Type IIA2 urethral duplication: Report of an unusual case

Objective This report describes a rare case of type IIA2 sagittal urethral   duplication. Summary background data The presentation, investigation, and  management of this rare anomaly are briefly discussed.Methods A 3½-year-old boy presented with urinary obstruction and recurrent urinary tract infection due to a stenosed dorsal urethra and segmental stenosis of the dominant ventral urethra. The child also had left-sided vesicoureteric reflux. Staged surgical management consisted of an initial vesicostomy followed by serial dilatation of the ventral urethral stricture, left ureteric reimplantation, and a 2-cm long distal urethrourethrostomy between the dorsal urethra, opening at the tip of the penis, and the ventral urethra, which had a hypospadic opening at the base of the glans.Results The functional and cosmetic outcomes were satisfactory.Conclusion The management needs to be individualizedas best suited for the patient.Keywords: urethra, urethral duplication, urethral strictur

Type IIA2 urethral duplication: report of an unusual case

This report describes a rare case of type IIA2 sagittal urethral duplication. The presentation, investigation, and management of this rare anomaly are briefly discussed. A 3½-year-old boy presented with urinary obstruction and recurrent urinary tract infection due to a stenosed dorsal urethra and segmental stenosis of the dominant ventral urethra. The child also had left-sided vesicoureteric reflux. Staged surgical management consisted of an initial vesicostomy followed by serial dilatation of the ventral urethral stricture, left ureteric reimplantation, and a 2-cm long distal urethrourethrostomy between the dorsal urethra, opening at the tip of the penis, and the ventral urethra, which had a hypospadic opening at the base of the glans. The functional and cosmetic outcomes were satisfactory. The management needs to be individualized as best suited for the patient.Keywords: urethra, urethral duplication, urethral strictur

Interaction-driven giant thermopower in magic-angle twisted bilayer graphene

Magic-angle twisted bilayer graphene has proved to be a fascinating platform to realize and study emergent quantum phases arising from the strong correlations in its flat bands. Thermal transport phenomena, such as thermopower, are sensitive to the particle-hole asymmetry, making them a crucial tool to probe the underlying electronic structure of this material. Here we have carried out thermopower measurements of magic-angle twisted bilayer graphene as a function of carrier density, temperature and magnetic field. We report the observation of an unusually large thermopower reaching a value of the order of 100 mu V K-1 at a low temperature of 1 K. The thermopower exhibits peak-like features that violate the Mott formula in close correspondence to the resistance peaks appearing around the integer filling of the moire bands, including the Dirac point. We show that the large thermopower peaks and their associated behaviour arise from the emergent highly particle-hole-asymmetric electronic structure, due to the sequential filling of the moire flat bands and the associated recovery of Dirac-like physics. Furthermore, the thermopower shows an anomalous peak around the superconducting transition, which points towards the possible role of superconducting fluctuations in magic-angle twisted bilayer graphene. Thermal transport measurements provide a complementary view of the electronic structure of a material to electronic transport. This technique is applied to twisted bilayer graphene, and highlights the particle-hole asymmetry of its band structure

Resistivity due to a Domain Wall in Ferromagnetic Metal

The resistivity due to a domain wall in ferromagnetic metallic wire is calculated based on the linear response theory. The interaction between conduction electrons and the wall is expressed in terms of a classical gauge field which is introduced by the local gauge transformation in the electron spin space. It is shown that the wall contributes to the decoherence of electrons and that this quantum correction can dominate over the Boltzmann resisitivity, leading to a decrease of resisitivity by nucleation of a wall. The conductance fluctuation due to the motion of the wall is also investigated. The results are compared with recent experiments.Comment: 9 pages, 3 figure

Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer's disease

Tau deposition in the brain is a pathological hallmark of many neurodegenerative disorders, including Alzheimer’s disease (AD). During the course of these tauopathies, tau spreads throughout the brain via synaptically-connected pathways. Such propagation of pathology is thought to be mediated by tau species (“seeds”) containing the microtubule binding region (MTBR) composed of either three repeat (3R) or four repeat (4R) isoforms. The tau MTBR also forms the core of the neuropathological filaments identified in AD brain and other tauopathies. Multiple approaches are being taken to limit tau pathology, including immunotherapy with anti-tau antibodies. Given its key structural role within fibrils, specifically targetting the MTBR with a therapeutic antibody to inhibit tau seeding and aggregation may be a promising strategy to provide disease-modifying treatment for AD and other tauopathies. Therefore, a monoclonal antibody generating campaign was initiated with focus on the MTBR. Herein we describe the pre-clinical generation and characterisation of E2814, a humanised, high affinity, IgG1 antibody recognising the tau MTBR. E2814 and its murine precursor, 7G6, as revealed by epitope mapping, are antibodies bi-epitopic for 4R and mono-epitopic for 3R tau isoforms because they bind to sequence motif HVPGG. Functionally, both antibodies inhibited tau aggregation in vitro. They also immunodepleted a variety of MTBR-containing tau protein species. In an in vivo model of tau seeding and transmission, attenuation of deposition of sarkosyl-insoluble tau in brain could also be observed in response to antibody treatment. In AD brain, E2814 bound different types of tau filaments as shown by immunogold labelling and recognised pathological tau structures by immunohistochemical staining. Tau fragments containing HVPGG epitopes were also found to be elevated in AD brain compared to PSP or control. Taken together, the data reported here have led to E2814 being proposed for clinical developmen

PedHunter 2.0 and its usage to characterize the founder structure of the Old Order Amish of Lancaster County

<p>Abstract</p> <p>Background</p> <p>Because they are a closed founder population, the Old Order Amish (OOA) of Lancaster County have been the subject of many medical genetics studies. We constructed four versions of Anabaptist Genealogy Database (AGDB) using three sources of genealogies and multiple updates. In addition, we developed PedHunter, a suite of query software that can solve pedigree-related problems automatically and systematically.</p> <p>Methods</p> <p>We report on how we have used new features in PedHunter to quantify the number and expected genetic contribution of founders to the OOA. The queries and utility of PedHunter programs are illustrated by examples using AGDB in this paper. For example, we calculated the number of founders expected to be contributing genetic material to the present-day living OOA and estimated the mean relative founder representation for each founder. New features in PedHunter also include pedigree trimming and pedigree renumbering, which should prove useful for studying large pedigrees.</p> <p>Results</p> <p>With PedHunter version 2.0 querying AGDB version 4.0, we identified 34,160 presumed living OOA individuals and connected them into a 14-generation pedigree descending from 554 founders (332 females and 222 males) after trimming. From the analysis of cumulative mean relative founder representation, 128 founders (78 females and 50 males) accounted for over 95% of the mean relative founder contribution among living OOA descendants.</p> <p>Discussion/Conclusions</p> <p>The OOA are a closed founder population in which a modest number of founders account for the genetic variation present in the current OOA population. Improvements to the PedHunter software will be useful in future studies of both the OOA and other populations with large and computerized genealogies.</p

Two randomised phase II trials of subcutaneous interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma

Histamine inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). Two randomised phase II trials of IL-2 with or without histamine dihydrochloride (HDC) in patients with metastatic renal cell carcinoma (mRCC) were run in parallel. A total of 41 patients were included in Manchester, UK and 63 in Aarhus, Denmark. The self-administered, outpatient regimen included IL-2 as a fixed dose, 18 MIU s.c. once daily, 5 days per week for 3 weeks followed by 2 weeks rest. Histamine dihydrochloride was added twice daily, 1.0 mg s.c., concomitantly with IL-2. A maximum of four cycles were given. The Danish study showed a statistically significant 1-year survival benefit (76 vs 47%, P=0.03), a trend towards benefit in both median survival (18.3 vs 11.4 months, P=0.07), time to PD (4.5 vs 2.2 months, P=0.13) and clinical benefit (CR+PR+SD) (58 vs 37%, P=0.10) in favour of IL-2/HDC, whereas the UK study was negative for all end points. Only three patients had grade 4 toxicity; however, two were fatal. A randomised phase III trial is warranted to clarify the potential role of adding histamine to IL-2 in mRCC

Single haplotype assembly of the human genome from a hydatidiform mole

A complete reference assembly is essential for accurately interpreting individual genomes and associating variation with phenotypes. While the current human reference genome sequence is of very high quality, gaps and misassemblies remain due to biological and technical complexities. Large repetitive sequences and complex allelic diversity are the two main drivers of assembly error. Although increasing the length of sequence reads and library fragments can improve assembly, even the longest available reads do not resolve all regions. In order to overcome the issue of allelic diversity, we used genomic DNA from an essentially haploid hydatidiform mole, CHM1. We utilized several resources from this DNA including a set of end-sequenced and indexed BAC clones and 100× Illumina whole-genome shotgun (WGS) sequence coverage. We used the WGS sequence and the GRCh37 reference assembly to create an assembly of the CHM1 genome. We subsequently incorporated 382 finished BAC clone sequences to generate a draft assembly, CHM1_1.1 (NCBI AssemblyDB GCA_000306695.2). Analysis of gene, repetitive element, and segmental duplication content show this assembly to be of excellent quality and contiguity. However, comparison to assembly-independent resources, such as BAC clone end sequences and PacBio long reads, indicate misassembled regions. Most of these regions are enriched for structural variation and segmental duplication, and can be resolved in the future. This publicly available assembly will be integrated into the Genome Reference Consortium curation framework for further improvement, with the ultimate goal being a completely finished gap-free assembly