Associations of changes in physical activity and sedentary time with weight recurrence after bariatric surgery: a 5-year prospective study.

BACKGROUND: Increasing physical activity and limiting sedentary time may minimize weight recurrence after bariatric surgery. However, few studies have evaluated potential associations of objectively-measured physical activity and sedentary time with post-surgical weight recurrence over time. AIMS: To evaluate associations of change in physical activity and sedentary time with weight recurrence after bariatric surgery. METHODS: Participants from the Oslo Bariatric Surgery Study, a prospective cohort study, wore an ActiGraph monitor for seven days at 1- and 5 years after surgery to assess daily physical activity and sedentary time. Participants' weight was measured at in-person clinic visits. Chi-square Test and Paired-samples T-test evaluated group differences and change over time, while Pearson's Correlation, multiple logistic and linear regression investigated associations between variables. RESULTS: Five years after surgery 79 participants (70.5% response rate, 81% female) (mean (sd) age: 54.0 (±9.3), BMI: 32.1 (±4.7)) had valid monitor data. Participants increased their sedentary time (71.4 minutes/day (95% CI: 54.2-88.6, p = <0.001)) and reduced daily steps (-1411.1 (95% CI: 737.8-208.4), p = <0.001), light physical activity (-54.1 min/day (95% CI: 40.9-67.2, p = <0.001)), and total physical activity (-48.2 (95% CI: 34.6-63.3), p = <0.001) from 1- to 5 years after surgery. No change was found for moderate-to-vigorous intensity physical activity. No associations were found between changes in steps, physical activity or sedentary time and weight recurrence. CONCLUSION: Participants increased sedentary time and decreased light- and total physical activity between 1- and 5 years post-surgery. Overall, changes in physical activity and sedentary time were not associated with weight recurrence. Interventions to help patients increase physical activity and limit sedentary time after bariatric surgery are needed.

Health benefits and risks during 10 years after Roux-en-Y gastric bypass.

BACKGROUND: Long-term evaluations 10 years after Roux-en-Y gastric bypass (RYGB) are limited. We report the development in weight and cardiovascular risk factors during 10 years after laparoscopic RYGB, with evaluation of gastrointestinal symptoms and quality of life (QoL) at 10-year follow-up. METHODS: We performed a prospective longitudinal cohort study. Patients operated with laparoscopic RYGB from May 2004 to November 2006 were invited to 10-year follow-up consultations. Gastrointestinal Symptom Rating Scale (GSRS) questionnaire and two QoL questionnaires were used for analyses of gastrointestinal symptoms and QoL. RESULTS: A total of 203 patients were operated; nine (4.4%) died during follow-up. Of 194 eligible patients, 124 (63.9%) attended 10-year follow-up consultations. Percent excess weight loss (%EWL) and percent total weight loss (%TWL) at 10 years were 53.0% and 24.1%, respectively. %EWL > 50% was seen in 53.2%. Significant weight regain (≥15%) from 2 to 10 years was seen in 63.3%. Remission rates of type 2 diabetes, dyslipidemia, and hypertension were 56.8%, 46.0%, and 41.4%, respectively. Abdominal operations beyond 30 days after RYGB were reported in 33.9%. Internal hernia and ileus (13.7%) and gallstone-related disease (9.7%) were the most common causes. Vitamin D deficiency (<50nmol/L) was seen in 33.3%. At 10 years, bothersome abdominal pain and indigestion symptoms (GSRS scores ≥3) were reported in 42.9% and 54.0%, respectively, and were associated with low QoL. CONCLUSION: We observed significant weight loss and remission of comorbidities 10 years after RYGB. Significant weight regain occurred in a substantial subset of patients. Gastrointestinal symptoms were common and negatively impacted QoL.

Anemia following Roux-en-Y gastric bypass for morbid obesity; a 5-year follow-up study.

OBJECTIVES: Patients are at risk of anemia post Roux-en-Y gastric bypass (RYGB). We sought to determine the prevalence of anemia and related nutritional deficiencies 5 years after RYGB and to evaluate adherence to nutritional supplements with iron, vitamin B12, and folate. MATERIAL AND METHODS: Patients operated with RYGB 2004-2006 were eligible for evaluation. Blood samples were collected and use of nutritional supplements was recorded preoperatively, and at outpatients' consultations 1, 2, and 5 years postoperatively. Of 203 patients operated, 184 (91%) completed the 5 year follow-up and were included in the study. Of these, 97% had valid measurements of hemoglobin both at baseline and after 5 years. RESULTS: During the 5 years after RYGB, the prevalence of anemia increased from 4% preoperatively to 24% in females, and from 0% to 7% in males. Ferritin levels decreased gradually in both genders. Iron deficiency increased from 6% preoperatively to 42% at 5 years in females, and from 0% to 9% in males. Vitamin B12 deficiency was not altered while folate deficiency decreased from 10% preoperatively to 1% at 5 years. Five years after surgery 25% reported the use of supplements with iron, while 83% used vitamin B12 and 65% used multivitamins with folate. CONCLUSIONS: We observed a long-term increase in anemia and iron deficiency after RYGB in both genders, but most pronounced in women. Our postoperative protocol for prevention of vitamin B12 and folate deficiencies appear acceptable. Iron status and iron supplementation seems to need stronger emphasis during follow-up after RYGB.

Application of the International Diabetes Federation and American Diabetes Association criteria in the assessment of metabolic control after bariatric surgery.

The International Diabetes Federation (IDF) and the American Diabetes Association (ADA) have introduced specific criteria to define the 'optimization' of the metabolic state and glycaemic 'remission' of type 2 diabetes mellitus (T2DM) after bariatric surgery, respectively. Our objective was to assess the percentage of patients achieving these criteria. Data were collected for body mass index, glycaemic markers, lipids, blood pressure, hypoglycaemia and medication usage from 396 morbidly obese T2DM patients who underwent bariatric surgery in two centres and followed up for 2 years. At year 1, 14% of patients achieved the IDF criteria and 38% the ADA criteria, whereas at 2 years 8 and 9% satisfied these criteria, respectively. A relatively low proportion of patients achieved optimization of the metabolic state and T2DM remission. These patients may potentially benefit from the combination of bariatric surgery and adjuvant medical therapy to achieve optimal metabolic outcomes.

Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: results from a large, consecutive Norwegian series.

BACKGROUND: Microsatellite instability (MSI) was suggested as a marker for good prognosis in colorectal cancer in 1993 and a systematic review from 2005 and a meta-analysis from 2010 support the initial observation. We here assess the prognostic impact and prevalence of MSI in different stages in a consecutive, population-based series from a single hospital in Oslo, Norway. PATIENTS AND METHODS: Of 1274 patients, 952 underwent major resection of which 805 were included in analyses of MSI prevalence and 613 with complete resection in analyses of outcome. Formalin-fixed tumor tissue was used for PCR-based MSI analyses. RESULTS: The overall prevalence of MSI was 14%, highest in females (19%) and in proximal colon cancer (29%). Five-year relapse-free survival (5-year RFS) was 67% and 55% (P = 0.030) in patients with MSI and MSS tumors, respectively, with the hazard ratio (HR) equal to 1.60 (P = 0.045) in multivariate analysis. The improved outcome was confined to stage II patients who had 5-year RFS of 74% and 56% respectively (P = 0.010), HR = 2.02 (P = 0.040). Examination of 12 or more lymph nodes was significantly associated with proximal tumor location (P < 0.001). CONCLUSIONS: MSI has an independent positive prognostic impact on stage II colorectal cancer patients after complete resection.

CLC and IFNAR1 are differentially expressed and a global immunity score is distinct between early- and late-onset colorectal cancer.

Colorectal cancer (CRC) incidence increases with age, and early onset of the disease is an indication of genetic predisposition, estimated to cause up to 30% of all cases. To identify genes associated with early-onset CRC, we investigated gene expression levels within a series of young patients with CRCs who are not known to carry any hereditary syndromes (n=24; mean 43 years at diagnosis), and compared this with a series of CRCs from patients diagnosed at an older age (n=17; mean 79 years). Two individual genes were found to be differentially expressed between the two groups, with statistical significance; CLC was higher and IFNAR1 was less expressed in early-onset CRCs. Furthermore, genes located at chromosome band 19q13 were found to be enriched significantly among the genes with higher expression in the early-onset samples, including CLC. An elevated immune content within the early-onset group was observed from the differentially expressed genes. By application of outlier statistics, H3F3A was identified as a top candidate gene for a subset of the early-onset CRCs. In conclusion, CLC and IFNAR1 were identified to be overall differentially expressed between early- and late-onset CRC, and are important in the development of early-onset CRC.

Randomized clinical trial of laparoscopic gastric bypass versus laparoscopic duodenal switch for superobesity.

BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic biliopancreatic diversion with duodenal switch (LDS) are surgical options for superobesity. A randomized trial was conducted to evaluate perioperative (30-day) safety and 1-year results. METHODS: Sixty patients with a body mass index (BMI) of 50-60 kg/m(2) were randomized to LRYGB or LDS. BMI, percentage of excess BMI lost, complications and readmissions were compared between groups. RESULTS: Patient characteristics were similar in the two groups. Mean operating time was 91 min for LRYGB and 206 min for LDS (P < 0.001). One LDS was converted to open surgery. Early complications occurred in four patients undergoing LRYGB and seven having LDS (P = 0.327), with no deaths. Median stay was 2 days after LRYGB and 4 days after LDS (P < 0.001). Four and nine patients respectively had late complications (P = 0.121). Mean BMI at 1 year decreased from 54.8 to 38.5 kg/m(2) after LRYGB and from 55.2 to 32.5 kg/m(2) after LDS; percentage of excess BMI lost was greater after LDS (74.8 versus 54.4 per cent; P < 0.001). CONCLUSION: LRYGB and LDS can be performed with comparable perioperative safety in superobese patients. LDS provides greater weight loss in the first year.

Changes in bone quality after Roux-en-Y gastric bypass: A prospective cohort study in subjects with and without type 2 diabetes.

BACKGROUND: Obesity and type 2 diabetes (T2D) are associated with an increased risk of skeletal fractures despite a normal areal bone mineral density (aBMD) and low bone turnover, possibly due to reduced bone material strength. Roux-en-Y gastric bypass (RYGB) enables a substantial and persistent weight loss and resolution of obesity related comorbidities such as T2D. However, the procedure induces a decrease in aBMD and increased bone turnover and fracture rate. To our knowledge, changes in bone material strength after RYGB have not been explored. This study aimed to evaluate changes in factors influencing bone quality; bone material strength, aBMD and bone turnover markers, in a population with morbid obesity undergoing RYGB and whether these changes differed in participants with and without T2D. We also sought to assess factors associated with bone material strength and bone mineral density in obese subjects before and after RYGB. METHODS: We examined 34 participants before and one year after RYGB, of whom 13 had T2D. Bone material strength index (BMSi) was evaluated by impact microindentation, aBMD and body composition by Dual energy X-ray absorptiometry, levels of bone turnover markers and calciotropic hormones were estimated from fasting serum samples. Participants with and without T2D were comparable before surgery, with the exception of glycosylated hemoglobin (HbA1c). RESULTS: Preoperatively, BMSi was inversely associated with BMI, ßunadjusted -1.1 (-1.9 to -0.28), R2=0.19, p=0.010, and this association remained significant after adjusting for age and gender. After RYGB the participants had lost a mean±SD of 33.9±10.9kg, 48.7±14.2 % of total body fat, increased physical activity, unchanged vitamin D levels, and all but one of the 13 participants with T2D were in diabetes remission. BMSi increased from 78.1±8.5 preoperatively to 82.0±6.4 one year after RYGB, corresponding to an increase of 4.0±9.8 in absolute units or 6.3±14.0 %, p=0.037. The increase was comparable in participants with and without T2D. In subjects with T2D, a larger decrease in HbA1c was associated with a larger increase in BMSi ßunadjusted -9.2 (-16.5 to -1.9), R2=0.47, p=0.019. Bone turnover markers (CTX-1 and PINP) increased by 195.1±133.5 % and 109.5±70.6 %, respectively. aBMD decreased by 3.9±5.5 % in the lumbar spine, 8.2±4.6 % in the femoral neck, 11.6±4.9 % in total hip and 9.4±3.8 % in total body. CONCLUSION: Our findings indicate that bone material strength improves despite an increase in bone turnover and a decrease in aBMD one year after RYGB. Trends were statistically comparable in participants with and without T2D. However, improved glucose control was associated with improved bone material strength in participants with T2D.

Incarcerated paraesophageal hernia complicated by pancreatic damage and unusual comorbidity: Two retrospective case series.

INTRODUCTION: About 1% of paraesophageal hernias (PEH) require emergency surgery due to obstruction or gangrene. We present two complicated cases of incarcerated PEH. Presentation of cases: A patient aged 18 with trisomy 21 was admitted after four days of vomiting and epigastric pain. CT scan revealed a large PEH. The stomach was massively dilated with compression of adjacent viscera and the celiac trunk. The stomach was repositioned laparoscopically and deflated by endoscopy in an attempt to avoid resection. During second look laparoscopy a gastrectomy was necessary. The patient was reoperated for intestinal obstruction, and treated for dehiscence of the esophagojejunostomy and a pancreatic fistula. A patient aged 65 with hereditary spastic paresis had two days history of emesis and epigastric pain. Upon arrival he was hemodynamically unstable and a CT scan revealed perforation of the herniated stomach. A subtotal gastrectomy without reconstruction was performed with vacuum closure of the abdomen. Later a gastrectomy was completed with a Roux-en-Y reconstruction. Except from reoperation for wound dehiscence after 14 days, the recovery was uneventful. DISCUSSION: Trisomy 21 and hereditary spastic paresis may increase the risk of developing PEH. Challenges in regard to symptom evaluation may delay diagnosis. The pressure of the dilated stomach can give rise to ischemic and mechanical damage from compression of major blood vessels and organs. Urgent diagnosis and gastric deflation is required. CONCLUSIONS: In patients with known PEH or with comorbidity that may increase the risk of PEH, this diagnosis should be considered early on.

Abdominal pain and symptoms before and after Roux-en-Y gastric bypass.

Background: Despite increased emphasis on patient-reported outcomes, few studies have focused on abdominal pain symptoms before and after Roux-en-Y gastric bypass (RYGB). The aim of this study was to quantify chronic abdominal pain (CAP) in relation to RYGB. Methods: Patients with morbid obesity planned for RYGB were invited to participate at a tertiary referral centre from February 2014 to June 2015. Participants completed a series of seven questionnaires before and 2 years after RYGB. CAP was defined as patient-reported presence of long-term or recurrent abdominal pain lasting for more than 3 months. Results: A total of 236 patients were included, of whom 209 (88·6 per cent) attended follow-up. CAP was reported by 28 patients (11·9 per cent) at baseline and 60 (28·7 per cent) at follow-up (P < 0·001). Gastrointestinal Symptom Rating Scale (GSRS) scores (except reflux scores) and symptoms of anxiety increased from baseline to follow-up. Most quality of life (QoL) scores (except role emotional, mental health and mental component scores) also increased. At follow-up, patients with CAP had higher GSRS scores than those without CAP, with large effect sizes for abdominal pain and indigestion syndrome scores. Patients with CAP had more symptoms of anxiety, higher levels of catastrophizing and lower QoL scores. Baseline CAP seemed to predict CAP at follow-up. Conclusion: The prevalence of CAP is higher 2 years after RYGB compared with baseline values.

Morbidity related to the use of a protective stoma in anterior resection for rectal cancer.

OBJECTIVE: To evaluate morbidity related to the use of a protective stoma in rectal resection for cancer. METHOD: Seventy-two patients undergoing anterior rectal resection for cancer combined with a protective stoma (1993-2005) were included. Loop ileostomy was applied in 61 patients, loop colostomy in 10, and end ileostomy in one. Data regarding the primary operation were recorded prospectively, and stoma complications retrospectively. RESULTS: Five patients (7%) developed stoma complications immediately after the primary operation, and 14/70 (20%) following hospital discharge. The stoma was closed in 62 (86%) patients after median 4 (range 1-11) months. Five patients (8%) developed complications in hospital after closure. Two patients (3%) died, one of ileal anastomotic leak and one of myocardial infarction. Five patients (8%) had late complications after closure. A total of 19 patients (26%) developed stoma related complications. Eight (11%) of these were reoperated. Premature stoma closure was necessary in two additional patients. Nine patients (13%) ended up with a permanent stoma. Fourteen (19%) patients developed signs of rectal anastomotic failure, six (8%) of whom needed reoperation. One died. CONCLUSION: Significant morbidity is related to the use of defunctioning stomas. A protective stoma cannot always prevent serious complications of a rectal anastomotic leak, and a proportion of the patients will not have the stoma closed.

Abdominal Pain After Roux-En-Y Gastric Bypass for Morbid Obesity.

BACKGROUND AND AIMS:: Roux-en-Y gastric bypass is widely used as treatment of morbid obesity. Weight loss, effects on obesity-related co-morbidities and quality of life are well documented post Roux-en-Y gastric bypass. Other outcome measures are less well studied. This review explores aspects of prevalence, diagnostic evaluations, etiology, and treatment of abdominal pain specific to Roux-en-Y gastric bypass. METHODS:: The review is based on PubMed searches and clinical experience with Roux-en-Y gastric bypass. Symptoms in the early postoperative phase (<30 days) were not included. RESULTS:: Based on limited evidence, up to about 30% of the patients may perceive recurrent abdominal pain post Roux-en-Y gastric bypass in the long term. A substantial subset of patients will need health-care evaluation for acute abdominal pain and hospital admission. The etiology of abdominal pain is heterogeneous and includes gallstone-related disease, intestinal obstruction, anastomotic ulcerations and strictures, intestinal dysmotility, dysfunctional eating, and food intolerance. Surgical treatment and guidance on diet and eating habits may allow symptom relief. The cause of pain remains undefined for a subset of patients. Impact of abdominal pain post Roux-en-Y gastric bypass on the perception of well-being, quality of life, and patient satisfaction with the procedure needs to be further evaluated and may be influenced by complex interactions between new symptoms post Roux-en-Y gastric bypass and relief of pre-existing symptoms. CONCLUSION:: Abdominal pain should be part of follow-up consultations post Roux-en-Y gastric bypass. Future studies should focus on combined evaluations before and after surgery to enlighten potential casual relationships between abdominal pain and Roux-en-Y gastric bypass.

Hepatic radiofrequency ablation using perfusion electrodes in a pig model: effect of the Pringle manoeuvre.

AIM: To assess the influence of the Pringle manoeuvre on volume and geometry of coagulations close to the portal vein using an impedance-controlled radiofrequency ablation system with perfusion electrodes. METHODS: Twelve pigs were randomly assigned to a control group (n = 6) and a group where the Pringle manoeuvre was applied during ablation (n = 6). One coagulation was made in each animal close to the portal vein. All animals were sacrificed 4 days after ablation, and the livers were removed for gross and histopathologic analysis. RESULTS: Effective coagulation volume in the Pringle group (10.8 +/- 5.0 cm(3)) was significantly increased (p = 0.03) compared to the control group (4.1 +/- 4.1 cm(3)). The efficacy ratio, defined as the effective coagulation volume divided by the coagulation volume, was not significantly different in the Pringle group (0.47 +/- 0.27) compared to the control group (0.33 +/- 0.22). The geometrical centre of the effective coagulation volume did not correspond to the position of the ablation electrode. Thermal damage of the gallbladder was found in three animals, all belonging to the Pringle group. CONCLUSIONS: The Pringle manoeuvre was associated with increased effective coagulation volume, but did not significantly influence the predictability of coagulation volume or geometry.

Self-Reported Eating Disorder Symptoms Before and After Gastric Bypass and Duodenal Switch for Super Obesity--a 5-Year Follow-Up Study.

BACKGROUND: This study assessed eating disorder pathology in persons with obesity before and after Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion with duodenal switch (DS), in a 5-year follow-up study. METHODS: Sixty participants with BMI 50-60 kg/m(2) were randomly assigned to RYGB (n = 31) or DS (n = 29). The participants completed the Eating Disorder Examination-Questionnaire (EDE-Q) before and 6 months, 1 year, 2 years, and 5 years after surgery. RESULTS: Before surgery, the prevalence of objective bulimic episodes was 29 % in the RYGB group and 32 % in the DS group. The prevalence improved during the first 12 months after surgery in both groups. After 5 years, the prevalence of objective bulimic episodes was 22 % in the RYGB group and 7 % in the DS group. The difference between groups throughout follow-up was non-significant (logistic regression model). A linear mixed model showed that global EDE-Q score was not a significant predictor for weight loss after surgery, but participants reporting objective bulimic episodes before surgery had significantly lower BMI than those with no episodes after 2 years (p = 0.042) and 5 years (p = 0.013). Global EDE-Q score was significantly lower in the DS group after 5 years (p = 0.009) (linear mixed model). CONCLUSIONS: Objective bulimic episodes but not global EDE-Q score before surgery predicted greater weight loss after RYGB and DS. The DS group had a significantly lower global EDE-Q score than the RYGB group 5 years after surgery.

A novel technique of Roux-en-Y gastric bypass reversal for postprandial hyperinsulinemic hypoglycaemia: A case report.

BACKGROUND: We describe an evaluation of the effects of partial Roux-en-Y gastric bypass (RYGB) reversal on postprandial hyperinsulinaemic hypoglycaemia, insulin and GLP-1 levels. CASE SUMMARY: A 37 year old man was admitted with neuroglycopenia (plasma-glucose 1.6mmol/l) 18 months after RYGB, with normal 72h fasting test and abdominal CT. Despite dietary modifications and medical treatment, the hypoglycaemic episodes escalated in frequency. Feeding by a gastrostomy tube positioned in the gastric remnant did not prevent severe episodes of hypoglycaemia. A modified reversal of the RYGB was performed. Mixed meal tests were done perorally (PO), through the gastrostomy tube 1 (GT1), 4 weeks (GT2) after placement and 4 weeks after reversal (POr), with assessment of glucose, insulin and GLP-1 levels. RESULTS: Plasma-glucose increased to a maximum of 9.6, 5.4, 6.5 and 5.8mmol/l at the PO, GT1, GT2 and POr tests respectively. The corresponding insulin levels were 2939, 731, 725 and 463pmol/l. A decrease of plasma-glucose followed: 2.2, 3.0, 3.9 and 2.9mmol/l respectively and insulin levels were suppressed at 150min: 45, 22, 21 and 14pmol/l, respectively. GLP-1 levels increased in the PO test (60min: 122pmol/l, 21 fold of basal), but was attenuated in the two latter tests (12-23pmol/l at 60min). CONCLUSIONS: Reduction of plasma-glucose, insulin and GLP-1 excursions and symptoms were seen after gastric tube placement and partial RYGB reversal. This attenuation of GLP-1 response to feeding could reflect an adaptation to nutrients.

Intra-operative visualisation of 3D temperature maps and 3D navigation during tissue cryoablation.

Thermotherapeutic tools are increasingly used for tissue ablation, although the intra-operative monitoring is not adequate for such procedures. This is a main challenge for more extensive use of any ablative technique. The present work focuses on treatment of hepatic tumours by cryo therapy. For any thermotherapeutic tool there are specific thermal conditions that have to be met to ensure treatment adequacy. A software tool was made to calculate and visualise 3D temperature distributions during hepatic cryoablation combined with a 3D intra-operative navigation system. This system aids the user in placing the cryoprobe using an optical tracking system and 3D visualisation of the probe placement in relation to the target anatomy and the planned trajectory. 3D temperature distributions are calculated and visualized intra-operatively. The system is integrated with an interventional Magnetic Resonance 0.5T scanner. The system was tested in an animal experiment, exemplifying the usefulness of the navigation system and its ability to give intuitive feedback to the user on thermodynamic conditions induced in the target region. The system constitutes a novel tool for enhanced intra-operative control during cryoablative procedures, and motivates for studies using this tool to investigate predictors applied as indicators of treatment adequacy and patient outcome.

Vitamin concentrations 5 years after gastric bypass.

BACKGROUND/OBJECTIVES: Few studies have investigated the effects of bariatric surgery on vitamin status in the long term. We examined changes in vitamin status up to 5 years after Roux-en-Y gastric bypass surgery. SUBJECTS/METHODS: Using a retrospectively maintained database of patients undergoing weight loss surgery, we identified all patients operated with Roux-en-Y gastric bypass at our tertiary care hospital during July 2004-May 2008. Data on vitamin concentrations and patient-reported intake of dietary supplements were collected up to July 2012. Linear mixed models were used to estimate changes in vitamin concentrations during follow-up, adjusting for age and sex. All patients were recommended daily oral multivitamin, calcium/vitamin D and iron supplements and 3-monthly intramuscular B-12 after surgery. RESULTS: Out of the 443 patients operated with gastric bypass, we included 441 (99.5%) patients with one or more measurements of vitamin concentrations (75.1% women; mean age 41.5 years, mean body mass index 46.1 kg/m(2) at baseline). At 5 years after surgery, the patients' estimated mean vitamin concentrations were either significantly higher (vitamin B-6, folic acid, vitamin B-12, vitamin C and vitamin A) or not significantly different (thiamine, 25-hydroxyvitamin D and lipid-adjusted vitamin E) compared with before surgery. Use of multivitamin, calcium/vitamin D and vitamin B-12 supplements was reported by 1-9% of patients before surgery, 79-84% of patients at 1 year and 52-83% of patients 5 years after surgery. CONCLUSIONS: In patients who underwent gastric bypass surgery, estimated vitamin concentrations were either significantly increased or unchanged up to 5 years after surgery.

Human sympathetic activation by alpha2-adrenergic blockade with yohimbine: Bimodal, epistatic influence of cytochrome P450-mediated drug metabolism.

BACKGROUND: alpha2-Adrenergic blockade responses suggest adrenergic dysfunction in hypertension. alpha2-Blockade is also used to treat autonomic dysfunction. However, pharmacokinetic determinants of yohimbine disposition are not understood. METHODS: We evaluated alpha2-blockade with intravenous yohimbine in 172 individuals. Specific cytochrome P450 (CYP) isoform-mediated metabolism was investigated. Results were evaluated by ANOVA and by maximum likelihood analysis for bimodality of response distributions. RESULTS: Yohimbine metabolism to 11-hydroxy-yohimbine displayed greater than 1000-fold variability, with 17 individuals showing no metabolism. Nonmetabolizers differed from others in ethnicity but not in age, sex, body habitus, blood pressure, heart rate, or family history of hypertension. Bimodality of metabolism was suggested by frequency histogram, as well as maximum likelihood and cluster analysis. Among ethnic groups, subjects of European ancestry had the highest frequency of nonmetabolism. In vitro oxidation suggested that the major route of metabolism (lowest Michaelis-Menten constant and greatest intrinsic clearance) was likely via CYP2D6 to 11-hydroxy-yohimbine. In vivo genotypes at both CYP2D6 and CYP3A4 were necessary to predict metabolism (overall F = 3.03, P =.005); an interaction of alleles at these 2 loci (interaction F = 3.05, P =.033) suggested an epistatic effect on drug metabolism in vivo. Nonmetabolizers had greater activation of sympathetic nervous system activity. Yohimbine increased blood pressure, an effect mediated hemodynamically by elevation of cardiac output rather than systemic vascular resistance. Blood pressure and cardiac output responses did not differ by metabolizer group. CONCLUSIONS: We conclude that heterogeneous, bimodally distributed yohimbine metabolism depends on common genetic variation in both CYP2D6 and CYP3A4 and contributes to differences in sympathetic neuronal response to alpha2-blockade. These results have implications for both diagnostic and therapeutic uses of this alpha2-antagonist.