Browsing by Subject "SPECTRUM"

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  • Li, Xia; Frechen, Sebastian; Moj, Daniel; Lehr, Thorsten; Taubert, Max; Hsin, Shih-hsuan; Mikus, Gerd; Neuvonen, Pertti J; Olkkola, Klaus; Saari, Teijo; Fuhr, Uwe (2020)
    Background Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. Objective This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail. Methods In vitro assays were carried out to explore time-dependent inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration-time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim(R). The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration-time curve (AUC), maximum concentration (C-max), and trough concentrations for multiple dosings (C-trough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration-time datasets over the full range of recommended intravenous and oral dosing regimens. Results The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregateC(max)ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregateC(max)ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1-2 mg/L to <5-6 mg/L forC(trough), while 400 mg twice daily might be more suitable for rapid metabolizers (RMs; *1/*17, *17/*17) and normal metabolizers (NMs; *1/*1). When the model was integrated with independently developed CYP3A4 substrate models (midazolam and alfentanil), the observed AUC change of substrates by voriconazole was inside the 90% confidence interval of the predicted AUC change, indicating that CYP3A4 inhibition was appropriately incorporated into the voriconazole model. Conclusions Both the in vitro assay and model-based simulations support TDI of CYP3A4 by voriconazole as a pivotal characteristic of this drug's PK. The PBPK model developed here could support individual dose adjustment of voriconazole according to genetic polymorphisms of CYP2C19, and DDI risk management. The applicability of modeling results for patients remains to be confirmed in future studies.
  • Baer, Robin M.; Kirschner, Stefan; Nieger, Martin; Bräse, Stefan (2018)
    Herein the addition of different thiols to the strained carbon-carbon bond of [1.1.1]propellane (1) is reported. The reaction pathway was investigated, addition reactions with substituted thiols, hydrogen sulfide and protected cysteine were performed, and further modifications of the products were verified. The clean reaction proceeds by a radical chain process, which was confirmed by different deuterium labelling experiments. It shows high functional-group tolerance, since halo-, hydroxy-, methoxy-, carboxy-, amino- and nitro-substituted thiols could be added to 1 with few by-products in 16-90% yield. Oxidation of the products allows tuning of the polarity and subsequent reactions of the products. The click-type reaction proceeds even faster with selenols, as was shown in a proof of concept. Thiol addition to 1 offers a facile tool for surface modification, conjugation and tuning of hydrophilicity in bio- and medicinal chemistry.
  • Kerr, Shona M.; Klaric, Lucija; Halachev, Mihail; Hayward, Caroline; Boutin, Thibaud S.; Meynert, Alison M.; Semple, Colin A.; Tuiskula, Annukka M.; Swan, Heikki; Santoyo-Lopez, Javier; Vitart, Veronique; Haley, Chris; Dean, John; Miedzybrodzka, Zosia; Aitman, Timothy J.; Wilson, James F. (2019)
    The Viking Health Study Shetland is a population-based research cohort of 2,122 volunteer participants with ancestry from the Shetland Isles in northern Scotland. The high kinship and detailed phenotype data support a range of approaches for associating rare genetic variants, enriched in this isolate population, with quantitative traits and diseases. As an exemplar, the c.1750G > A; p.Gly584Ser variant within the coding sequence of the KCNH2 gene implicated in Long QT Syndrome (LQTS), which occurred once in 500 whole genome sequences from this population, was investigated. Targeted sequencing of the KCNH2 gene in family members of the initial participant confirmed the presence of the sequence variant and identified two further members of the same family pedigree who shared the variant. Investigation of these three related participants for whom single nucleotide polymorphism (SNP) array genotypes were available allowed a unique shared haplotype of 1.22 Mb to be defined around this locus. Searching across the full cohort for this haplotype uncovered two additional apparently unrelated individuals with no known genealogical connection to the original kindred. All five participants with the defined haplotype were shown to share the rare variant by targeted Sanger sequencing. If this result were verified in a healthcare setting, it would be considered clinically actionable, and has been actioned in relatives ascertained independently through clinical presentation. The General Practitioners of four study participants with the rare variant were alerted to the research findings by letters outlining the phenotype (prolonged electrocardiographic QTc interval). A lack of detectable haplotype sharing between c.1750G > A; p.Gly584Ser chromosomes from previously reported individuals from Finland and those in this study from Shetland suggests that this mutation has arisen more than once in human history. This study showcases the potential value of isolate population-based research resources for genomic medicine. It also illustrates some challenges around communication of actionable findings in research participants in this context.
  • Rees, E.; Kirov, G.; Walters, J. T.; Richards, A. L.; Howrigan, D.; Kavanagh, D. H.; Pocklington, A. J.; Fromer, M.; Ruderfer, D. M.; Georgieva, L.; Carrera, N.; Gormley, P.; Palta, P.; Williams, H.; Dwyer, S.; Johnson, J. S.; Roussos, P.; Barker, D. D.; Banks, E.; Milanova, V.; Rose, S. A.; Chambert, K.; Mahajan, M.; Scolnick, E. M.; Moran, J. L.; Tsuang, M. T.; Glatt, S. J.; Chen, W. J.; Hwu, H-G; Neale, B. M.; Palotie, A.; Sklar, P.; Purcell, S. M.; McCarroll, S. A.; Holmans, P.; Owen, M. J.; O'Donovan, M. C.; Taiwanese Trios Exome Sequencing C (2015)
    Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF
  • Savelainen, Matti; Väliviita, Jussi; Walia, Parampreet; Rusak, Stanislav; Kurki-Suonio, Hannu (2013)
  • Panahi, Mahmod; Mesri, Naeimeh Yousefi; Samuelsson, Eva-Britt; Coupland, Kirsten G.; Forsell, Charlotte; Graff, Caroline; Tikka, Saara; Winblad, Bengt; Viitanen, Matti; Karlström, Helena; Sundström, Erik; Behbahani, Homira (2018)
    Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial fatal progressive degenerative disorder. One of the pathological hallmarks of CADASIL is a dramatic reduction of vascular smooth muscle cells (VSMCs) in cerebral arteries. Using VSMCs from the vasculature of the human umbilical cord, placenta and cerebrum of CADASIL patients, we found that CADASIL VSMCs had a lower proliferation rate compared to control VSMCs. Exposure of control VSMCs and endothelial cells (ECs) to media derived from CADASIL VSMCs lowered the proliferation rate of all cells examined. By quantitative RT-PCR analysis, we observed increased Transforming growth factor-beta (TGF beta) gene expression in CADASIL VSMCs. Adding TGF beta-neutralizing antibody restored the proliferation rate of CADASIL VSMCs. We assessed proliferation differences in the presence or absence of TGF beta-neutralizing antibody in ECs co-cultured with VSMCs. ECs co-cultured with CADASIL VSMCs exhibited a lower proliferation rate than those co-cultured with control VSMCs, and neutralization of TGF beta normalized the proliferation rate of ECs co-cultured with CADASIL VSMCs. We suggest that increased TGF beta expression in CADASIL VSMCs is involved in the reduced VSMC proliferation in CADASIL and may play a role in situ in altered proliferation of neighbouring cells in the vasculature.
  • Müller, Eric; Büchner, Bernd; Habenicht, Carsten; Koenig, Andreas; Knupfer, Martin; Berger, Helmuth; Huotari, Simo (2016)
    We report the behavior of the charge carrier plasmon of 2H-transition metal dichalcogenides (TMDs) as a function of intercalation with alkali metals. Intercalation and concurrent doping of the TMD layers have a substantial impact on plasmon energy and dispersion. While the plasmon energy shifts are related to the intercalation level as expected within a simple homogeneous electron gas picture, the plasmon dispersion changes in a peculiar manner independent of the intercalant and the TMD materials. Starting from a negative dispersion, the slope of the plasmon dispersion changes sign and grows monotonously upon doping. Quantitatively, the increase of this slope depends on the orbital character (4d or 5d) of the conduction bands, which indicates a decisive role of band structure effects on the plasmon behavior.
  • Hikmat, Omar; Naess, Karin; Engvall, Martin; Klingenberg, Claus; Rasmussen, Magnhild; Tallaksen, Chantal M. E.; Brodtkorb, Eylert; Fiskerstrand, Torunn; Isohanni, Pirjo; Uusimaa, Johanna; Darin, Niklas; Rahman, Shamima; Bindoff, Laurence A. (2018)
    Objective: Epilepsy is common in individuals with mutations in POLG, the gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma. Early recognition and aggressive seizure management are crucial for patient survival. Disruption of the blood-brain barrier (BBB) is implicated in various neurological disorders including epilepsy. The aim of this study was to assess whether POLG-related disease is associated with BBB dysfunction and what clinical implications this has for patients. Methods: Our retrospective study used data from 83 patients with pathogenic POLG mutations from 4 countries-Norway, Sweden, Finland, and the United Kingdom. Data were collected using a structured questionnaire. We used the presence of raised cerebrospinal fluid (CSF) protein and a raised CSF/serum ratio of albumin (Q-alb) to evaluate the integrity of the blood-CSF bather. Results: Raised CSF protein was found in 70% of patients (n = 58/83) and appeared to be associated with the most severe phenotypes. In those in whom it was measured, the Q-alb ratio was markedly elevated (n = 18). The majority of those with epilepsy (n = 50/66, 76%) had raised CSF protein, and this preceded seizure debut in 75% (n = 15/20). The median survival time from symptom onset for those with raised CSF protein was decreased (13 months) compared to those with normal CSF protein (32 months). Significance: Our results indicate that there is disruption of the BBB in POLG-related disease, as evidenced by a raised CSF protein and Q-alb ratio. We also find that raised CSF protein is a common finding in patients with POLG disease. Our data suggest that the presence of BBB dysfunction predicts a poorer outcome, and elevated CSF protein may therefore be an additional biomarker both for early diagnosis and to identify those at high risk of developing epilepsy.
  • Turc, L.; Roberts, O. W.; Archer, M. O.; Palmroth, M.; Battarbee, M.; Brito, T.; Ganse, U.; Grandin, M.; Pfau-Kempf, Y.; Escoubet, C. P.; Dandouras, I. (2019)
    The foreshock, extending upstream of Earth's bow shock, is a region of intense electromagnetic wave activity and nonlinear phenomena, which can have global effects on geospace. It is also the first geophysical region encountered by solar wind disturbances journeying toward Earth. Here, we present the first observations of considerable modifications of the foreshock wave field during extreme events of solar origin called magnetic clouds. Cluster's multispacecraft data reveal that the typical quasi-monochromatic foreshock waves can be completely replaced by a superposition of waves each with shorter correlation lengths. Global numerical simulations further confirm that the foreshock wave field is more intricate and organized at smaller scales. Ion measurements suggest that changes in shock-reflected particle properties may cause these modifications of the wave field. This state of the foreshock is encountered only during extreme events at Earth, but intense magnetic fields are typical close to the Sun or other stars.
  • Lipska-Zietkiewicz, Beata Stefania; Ozaltin, Fatih; Hölttä, Tuula; Bockenhauer, Detlef; Berody, Sandra; Levtchenko, Elena; Vivarelli, Marina; Webb, Hazel; Haffner, Dieter; Schaefer, Franz; Boyer, Olivia (2020)
    Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders presenting with massive proteinuria within the first 3 months of life almost inevitably leading to end-stage kidney disease. The Work Group for the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Pediatric Nephrology (ESPN) has developed consensus statement on genetic aspects of CNS diagnosis and management. The presented expert opinion recommends genetic diagnostics as the key diagnostic test to be ordered already during the initial evaluation of the patient, discusses which phenotyping workup should be performed and presents known genotype-phenotype correlations.
  • Bettoni, Dario; Domenech, Guillem; Rubio, Javier (2019)
    The combination of non-minimal couplings to gravity with the post-inflationary kinetic-dominated era typically appearing in quintessential inflation scenarios may lead to the spontaneous symmetry breaking of internal symmetries and its eventual restoration at the onset of radiation domination. On general grounds, the breaking of these symmetries leads to the generation of short-lived topological defects that tend to produce gravitational waves until the symmetry is restored. We study here the background of gravitational waves generated by a global cosmic string network following the dynamical symmetry breaking and restoration of a U(1) symmetry. The resulting power spectrum depends on the duration of the heating process and it is potentially detectable, providing a test on the existence of non-minimal couplings to gravity and the characteristic energy scale of post-inflationary physics.
  • Niestroj, Lisa-Marie; Du, Juanjiangmeng; Nothnagel, Michael; May, Patrick; Palotie, Aarno; Daly, Mark J.; Nürnberg, Peter; Blümcke, Ingmar; Lal, Dennis (2018)
    Objective Increasing availability of surgically resected brain tissue from patients with focal epilepsy and focal cortical dysplasia or low-grade glioneuronal tumors has fostered large-scale genetic examination. However, assessment of pathogenicity of germ line and somatic variants remains difficult. Here, we present a state-of-the-art evaluation of reported genes and variants associated with epileptic brain lesions. Methods Results We critically reevaluated the pathogenicity for all neuropathology-associated variants reported to date in the PubMed and ClinVar databases, including 101 neuropathology-associated missense variants encompassing 11 disease-related genes. We assessed gene variant tolerance and classified all identified missense variants according to guidelines from the American College of Medical Genetics and Genomics (ACMG). We further extended the bioinformatic variant prediction by introducing a novel gene-specific deleteriousness ranking for prediction scores. Application of ACMG guidelines and in silico gene variant tolerance analysis classified only seven of 11 genes to be likely disease-associated according to the reported disease mechanism, whereas 61 (60.4%) of 101 variants of those genes were classified as of uncertain significance, 37 (36.6%) as being likely pathogenic, and 3 (3%) as being pathogenic. Significance We concluded that the majority of neuropathology-associated variants reported to date do not have enough evidence to be classified as pathogenic. Interpretation of lesion-associated variants remains challenging, and application of current ACMG guidelines is recommended for interpretation and prediction.
  • Siikamaki, H.; Kivela, P.; Fotopoulos, M.; Ollgren, J.; Kantele, A. (2015)
    The number of international tourist arrivals reached 1,000 million in 2012. Assessment of travellers' health problems has relied on proportionate morbidity data. Given the lack of data on number of visitors to each region, incidences have been impossible to calculate. This study, largest yet reporting travellers' health problems, is the first to present incidence of illness and injury. Data on Finnish travellers with health problems abroad during 2010 to 2012 were retrieved from the database of an assistance organisation, SOS International, covering 95% of those requiring aid abroad. The numbers were compared with those of Finnish travellers in the database of the Official Statistics of Finland. The SOS International database included 50,710 cases: infections constituted the most common health problem (60%), followed by injuries (14%), diseases of skin (5%), musculoskeletal system and connective tissue (5%), digestive tract (3%), and vascular system (2%). Gastroenteritis (23%) and respiratory infections (21%) proved the most frequent diagnoses. Overall incidence of illness or injury was high in Africa (97.9/100,000 travel days; 95% Bayesian credible interval (BCI): 53.1-145.5), southern Europe plus the eastern Mediterranean (92.3; 95% BCI: 75.4-110.1) and Asia (65.0; 95% BCI: 41.5-87.9). The data show significant differences between geographical regions, indicating the main risks and thus providing destination-specific tools for travellers' healthcare.
  • Venhoranta, Heli; Pausch, Hubert; Flisikowski, Krzysztof; Wurmser, Christine; Taponen, Juhani; Rautala, Helena; Kind, Alexander; Schnieke, Angelika; Fries, Ruedi; Lohi, Hannes; Andersson, Magnus (2014)
  • Ramesh, R.; Kumari, A.; Kathiravan, C.; Ketaki, D.; Rajesh, M.; Vrunda, M. (2020)
    We carried out a statistical study of the "quiet" solar corona during the descending phase of the Sunspot Cycle 24 (i.e., January 2015 to May 2019) using data obtained with the Gauribidanur RAdioheliograPH (GRAPH) at 53 and 80 MHz simultaneously. Our results show that the equatorial (east-west) diameters of the solar corona at the above two frequencies shrunk steadily. The decrease was found to be due to a gradual reduction in the coronal electron density (N-e). Independent estimates ofN(e)in the equatorial region of the "background" corona using white-light coronagraph observations indicate a decline consistent with our findings.
  • Schwarz, N.; Hahn, A.; Bast, T.; Mueller, S.; Loeffler, H.; Maljevic, S.; Gaily, E.; Prehl, I.; Biskup, S.; Joensuu, T.; Lehesjoki, A. -E.; Neubauer, B. A.; Lerche, H.; Hedrich, U. B. S. (2016)
    Mutations in SCN2A cause epilepsy syndromes of variable severity including neonatal-infantile seizures. In one case, we previously described additional childhood-onset episodic ataxia. Here, we corroborate and detail the latter phenotype in three further cases. We describe the clinical characteristics, identify the causative SCN2A mutations and determine their functional consequences using whole-cell patch-clamping in mammalian cells. In total, four probands presented with neonatal-onset seizures remitting after five to 13 months. In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly. While this mutation occurred de novo in both patients, one of them carries an additional known variant on the same SCN2A allele, inherited from the unaffected father (p.Gly1522Ala). Whereas p.Arg1882Gly alone shifted the activation curve by -4 mV, the combination of both variants did not affect activation, but caused a depolarizing shift of voltage-dependent inactivation, and a significant increase in Na+ current density and protein production. p.Gly1522Ala alone did not change channel gating. The third new proband carries the same de novo SCN2A gain-of-function mutation as our first published case (p.Ala263Val). Our findings broaden the clinical spectrum observed with SCN2A gain-of-function mutations, showing that fairly different biophysical mechanisms can cause a convergent clinical phenotype of neonatal seizures and later onset episodic ataxia.
  • Durcik, Martina; Lovison, Denise; Skok, Žiga; Durante Cruz, Cristina; Tammela, Päivi; Tomašič, Tihomir; Benetto Tiz, Davide; Draskovits, Gábor; Nyerges, Ákos; Pál, Csaba; Ilaš, Janez; Peterlin Mašič, Lucija; Kikelj, Danijel; Zidar, Nace (2018)
    The ATP binding site located on the subunit B of DNA gyrase is an attractive target for the development of new antibacterial agents. In recent decades, several small-molecule inhibitor classes have been discovered but none has so far reached the market. We present here the discovery of a promising new series of N-phenylpyrrolamides with low nanomolar IC50 values against DNA gyrase, and submicromolar IC50 values against topoisomerase IV from Escherichia coil and Staphylococcus aureus. The most potent compound in the series has an IC50 value of 13 nM against E. coil gyrase. Minimum inhibitory concentrations (MICs) against Gram-positive bacteria are in the low micromolar range. The oxadiazolone derivative with an IC50 value of 85 nM against E. coli DNA gyrase displays the most potent antibacterial activity, with MIC values of 1.56 mu M against Enterococcus faecalis, and 3.13 mu M against wild type S. aureus, methicillinresistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). The activity against wild type E. coli in the presence of efflux pump inhibitor phenylalanine-arginine beta-naphthylamide (PA beta N) is 4.6 mu M. (C) 2018 Elsevier Masson SAS. All rights reserved.
  • Vacca, V.; Murgia, M.; Govoni, F.; Loi, F.; Vazza, F.; Finoguenov, A.; Carretti, E.; Feretti, L.; Giovannini, G.; Concu, R.; Melis, A.; Gheller, C.; Paladino, R.; Poppi, S.; Valente, G.; Bernardi, G.; Boschin, W.; Brienza, M.; Clarke, T. E.; Colafrancesco, S.; Ensslin, T. A.; Ferrari, C.; de Gasperin, F.; Gastaldello, F.; Girardi, M.; Gregorini, L.; Johnston-Hollitt, M.; Junklewitz, H.; Orru, E.; Parma, P.; Perley, R.; Taylor, G. B. (2018)
    We report the detection of diffuse radio emission which might be connected to a large-scale filament of the cosmic web covering a 8 degrees x 8 degrees area in the sky, likely associated with a z approximate to 0.1 overdensity traced by nine massive galaxy clusters. In this work, we present radio observations of this region taken with the Sardinia Radio Telescope. Two of the clusters in the field host a powerful radio halo sustained by violent ongoing mergers and provide direct proof of intracluster magnetic fields. In order to investigate the presence of large-scale diffuse radio synchrotron emission in and beyond the galaxy clusters in this complex system, we combined the data taken at 1.4 GHz with the Sardinia. Radio Telescope with higher resolution data taken with the NRAO VIA Sky Survey. We found 28 candidate new sources with a size larger and X-ray emission fainter than known diffuse large-scale synchrotron cluster sources for a given radio power. This new population is potentially the tip of the iceberg of a class of diffuse large-scale synchrotron sources associated with the filaments of the cosmic web. In addition, we found in the field a candidate new giant radio galaxy.
  • Tuominen, S; Juvonen, V.; Amberla, K; Jolma, T; Rinne, JO; Tuisku, S; Kurki, T; Marttila, R; Pöyhönen, M; Savontaus, ML; Viitanen, M; Kalimo, H (2001)
    Background and Purpose-CADASIL is an autosomal dominant arteriopathy, characterized by multiple brain infarcts, cognitive decline, and finally dementia, which is caused by mutations in Notch3 gene encoding a Notch3 receptor protein. We describe the clinical, neuropsychological, imaging, genetic, and skin biopsy findings in a CADASIL patient homozygous for the C475T mutation resulting in R133C amino acid substitution, in comparison to 9 age-matched heterozygous patients with the same mutation. Methods-The patients were examined clinically and neuropsychologically and with MRI and positron emission tomography for assessment of cerebral blood flow. The gene defect was analyzed by sequencing the products of polymerase chain reaction of exons 3 and 4 of the Notch3 gene. Dermal arteries were analyzed electron microscopically. Results-The homozygous patient had his first-ever stroke at age 28 years. This is markedly earlier than the average, but the patient's heterozygous son had his first transient ischemic attack-like episode at the same age and another heterozygous patient had his first-ever stroke when only 2 years older. He was neuropsychologically more severely deteriorated than all but 1 of the heterozygous patients. These 2 patients had the most severe (confluent grade D) white matter MRI changes. Positron emission tomography showed markedly reduced cerebral blood flow. Skin biopsy revealed profuse deposits of granular osmiophilic material. The progression of disease in the homozygous case was, however, slower than in the most severely affected heterozygous patient. Conclusions-Our homozygous patient's phenotype is within the clinical spectrum of CADASIL, although at its severe end. Thus, CADASIL may follow the classic definition of a dominant disease, according to which the heterozygous and homozygous patients are clinically indistinguishable.
  • Ade, P. A. R.; Aghanim, N.; Armitage-Caplan, C.; Arnaud, M.; Ashdown, M.; Atrio-Barandela, F.; Aumont, J.; Baccigalupi, C.; Banday, A. J.; Barreiro, R. B.; Battaner, E.; Benabed, K.; Benoit, A.; Benoit-Levy, A.; Bernard, J. -P.; Bersanelli, M.; Bertincourt, B.; Bielewicz, P.; Bobin, J.; Bock, J. J.; Bond, J. R.; Borrill, J.; Bouchet, F. R.; Boulanger, F.; Bridges, M.; Bucher, M.; Burigana, C.; Cardoso, J. -F.; Catalano, A.; Challinor, A.; Chamballu, A.; Chary, R. -R.; Chen, X.; Chiang, H. C.; Chiang, L. -Y; Christensen, P. R.; Church, S.; Clements, D. L.; Colombi, S.; Colombo, L. P. L.; Combet, C.; Couchot, F.; Coulais, A.; Crill, B. P.; Curto, A.; Cuttaia, F.; Danese, L.; Davies, R. D.; de Bernardis, P.; de Rosa, A.; de Zotti, G.; Delabrouille, J.; Delouis, J. -M.; Desert, F. -X.; Dickinson, C.; Diego, J. M.; Dole, H.; Donzelli, S.; Dore, O.; Douspis, M.; Dupac, X.; Efstathiou, G.; Ensslin, T. A.; Eriksen, H. K.; Filliard, C.; Finelli, F.; Forni, O.; Frailis, M.; Franceschi, E.; Galeotta, S.; Ganga, K.; Giard, M.; Giardino, G.; Giraud-Heraud, Y.; Gonzalez-Nuevo, J.; Gorski, K. M.; Gratton, S.; Gregorio, A.; Gruppuso, A.; Hansen, F. K.; Hanson, D.; Harrison, D.; Helou, G.; Henrot-Versille, S.; Hernandez-Monteagudo, C.; Herranz, D.; Hildebrandt, S. R.; Hivon, E.; Hobson, M.; Holmes, W. A.; Hornstrup, A.; Hovest, W.; Huffenberger, K. M.; Jaffe, A. H.; Jaffe, T. R.; Jones, W. C.; Juvela, M.; Keihanen, E.; Keskitalo, R.; Kisner, T. S.; Kneissl, R.; Knoche, J.; Knox, L.; Kunz, M.; Kurki-Suonio, H.; Lagache, G.; Lamarre, J. -M.; Lasenby, A.; Laureijs, R. J.; Lawrence, C. R.; Le Jeune, M.; Lellouch, E.; Leonardi, R.; Leroy, C.; Lesgourgues, J.; Liguori, M.; Lilje, P. B.; Linden-Vornle, M.; Lopez-Caniego, M.; Lubin, P. M.; Macias-Perez, J. F.; Maffei, B.; Mandolesi, N.; Maris, M.; Marshall, D. J.; Martin, P. G.; Martinez-Gonzalez, E.; Masi, S.; Massardi, M.; Matarrese, S.; Matthai, F.; Maurin, L.; Mazzotta, P.; McGehee, P.; Meinhold, P. R.; Melchiorri, A.; Mendes, L.; Mennella, A.; Migliaccio, M.; Mitra, S.; Miville-Deschenes, M. -A.; Moneti, A.; Montier, L.; Moreno, R.; Morgante, G.; Mortlock, D.; Munshi, D.; Murphy, J. A.; Naselsky, P.; Nati, F.; Natoli, P.; Netterfield, C. B.; Norgaard-Nielsen, H. U.; Noviello, F.; Novikov, D.; Novikov, I.; Osborne, S.; Oxborrow, C. A.; Paci, F.; Pagano, L.; Pajot, F.; Paladini, R.; Paoletti, D.; Partridge, B.; Pasian, F.; Patanchon, G.; Pearson, T. J.; Perdereau, O.; Perotto, L.; Perrotta, F.; Piacentini, F.; Piat, M.; Pierpaoli, E.; Pietrobon, D.; Plaszczynski, S.; Pointecouteau, E.; Polenta, G.; Ponthieu, N.; Popa, L.; Poutanen, T.; Pratt, G. W.; Prezeau, G.; Prunet, S.; Puget, J. -L.; Rachen, J. P.; Reinecke, M.; Remazeilles, M.; Renault, C.; Ricciardi, S.; Riller, T.; Ristorcelli, I.; Rocha, G.; Rosset, C.; Roudier, G.; Rusholme, B.; Santos, D.; Savini, G.; Scott, D.; Shellard, E. P. S.; Spencer, L. D.; Starck, J. -L.; Stolyarov, V.; Stompor, R.; Sudiwala, R.; Sunyaev, R.; Sureau, F.; Sutton, D.; Suur-Uski, A. -S.; Sygnet, J. -F.; Tauber, J. A.; Tavagnacco, D.; Techene, S.; Terenzi, L.; Tomasi, M.; Tristram, M.; Tucci, M.; Umana, G.; Valenziano, L.; Valiviita, J.; Van Tent, B.; Vielva, P.; Villa, F.; Vittorio, N.; Wade, L. A.; Wandelt, B. D.; Yvon, D.; Zacchei, A.; Zonca, A. (2014)