White matter hyperintensity genetic risk factor TRIM47 regulates autophagy in brain endothelial cells.

White matter hyperintensity (WMH) is strongly correlated with age-related dementia and hypertension, but its pathogenesis remains obscure. GWAS identified TRIM47 at 17q25 locus as a top genetic risk factor for WMH formation. TRIM family is a class of E3 ubiquitin ligase with pivotal functions in autophagy, which is critical for brain endothelial cell (ECs) remodeling during hypertension. We hypothesize that TRIM47 regulates autophagy and its loss-of-function disturbs cerebrovasculature. Based on transcriptomics and immunohistochemistry, TRIM47 is found selectively expressed by brain ECs in human and mouse, and its transcription is upregulated by artificially-induced autophagy while downregulated in hypertension-like conditions. Using in silico simulation, immunocytochemistry and super-resolution microscopy, we identified the highly conserved binding site between TRIM47 and the LIR (LC3-interacting region) motif of LC3B. Importantly, pharmacological autophagy induction increased Trim47 expression on mouse ECs (b.End3) culture, while silencing Trim47 significantly increased autophagy with ULK1 phosphorylation induction, transcription and vacuole formation. Together, we confirm that TRIM47 is an endogenous inhibitor of autophagy in brain ECs, and such TRIM47-mediated regulation connects genetic and physiological risk factors for WMH formation but warrants further investigation. SUMMARY STATEMENT: TRIM47, top genetic risk factor for white matter hyperintensity formation, is a negative regulator of autophagy in brain endothelial cells and implicates a novel cellular mechanism for age-related cerebrovascular changes.

Curriculum for training in endoscopic mucosal resection in the colon: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement.

Endoscopic mucosal resection (EMR) is the standard of care for the complete removal of large (≥ 10 mm) nonpedunculated colorectal polyps (LNPCPs). Increased detection of LNPCPs owing to screening colonoscopy, plus high observed rates of incomplete resection and need for surgery call for a standardized approach to training in EMR. 1 : Trainees in EMR should have achieved basic competence in diagnostic colonoscopy, < 10-mm polypectomy, pedunculated polypectomy, and common methods of gastrointestinal endoscopic hemostasis. The role of formal training courses is emphasized. Training may then commence in vivo under the direct supervision of a trainer. 2 : Endoscopy units training endoscopists in EMR should have specific processes in place to support and facilitate training. 3: A trained EMR practitioner should have mastered theoretical knowledge including how to assess an LNPCP for risk of submucosal invasion, how to interpret the potential difficulty of a particular EMR procedure, how to decide whether to remove a particular LNPCP en bloc or piecemeal, whether the risks of electrosurgical energy can be avoided for a particular LNPCP, the different devices required for EMR, management of adverse events, and interpretation of reports provided by histopathologists. 4: Trained EMR practitioners should be familiar with the patient consent process for EMR. 5: The development of endoscopic non-technical skills (ENTS) and team interaction are important for trainees in EMR. 6: Differences in recommended technique exist between EMR performed with and without electrosurgical energy. Common to both is a standardized technique based upon dynamic injection, controlled and precise snare placement, safety checks prior to the application of tissue transection (cold snare) or electrosurgical energy (hot snare), and interpretation of the post-EMR resection defect. 7: A trained EMR practitioner must be able to manage adverse events associated with EMR including intraprocedural bleeding and perforation, and post-procedural bleeding. Delayed perforation should be avoided by correct interpretation of the post-EMR defect and treatment of deep mural injury. 8: A trained EMR practitioner must be able to communicate EMR procedural findings to patients and provide them with a plan in case of adverse events after discharge and a follow-up plan. 9: A trained EMR practitioner must be able to detect and interrogate a post-endoscopic resection scar for residual or recurrent adenoma and apply treatment if necessary. 10: Prior to independent practice, a minimum of 30 EMR procedures should be performed, culminating in a trainer-guided assessment of competency using a validated assessment tool, taking account of procedural difficulty (e. g. using the SMSA polyp score). 11: Trained practitioners should log their key performance indicators (KPIs) of polypectomy during independent practice. A guide for target KPIs is provided in this document.

Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte-derived lipid transport.

Carriers of the APOE4 (apolipoprotein E ε4) variant of the APOE gene are subject to several age-related health risks, including Alzheimer's disease (AD). The deficient lipid and cholesterol transport capabilities of the APOE4 protein are one reason for the altered risk profile. In particular, APOE4 carriers are at elevated risk for sporadic AD. While deposits o misfolded proteins are present in the AD brain, white matter (WM) myelin is also disturbed. As myelin is a lipid- and cholesterol-rich structure, the connection to APOE makes considerable biological sense. To explore the APOE-WM connection, we have analyzed the impact of human APOE4 on oligodendrocytes (OLs) of the mouse both in vivo and in vitro. We find that APOE proteins is enriched in astrocytes but sparse in OL. In human APOE4 (hAPOE4) knock-in mice, myelin lipid content is increased but the density of major myelin proteins (MBP, MAG, and PLP) is largely unchanged. We also find an unexpected but significant reduction of cell density of the OL lineage (Olig2+ ) and an abnormal accumulation of OL precursors (Nkx 2.2+ ), suggesting a disruption of OL differentiation. Gene ontology analysis of an existing RNA-seq dataset confirms a robust transcriptional response to the altered chemistry of the hAPOE4 mouse brain. In culture, the uptake of astrocyte-derived APOE during Lovastatin-mediated depletion of cholesterol synthesis is sufficient to sustain OL differentiation. While endogenous hAPOE protein isoforms have no effects on OL development, exogenous hAPOE4 abolishes the ability of very low-density lipoprotein to restore myelination in Apoe-deficient, cholesterol-depleted OL. Our data suggest that APOE4 impairs myelination in the aging brain by interrupting the delivery of astrocyte-derived lipids to the oligodendrocytes. We propose that high myelin turnover and OL exhaustion found in APOE4 carriers is a likely explanation for the APOE-dependent myelin phenotypes of the AD brain.

Wide-field piecemeal cold snare polypectomy of large sessile serrated polyps without a submucosal injection is safe.

BACKGROUND AND STUDY AIMS : Large series suggest endoscopic mucosal resection is safe and effective for the removal of large (≥ 10 mm) sessile serrated polyps (SSPs), but it exposes the patient to the risks of electrocautery, including delayed bleeding. We examined the feasibility and safety of piecemeal cold snare polypectomy (pCSP) for the resection of large SSPs. METHODS: Sequential large SSPs (10 - 35 mm) without endoscopic evidence of dysplasia referred over 12 months to a tertiary endoscopy center were considered for pCSP. A thin-wire snare was used in all cases. Submucosal injection was not performed. High definition imaging of the defect margin was used to ensure the absence of residual serrated tissue. Adverse events were assessed at 2 weeks and surveillance was planned for between 6 and 12 months. RESULTS: 41 SSPs were completely removed by pCSP in 34 patients. The median SSP size was 15 mm (interquartile range [IQR] 14.5 - 20 mm; range 10 - 35 mm). The median procedure duration was 4.5 minutes (IQR 1.4 - 6.3 minutes). There was no evidence of perforation or significant intraprocedural bleeding. At 2-week follow-up, there were no significant adverse events, including delayed bleeding and post polypectomy syndrome. First follow-up has been undertaken for 15 /41 lesions at a median of 6 months with no evidence of recurrence. CONCLUSIONS: There is potential for pCSP to become the standard of care for non-dysplastic large SSPs. This could reduce the burden of removing SSPs on patients and healthcare systems, particularly by avoidance of delayed bleeding.

A standardized imaging protocol for the endoscopic prediction of dysplasia within sessile serrated polyps (with video).

BACKGROUND AND AIMS: Dysplasia within sessile serrated polyps (SSPs) is difficult to detect and may be mistaken for an adenoma, risking incomplete resection of the background serrated tissue, and is strongly implicated in interval cancer after colonoscopy. The use of endoscopic imaging to detect dysplasia within SSPs has not been systematically studied. METHODS: Consecutively detected SSPs ≥8 mm in size were evaluated by using a standardized imaging protocol at a tertiary-care endoscopy center over 3 years. Lesions suspected as SSPs were analyzed with high-definition white light then narrow-band imaging. A demarcated area with a neoplastic pit pattern (Kudo type III/IV, NICE type II) was sought among the serrated tissue. If this was detected, the lesion was labeled dysplastic (sessile serrated polyp with dysplasia); if not, it was labeled non-dysplastic (sessile serrated polyp without dysplasia). Histopathology was reviewed by 2 blinded specialist GI pathologists. RESULTS: A total of 141 SSPs were assessed in 83 patients. Median lesion size was 15.0 mm (interquartile range 10-20), and 54.6% were in the right side of the colon. Endoscopic evidence of dysplasia was detected in 36 of 141 (25.5%) SSPs; of these, 5 of 36 (13.9%) lacked dysplasia at histopathology. Two of 105 (1.9%) endoscopically designated non-dysplastic SSPs had dysplasia at histopathology. Endoscopic imaging, therefore, had an accuracy of 95.0% (95% confidence interval [CI], 90.1%-97.6%) and a negative predictive value of 98.1% (95% CI, 92.6%-99.7%) for detection of dysplasia within SSPs. CONCLUSIONS: Dysplasia within SSPs can be detected accurately by using a simple, broadly applicable endoscopic imaging protocol that allows complete resection. Independent validation of this protocol and its dissemination to the wider endoscopic community may have a significant impact on rates of interval cancer. (Clinical trial registration number: NCT03100552.).

Lesson of the month 2: a case of coma in a Parkinson's patient: a combination of fatigue, dehydration and high protein diet over the New Year period?

Although motor fluctuation can often be severe in Parkinson's disease (PD), it is rare for an 'off period' to result in coma. The case presented here is of a patient with longstanding PD who was admitted to our hospital with a Glasgow Coma Scale of three after missing just one or two doses of her medication. Investigation for infective, neurovascular and metabolic causes of coma were negative and the patient recovered very rapidly following reinstitution of dopaminergic therapy via nasogastric tube. This case highlights how florid the presentation of motor fluctuations in PD can be and the importance of restarting treatment as quickly as possible. Guidance is provided on how to administer dopaminergic medications in patients who are unable to swallow.

A case of Conn's syndrome revealed after oral sodium phosphate (Fleet) preparation for colonoscopy.

Oral sodium phosphate solutions (Fleet Mcneil Consumer Healthcare, Guelph, Ontario, Canada) are commonly used as bowel cleansing agents in preparation for colonoscopic exams; however, serious electrolyte disorders associated with oral sodium phosphate use have been described in case reports including hyperphosphatemia, hypocalcemia, hypomagnesemia, hypernatremia, and hypokalemia. We describe a 57-year-old patient with a past history of resistant hypertension who experienced severe symptomatic hypokalemia following colonic cleansing with an oral sodium phosphate solution. Further investigations revealed a serum aldosterone of 691 pmol/L and a serum renin level of 0.02 ng/L/s with a corresponding aldosterone-to-renin ration of 34550:1. The patient was subsequently diagnosed with primary aldosteronism secondary to an adenoma of the adrenal gland. Bilateral adrenal venous sampling revealed excessive levels of aldosterone in the left adrenal vein prior to definitive surgery. This case indicates that an oral sodium phosphate bowel preparation, though safe for most patients, can be complicated by a previously not diagnosed endocrine disease like the primary aldosteronism (Conn's syndrome) reported here. This is the first report of a Conn's syndrome diagnosed after bowel cleansing with a sodium phosphate solution.

Cardiac dysfunction in cirrhosis.

Cirrhosis is known to be associated with numerous cardiovascular abnormalities. These include increased cardiac output and decreased arterial pressure and total peripheral resistance. Despite this increased baseline cardiac output, patients with cirrhosis show an attenuated systolic and diastolic function in the face of pharmacological, physiological and surgical stresses, as well as cardiac electrical abnormalities such as QT prolongation. These abnormalities have been termed cirrhotic cardiomyopathy. The pathogenic mechanisms that underlie this syndrome include impairment of the beta-adrenergic receptor signalling, cardiomyocyte plasma membrane function, intracellular calcium kinetics, and humoral factors such as endogenous cannabinoids, nitric oxide and carbon monoxide. Cirrhotic cardiomyopathy is believed to contribute to the cardiac dysfunction that can be observed in patients with transjugular intrahepatic portosystemic stent-shunt insertion and liver transplantation. Insufficient cardiac contractile function may also play a role in the pathogenesis of hepatorenal syndrome precipitated by spontaneous bacterial peritonitis. In this review, the clinical features, pathogenic mechanisms, clinical consequences and management options for cirrhotic cardiomyopathy are discussed.