Farnesoid X receptor - a molecular predictor of weight loss after vertical sleeve gastrectomy?

OBJECTIVE: To determine the expression of the bile acid receptor, farnesoid X (FXR), in human gastric mucosa and investigate correlations between expression and body-mass index (BMI) and in patients with obesity, with changes in weight and BMI following vertical sleeve gastrectomy (VSG). METHODS: Human gastric mucosa was obtained from normal/overweight individuals (macroscopically-normal tissue following surgery for malignancy) or from patients with obesity (VSG). The expression of FXR and its isoforms (FXRα, FXRß) were examined by quantitative PCR and compared with the G protein-coupled bile acid receptor, GPBA. In patients with obesity, changes in BMI and weight loss were determined following VSG. RESULTS: FXRα was the predominant isoform in normal/overweight individuals. FXR expression was higher in patients with obesity but GPBA receptor expression was unchanged. For those with obesity (n = 19), no correlation was found between FXR expression and change in Body-Mass Index (BMI)/month or weight loss/month, taken 3 ± 1 months after surgery, or in BMI or weight at surgery. CONCLUSIONS: Obesity is associated with increased FXR expression in the gastric mucosa. The findings are preliminary but suggest that this increase in FXR expression is a consequence of obesity, rather than its cause.

Drugs acting at 5-HT4 , D2 , motilin, and ghrelin receptors differ markedly in how they affect neuromuscular functions in human isolated stomach.

BACKGROUND: Progress in identifying safer, effective drugs to increase gastric emptying is impeded by failed clinical trials. One potential reason for failure is lack of translation from animal models to the human condition. To make progress, the actions of existing drugs and new therapeutic candidates need to be understood in human isolated stomach. METHODS: Neuromuscular activities were evoked in human gastric antrum circular muscle by electrical field stimulation (EFS), defined phenotypically using pharmacological tools. KEY RESULTS: EFS evoked cholinergically mediated contractions, attenuated by simultaneous nitrergic activation. The 5-HT4 receptor agonist/D2 antagonist metoclopramide and the selective 5-HT4 agonist prucalopride, facilitated contractions in the absence (respectively, Emax 95 ± 29% and 42 ± 9%, n = 3-6 each concentration) and presence (139 ± 38%, 55 ± 13%, n = 3-5) of the NO synthase inhibitor L-NAME, without affecting submaximal contractions to carbachol; the 5-HT4 antagonist SB204070 prevented facilitation by metoclopramide 100 µM (respectively, -5 (range -26 to 34) and 167 (12-1327)% in presence and absence; n = 5-6). The selective motilin receptor agonist camicinal provided considerably greater facilitation (478 (12-2080)% at 30 µM, n = 8). Domperidone (0.001-100 µM; n = 3-6) and acylated or des-acylated ghrelin (1-300 nM; n = 2-4) had no consistent activity, even with protease inhibitors. CONCLUSIONS & INFERENCES: 5-HT4 receptor agonists show different efficacies. Motilin receptor activation has greater potential to increase gastric emptying, whereas ghrelin and D2 receptor antagonism have no direct activity. Drugs stimulating human gastric motility directly can act regardless of disease mechanisms, whereas drugs without direct activity but an ability to block nausea/vomiting may be effective only if these symptoms exist.

Endoscopic transesophageal vs. thoracoscopic removal of mediastinal lymph nodes: a prospective randomized trial in a long term animal survival model.

BACKGROUND AND STUDY AIMS: In cases where biopsies remain inconclusive, removal of mediastinal lymph nodes for further analysis requires surgical means. Natural orifice transluminal endoscopic surgery (NOTES) procedures allow incision/closure of the gut wall, which might enable endoscopic excision of pre-marked nodes. The aims of the current study were to investigate the feasibility, safety, and reproducibility of lymph node generation in an animal model to enable endoscopic ultrasound-guided (EUS) lymph node removal (ELR) using transesophageal NOTES access/closure and to compare this procedure with thoracoscopic lymph node removal (TLR) in a randomized long term survival animal study. PATIENTS AND METHODS: Lymph node creation using graphite injection was performed in 12 pigs. After randomization into ELR and TLR groups, lymph nodes were marked with newly developed anchors under EUS guidance and removed using either ELR or TLR. ELR included incision of the esophageal wall and closure after lymph node removal. The main outcome measures were success in lymph node generation, technical success of lymph node removal, complications, and comparability of ELR and TLR. RESULTS: Generation of lymph nodes proved successful in all animals in 46/48 sites injected (96 %). Anchors were placed through the selected nodes in a mean of 9.4 minutes. TLR and ELR were successful in all cases. One bleeding occurred during esophageal incision in ELR, which was stopped endoscopically. After lymph node removal, endoscopic suturing of the incision took a mean of 18 minutes. Procedure time was longer for ELR than TLR (mean 48 vs. 42 minutes). All animals survived the procedures. Autopsy after 4 weeks showed two thoracic wall abscesses in the TLR group and none in the ELR group.  Microscopic analysis revealed well healed esophageal scars. CONCLUSION: ELR proved to be feasible in this limited sample size and complications were not observed more frequently in this group than in the TLR group.

Beyond NOTES: randomized controlled study of different methods of flexible endoscopic hemostasis of artificially induced hemorrhage, via NOTES access to the peritoneal cavity.

BACKGROUND AND STUDY AIM: Significant hemorrhage is a likely complication during natural orifice transluminal endoscopic surgery (NOTES) procedures. We tested three different prototype devices (involving endoscopic suturing, monopolar forceps, and forced argon plasma coagulation [FAPC]) for treatment of acute bleeding in a survival animal model. METHOD: Using transgastric access (TGA) or transvaginal access (TVA), the endoscope was introduced into the peritoneal cavity and the first side-branch of the gastroepiploic artery (1aGE) was cut before the different hemostatic methods were applied. RESULTS: Sutures could not be placed quickly enough before vision was inhibited. With monopolar forceps via TGA, the time to control bleeding was 10 - 140 s (mean 58 +/- 41 s) and with TVA it was 25 - 115 s (mean 57 +/- 26 s) (P = 0.54). It was not possible to stop the bleeding in 4/6 animals with TGA access and in 3/6 with TVA, and FAPC was needed to entirely stop it, taking a further 10 - 280 s (TGA mean 126 +/- 90 s, 34 - 242 s; TVA mean 152 +/- 61 s; P = 0.42). Using FAPC with TGA took 4 - 72 s (mean 28 +/- 20 s) to stop the bleeding, and 16 - 41 s (mean 24 +/- 9.4 s) with TVA ( P = 0.64). As the FAPC technique was relatively so much better, additional treatment of bleeding from the main gastroepiploic artery (aGe) was added in four cases for each method of access; this was successful but took significantly longer, with TGA at 10 - 260 s and with TVA at 30 - 172 s (means 98 +/- 82, 117 +/- 54 s, respectively; not significant). CONCLUSION: Regarding the three methods tested, the new prototype FAPC device allowed hemostasis of notable bleeding from a major vessel even more quickly than forceps coagulation of a bleeding side branch. More studies are needed to further explore this potentially very valuable tool.

Physiological and symptomatic outcome after laparoscopic gastric fundoplication.

The complications of open antireflux operations may be reduced by laparoscopic techniques. Fifteen patients of median age 42 (range 16-79) years with gastro-oesophageal reflux underwent laparoscopic fundoplication. Preoperative and postoperative assessment was by clinical scoring, oesophageal pH measurement and manometry. Median (range) operating time was 115 (60-210) min and hospital stay 3 (1-6) days, with no conversions to open operation and only one minor wound infection. Four patients had occasional reflux symptoms on postoperative assessment at a median of 7 weeks and nine had occasional dysphagia. Median DeMeester symptom scores improved from 4 to 1.5 (P = 0.001). There were significant increases in both lower oesophageal sphincter pressure and length. The nocturnal proportion of time at pH < 4 decreased from 9.6 to 0.05 per cent (P = 0.02), although the drop in total proportion of time at pH < 4 (10.4 to 2.2 per cent) was not statistically significant (P = 0.08). Early objective results of laparoscopic fundoplication show improved symptoms, decreased acid reflux and altered lower sphincter function. The procedure combines the benefits of early mobilization and reduced morbidity with the efficacy of the traditional open operation.

An observer blind trial of co-amoxiclav versus cefuroxime plus metronidazole in the prevention of postoperative wound infection after general surgery.

A consecutive series of 509 patients undergoing abdominal surgery were entered into a randomized, observer and patient blind, controlled, prospective, study to evaluate the efficiency of co-amoxiclav ('Augmentin', SmithKline Beecham, UK) compared with cefuroxime ('Zinacef', Glaxo, UK) plus metronidazole (Flagyl, M&B, UK) for the prevention of postoperative wound infections. One or three doses of antibiotics were given depending on the type of surgery and operative factors. Co-amoxiclav was given to 230 patients with a total wound infection rate of 5.6% and cefuroxime plus metronidazole were given to 225 patients with a total wound infection rate of 3%. The difference between infection rates was not significant. Both groups were comparable in terms of demographic details, type and duration of surgery, risk factors associated with surgical procedures and postoperative management. Although not statistically significant, a difference in the wound infection rate for those patients undergoing colorectal surgery was seen: 8/69 for the co-amoxiclav group and 2/79 for the cefuroxime/metronidazole group. The estimated cost to our hospital (October, 1993) of one dose of co-amoxiclav was less that half the cost of cefuroxime and metronidazole. This study demonstrates that co-amoxiclav is an effective prophylactic antibiotic for abdominal surgery.

Subcutaneous mastectomy with immediate reconstruction as treatment for early breast cancer.

Subcutaneous mastectomy and axillary dissection combined with immediate reconstruction was used to treat primary breast cancer in a consecutive series of 111 patients. Local recurrence occurred in 19 patients (17 per cent) during a mean follow-up of 30 (range 6-60) months. Complete control of local disease was achieved in all patients except one, who had terminal disease. Prophylactic radiotherapy was avoided for 83 per cent of patients, and good cosmetic results were obtained in 89 per cent. These results support the use of this technique in the treatment of early breast cancer.