Gastrointestinal pH, Motility Patterns, and Transit Times After Roux-en-Y Gastric Bypass.

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.

Survival and Long-Term Biochemical Cure in Medullary Thyroid Carcinoma in Denmark 1997-2014: A Nationwide Study.

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.

Completeness of RET testing in patients with medullary thyroid carcinoma in Denmark 1997-2013: a nationwide study.

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.

Replication of newly proposed TNM staging system for medullary thyroid carcinoma: a nationwide study.

A recent study proposed new TNM groupings for better survival discrimination among stage groups for medullary thyroid carcinoma (MTC) and validated these groupings in a population-based cohort in the United States. However, it is unknown how well the groupings perform in populations outside the United States. Consequently, we conducted the first population-based study aiming to evaluate if the recently proposed TNM groupings provide better survival discrimination than the current American Joint Committee on Cancer (AJCC) TNM staging system (seventh and eighth edition) in a nationwide MTC cohort outside the United States. This retrospective cohort study included 191 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. In multivariate analysis, hazard ratios for overall survival under the current AJCC TNM staging system vs the proposed TNM groupings with stage I as reference were 1.32 (95% CI: 0.38-4.57) vs 3.04 (95% CI: 1.38-6.67) for stage II, 2.06 (95% CI: 0.45-9.39) vs 3.59 (95% CI: 1.61-8.03) for stage III and 5.87 (95% CI: 2.02-17.01) vs 59.26 (20.53-171.02) for stage IV. The newly proposed TNM groupings appear to provide better survival discrimination in the nationwide Danish MTC cohort than the current AJCC TNM staging. Adaption of the proposed TNM groupings by the current AJCC TNM staging system may potentially improve accurateness in survival discrimination. However, before such an adaption further population-based studies securing external validity are needed.

Incidence and prevalence of multiple endocrine neoplasia 2A in Denmark 1901-2014: a nationwide study.

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.

Incidence and prevalence of sporadic and hereditary MTC in Denmark 1960-2014: a nationwide study.

Recent studies have shown a significant increase in the temporal trend of medullary thyroid carcinoma (MTC) incidence. However, it remains unknown to which extent sporadic medullary thyroid carcinoma (SMTC) and hereditary MTC (HMTC) affect the MTC incidence over time. We conducted a nationwide retrospective study using previously described RET and MTC cohorts combined with review of medical records, pedigree comparison and relevant nationwide registries. The study included 474 MTC patients diagnosed in Denmark between 1960 and 2014. In the nationwide period from 1997 to 2014, we recorded a mean age-standardized incidence of all MTC, SMTC and HMTC of 0.19, 0.13 and 0.06 per 100,000 per year, respectively. The average annual percentage change in incidence for all MTC, SMTC and HMTC were 1.0 (P = 0.542), 2.8 (P = 0.125) and -3.1 (P = 0.324), respectively. The corresponding figures for point prevalence at January 1, 2015 were 3.8, 2.5 and 1.3 per 100,000, respectively. The average annual percentage change in prevalence from 1998 to 2015 for all MTC, SMTC and HMTC was 2.8 (P < 0.001), 3.8 (P < 0.001) and 1.5 (P = 0.010), respectively. We found no significant change in the incidence of all MTC, SMTC and HMTC possibly due to our small sample size. However, due to an increasing trend in the incidence of all MTC and opposing trends of SMTC (increasing) and HMTC (decreasing) incidence, it seems plausible that an increase for all MTC seen by others may be driven by the SMTC group rather than the HMTC group.

Founder Effect of the RETC611Y Mutation in Multiple Endocrine Neoplasia 2A in Denmark: A Nationwide Study.

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.

Distribution of RET Mutations in Multiple Endocrine Neoplasia 2 in Denmark 1994-2014: A Nationwide Study.

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.

Circulating levels of insulin-like growth factor-II/mannose-6-phosphate receptor in obesity and type 2 diabetes.

OBJECTIVE: The extracellular domain of the insulin-like growth factor II/mannose-6-phosphate receptor (IGF-II/M6P-R) is present in the circulation, but its relationship with plasma IGF-II is largely unknown. As IGF-II appears to be nutritionally regulated, we studied the impact of obesity, type 2 diabetes (T2D) and weight loss on circulating levels of IGF-II and its soluble receptor. METHODS: Twenty-three morbidly obese non-diabetic subjects were studied before and after gastric banding (GB), reducing their BMI from 59.3+/-1.8 to 52.7+/-1.6 kg/m(2). Lean controls (n=10, BMI 24.2+/-0.5 kg/m(2)), moderately obese controls (n=21, BMI 31.8+/-1.0 kg/m(2)) and obese T2D patients (n=20, BMI 32.3+/-0.8 kg/m(2)) were studied before and after a hyperinsulinaemic euglycaemic clamp. RESULTS: Morbidly obese subjects had elevated IGF-II/M6P-R and IGF-II levels, which both decreased following GB (IGF-II/M6P-R: from 0.97+/-0.038 to 0.87+/-0.030 nmol/l, P=0.001; IGF-II: from 134+/-7 to 125+/-6 nmol/l, P=0.01), as did fasting plasma glucose and insulin (P<0.05). However, the metabolic parameters correlated with neither IGF-II nor IGF-II/M6P-R. Obese diabetics had increased IGF-II/M6P-R as compared with lean and obese controls (0.82+/-0.031 vs. 0.70+/-0.033 vs. 0.74+/-0.026 nmol/l; P<0.03) and levels were unaffected by clamp. In the latter cohort, IGF-II/M6P-R but not IGF-II correlated with HbA1c, and fasting plasma C-peptide, insulin and glucose (0.34

[The effect of tesofensine on body weight and body composition in obese subjects--secondary publication]. / Effekt af tesofensine på kropsvaegt og kropssammensaetning hos svaert overvaegtige--sekundaerpublikation.

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.

Weight loss after gastric banding is associated with pouch pressure and not pouch emptying rate.

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.

Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Weight-loss drugs produce an additional mean weight loss of only 3-5 kg above that of diet and placebo over 6 months, and more effective pharmacotherapy of obesity is needed. We assessed the efficacy and safety of tesofensine-an inhibitor of the presynaptic uptake of noradrenaline, dopamine, and serotonin-in patients with obesity. METHODS: We undertook a phase II, randomised, double-blind, placebo-controlled trial in five Danish obesity management centres. After a 2 week run-in phase, 203 obese patients (body-mass index 30-

The effect of weight loss after gastric banding on the molecular distribution of serum adiponectin.

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.

Characteristics of the Danish families with multiple endocrine neoplasia type 1.

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.

[Obesity in Denmark--why has it not gone so badly?]. / Adipositas i Danmark--hvorfor er det ikke gået så galt?

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.

[Lifestyle intervention in the treatment of severe obesity]. / Livsstilsintervention i behandlingen af svaer fedme.

INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: At baseline, the participants' average body mass index (BMI: kg/m2) was 44 +- 1; the BMI was reduced by 11% after the stay (p<0.001). Body weight was reduced by 14 +- 4 kg (p<0.001), corresponding to 76% of the desired weight loss. The subjects' fat mass was reduced by 4% (p<0.001), and their maximal oxygen uptake was enhanced by 25% (p<0.001). 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% (p<0.05) in HDL level. After the intervention, oral glucose tolerance was significantly improved (p<0.001). CONCLUSION: 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.

[Guidelines for treatment of overweight/obesity, 2006]. / Retningslinjer for behandling af overvaegt/fedme anno 2006.

Guidelines for evaluation and treatment of overweight and obesity in adults in Denmark are given. These guidelines are evidence-based and are similar to international guidelines.