Effect of FADS1 SNPs rs174546, rs174547 and rs174550 on blood fatty acid profiles and plasma free oxylipins.

Introduction: Previous studies have indicated that activity of fatty acid desaturase 1 (FADS1), is involved in cardiometabolic risk. Recent experimental data have shown that FADS1 knockdown can promote lipid accumulation and lipid droplet formation in liver cells. In this study, we aimed to characterize whether different FADS1 genotypes affect liver fat content, essential fatty acid content and free oxylipin mediators in the blood. Methods: We analyzed the impact of FADS1 single-nucleotide polymorphisms (SNPs) rs174546, rs174547, and rs174550 on blood fatty acids and free oxylipins in a cohort of 85 patients from an academic metabolic medicine outpatient center. Patients were grouped based on their genotype into the homozygous major (derived) allele group, the heterozygous allele group, and the homozygous minor (ancestral) allele group. Omega-3 polyunsaturated fatty acids (n-3 PUFA) and omega-6 polyunsaturated fatty acids (n-6 PUFA) in the blood cell and plasma samples were analyzed by gas chromatography. Free Oxylipins in plasma samples were analyzed using HPLC-MS/MS. Liver fat content and fibrosis were evaluated using Fibroscan technology. Results: Patients with the homozygous ancestral (minor) FADS1 genotype exhibited significantly lower blood levels of the n-6 PUFA arachidonic acid (AA), but no significant differences in the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). There were no significant differences in liver fat content or arachidonic acid-derived lipid mediators, such as thromboxane B2 (TXB2), although there was a trend toward lower levels in the homozygous ancestral genotype group. Discussion: Our findings suggest that FADS1 genotypes influence the blood levels of n-6 PUFAs, while not significantly affecting the n-3 PUFAs EPA and DHA. The lack of significant differences in liver fat content and arachidonic acid-derived lipid mediators suggests that the genotype-related variations in fatty acid levels may not directly translate to differences in liver fat or inflammatory lipid mediators in this cohort. However, the trend towards lower levels of certain lipid mediators in the homozygous ancestral genotype group warrants further investigation to elucidate the underlying mechanisms of different FADS1 genotypes and potential implications for cardiometabolic risk.

Correlation between Obesity and Socioeconomic and Psychological Characteristics of Students Attending Different Rural School Types.

We examined the prevalence of obesity in two types of schools-a comprehensive school and a grammar school-in a rural German region of Brandenburg. METHODS: In a cross-sectional study, BMI values were measured in 114 students in grades 5, 7, and 10. In addition to the demographic data, data on nutrition, physical activity, and mental well-being were collected using a questionnaire. RESULTS: A total of 44% (11/25) of the comprehensive school students and 15% (13/89) of the high school students are overweight, and 24% (6/25) of the comprehensive school pupils and 6% (5/89) of the grammar school pupils (p = 0.009) are obese. In addition, 91% (10/11) of the students with obesity, 36% (4/11) of the students with pre-obesity, and 31% (26/84) of the normal-weight students (p = 0.001) are concerned about their weight. Among the children with obesity, 82% (9/11) are afraid of gaining weight. In addition, 6% (5/82) of the normal-weight students, 25% (3/12) of the students with pre-obesity, and 70% (7/10) of the students with obesity feel restricted by their weight when exercising. CONCLUSION: School attendance and parental socioeconomic status appear to correlate with students' weight statuses. There is a high level of suffering, and they feel uncomfortable with their bodies and worry about weight regulation.

Circulating Omega-3 Polyunsaturated Fatty Acids Levels in Coronary Heart Disease: Pooled Analysis of 36 Observational Studies.

Long-chain n-3 polyunsaturated fatty acid (PUFA) supplementation has shown potential benefits in the prevention of coronary heart disease (CHD); however, the impact of omega-3 fatty acid levels on CHD risk remains a subject of debate. Here, we aimed to investigate the association between n-3 PUFA levels and the risk of CHD, with particular reference to the subtypes of n-3 PUFA. METHODS: Prospective studies and retrospective case-control studies analyzing n-3 PUFA levels in CHD, published up to 30 July 2022, were selected. A random effects meta-analysis was used for pooled assessment, with relative risks (RRs) expressed as 95% confidence intervals (CIs) and standardized mean differences expressed as weight mean differences (WMDs). Subgroup and meta-regression analyses were conducted to assess the impact of n-3 PUFA exposure interval on the CHD subtype variables of the study. RESULTS: We included 20 prospective studies (cohort and nested case-control) and 16 retrospective case-control studies, in which n-3 PUFAs were measured. Higher levels of n-3 PUFAs (ALA, EPA, DPA, DHA, EPA + DHA, total n-3 PUFAs) were associated with a reduced risk of CHD, with RRs (95% CI) of 0.89 (0.81, 0.98), 0.83 (0.72, 0.96); 0.80 (0.67,0.95), 0.75 (0.64, 0.87), 0.83 (0.73, 0.95), and 0.80 (0.70, 0.93), respectively, p < 0.05. CHD patients had significantly lower n-3 PUFA levels compared to healthy controls (p < 0.05). In the subgroup analysis, a significant inverse trend was found for both fatal CHD and non-fatal CHD with n-3 PUFA (EPA + DHA) levels. Also, the link between n-3 PUFA levels in erythrocytes with total CHD was generally stronger than other lipid pools. CONCLUSIONS: n-3 PUFAs are significantly related to CHD risk, and these findings support the beneficial effects of n-3 PUFAs on CHD.

Changing from lipoprotein apheresis to evolocumab treatment lowers circulating levels of arachidonic acid and oxylipins.

Background and aims: Previous studies have shown that lipoprotein apheresis can modify the plasma lipidome and pro-inflammatory and pro-thrombotic lipid mediators. This has not been examined for treatment with protein convertase subtilisin/kexin type 9 inhibitors such as evolocumab, which are increasingly used instead of lipoprotein apheresis in treatment-resistant familial hypercholesterolemia. The aim of this study was to compare the effects of evolocumab treatment and lipoprotein apheresis on the fatty acid profile and on formation of lipid mediators in blood samples. Methods: We analyzed blood samples from 37 patients receiving either lipoprotein apheresis or evolocumab treatment as part of a previous study. Patients were stratified according to receiving lipoprotein apheresis (n = 19) and evolocumab treatment (n = 18). Serum fatty acid analysis was performed using gas chromatography flame ionization detection and plasma oxylipin analysis was done using liquid chromatography tandem mass spectrometry. Results: Changing from lipoprotein apheresis to evolocumab treatment led to lower levels of omega-6 polyunsaturated fatty acid (n-6 PUFA) including arachidonic acid, dihomo-γ-linolenic acid and linoleic acid. Moreover, several n-6 PUFA-derived oxylipins were reduced after evolocumab treatment. Conclusions: Given that arachidonic acid, either directly or as a precursor, is associated with the development of inflammation and atherosclerosis, evolocumab-mediated reductions of arachidonic acid and its metabolites might have an additional beneficial effect to lower cardiovascular risk.

Delineating endogenous Cushing's syndrome by GC-MS urinary steroid metabotyping.

BACKGROUND: Diagnosing Cushing's syndrome (CS) is highly complex. As the diagnostic potential of urinary steroid metabolome analysis by gas chromatography-mass spectrometry (GC-MS) in combination with systems biology has not yet been fully exploited, we studied a large cohort of patients with CS. METHODS: We quantified daily urinary excretion rates of 36 steroid hormone metabolites. Applying cluster analysis, we investigated a control group and 168 patients: 44 with Cushing's disease (CD) (70% female), 18 with unilateral cortisol-producing adrenal adenoma (83% female), 13 with primary bilateral macronodular adrenal hyperplasia (PBMAH) (77% female), and 93 ruled-out CS (73% female). FINDINGS: Cluster-Analysis delineated five urinary steroid metabotypes in CS. Metabotypes 1, 2 and 3 revealing average levels of cortisol and adrenal androgen metabolites included patients with exclusion of CS or and healthy controls. Metabotype 4 reflecting moderately elevated cortisol metabolites but decreased DHEA metabolites characterized the patients with unilateral adrenal CS and PBMAH. Metabotype 5 showing strong increases both in cortisol and DHEA metabolites, as well as overloaded enzymes of cortisol inactivation, was characteristic of CD patients. 11-oxygenated androgens were elevated in all patients with CS. The biomarkers THS, F, THF/THE, and (An + Et)/(11ß-OH-An + 11ß-OH-Et) correctly classified 97% of patients with CS and 95% of those without CS. An inverse relationship between 11-deoxygenated and 11-oxygenated androgens was typical for the ACTH independent (adrenal) forms of CS with an accuracy of 95%. INTERPRETATION: GC-MS based urinary steroid metabotyping allows excellent identification of patients with endogenous CS and differentiation of its subtypes. FUNDING: The study was funded by the Else Kröner-Fresenius-Stiftung and the Eva-Luise-und-Horst-Köhler-Stiftung.

Bioactive oxylipins in type 2 diabetes mellitus patients with and without hypertriglyceridemia.

Objective: Dyslipidemia, in particular elevated triglycerides (TGs) contribute to increased cardiovascular risk in type 2 diabetes mellitus (T2DM). In this pilot study we aimed to assess how increased TGs affect hepatic fat as well as polyunsaturated fatty acid (PUFA) metabolism and oxylipin formation in T2DM patients. Methods: 40 patients with T2DM were characterized analyzing routine lipid blood parameters, as well as medical history and clinical characteristics. Patients were divided into a hypertriglyceridemia (HTG) group (TG ≥ 1.7mmol/l) and a normal TG group with TGs within the reference range (TG < 1.7mmol/l). Profiles of PUFAs and their oxylipins in plasma were measured by gas chromatography and liquid chromatography/tandem mass spectrometry. Transient elastography (TE) was used to assess hepatic fat content measured as controlled attenuation parameter (CAP) (in dB/m) and the degree of liver fibrosis measured as stiffness (in kPa). Results: Mean value of hepatic fat content measured as CAP as well as body mass index (BMI) were significantly higher in patients with high TGs as compared to those with normal TGs, and correlation analysis showed higher concentrations of TGs with increasing CAP and BMI scores in patients with T2DM. There were profound differences in plasma oxylipin levels between these two groups. Cytochrome P450 (CYP) and lipoxygenase (LOX) metabolites were generally more abundant in the HTG group, especially those derived from arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), γ-linolenic acid (γ-LA), and α-linolenic acid (α-LA), and a strong correlation between TG levels and plasma metabolites from different pathways was observed. Conclusions: In adult patients with T2DM, elevated TGs were associated with increased liver fat and BMI. Furthermore, these patients also had significantly higher plasma levels of CYP- and LOX- oxylipins, which could be a novel indicator of increased inflammatory pathway activity, as well as a novel target to dampen this activity.

Granulomatosis with polyangiitis in a patient with polydipsia, facial nerve paralysis, and severe otologic complaints: a case report and review of the literature.

BACKGROUND: Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a necrotizing vasculitis with granulomatous inflammation that belongs to the class of antineutrophil cytoplasmic antibodies-positive diseases. It occurs in a localized and a systemic form and may present with a variety of symptoms. Involvement of the upper respiratory tract is very common, while neurologic, endocrinological, and nephrological dysfunction may occur. CASE PRESENTATION: We describe the case of a 29-year-old Central European male patient presenting with severe bilateral sensorineural hearing loss, otorrhea, and one-sided facial nerve paralysis. The patient was unsuccessfully treated with i.v. antibiotics at another hospital in Berlin, and tympanic tubes were inserted. After presentation to our emergency room, he was hospitalized and further diagnostics started. Increased fluid intake and 12 kg weight gain over the last months were reported. The patient was diagnosed with granulomatosis with polyangiitis and diabetes insipidus. The patient's condition improved after treatment with rituximab. DISCUSSION: A comprehensive PubMed search of all articles with granulomatosis with polyangiitis and diabetes insipidus was conducted to assess which combination of symptoms occurs simultaneously and whether other parts of the pituitary are commonly involved. The 39 selected articles, describing 61 patients, showed that ear-nose-throat involvement occurred most commonly, in 71% of cases. Of patients, 59% had involvement of the anterior pituitary gland, while true panhypopituitarism occurred in 13% of cases. Only one case report featured the same set of symptoms as described herein. CONCLUSION: Granulomatosis with polyangiitis is a highly variable disease, commonly involving the upper airways, but that may present with symptoms solely related to the pituitary gland. Clinicians should have a low threshold to investigate for granulomatosis with polyangiitis in patients with therapy-resistant otorrhea. Patients may present with a complex set of symptoms, and integrating different specialists when additional symptoms occur may lead to faster diagnosis.

Association of Interleukin-1 Beta and Interleukin-1 Receptor Antagonist Gene Polymorphisms and Plasma Levels with Diabetic Nephropathy.

Objective: We investigated the relationships between interleukin- (IL-) 1ß and IL-1 receptor antagonist (IL-1Ra) gene polymorphism and plasma levels in patients with diabetic nephropathy (DN). Methods: The genotype and allele frequency distribution of IL-1ß and IL-1Ra in 61 patients with DN and 48 healthy controls (HCs) were determined by kompetitive allele-specific PCR (KASP), and the plasma concentrations of IL-1ß and IL-1Ra in DN patients and HCs were measured by enzyme-linked immunosorbent assays (ELISA). Results: Significant differences were detected in the distribution of IL-1ß (-511C/T) genotype and allele frequencies between the DN and HC groups (P < 0.05), with the T genotype being more frequent in DN patients than HCs (OR = 2.84, 95% CI: 1.489-5.416). The IL-1ß (+3953C/T) and IL-1Ra (+8006C/T) genotypes and allele frequencies were not significantly different between the two groups (P > 0.05). The plasma IL-1ß level was significantly higher (P < 0.01), while the plasma IL-1Ra concentration was significantly lower in the DN group than the HC group (P < 0.05). Furthermore, the plasma IL-1ß level was significantly different between IL-1ß (-511C/T) locus variants (P < 0.05). Conclusion: The IL-1ß (-511C/T) gene polymorphism was significantly associated with DN risk in the population of northern Guangxi, China, and the T allele maybe responsible for genetic susceptibility to DN.

The effects of omega-3 fatty acids in type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: The effect of omega-3 polyunsaturated fatty acids (n-3 PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on cardiovascular risk modification in type 2 diabetes and related complications remain unclear. We aim to assess the published effects of n-3 PUFA interventions on lipid risk factors in type 2 diabetes. METHODS: We searched the literature on Pubmed, Embase, CENTRAL, and Web of Science databases in order to perform a pooled analysis of randomized clinical trials (RCTs) assessing n-3 PUFA interventions in type 2 diabetes. The primary outcomes analyzed were the effect of n -3 PUFAs on metabolic biomarkers in type 2 diabetes. RESULTS: 46 RCTs involving 4991 patients with type 2 diabetes were identified for further analysis. Analysis of results showed that n-3 PUFAs interventions significantly improved total cholesterol (TC, WMD = -0.22; 95% CI: -0.32∼ -0.11), triglyceride (TG,WMD = -0.36; 95% CI: -0.48∼-0.25), high-density lipoprotein cholesterol (HDL-C,WMD = 0.05; 95% CI: 0.02∼ 0.08), hemoglobin A1c (HbA1c, WMD = -0.19; 95% CI: -0.31∼-0.06) and C-reactive protein (CRP,WMD = -0.40; 95% CI: -0.74∼-0.07) levels compared to controls (p < 0.05). There was no significant effect on renal function, fasting blood sugar (FBS), insulin resistance (HOMA-IR), low-density lipoprotein cholesterol (LDL-C), adiponectin and leptin (p > 0.05). CONCLUSIONS: The results of this systematic review suggest that n-3 PUFAs can improve cardiovascular risk factors in type 2 diabetes.

NUCB2/nesfatin-1 is associated with severity of eating disorder symptoms in female patients with obesity.

BACKGROUND: Nesfatin-1 has been described as an anorexigenic peptide. Comprehensive evidence also points towards an involvement of nesfatin-1 in the modulation of emotional pathways with a sex-specific regulation of nesfatin-1 in association with anxiety. Although the implication of nesfatin-1 in the regulation of food intake is well-established in animals, data in humans are lacking. Therefore, we investigated a possible association of circulating NUCB2/nesfatin-1 with eating disorder symptoms in female and male patients displaying a wide range of body weight. METHODS: We enrolled 243 inpatients (177 female, 66 male) hospitalized due to anorexia nervosa (n = 66) or obesity (n = 144) or with normal weight and suffering from somatoform, adjustment, depressive or anxiety disorders (n = 33). Plasma samples (NUCB2/nesfatin-1 levels measured by ELISA) and measures of eating disorder symptoms (by EDI-2, range 0-100) were obtained within three days after admission. RESULTS: The study population displayed a distinct prevalence of eating disorder symptoms with female patients with anorexia nervosa (+ 77.0%, p < 0.001) and obesity (+ 87.9%, p < 0.001) reported significantly higher EDI-2 scores than normal weight patients of the same sex. Accordingly, males with anorexia nervosa (+ 39.7%, p < 0.05) and obesity (+ 51.7%, p < 0.001) had significantly higher EDI-2 scores than males with normal weight. Within the same BMI group, women displayed significantly higher scores than men (+ 21.4%, p < 0.05 in patients with anorexia nervosa, + 18.8%, p < 0.001 in participants with obesity). We observed a positive correlation between NUCB2/nesfatin-1 levels and EDI-2 total scores in female patients with obesity (r = 0.285, p = 0.015), whereas no associations were found in other subgroups. A positive correlation between NUCB2/nesfatin-1 levels and BMI was only observed in the male study population (r = 0.315, p = 0.018). CONCLUSIONS: NUCB2/nesfatin-1 plasma levels were positively associated with EDI-2 total scores in women with obesity, while no association was observable in men. The lacking association of NUCB2/nesfatin-1 and EDI-2 total scores in female patients with anorexia nervosa might be due to already low NUCB2/nesfatin-1 plasma levels. Whether NUCB2/nesfatin-1 is selectively involved in eating behavior in women with obesity will have to be further investigated.

Essential Polyunsaturated Fatty Acids in Blood from Patients with and without Catheter-Proven Coronary Artery Disease.

Coronary artery disease (CAD) is the leading cause of death worldwide. Statins reduce morbidity and mortality of CAD. Intake of n-3 polyunsaturated fatty acid (n-3 PUFAs), particularly eicosapentaenoic acid (EPA), is associated with reduced morbidity and mortality in patients with CAD. Previous data indicate that a higher conversion of precursor fatty acids (FAs) to arachidonic acid (AA) is associated with increased CAD prevalence. Our study explored the FA composition in blood to assess n-3 PUFA levels from patients with and without CAD. We analyzed blood samples from 273 patients undergoing cardiac catheterization. Patients were stratified according to clinically relevant CAD (n = 192) and those without (n = 81). FA analysis in full blood was performed by gas chromatography. Indicating increased formation of AA from precursors, the ratio of dihomo-gamma-linolenic acid (DGLA) to AA, the delta-5 desaturase index (D5D index) was higher in CAD patients. CAD patients had significantly lower levels of omega-6 polyunsaturated FAs (n-6 PUFA) and n-3 PUFA, particularly EPA, in the blood. Thus, our study supports a role of increased EPA levels for cardioprotection.

Efficacy of Temozolomide Therapy in Patients With Aggressive Pituitary Adenomas and Carcinomas-A German Survey.

CONTEXT: Despite growing evidence that temozolomide (TMZ) therapy is effective for the treatment of aggressive pituitary tumors (APTs) or carcinomas (PCs), individual therapy decisions remain challenging. OBJECTIVE: We therefore aimed to report on clinical characteristics leading to initiation of TMZ therapy and to add evidence on TMZ long-term effectiveness. DESIGN AND SUBJECTS: Retrospective survey on TMZ treatment in patients with APTs or PCs. TMZ therapy was initiated in 47 patients (22 females) with APTs (n = 34) or PCs (n = 13). Mean age at diagnosis was 45 ± 15 years. The immunohistochemical subtypes were corticotroph (n = 20), lactotroph (n = 18), and nonfunctioning (n = 9) tumors. TMZ therapy started 8 years after initial diagnosis using a standard regimen (median 6 cycles) for the majority of patients. RESULTS: Long-term radiological response to TMZ after a median follow-up of 32 months with 4 patients still on TMZ therapy was tumor regression for 9 (20%), stable disease for 8 (17%), and tumor progression for 29 patients (63%) (outcome data available for 46 patients). Progression occurred 16 months after initiation of TMZ. Median estimated progression-free survival was 23 months. Disease stabilization and median progression-free survival did not differ between patients with APTs or PCs. Predictors of tumor response were not identified. Overall, TMZ was well tolerated. CONCLUSION: We performed a nationwide survey on TMZ therapy in patients with APTs and PCs. While early response rates to TMZ are promising, long-term outcome is less favorable. Prolonged TMZ administration should be considered. We were not able to confirm previously reported predictors of tumor response to TMZ.

The Role of Objectively Measured, Altered Physical Activity Patterns for Body Mass Index Change during Inpatient Treatment in Female Patients with Anorexia Nervosa.

Increased physical activity (PA) affects outcomes in patients with anorexia nervosa (AN). To objectively assess PA patterns of hospitalized AN patients in comparison with healthy, outpatient controls (HC), and to analyze the effect of PA on Body Mass Index (BMI) change in patients with AN, we measured PA in 50 female patients with AN (median age = 25 years, range = 18⁻52 years; mean BMI = 14.4 ± 2.0 kg/m²) at the initiation of inpatient treatment and in 30 female healthy controls (median age = 26 years, range = 19⁻53 years; mean BMI = 21.3 ± 1.7 kg/m²) using the SenseWear™ armband. Duration of inpatient stay and weight at discharge were abstracted from medical records. Compared with controls, AN patients spent more time in very light-intensity physical activity (VLPA) (median VLPA = 647 vs. 566 min/day, p = 0.004) and light-intensity physical activity (LPA) (median LPA = 126 vs. 84 min/day, p < 0.001) and less time in moderate-intensity physical activity (MPA) (median MPA = 82 vs. 114 min/day, p = 0.022) and vigorous physical activity (VPA) (median VPA = 0 vs. 16 min/day, p < 0.001). PA and BMI increase were not associated in a linear model, and BMI increase was mostly explained by lower admission BMI and longer inpatient stay. In a non-linear model, an influence of PA on BMI increase seemed probable (jack knife validation, r² = 0.203; p < 0.001). No direct association was observed between physical inactivity and BMI increase in AN. An altered PA pattern exists in AN patients compared to controls, yet the origin and consequences thereof deserve further investigation.

[Diabetes Mellitus Type 2: Recent Publications and New Drugs]. / Typ-2-Diabetes: Nach Metformin ­ Verändern neue Studien die Therapie?

Since 2013 several placebo-controlled cardiovascular outcomes trails on new classes of glucose-lowering agents in addition to standard care have been reported. These trails were designed to demonstrate non-inferiority to placebo with regard to cardiovascular safety for patients with type 2 diabetes mellitus at high cardiovascular risk.For the glucagon-like peptide 1 (GLP-1)-receptor agonists liraglutide and semaglutide as well as for the sodium-glucose cotransporter-2 (SGLT-2) inhibitors empagliflozin and canagliflozin statistically significant reductions of the primary composite outcome (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) were demonstrated. Cardiovascular outcomes trails for the dipeptidyl peptidase-4 (DPP-4) inhibitors saxagliptin, alogliptin, and sitagliptin did not show statistically significant differences for major cardiovascular events between treatment and placebo groups.Therefore, for patients with established cardiovascular disease who do not achieve sufficient blood glucose control on metformin monotherapy GLP-1-receptor agonists and SGLT-2 inhibitors should be favoured for diabetes therapy intensification. However, the use of DPP-4 inhibitors should be considered for patients who are in need of a well-tolerated and safe oral glucose-lowering therapy.

Leptin and Physical Activity in Adult Patients with Anorexia Nervosa: Failure to Demonstrate a Simple Linear Association.

High physical activity (PA) in patients with anorexia nervosa (AN) is hypothesized to be, at least in part, a consequence of hypoleptinemia. However, most studies on the association of leptin and PA in AN were performed in adolescents or young adults, and PA was generally measured with subjective tools. We aimed to explore the association of leptin and PA in adults with AN using an objective technique to quantify PA. Using a cross-sectional, observational design, we analyzed body fat (bioelectrical impedance), PA (accelerometry, SenseWear™ armband) and plasma leptin (ELISA) in 61 women with AN (median age: 25 years, range: 18-52 years; median BMI: 14.8 ± 2.0 kg/m²) at the start of hospitalization. Results indicated a mean step count per day of 12,841 ± 6408 (range: 3956-37,750). Leptin was closely associated with BMI and body fat (ρ = 0.508 and ρ = 0.669, p < 0.001), but not with steps (ρ = 0.015, p = 0.908). Moreover, no significant association was observed between BMI and steps (ρ = 0.189, p = 0.146). In conclusion, there was no simple, linear association of leptin and PA, highlighting the need for more complex and non-linear models to analyze the association of leptin and PA in adults with AN in future studies.

Alterations of circulating NUCB2/nesfatin-1 during short term therapeutic improvement of anxiety in obese inpatients.

In addition to its anorexigenic properties in the neuroendocrine regulation of hunger and satiety, mounting evidence indicates a role for NUCB2/nesfatin-1 in the regulation of emotional stress responses which seems to occur in a sex-specific way. In the present study, we investigated the association of NUCB2/nesfatin-1 plasma levels with anxiety, depressiveness and perceived stress in obese men and women and their alterations during inpatient treatment. We expected a decrease of NUCB2/nesfatin-1 levels in female and an increase in male patients reporting a relevant alleviation of anxiety. We analyzed 69 inpatients (44 female, 25 male; body mass index, mean: 50.2±9.5kg/m2, range: 31.8-76.5kg/m2; mean age: 45.0±12.4years) hospitalized due to morbid obesity with mental (not necessarily anxiety disorders) and somatic comorbidities. NUCB2/nesfatin-1 plasma levels were measured by ELISA. Anxiety (GAD-7), depressiveness (PHQ-9) and perceived stress (PSQ-20) were concurrently determined as patient-reported outcomes. All measurements were carried out at the initiation of and during inpatient treatment when a clinically meaningful improvement of anxiety was achieved (≥5 points on GAD-7) or missed (±1 point). NUCB2/nesfatin-1 was positively correlated with anxiety scores in women at the beginning of (r=0.411; p=0.006) and during (r=0.301; p=0.047) inpatient treatment. In men, a significant negative correlation was observed following treatment (r=-0.469; p=0.018), while at the outset of treatment only a trend was observed (r=-0.381; p=0.059). Unexpectedly, neither women (n=19; at beginning vs. during treatment; 0.49±1.00ng/ml vs. 0.38±0.72ng/ml; p=0.687) nor men (n=9; 0.17±0.31ng/ml vs. 0.19±0.36ng/ml; p=0.427) who improved in anxiety scores (p<0.001) displayed significant changes of NUCB2/nesfatin-1 plasma levels, although the direction of change was as expected with a decrease in women (-23.3%) and an increase in men (+12.4%). In addition, the change of NUCB2/nesfatin-1 was not explained by the course of anxiety (women: p=0.587; men: p=0.373). In conclusion, women and men showed an inverse association between NUCB2/nesfatin-1 and anxiety with a positive correlation in women and a negative correlation in men (although this correlation was not statistically significant in men at the beginning of treatment). However, no significant change of NUCB2/nesfatin-1 following improvement of anxiety has been observed. This might be due to the short observation interval, or due to too small anxiety improvements associated with too low baseline anxiety levels.

Phoenixin is negatively associated with anxiety in obese men.

Phoenixin was recently identified in the rat hypothalamus and initially implicated in reproductive functions. A subsequent study described an anxiolytic effect of the peptide. The aim of the study was to investigate a possible association of circulating phoenixin with anxiety in humans. We therefore enrolled 68 inpatients with a broad spectrum of psychometrically measured anxiety (GAD-7). We investigated men since a menstrual cycle dependency of phoenixin has been assumed. Obese subjects were enrolled since they often report psychological comorbidities. In addition, we also assessed depressiveness (PHQ-9) and perceived stress (PSQ-20). Plasma phoenixin levels were measured using a commercial ELISA. First, we validated the ELISA kit performing a spike-and-recovery experiment showing a variance of 6.7±8.8% compared to the expected concentrations over the whole range of concentrations assessed, while a lower variation of 1.6±0.8% was observed in the linear range of the assay (0.07-2.1ng/ml). We detected phoenixin in the circulation of obese men at levels of 0.68±0.50ng/ml. These levels showed a negative association with anxiety scores (r=-0.259, p=0.043), while no additional associations with other psychometric parameters were observed. In summary, phoenixin is present in the human circulation and negatively associated with anxiety in obese men, a population often to report comorbid anxiety.

Plasma kisspeptin and ghrelin levels are independently correlated with physical activity in patients with anorexia nervosa.

While physical hyperactivity represents a frequent symptom of anorexia nervosa and may have a deleterious impact on the course of the disease, the underlying mechanisms are poorly understood. Since several food intake-regulatory hormones affect physical activity, the aim of the study was to investigate the association of physical activity with novel candidate hormones (kisspeptin, ghrelin, oxyntomodulin, orexin-A, FGF-21, R-spondin-1) possibly involved in patients with anorexia nervosa. Associations with psychometric parameters and body composition were also assessed. We included 38 female anorexia nervosa inpatients (body mass index, BMI, mean ± SD: 14.8 ± 1.7 kg/m2). Physical activity was evaluated using portable armband devices, body composition by bioelectrical impedance analysis. Blood withdrawal (hormones measured by ELISA) and psychometric assessment of depressiveness (PHQ-9), anxiety (GAD-7), perceived stress (PSQ-20) and disordered eating (EDI-2) were performed at the same time. Patients displayed a broad spectrum of physical activity (2479-26,047 steps/day) which showed a negative correlation with kisspeptin (r = -0.41, p = 0.01) and a positive association with ghrelin (r = 0.42, p = 0.01). The negative correlation with oxyntomodulin (r = -0.37, p = 0.03) was lost after consideration of potential confounders by regression analysis. No correlations were observed between physical activity and orexin-A, FGF-21 and R-spondin-1 (p > 0.05). Kisspeptin was positively correlated with BMI and body fat mass and negatively associated with the interpersonal distrust subscale of the EDI-2 (p < 0.01). Depressiveness, anxiety, and perceived stress did not correlate with kisspeptin or any other of the investigated hormones (p > 0.05). In conclusion, kisspeptin is inversely and ghrelin positively associated with physical activity as measured by daily step counts in anorexia nervosa patients suggesting an implication of these peptide hormones in the regulation of physical activity in anorexia nervosa.

Heterozygous inactivating CaSR mutations causing neonatal hyperparathyroidism: function, inheritance and phenotype.

BACKGROUND: Homozygous inactivating mutations of the calcium-sensing receptor (CaSR) lead to neonatal severe hyperparathyroidism (NSHPT), whereas heterozygous inactivating mutations result in familial hypocalciuric hypercalcemia (FHH). It is unknown why in some cases heterozygous CaSR mutations cause neonatal hyperparathyroidism (NHPT) clinically similar to NSHPT but with only moderately elevated serum calcium. METHODS: A literature survey was conducted to identify patients with heterozygous CaSR mutations and NHPT. The common NHPT CaSR mutants R185Q and R227L were compared with 15 mutants causing only FHH in the heterozygous state. We studied in vitro calcium signaling including the functional consequences of co-expression of mutant and wild-type (wt) CaSR, patients' phenotype, age of disease manifestation and mode of inheritance. RESULTS: All inactivating CaSR mutants impaired calcium signaling of wt-CaSR regardless of the patients' clinical phenotype. The absolute intracellular calcium signaling response to physiologic extracellular calcium concentrations in vitro showed a high correlation with patients' serum calcium concentrations in vivo, which is similar in NHPT and FHH patients with the same genotype. Pedigrees of FHH families revealed that paternal inheritance per se does not necessarily lead to NHPT but may only cause FHH. CONCLUSIONS: There is a significant correlation between in vitro functional impairment of the CaSR at physiologic calcium concentrations and the severity of alterations in calcium homeostasis in patients. Whether a particular genotype leads to NHPT or FHH appears to depend on additional predisposing genetic or environmental factors. An individual therapeutic approach appears to be warranted for NHPT patients.

Evaluation of a Portable Armband Device to Assess Resting Energy Expenditure in Patients With Anorexia Nervosa.

BACKGROUND: In women with anorexia nervosa (AN), resting energy expenditure (REE) is decreased due to reduced energy intake and severe underweight. The assessment of REE allows estimating individual metabolic downregulation and better understanding body weight regulatory mechanisms in severely underweight patients with AN. However, REE predictive equations are known to have considerable shortcomings in patients with AN. Our aim was to evaluate a portable armband device (SenseWear armband [SWA]; BodyMedia, Inc, Pittsburgh, PA) for the assessment of REE against the measurement with indirect calorimetry (IC) as the reference method. METHODS: We assessed REE simultaneously by IC and SWA in 50 women with AN at the start of inpatient therapy and calculated REE using 2 predictive equations. RESULTS: Reliable data for IC measurement were obtained for 34 patients (age: 27.0 ± 8.0 years; body mass index: 14.4 ± 2.0 kg/m²). REE assessed with SWA was overestimated by 23% ± 27% compared with REE measured by IC (1166 ± 174 vs 979 ± 198 kcal/d, P < .001). REE estimation with SWA gave an accurate prediction within 10% deviation of REE measured with IC in 35% of the patients. In contrast, REE calculated with 2 predictive equations underestimated REE measured with IC by -26% ± 17% and -5% ± 20%, respectively. CONCLUSIONS: A mean difference of 187 kcal/d between both techniques for the assessment of REE may be of methodological relevance. Therefore, SWA and IC are not interchangeable methods for the assessment of REE in underweight females with AN.