A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Multimodal decoding of human liver regeneration.

The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine.

Short communication: Prevalence of deleterious variants causing recessive disorders in Italian Chianina, Marchigiana and Romagnola cattle.

In the last two decades, the molecular cause of six monogenic autosomal recessive disorders has been identified in native Italian beef cattle: two different ATP2A1 variants for the pseudomyotonia congenita, the first in Chianina and Romagnola (PMT1) and the second in Romagnola (PMT2); a KDM2B variant for the paunch calf syndrome (PCS) in Marchigiana and Romagnola; a NID1 variant for the congenital cataract (CC) in Romagnola; a LAMB1 variant for the hemifacial microsomia (HFM) in Romagnola; an ABCA12 variant for the ichthyosis fetalis (IF) in Chianina and a FA2H variant for the ichthyosis congenita (IC) in Chianina. The aim of this study was to evaluate the potential impact of these disorders in the affected Italian populations. For this purpose, 3331 Chianina, 2812 Marchigiana and 1680 Romagnola bulls born in the last 40 years were considered. The allelic frequency (AF) of the variant for PMT1 was 1.0% in Romagnola, 4.6% in Marchigiana and 5.9% in Chianina. The AF of the variant for PMT2 was 3.3% in Romagnola and 0% in the other two breeds. The AF of the variant for PCS was 11.7% in Romagnola, 2.0% in Marchigiana and 0% in Chianina. The AF of the variants for CC, HFM, IF and IC resulted below 3%, being the variants detected only in the breed populations in which they were previously reported. Considering a selected male population in the single breed, Chianina showed carrier prevalence of 11.9% for PMT1, 7.7% for IC and 6.4% for IF. Romagnola showed carrier prevalence of 23.4% for PCS, 6.7% for PMT2, 4.1% for HFM, 3.2% for CC and 2.0% for PMT1. Marchigiana showed carrier prevalence of 9.1% for PMT1 and 4.0% for PCS. With respect to the Romagnola cattle, the concerning presence of a total of five defect alleles in the population hampers a general approach based on the prevention of carriers from artificial insemination. However, identification of carriers may allow conscious mating to prevent the risk of homozygous descendants as well as the spread of heterozygous offspring. Therefore, systematic genotyping for all seven known harmful alleles is recommended to prevent risk mating between carriers, in particular to avoid the occurrence of affected offspring.

Arbovirus serosurvey (Orthobunyavirus, Flavivirus, and Alphavirus) in a draft horse population from Santa Fe, Argentina (2013-2016).

In the present study, we serosurveyed the exposure of 222 draft horses to different arboviruses in the city of Santa Fe, Argentina. Plaque reduction neutralization tests confirmed exposure to Fort Sherman virus (FSV), Saint Louis encephalitis virus (SLEV), West Nile virus (WNV), and Río Negro virus (RNV). Apparently, Western and Eastern equine encephalitis viruses did not circulate in the population tested. The confirmation of five seroconversions for WNV, FSV, and SLEV and the association between prevalence and age are indicative of recent circulation. These results highlight the importance of considering draft horses in arboviral surveillance in urban and rural areas of developing countries.

Vitamin D status and associated genetic polymorphisms in a cohort of UK children with non-alcoholic fatty liver disease.

BACKGROUND: Vitamin D deficiency has been associated with non-alcoholic fatty liver disease (NAFLD). However, the role of polymorphisms determining vitamin D status remains unknown. OBJECTIVES: The objectives of this study were to determine in UK children with biopsy-proven NAFLD (i) their vitamin D status throughout a 12-month period and (ii) interactions between key vitamin D-related genetic variants (nicotinamide adenine dinucleotide synthase-1/dehydrocholesterol reductase-7, vitamin D receptor, group-specific component, CYP2R1) and disease severity. METHODS: In 103 paediatric patients with NAFLD, serum 25-hydroxyvitamin D (25OHD) levels and genotypes were determined contemporaneously to liver biopsy and examined in relation to NAFLD activity score and fibrosis stage. RESULTS: Only 19.2% of children had adequate vitamin D status; most had mean 25OHD levels considered deficient (<25 nmol·L-1 , 25.5%) or insufficient (<50 nmol·L-1 , 55.3%). Patients had significantly lower 25OHD levels in winter months (95% CI: 22.7-31.2 nmol·L-1 ) when compared with spring (30.5-42.1 nmol·L-1 ; P = 0.0089), summer (36.3-47.2 nmol·L-1 ; P < 0.0001) and autumn (34.2-47.5 nmol·L-1 ; P = 0.0003). Polymorphisms in the nicotinamide adenine dinucleotide synthase-1/dehydrocholesterol reductase-7 (rs3829251, rs12785878) and vitamin D receptor (rs2228570) genes were independently associated with increased steatosis; while a group-specific component variant (rs4588) was associated with increased inflammation in liver biopsies. CONCLUSIONS: Children with NAFLD in the UK have particularly low winter vitamin D status, with vitamin D insufficiency prevalent throughout the year. Polymorphisms in the vitamin D metabolic pathway are associated with histological severity of paediatric NAFLD.

Quality improvement program of adult urinary tract infection management: Review and impact.

OBJECTIVE: A quality improvement program for adult urinary tract infection management was established to avoid unnecessary antibiotic treatment and to promote adequate prescription, associated with financial and time savings. METHODS: Management was integrated into a three-step approach: clinical diagnosis, bacteriological diagnosis, and therapeutic decision. For each step, areas for improvement were prioritized and implemented through corrective measures and key messages, measured by indicators. This program was applied to the whole hospital, which includes an emergency department and hospital units (672 beds). RESULTS: The diffusion of new recommendations on clinical diagnosis helped limit the use of Urine Dipstick Tests (UDT) and identify situations requiring the prescription of urine cytobacteriological test (UCBE) and antibiotic treatment: decreased annual consumption of UDTs (34%) and UCBEs (25%). The implementation of a new sampling system for UCBEs was associated with a 21% increase in conclusive analysis. Results of antimicrobial susceptibility testing were also optimized. Trainings on the proper use of antibiotics led to a 5.0% decline in global consumption. Only 23 antibiotic prescriptions for UTI resulted in pharmaceutical advice to prescribers in 2014. CONCLUSION: The program is part of a practice improvement strategy. Integrating the management of urinary tract infections into a global process helped improve each step of patient management.

Review article: the investigation and management of rectal neuroendocrine tumours.

BACKGROUND: Rectal neuroendocrine tumours (NETs) are increasingly identified at endoscopy possibly as a result of bowel cancer screening programmes. AIM: To present a review of the literature to aid clinicians in the diagnosis and management of rectal neuroendocrine tumours. METHODS: A literature search was conducted through MEDLINE using search terms: rectal, rectum, carcinoid, NET, therapy, endoscopy, mucosal resection, submucosal dissection. Relevant articles were identified through manual review with reference lists reviewed for additional articles. RESULTS: The incidence of rectal neuroendocrine tumours is approximately 1 per 100 000 population per year with the majority (80-90%) being <1 cm and localised to the submucosa. Metastatic disease is infrequent (<20%) with risk factors including size, atypical appearance, grade and depth of invasion. The primary resection modality influences complete resection rates and the need for secondary therapy. A thorough pre-resection diagnostic work up is required for lesions that are at higher risk of invasion and metastasis. Device-assisted endoscopic mucosal resection and endoscopic submucosal dissection are used to resect localised rectal neuroendocrine tumours <2 cm. Transanal surgery is also used to resect localised 1-2 cm rectal neuroendocrine tumours. Oncological surgical resection is used for rectal neuroendocrine tumours that are >2 cm or with invasion and regional disease. The treatment of advanced disease is multimodal. CONCLUSIONS: The long-term tumour biology of small rectal neuroendocrine tumours remains unclear. There is uncertain impact from bowel cancer screening programmes on rectal neuroendocrine tumour incidence, morbidity and mortality. Referral to neuroendocrine tumour centres for patients with locally advanced disease or metastatic disease is recommended.

Liver Transplantation After Ex Vivo Normothermic Machine Preservation: A Phase 1 (First-in-Man) Clinical Trial.

The number of donor organs suitable for liver transplantation is restricted by cold preservation and ischemia-reperfusion injury. We present the first patients transplanted using a normothermic machine perfusion (NMP) device that transports and stores an organ in a fully functioning state at 37°C. In this Phase 1 trial, organs were retrieved using standard techniques, attached to the perfusion device at the donor hospital, and transported to the implanting center in a functioning state. NMP livers were matched 1:2 to cold-stored livers. Twenty patients underwent liver transplantation after NMP. Median NMP time was 9.3 (3.5-18.5) h versus median cold ischaemia time of 8.9 (4.2-11.4) h. Thirty-day graft survival was similar (100% NMP vs. 97.5% control, p = 1.00). Median peak aspartate aminotransferase in the first 7 days was significantly lower in the NMP group (417 IU [84-4681]) versus (902 IU [218-8786], p = 0.03). This first report of liver transplantation using NMP-preserved livers demonstrates the safety and feasibility of using this technology from retrieval to transplantation, including transportation. NMP may be valuable in increasing the number of donor livers and improving the function of transplantable organs.

Trans-physeal anterior cruciate ligament reconstruction in adolescents.

PURPOSE: The aim of the study was to evaluate, in a group of adolescents, the onset of varus-valgus deviations in the sagittal plane after performing a trans-tibial trans-epiphyseal technique of ACL reconstruction with a follow-up of at least 2 years. METHODS: Seventy-one patients aged 12-15 years old (Tanner scale 3 and 4) have undergone ACL reconstruction with STG using arthroscopy. All patients were evaluated clinically using the visual analogue scale (VAS), the Lysholm score and the Tegner activity score at the time of surgery. All patients were reevaluated after a follow-up period of at least 2 years (T1) using the VAS, the Lysholm score, the Tegner activity score and radiographic studies in order to compare the operated limb with the healthy control limb. RESULTS: Valgus difference exceeding 2° in the knee axis between the operated limb and the healthy control limb was observed only in three patients (4.2%: 95% CI 0.88-11.86%). The average difference was <1° (0.3°, 95% CI 0.0-0.55). CONCLUSION: The trans-tibial trans-epiphyseal technique of ACL reconstruction, according to the results obtained, seems to be a valid alternative procedure, when performed by a skilled orthopaedic surgeon, offering an excellent safety profile and at the same time very good clinical results. LEVEL OF EVIDENCE: IV.

Groin Pain Syndrome Italian Consensus Conference on terminology, clinical evaluation and imaging assessment in groin pain in athlete.

The nomenclature and the lack of consensus of clinical evaluation and imaging assessment in groin pain generate significant confusion in this field. The Groin Pain Syndrome Italian Consensus Conference has been organised in order to prepare a consensus document regarding taxonomy, clinical evaluation and imaging assessment for groin pain. A 1-day Consensus Conference was organised on 5 February 2016, in Milan (Italy). 41 Italian experts with different backgrounds participated in the discussion. A consensus document previously drafted was discussed, eventually modified, and finally approved by all members of the Consensus Conference. Unanimous consensus was reached concerning: (1) taxonomy (2) clinical evaluation and (3) imaging assessment. The synthesis of these 3 points is included in this paper. The Groin Pain Syndrome Italian Consensus Conference reached a consensus on three main points concerning the groin pain syndrome assessment, in an attempt to clarify this challenging medical problem.

Why menisci show higher healing rate when repaired during ACL reconstruction? Growth factors release can be the explanation.

PURPOSE: Healing rate of meniscus repair is higher when the suture is associated with anterior cruciate ligament reconstruction. A possible explanation can be a different pattern of release of growth factors between anterior cruciate ligament reconstruction and isolated meniscus surgery. Hypothesis of this study is that the concentrations of bFGF, TGF-ß and platelet-derived growth factor (PDGF) in joint fluid, immediately after single-bundle anterior cruciate ligament reconstruction and arthroscopic partial meniscectomy, can be different. METHODS: Twenty consecutive patients underwent partial medial meniscectomy and twenty consecutive patients underwent single-bundle anterior cruciate ligament reconstruction with hamstring grafts were enrolled in the study. Thirty minutes after the end of the surgical procedure, a sample of joint fluid, as well of venous blood, was collected from all the patients. Concentrations of growth factors were determined by enzyme-linked immunosorbent assay. RESULTS: The peripheral blood concentration of TGF-ß, bFGF and PDGF was comparable between partial meniscectomy and anterior cruciate ligament reconstruction groups. No differences between the two surgical techniques were also found in term of TGF-ß and bFGF joint fluid concentration, whereas joint PDGF concentration of anterior cruciate ligament reconstruction patients was significantly higher than the one found in partial meniscectomy patients. CONCLUSIONS: A significant growth factors release was detected in the knee joint during arthroscopic surgery. PDGF concentration was significantly higher in anterior cruciate ligament reconstructed knee than in the meniscectomy group. PDGF can play an important role enhancing the healing response of meniscus suture and can be one of the biological reasons of the higher meniscal healing rate in anterior cruciate ligament reconstructed knee.

High accuracy in knee alignment and implant placement in unicompartmental medial knee replacement when using patient-specific instrumentation.

PURPOSE: The influence of patient-specific instrumentations on the accuracy of unicompartmental medial knee replacement remains unclear. The goal of this study was to examine the ability of patient-specific instrumentation to accurately reproduce postoperatively what the surgeon had planned preoperatively. METHODS: Twenty consecutive patients (20 knees) who suffered from isolated unicompartmental medial osteoarthritis of the knee and underwent medial knee replacement using newly introduced magnetic resonance imaging-based patient-specific instrumentation were assessed. This assessment recorded the following parameters: (1) the planned and the postoperative mechanical axis acquired through long-leg AP view radiographies; (2) the planned and the postoperative tibial slope acquired by means of standard AP and lateral view radiographies; and (3) the postoperative fit of the implanted components to the bone in coronal and sagittal planes. The hypothesis of the study was that there was no statistically significant difference between postoperative results and preoperatively planned values. RESULTS: The study showed that (1) the difference between the postoperative mechanical axis (mean 1.9° varus ± 1.2° SD) and the planned mechanical axis (mean 1.8° varus ± 1.2° SD) was not statistically significant; (2) the difference between the postoperative tibial slope (mean 5.2° ± 0.6° SD) and the planned tibial slope (mean 5.4° ± 0.6° SD) was statistically significant (p = 0.008); and (3) the postoperative component fit to bone in the coronal and sagittal planes was accurate in all cases; nevertheless, in one knee, all components were implanted one size smaller than preoperatively planned. Moreover, in two additional cases, one size thinner and one size thicker of the polyethylene insert were used. CONCLUSIONS: This study suggests that overall patient-specific instrumentation was highly accurate in reproducing postoperatively what the surgeon had planned preoperatively in terms of mechanical axis, tibial slope and component fit to bone. LEVEL OF EVIDENCE: IV.

Review article: the investigation and management of gastric neuroendocrine tumours.

BACKGROUND: Gastric carcinoids (GCs) or neuroendocrine tumours (NETs) are increasingly identified at endoscopy, and account for 0.6-2% of all gastric polyps identified. The SEER database in the US has demonstrated a rising incidence of gastric NETs amongst all NETs; from 2.2% between 1950 and 1969 to 6.0% between 2000 and 2007. AIM: To review the literature and assist clinicians in managing patients with GCs. METHODS: A literature search was conducted through MEDLINE using search terms: gastric, carcinoid, neuroendocrine tumour, therapy, endoscopy, mucosal resection, submucosal dissection. Relevant articles were identified through manual review. The reference lists of these articles were reviewed to include further appropriate articles. RESULTS: There are three types of GCs with important epidemiological, pathophysiological, histological and endoscopic differences that affect prognosis and management. Type 1 and 2 GCs develop in the context of hypergastrinaemia that originates from achlorhydria in atrophic gastritis and a gastrinoma, respectively. Type 3 GCs occur sporadically and independent of gastrin. The histological type, grade and Ki67 index are used to determine prognosis and direct clinical management. Type 1 GCs >1 cm in size and type 2 GCs should be assessed for invasion beyond the submucosa with EUS prior to endoscopic resection with EMR or ESD. Type 3 GCs should be managed as per recommendations for gastric adenocarcinoma. The treatment of advanced disease is multimodal. CONCLUSIONS: Patients with gastric carcinoids should be discussed in a specialist neuroendocrine tumour multidisciplinary meeting to ensure all treatment options are explored in localised and advanced disease. Areas of controversy exist that need further research.

Autologous collagen-induced chondrogenesis technique (ACIC) for the treatment of chondral lesions of the talus.

PURPOSE: Autologous collagen-induced chondrogenesis technique (ACIC) combines microfractures with the use of an injectable atelocollagen matrix that allows performing the whole cartilage repair treatment arthroscopically. The aim of this study was to evaluate the in vitro cytocompatibility of this biomaterial using human bone marrow mesenchymal stem cells and human chondrocytes. Moreover, the preliminary data of five patients affected by chondral lesion of the talus treated with the ACIC technique are shown. METHODS: Human bone marrow mesenchymal stem cells and human chondrocytes were seeded on solid and pre-solid atelocollagen scaffolds. Cell-scaffold constructs were cultured for 7 days and then prepared for histological analyses. Arthroscopic ACIC was performed in five patients affected by chondral lesions of the talus; they were clinically evaluated with AOFAS, VAS and Tegner score before and then after 6 months from surgery. RESULTS: In vitro results showed that both bone marrow mesenchymal stem cells and chondrocytes were able to efficiently colonize the whole construct, from the surface to the core, only when seeded on the pre-solid atelocollagen scaffold, but not on its solid form. No adverse events were observed in the patients treated with the ACIC technique; a significant improvement in VAS pain scale and in AOFAS score was found at 6 months follow up. CONCLUSION: Injectable atelocollagen can be considered a feasible scaffold for cartilage repair treatment, in particular if used in its pre-solid form. ACIC leads to good clinical results in the treatment for chondral lesions of the talus even if longer follow-up and a higher number of patients are necessary to confirm these data. LEVEL OF EVIDENCE: IV.

Hepatopathy of Mauriac syndrome: a retrospective review from a tertiary liver centre.

BACKGROUND: Mauriac syndrome is characterised by growth failure, cushingoid appearance and hepatomegaly which occurs in patients with insulin dependent diabetes and was first described shortly after the introduction of insulin as a treatment for the condition. OBJECTIVE: To describe the clinical features, histological findings and outcome of young people with glycogenic hepatopathy, the hepatic manifestation of Mauriac syndrome (MS). DESIGN: Retrospective cohort study. PATIENTS: Young people with glycogenic hepatopathy. SETTING: Tertiary paediatric hepatology unit. RESULTS: Thirty-one young people (16 M), median age of 15.1 years (IQR 14-16.2) presented within the study period. Median age of diagnosis of diabetes was 10 years (IQR 8-11). Median insulin requirement was 1.33 units/kg/day; median HbA1c was 96.7 mmol/mol (IQR 84.7-112.0). Growth was impaired: median height z-score was -1.01 (-1.73 to 0.4) and median body mass index (BMI) z-score was 0.28 (-0.12 to 0.67). Hepatomegaly was universal with splenomegaly in 16%. Transaminases were abnormal with a median aspartate aminotransferase (AST) of 76 IU/L and gamma glutamyltransferase of 71 IU/L. Liver biopsy was undertaken in 19 (61%). All showed enlarged hepatocytes with clear cytoplasm with glycogenated nuclei in 17. Steatosis was present in the majority. Inflammation was present in 8 (42%). Fibrosis was seen in 14 (73%) and was generally mild though 2 had bridging fibrosis. Megamitochondria were described in 7. Presence of megamitochondria correlated with AST elevation (p=0.026) and fibrosis on biopsy (p=0.007). At follow-up 17 children had normal or improved transaminases, in 13 there was no change. Transaminases followed the trend of the child's HbA1c. CONCLUSIONS: Despite modern insulin regimens and monitoring in children with type 1 diabetes, MS still exists. Significant steatosis, inflammation and fibrosis were all seen in liver biopsies.

Genetics of slaughter precocity, carcass weight, and carcass weight gain in Chianina, Marchigiana, and Romagnola young bulls under protected geographical indication.

The aim of this study was to estimate the heritability and genetic correlation of age at slaughter (AS), as an indicator of slaughter precocity, carcass weight (CW), and CW gain (CWG = CW × AS(-1)) obtained from young bulls of 3 Italian autochthonous beef cattle breeds [i.e., Chianina (CHI), Marchigiana (MAR), and Romagnola (ROM)]. In addition, the study aimed at evaluating the effect of corrected or uncorrected CW for AS, and analyzing the relationship between adjusted or unadjusted CW with CWG in term of changes in rank correlation in groups of sires with high accuracy. Data were obtained from the Consortium of protected geographical indication (PGI) "Vitellone Bianco dell'Appennino Centrale" (i.e., white young bull of Central Apennines), approved by the European Union. After editing, 20,872 complete records were retained for subsequent Bayesian analysis. Univariate animal model produced h(2) estimates of medium value for AS (i.e., from 0.28 for CHI to 0.39 for the ROM breed). The CW presented h(2) estimates less than AS, ranging from 0.13 for CHI to 0.24 for ROM bulls. The adjustment of CW by AS (CWU-AS) increased the h(2) values for CW in all breeds (i.e., from 0.20 to 0.29). Point estimate of genetic correlations between AS and CW obtained by a bivariate analysis were moderate to low, and negative in all breeds (from -0.08 to -0.29). Rerankings of sire for univariate CW (CWU) analysis and CWU-AS were more noticeable for CHI and ROM (rank correlation of 0.875 and 0.897, respectively) than for the MAR breed (rank correlation of 0.967). Comparing bivariate EBV for CW with EBV for CWU or CWU-AS increased rank correlation to 0.937 for ROM, but for CHI it remained lower (i.e., 0.861), indicating a possible large reranking of sires by correcting CW for AS in this breed. Daily CWG presented h(2) estimates greater than CW and similar or greater than AS. It appears to be a good indicator of instant growth rate capacity of the animal but lacking information on the endpoint of fattening in terms of age and weight. Field slaughter data for the CHI, MAR, and ROM breeds under the PGI labeling indicate that AS is not a mere environmental factor to be corrected for but trait subjected to genetic control. Because of its economic relevance in fattening, age at slaughter, as an indicator of slaughter precocity, could become a trait requiring careful consideration for selection of beef breeds.

Human liver regeneration is characterized by the coordinated expression of distinct microRNA governing cell cycle fate.

In the absence of adequate compensatory regeneration, overwhelming liver damage can cause acute liver failure (ALF) and death without emergent liver transplantation (LT). Auxiliary LT produces satisfactory outcomes in this setting, with the prospect of native liver regeneration sustaining long-term survival. Since animal models only partially recapitulate human liver regeneration, we investigated the molecular mechanisms controlling it in this unique LT setting, as an exemplar of human liver regeneration. We demonstrate coordinated changes in expression of microRNA (miRNA) during regeneration that drive proliferation, innate immunity and angiogenesis. In contrast, failed regeneration in a similar cohort is associated with distinct miRNA enforcing cell cycle inhibition and DNA methylation. The miRNA expression associated with successful or failed regeneration when recapitulated in vitro, triggered expression of cardinal regeneration-linked genes promoting cell cycle entry or inhibition, respectively. Furthermore, inhibition of miRNA 150, 663 and 503, whose downregulation is associated with successful regeneration, induced cell proliferation which a key determinant of successful regeneration. Our data indicate that human liver regeneration may be orchestrated by distinct miRNA controlling key regeneration-linked processes including hepatocyte proliferation. To our knowledge this is the first characterization of molecular processes associated with human liver regeneration.

ENETS TNM Staging Predicts Prognosis in Small Bowel Neuroendocrine Tumours.

Introduction. Small bowel neuroendocrine tumours (NETs) are the most common type of gastrointestinal neuroendocrine tumours. The incidence and prevalence of these tumours are on the rise. The aims of this study were to determine prognostic clinicopathological features and whether the ENETS TNM staging system predicts prognosis and also. Method. Clinical data was collected retrospectively from 138 patients with histologically proven small bowel NETs managed at King's College Hospital. Histology was reviewed and small bowels tumours, were staged according to the ENETS TNM staging system. Results. Median age was 65 years (range 29-87). The 5-year survival was 79.5% and the 10-year survival was 48.5%. Resection of the primary tumour was associated with improved survival (120 versus 56 months, P < 0.05). On multivariate analysis prognostic factors were primary tumour resection and not having a carcinoid heart disease. TNM staging significantly separated survival of stage 2 and stage 3 from stage 4 NETs. Conclusion. Small bowel primary tumour resection and not having carcinoid heart disease are prognostic factors. The ENETS TNM staging and grading system appears to be of prognostic relevance to small bowel NETs.