Williams Syndrome: from genes to clinical features

It all started with the discovery of a narrowing of the ascending aorta, beginning at the superior margin of the sinus of Valsalva in 1842 by N. Chevers (Burn, 1986;Chevers, 1842). This narrowing was named supravalvular aortic stenosis (SVAS) in 1930 by L. Mencarelli (Burn, 1986;Beuren, 1972;Mencarelli, 1930). It can vary from slight to severe concentric constriction to hypoplasia of the entire aorta (Beuren, 1972). In 1961 J.C. Williams and colleagues from New Zealand were the first to suggest that SVAS could be part of a previously unrecognized syndrome. They published the findings of four individuals with SVAS in association with mental retardation and a peculiar facial appearance (Williams et al., 1961). A year later Dr. Alois J. Beuren, a pediatric cardiologist from Germany, independently described four individuals with essentially the same findings and expanded the phenotype with peripheral pulmonary artery stenosis and dental anomalies (Beuren et al., 1962). In 1963 J. Black an R. Bonham-Carter noticed that the faces of individuals with infantile hypercalcemia (Fanconi et al., 1952) and the faces of the individuals described by Williams and Beuren had much in common (Black and Carter, 1963). It was Dr. Beuren who presented in 1972 compelling evidence that “Williams-Beuren syndrome” and infantile hypercalcemia are the same disorder (Beuren, 1972). In retrospect, E. Oppenheimer (Oppenheimer, 1938) was probably the first to describe an individual with the features of Williams syndrome: “ partial atresia of the main branches of the pulmonary artery occuring in infancy and accompanied by calcification of the pulmonary artery and aorta”. Naming the syndrome has been problematic. The disorder has been known in the past as the idiopathic hypercalcemia-supravalvular aortic stenosis syndrome in spite of the fact that both features are frequently absent. Because the faces in patients with infantile hypercalcemia were called “elfin facies” the term “elfin face” syndrome has been used in the past. But as stated by J. Burn who has never seen an elf this term should be dropped (Burn, 1986). Nowadays most authors use the name Williams syndrome (WS) although some authors prefer the name Williams-Beuren syndrome. We will use the name Williams syndrome. Today Williams syndrome (WS, OMIM #194050) is a well recognized multisystem genetic condition. Hundreds of individuals have been described in the medical literature and the data have been summarised in several reviews (Tassabehji, 2003;Bellugi et al., 1999). WS is caused by a submicroscopic hemizygous deletion of 1.55-1.84 Mb on chromosome 7q11.23, encompassing about 25 -30 genes. The exact links between the missing genes and the phenotype of WS is yet to be fully explored

Морфология и трехмерные изображения рудника-пещеры Кан-и-Гут

Путём сравнительного анализа и компьютерной обработки данных чертежей и схем из разных источников впервые получена пространственная (3D) модель одного из самых сложных в морфологическом отношении подземелий смешанного типа – рудника-пещеры Кан-и-Гут (Кыргызстан). Описана методика перевода графических данных в цифровой формат. Найдены основные морфометрические параметры полости, представлены трехмерные изображения основных его отделов, обсуждается их морфология. В ряде полостей рудника-пещеры выявлены существенные изменения, произошедшие за последние 50 лет вследствие масштабных обрушений.Шляхом порівняльного аналізу і комп’ютерної обробки даних креслень і схем з різних джерел вперше отримана просторова (3d) модель одного з найскладніших в морфологічному відношенні підземель змішаного типа – копальні-печери Кан-і-Гут (Киргизстан). Описана методика переведення графічних даних в цифровий формат. Знайдені основні морфометричні параметри порожнини, представлені тривимірні зображення основних його відділів, обговорюється їх морфологія. У ряді порожнин копальні-печери виявлені істотні зміни, події за останніх 50 років унаслідок масштабних обвалень.Kan-i-Gut mined cave, located in Kyrgyzstan, is one of the most morphologically complex cavities of mixed genesis. For the first time, a 3D model was developed for this cave by comparative analyses and computer processing of cave maps and mine surveyor plan and profile, obtained from different sources. The methodology of transferring graphical data into digital format is described. Primary morphometric parameters of the mined cave are gathered, and 3D images of its main parts are presented. Essential morphological changes due to vast collapses during the last 50 years were discovered

Exhaustion of the CD8+ T cell compartment in patients with mutations in phosphoinositide 3-kinase delta

Pathogenic gain-of-function mutations in the gene encoding phosphoinositide 3-kinase delta (PI3Kδ) cause activated PI3Kδ syndrome (APDS), a disease characterized by humoral immunodeficiency, lymphadenopathy, and an inability to control persistent viral infections including Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections. Understanding the mechanisms leading to impaired immune response is important to optimally treat APDS patients. Immunosenescence of CD8+ T cells was suggested to contribute to APDS pathogenesis. However, the constitutive activation of T cells in APDS may also result in T cell exhaustion. Therefore, we studied exhaustion of the CD8+ T cell compartment in APDS patients and compared them with healthy controls and HIV patients, as a control for exhaustion. The subset distribution of the T cell compartment of APDS patients was comparable with HIV patien

Computational Nuclear Physics and Post Hartree-Fock Methods

We present a computational approach to infinite nuclear matter employing Hartree-Fock theory, many-body perturbation theory and coupled cluster theory. These lectures are closely linked with those of chapters 9, 10 and 11 and serve as input for the correlation functions employed in Monte Carlo calculations in chapter 9, the in-medium similarity renormalization group theory of dense fermionic systems of chapter 10 and the Green's function approach in chapter 11. We provide extensive code examples and benchmark calculations, allowing thereby an eventual reader to start writing her/his own codes. We start with an object-oriented serial code and end with discussions on strategies for porting the code to present and planned high-performance computing facilities.Comment: 82 pages, to appear in Lecture Notes in Physics (Springer), "An advanced course in computational nuclear physics: Bridging the scales from quarks to neutron stars", M. Hjorth-Jensen, M. P. Lombardo, U. van Kolck, Editor

Vortex Dynamics and the Hall-Anomaly: a Microscopic Analysis

We present a microscopic derivation of the equation of motion for a vortex in a superconductor. A coherent view on vortex dynamics is obtained, in which {\it both} hydrodynamics {\it and} the vortex core contribute to the forces acting on a vortex. The competition between these two provides an interpretation of the observed sign change in the Hall angle in superconductors with mean free path $l$ of the order of the coherence length $\xi$ in terms of broken particle-hole symmetry, which is related to details of the microscopic mechanism of superconductivity.Comment: 12 pages, late

Performance of triage systems in emergency care: a systematic review and meta-analysis

Objective To assess and compare the performance of triage systems for identifying high and low-urgency patients in the emergency department (ED). Design Systematic review and meta-analysis. Data sources EMBASE, Medline OvidSP, Cochrane central, Web of science and CINAHL databases from 1980 to 2016 with the final update in December 2018. Eligibility criteria Studies that evaluated an emergency medical triage system, assessed validity using any reference standard as proxy for true patient urgency and were written in English. Studies conducted in low(er) income countries, based on case scenarios or involving less than 100 patients were excluded. Review methods Reviewers identified studies, extracted data and assessed the quality of the evidence independently and in duplicate. The Quality Assessment of studies of Diagnostic Accuracy included in Systematic Reviews -2 checklist was used to assess risk of bias. Raw data were extracted to create 2×2 tables and calculate sensitivity and specificity. ED patient volume and casemix severity of illness were investigated as determinants of triage systems’ performance. Results Sixty-six eligible studies evaluated 33 different triage systems. Comparisons were restricted to the three triage systems that had at least multiple evaluations using the same reference standard (Canadian Triage and Acuity Scale, Emergency Severity Index and Manchester Triage System). Overall, validity of each triage system to identify high and low-urgency patients was moderate to good, but performance was highly variable. In a subgroup analysis, no clear association was found between ED patient volume or casemix severity of illness and triage systems’ performance. Conclusions Established triage systems show a reasonable validity for the triage of patients at the ED, but performance varies considerably. Important research questions that remain are what determinants influence triage systems’ performance and how the performance of existing triage systems can be improved

What Works When Treating Granulomatous Disease in Genetically Undefined CVID? A Systematic Review

Background: Granulomatous disease is reported in at least 8–20% of patients with common variable immunodeficiency (CVID). Granulomatous disease mainly affects the lungs, and is associated with significantly higher morbidity and mortality. In half of patients with granulomatous disease, extrapulmonary manifestations are found, affecting e.g. skin, liver, and lymph nodes. In literature various therapies have been reported, with varying effects on remission of granulomas and related clinical symptoms. However, consensus recommendations for optimal management of extrapulmonary granulomatous disease are lacking. Objective: To present a literature overview of the efficacy of currently described therapies for extrapulmonary granulomatous disease in CVID (CVID+EGD), compared to known treatment regimens for pulmonary granulomatous disease in CVID (CVID+PGD). Methods: The following databases were searched: Embase, Medline (Ovid), Web-of-Science Core Collection, Cochrane Central, and Google Scholar. Inclusion criteria were 1) CVID patients with granulomatous disease, 2) treatment for granulomatous disease reported, and 3) outcome of treatment reported. Patient characteristics, localization of granuloma, treatment, and association with remission of granulomatous disease were extracted from articles. Results: We identified 64 articles presenting 95 CVID patients with granulomatous disease, wherein 117 different treatment courses were described. Steroid monotherapy was most frequently described in CVID+EGD (21 out of 53 treatment courses) and resulted in remission in 85.7% of cases. In CVID+PGD steroid monotherapy was described in 15 out of 64 treatment courses, and was associated with remission in 66.7% of cases. Infliximab was reported in CVID+EGD in six out of 53 treatment courses and was mostly used in granulomatous disease affecting the skin (four out of six cases). All patients (n = 9) treated with anti-TNF-α therapies (infliximab and etanercept) showed remission of extrapulmonary granulomatous disease. Rituximab with or without azathioprine was rarely used for CVID+EGD, but frequently used in CVID+PGD where it was associated with remission of granulomatous disease in 94.4% (17 of 18 treatment courses). Conclusion: Although the number of CVID+EGD patients was limited, data indicate that steroid monotherapy often results in remission, and that anti-TNF-α treatment is effective for granulomatous disease affecting the skin. Also, rituximab with or without azathioprine was mainly described in CVID+PGD, and only in few cases of CVID+EGD

Hall-conductivity sign change and fluctuations in amorphous Nbx_{x}Ge1−x_{1-x} films

The sign change in the Hall conductivity has been studied in thin amorphous Nb$_{1-x}$Ge$_x (x\approx$0.3) films. By changing the film thickness it is shown that the field at which the sign reversal occurs shifts to lower values (from above to below the mean-field transition field $H_{c2}$) with increasing film thickness. This effect can be understood in terms of a competition between a positive normal and a negative fluctuation contribution to the Hall conductivity.Comment: 5 pages, 4 figures, to appear in Phys. Rev.

Effective Lagrangian Approach to pion photoproduction from the nucleon

We present a pion photoproduction model on the free nucleon based on an Effective Lagrangian Approach (ELA) which includes the nucleon resonances ($\Delta(1232)$, N(1440), N(1520), N(1535), $\Delta (1620)$, N(1650), and $\Delta (1700)$), in addition to Born and vector meson exchange terms. The model incorporates a new theoretical treatment of spin-3/2 resonances, first introduced by Pascalutsa, avoiding pathologies present in previous models. Other main features of the model are chiral symmetry, gauge invariance, and crossing symmetry. We use the model combined with modern optimization techniques to assess the parameters of the nucleon resonances on the basis of world data on electromagnetic multipoles. We present results for electromagnetic multipoles, differential cross sections, asymmetries, and total cross sections for all one pion photoproduction processes on free nucleons. We find overall agreement with data from threshold up to 1 GeV in laboratory frame.Comment: Misprints corrected. 60 pages. 33 figures.5 tables. Accepted for publication in Annals of Physics (NY

Self-consistent Green's function approaches

We present the fundamental techniques and working equations of many-body Green's function theory for calculating ground state properties and the spectral strength. Green's function methods closely relate to other polynomial scaling approaches discussed in chapters 8 and 10. However, here we aim directly at a global view of the many-fermion structure. We derive the working equations for calculating many-body propagators, using both the Algebraic Diagrammatic Construction technique and the self-consistent formalism at finite temperature. Their implementation is discussed, as well as the inclusion of three-nucleon interactions. The self-consistency feature is essential to guarantee thermodynamic consistency. The pairing and neutron matter models introduced in previous chapters are solved and compared with the other methods in this book.Comment: 58 pages, 14 figures, Submitted to Lect. Notes Phys., "An advanced course in computational nuclear physics: Bridging the scales from quarks to neutron stars", M. Hjorth-Jensen, M. P. Lombardo, U. van Kolck, Editor