The minimal incubation period from the onset of Barrett's oesophagus to symptomatic adenocarcinoma

Background:The interval between the onset of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) can be termed the incubation period. However, the unrecorded onset of BO precludes its direct observation.Methods:Determining the range of intervals between BO diagnosis and OAC within the longest observational BO follow-up study. Exclusion criteria were presence of high-grade dysplasia (HGD) or OAC at baseline, death within <2 years of BO diagnosis, oesophagectomy without HGD/OAC and loss to follow-up. A total of 133 patients (M/F 73/60) were taken into account.Results:In 1967 person years of follow-up there were 13 cases of HGD/OAC, (0.66% p.a.; 95% CI 0.58-0.74), 96 patients died without HGD/OAC and 24 survived without HGD/OAC. The mean intervals between BO diagnosis and either HGD/OAC, death or end of follow-up were 10.8, 12.6 and 25.5 years, respectively, and the mean ages at endpoint were 72.5, 80.0 and 68.3 years, respectively. The survivors without HGD/OAC had a lower age at BO diagnosis (mean 42.8 vs 61.2 and 67.4 years, P=0.001). Baseline presence of low-grade dysplasia was associated with progression to HGD/OAC (log rank P=0.001).Conclusion:The Rotterdam BO follow-up cohort revealed a long incubation period between onset of BO and development of HGD/OAC, in patients without HGD/OAC at baseline as illustrated by 24 patients diagnosed with BO at a young age and followed for a mean period of 25.5 years. Their tumour-free survival established a minimum incubation period, suggesting a true incubation period of three decades or more

Portal Embolisation as Treatment of Severe Portal Hypertension Due to Idiopathic Intrahepatic Arterioportal Fistula:A Case Report

Intrahepatic arterioportal fistula (IAPF) is a rare cause of portal hypertension. Treatment is usually aimed at restoring the normal portal hemodynamics by obliterating the shunt. This report describes a case of idiopathic IAPF with severe portal hypertension complicated by portal enteropathy with vomiting, gastrointestinal hemorrhage and sepsis. The patient was successfully treated with portal embolization.</p

Outflow obstruction after living donor liver transplantation managed with a temporary vena cava filter:A case report

Introduction: Outflow obstruction is a rare but critical vascular complication in liver transplantation, which may lead to graft loss and mortality. We report a case of caval vein outflow obstruction due to retrohepatic compression after living donor liver transplantation (LDLT), which was managed by temporary implantation of a vena cava filter. Presentation of case: A 63-year-old male with end stage liver disease presented with caval vein outflow obstruction and massive ascites 12 days after right lobe LDLT. We opted for a minimally invasive approach and implanted a vena cava filter at the compressed site through transjugular route. The patient's ascites drainage significantly decreased and graft function maintained stable after the intervention. On day 50 posttransplant, the filter was successfully removed and the patient was discharged without complications. Discussion: Outflow obstruction after liver transplantation can result from anastomotic stenosis, graft size mismatch, thrombosis or compression of the outflow tract. Various management strategies have been employed both peri- and posttransplant, ranging from surgical interventions to minimally-invasive techniques. The treatment strategy should be tailored to the individual case, considering the timing of presentation and the specific cause for the obstruction. Conclusion: We successfully managed a case of compressive outflow obstruction by temporary implantation of a vena cava filter after LDLT. The vena cava filter was safely removed under angiography.</p

Characterisation of the TBR1 interactome: variants associated with neurodevelopmental disorders disrupt novel protein interactions

TBR1 is a neuron-specific transcription factor involved in brain development and implicated in a neurodevelopmental disorder (NDD) combining features of autism spectrum disorder (ASD), intellectual disability (ID) and speech delay. TBR1 has been previously shown to interact with a small number of transcription factors and co-factors also involved in NDDs (including CASK, FOXP1/2/4 and BCL11A), suggesting that the wider TBR1 interactome may have a significant bearing on normal and abnormal brain development. Here we have identified approximately 250 putative TBR1-interaction partners by affinity purification coupled to mass spectrometry. As well as known TBR1-interactors such as CASK, the identified partners include transcription factors and chromatin modifiers, along with ASD- and ID-related proteins. Five interaction candidates were independently validated using bioluminescence resonance energy transfer assays. We went on to test the interaction of these candidates with TBR1 protein variants implicated in cases of NDD. The assays uncovered disturbed interactions for NDD-associated variants and identified two distinct protein-binding domains of TBR1 that have essential roles in protein–protein interaction

The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour

Members of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with multiple neurodevelopmental disorders, although their exact roles in disease remain unclear. For example, nuclear receptor coactivator 7 (NCOA7) has been associated with autism, although almost nothing is known regarding the mode-of-action of this TLDc protein in the nervous system. Here we investigated the molecular function of NCOA7 in neurons and generated a novel mouse model to determine the consequences of deleting this locus in vivo. We show that NCOA7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase in the brain and demonstrate that this protein is required for normal assembly and activity of this critical proton pump. Neurons lacking Ncoa7 exhibit altered development alongside defective lysosomal formation and function; accordingly, Ncoa7 deletion animals exhibited abnormal neuronal patterning defects and a reduced expression of lysosomal markers. Furthermore, behavioural assessment revealed anxiety and social defects in mice lacking Ncoa7. In summary, we demonstrate that NCOA7 is an important V-ATPase regulatory protein in the brain, modulating lysosomal function, neuronal connectivity and behaviour; thus our study reveals a molecular mechanism controlling endolysosomal homeostasis that is essential for neurodevelopment

On subsequential spaces

AbstractSimple generators for the coreflective category of subsequential spaces, one of them countable, are constructed. Every such must have subsequential order ω1. Subsequentialness is a local property and a countable property, both in a strong sense. A T2-subsequential space may be pseudocompact without being sequential, in contrast to T2-subsequential compact (countably compact, sequentially compact) spaces all being sequential. A compact subsequential space need not be sequential

The Yield of Routine Post-Operative Doppler Ultrasound to Detect Early Post-Liver Transplantation Vascular Complications

Early detection of liver transplantation (LT) vascular complications enables timely management. Our aim was to assess if routine Doppler ultrasound (rDUS) improves the detection of hepatic artery thrombosis (HAT), portal vein thrombosis (PVT) and hepatic venous outflow obstruction (HVOO). We retrospectively analysed timing and outcomes, number needed to diagnose one complication (NND) and positive predictive value (PPV) of rDUS on post-operative day (POD) 0,1 and 7 in 708 adult patients who underwent primary LT between 2010–2022. We showed that HAT developed in 7.1%, PVT in 8.2% and HVOO in 3.1% of patients. Most early complications were diagnosed on POD 0 (26.9%), 1 (17.3%) and 5 (17.3%). rDUS correctly detected 21 out of 26 vascular events during the protocol days. PPV of rDUS was 53.8%, detection rate 1.1% and NND was 90.5. Median time to diagnosis was 4 days for HAT and 47 days for PVT and 21 days for HVOO. After intervention, liver grafts were preserved in 57.1%. In conclusion, rDUS protocol helps to detect first week’s vascular events, but with low PPV and a high number of ultrasounds needed.</p

Induced pluripotent stem cells from subjects with Lesch-Nyhan disease

Lesch-Nyhan disease (LND) is an inherited disorder caused by pathogenic variants in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine–guanine phosphoribosyltransferase (HGprt). We generated 6 induced pluripotent stem cell (iPSC) lines from 3 individuals with LND, along with 6 control lines from 3 normal individuals. All 12 lines had the characteristics of pluripotent stem cells, as assessed by immunostaining for pluripotency markers, expression of pluripotency genes, and differentiation into the 3 primary germ cell layers. Gene expression profiling with RNAseq demonstrated significant heterogeneity among the lines. Despite this heterogeneity, several anticipated abnormalities were readily detectable across all LND lines, including reduced HPRT1 mRNA. Several unexpected abnormalities were also consistently detectable across the LND lines, including decreases in FAR2P1 and increases in RNF39. Shotgun proteomics also demonstrated several expected abnormalities in the LND lines, such as absence of HGprt protein. The proteomics study also revealed several unexpected abnormalities across the LND lines, including increases in GNAO1 decreases in NSE4A. There was a good but partial correlation between abnormalities revealed by the RNAseq and proteomics methods. Finally, functional studies demonstrated LND lines had no HGprt enzyme activity and resistance to the toxic pro-drug 6-thioguanine. Intracellular purines in the LND lines were normal, but they did not recycle hypoxanthine. These cells provide a novel resource to reveal insights into the relevance of heterogeneity among iPSC lines and applications for modeling LND