43 research outputs found
Familial medullary thyroid carcinoma: Clinical variability and low aggressiveness associated with RET mutation at codon 804
No full textSixty-one heterozygotes harboring the germline V804L mutation of the RET protooncogene were identified in five independent families. A total of 31 subjects underwent surgery. Histology identified C cell hyperplasia in 30 cases, isolated in 12 and associated with medullary thyroid carcinoma (MTC) in 18. Six patients with MTC had lymph node metastases. Among the 14 patients with basal detectable calcitonin (CT) level, 12 had MTC and 2 had isolated C cell hyperplasia. In most individuals carrying 804 RET mutation, C cell disease displayed late onset and an indolent course; a pentagastrin test was negative in the majority of heterozygotes during the first 2 decades and was positive in only half of them during the third and fourth decades of life. Interestingly, concomitant somatic M918T was detected in a 12-yr-old girl with MTC and was likely to be responsible for both the early clinical appearance and the aggressiveness of the disease. Our data show that in these gene carriers, surgery may be postponed to the fourth decade of life or until the pentagastrin stimulation test becomes positive. Indeed, our data should be confirmed on a larger series of V804L carriers, but may offer a balanced strategy to keep under control and prevent development of the full disease phenotype
Fitness Ranking of Individual Mutants Drives Patterns of Epistatic Interactions in HIV-1
No full textThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
UvA-DARE (Digital Academic Repository) Link to publication Citation for published version (APA): Evaluation of Complex Inheritance Involving the Most Common Bardet-Biedl Syndrome Locus (BBS1)
No full textGeneral rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 02 Jul 2019 Am. J. Hum. Genet. 72:429-437, 2003 429 Bardet-Biedl syndrome (BBS) is a genetic disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism. Patients with BBS are also at increased risk for diabetes mellitus, hypertension, and congenital heart disease. BBS is known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6). Although these loci were all mapped on the basis of an autosomal recessive mode of inheritance, it has recently been suggested-on the basis of mutation analysis of the identified BBS2, BBS4, and BBS6 genes-that BBS displays a complex mode of inheritance in which, in some families, three mutations at two loci are necessary to manifest the disease phenotype. We recently identified BBS1, the gene most commonly involved in Bardet-Biedl syndrome. The identification of this gene allows for further evaluation of complex inheritance. In the present study we evaluate the involvement of the BBS1 gene in a cohort of 129 probands with BBS and report 10 novel BBS1 mutations. We demonstrate that a common BBS1 missense mutation accounts for ∼80% of all BBS1 mutations and is found on a similar genetic background across populations. We show that the BBS1 gene is highly conserved between mice and humans. Finally, we demonstrate that BBS1 is inherited in an autosomal recessive manner and is rarely, if ever, involved in complex inheritance. Evaluation of Complex Inheritance Involving the Most Common Bardet-Biedl Syndrome Locus (BBS1
The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3
No full textThe sorting of signaling receptors into and out of cilia relies on the BBSome, a complex of Bardet-Biedl syndrome (BBS) proteins, and on the intraflagellar transport (IFT) machinery. GTP loading onto the Arf-like GTPase ARL6/BBS3 drives assembly of a membrane-apposed BBSome coat that promotes cargo entry into cilia, yet how and where ARL6 is activated remains elusive. Here, we show that the Rab-like GTPase IFT27/RABL4, a known component of IFT complex B, promotes the exit of BBSome and associated cargoes from cilia. Unbiased proteomics and biochemical reconstitution assays show that, upon disengagement from the rest of IFT-B, IFT27 directly interacts with the nucleotide-free form of ARL6. Furthermore, IFT27 prevents aggregation of nucleotide-free ARL6 in solution. Thus, we propose that IFT27 separates from IFT-B inside cilia to promote ARL6 activation, BBSome coat assembly, and subsequent ciliary exit, mirroring the process by which BBSome mediates cargo entry into cilia
Systematic timing errors in laser-based transit-time velocimetry
No full textLaser diagnostics for measuring velocity or acceleration are based either on transit-time or Doppler effect. Transit-time techniques rely on the displacement of tracers during a given amount of time. Tracers can be either particles (Particle Image Velocimetry, Particle Tracking Velocimetry) or molecules (Molecular Tagging Velocimetry). In these diagnostics, the velocity or acceleration is controlled by the timing of lasers that are used in dual, triple, or quadruple pulse mode. Of all the sources of uncertainties associated with these techniques, timing has been considered negligible except for occasional misfires or very high-speed flows (? 10 km/s). However, in Q-switched lasers, such as Nd:YAG or Nd:YLF, a systematic bias was measured between the triggered pulse separation (?t) and actual pulse separation values. Several different lasers from various manufacturers were characterized and it was found that the timing uncertainty has a complex relation to the laser power, frequency, and in some cases the triggered ?t. When such lasers are used in a dual cavity configuration, errors vary up to 0.5 ?s and up to 1 ?s for single cavity lasers with dual pulse capabilities. Such large discrepancy can lead to very significant systematic errors in measurements. The various reasons for these discrepancies are discussed and several different approaches are proposed to measure and correct this source of uncertainty
Treatment of severe elbow dysplasia in dogs using arthroscopy
No full textDogs with elbow dysplasia often develop severe lameness in one or both fore legs, associated with
severe and crippling degenerative joint disease. Conservative treatment is generally ineffective and
elbow arthrodesis does not provide satisfactory functional results. Arthroscopic osteo-capsular
arthroplasty produced good and excellent results in 35 of the 42 elbows reviewed by the author
(86%). It may be recommended without reservation in dogs with severe and crippling degenerative
joint disease of the elbow.Les chiens atteints de
dysplasie du coude développent souvent une boiterie sévère d'un ou des deux antérieurs,
associée à une arthrose sévère et invalidante. Le traitement conservateur est la plupart du
temps inefficace et l'arthrodèse du coude ne donne pas de résultats fonctionnels
satisfaisants. L'arthroplastie huméro-radio-ulnaire est une technique de parage de
l'articulation du coude sous arthroscopie. La technique a donné de bons et excellents
résultats sur 35 des 41 coudes revus par l'auteur (86 %). Elle peut être recommandée sans
hésitation chez tous les chiens atteints d'une arthrose sévère et invalidante du
coude
New ophthalmosaurid ichthyosaurs from the European lower cretaceous demonstrate extensive ichthyosaur survival across the Jurassic–Cretaceous boundary
No full textBackground
Ichthyosauria is a diverse clade of marine amniotes that spanned most of the Mesozoic. Until recently, most authors interpreted the fossil record as showing that three major extinction events affected this group during its history: one during the latest Triassic, one at the Jurassic–Cretaceous boundary (JCB), and one (resulting in total extinction) at the Cenomanian-Turonian boundary. The JCB was believed to eradicate most of the peculiar morphotypes found in the Late Jurassic, in favor of apparently less specialized forms in the Cretaceous. However, the record of ichthyosaurs from the Berriasian–Barremian interval is extremely limited, and the effects of the end-Jurassic extinction event on ichthyosaurs remains poorly understood.
Methodology/Principal Findings
Based on new material from the Hauterivian of England and Germany and on abundant material from the Cambridge Greensand Formation, we name a new ophthalmosaurid, Acamptonectes densus gen. et sp. nov. This taxon shares numerous features with Ophthalmosaurus, a genus now restricted to the Callovian–Berriasian interval. Our phylogenetic analysis indicates that Ophthalmosauridae diverged early in its history into two markedly distinct clades, Ophthalmosaurinae and Platypterygiinae, both of which cross the JCB and persist to the late Albian at least. To evaluate the effect of the JCB extinction event on ichthyosaurs, we calculated cladogenesis, extinction, and survival rates for each stage of the Oxfordian–Barremian interval, under different scenarios. The extinction rate during the JCB never surpasses the background extinction rate for the Oxfordian–Barremian interval and the JCB records one of the highest survival rates of the interval.
Conclusions/Significance
There is currently no evidence that ichthyosaurs were affected by the JCB extinction event, in contrast to many other marine groups. Ophthalmosaurid ichthyosaurs remained diverse from their rapid radiation in the Middle Jurassic to their total extinction at the beginning of the Late Cretaceous
Cirurgia ortopédica de animais de companhia
No full textRelatório de Estágio Final, Mestrado Integrado em Medicina VeterináriaConsiderando a crescente valorização e importância dos animais de companhia nas famílias dos dias de hoje, é preciso ter também em conta a crescente necessidade de proporcionar uma vida mais confortável, saudável e feliz aos mesmos. O tratamento da patologia do foro ortopédico é frequentemente necessário em clínica de animais de companhia. Em muitos casos, este passa apenas por tratamento médico/conservativo (talas e bandagens, por exemplo), contudo noutros casos é imprescindível a realização de tratamento cirúrgico. Dependendo da gravidade da lesão, o tratamento cirúrgico pode ir desde a aplicação de implantes ósseos, como sejam placas e parafusos ósseos até à necessidade de amputação total de um membro ou colocação de uma prótese. O presente relatório de estágio final foi elaborado no âmbito da conclusão do Mestrado Integrado em Medicina Veterinária e teve por objetivo inicial, demonstrar as atividades práticas realizadas durante o estágio curricular, que teve a duração de seis meses. Seguidamente é feita uma breve abordagem aos princípios básicos da cirurgia ortopédica, seguida da descrição e discussão de quatro casos clínicos desta área cirúrgica, que suscitaram especial interesse na autora deste trabalho. O primeiro e segundo casos clínicos são alusivos a dois animais que se apresentaram à consulta com diagnóstico de displasia da anca. Apesar da patologia ser a mesma, as consequências desta presentes nos animais, de destacar a osteoartrite, e a diferença de idades entre os dois levou à indicação e realização de dois tratamentos distintos e com diferentes objetivos. O terceiro caso é referente a um cão de raça Pastor Alemão com severa hiperextensão de ambas as articulações dos carpos direito e esquerdo, que apresentava uma posição dos membros plantígrada, quando em estação. O tratamento cirúrgico desta condição passou pela realização de artrodese total de ambos os carpos. O quarto e último caso apresentado neste relatório descreve a história de uma cadela com claudicação e atrofia severa do membro pélvico direito, à qual foi diagnosticada uma má união do fémur direito por outro médico veterinário. Este indicou aos tutores que a realização de cirurgia corretiva estaria contraindicada nesta situação, recomendando sessões de osteopatia. Acabou por se realizar a cirurgia (osteotomia corretiva) e houve uma total recuperação do estado clínico do animal, apesar deste continuar a apresentar uma ligeira atrofia do membro.Considering the growing appreciation and importance of companion animals in the families of today, it is also necessary to take into account the growing need to provide a more comfortable, healthy and happy life for them. The treatment of orthopedic pathologies is often necessary in small animal clinics. In many cases, this consists only of medical/conservative treatment (splints and bandages, for example); however, in other cases it is essential to carry out surgical treatment. Depending on the severity of the injury, surgical treatment can range from an application of bone implants such as bone plates and screws, to the need for total amputation of a limb or placement of a prosthesis. This final internship report was carried out within the scope of the conclusion of the Integrated Master in Veterinary Medicine, and its first goal is to demonstrate the practical activities carried out during the curricular internship, lasting a total of six months. Consequently, a brief approach to the basic principles of orthopedic surgery is introduced, followed by the description and discussion of four clinical cases in this surgical area, which aroused special interest in the author of this work. The first and second clinical cases allude to two animals that came to the consultation with a diagnosis of hip dysplasia. Although the pathology is the same, the consequences of this, present in animals, highlight osteoarthritis, and the difference in age between the two led to the indication and performance of two different treatments with different objectives. The third case refers to a German shepherd dog with severe hyperextension of both right and left carpal joints, which presented to clinic with a plantigrade position of the limbs, when in stationary. The surgical treatment of this condition involved completing total arthrodesis of both carpals. The fourth and final case presented in this report describes the medical story of a dog with lameness and sever atrophy of the right pelvic limb, who was diagnosed with a malunion of the right femur by another veterinarian. The latter indicated to the tutors that performing corrective surgery would be contraindicated in this situation, recommending osteopathic sessions. Eventually the surgery (corrective osteotomy) was performed and there was a complete recovery of the animal’s clinical status, despite continued present of a slight atrophy of the limb
Retinitis Pigmentosa GTPase Regulator (RPGR) protein isoforms in mammalian retina:insights into X-linked Retinitis Pigmentosa and associated ciliopathies
No full textMutations in the cilia-centrosomal protein Retinitis Pigmentosa GTPase Regulator (RPGR) are a frequent cause of retinal degeneration. The RPGR gene undergoes complex alternative splicing and encodes multiple protein isoforms. To elucidate the function of major RPGR isoforms (RPGR 1-19 and RPGR ORF15), we have generated isoform-specific antibodies and examined their expression and localization in the retina. Using sucrose-gradient centrifugation, immunofluorescence and co-immunoprecipitation methods, we show that RPGR isoforms localize to distinct sub-cellular compartments in mammalian photoreceptors and associate with a number of cilia-centrosomal proteins. The RCC1-like domain of RPGR, which is present in all major RPGR isoforms, is sufficient to target it to the cilia and centrosomes in cultured cells. Our findings indicate that multiple isotypes of RPGR may perform overlapping yet somewhat distinct transport-related functions in photoreceptors
Author response: A recombinant BBSome core complex and how it interacts with ciliary cargo
No full textCilia are small, antenna-like structures on the surface of eukaryotic cells that harbor a unique set of sensory proteins, including GPCRs and other membrane proteins. The transport of these proteins involves the BBSome, an eight-membered protein complex that is recruited to ciliary membranes by the G-protein Arl6. BBSome malfunction leads to Bardet-Biedl syndrome, a ciliopathy with severe consequences. Short ciliary targeting sequences (CTS) have been identified that trigger the transport of ciliary proteins. However, mechanistic studies that relate ciliary targeting to BBSome binding are missing. Here we used heterologously expressed BBSome subcomplexes to analyze the complex architecture and to investigate the binding of GPCRs and other receptors to the BBSome. A stable heterohexameric complex was identified that binds to GPCRs with interactions that only partially overlap with previously described CTS, indicating a more complex recognition than anticipated. Arl6•GTP does not affect these interactions, suggesting no direct involvement in cargo loading/unloading.</jats:p
