Potassium channel dysfunction in human neuronal models of Angelman syndrome

Disruptions in the ubiquitin protein ligase E3A (UBE3A) gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases

'Isolated' left ventricular diastolic dysfunction - The condition need to be redefined

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Observed performance of a short diaphragm wall panel

The construction in Hong Kong of a 40 m deep excavated, large, rectangular-section barrette (i.e, a short diaphragm wall panel, 2.8 m long by 0.8 m wide) in sedimentary and weathered soils under bentonite has been heavily instrumented and closely monitored. During excavation, the maximum measured horizontal ground movements were only a few millimetres,,vith similar subsurface settlements around the panel. On the basis of three-dimensional numerical simulations of the excavation of the trench, an average mobilized shear strain greater than 0.1\% around the excavated trench can be deduced, At the soil-wall interface, the initial lateral earth pressures decreased to hydrostatic bentonite pressures during excavation and increased above their initial K-0 pressures after concreting. The measured lateral pressures just after concreting support a theoretical bilinear pressure envelope

Field studies of well-instrumented barrette in Hong Kong

A large excavated rectangular pile (barrette) with lateral earth pressure and pore-water pressure cells was successfully constructed and tested in a sequence of marine, alluvial, and weathered granite soils. A ``soft'' base formed beneath the bottom of the barrette permitted over 100 mm of Vertical settlement, completely mobilizing the shaft friction at the barrette-soil interface. During the vertical load tests, an unusual and complex response of pore-water pressures and earth pressures at the barrette-soil interface was measured. During each vertical loading cycle (except the last one) and before interface slippage of the barrette occurred, excess positive pore-water pressures were recorded in all soil layers. Upon the initiation of slip at the barrette-soil interface, a sudden drop in the measured pore pressures as well as a substantial drop in lateral earth pressures generally resulted. Subsequent loading or unloading slippage events did not show the same dramatic behavior unless a period of consolidation/recovery was allowed first. This implies that caution must be used in design of barrettes relying heavily on skin friction when shearing induces contractive soil behavior. The current test results indicated that the empirical uncorrected SPT-N value approach and the effective stress beta-method were inconsistent

Relation of aspirin resistance to coronary flow reserve in patients undergoing elective percutaneous coronary Intervention

Previous studies have shown that more complete platelet inhibition improves the coronary flow reserve (CFR), a measure of microvascular integrity, in patients undergoing percutaneous coronary intervention (PCI). We hypothesized that patients with aspirin resistance would have impaired CFR after elective PCI. We used VerifyNow Aspirin to determine the response to aspirin in 117 consecutive patients who underwent elective single-lesion PCI. The assay results are expressed quantitatively in Aspirin Reaction Units based on the degree of platelet aggregation. All patients received a 300-mg loading dose of clopidogrel >12 hours before and a 75-mg maintenance dose the morning of PCI. CFR was estimated using the Thrombolysis In Myocardial Infarction frame count method. Of the 117 patients, 22 (18.8%) were aspirin resistant. The clinical, angiographic, and procedural characteristics of the aspirin-sensitive and -resistant patients were balanced. All patients underwent successful PCI with <50% residual diameter stenosis and Thrombolysis In Myocardial Infarction grade 3 flow after PCI. Aspirin-resistant patients had a lower CFR than the aspirin-sensitive patients (1.42 ± 0.35 vs 1.80 ± 0.64, p = 0.018). Univariate correlates of CFR included the Aspirin Reaction Unit (r = -0.227, p = 0.014) and post-PCI creatine kinase-MB elevation (p = 0.048). Multivariate linear regression analysis revealed the Aspirin Reaction Unit to be the only independent determinant of CFR after PCI (r2 = 0.051, p = 0.014). Thus, aspirin resistance was associated with impaired CFR in patients who underwent elective PCI, implicating insufficient aspirin-induced platelet inhibition as a cause of microvascular dysfunction by distal atherothrombotic embolization and/or spasm. © 2005 Elsevier Inc. All rights reserved.link_to_subscribed_fulltex

Macrophage inhibitory cytokine-1/growth differentiation factor-15 as a predictor of colonic neoplasia

Background: Serum macrophage inhibitory cytokine-1 (MIC-1/GDF15) concentration has been associated with colonic adenomas and carcinoma. Aims: To determine whether circulating MIC-1/GDF15 serum concentrations are higher in the presence of adenomas and whether the level decreases after excision. Methods: Patients were recruited prospectively from a single centre and stratified into five groups: no polyps (NP); hyperplastic polyps (HP); sessile serrated ademona (SSA); adenomas (AP); and colorectal carcinoma (CRC). Blood samples were collected immediately before and 4 weeks after colonoscopy. MIC-1/GDF15 serum levels were quantified using ELISA. Results: Participants (n=301) were stratified as: NP; n=116 (52%), HP; n=37 (12%), SSA; n=19 (7%), AP; n=68 (23%); and CRC; n=3 (1%). Patients were excluded from the study due to nondiagnostic pathology (n=9, 3%) and exclusion criteria (n=20, 6%). In the 272 remaining subjects (M=149; F=123), age (P=.005), history of colonic polyps (P=.003) and family history of colonic polyps (P=.002) were associated with presence of adenomas. Baseline median MIC-1/GDF15 serum levels increased significantly from NP 609 (460-797) pg/mL, HP 582 (466-852) pg/mL, SSA 561 (446-837) pg/mL to AP 723 (602-1122) pg/mL and CRC 1107 (897-1107) pg/mL; (P<.001). In the pre- and postpolypectomy paired adenoma samples median MIC-1/GDF15 reduced significantly from 722 (603-1164) pg/mL to 685 (561-944) pg/mL (P=.002). A ROC analysis for serum MIC-1/GDF15 to identify adenomatous polyps indicated an area under the curve of 0.71. Conclusions: Our data suggest that serum MIC-1/GDF15 has the diagnostic characteristics to increase the detection of colonic neoplasia and improve screening

Choline transporter: an additional marker of cholinergic nerves in the enteric nervous system

Purpose: The cholinergic circuitry of the enteric nervous system (ENS) is labelled using antibodies against molecules involved in acetylcholine (ACh) synthesis and release. A new component of ACh synthesis, the high affinity choline transporter (CHT), which is essential in the uptake of choline into cholinergic nerves, has been isolated and cloned. Recently, antiserum against CHT has been used in the central nervous system to label cholinergic nerves, but has not been located in the ENS. The aim of this study was to localise CHT immunoreactivity (IR) within rat and human intestine and determine if CHT colocalised with other cholinergic markers in the ENS. Methods: Segments of rat (n = 3) ileum and colon and human paediatric (n = 3) colon were fixed, prepared for sections and wholemounts and incubated with antisera against the full length human CHT sequence, followed by a fluorescent secondary antibody. Tissue was double labelled using antibodies to neuronal nitric oxide synthase (nNOS), common choline acetyltransferase (cChAT), substance P (SP) and vesicular acetylcholine transporter (VAChT). Colocalisation was quantitated in 3 confocal images from each segment. Results: In human and rat intestine, CHT-IR was present in nerve fibres in the circular muscle and myenteric ganglia and in myenteric nerve cell bodies. In human colon, CHT-IR was present in almost all VAChT-IR cholinergic nerve fibres in the circular muscle and myenteric ganglia. In contrast, in the rat only 56% of circular muscle VAChT-IR nerve fibres were CHT-IR, with this accounting for 79% of CHT-IR nerve fibres. In the myenteric ganglia, 48% of VAChT-IR nerve fibres were CHT-IR, accounting for 50% of CHT-IR nerve fibres. Surprisingly, no CHT-IR nerve cell bodies were cChAT-IR. Yet, 40% of CHT-IR nerve cell bodies were SP-IR (tachykinergic), accounting for 12% of SP-IR nerve cell bodies. In both species, there was little localisation of CHT-IR in nitrergic NOSIR inhibitory nerve fibres. Conclusions: In human paediatric colon, there was almost complete colocalisation of CHT-IR and VAChT-IR in nerve fibres in the circular muscle and myenteric ganglia. Therefore the CHT antisera would be useful for studying the enteric cholinergic circuitry in human intestine and complimentary to currently used labels. In rat, CHT-IR identified VAChT-IR positive, VAChT-IR negative nerve fibres and cChAT-IR negative cell bodies. This result suggests the antibody does not bind to all the cholinergic circuitry identified by cChAT-IR or VAChT-IR. Further studies are needed to determine if the CHT antibody is specifically labelling cholinergic nerves in the rat.Andrea M. Harrington, Margaret Lee, Sim-Yee Ong, Eric Yong, Pam Farmer, John M. Hutson and Bridget R. Southwel

Patients with coronary artery disease had high prevalanece of colorectal cancer and adenoma: END-results of metabolic syndrome and smoking

Background: Our previous study showed an association between colorectal neoplasm (CN) and coronary artery disease (CAD), probably due to sharing of common risk factors. Aim: To investigate the prevalence of CN in patients with and without CAD in those aged ≥50 years prospectively and to identify the underlying risk factors. Methods: Patients were recruited for screening colonoscopy after undergoing coronary angiography. They were defined as CAD+ (n=206) if ≥50% diameter stenosis was observed in any one of the major coronary arteries, and CAD- (n=208) if not. A second age and sex matched control group was recruited from the general population (n=207). The prevalence of colonic lesions and underlying risk factors was compared by Pearson chi-square test. A bivariate logistic regression analysis was performed to adjust for age and sex and to identify independent risk factors. Results: The prevalence of the lesions in the CAD+, CAD- and general population group were 40.3%, 28.8%, and 32.9% (p=0.045) for endoscopic polyp, 34.0%, 18.8%, and 20.8% (p<0.0001) for CN, 18.4%, 8.7%, and 5.8% (p<0.00001) for advanced lesion, and 4.4%, 0.5%, and 1.4% (p=0.014) for cancer, respectively. All except one cancers were detected at early stage. After adjusting for age and sex, smoking history (OR: 4.74, CI: 1.38 to 19) and metabolic syndrome (OR: 5.99; CI: 1.43 to 28.0) were independent factors for the coexistence of CAD and advanced lesion. Conclusion: Life style modification is important to prevent the development of both CAD and advanced colonic lesions simultaneously. CAD+ is a surrogate marker for high prevalence of CN, necessitating immediate colonoscopy screening.link_to_subscribed_fulltex