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Background: Studies investigating the underlying pathophysiology are needed to help explain and understand the postoperative complications following Roux-en-Y gastric bypass (RYGB) surgery. This study aimed to characterize segmental gastrointestinal pH profiles, motility measures, and transit times in patients with RYGB. Materials and Methods: Nineteen patients with RYGB underwent a standardized wireless motility capsule assessment. The oro-cecal segment was defined from capsule ingestion until the passage of the ileocecal junction. Segmental median pH, motility index, and transit time were determined for the oro-cecal and colonic segment as well as for the first and last hour of both these segments. For comparison to reference values, data from 17 healthy age- and gender-matched controls was used. A mixed effect model was used to describe differences between groups. Results: Median pH was high in patients with RYGB during the first hour of the oro-cecal segment (6.45 ± 0.4 vs 3.65 ± 1.55 pH units for healthy controls; P < 0.001), as well as during the entire oro-cecal segment (6.97 ± 0.4 vs 5.51 ± 1.1 pH units; P < 0.001). The same was evident for the median motility index (152 ± 64 vs 35.8 ± 31.1 mmHg*sec/min; P < 0.001 and 130 ± 65.9 vs 89.1 ± 20 mmHg*sec/min; P < 0.012, respectively). Median motility index was low the first hour of the colon (55.2 ± 45.7 vs 122 ± 77.9 mmHg*sec/min; P < 0.002). Additionally, patients had short oro-cecal transit time (5.8 ± 1.6 vs 7.6 ± 1.4 h; P < 0.001) and long colonic transit time (29.4 ± 17.5 vs 19.6 ± 12.2 h; P = 0.048). Conclusions: In patients with RYGB, the oro-cecal segment was characterized by an alkaline intraluminal environment, high motility activity, and short transit time. In contrast, colonic transit time was long. Graphical abstract: [Figure not available: see fulltext.]

BACKGROUND: Survival of medullary thyroid carcinoma (MTC) subgroups in relation to the general population is poorly described. Data on the factors predicting long-term biochemical cure in MTC patients are nonexistent at a population level. A nationwide retrospective cohort study of MTC in Denmark from 1997 to 2014 was conducted, aiming to detect subgroups with survival similar to that of the general population and to identify prognostic factors for disease-specific survival and long-term biochemical cure.METHODS: The study included 220 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. As a representative sample of the general population, a reference population matched 50:1 to the MTC cohort was used.RESULTS: Patients diagnosed with hereditary MTC by screening (hazard ratio [HR] = 1.5 [confidence interval (CI) 0.5-4.3]), patients without regional metastases (HR = 1.4 [CI 0.9-2.3]), and patients with stage I (HR = 1.3 [CI 0.6-3.1]), stage II (HR = 1.1 [CI 0.6-2.3]), and III (HR = 1.3 [CI 0.4-4.2]) disease had an overall survival similar to the reference population. On multivariate analysis, the presence of distant metastases (HR = 12.3 [CI 6.0-25.0]) predicted worse disease-specific survival, while the absence of regional lymph node metastases (odds ratio = 40.1 [CI 12.0-133.7]) was the only independent prognostic factor for long-term biochemical cure.CONCLUSIONS: Patients with hereditary MTC diagnosed by screening, patients without regional metastases, and patients with stages I, II, and III disease may have similar survival as the general population. The presence of distant metastases predicted worse disease-specific survival, while the absence of regional metastases predicted long-term biochemical cure.

Background The completeness of REarranged during Transfection (RET) testing in patients with medullary thyroid carcinoma (MTC) was recently reported as 60%. However, the completeness on a population level is unknown. Similarly, it is unknown if the first Danish guidelines from 2002, recommending RET testing in all MTC patients, improved completeness in Denmark. We conducted a nationwide retrospective cohort study aiming to evaluate the completeness of RET testing in the Danish MTC cohort. Additionally, we aimed to assess the completeness before and after publication of the first Danish guidelines and characterize MTC patients who had not been tested. Methods The study included 200 patients identified from the nationwide Danish MTC cohort 1997-2013. To identify RET tested MTC patients before December 31, 2014, the MTC cohort was cross-checked with the nationwide Danish RET cohort 1994-2014. To characterize MTC patients who had not been RET tested, we reviewed their medical records and compared them with MTC patients who had been tested. Results Completeness of RET testing in the overall MTC cohort was 87% (95% CI: 0.81-0.91; 173/200). In the adjusted MTC cohort, after excluding patients diagnosed with hereditary MTC by screening, completeness was 83% (95% CI: 0.76-0.88; 131/158). Completeness was 88% (95% CI: 0.75-0.95; 42/48) and 81% (95% CI: 0.72-0.88) (89/110) before and after publication of the first Danish guidelines, respectively. Patients not RET tested had a higher median age at diagnosis compared to those RET tested. Median time to death was shorter in those not tested relative to those tested. Conclusion The completeness of RET testing in MTC patients in Denmark seems to be higher than reported in other cohorts. No improvement in completeness was detected after publication of the first Danish guidelines. In addition, data indicate that advanced age and low life expectancy at MTC diagnosis may serve as prognostic indicators to identify patients having a higher likelihood of missing the compulsory RET test.

The physiological changes following Roux-en-Y gastric bypass (RYGB) surgery may impact drug release from mechanistically different controlled-release tablets, making generic substitution inappropriate. This study aimed to characterise the pharmacokinetic-pharmacodynamic relationships of oxycodone from a lipid-based and water-swellable controlled-release tablet in RYGB patients. Twenty RYGB patients received 10-mg oral solution oxycodone or 20-mg controlled-release (water-swellable or lipid-based) oxycodone in a three-way, randomised, semiblinded and cross-over study. Blood sampling and pupillary recordings were conducted over a 24-h period. A previously established pharmacokinetic-pharmacodynamic model of these three formulations in healthy volunteers was used in the analysis as a reference model. No differences in absorption kinetics were seen between controlled-release formulations in patients. However, the absorption lag time was 11.5 min in patients vs 14 min in healthy volunteers for controlled-release tablets (P

BACKGROUND: Germline mutations of the REarranged during Transfection (RET) proto-oncogene cause multiple endocrine neoplasia 2 (MEN2). It is unclear whether the distribution of RET mutations varies among populations. The first nationwide study of the distribution of RET mutations was conducted, and the results were compared to those of other populations.METHODS: This retrospective cohort study included 1583 patients who underwent RET gene testing in one of three centers covering all of Denmark between September 1994 and December 2014. Primary testing method was Sanger sequencing, which included exons 8-11 and 13-16. Mutations were defined according to the ARUP database July 1, 2016.RESULTS: RET mutations were identified in 163 patients from 36 apparently unrelated families. Among the 36 families 13 (36.1%) carried mutations in codon 611, four (11.1%) in codon 618, three (8.3%) in codon 620, one (2.8%) in codon 631, six (16.7%) in codon 634, one (2.8%) in codon 790, one (2.8%) in codon 804, one (2.8%) in codon 852, one (2.8%) in codon 883, and five (13.9%) in codon 918. Among the 13 families with codon 611 mutations, 12 had the p.C611Y mutation.CONCLUSIONS: The distribution of RET mutations in Denmark appears to differ from that of other populations. Mutations in codon 611 were the most prevalent, followed by more frequently reported mutations. This might be due to a possible founder effect for the p.C611Y mutation. However, further studies are needed to find possible explanations for the skewed mutational spectrum in Denmark.

Jes Sloth Mathiesen,1,2 Jens Peter Kroustrup,3 Peter Vestergaard,3,4 Kirstine Stochholm,5,6 Per Løgstrup Poulsen,5 Åse Krogh Rasmussen,7 Ulla Feldt-Rasmussen,7 Sten Schytte,8 Henrik Baymler Pedersen,9 Christoffer Holst Hahn,10 Jens Bentzen,11 Sören Möller,2,12 Mette Gaustadnes,13 Maria Rossing,14 Finn Cilius Nielsen,14 Kim Brixen,2 Anja Lisbeth Frederiksen,2,15 Christian Godballe1 1Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark; 2Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 3Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 4Steno Diabetes Center North Jutland, Aalborg, Denmark; 5Department of Internal Medicine and Endocrinology, Aarhus University Hospital, DK-8000 Aarhus, Denmark; 6Center for Rare Diseases, Aarhus University Hospital, Aarhus N, Denmark; 7Department of Medical Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark; 8Department of ORL Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark; 9Department of ORL Head and Neck Surgery, Aalborg University Hospital, Aalborg, Denmark; 10Department of ORL Head and Neck Surgery, Copenhagen University Hospital, Copenhagen, Denmark; 11Department of Oncology, Herlev Hospital, Herlev, Denmark; 12Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark; 13Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; 14Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark; 15Department of Clinical Genetics, Odense University Hospital, Odense, Denmark Background: The incidence and prevalence of multiple endocrine neoplasia 2A (MEN2A) have only been reported once in a nationwide setting. However, it is unclear whether the figures are representative of other populations, as the major component of the syndrome, hereditary medullary thyroid carcinoma (MTC), has been reported as rare in the same country. We conducted a nationwide retrospective cohort study of MEN2A in Denmark from 1901 to 2014, aiming to describe the incidence and prevalence. Methods: This study included 250 unique MEN2A patients born or resident in Denmark before December 31, 2014. Patients were identified through the Danish REarranged during Transfection (RET) cohort, linkage of MEN2A pedigrees, the Danish MTC cohort, a nationwide collaboration of MEN2 centers, cross-checking of other relevant cohorts, and a systematic literature search. Results: The incidence from 1971 to 2000 was 28 (95% CI: 21–37) per million live births per year. Incidence for the specific mutations or for the overall MEN2A group did not change significantly from 1901 to 2014 (P>0.05). Point prevalence at January 1, 2015, was 24 per million (95% CI: 20–28). Conclusion: The incidence and prevalence of MEN2A in Denmark seem higher than those reported in other countries. This is likely explained by the Danish C611Y founder effect. Also, our data indicate no significant change in MEN2A incidence during the last century. Keywords: multiple endocrine neoplasia 2A, incidence, prevalence, Denmark

Background: Multiple endocrine neoplasia (MEN) 2A and 2B are caused by REarranged during Transfection (RET) germline mutations. In a recent nationwide study, an unusually high prevalence (33%) of families with the C611Y mutation was reported, and it was hypothesized that this might be due to a founder effect. The first nationwide study of haplotypes in MEN2A families was conducted, with the aim of investigating the relatedness and occurrence of de novo mutations among Danish families carrying similar mutations. Methods: The study included 21 apparently unrelated MEN2A families identified from a nationwide Danish RET cohort from 1994 to 2014. Twelve, two, two, three, and two families carried the C611Y, C618F, C618Y, C620R, and C634R mutations, respectively. Single nucleotide polymorphism chip data and identity by descent analysis were used to assess relatedness. Results: A common founder mutation was found among all 12 C611Y families and between both C618Y families. No relatedness was identified in the remaining families. Conclusion: The data suggest that all families with the C611Y germline mutation in Denmark originate from a recent common ancestor, probably explaining the unusually high prevalence of this mutation. Additionally, the results indicate that the C611Y mutation rarely arises de novo, thus underlining the need for thorough multigenerational genetic work up in carriers of this mutation.

Multiple endocrine neoplasia (MEN) 2A and 2B are caused by REarranged during Transfection (RET) germline mutations. In a recent nationwide study, an unusually high prevalence (33%) of families with the C611Y mutation was reported, and it was hypothesized that this might be due to a founder effect. The first nationwide study of haplotypes in MEN2A families was conducted, with the aim of investigating the relatedness and occurrence of de novo mutations among Danish families carrying similar mutations.The study included 21 apparently unrelated MEN2A families identified from a nationwide Danish RET cohort from 1994 to 2014. Twelve, two, two, three, and two families carried the C611Y, C618F, C618Y, C620R, and C634R mutations, respectively. Single nucleotide polymorphism chip data and identity by descent analysis were used to assess relatedness.A common founder mutation was found among all 12 C611Y families and between both C618Y families. No relatedness was identified in the remaining families.The data suggest that all families with the C611Y germline mutation in Denmark originate from a recent common ancestor, probably explaining the unusually high prevalence of this mutation. Additionally, the results indicate that the C611Y mutation rarely arises de novo, thus underlining the need for thorough multigenerational genetic work up in carriers of this mutation.

Extract: Multiple endocrine neoplasia 2B (MEN2B) is an autosomal dominant inherited cancer syndrome associating medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), ganglioneuromatosis of the aerodigestive tract and facial, ophthalmologic and skeletal abnormalities. MEN2B is caused by the M918T and A883F mutation of the REarranged during Transfection (RET) proto-oncogene in approximately 95% and

OBJECTIVE: To describe three cases of Cushing's disease in children with multiple endocrine neoplasia type 1 (MEN1), as clinical manifestations of MEN1 are very rare in childhood. DESIGN AND METHODS: A retrospective review of three cases of Cushing's disease diagnosed between 1997 and 1999. Genetic screening for MEN1 gene mutation was performed in each patient. RESULTS: An ACTH-secreting microadenoma was diagnosed in three children, aged 11-13 years, presenting with growth retardation and weight gain over a period of 3-4 years. All patients had successful transsphenoidal adenomectomies. Primary hyperparathyroidism was subsequently diagnosed in two of the patients, and in the monozygotic twin of one of the patients. A new mutation in the MEN1 gene (Tyr351His) was identified in two of the patients and the affected members of their families. In the third patient a de novo MEN1 gene mutation (Leu444Pro) was found. CONCLUSIONS: MEN1 has to be considered in all children with tumours of the pituitary gland, and in those presenting with primary hyperparathyroidism. The children and their families should be advised to seek genetic counselling. We suggest that careful growth records be kept for children at risk of developing inherited MEN1 and, in the event of a decelerating growth rate, further diagnostic evaluation be undertaken with regards to ACTH-secreting pituitary tumours.

Extent of intra-abdominal fat had significant linear relations with six metabolic coronary risk factors: systolic and diastolic blood pressure, fasting blood concentrations of glucose, high density lipoprotein (HDL) cholesterol, triglyceride, and plasminogen activator inhibitor-1. Tumor necrosis factor-alpha and adiponectin can be biological mediators from the intra-abdominal fat to the metabolic coronary risk factors. Complementarily, we describe a new study that will analyze the gene expression in intra-abdominal and subcutaneous fat on mRNA and protein level using high throughput methods. The study will elucidate further whether intra-abdominal obesity is the common denominator for the different components of the metabolic syndrome.

DNA testing is of great importance in families with multiple endocrine neoplasia (MEN) type 2A to identify non-mutant carrying family members and asymptomatic mutation carriers, and also to confirm the diagnosis in patients who already show clinical or biochemical signs of disease. Several point mutations of the RET proto-oncogene on exons 10 and 11 are associated with the disease, which is characterized by medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. The aim of the present study was to develop and evaluate a simple method, which indicates the mutational status of members of families where the site of the point mutation is known. The method is illustrated by the detection of mutation TGC--TAC of codon 611, which is one of the well-known mutations associated with MEN 2A. The method involves the PCR technique with allele-specific primers and detection of the amplified sequences with biotinylated probes. There was a clear-cut difference between the readings from affected and unaffected subjects. The subjects had been evaluated independently and all subjects harboring the mutation also had clinical disease. The method provides a simple and reliable diagnostic tool for DNA screening of members of families with a known mutation of the RET-gene.

Low health-related quality of life among morbidly obese subjects is well-known. However, the relationship may not be simple. We aim to examine the association between pre-operative expectations and health-related quality of life and long-term changes in health-related quality of life after gastric banding. The questionnaires were answered twice: before and five years after gastric banding. Short Form-36 assessed health-related quality of life. Obesity specific questions were used to assess the subjects' attribution of impairment to morbid obesity and their expectations to changes as a result of weight loss. The subjects attribute morbid obesity as a major reason for their impairments in state of health, physical activity, pain and work capacity. As a result of weight loss, the subjects expect improvements even within fields which they did not consider to be impaired due to morbid obesity. We found an inverse association between high expectations and mental component summary score at baseline. At follow-up having expectations fully fulfilled was associated with a higher mental component summary score than having expectations fulfilled only to a fair extension and not having expectations fulfilled. Physical component summary was statistically significant improved at follow-up Morbidly obese subjects' attributions of low general well-being combined with their expectations may be a central part of understanding the mechanisms involved in the association between morbid obesity and low health-related quality of life. Furthermore the impact of morbid obesity on health-related quality of life may be reduced if healthprofessionals bridge the gap between morbidly obese subjects' expectations and their experience.

Results from a phase II trial with Tesofensine for treatment of obesity are presented. In total 203 obese persons were randomised to treatment with Tesofensine 0.25, 0.5, or 1.0 mg, or placebo daily for 24 weeks. Treatment with Tesofensine resulted in a mean weight reduction of 4.5, 9.2 and 10.6% higher than that of placebo for 0.25, 0.5 and 1.0 mg, respectively. Tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved anti-obesity drugs. Findings of safety and efficacy of 0.5 mg Tesofensine need confirmation in phase III trials.

Udgivelsesdato: 2009 BACKGROUND: Morbid obesity defined as BMI > 40 is a growing problem. It is primarily treated with diet, lifestyle changes, and medicine. However, at present, surgery remains the only effective option for the management. METHODS: Seventeen patients were studied 2 months after laparoscopic gastric banding. The aims were to evaluate the association between (1) the extent of pouch filling and satiety, (2) gastric emptying and weight loss, and (3) the pouch pressure during a meal and the sensation of satiety and weight loss. RESULTS: The preoperative weight was 146 kg (range 108-202 kg). The average weight loss was 21 kg between the banding and the examination. The half time (T (50%)) for the pouch emptying was 3 min (quartiles 3-12.5) and the time to 90% of pouch emptying (T (90%)) was 40 min (24.5-60). The sensation of satiety lasted 75 min (57.5-105), and the feeling of hunger started after 90 min (40-90). Neither T (50%) nor T (90%) correlated to the weight loss (R = 0.006, P > 0.5 and R = 0.1, P > 0.5). The sensation of satiety did not correlate to T (50%) or T (90%) (R = 0.6, P = 0.12 and R = 0.5, P = 0.15). No association was found between the sensory data and the pressure decline. Significant association was found between the load of the meal expressed as the area under the pouch pressure curve and the weight loss (R = 0.786, P = 0.015). CONCLUSION: The satiety sensation lasted much longer than the pouch emptying and the pressure increase. The pressure load correlated to the weight loss. This indicates that neuroendocrine mechanisms caused by the accumulated mechanical load are most important for maintaining satiety.

The above article has been retracted by the authors, as they have withdrawn the data upon which it was based.The retraction was made before the article reached its final form in the publication process. However, the authors' manuscript, prior to copy editing, page layout and proofing, was initially made available online upon acceptance as an Accepted Preprint.

The prevalence of overweight and obesity is escalating globally, and in Denmark more than 10% of the population are now severely overweight. The aim of this study was to estimate the short-term health effects of 15 weeks of intensive lifestyle intervention composed of physical activity, dietary changes and personal development in severely obese subjects of both sexes.The 27 subjects were weighed weekly. Fat percentage, abdominal circumference, maximum oxygen uptake, heart rate, oral glucose tolerance and blood lipids were measured at baseline and in week 15. The intensive lifestyle intervention was completed under supervision at a stay at Ebeltoft Kurcenter, and the goal was a weight loss of approximately 1% per week.At baseline, the participants' average body mass index (BMI: kg/m2) was 44 +- 1; the BMI was reduced by 11% after the stay (p0.001). Body weight was reduced by 14 +- 4 kg (p0.001), corresponding to 76% of the desired weight loss. The subjects' fat mass was reduced by 4% (p0.001), and their maximal oxygen uptake was enhanced by 25% (p0.001). Concerning the blood lipids, total cholesterol was reduced by 8% (p = 0.03); there was no significant change in LDL level and a reduction of 15% (p0.05) in HDL level. After the intervention, oral glucose tolerance was significantly improved (p0.001).After 15 weeks of intensive lifestyle intervention, there were significant improvements in aerobic fitness and metabolic risk parameters, and the observed weight loss was equivalent to that obtained by surgical treatment. Decisive in the choice of obesity treatment will continue to be the extent of success in permanent weight loss.

In the Western world the number of obese people is increasing, but in Denmark the incidence is not on the same scale as in the USA. Although several factors may be of importance, Danes are more physically active and their intake of beverages with added sugar is less than in the American population.

Multiple endocrine neoplasia type 1 (MEN1) is caused by autosomal dominantly inherited mutations in the MEN1 gene. Here, we report 25 MEN1 mutations - of which 12 are novel - found in 36 Danish families with MEN1 or variant MEN1 disease. Furthermore, one FIHP family was found to have an earlier reported mutation. The mutations were predominantly found in exons 9 and 10 encoding the C-terminal part of menin. Seven of the mutations were missense mutations, changing conserved residues. Furthermore screening of 93 out of 153 consecutive patients with primary hyperparathyroidism (pHPT) identified five mutation carriers. Two of these belonged to known MEN1 families, whereas the only MEN1-related disease in the other three was pHPT. Screening of 96 consecutive patients with fore-/midgut endocrine tumours revealed five mutation carries out of 28 patients with sporadic gastrinomas, whereas no mutations were found in 68 patients with other fore-/midgut endocrine tumours. Moreover, screening of 60 consecutive patients with primary prolactinoma did not identify any mutation carriers. Our data indicate that MEN1 mutation screening is efficient in patients with familial MEN1. Screening should also be offered to patients with pHPT or gastrinomas after thorough investigation into the family history. In contrast, sporadic carcinoid tumours or primary prolactinomas are rarely associated with germ-line MEN1 mutations.