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1.  mTOR signaling in liver regeneration: Rapamycin combined with growth factor treatment 
AIM: To investigate the effects of mammalian target of rapamycin (mTOR) inhibition on liver regeneration and autophagy in a surgical resection model.
METHODS: C57BL/6 mice were subjected to a 70% partial hepatectomy (PH) and treated intraperitoneally every 24 h with a combination of the mTOR inhibitor rapamycin (2.5 mg/kg per day) and the steroid dexamethasone (2.0 mg/kg per day) in phosphate buffered saline (PBS) or with PBS alone as vehicle control. In the immunosuppressant group, part of the group was treated subcutaneously 4 h prior to and 24 h after PH with a combination of human recombinant interleukin 6 (IL-6; 500 μg/kg per day) and hepatocyte growth factor (HGF; 100 μg/kg per day) in PBS. Animals were sacrificed 2, 3 or 5 d after PH and liver tissue and blood were collected for further analysis. Immunohistochemical staining for 5-Bromo-2’-deoxyuridine (BrdU) was used to quantify hepatocyte proliferation. Western blotting was used to detect hepatic microtubule-associated protein 1 light chain 3 (LC3)-II protein expression as a marker for autophagy. Hepatic gene expression levels of proliferation-, inflammation- and angiogenesis-related genes were examined by real-time reverse transcription-polymerase chain reaction and serum bilirubin and transaminase levels were analyzed at the clinical chemical core facility of the Erasmus MC-University Medical Center.
RESULTS: mTOR inhibition significantly suppressed regeneration, shown by decreased hepatocyte proliferation (2% vs 12% BrdU positive hepatocyte nuclei at day 2, P < 0.01; 0.8% vs 1.4% at day 5, P = 0.02) and liver weight reconstitution (63% vs 76% of initial total liver weight at day 3, P = 0.04), and furthermore increased serum transaminase levels (aspartate aminotransferase 641 U/L vs 185 U/L at day 2, P = 0.02). Expression of the autophagy marker LC3-II, which was reduced during normal liver regeneration, increased after mTOR inhibition (46% increase at day 2, P = 0.04). Hepatic gene expression showed an increased inflammation-related response [tumor necrosis factor (TNF)-α 3.2-fold upregulation at day 2, P = 0.03; IL-1Ra 6.0-fold upregulation at day 2 and 42.3-fold upregulation at day 5, P < 0.01] and a reduced expression of cell cycle progression and angiogenesis-related factors (HGF 40% reduction at day 2; vascular endothelial growth factor receptor 2 50% reduction at days 2 and 5; angiopoietin 1 60% reduction at day 2, all P ≤ 0.01). Treatment with the regeneration stimulating cytokine IL-6 and growth factor HGF could overcome the inhibitory effect on liver weight (75% of initial total liver weight at day 3, P = 0.02 vs immunosuppression alone and P = 0.90 vs controls) and partially reversed gene expression changes caused by rapamycin (TNF-α and IL-1Ra levels at day 2 were restored to control levels). However, no significant changes in hepatocyte proliferation, serum injury markers or autophagy were found.
CONCLUSION: mTOR inhibition severely impairs liver regeneration and increases autophagy after PH. These effects are partly reversed by stimulation of the IL-6 and HGF pathways.
doi:10.5500/wjt.v3.i3.36
PMCID: PMC3832859  PMID: 24255881
Hepatocyte proliferation; Autophagy; Microtubule-associated protein 1 light chain 3; Partial hepatectomy; Rapamycin
2.  Functional Differences between Human NKp44− and NKp44+ RORC+ Innate Lymphoid Cells 
Human RORC+ lymphoid tissue inducer cells are part of a rapidly expanding family of innate lymphoid cells (ILC) that participate in innate and adaptive immune responses as well as in lymphoid tissue (re) modeling. The assessment of a potential role for innate lymphocyte-derived cytokines in human homeostasis and disease is hampered by a poor characterization of RORC+ innate cell subsets and a lack of knowledge on the distribution of these cells in adults. Here we show that functionally distinct subsets of human RORC+ innate lymphoid cells are enriched for secretion of IL-17a or IL-22. Both subsets have an activated phenotype and can be distinguished based on the presence or absence of the natural cytotoxicity receptor NKp44. NKp44+ IL-22 producing cells are present in tonsils while NKp44− IL-17a producing cells are present in fetal developing lymph nodes. Development of human intestinal NKp44+ ILC is a programmed event that is independent of bacterial colonization and these cells colonize the fetal intestine during the first trimester. In the adult intestine, NKp44+ ILC are the main ILC subset producing IL-22. NKp44− ILC remain present throughout adulthood in peripheral non-inflamed lymph nodes as resting, non-cytokine producing cells. However, upon stimulation lymph node ILC can swiftly initiate cytokine transcription suggesting that secondary human lymphoid organs may function as a reservoir for innate lymphoid cells capable of participating in inflammatory responses.
doi:10.3389/fimmu.2012.00072
PMCID: PMC3342004  PMID: 22566953
innate lymphoid cells; human; IL-22; IL-17a; lymph node; tonsil; fetal; RORC
3.  Endoscopic bilateral adrenalectomy in patients with ectopic Cushing’s syndrome 
Surgical Endoscopy  2011;26(4):1140-1145.
Background
Bilateral adrenalectomy (BLA) is a treatment option to alleviate symptoms in patients with ectopic Cushing’s syndrome (ECS) for whom surgical treatment of the responsible nonpituitary tumor is not possible. ECS patients have an increased risk for complications, because of high cortisol levels, poor clinical condition, and metabolic disturbances. This study aims to evaluate the safety and long-term efficacy of endoscopic BLA for ECS.
Methods
From 1990 to present, 38 patients were diagnosed and treated for ECS in the Erasmus University Medical Center, a tertiary referral center. Twenty-four patients were treated with BLA (21 endoscopic, 3 open), 9 patients were treated medically, and 5 patients could be cured by complete resection of the adrenocorticotropic hormone (ACTH)-producing tumor. The medical records were retrospectively reviewed and entered into a database. For evaluation of the efficacy of BLA, preoperative biochemical and physical symptoms were assessed and compared with postoperative data.
Results
Endoscopic BLA was successfully completed in 20 of the 21 patients; one required conversion to open BLA. Intraoperative complications occurred in two (10%) patients, and postoperative complications occurred in three (14%) patients. Median hospitalization was 9 (2–95) days, and median operating time was 246 (205–347) min. Hypercortisolism was resolved in all patients. Improvements of hypertension, body weight, Cushingoid appearance, impaired muscle strength, and ankle edema were achieved in 87, 90, 65, 61, and 78% of the patients, respectively. Resolution of diabetes, hypokalemia, and metabolic alkalosis was achieved in 33, 89, and 80%, respectively.
Conclusion
Endoscopic BLA is a safe and effective treatment for patients with ectopic Cushing’s syndrome.
doi:10.1007/s00464-011-2020-7
PMCID: PMC3310978  PMID: 22044978
Bilateral adrenalectomy; Endoscopic; Cushing’s syndrome; Ectopic
4.  Detailed Kinetics of the Direct Allo-Response in Human Liver Transplant Recipients: New Insights from an Optimized Assay 
PLoS ONE  2010;5(12):e14452.
Conventional assays for quantification of allo-reactive T-cell precursor frequencies (PF) are relatively insensitive. We present a robust assay for quantification of PF of T-cells with direct donor-specificity, and establish the kinetics of circulating donor-specific T cells after liver transplantation (LTx). B cells from donor splenocytes were differentiated into professional antigen-presenting cells by CD40-engagement (CD40-B cells). CFSE-labelled PBMC from LTx-recipients obtained before and at several time points after LTx, were stimulated with donor-derived or 3rd party CD40-B cells. PF of donor-specific T cells were calculated from CFSE-dilution patterns, and intracellular IFN-γ was determined after re-stimulation with CD40-B cells. Compared to splenocytes, stimulations with CD40-B cells resulted in 3 to 5-fold higher responding T-cell PF. Memory and naïve T-cell subsets responded equally to allogeneic CD40-B cell stimulation. Donor-specific CD4+ and CD8+ T-cell PF ranged from 0.5 to 19% (median: 5.2%). One week after LTx, PF of circulating donor-specific CD4+ and CD8+ T cells increased significantly, while only a minor increase in numbers of T cells reacting to 3rd party allo-antigens was observed. One year after LTx numbers of CD4+ and CD8+ T cells reacting to donor antigens, as well as those reacting to 3rd party allo-antigens, were slightly lower compared to pre-transplant values. Moreover, CD4+ and CD8+ T cells responding to donor-derived, as well as those reacting to 3rd party CD40-B cells, produced less IFN-γ. In conclusion, our alternative approach enables detection of allo-reactive human T cells at high frequencies, and after application we conclude that donor-specific T-cell PF increase immediately after LTx. However, no evidence for a specific loss of circulating T-cells recognizing donor allo-antigens via the direct pathway up to 1 year after LTx was obtained, underscoring the relative insensitiveness of previous assays.
doi:10.1371/journal.pone.0014452
PMCID: PMC3012075  PMID: 21206923
5.  Physical fitness, fatigue, and quality of life after liver transplantation 
Fatigue is often experienced after liver transplantation. The aims of this cross-sectional study were to assess physical fitness (cardiorespiratory fitness, neuromuscular fitness, body composition) in liver transplant recipients and to explore whether physical fitness is related to severity of fatigue. In addition, we explored the relationship between physical fitness and health-related quality of life. Included were 18 patients 1–5 years after transplantation (aged 48.0 ± 11.8 years) with varying severity of fatigue. Peak oxygen uptake during cycle ergometry, 6-min walk distance, isokinetic muscle strength of the knee extensors, body mass index, waist circumference, skinfold thickness, severity of fatigue, and health-related quality of life were measured. Cardiorespiratory fitness in the liver transplant recipients was on average 16–34% lower than normative values (P ≤ 0.05). Furthermore, the prevalence of obesity seemed to be higher than in the general population (17 vs. 10%). We found no deficit in neuromuscular fitness. Cardiorespiratory fitness was the only fitness component that was related with severity of fatigue (rs = −0.61 to rs = -0.50, P ≤ 0.05). Particularly cardiorespiratory fitness was related with several aspects of health-related quality of life (rs = 0.48 to rs = 0.70, P ≤ 0.05). Results of our study imply that cardiorespiratory fitness and body composition are impaired in liver transplant recipients and that fitness is related with severity of fatigue (only cardiorespiratory fitness) and quality of life (particularly cardiorespiratory fitness) in this group. These findings have implications for the development of rehabilitation programs for liver transplant recipients.
doi:10.1007/s00421-007-0435-6
PMCID: PMC1914221  PMID: 17364193
Liver transplantation; Fatigue; Peak oxygen uptake; Isokinetic muscle strength; Body composition
6.  Optimizing intensive care capacity using individual length-of-stay prediction models 
Critical Care  2007;11(2):R42.
Introduction
Effective planning of elective surgical procedures requiring postoperative intensive care is important in preventing cancellations and empty intensive care unit (ICU) beds. To improve planning, we constructed, validated and tested three models designed to predict length of stay (LOS) in the ICU in individual patients.
Methods
Retrospective data were collected from 518 consecutive patients who underwent oesophagectomy with reconstruction for carcinoma between January 1997 and April 2005. Three multivariable linear regression models for LOS, namely preoperative, postoperative and intra-ICU, were constructed using these data. Internal validation was assessed using bootstrap sampling in order to obtain validated estimates of the explained variance (r2). To determine the potential gain of the best performing model in day-to-day clinical practice, prospective data from a second cohort of 65 consecutive patients undergoing oesophagectomy between May 2005 and April 2006 were used in the model, and the predictive performance of the model was compared with prediction based on mean LOS.
Results
The intra-ICU model had an r2 of 45% after internal validation. Important prognostic variables for LOS included greater patient age, comorbidity, type of surgical approach, intraoperative respiratory minute volume and complications occurring within 72 hours in the ICU. The potential gain of the best model in day-to-day clinical practice was determined relative to mean LOS. Use of the model reduced the deficit number (underestimation) of ICU days by 65 and increased the excess number (overestimation) of ICU days by 23 for the cohort of 65 patients. A conservative analysis conducted in the second, prospective cohort of patients revealed that 7% more oesophagectomies could have been accommodated, and 15% of cancelled procedures could have been prevented.
Conclusion
Patient characteristics can be used to create models that will help in predicting LOS in the ICU. This will result in more efficient use of ICU beds and fewer cancellations.
doi:10.1186/cc5730
PMCID: PMC2206463  PMID: 17389032

Results 1-6 (6)