Identification of nuclear genes responsible for respiratory chain disorders in childhood.

The primary aim of this work was to identify novel mutations in genes that cause mitochondrial disorders. Due to the clinical and genetic heterogeneity among these patients, a variety of analytical approaches were used. In patients from pedigrees which exhibited maternal inheritance or in whom cybrid cell studies indicated a mitochondrial mutation, mitochondrial DNA (mtDNA) was sequenced. A novel mutation in a subunit of complex I (ND3) was identified in a patient with cardiomyopathy. The functional relationship between mutant load and complex I activity, lactate/pyruvate ratios and oxygen consumption was investigated. However, the pathogenic status of this mutation remains uncertain. Where a mtDNA mutation had been excluded or other factors such as consanguinity suggested involvement of a nuclear gene, results from respiratory chain (RC) enzyme assays were used to prioritise candidate genes for sequence analysis. A homozygous G555E mutation was discovered in the flavoprotein subunit of succinate dehydrogenase in a patient with late-onset Leigh syndrome and complex II deficiency. Another patient has previously been described with the same mutation but presented with a substantially more severe lethal infantile form of the disease. Fibroblast cultures derived from both patients were used to compare the activities and stability of RC enzymes in order to explain this phenotypic variability. In consanguineous pedigrees where analysis of candidate genes had proved unsuccessful, homozygosity mapping was used to search for novel nuclear genes involved with mitochondrial disorders. A novel gene for complex I deficiency was mapped to 5 genetic regions in an Israeli family using the new 10K SNP chip from Affymetrix. Analysis of eight candidate genes (including NDUFV2 and AFG3L2) was negative. In another highly consanguineous Israeli pedigree with mtDNA depletion, microsatellite analysis was used to narrow a candidate region on chromosome 13 down to 20Mb. A complex rearrangement was found in this region in a gene called SUCLA2. This gene codes for a citric acid cycle protein, which is thought to affect mitochondrial nucleotide pools via an interaction with nucleoside diphosphate kinase. Mutations in the gene for mitochondrial DNA polymerase gamma were found in 13/17 paediatric patients in the majority of whom Southern blots had indicated depletion of mtDNA, and also in a three-generation pedigree with premature external ophthalmoplegia associated with early menopause

Contact tracing investigation after professional exposure to tuberculosis in a Swiss hospital using both tuberculin skin test and IGRA.

SETTING: A 950 bed teaching hospital in Switzerland. AIM: To describe the result of a contact investigation among health care workers (HCW) and patients after exposure to a physician with smear-positive pulmonary tuberculosis in a hospital setting using standard tuberculin skin tests (TST) and Interferon-gamma release assay (IGRA). METHOD: HCW with a negative or unknown TST at hiring had a TST two weeks after the last contact with the index case (T0), repeated six weeks later if negative (T6). All exposed HCW had a T-SPOT.TB at T0 and T6. Exposed patients had a TST six weeks after the last contact, and a T-SPOT.TB if the TST was positive. RESULTS: Among 101 HCW, 17/73 (22%) had a positive TST at T0. TST was repeated in 50 at T6 and converted from negative to positive in eight (16%). Twelve HCW had a positive T-SPOT.TB at T0 and ten converted from negative to positive at T6. Seven HCW with a positive T-SPOT.TB reverted to negative at T6 or at later controls, most of them with test values close to the cut-off. Among 27 exposed patients tested at six weeks, ten had a positive TST, five of them confirmed by a positive T-SPOT.TB. CONCLUSIONS: HCW tested twice after exposure to a case of smear-positive pulmonary TB demonstrated a possible conversion in 10% with T-SPOT and 16% with TST. Some T-SPOT.TB reverted from positive to negative during the follow-up, mostly tests with a value close to the cut-off. Due to the variability of the test results, it seems advisable to repeat the test with values close to the cut-off before diagnosing the presence of a tuberculous infection

Quantum Mechanics of Multi-Prong Potentials

We describe the bound state and scattering properties of a quantum mechanical particle in a scalar $N$-prong potential. Such a study is of special interest since these situations are intermediate between one and two dimensions. The energy levels for the special case of $N$ identical prongs exhibit an alternating pattern of non-degeneracy and $(N-1)$ fold degeneracy. It is shown that the techniques of supersymmetric quantum mechanics can be used to generate new solutions. Solutions for prongs of arbitrary lengths are developed. Discussions of tunneling in $N$-well potentials and of scattering for piecewise constant potentials are given. Since our treatment is for general values of $N$, the results can be studied in the large $N$ limit. A somewhat surprising result is that a free particle incident on an $N$-prong vertex undergoes continuously increased backscattering as the number of prongs is increased.Comment: 17 pages. LATEX. On request, TOP_DRAW files or hard copies available for 7 figure

CALING (Corpus de Accesibilidad Lingüística) Corpus : accessibility and real informants evaluation

There is strong evidence that rare copy number variants (CNVs) have a role in susceptibility to autism spectrum disorders (ASDs). Much research has focused on how CNVs mediate a phenotypic effect by altering gene expression levels. We investigated an alternative mechanism whereby CNVs combine the 5' and 3' ends of two genes, creating a 'fusion gene'. Any resulting mRNA with an open reading frame could potentially alter the phenotype via a gain-of-function mechanism. We examined 2382 and 3096 rare CNVs from 996 individuals with ASD and 1287 controls, respectively, for potential to generate fusion transcripts. There was no increased burden in individuals with ASD; 122/996 cases harbored at least one rare CNV of this type, compared with 179/1287 controls (P=0.89). There was also no difference in the overall frequency distribution between cases and controls. We examined specific examples of such CNVs nominated by case-control analysis and a candidate approach. Accordingly, a duplication involving REEP1-POLR1A (found in 3/996 cases and 0/1287 controls) and a single occurrence CNV involving KIAA0319-TDP2 were tested. However, no fusion transcripts were detected by RT-PCR. Analysis of additional samples based on cell line availability resulted in validation of a MAPKAPK5-ACAD10 fusion transcript in two probands. However, this variant was present in controls at a similar rate and is unlikely to influence ASD susceptibility. In summary, although we find no evidence that fusion-gene generating CNVs lead to ASD susceptibility, discovery of a MAPKAPK5-ACAD10 transcript with an estimated frequency of ~1/200 suggests that gain-of-function mechanisms should be considered in future CNVs studies

New Eaxactly Solvable Hamiltonians: Shape Invariance and Self-Similarity

We discuss in some detail the self-similar potentials of Shabat and Spiridonov which are reflectionless and have an infinite number of bound states. We demonstrate that these self-similar potentials are in fact shape invariant potentials within the formalism of supersymmetric quantum mechanics. In particular, using a scaling ansatz for the change of parameters, we obtain a large class of new, reflectionless, shape invariant potentials of which the Shabat-Spiridonov ones are a special case. These new potentials can be viewed as q-deformations of the single soliton solution corresponding to the Rosen-Morse potential. Explicit expressions for the energy eigenvalues, eigenfunctions and transmission coefficients for these potentials are obtained. We show that these potentials can also be obtained numerically. Included as an intriguing case is a shape invariant double well potential whose supersymmetric partner potential is only a single well. Our class of exactly solvable Hamiltonians is further enlarged by examining two new directions: (i) changes of parameters which are different from the previously studied cases of translation and scaling; (ii) extending the usual concept of shape invariance in one step to a multi-step situation. These extensions can be viewed as q-deformations of the harmonic oscillator or multi-soliton solutions corresponding to the Rosen-Morse potential.Comment: 26 pages, plain tex, request figures by e-mai

Pretransplant dyslipidaemia influences primary graft dysfunction after lung transplantation

OBJECTIVES: Primary graft dysfunction (PGD) is a major cause of mortality within the first year following lung transplantation. Pulmonary hypertension, elevated body mass index (BMI), prolonged ischaemic time of the graft, intraoperative blood transfusions >1000 ml and the use of cardiopulmonary bypass or extracorporeal membrane oxygenation increase the risk for PGD. We aimed to evaluate whether dyslipidaemia is an additional risk factor for the development of PGD. METHODS: We retrospectively analysed demographic and clinical data of 264 patients who received their first bilateral lung transplantation between March 2000 and October 2013 at our institution. The endpoint was PGD grade 3 at any time, defined according to the International Society for Heart and Lung Transplantation (ISHLT) criteria. Fasting lipid profiles at listing time or just before transplantation (baseline) were documented and dyslipidaemia was defined as any of the parameters being out of range. Comparisons of continuous variables between patients with PGD grade 3 and patients without were performed with the Mann-Whitney U-test, whereas proportions were compared with the χ(2) test. Continuous variables were presented as arithmetic means with standard deviation for ease of comparison, but levels of statistical significance were computed using the appropriate non-parametric statistical test. To identify PGD risk factors, a forward stepwise logistic regression model was used. RESULTS: PGD occurred in 63 recipients (24%). Pretransplant dyslipidaemia was documented in 153 recipients (58%) and was significantly more prevalent among recipients developing PGD (45 vs 108, P < 0.013). Despite various underlying pulmonary pathologies, higher triglyceride (TG) levels (1.41 ± 0.78 vs 1.16 ± 0.78, P < 0.012), lower high-density lipoprotein-cholesterol (HDL-C) concentrations (1.24 ± 0.55 vs 1.57 ± 0.71, P < 0.0005) and higher cholesterol/HDL-C values (3.80 ± 2.02 vs 3.00 ± 0.92, P < 0.0005) were associated with a lower incidence of PGD. Patients with PGD had significantly longer ischaemic time (350 ± 89 vs 322 ± 91, P = 0.017) and higher BMI (23 ± 5 vs 21 ± 4.4, P < 0.007). CONCLUSION: Dyslipidaemia seems to be an independent risk factor for PGD after lung transplantation: low circulating levels of HDL-C and hypertriglyceridaemia increase the incidence of PGD. Even if HDL-C levels are difficult to alter today, triglyceride and cholesterol levels can be addressed therapeutically and may have a positive influence on the development of PGD

Unitarity and the Bethe-Salpeter Equation

We investigate the relation between different three-dimensional reductions of the Bethe-Salpeter equation and the analytic structure of the resultant amplitudes in the energy plane. This correlation is studied for both the $\phi^2\sigma$ interaction Lagrangian and the $\pi N$ system with $s$-, $u$-, and $t$-channel pole diagrams as driving terms. We observe that the equal-time equation, which includes some of the three-body unitarity cuts, gives the best agreement with the Bethe-Salpeter result. This is followed by other 3-D approximations that have less of the analytic structure.Comment: 17 pages, 8 figures; RevTeX. Version accepted for publication in Phys. Rev.

Semiclassical Approach to Quantum-mechanical Problems with Broken Supersymmetry

The semiclassical WKB approximation method is reexamined in the context of nonrelativistic quantum-mechanical bound-state problems with broken supersymmetry (SUSY). This gives rise to an alternative quantization condition (denoted by BSWKB) which is different from the standard WKB formula and also different from the previously studied supersymmetric (SWKB) formula for unbroken SUSY. It is shown that to leading order in ħ, the BSWKB condition yields exact energy eigenvalues for shape-invariant potentials with broken SUSY (harmonic oscillator, Pöschl-Teller I and II) which are known to be analytically solvable. Further, we show explicitly that the higher-order corrections to these energy eigenvalues, up to sixth order in ħ, vanish identically. We also consider a number of examples of potentials with broken supersymmetry that are not analytically solvable. In particular, for the broken SUSY superpotential W=Ax2d [A\u3e0, d=(integer)], we evaluate contributions up to the sixth order and show that these results are in excellent agreement with numerical solutions of the Schrödinger equation. While the numerical BSWKB results in lowest order are not always better than the corresponding WKB results, they are still a considerable improvement because they guarantee equality of the corresponding energy eigenvalues for the supersymmetric partner potentials V+ and V-. This is of special importance in those situations where these partner potentials are not related by parity

Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment

Peer reviewedPublisher PD