Plasma Metabolomic and Lipidomic Profiling of Metabolic Dysfunction-Associated Fatty Liver Disease in Humans Using an Untargeted Multiplatform Approach.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex disorder that is implicated in dysregulations in multiple biological pathways, orchestrated by interactions between genetic predisposition, metabolic syndromes and environmental factors. The limited knowledge of its pathogenesis is one of the bottlenecks in the development of prognostic and therapeutic options for MAFLD. Moreover, the extent to which metabolic pathways are altered due to ongoing hepatic steatosis, inflammation and fibrosis and subsequent liver damage remains unclear. To uncover potential MAFLD pathogenesis in humans, we employed an untargeted nuclear magnetic resonance (NMR) spectroscopy- and high-resolution mass spectrometry (HRMS)-based multiplatform approach combined with a computational multiblock omics framework to characterize the plasma metabolomes and lipidomes of obese patients without (n = 19) or with liver biopsy confirmed MAFLD (n = 63). Metabolite features associated with MAFLD were identified using a metabolome-wide association study pipeline that tested for the relationships between feature responses and MAFLD. A metabolic pathway enrichment analysis revealed 16 pathways associated with MAFLD and highlighted pathway changes, including amino acid metabolism, bile acid metabolism, carnitine shuttle, fatty acid metabolism, glycerophospholipid metabolism, arachidonic acid metabolism and steroid metabolism. These results suggested that there were alterations in energy metabolism, specifically amino acid and lipid metabolism, and pointed to the pathways being implicated in alerted liver function, mitochondrial dysfunctions and immune system disorders, which have previously been linked to MAFLD in human and animal studies. Together, this study revealed specific metabolic alterations associated with MAFLD and supported the idea that MAFLD is fundamentally a metabolism-related disorder, thereby providing new perspectives for diagnostic and therapeutic strategies.

[Outpatient surgery in France in 2014]. / La chirurgie ambulatoire en France en 2014.

The outpatient surgery is still relatively underdeveloped in France, despite the benefits for patients and for hospital teams. The obstacles to its development are cultural as well as financial.

Effect of postoperative antibiotic administration on postoperative infection following cholecystectomy for acute calculous cholecystitis: a randomized clinical trial.

IMPORTANCE: Ninety percent of cases of acute calculous cholecystitis are of mild (grade I) or moderate (grade II) severity. Although the preoperative and intraoperative antibiotic management of acute calculous cholecystitis has been standardized, few data exist on the utility of postoperative antibiotic treatment. OBJECTIVE: To determine the effect of postoperative amoxicillin plus clavulanic acid on infection rates after cholecystectomy. DESIGN, SETTING, AND PATIENTS: A total of 414 patients treated at 17 medical centers for grade I or II acute calculous cholecystitis and who received 2 g of amoxicillin plus clavulanic acid 3 times a day while in the hospital before and once at the time of surgery were randomized after surgery to an open-label, noninferiority, randomized clinical trial between May 2010 and August 2012. INTERVENTIONS: After surgery, no antibiotics or continue with the preoperative antibiotic regimen 3 times daily for 5 days. MAIN OUTCOMES AND MEASURES: The proportion of postoperative surgical site or distant infections recorded before or at the 4-week follow-up visit. RESULTS: An imputed intention-to-treat analysis of 414 patients showed that the postoperative infection rates were 17% (35 of 207) in the nontreatment group and 15% (31 of 207) in the antibiotic group (absolute difference, 1.93%; 95% CI, -8.98% to 5.12%). In the per-protocol analysis, which involved 338 patients, the corresponding rates were both 13% (absolute difference, 0.3%; 95% CI, -5.0% to 6.3%). Based on a noninferiority margin of 11%, the lack of postoperative antibiotic treatment was not associated with worse outcomes than antibiotic treatment. Bile cultures showed that 60.9% were pathogen free. Both groups had similar Clavien complication severity outcomes: 195 patients (94.2%) in the nontreatment group had a score of 0 to I and 2 patients (0.97%) had a score of III to V, and 182 patients (87.8%) in the antibiotic group had a score of 0 to I and 4 patients (1.93%) had a score of III to V. CONCLUSIONS AND RELEVANCE: Among patients with mild or moderate calculous cholecystitis who received preoperative and intraoperative antibiotics, lack of postoperative treatment with amoxicillin plus clavulanic acid did not result in a greater incidence of postoperative infections. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01015417.

Oxidation of hydrogen sulfide by human liver mitochondria.

Hydrogen sulfide (H2S) is the third gasotransmitter discovered. Sulfide shares with the two others (NO and CO) the same inhibiting properties towards mitochondrial respiration. However, in contrast with NO or CO, sulfide at concentrations lower than the toxic (µM) level is an hydrogen donor and a substrate for mitochondrial respiration. This is due to the activity of a sulfide quinone reductase found in a large majority of mitochondria. An ongoing study of the metabolic state of liver in obese patients allowed us to evaluate the sulfide oxidation capacity with twelve preparations of human liver mitochondria. The results indicate relatively high rates of sulfide oxidation with a large variability between individuals. These observations made with isolated mitochondria appear in agreement with the main characteristics of sulfide oxidation as established before with the help of cellular models.

[Post-hospital home care after ambulatory surgery]. / Relais hôpital-ville en chirurgie ambulatoire.

Ambulatory surgery should correspond to mastered acts performed on selected patients. This makes home care unnecessary in the vast majority of the cases. The development of outpatient surgery toward more complex procedures on more vulnerable patients would justify a specific home care in some circumstances. Justification of an overnight hospitalization only because the need for the patient to be reassured on experienced symptoms, supervision of analgesic device, wound incision overseeing or drains removal appears questionable. Home care after ambulatory surgery may be considered as several different modalities. The involvement of general practitioners, home nurses and telemedicine have to be explored for several procedures. Evolutions of surgical and anesthetic practices toward less invasive procedures, as well as improvement in patient's information, are the major challenges for the future of outpatient surgery.

[Ambulatory surgery: an evolution of both the surgical technics and the way of care. To excellence in surgery]. / Chirurgie ambulatoire : évolution des techniques et de la prise en charge chirurgicale. Vers une chirurgie d'excellence.

Day-case surgery has been made possible thanks to the development of surgical techniques such as video-assisted surgery. Mini-invasive surgery reduces the incisional size, decreases postoperative pain, and the duration of postoperative rehabilitation. Robot-assisted surgery is a new technical improvement which increases safety and accuracy of surgical procedures. Laser surgery decreases the risk of postoperative bleeding allowing day-case ablation of the prostate to be performed. Improvement in surgical management is related to: Day-case surgery is demanding, leading to surgeons, anaesthetists and all health care providers to better control patients' management, in order to improve health care quality and safety.

Malignant transformation of abdominal wall endometriosis: case report and literature review.

In recent years we have seen an increase in the frequency of cesarean sections. We present a case report of an endometrioid adenocarcinoma arising from abdominal wall endometriosis in a patient with a history of cesarean sections and describe its diagnostic and therapeutic management.

Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial.

BACKGROUND: Researchers have suggested that antibiotics could cure acute appendicitis. We assessed the efficacy of amoxicillin plus clavulanic acid by comparison with emergency appendicectomy for treatment of patients with uncomplicated acute appendicitis. METHODS: In this open-label, non-inferiority, randomised trial, adult patients (aged 18-68 years) with uncomplicated acute appendicitis, as assessed by CT scan, were enrolled at six university hospitals in France. A computer-generated randomisation sequence was used to allocate patients randomly in a 1:1 ratio to receive amoxicillin plus clavulanic acid (3 g per day) for 8-15 days or emergency appendicectomy. The primary endpoint was occurrence of postintervention peritonitis within 30 days of treatment initiation. Non-inferiority was shown if the upper limit of the two-sided 95% CI for the difference in rates was lower than 10 percentage points. Both intention-to-treat and per-protocol analyses were done. This trial is registered with ClinicalTrials.gov, number NCT00135603. FINDINGS: Of 243 patients randomised, 123 were allocated to the antibiotic group and 120 to the appendicectomy group. Four were excluded from analysis because of early dropout before receiving the intervention, leaving 239 (antibiotic group, 120; appendicectomy group, 119) patients for intention-to-treat analysis. 30-day postintervention peritonitis was significantly more frequent in the antibiotic group (8%, n=9) than in the appendicectomy group (2%, n=2; treatment difference 5·8; 95% CI 0·3-12·1). In the appendicectomy group, despite CT-scan assessment, 21 (18%) of 119 patients were unexpectedly identified at surgery to have complicated appendicitis with peritonitis. In the antibiotic group, 14 (12% [7·1-18·6]) of 120 underwent an appendicectomy during the first 30 days and 30 (29% [21·4-38·9]) of 102 underwent appendicectomy between 1 month and 1 year, 26 of whom had acute appendicitis (recurrence rate 26%; 18·0-34·7). INTERPRETATION: Amoxicillin plus clavulanic acid was not non-inferior to emergency appendicectomy for treatment of acute appendicitis. Identification of predictive markers on CT scans might enable improved targeting of antibiotic treatment. FUNDING: French Ministry of Health, Programme Hospitalier de Recherche Clinique 2002.

Influence of mesh type on the quality of early outcomes after inguinal hernia repair in ambulatory setting controlled study: Glucamesh® vs Polypropylene®.

BACKGROUND: Early post-operative pain after inguinal hernia repair delays management in ambulatory setting. The type of mesh used for repair appears to influence their incidence. AIMS: The aim of this randomized, prospective study using the alternation principle was to compare post-operative early pain and the quality of life of patients operated on for inguinal hernia depending on the type of mesh used and their impact on management in ambulatory setting. PATIENTS AND METHODS: Fifty successive patients were included prospectively. Hernia repair was performed using the Lichtenstein procedure with two types of mesh, namely standard polypropylene 100 g/m² (Prolène®) or light polypropylene (55 g/m²) with a natural beta-D-glucan coating (Glucamesh®). The main assessment criterion was post-operative pain evaluated twice daily by the patient for 7 days, using the visual analogue scale (VAS) and their use of analgesics. The secondary assessment criteria were the rate of unscheduled admissions the evening of the intervention and the hospital length of stay and the quality of life evaluated by the SF12 questionnaire at pre-operative stage and on days 7 and 30. RESULTS: The two groups were comparable. The operative durations were identical (38.8±10.2 vs 48±15.4 min). On the evening of the intervention before discharge, the pain was less intense in the Glucamesh® group (mean VAS score 21.6±2.4 vs 31.7±6.2, p=0.02). On day 4, 20% of patients from the Glucamesh® group and none of the patients from the Prolène® group had a VAS score of 0 (p=0.02). There were no unscheduled admissions in either group, but the hospital stay was significantly shorter in the Glucamesh® group compared with the Prolène® group (288±35 vs 360±48 min, p=0.02). The post-operative quality of life evaluated by the SF12 questionnaire from day 7 to day 30 was the same in both groups (38±4.8 vs 37±5.2) and altered as at pre-operative stage compared with a control population (normal=50). CONCLUSIONS: This randomized, prospective study showed that the use of a self-adhesive, light mesh, reducing the fixation sutures and coated with factors favouring tissue integration, such as the Glucamesh® prosthesis, significantly reduced early post-operative pain compared with conventional prostheses and could increase the percentage of patients likely to undergo an ambulatory hernia repair.

How to perform a thyroidectomy in an outpatient setting.

PURPOSE: In France, the current practice for postoperative care of thyroidectomy is still inpatient care. No series of outpatient thyroidectomy has been reported. The aim of this work was to assess the acceptability, feasibility, and safety of outpatient unilateral thyroid lobectomy in a university hospital. MATERIALS AND METHODS: The procedure was proposed to patients presenting with nodule(s) in one lobe of the thyroid and fulfilling predetermined inclusion criteria. The surgical protocol included no drainage and, progressively, no dressing. Standard anesthetic, analgesic, and antiemetic protocols were used. Unplanned admission, complication, and re-operation rates were evaluated. RESULTS: Among 153 unilateral thyroid lobectomies performed, 95 (62%) were planned for outpatient surgery. The proportion of outpatient unilateral thyroid lobectomies increased during an 8-year period from 36% to 90%. One patient was re-operated because local hemorrhage was diagnosed in the recovery room. He was discharge the next day. Eighteen patients (13.7%) were admitted because of nausea (n = 6), dizziness, and physical discomfort mostly due to anxiety (n = 5). Seventy-seven patients were discharged as planned 6 to 8 h after the operation. No patient was readmitted. CONCLUSIONS: Outpatient unilateral thyroid lobectomy is feasible and safe in the setting of appropriate facilities and management protocol. Strict control of postoperative nausea is essential, and a preoperative education for ambulatory surgery is useful to minimize patient anxiety and increase acceptability.

First description of the surgical anatomy of the cynomolgus monkey liver.

No detailed description of nonhuman primate liver anatomy has been reported and little is known about the similarity between such livers and human liver. The cynomolgus monkey (Macaca fascicularis) was used to establish a preclinical model of genetically modified hepatocytes auto transplantation. Here, we report information gleaned from careful observation and notes obtained from 59 female cynomolgus monkeys undergoing 44 anatomical hepatic resections, 12 main portal vein division dissections and selective branch ligations, and 46 portographies. Additionally, three anatomical liver dissections after total resection at autopsy were performed and served to confirm peroperative observations and for photography to provide illustrations. Our results indicate that the cynomolgus monkey liver has four lobes: the median (the largest), the right and left lateral, and the caudate lobes. In 60% (N=20) of individuals the portal bifurcates into right and left portal veins, in the remaining 40% (N=14) the portal vein trifurcates into right anterior, right posterior, and left portal veins. The anatomy and branching pattern of the hepatic artery and bile ducts closely follow those of the portal branches. Functionally, the cynomolgus monkey liver can be divided into eight independent segments. Thus, we report the first detailed description of the hepatic and portal surgical anatomy of the cynomolgus monkey. The cynomolgus monkey liver is more similar to the human liver than are livers of any small or large nonprimate mammals that have been described.

Day-case laparoscopic cholecystectomy: results of 211 consecutive patients.

OBJECTIVES: The purpose of this work was to evaluate the feasibility and outcome of elective laparoscopic cholecystectomy as a day-case procedure in a French university hospital. METHODS: Since the creation of a surgical day-care centre in 1999, patients without severe chronic disease and anticoagulant therapy were selected for elective laparoscopic cholecystectomy. They were admitted and operated on in the morning hours and discharged after a double check by the surgeon and an anaesthetist 4 to 6 hours later. They were contacted by telephone the day subsequent to surgery and were seen in the outpatient unit 8 to 10 days after. RESULTS: Two hundred eleven laparoscopic cholecystectomies were performed in day-care surgery from January 1999 to December 2005. The proportion of day-case management increased during the six-year period from 32% to 53%. Eighteen percent of patients had an overnight admission. The overall complication rate was 1.8%. None of the patients had an emergency readmission. Incapacity duration went from 1 to 15 days. CONCLUSION: These results suggest that laparoscopic cholecystectomy can be routinely performed as a day-case procedure.

Efficient hepatocyte engraftment in a nonhuman primate model after partial portal vein embolization.

BACKGROUND: Hepatocyte transplantation could be an alternative to whole liver transplantation for the treatment of metabolic liver diseases. However, the results of clinical investigations suggest that the number of engrafted hepatocytes was insufficient to correct metabolic disorders. This may partly result from a lack of proliferation of transplanted hepatocytes. In rodents, portal ligation enhances hepatocyte engraftment after transplantation. We investigated the effects of partial portal ligation and embolization on engraftment and proliferation of transplanted hepatocytes in primates. METHODS: Hepatocyte autotransplantation was performed in Macaca monkeys. The left lateral lobe was resected for hepatocyte isolation. The first group of monkeys underwent surgical ligation of the left and right anterior portal branches; in the second group, the same portal territories were obstructed by embolization with biological glue. To evaluate the proportion of cell engraftment hepatocytes were Hoechst-labeled and transplanted via the portal vein. Cell proliferation was measured by BrdU incorporation. RESULTS: Hepatocyte proliferation was induced by both procedures but it was significantly higher after partial portal embolization (23.5% and 11.2% of dividing hepatocytes on days 3 and 7) than after ligation (3% and 0.8%). Hepatocytes engrafted more efficiently after embolization than after ligation. They proliferated and participated to liver regeneration representing 10% of the liver mass on day seven and their number remained constant on day 15. CONCLUSIONS: These data suggest that partial portal embolization of the recipient liver improves engraftment of transplanted hepatocytes in a primate preclinical model providing a new strategy for hepatocyte transplantation.

Usefulness of abdominal CT scan in severe peritoneal sepsis linked to primary peritonitis.

We report 2 cases of primary group A streptococcal peritonitis in which emergency abdominal CT scan ruled out a hollow viscus perforation, or necrosis, avoiding unnecessary laparotomy. These cases highlight the usefulness of abdominal CT scan and suggest that blind surgical exploration has no advantages.

Laparoscopic hepatic resection for hepatocellular carcinoma. Retrospective study of 12 patients.

AIMS: To assess the results of laparoscopic liver resection for hepatocellular carcinoma. PATIENTS AND METHODS: From 1998 to 2003, 12 laparoscopic liver resections for hepatocellular carcinoma were performed. RESULTS: There were no operative complications and no deaths. Conversion to laparotomy was required in one patient (8%) and transfusion in three patients (25%). One patient died of liver failure. Postoperative complications occurred in three patients (25%): trocar site bleeding, cardiac failure and biliary collection. The mean hospital stay was 5 days. No ascites and no transient liver failure occurred. During the mean follow up of 15 months the recurrence rate was 45.5%. No port site or peritoneal metastases were observed. Treatment of recurrence was second resection in two patients and microwave coagulation therapy in two other patients. Mean survival was 24 months. CONCLUSION: Laparoscopic liver resection is feasible in hepatocellular carcinoma if the tumor is unique, smaller than 5 centimeters and located in the left lateral segments or in the anterior or inferior segments of the right liver. Postoperative morbidity is low and long-term results seem to be similar to laparotomy.

Portal branch ligation induces efficient retrovirus-mediated gene delivery in rat liver.

BACKGROUND: The in vivo transduction of hepatocytes with conventional retrovirus vectors requires the induction of cell division and this can currently only be achieved by invasive surgery or by inducing severe liver damage. We hypothesised that partial portal branch ligation (PBL) could induce hepatocyte proliferation and efficient gene transfer in the rat. METHODS: We ligated the portal branch serving 70% of the liver and measured the kinetics of liver mass restoration and cell proliferation and the distribution of dividing hepatocytes after administration of 5-bromo-2'-deoxyuridine. The efficiency of retrovirus-mediated gene transfer after PBL was tested by use of beta-galactosidase-expressing recombinant retroviruses. The viruses were administered in a single injection via the portal vein at different times after PBL and the livers of transduced animals were analysed 4 days later. RESULTS: We found that the number of cycling hepatocytes remained stable between 24 and 44 h after PBL (approximately 12.5%). Although there was a high level of inter-animal variability, hepatocyte proliferation was always initiated in the same lobe of the liver. In animals that had undergone PBL, 19% of hepatocytes were transduced 28 h after the administration of a single high-titre injection of retroviruses, mainly around the portal spaces. CONCLUSIONS: PBL can mediate the efficient transduction of hepatocytes in vivo after a single intravenous injection of recombinant retroviruses. This approach is feasible in humans.

Improved gene transfer selectivity to hepatocarcinoma cells by retrovirus vector displaying single-chain variable fragment antibody against c-Met.

Engineered retroviruses are widely used vectors for cancer gene therapy approaches. However, the ability to target cells of therapeutic interest while controlling the expression of the transferred genes would improve both the efficiency and the safety of viral vectors. In this study, we investigated the ability of a retroviral amphotropic envelope displaying single-chain variable-fragment (scFv) directed against the c-Met receptor, to target the entry of recombinant retroviruses to human hepatocarcinoma cells. Four single-chain antibody fragments directed against the c-Met receptor were generated and inserted into the viral envelope protein as an N-terminal fusion. The modified envelopes were incorporated into virus particles and one of the chimeric viruses, 3D6-Env, transduced preferentially human hepatoma cells rather than proliferating human hepatocytes. In another construct, the urokinase cleavage site was inserted between the scFv moiety and the envelope. Chimeric scFv-urokinase-Env viruses transduced hepatoma cells with a similar efficiency to that of the control virus and their infectivity in human hepatocytes remained low. These results indicate that amphotropic retroviruses with engineered envelopes to display scFv directed against the c-Met receptor can efficiently and selectively deliver genes into hepatoma cells.

Abdominal pain and ketonuria in an 11-year-old girl five months after abdominal trauma.

Five months after an abdominal trauma, a 11-year-old girl was admitted for abdominal pain, hyperglycemia, and ketonuria, which led to the diagnosis of left diaphragmatic rupture with gastric necrosis and perforation. The girl died soon after operation.