Electron-phonon induced spin relaxation in InAs quantum dots

We have calculated spin relaxation rates in parabolic quantum dots due to the phonon modulation of the spin-orbit interaction in presence of an external magnetic field. Both, deformation potential and piezoelectric electron-phonon coupling mechanisms are included within the Pavlov-Firsov spin-phonon Hamiltonian. Our results have demonstrated that, in narrow gap materials, the electron-phonon deformation potential and piezoelectric coupling give comparable contributions as spin relaxation processes. For large dots, the deformation potential interaction becomes dominant. This behavior is not observed in wide or intermediate gap semiconductors, where the piezoelectric coupling, in general, governs the spin relaxation processes. We also have demonstrated that spin relaxation rates are particularly sensitive to the Land\'e $g$-factor.Comment: 4 pages, 2 figures, to be appear in Physica E: Proceedings of the 11 International Conference on Narrow Gap Semiconductor

Estudo Português de Hipercolesterolemia Familiar

A Hipercolesterolemia Familiar (FH) é uma doença autossómica dominante que se caracteriza, a nível clínico, por níveis elevados de colesterol LDL, levando ao aparecimento prematuro de doenças cardiovasculares (DCV). A nível genético esta doença caracteriza-se, principalmente, por mutações em três genes: LDLR, APOB e PCSK9. Estima-se que em Portugal existam cerca de 20 000 doentes com FH. A identificação clínica de FH é possível mas apenas o estudo molecular confirma a presença da doença. O Estudo Português de Hipercolesterolemia Familiar (EPFH) tem como objectivo principal identificar a causa genética da dislipidémia em doentes com diagnóstico clínico de FH. O EPHF recebeu desde 1999, para realização do estudo molecular, 486 casos-index com diagnóstico clínico de FH e 858 familiares. O estudo molecular é realizado em 3 fases. Fase I: Identificação de mutações nos genes APOB e LDLR. Fase II: Pesquisa de grandes rearranjos no gene LDLR por MLPA. Fase III: Pesquisa de mutações no gene PCSK9. A pesquisa de mutações nos genes APOB e PCSK9 é realizada por amplificação dos fragmentos a estudar e sequenciação directa. No gene LDLR os 18 exões são amplificados dos 18 exôes por PCR e analisados por DHPLC e sequenciação. Até à data foram identificados um total de 504 doentes com um defeito genético num dos três genes estudados: 3 doentes com mutação no gene PCSK9, 12 doentes com mutação no gene APOB e 438 doentes com mutação no gene LDLR (7 dos quais em homozigotia ou heterozigotia composta). No gene LDLR foram encontradas 89 mutações diferentes, que incluem 43 mutações missense,17 delecções/inserções, 6 nonsense, 12 mutações de splicing, 4 grandes delecções e 2 no promotor e 1no codão stop. As mutações mais comuns na população portuguesa são: p.A431T (11%), p.D224N (6,9%) e p.R406W (6,2%). Foram efectuados funcionais em algumas mutações de splicing e comprovou-se a sua patogeneicidade em 6 alterações (c.-135C>G; c.-190+4insTG; c.313+6T>C; c.818-2A>G; c.2389G>T (V776L); c.2547+1G>A). Foram também efectuados estudos funcionais para 5 alterações missense não descritas anteriormente (p.V429L, p.W490R, p.S648P, p.P685S e p.V859M), verificou-se que apenas a alteração p.V859M não é patogenica. No gene APOB foi identificada a mutação mais comum (p.Arg3527Gln) e também a mutação p.Tyr3560Cys. No gene PCSK9 foi encontrada uma única alteração, p.Asp374His. A FH esta sub-diagnosticada no nosso País, esforços têm de ser conduzidos para identificar estes doentes, ainda em idade jovem, de modo a que seja evitado o aparecimento da DCV prematura, e no caso mais extremo a morte prematura como observado em algumas famílias. O diagnóstico e aconselhamento genético da FH é importante para a correcta percepção e prevenção do risco familiar de DCV. O estudo molecular fundamenta a instituição de terapêutica farmacológica adequada e a adopção de um estilo de vida saudável reduzindo substancialmente o risco cardiovascular. Nas crianças e adolescentes o diagnóstico genético é ainda mais importante, uma vez que se sabe que o risco cardiovascular é elevado, mas evitável, se medidas preventivas forem colocadas em prática. O futuro passa pela prevenção em vez da resolução tardia das complicações cardiovasculares inerentes a esta patologia

Genetic diagnosis of familial hypercholesterolaemia: the importance of functional analysis of potential splice-site mutations

Familial hypercholesterolemia (FH) results from defective low-density lipoprotein receptor (LDLR) activity, mainly due to LDLR gene defects. Of the many different LDLR mutations found in patients with FH, about 6% of single base substitutions are located near or within introns, and are predicted to result in exon skipping, retention of an intron, or activation of cryptic sites during mRNA splicing. This paper reports on the Portuguese FH Study, which found 10 such mutations, 6 of them novel. For the mutations that have not been described before or those whose effect on function have not been analysed, their effect on splicing was investigated, using reverse transcriptase PCR analysis of LDLR mRNA from freshly isolated blood mononuclear cells. Two of these variants (c.313+6 T-->C, c.2389G-->T (p.V776L)) caused exon skipping, and one caused retention of an intron (c.1359-5C-->G), whereas two others (c.2140+5 G-->A and c.1061-8T-->C) had no apparent effect. Any effect of c.1185G-->C (p.V374V) on splicing could not be determined because it was on an allele with a promoter mutation (-42C-->G) that was probably not transcribed. Variants in four patients lost to follow-up could not be tested experimentally, but they almost certainly affect splicing because they disrupt the invariant AG or GT in acceptor (c.818-2A-->G) or donor (c.1060+1G-->A, c.1845+1delG and c.2547+1G-->A) spice sites. These findings emphasise that care must be taken before reporting the presence or absence of a splice-site mutation in the LDLR gene for diagnostic purposes. The study also shows that relatively simple, quick and inexpensive RNA assays can evaluate putative splicing mutations that are not always predictable by available software, thereby reducing genetic misdiagnosis of patients with FH

Diagnóstico molecular de hipercolesterolemia familiar: uma ferramenta importante para a estratificação do risco cardiovascular

Familial hypercholesterolemia (FH) is associated with an increased risk of premature coronary heart disease. Molecular identification of these patients can reduce the burden of mortality from cardiovascular disorders simply by the correct identification of the disease early in life, followed by counseling and appropriate lifestyle modifications, and therapeutic measures when required. Recent studies show that, in Portugal, this disease is severely under-diagnosed. After more than 10 years of research through the Portuguese FH Study, it is now possible to translate the original research results into clinical application. AIMS: The main aims of the present work were to determine whether clinical characterization is sufficient to identify these individuals at high risk of developing CHD and to evaluate the clinical applicability of molecular diagnosis for FH. METHODS: All patients described in this study were recruited for the Portuguese FH Study. The diagnostic criteria used to select the index patients were adapted from the Simon Broome Heart Research Trust. To analyze the usefulness of the molecular diagnosis, graphs of total and LDL cholesterol values by age were constructed for 622 possible FH patients. The lipid profile of patients genetically identified as having FH, before and under medication, were analyzed to assess whether these patients were receiving appropriate treatment. The data are shown separately for children and adults and for female and male propositi (index cases and hypercholesterolemic relatives), both with and without a detectable mutation in the LDLR gene. RESULTS: The Portuguese FH Study has already genetically identified 404 individuals (171 index patients and 233 relatives) among more than one thousand individuals sent for study. A total of 78 different mutations in the LDLR gene were found in 171 index patients, 2 different mutations were found in the apoB gene of 4 patients and 2 patients had a unique PCSK9 mutation. Statistical analysis revealed that there are significant differences between total cholesterol (p < 0.001) and apoB (p = 0.026) values in the group of children (male and female) with and without a mutation in LDLR. For female children LDL values were also significantly different (p < 0.001) between subgroups but for male children this difference did not reach statistical significance. In adult women there is a statistically significant difference for total cholesterol (p = 0.049), LDL cholesterol (p = 0.031) and apoB (p = 0.003) values in the subgroups with and without a LDLR mutation. In adult males there is a statistical difference for total cholesterol (p = 0.002). LDL cholesterol (p = 0.003) and apoB (p = 0.0023) in subgroups with and without an LDLR mutation. Nevertheless there was considerable dispersion of values and individually it is not possible to distinguish between patients with and without a mutation in the LDLR gene, based only on lipid profile. CONCLUSIONS: By analysis of the clinical data of 696 possible FH patients, the present report shows evidence that clinical characterization is not sufficient to distinguish between patients with genetic or environmental dyslipidemia, and so molecular diagnosis is useful in clinical practice, allowing correct identification of FH patients and their relatives, and the early implementation of therapeutic measures to reduce the elevated cardiovascular risk of these patients. In general, molecular diagnosis of FH is feasible and could be obtained in 1-2 months if the technology is available. In Portugal the test will be offered to the population by our Institute at a cost of about 500 euros, like many other genetic tests or exams such as nuclear magnetic resonance

Familial hypercholesterolaemia in Portugal

Familial hypercholesterolaemia (FH) is characterised clinically by an increased level of circulating LDL cholesterol that leads to lipid accumulation in tendons and arteries, premature atherosclerosis and increased risk of coronary heart disease (CHD). Although Portugal should have about 20,000 cases, this disease is severely under-diagnosed in our country, this being the first presentation of Portuguese data on FH. A total of 602 blood samples were collected from 184 index patients and 418 relatives from several centres throughout Portugal. Fifty-three different mutations were found in 83 index patients, 79 heterozygous and 4 with two defective LDLR alleles. Additionally, 4 putative alterations were found in 8 patients but were not considered mutations causing disease, mainly because they did not co-segregate with hypercholesterolaemia in the families. Three unrelated patients were found to be heterozygous for the APOB(3500) mutation and two unrelated patients were found to be heterozygous for a novel mutation in PCSK9, predicted to cause a single amino acid substitution, D374H. Cascade screening increased the number of FH patients identified genetically to 204. The newly identified FH patients are now receiving counselling and treatment based on the genetic diagnosis. The early identification of FH patients can increase their life expectancy and quality of life by preventing the development of premature CHD if patients receive appropriate pharmacological treatment

Familial hypercholesterolemia: Molecular characterization of possible cases from the Azores Islands (Portugal)

Familial hypercholesterolemia (FH) is an autosomal dominant disorder of the cholesterol metabolism, which constitutes a risk factor for coronary arterial disease (CAD). In the Azores Islands (Portugal), where mortality from CAD doubles its rate comparatively to the rest of the country and where a high frequency of dyslipidemia has been reported, the prevalence and distribution of FH remain unknown. The molecular characterization of a group of 33 possible cases of FH of Azorean background was undertaken in this study. A DNA array was initially used to search mutations in the LDLR, APOB and PCSK9 loci in 10 unrelated possible cases of FH. No mutations were detected in the array; after sequencing the full LDLR gene, 18 variants were identified, corresponding to two missense (c.806G > A; c.1171G > A) and sixteen synonymous alterations. Six of the synonymous variants which are consistently described in the literature as associated with altered cholesterol levels were used to build haplotypes. The most frequent haplotype corresponded to TTCGCC (45%), a "risk" haplotype, formed exclusively by alleles that were reported to increase cholesterol levels. Some of the variants detected in the full sequencing of the LDLR gene fell within the ligand-binding domain of this gene, defined by exons 2 to 6. To add information as to the role of such variants, these exons were sequenced in the remaining 23 possible FH cases. Two missense alterations (c.185C > T; c.806G > A) were found in this subset of possible FH cases. The missense alteration c.185C > T, identified in one individual, is novel for the Portuguese population. In silico analysis was not conclusive for this alteration, whose role will have to be further investigated. This study represents the first approach to the establishment of the mutational profile of FH in the Azores Islands.This work was supported by the project entitled “High prevalence pathologies in the Azores: genetic and biochemical markers” with reference (M2.1.2/I/026/2008) funded by SRCTE. M. R. receives a PhD fellowship (M3.1.2/F/006/2011) from Fundo Regional para a Ciência. T.C. receives a post-doctoral fellowships from Fundação para a Ciência e a Tecnologia (SFRH/BPD/38659/ 2007) and N. K. (M3.1.7/F/002/2008) and A. R. (M3.1.7/F/031/2011) both receives post-doctoral fellowships from Fundo Regional para a Ciência

Cardiovascular risk profile of high school students: A cross-sectional study

INTRODUCTION: Disease prevention should begin in childhood and lifestyles are important risk determinants of cardiovascular disease. Awareness and monitoring of risk is essential in preventive strategies. AIM: To characterize cardiovascular risk and the relationships between certain variables in adolescents. METHODS: In a cross-sectional study, 854 adolescent schoolchildren were surveyed, mean age 16.3±0.9 years. Data collection included questionnaires, physical examination, charts for 10-year relative risk of mortality, and biochemical assays. In the statistical analysis continuous variables were studied by the Student's t test and categorical variables by the chi-square test and Fisher's exact test, and each risk factor was entered as a dependent variable in logistic regression analysis. RESULTS: Physical activity was insufficient in 81% of students. The daily consumption of soup, salad or vegetables, and fruit was, respectively, 37%, 39% and 21%. A minority (6%) took ≤3 and 77% took ≥5 meals a day. The prevalence of each risk factor was as follows: overweight 16%; smoking 13%; hypertension 11%; impaired glucose metabolism 9%; hypertriglyceridemia 9%; and hypercholesterolemia 5%. Out-of-school physical activity, hypertension and overweight were more prevalent in males (p<0.001). Females had higher levels of cholesterol (p<0.005) and triglycerides (p<0.001). A quarter of the adolescents had a relative risk score for 10-year cardiovascular mortality of ≥2. Overweight showed a positive association with blood pressure, changes in glucose metabolism and triglycerides, and a negative association with number of daily meals. CONCLUSIONS: The results demonstrate the need for action in providing and encouraging healthy choices for adolescents, with an emphasis on behavioral and lifestyle changes aimed at individuals, families and communitie

Tensor gauge fields in arbitrary representations of GL(D,R): II. Quadratic actions

Quadratic, second-order, non-local actions for tensor gauge fields transforming in arbitrary irreducible representations of the general linear group in D-dimensional Minkowski space are explicitly written in a compact form by making use of Levi-Civita tensors. The field equations derived from these actions ensure the propagation of the correct massless physical degrees of freedom and are shown to be equivalent to non-Lagrangian local field equations proposed previously. Moreover, these actions allow a frame-like reformulation a la MacDowell-Mansouri, without any trace constraint in the tangent indices.Comment: LaTeX, 53 pages, no figure. Accepted for publication in Communications in Mathematical Physics. Local Fierz-Pauli programme achieved by completing the analysis of Labastid

Sports-related sudden cardiac deaths in the young population of Switzerland.

In Switzerland, ECG screening was first recommended for national squad athletes in 1998. Since 2001 it has become mandatory in selected high-risk professional sports. Its impact on the rates of sports-related sudden cardiac death (SCD) is unknown. We aimed to study the incidence, causes and time trends of sports-related SCD in comparison to SCD unrelated to exercise in Switzerland. We reviewed all forensic reports of SCDs of the German-speaking region of Switzerland in the age group of 10 to 39 years, occurring between 1999 and 2010. Cases were classified into three categories based on whether or not deaths were associated with sports: no sports (NONE), recreational sports (REC), and competitive sports (COMP). Over the 12-year study period, 349 SCD cases were recorded (mean age 30±7 years, 76.5% male); 297 cases were categorized as NONE, 31 as REC, and 21 as COMP. Incidences of SCD per 100,000 person-years [mean (95% CI)] were the lowest in REC [0.43 (0.35-0.56)], followed by COMP [1.19 (0.89-1.60)] and NONE [2.46 (2.27-2.66)]. In all three categories, coronary artery disease (CAD) with or without acute myocardial infarction (MI) was the most common cause of SCD. Three professional athletes were identified in COMP category which all had SCD due to acute MI. There were no time trends, neither in overall, nor in cause-specific incidences of SCD. The incidence of SCD in young individuals in Switzerland is low, both related and unrelated to sports. In regions, like Switzerland, where CAD is the leading cause of SCD associated with competitions, screening for cardiovascular risk factors in addition to the current PPS recommendations might be indicated to improve detection of silent CAD and further decrease the incidence of SCD

Quantized conductance coincides with state instability and excess noise in tantalum oxide memristors

Tantalum oxide memristors can switch continuously from a low-conductance semiconducting to a high-conductance metallic state. At the boundary between these two regimes are quantized conductance states, which indicate the formation of a point contact within the oxide characterized by multistable conductance fluctuations and enlarged electronic noise. Here, we observe diverse conductance-dependent noise spectra, including a transition from 1/f 2 (activated transport) to 1/f (flicker noise) as a function of the frequency f, and a large peak in the noise amplitude at the conductance quantum GQ¼2e2/h, in contrast to suppressed noise at the conductance quantum observed in other systems. We model the stochastic behaviour near the point contact regime using Molecular Dynamics–Langevin simulations and understand the observed frequency-dependent noise behaviour in terms of thermally activated atomic-scale fluctuations that make and break a quantum conductance channel. These results provide insights into switching mechanisms and guidance to device operating ranges for different applications