Effects of autophagy inhibition by chloroquine on hepatic stellate cell activation in CCl4-induced acute liver injury mouse model.

BACKGROUND AND AIM: Hepatic stellate cells (HSCs) activation, a critical event in liver fibrosis, has been recently shown to be related to autophagy. Determine whether chloroquine (CQ) could affect (i) the activation of HSC in vivo and (ii) the hepatic damage in a mice acute liver injury model. METHODS: The acute liver injury was induced in BALB/c mice by carbon tetrachloride (CCl4 group); 24 h before and after CCl4 administration animals were treated by CQ (CCl4  + CQ group). As control, mice treated by olive oil were considered. After 48 h from CCl4 /olive oil administration, blood samples, liver tissues, and HSCs were harvested for analysis. RESULTS: In vivo, CQ attenuates CCl4 -induced acute liver damage as evidenced by (i) the reduction of liver enlargement, (ii) the reduction of liver swelling and necrosis also supported by a certain decrease of circulating transaminases level, and (iii) the reduction of liver fibrosis evaluated by collagen deposition and α-sma protein expression. In HSCs isolated from CQ treated group, we observed the inhibition of autophagy proved by the increase in p62 protein and the decrease of lc3 protein. In addition, CQ reduced the expression of the HSCs activation markers α-sma/collagen-I and down-regulated the expression of the proliferative marker ki67. CONCLUSION: The autophagy attenuation exerted by CQ together with the reduction of the expression of the proliferation marker in HSCs can lessen the acute liver damage potentially opening the way to novel therapeutic approaches for hepatic fibrosis.

Correction to: Strengthening Surgery Strengthens Health Systems: A New Paradigm and Potential Pathway for Horizontal Development in Low- and Middle-Income Countries.

In the original article, Ziad C. Sifri's first and last names were interchanged. It is correct as reflected here.

Strengthening Surgery Strengthens Health Systems: A New Paradigm and Potential Pathway for Horizontal Development in Low- and Middle-Income Countries.

Global health is transitioning toward a focus on building strong and sustainable health systems in developing countries; however, resources, funding, and agendas continue to concentrate on "vertical" (disease-based) improvements in care. Surgical care in low- and middle-income countries (LMICs) requires the development of health systems infrastructure and can be considered an indicator of overall system readiness. Improving surgical care provides a scalable gateway to strengthen health systems in multiple domains. In this position paper by the Society of University Surgeons' Committee on Global Academic Surgery, we propose that health systems development appropriately falls within the purview of the academic surgeon. Partnerships between academic surgical institutions and societies from high-income and resource-constrained settings are needed to strengthen advocacy and funding efforts and support development of training and research in LMICs.

Global Surgery: Effective Involvement of US Academic Surgery: Report of the American Surgical Association Working Group on Global Surgery.

: There is an unacceptably high burden of death and disability from conditions that are treatable by surgery, worldwide and especially in low- and middle-income countries (LMICs). The major actions to improve this situation need to be taken by the surgical communities, institutions, and governments of the LMICs. The US surgical community, including the US academic surgical community, has, however, important roles to play in addressing this problem. The American Surgical Association convened a Working Group to address how US academic surgery can most effectively decrease the burden from surgically treatable conditions in LMICs. The Working Group believes that the task will be most successful (1) if the epidemiologic pattern in a given country is taken into account by focusing on those surgically treatable conditions with the highest burdens; (2) if emphasis is placed on those surgical services that are most cost-effective and most feasible to scale up; and (3) if efforts are harmonized with local priorities and with existing global initiatives, such as the World Health Assembly with its 2015 resolution on essential surgery. This consensus statement gives recommendations on how to achieve those goals through the tools of academic surgery: clinical care, training and capacity building, research, and advocacy. Through all of these, the ethical principles of maximally and transparently engaging with and deferring to the interests and needs of local surgeons and their patients are of paramount importance. Notable benefits accrue to US surgeons, trainees, and institutions that engage in global surgical activities.

Guidelines and checklists for short-term missions in global pediatric surgery: Recommendations from the American Academy of Pediatrics Delivery of Surgical Care Global Health Subcommittee, American Pediatric Surgical Association Global Pediatric Surgery Committee, Society for Pediatric Anesthesia Committee on International Education and Service, and American Pediatric Surgical Nurses Association, Inc. Global Health Special Interest Group.

Pediatric surgeons, anesthesia providers, and nurses from North America and other high-income countries are increasingly engaged in resource-limited areas, with short-term missions as the most common form of involvement. However, consensus recommendations currently do not exist for short-term missions in pediatric general surgery and associated perioperative care. The American Academy of Pediatrics (AAP) Delivery of Surgical Care Subcommittee and American Pediatric Surgical Association (APSA) Global Pediatric Surgery Committee, with the American Pediatric Surgical Nurses Association, Inc. (APSNA) Global Health Special Interest Group, and the Society for Pediatric Anesthesia (SPA) Committee on International Education and Service generated consensus recommendations for short-term missions based on extensive experience with short-term missions. Three distinct, but related areas were identified: (i) Broad goals of surgical partnerships between high-income countries and low- and middle-income countries. A previous set of guidelines published by the Global Paediatric Surgery Network Collaborative (GPSN) was endorsed by all groups; (ii) Guidelines for the conduct of short-term missions were developed, including planning, in-country perioperative patient care, post-trip follow-up, and sustainability; and (iii) travel and safety considerations critical to short-term mission success were enumerated. A diverse group of stakeholders developed these guidelines for short-term missions in low- and middle-income countries. These guidelines may be a useful tool to ensure safe, responsible, and ethical short-term missions given increasing engagement of high-income country providers in this work.

Autophagy Inhibitor Chloroquine Downmodulates Hepatic Stellate Cell Activation and Liver Damage in Bile-Duct-Ligated Mice.

Hepatic stellate cell (HSC) activation via the autophagy pathway is a critical factor in liver fibrogenesis. This study tests the hypothesis that chloroquine (CQ) treatment can prevent autophagy and HSC activation in vitro and in vivo in bile-duct-ligated (BDL) mice. Sham-operated and BDL mice were treated with either PBS or CQ in two 60 mg/kg doses the day (D) before and after surgery. On day 2 (2D), HSCs were isolated, and their biological activities were evaluated by measuring intracellular lipid content, α-sma/collagen, and expression of autophagy lc3, sqstm1/p62 markers. The treatment efficacy on liver function was evaluated with serum albumin, transaminases (AST/ALT), and hepatic histology. Primary HSCs were treated in vitro for 24 h with CQ at 0, 2.5, 5, 10, 30, and 50 µM. Autophagy and HSC activation were assessed after 2D of treatment. CQ treatment improved serum AST/ALT, albumin, and bile duct proliferation in 2D BDL mice. This is associated with a suppression of HSC activation, shown by higher HSC lipid content and collagen I staining, along with the blockage of HSC autophagy indicated by an increase in p62 level and reduction in lc3 staining. CQ 5 µM inhibited autophagy in primary HSCs in vitro by increasing p62 and lc3 accumulation, thereby suppressing their in vitro activation. The autophagy inhibitor CQ reduced HSC activation in vitro and in vivo. CQ improved liver function and reduced liver injury in BDL mice.

C/EBPα and C/EBPß binding proteins modulate hepatocyte apoptosis through iNOS signaling pathway.

Inducible nitric oxide synthase (iNOS) and nitric oxide (NO) involve many pathophysiologic conditions. The expression of iNOS is regulated at multiple stages. Presently, the regulatory details of iNOS signaling are still unclear. This study aimed to investigate the regulatory role of C/EBPα and C/EBPß in iNOS signaling pathway. By employing the techniques such as EMSA, ChIP assay, site-directed mutagenesis, and siRNA silencing, the relationship between iNOS and C/EBPα/C/EBPß in rat hepatocytes was clarified. iNOS promoter was the direct transcriptional targets of the C/EBPα, C/EBPß, and NF-κB binding proteins. There was the interactive influence between NF-κB and C/EBPα/C/EBPß. The expression of iNOS was modulated by C/EBPα/C/EBPß transcription factors. Moreover, the iNOS expression mediated glycochenodeoxycholate (GCDC)-induced apoptosis in hepatocytes. C/EBPα/C/EBPß binding proteins could affect the GCDC-induced apoptosis through iNOS cascade. These findings indicate that C/EBPα and C/EBPß regulate the iNOS expression, which may further modify cell responses such as apoptosis and cell survival.

Survivin signaling is regulated through nuclear factor-kappa B pathway during glycochenodeoxycholate-induced hepatocyte apoptosis.

UNLABELLED: Hepatocytes in primary culture undergo apoptosis upon exposure to glycochenodeoxycholate (GCDC). The signaling mechanisms of GCDC-induced apoptosis remain unclear. To investigate the role of antiapoptotic genes, we compared apoptotic response in primary hepatocytes following GCDC treatment. The hepatocytes from adult Sprague-Dawley rats were cultured in collagen-coated dishes and treated with GCDC in varying concentrations, or the same concentration at different time intervals. Apoptosis was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, DNA fragmentation assay, and caspase assays. Expression of apoptosis-related genes and proteins was evaluated by RT-PCR, quantitative real-time PCR (qRT-PCR), and Western blotting, respectively. The DNA-binding property of a nuclear protein was assessed by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay. An interesting result was that GCDC caused hepatocyte apoptosis to display a biphasic phenomenon at a dosage of 50µM, whereas it was not found at higher dosages such as 200µM. GCDC stimulated the expression of antiapoptotic Survivin, which also presented a biphasic response. The activation of nuclear factor-kappaB (NF-κB) corresponded with the up-regulation of Survivin. The inhibitor of NF-κB, BAY 11-7082, suppressed the expression of Survivin and simultaneously eliminated the biphasic response. The expression of Survivin was transcriptionally mediated by the activation of NF-κB, as shown by EMSA and ChIP assay. CONCLUSIONS: These results demonstrated that a low dosage of GCDC induced the hepatocyte apoptosis to exhibit the biphasic response, which was regulated by the expression of Survivin through NF-κB signaling pathway.

The first six years of the APSA Travel Fellowship Program: Impact and lessons learned.

INTRODUCTION: The American Pediatric Surgical Association (APSA) travel fellowship was established in 2013 to allow pediatric surgeons from low- and middle-income countries to attend the APSA annual meeting. Travel fellows also participated in various clinical and didactic learning experiences during their stay in North America. METHODS: Previous travel fellows completed a survey regarding their motivations for participation in the program, its impact on their practice in their home countries, and suggestions for improvement of the fellowship. RESULTS: Eleven surgeons participated in the travel fellowship and attended the annual APSA meetings in 2013-2018. The response rate for survey completion was 100%. Fellows originated from 9 countries and 3 continents and most fellows worked in government practice (n=8, 73%). Nine fellows (82%) spent >3 weeks participating in additional learning activities such as courses and clinical observerships. The most common reasons for participation were networking (n=11, 100%), learning different ways of providing care (n=10, 90.9%), new procedural techniques (n=9, 81.8%), exposure to a different medical culture (n=10, 90.9%), and engaging in research (n=8, 72.7%). Most of the fellows participated in a structured course: colorectal (n= 6, 55%), laparoscopy (n=2, 18%), oncology (n=2, 18%), leadership skills (n=1, 9%), and safety and quality initiatives (n=1, 9%). Many fellows participated in focused clinical mentorships: general pediatric surgery (n=9, 82%), oncology (n=5, 45%), colorectal (n=3, 27%), neonatal care (n=2, 18%) and laparoscopy (n=2, 18%). Upon return to their countries, fellows reported that they were able to improve a system within their hospital (n=7, 63%), expand their research efforts (n=6, 54%), or implement a quality improvement initiative (n=6, 54%). CONCLUSIONS: The APSA travel fellowship is a valuable resource for pediatric surgeons in low- and middle-income countries. After completion of these travel fellowships, the majority of these fellows have implemented important changes in their hospital's health systems, including research and quality initiatives, to improve pediatric surgical care in their home countries. LEVEL OF EVIDENCE: This is not a clinical study. Therefore, the table that lists levels of evidence for "treatment study", "prognosis study", "study of diagnostic test" and "cost effectiveness study" does not apply to this paper.

Optimization of the isolation procedure and culturing conditions for hepatic stellate cells obtained from mouse.

Liver fibrosis (LF) mortality rate is approximately 2 million per year. Irrespective of the etiology of LF, a key element in its development is the transition of hepatic stellate cells (HSCs) from a quiescent phenotype to a myofibroblast-like cell with the production of fibrotic proteins. It is necessary to define optimal isolation and culturing conditions for good HSCs yield and proper phenotype preservation for studying the activation of HSCs in vitro. In the present study, the optimal conditions of HSC isolation and culture were examined to maintain the HSC's undifferentiated phenotype. HSCs were isolated from Balb/c mice liver using Nycodenz, 8, 9.6, and 11%. The efficiency of the isolation procedure was evaluated by cell counting and purity determination by flow cytometry. Quiescent HSCs were cultured in test media supplemented with different combinations of fetal bovine serum (FBS), glutamine (GLN), vitamin A (vitA), insulin, and glucose. The cells were assessed at days 3 and 7 of culture by evaluating the morphology, proliferation using cell counting kit-8, lipid storage using Oil Red O (ORO) staining, expression of a-smooth muscle actin, collagen I, and lecithin-retinol acyltransferase by qRT-PCR and immunocytochemistry (ICC). The results showed that Nycodenz, at 9.6%, yielded the best purity and quantity of HSCs. Maintenance of HSC undifferentiated phenotype was achieved optimizing culturing conditions (serum-free Dulbecco's Modified Eagle's Medium (DMEM) supplemented with glucose (100 mg/dl), GLN (0.5 mM), vitA (100 µM), and insulin (50 ng/ml)) with a certain degree of proliferation allowing their perpetuation in culture. In conclusion, we have defined optimal conditions for HSCs isolation and culture.

An academic career in global surgery: a position paper from the Society of University Surgeons Committee on Academic Global Surgery.

In recent years, as the high burden of surgical disease and poor access to surgical care in low- and middle-income countries have gained recognition as major public health problems, interest in global health has surged among surgical trainees and faculty. Traditionally, clinical volunteerism was at the forefront of the high-income country response to the significant burden of surgical disease in low- and middle-income countries. However, sustainable strategies for providing surgical care in low- and middle-income countries increasingly depend on bilateral clinical, research, and education collaborations to ensure effective resource allocation and contextual relevance. Academic global surgery creates avenues for interested surgeons to combine scholarship and education with their clinical global surgery passions through incorporation of basic/translational, education, clinical outcomes, or health services research with global surgery. Training in global health, either within residency or through advanced degrees, can provide the necessary skills to develop and sustain such initiatives. We further propose that creating cross-continental, bidirectional collaborations can maximize funding opportunities. Academic institutions are uniquely positioned to lead longitudinal and, importantly, sustainable global surgery efforts. However, for the individual global surgeon, the career path forward may be unclear. This paper reviews the development of academic global surgery, delineates the framework and factors critical to training global surgeons, and proposes models for establishing an academic career in this field. Overall, with determination, the academic global surgeon will not only carve out a niche of expertise but will define this critical field for future generations.

Guidelines and checklists for short-term missions in global pediatric surgery: Recommendations from the American Academy of Pediatrics Delivery of Surgical Care Global Health Subcommittee, American Pediatric Surgical Association Global Pediatric Surgery Committee, Society for Pediatric Anesthesia Committee on International Education and Service, and American Pediatric Surgical Nurses Association, Inc. Global Health Special Interest Group.

INTRODUCTION: Pediatric surgeons, anesthesia providers, and nurses from North America and other high-income countries (HICs) are increasingly engaged in resource-limited areas, with short-term missions (STMs) as the most common form of involvement. However, consensus recommendations currently do not exist for STMs in pediatric general surgery and associated perioperative care. METHODS: The American Academy of Pediatrics (AAP) Delivery of Surgical Care Subcommittee and American Pediatric Surgical Association (APSA) Global Pediatric Surgery Committee, with the American Pediatric Surgical Nurses Association, Inc. (APSNA) Global Health Special Interest Group, and the Society for Pediatric Anesthesia (SPA) Committee on International Education and Service generated consensus recommendations for STMs based on extensive experience with STMs. RESULTS: Three distinct, but related areas were identified: 1) Broad goals of surgical partnerships between HICs- and low and middle-income countries (LMICs). A previous set of guidelines published by the Global Paediatric Surgery Network Collaborative (GPSN), was endorsed by all groups; 2) Guidelines for the conduct of STMs were developed, including planning, in-country perioperative patient care, post-trip follow-up, and sustainability; 3) travel and safety considerations critical to STM success were enumerated. CONCLUSION: A diverse group of stakeholders developed these guidelines for STMs in LMICs. These guidelines may be a useful tool to ensure safe, responsible, and ethical STMs given increasing engagement of HIC providers in this work. LEVEL OF EVIDENCE: 5.

Initial experience with the adjustable gastric band in morbidly obese US adolescents and recommendations for further investigation.

BACKGROUND: The public health crisis of obesity has spread to the pediatric population. In morbidly obese (MO) adolescents, early weight loss intervention can reduce and prevent obesity-related comorbidities and mortality and improve quality of life. The present study was performed to evaluate weight loss efficacy and safety of "off-label" laparoscopic adjustable gastric banding (LAGB) procedures performed in MO adolescents by our adult bariatric program. PATIENTS AND METHODS: We retrospectively reviewed data from 716 LAGB procedures performed on an off-label basis in adults and 24 adolescent patients ages 14 to 20 years by the adult bariatric program at our institution between 2001 and 2006. RESULTS: There was no mortality. Average operative time was 45 minutes, length of stay for adolescents was 15 hours, and weight loss outcome and overall surgical complication rates are comparable between adolescents and adults. For adolescent subjects, baseline mean preoperative body mass index was 49 kg/m and average excess weight loss rates were 22%, 34%, 52%, 42%, and 42% at 3, 6, 12, 24, and 36 months, respectively. The overall complication rate was 29%, with a 25% incidence of pouch enlargement in adolescents (vs 18% in adult patients; P = ns). Two of 24 adolescent patients (8.4%) required laparoscopic band repositioning (vs 1.5% of adult patients; P = 0.06). CONCLUSIONS: LAGB is an effective and safe surgical weight loss modality for MO adolescent subjects. Vigilant follow-up for LAGB-related complications and intensive postoperative behavioral management are important for improving long-term success. We recommend continued investigation of long-term efficacy and safety of LAGB in this population.

Short-term outcome in the first 10 morbidly obese adolescent patients in the FDA-approved trial for laparoscopic adjustable gastric banding.

BACKGROUND: We received the LAP-BAND Investigational Device Exemption (IDE) from the US Food and Drug Administration in December 2004 to conduct a prospective longitudinal trial examining the safety and efficacy of laparoscopic adjustable gastric banding (LAGB) in morbidly obese adolescents ages 14 to 17 years. OBJECTIVES: To report the short-term results of LAGB in the first 10 adolescents with complete 9 months of follow-up. PATIENTS AND METHODS: Baseline characteristics and outcome data were analyzed in 10 patients enrolled between March 2005 and February 2006. RESULTS: All of the patients were girls. Their mean body mass index (+/-SD) was 50 +/- 13 kg/m, and excess weight was 171 +/- 79 pounds. Comorbidities included depression (3 patients), sleep apnea (3), hypertension (6), dyslipidemia (7), insulin resistance (9), metabolic syndrome (9), and steatohepatitis (in 4 of 5 patients with liver biopsy). Operative time was 45 +/- 9 minutes, and discharges were within 23 hours of surgery. Band-related complications were as follows: 2 dehydration, 1 pouch dilation, and 1 port revision. All of the patients lost weight, with a 9-month excess weight loss of 30% +/- 16% (range 14%-57%). Hypertension and the metabolic syndrome were resolved in 100% of patients (P = 0.04) and 80% of the patients (P = 0.01), respectively, along with significant improvement in the Pediatric Quality of Life and Beck Depression Inventory scores and a trend toward improvement in high-density lipoprotein cholesterol abnormalities (P = 0.08). CONCLUSIONS: At short-term follow-up, weight loss occurred with minimal complications, leading to early resolution of major obesity-related comorbidities. Continued evaluation of the long-term safety and efficacy of LAGB as a surgical adjunct to a comprehensive obesity treatment program is warranted.

Biliary atresia in Vietnam: Management and the burden of disease.

BACKGROUND: Biliary atresia is an idiopathic, neonatal liver disease of the bile ducts. The natural evolution of biliary atresia is known in developed countries. This study describes the clinical course of biliary atresia in Vietnam, a developing country. METHODS: Chart reviews were undertaken of patients treated with or without the Kasai procedure between January 2010 and July 2013 at a children's hospital in Vietnam. RESULTS: Of 287 children with biliary atresia, 149 (52%) were treated without the Kasai procedure and 138 (48%) were treated with the Kasai procedure. Median age at diagnosis was 2.4 months for children treated without the Kasai procedure vs 2.3 months for those treated with the procedure. The percentages of patients in the group treated without the Kasai procedure presenting at <2 months, 2 to <3 months, 3 to <4 months, 4-6 months, and >6 months of age were 31%, 35%, 15%, 10%, and 9%, respectively, compared to those treated with the Kasai procedure at 36% (P = .38), 44% (P = .12), 16% (P = 1.0), 4% (P = .037), and 0% (P < .001), respectively. The group treated without the Kasai procedure had 1- and 2-year survivals of 52% and 28%, respectively (median survival 6.6 months); in contrast, the group treated with the Kasai procedure had 1- and 2-year transplant-free survivals of 84% and 71%. No patients were treated by liver transplantation because of lack of a liver transplantation program in Vietnam. CONCLUSION: The majority of biliary atresia in Vietnam remains untreated despite early presentation and reasonable outcomes after a Kasai procedure relative to Western countries. These data illustrate the high health care burden for biliary atresia in Vietnam and the need to improve education about biliary atresia and its treatment.

Foxa2 may modulate hepatic apoptosis through the cIAP1 pathway.

UNLABELLED: Hepatocyte apoptosis is a ubiquitous feature of chronic liver injury, but the molecular mechanism remains to be determined. The liver-enriched Foxa2 transcription factor has been implicated in inflammation and neoplasia. Foxa2 may play a role in the regulation of apoptosis. This study aimed to investigate the relationship between Foxa2 and hepatic apoptosis. Apoptosis was induced with different causative factors as measured by caspase activity and TUNEL assay. Results showed that the apoptotic injury was associated with a downregulation of Foxa2. Foxa2-expressing vectors decreased apoptosis, whereas siRNA silencing of Foxa2 increased apoptosis in HepG2 cells. Foxa2 was correlated with expression profiling of anti-apoptotic genes cIAP1, cIAP2, XIAP, and survivin. Significantly, the cIAP1 expression was decreased by siRNA silencing of Foxa2, but increased by Foxa2-expressing vectors. The promoter of cIAP1 had specific DNA sequences that could be bound by Foxa2 nuclear protein as demonstrated by EMSA and gel supershift assay. The cIAP1 promoter was also occupied by Foxa2 nuclear factor through ChIP assay. Deletion of putative Foxa2 binding domains in cIAP1 promoter significantly reduced its promoter activity. CONCLUSION: A mechanism by which Foxa2 transcription factor modulates hepatic apoptosis may be through cIAP1 signaling pathway. Foxa2 can be a potential target for therapeutic intervention in liver diseases.

Nonalcoholic fatty liver disease in severely obese adolescent and adult patients.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is increasingly an indication for liver transplantation in adults. While severe obesity (SO, BMI ≥40 kg m(-2) ) in adults is long standing, it is recent in duration in adolescents. With adolescent obesity on the rise, NAFLD is becoming the most frequent liver disease in adolescents. The hypothesis that SO adolescents and adults have different severity of NAFLD because of longer duration of obesity in SO adults was tested. DESIGN AND METHODS: Preoperative clinical data, NAFLD activity and NASH (Nonalcoholic steatohepatitis) scores from intraoperative liver biopsies were extracted from a prospective database of consecutively operated SO adolescents and adults (n = 24 each). Fasting preoperative serum inflammatory mediators were evaluated by ELISA. RESULTS: Other than age, baseline BMI, ethnicity and gender distribution, the incidence and extent of dyslipidemia, hypertension, and metabolic syndrome were comparable between groups. Histologic scores for steatosis and inflammation were similar. Adolescents have significantly higher NASH incidence, hepatocyte injury scores and fibrosis. This was associated with higher serum C-reactive protein and sCD14 levels. CONCLUSION: For comparable BMI and metabolic profile, SO adolescents have more advanced liver damage, more severe systemic inflammation, suggesting differences in NAFLD etiologies and more aggressive disease progression in the young obese population.

Pathophysiologic role of hepatocyte nuclear factor 6.

Hepatocyte nuclear factor 6 (HNF6) is one of liver-enriched transcription factors. HNF6 utilizes the bipartite onecut-homeodomain sequence to localize the HNF6 protein to the nuclear compartment and binds to specific DNA sequences of numerous target gene promoters. HNF6 regulates an intricate network and mediates complex biological processes that are best known in the liver and pancreas. The function of HNF6 is correlated to cell proliferation, cell cycle regulation, cell differentiation and organogenesis, cell migration and cell-matrix adhesion, glucose metabolism, bile homeostasis, inflammation and so on. HNF6 controls the transcription of its target genes in different ways. The details of the regulatory pathways and their mechanisms are still under investigation. Future study will explore HNF6 novel functions associated with apoptosis, oncogenesis, and modulation of the inflammatory response. This review highlights recent progression pertaining to the pathophysiologic role of HNF6 and summarizes the potential mechanisms in preclinical animal models. HNF6-mediated pathways represent attractive therapeutic targets for the treatment of the relative diseases such as cholestasis.

Pediatric obesity.

Childhood obesity is a tremendous burden for children, their families, and society. Obesity prevention remains the ultimate goal but rapid development and deployment of effective nonsurgical treatment options is not currently achievable given the complexity of this disease. Surgical options for adolescent obesity have been proven to be safe and effective and should be offered. The development of stratified protocols of increasing intensity should be individualized for patients based on their disease severity and risk factors. These protocols should be offered in multidisciplinary, cooperative clinical trials to critically evaluate and develop optimal treatment strategies for morbid obesity.

Patterns of surgical weight loss and resolution of metabolic abnormalities in superobese bariatric adolescents.

PURPOSE: The aim of the study was to compare the baseline and the 18-month follow-up for weight and metabolic characteristics of superobese (SO) (body mass index [BMI] ≥50 kg/m(2)) and morbidly obese (MO) (BMI <50 kg/m(2)) adolescents who participated in a prospective longitudinal study of gastric banding delivered in an adolescent multidisciplinary treatment program. METHODS: Clinical information was extracted from an institutional review board-approved database of bariatric adolescents. Fasting cytokine and acute phase protein serum levels were analyzed by enzyme-linked immunosorbent assay. Liver histopathologies were assessed using the Kleiner's classification score. RESULTS: Other than BMI, MO (n = 11) and SO (n = 7) patients have similar degree of insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease. Serum C-reactive protein (10.2 ± 5.6 SO vs 4 ± 3.9 µg/mL MO [P < .02]) and leptin (71 ± 31 SO vs 45 ± 28 MO ng/mL [P = .04]) were more elevated in SO patients. Although weight loss is similar (30 ± 19 kg MO vs 28 ± 12 kg SO, P = .8 at 18 months; mean percent change in BMI, 22.8% ± 11.6% vs 20.5% ± 10.3% SO, P = .2), SO patients has less resolution of insulin resistance and dyslipidemia but experienced significantly improved health-related quality of life. CONCLUSIONS: The SO adolescents demonstrate equivalent short-term weight loss and improved quality of life but delayed metabolic response to a gastric banding-based weight loss treatment program compared with MO patients, illustrating the importance of early referral for timely intervention of MO patients.