfamily includes four members (FGFs 11–14) of the structurally related FGF superfamily. Previous studies showed that the iFGFs interact directly with the pore-forming (α) subunits of voltage-gated sodium (Nav) channels and regulate the functional properties of sodium channel currents. Sequence heterogeneity among the iFGFs is thought to confer specificity to this regulation. Here, we demonstrate that the two N-terminal alternatively spliced FGF14 variants, FGF14-1a and FGF14-1b, differentially regulate currents produced by Nav1.2-and Nav1.6 channels. FGF14-1b, but not FGF14-1a, attenuates both Nav1.2 and Nav1.6 current densities. In contrast, co-expression of an FGF14 mutant, lacking the N-terminus, increased Nav1.6 current densities. In neurons, both FGF14-1a and FGF14-1b localized at the axonal initial segment, and deletion of the N-terminus abolished this localization. Thus, the FGF14 N-terminus is required for targeting and functional regulation of Nav channels, suggesting an important function for FGF14 alternative splicing in regulating neuronal excitability.
doi:10.1016/j.mcn.2009.05.007
PMCID: PMC2832592  PMID: 19465131
16.  Serum Concentrations of Fibroblast Growth Factors 19 and 21 in Women with Gestational Diabetes Mellitus: Association with Insulin Resistance, Adiponectin, and Polycystic Ovary Syndrome History 
PLoS ONE  2013;8(11):e81190.
Background
Fibroblast growth factor 19 (FGF19) and FGF21 are considered to be novel adipokines that improve glucose tolerance and insulin sensitivity. In the current study, we investigated serum FGF19 and FGF21 levels in patients with gestational diabetes mellitus (GDM) and explored their relationships with anthropometric and endocrine parameters.
Method
Serum FGF19 and FGF21 levels were determined by enzyme-linked immunosorbent assay (ELISA) in patients with GDM (n = 30) and healthy pregnant controls (n = 60) matched for maternal and gestational age. Serum FGF19 and FGF21 levels were correlated with anthropometric, metabolic, and endocrine parameters.
Results
Circulating levels of FGF19 were significantly reduced in patients with GDM relative to healthy pregnant subjects, whereas FGF21 levels were increased in GDM patients. Serum FGF19 levels independently and inversely correlated with insulin resistance (increased homeostasis model assessment of insulin resistance, HOMA-IR) and were positively related to serum adiponectin in both groups. In contrast, serum FGF21 levels independently and positively correlated with insulin resistance and serum triglycerides and were inversely related to serum adiponectin. In addition, in the combined population of both groups, those women with preconception polycystic ovary syndrome (PCOS) history had the lowest levels of FGF19, which were significantly lower than those in GDM patients without PCOS history and those in controls without PCOS history.
Conclusions
Circulating FGF19 levels are reduced in GDM patients, in contrast with FGF21 levels. Both serum FGF19 and FGF21 levels are strongly related to insulin resistance and serum levels of adiponectin. Considering the different situation between FGF19 and FGF21, we suggest that reduced serum FGF19 levels could be involved in the pathophysiology of GDM, while increased serum FGF21 levels could be in a compensatory response to this disease.
doi:10.1371/journal.pone.0081190
PMCID: PMC3834317  PMID: 24260557
17.  Comparison of a high-carbohydrate and high-protein breakfast effect on plasma ghrelin, obestatin, NPY and PYY levels in women with anorexia and bulimia nervosa 
Background
The present study investigated plasma levels of gut-brain axis peptides ghrelin, obestatin, NPY and PYY after consumption of a high-carbohydrate (HC) and high-protein (HP) breakfast in patients with anorexia nervosa, bulimia nervosa and in healthy controls. These peptides play an important role in regulation of energy homeostasis and their secretion is disturbed under condition of eating disorders. As various types of consumed macronutrients may induce different plasma hormone responses, so we examined these responses in women patients with eating disorders and compared them with those of healthy controls.
Methods
We examined plasma hormone responses to HC and HP breakfast in patients with AN (n = 14; age: 24.6 ± 1.8 years, BMI: 15.3 ± 0.7), BN (n = 15; age: 23.2 ± 1.7 years, BMI: 20.5 ± 0.9) and healthy controls (n = 14; age: 24.9 ± 1.4 years, BMI: 21.1 ± 0.8). Blood samples were drawn from the cubital vein, the first blood drawn was collected before meal, and then 30, 60, 90, 120 and 150 min after breakfast consumption. Plasma hormone levels were determined by commercially available RIA kits.
Results
Fasting and postprandial plasma obestatin levels were significantly increased in both AN and BN patients, while plasma ghrelin levels were significantly increased in AN patients only. After breakfast consumption, plasma levels of ghrelin and obestatin decreased, although they were still above the range of values of healthy controls. Fasting NPY plasma levels were significantly increased in AN and BN patients and did not change postprandially. Fasting PYY levels were comparable in AN, BN and healthy controls, but postprandially significantly increased after HP breakfast in AN and BN patients. Different reactions to breakfast consumption was found for ghrelin and PYY among investigated groups, while for obestatin and NPY these reactions were similar in all groups.
Conclusions
Significant increase of obestatin and NPY in AN and BN patients may indicate their important role as the markers of eating disorders. Different reactions of ghrelin and PYY to breakfast consumption among groups suggest that role of these hormones in regulation of energy homeostasis can be adjusted in dependence to acute status of eating disorder.
doi:10.1186/1743-7075-9-52
PMCID: PMC3533897  PMID: 22681985
Ghrelin; Obestatin; NPY; PYY; Anorexia nervosa; Bulimia nervosa; High-carbohydrate breakfast; High-protein breakfast
18.  An Examination of Eating Patterns in Community Women with Bulimia Nervosa and Binge Eating Disorder 
Objective
To better understand the eating patterns of persons with eating disorders.
Method
This study investigated typical eating behavior (meal frequency and snacking) and atypical eating behavior among 311 community women with online questionnaires. Participants were classified with bulimia nervosa (BN; n = 39), binge eating disorder (BED; n = 69), or controls (CON; n = 203).
Results
In terms of typical eating behaviors, the BN group ate significantly fewer meals, particularly lunches, than the other two groups. Atypical eating, such as nibbling, eating double meals and nocturnal eating, was significantly more common in the eating disorder groups. More frequent breakfast consumption was associated with lower BMI in the BED and CON groups, and more frequent meal consumption was associated with less binge eating in the BED group only.
Discussion
Our study revealed differences in typical and atypical eating patterns, and associations with weight and eating disorder behaviors among eating disorder and control groups.
doi:10.1002/eat.20853
PMCID: PMC3646558  PMID: 21997425
obesity; binge eating; bulimia; eating disorders; eating behavior
19.  Negative Affect and Neural Response to Palatable Food Intake in Bulimia Nervosa 
Appetite  2012;58(3):964-970.
Binge eating is often preceded by reports of negative affect, but the mechanism by which affect may lead to binge eating is unclear. This study evaluated the effect of negative affect on neural response to anticipation and receipt of palatable food in women with bulimia nervosa (BN) versus healthy controls. We also evaluated connectivity between the amygdala and reward-related brain regions. Females with and without BN (N = 26) underwent functional magnetic resonance imaging (fMRI) during receipt and anticipated receipt of chocolate milkshake and a tasteless solution. We measured negative affect just prior to the scan. Women with BN showed a positive correlation between negative affect and activity in the putamen, caudate, and pallidum during anticipated receipt of milkshake (versus tasteless solution). There were no significant relations between negative affect and receipt of milkshake. Connectivity analyses revealed a greater relation of amygdala activity to activation in the left putamen and insula during anticipated receipt of milkshake in the bulimia group relative to the control group. The opposite pattern was found for the taste of milkshake; the control group showed a greater relation of amygdala activity to activation in the left putamen and insula in response to milkshake receipt than the bulimia group. Results show that as negative affect increases, so does responsivity of reward regions to anticipated intake of palatable food, implying that negative affect may increase the reward value of food for individuals with bulimia nervosa or that negative affect has become a conditioned cue due to a history of binge eating in a negative mood.
doi:10.1016/j.appet.2012.02.051
PMCID: PMC3589569  PMID: 22387716
bulimia nervosa; negative affect; fMRI; reward
20.  Dysregulation of Brain Reward Systems in Eating Disorders: Neurochemical Information from Animal Models of Binge Eating, Bulimia Nervosa, and Anorexia Nervosa 
Neuropharmacology  2011;63(1):87-96.
Food intake is mediated, in part, through brain pathways for motivation and reinforcement. Dysregulation of these pathways may underlay some of the behaviors exhibited by patients with eating disorders. Research using animal models of eating disorders has greatly contributed to the detailed study of potential brain mechanisms that many underlie the causes or consequences of aberrant eating behaviors. This review focuses on neurochemical evidence of reward-related brain dysfunctions obtained through animal models of binge eating, bulimia nervosa, or anorexia nervosa. The findings suggest that alterations in dopamine (DA), acetylcholine (ACh) and opioid systems in reward-related brain areas occur in response to binge eating of palatable foods. Moreover, animal models of bulimia nervosa suggest that while bingeing on palatable food releases DA, purging attenuates the release of ACh that might otherwise signal satiety. Animal models of anorexia nervosa suggest that restricted access to food enhances the reinforcing effects of DA when the animal does eat. The activity-based anorexia model suggests alterations in mesolimbic DA and serotonin occur as a result of starvation coupled with excessive wheel running. These findings with animal models complement data obtained through neuroimaging and pharmacotherapy studies of clinical populations. Finally, information on the neurochemical consequences of the behaviors associated with these eating disorders will be useful in understanding these complex disorders and may inform future therapeutic approaches, as discussed here.
doi:10.1016/j.neuropharm.2011.11.010
PMCID: PMC3366171  PMID: 22138162
acetylcholine; binge eating; clinical studies; dopamine; eating disorders; opioids; rat; serotonin
21.  Significance of Overvaluation of Shape/Weight in Binge Eating Disorder: Comparative Study with Overweight and Bulimia Nervosa 
Obesity (Silver Spring, Md.)  2009;18(3):499-504.
Increasing empirical evidence supports the validity of binge eating disorder (BED) and its inclusion as a formal diagnosis in the DSM-V. Contention exists regarding the criteria for BED, including whether, like bulimia nervosa (BN), it should be characterized by overvaluation of shape/weight. This study examined the significance of overvaluation for BED using two complementary comparisons groups. Participants were 324 women who completed self-report instruments as part of an internet study. Analyses compared BMI, eating disorder (ED) features, and depressive levels in four groups: 123 overweight participants without ED, 47 BED participants who do not overvalue shape/weight, 101 BED participants who overvalue shape/weight, and 53 BN participants. Both BED groups had significantly greater ED psychopathology than the overweight group. Within BED, the group with overvaluation had significantly greater ED psychopathology and depressive levels despite no differences in binge eating. BED with overvaluation and BN groups differed little from each other but had significantly higher ED psychopathology and depressive levels than the other groups. Group differences existed despite similar age and BMI across the groups, as well as when controlling for group differences in depression levels. These findings provide further support for the validity of BED and suggest that overvaluation of shape/weight, which provides important information about BED severity, warrants consideration as either a diagnostic specifier or as a dimensional severity rating. Although inclusion of overvaluation of shape/weight could be considered as a required criterion for BED, this would exclude a substantial proportion of BED patients with clinically significant problems.
doi:10.1038/oby.2009.280
PMCID: PMC2845446  PMID: 19713949
shape and weight concerns; binge eating disorder; bulimia nervosa; obesity; body image; diagnosis
22.  Deficient Activity in the Neural Systems That Mediate Self-regulatory Control in Bulimia Nervosa 
Archives of general psychiatry  2009;66(1):51-63.
Context
Disturbances in neural systems that mediate voluntary self-regulatory processes may contribute to bulimia nervosa (BN) by releasing feeding behaviors from regulatory control.
Objective
To study the functional activity in neural circuits that subserve self-regulatory control in women with BN.
Design
We compared functional magnetic resonance imaging blood oxygenation level–dependent responses in patients with BN with healthy controls during performance of the Simon Spatial Incompatibility task.
Setting
University research institute.
Participants
Forty women: 20 patients with BN and 20 healthy control participants.
Main Outcome Measure
We used general linear modeling of Simon Spatial Incompatibility task–related activations to compare groups on their patterns of brain activation associated with the successful or unsuccessful engagement of self-regulatory control.
Results
Patients with BN responded more impulsively and made more errors on the task than did healthy controls; patients with the most severe symptoms made the most errors. During correct responding on incongruent trials, patients failed to activate frontostriatal circuits to the same degree as healthy controls in the left inferolateral prefrontal cortex (Brodmann area [BA] 45), bilateral inferior frontal gyrus (BA 44), lenticular and caudate nuclei, and anterior cingulate cortex (BA 24/32). Patients activated the dorsal anterior cingulate cortex (BA 32) more when making errors than when responding correctly. In contrast, healthy participants activated the anterior cingulate cortex more during correct than incorrect responses, and they activated the striatum more when responding incorrectly, likely reflecting an automatic response tendency that, in the absence of concomitant anterior cingulate cortex activity, produced incorrect responses.
Conclusions
Self-regulatory processes are impaired in women with BN, likely because of their failure to engage frontostriatal circuits appropriately. These findings enhance our understanding of the pathogenesis of BN by pointing to functional abnormalities within a neural system that subserves self-regulatory control, which may contribute to binge eating and other impulsive behaviors in women with BN.
doi:10.1001/archgenpsychiatry.2008.504
PMCID: PMC2759684  PMID: 19124688
23.  P8 - Measurement of Fibroblast Growth Factor-23 (FGF23) in the Serum of Patients Affected by Juvenile Systemic Lupus Erythematosus: A Possible Marker of Kidney Damage 
The phospatonins are a new group of hormones involved in the regulation of phosphate, vitamin D and bone mineralisation. The most well-known phospatonin is fibroblast growth factor-23 (FGF23), a molecule whose action on target tissues is mediated by membrane receptors (FGFRs) together with the cofactor Klotho. There is known to be an association between FGF23 levels and chronic renal insufficiency (CRI) and, in particular, FGF23 is a factor in mortality due to cardiac complications in these subjects. Furthermore, FGF23 is involved in the pathogenesis of vascular calcifications. Scientific observations have shown that vascular and renal alterations are a negative prognostic factor in subjects affected by juvenile systemic lupus erythematosus (SLE). In this study, we measured FGF23 in a group of 53 patients (46 females, 7 males, mean age 13.3 ± 5.6) with juvenile SLE diagnosed before the age of 18 years. Twelve of the 53 patients had kidney damage. All the patients were treated with corticosteroids, hydroxychloroquine, azathioprine, cyclophosphamide, and Cellcept (MMF). Two were refractory to treatment with rituximab. At the time of recruitment 28/53 were receiving hydroxychloroquine and the others low doses of prednisone and MMF or azathioprine. One patient was on dialysis for CRI. All the patients with glomerulonephritis underwent a renal biopsy within the first 6 months: 4WHO IIA, 6 IIB, 10 III, 5 IV. We recruited 35 control patients.
We evaluated the lipid profile in all the patients (total cholesterol, LDL, HDL and triglycerides), assessed kidney function (serum creatinine, creatinine clearance, proteinuria, microalbuminuria), performed renal biospies (only on those with kidney damage) and evaluated bone mass.
FGF23 was measured using the ELISA method (Immunotopics Inc. San Clemente, CA, USA).
Serum levels of FGF23 were found to be significantly raised in the SLE patients compared with the controls (Student’s t-test: 67.1±40SD vs 5±3.2SD pg/ml). Statistical analysis using the Mann-Whitney U Test showed that the patients with kidney damage had higher FGF23 levels compared with the patients without kidney damage (45.3±20 vs 13.77±9.2 SD pg/ml; p=0. 0001); finally, ANCOVA showed that the patients with severe kidney damage (WHO III–IV) had higher values compared with the patients in the WHO IIA–IIB stages (52.5±21 and 58.5±15 pg/ml respectively vs 13.7±9 and 35±10 pg/ml, p=0.004). No significant correlation emerged between FGF23 levels and lipid profile and cardiac function. Nevertheless, we did observe a trend towards a correlation between FGF23 and HDL (Pearson’s correlation test r-0. 07; p=n.s.) In conclusion, serum FGF23 was raised in patients with juvenile SLE and appeared to be correlated with kidney damage. Although further studies are needed, it appears that FGF23 could be an important marker for early identification of renal insufficiency.
PMCID: PMC3213795
24.  Quality of life in anorexia nervosa, bulimia nervosa and eating disorder not-otherwise-specified 
Background
This study aimed to assess differences in Quality of Life (QoL) across eating disorder (ED) diagnoses, and to examine the relationship of QoL to specific clinical features.
Results
199 patients with a diagnosed ED completed the Clinical Impairment Assessment (CIA) [Cognitive Behavior Therapy and Eating Disorders, 315–318, 2008] and the Eating Disorders Examination (EDE) [Int J Eat Disord 6:1–8]. Differences between diagnostic groups were examined, as were differences between restrictive and binge-purge subtypes.
CIA scores and EDE scores were positively correlated and higher in groups with binge-purge behaviours. CIA scores were not correlated with BMI, illness duration or frequency of bingeing/purging behaviours, except in the binge-purge AN group, where CIA scores negatively correlated with BMI.
Conclusions
Patients with EDs have poor QoL and impairment increases with illness severity. Patients with binge/purge diagnoses are particularly impaired. It remains unclear which clinical features best predict the degree of impairment experienced by patients with EDs.
doi:10.1186/2050-2974-1-43
PMCID: PMC4081766  PMID: 24999421
Eating disorders; Anorexia nervosa; Bulimia nervosa; Clinical impairment assessment; Functional impairment; Quality of life
25.  Picking and nibbling: Frequency and associated clinical features in bulimia nervosa, anorexia nervosa and binge eating disorder 
Picking and nibbling (P&N) is a newly studied eating behavior characterized by eating in an unplanned and repetitious manner in between meals and snacks. This behavior seems to be related to poorer weight loss outcomes after bariatric surgery for weight loss in severely obese patients, but clarification is still required regarding its value in other clinical samples.
Objective:
The purpose of this study was to investigate the frequency of P&N across different eating disorder samples, as well as to examine its association with psychopathological eating disorder features.
Methods:
Our sample included treatment-seeking adult participants, recruited for five different clinical trials: 259 binge eating disorder (BED); 264 bulimia nervosa (BN) and 137 anorexia nervosa (AN). Participants were assessed using the Eating Disorders Examination interview before entering the clinical trials.
Results:
P&N was reported by 44% of the BED; 57.6% of the BN and 34.3% of the AN participants. No association was found between P&N and BMI, the presence of compensatory behaviors, binge eating or any of the EDE subscales.
Discussion:
This study suggests that P&N behavior is highly prevalent across eating disorder diagnoses. Our findings suggest that P&N is not associated with psychopathology symptoms or other eating disordered behaviors.
doi:10.1002/eat.22167
PMCID: PMC4009470  PMID: 23922133
Picking and nibbling; eating behaviors;  eating disordered behaviors

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