Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)-A European Society of Organ Transplantation (ESOT) Consensus Statement.

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines' Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation.

Primary Ewing sarcoma of the kidney: A series of four cases.

INTRODUCTION: Ewing sarcoma (ES), the neuroectodermal derived tumour typically occurs in the bone and soft tissue of children and young adults. Primary ES of the kidney is strikingly rare and only a few cases and small case series have been documented. Due to the highly aggressive nature of this neoplasm, distinction from other morphological mimickers is truly indispensable in terms of treatment and prognosis. Here we describe the clinicopathological features of four cases of primary ES of the kidney with special emphasis on one case having extensive neural differentiation postneo- adjuvant chemotherapy (NACT). Extensive neural differentiation in renal ES has not been documented to date. CASE SERIES: Four patients (age range from 15-35 years) had kidney mass and multiple distant metastases at first presentation. Primary diagnosis of Ewing sarcoma was rendered by histopathology with the help of immunohistochemistry on core biopsy material. Tumour cells in all cases showed diffuse membranous CD99, nuclear FLI-1 and NKX2.2. Two of the patients had undergone radical nephrectomy followed by combination chemotherapy. Another two patients were first treated with neo-adjuvant chemotherapy (NACT) followed by radical nephrectomy. In one of them, histopathological examination of nephrectomy specimens revealed extensive neural differentiation. The adrenal gland was free in all four cases. The follow-up period was 12 -24 months. Three patients had survived and one of them became disease-free. CONCLUSION: Primary ES of the kidney is a rare and lethal entity. Due to overwhelming rarity, chemotherapy protocol has not been standardised and followed as ES in bone/soft tissue. Histopathological confirmation and prompt initiation of treatment may improve patient survival and outcome.

Insert devices for faecal incontinence.

BACKGROUND: Faecal incontinence (FI) affects 1-19% of the general population and carries significant physical and psychological morbidity. Treatment strategies vary greatly with respect to morbidity and efficacy and relatively little is known regarding the role of mechanical devices such as anal and vaginal inserts. This is an up-to-date systematic review of the use of these devices in the management of patients with FI. METHODS: A systematic electronic search was performed of the Medline, Pubmed and Embase databases using the key words and/or MeSH 'anal plug', 'anal insert', 'vaginal insert' and 'faecal incontinence'. Only articles that reported clinical outcomes for these devices for FI in the English language were included. Review articles were excluded to avoid duplication of data. RESULTS: Thirteen articles fulfilled the eligibility criteria. Two articles reported outcomes for the Eclipse vaginal insert and 11 articles reported on three types of anal inserts; the Coloplast 'Tulip' design (6), the Procon/ProTect device (2) and the Renew insert (3). When tolerated, both anal and vaginal inserts significantly improved continence, bowel function and quality of life where reported. Adverse effects included discomfort, leakage and slippage. Long-term compliance and benefit are yet to be determined. CONCLUSIONS: Vaginal and anal inserts may be a useful treatment for FI. Better quality of evidence is needed to define its effectiveness.

Negative pressure therapy for stoma closure sites-a nonrandomised case control study.

AIM: The PICO (Smith & Nephew, UK) dressing is a single use negative pressure wound therapy (NPWT) system that is designed to be used for up to 7 days for closed wounds. We aimed to assess its use for stoma closure wounds. METHOD: We conducted a retrospective analysis of stoma reversal wounds from April 2018 to June 2019. The wound was partially closed with an absorbable subcutaneous suture in a purse-string fashion. A 15 cm × 15 cm PICO dressing was applied directly over this wound. A control group who had received partial purse string closure with packing over the same time period was identified. Patients were contacted and information collected using a questionnaire. The primary outcome measure was the number of visits for dressing changes in the community. Further information was collected about length of stay, time to resolution of pain and return to work. RESULTS: On average, the patients with PICO dressings attended the community nurses 1.9 times. The patients in the PICO group stated it took 1-2 weeks to return to full work/daily activities. The control group averaged attending the community nurse 11.9 times, and 33% had not returned to work/daily activities in 1-2 weeks. CONCLUSION: Those who had a PICO dressing required fewer visits to the community nurse and the majority were able to return to work or resume usual activities within 1 to 2 weeks. This pilot study suggests that negative pressure dressings may be a useful aid for stoma closure site wounds.

Pregnancy outcomes in women with primary biliary cholangitis and primary sclerosing cholangitis: a retrospective cohort study.

OBJECTIVE: To determine maternal, obstetric and neonatal outcomes in a cohort of women with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). DESIGN: Retrospective cohort study. SETTING: Ten specialist centres managing pregnant women with liver disease. POPULATION: Women with a diagnosis of PBC and PSC and a pregnancy of ≥20 completed weeks of gestation. METHODS: Retrospective case notes review. MAIN OUTCOME MEASURES: Adverse outcomes were defined as: maternal - development of ascites, variceal bleeding, encephalopathy and jaundice; obstetric events - gestational hypertension, pre-eclampsia and postpartum haemorrhage; and neonatal - stillbirth, preterm delivery and admission to neonatal unit. The relationship of alanine transferase (ALT) and bile acid levels with gestation at delivery was studied. RESULTS: The first recorded pregnancies of 34 women with PSC and 27 women with PBC were analysed. There were 60 live births and one intrapartum stillbirth that did not occur in the context of maternal cholestasis. The overall median gestation of delivery was 38 weeks but the rate of preterm birth was 28% (17/61 deliveries), 76% (13/17) of which were spontaneous. Gestation at birth negatively correlated with maternal serum ALT concentration at booking (P = 0.017) and serum bile acid concentration during pregnancy (P = 0.016). There were no other significant correlations and maternal and neonatal outcomes were good. CONCLUSIONS: Pregnancy in PBC and PSC is well tolerated, but women should be counselled regarding the increased risk of preterm birth. Measurement of maternal ALT and bile acids may help identify women at risk of preterm delivery. TWEETABLE ABSTRACT: Pregnancy in women with PBC and PSC is well tolerated; however, rates of preterm birth are high and are related to maternal bile acid levels.

Analysis of HLA-G expression in renal tissue in lupus nephritis: a pilot study.

BACKGROUND: The study aimed to investigate whether HLA-G antigen is expressed in the kidneys of patients affected by lupus nephritis (LN) and whether its detection in renal biopsies could be adopted as a marker of treatment response and prognosis. METHODS: Thirty renal biopsies from patients with LN were selected and analyzed through immunohistochemistry. Laboratory and clinical data were retrospectively collected at baseline, 6 and 12 months and at the latest clinical appointment. A number of patients (63.3%) were treated with rituximab (RTX) +/- methylprednisolone in the induction phase. The expression of HLA-G in glomeruli, tubules and infiltrating cells was examined and compared between lupus patients who achieved either complete or partial renal response and those who did not respond to treatment. RESULTS: HLA-G staining was observed in the glomeruli of 20 of 30 samples from patients with LN. The expression of the antigen was detected in podocytes, along glomerular capillary walls, on parietal glomerular epithelial cells and within the juxtaglomerular apparatus. Seventy per cent of patients whose glomeruli expressed HLA-G achieved partial or complete response at 6 months and 75% at the latest available follow up compared with 30% and 40%, respectively, of those who did not show any expression. The pattern of staining in tubules and infiltrating cells was highly variable precluding any clinical correlation. CONCLUSION: This study demonstrates that HLA-G is expressed in renal tissue in LN. Our retrospective data suggest that its expression could correlate with response to treatment.

The impact of ileal pouch-anal anastomosis on graft survival following liver transplantation for primary sclerosing cholangitis.

BACKGROUND: Liver transplantation is the only life-extending intervention for primary sclerosing cholangitis (PSC). Given the co-existence with colitis, patients may also require colectomy; a factor potentially conferring improved post-transplant outcomes. AIM: To determine the impact of restorative surgery via ileal pouch-anal anastomosis (IPAA) vs retaining an end ileostomy on liver-related outcomes post-transplantation. METHODS: Graft survival was evaluated across a prospectively accrued transplant database, stratified according to colectomy status and type. RESULTS: Between 1990 and 2016, 240 individuals with PSC/colitis underwent transplantation (cumulative 1870 patient-years until first graft loss or last follow-up date), of whom 75 also required colectomy. A heightened incidence of graft loss was observed for the IPAA group vs those retaining an end ileostomy (2.8 vs 0.4 per 100 patient-years, log-rank P = 0.005), whereas rates between IPAA vs no colectomy groups were not significantly different (2.8 vs 1.7, P = 0.1). In addition, the ileostomy group experienced significantly lower graft loss rates vs. patients retaining an intact colon (P = 0.044). The risks conferred by IPAA persisted when taking into account timing of colectomy as related to liver transplantation via time-dependent Cox regression analysis. Hepatic artery thrombosis and biliary strictures were the principal aetiologies of graft loss overall. Incidence rates for both were not significantly different between IPAA and no colectomy groups (P = 0.092 and P = 0.358); however, end ileostomy appeared protective (P = 0.007 and 0.031, respectively). CONCLUSION: In PSC, liver transplantation, colectomy + IPAA is associated with similar incidence rates of hepatic artery thrombosis, recurrent biliary strictures and re-transplantation compared with no colectomy. Colectomy + end ileostomy confers more favourable graft outcomes.

Melatonin modulated autophagy and Nrf2 signaling pathways in mice with colitis-associated colon carcinogenesis.

Colon carcinogenesis is long known to be associated with ulcerative colitis (UC), a chronic gastrointestinal disorder. Various pre-clinical and clinical studies have shown that melatonin (MEL) has beneficial effects in cancer. However, elucidation of the detailed molecular mechanisms involved in MEL-mediated protection against the colon carcinogenesis deserves further investigation. The present study was aimed at deciphering the effect of MEL on autophagy and Nrf2 signaling pathways in a mouse model of colitis-associated colon carcinogenesis (CACC). For the induction of CACC, male Swiss Albino mice were administered a single ip injection of 20 mg 1, 2-dimethylhydrazine dihydrochloride (DMH)/kg bw, followed by 3 cycles of 3% w/v dextran sulfate sodium (DSS) in drinking water treatment initiated 1 wk after DMH injection. One week after the initiation of DSS treatment, MEL was administered at the dose of 1 mg/kg, bw, po for 8 and 18 wk. Mice were sacrificed at 10 and 20 wk after DMH injection. MEL treatment decreased the progression of CACC by down regulating the process of autophagy as revealed by the expression pattern of various autophagy markers such as Beclin-1, LC3B-II/LC3B-I ratio and p62. These findings were accompanied with the increased expression of Nrf2 and the associated antioxidant enzymes, NAD(P)H: quinone oxidoreductase (NQO-1) and heme oxygenase-1 (HO-1) in the colon of mice with CACC. MEL intervention reduced autophagy by ameliorating inflammation and oxidative stress in the colon of mice with CACC. We conclude that MEL treatment attenuates the progression of CACC in mice by modulating autophagy and Nrf2 signaling pathways.

Mechanistic insight into beta-carotene-mediated protection against ulcerative colitis-associated local and systemic damage in mice.

PURPOSE: Ulcerative colitis (UC), a chronic gastrointestinal disorder, is a debilitating disease affecting many people across the globe. Research suggests that the levels of several antioxidants, including ß-carotene (ß-CAR), decrease in the serum of patients with UC. The present study was aimed at elucidating the molecular mechanisms involved in ß-CAR-mediated protection against UC in mice. METHODS: UC was induced in mice using 3%w/v dextran sulfate sodium in drinking water for two cycles; one cycle comprised of 7 days of dextran sulfate sodium-treated water followed by 14 days of normal drinking water. ß-CAR was administered at the doses of 5, 10 and 20 mg/kg bw/day, po throughout the experiment. The effect of ß-CAR in mice with UC was evaluated using biochemical parameters, histological evaluation, comet and micronucleus assays, immunohistochemistry and Western blot analysis. RESULTS: The results indicated that ß-CAR treatment ameliorated the severity of UC by modulating various molecular targets such as nuclear factor-kappa B, cyclooxygenase-2, interleukin 17, signal transducer and activator of transcription 3, nuclear erythroid 2-related factor 2, matrix metalloproteinase-9 and connective tissue growth factor. Further, ß-CAR treatment maintained the gut integrity by increasing the expression of a tight junction protein, occludin, which was decreased in the colon of mice with UC. Also ß-CAR treatment significantly reduced UC-associated elevated plasma lipopolysaccharide level, systemic inflammation and genotoxicity. CONCLUSION: ß-CAR ameliorated UC-associated local and systemic damage in mice by acting on multiple targets.

Dextran sulfate sodium-induced ulcerative colitis leads to testicular toxicity in mice: Role of inflammation, oxidative stress and DNA damage.

Ulcerative colitis is associated with an alteration in gonadal hormones and affects testicular weight in rodents. However, association of ulcerative colitis with testicular damage is not clearly known. Ulcerative colitis was induced using 5% (w/v) dextran sulfate sodium in normal drinking water for 1, 7-day cycle in short-term study and 2.5% (w/v) dextran sulfate sodium in normal drinking water for 4 cycles with 2 weeks remission period between each cycle in long-term study. Ulcerative colitis was associated with a significant increase in inflammation, oxidative stress, DNA damage in testes and sperm DNA damage and a significant decrease in the epididymal sperm count and 3ß-HSD expression. No difference was observed in the plasma testosterone levels between control and treatment groups. In the present study, ulcerative colitis was associated with testicular damage, and juvenile mice were found to be more sensitive than adult mice.

Withaferin A: a proteasomal inhibitor promotes healing after injury and exerts anabolic effect on osteoporotic bone.

Withania somnifera or Ashwagandha is a medicinal herb of Ayurveda. Though the extract and purified molecules, withanolides, from this plant have been shown to have different pharmacological activities, their effect on bone formation has not been studied. Here, we show that one of the withanolide, withaferin A (WFA) acts as a proteasomal inhibitor (PI) and binds to specific catalytic ß subunit of the 20S proteasome. It exerts positive effect on osteoblast by increasing osteoblast proliferation and differentiation. WFA increased expression of osteoblast-specific transcription factor and mineralizing genes, promoted osteoblast survival and suppressed inflammatory cytokines. In osteoclast, WFA treatment decreased osteoclast number directly by decreasing expression of tartarate-resistant acid phosphatase and receptor activator of nuclear factor kappa-B (RANK) and indirectly by decreasing osteoprotegrin/RANK ligand ratio. Our data show that in vitro treatment of WFA to calvarial osteoblast cells decreased expression of E3 ubiquitin ligase, Smad ubiquitin regulatory factor 2 (Smurf2), preventing degradation of Runt-related transcription factor 2 (RunX2) and relevant Smad proteins, which are phosphorylated by bone morphogenetic protein 2. Increased Smurf2 expression due to exogenous treatment of tumor necrosis factor α (TNFα) to primary osteoblast cells was decreased by WFA treatment. This was corroborated by using small interfering RNA against Smurf2. Further, WFA also blocked nuclear factor kappa-B (NF-kB) signaling as assessed by tumor necrosis factor stimulated nuclear translocation of p65-subunit of NF-kB. Overall data show that in vitro proteasome inhibition by WFA simultaneously promoted osteoblastogenesis by stabilizing RunX2 and suppressed osteoclast differentiation, by inhibiting osteoclastogenesis. Oral administration of WFA to osteopenic ovariectomized mice increased osteoprogenitor cells in the bone marrow and increased expression of osteogenic genes. WFA supplementation improved trabecular micro-architecture of the long bones, increased biomechanical strength parameters of the vertebra and femur, decreased bone turnover markers (osteocalcin and TNFα) and expression of skeletal osteoclastogenic genes. It also increased new bone formation and expression of osteogenic genes in the femur bone as compared with vehicle groups (Sham) and ovariectomy (OVx), Bortezomib (known PI), injectible parathyroid hormone and alendronate (FDA approved drugs). WFA promoted the process of cortical bone regeneration at drill-holes site in the femur mid-diaphysis region and cortical gap was bridged with woven bone within 11 days of both estrogen sufficient and deficient (ovariectomized, Ovx) mice. Together our data suggest that WFA stimulates bone formation by abrogating proteasomal machinery and provides knowledge base for its clinical evaluation as a bone anabolic agent.