Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 49
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Perinatol ; 39(12): 1611-1619, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31395954

RESUMO

OBJECTIVE: To determine the proportion of infant deaths occurring in the setting of a confirmed genetic disorder. STUDY DESIGN: A retrospective analysis of the electronic medical records of infants born from 1 January, 2011 to 1 June, 2017, who died prior to 1 year of age. RESULTS: Five hundred and seventy three deceased infants were identified. One hundred and seventeen were confirmed to have a molecular or cytogenetic diagnosis in a clinical diagnostic laboratory and an additional seven were diagnosed by research testing for a total of 124/573 (22%) diagnosed infants. A total of 67/124 (54%) had chromosomal disorders and 58/124 (47%) had single gene disorders (one infant had both). The proportion of diagnoses made by sequencing technologies, such as exome sequencing, increased over the years. CONCLUSIONS: The prevalence of confirmed genetic disorders within our cohort of infant deaths is higher than that previously reported. Increased efforts are needed to further understand the mortality burden of genetic disorders in infancy.

2.
J Sports Sci ; 37(21): 2506-2512, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31362579

RESUMO

The study assesses the test-retest reliability of movement and physiological measures during a simulated rugby match that employed activities performed in a stochastic order. Twenty male rugby players (21.4 ± 2.1 y) completed two trials of a 2 × 23 min rugby movement simulation protocol during which the order of events was performed in a stochastic order, with 7-10 days between trials. Movement characteristics, heart rate (HR), RPE, maximum voluntary contraction (MVC), voluntary activation (VA%) of the quadriceps, Stroop test and subjective task load rating (NASA-TLX) were measured. The most reliable measures of external load was relative distance (typical error [TE] and CV% = 1.5-1.6 m min-1 and 1.4-1.5%, respectively), with all other movement characteristics possessing a CV% <5%. The most reliable measure of internal load, neuromuscular function and perceptual measures were for %HRmax (TE and CV% = 1.4-1.7% and 1.4-2.1%, respectively), MVC before (TE and CV% = 10.8-14.8 N·m and 3.8-4.6%, respectively), and average RPE (TE and CV% = 0.5-0.8 AU and 3.6-5.5%, respectively). The Stroop test, NASA-TLX and blood lactate produced the least reliable measures (CV% >5%). Future studies can confidently examine changes in several perceptual, neuromuscular, physiological and movement measures related to rugby activity using stochastic movements.

3.
Skelet Muscle ; 8(1): 23, 2018 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-30060766

RESUMO

BACKGROUND: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration. METHODS: Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants. RESULTS: Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase. CONCLUSIONS: Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.


Assuntos
Variação Genética , Distrofia Muscular do Cíngulo dos Membros/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Distroglicanas/metabolismo , Feminino , Predisposição Genética para Doença , Glicosilação , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Mutação , Fenótipo , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
4.
Brain ; 141(8): 2299-2311, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29985992

RESUMO

The transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes.


Assuntos
Transtornos do Neurodesenvolvimento/genética , Proteínas Repressoras/genética , Proteínas Repressoras/fisiologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/fisiologia , Adolescente , Animais , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica/genética , Mutação em Linhagem Germinativa , Haploinsuficiência , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Linfócitos/patologia , Linfócitos/fisiologia , Masculino , Camundongos , Mutação , Proteínas Repressoras/metabolismo , Linfócitos T/fisiologia , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/metabolismo
5.
Beilstein J Nanotechnol ; 8: 2339-2344, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29181290

RESUMO

The development of methods to produce nanoscale features with tailored chemical functionalities is fundamental for applications such as nanoelectronics and sensor fabrication. The molecular-ruler process shows great utility for this purpose as it combines top-down lithography for the creation of complex architectures over large areas in conjunction with molecular self-assembly, which enables precise control over the physical and chemical properties of small local features. The molecular-ruler process, which most commonly uses mercaptoalkanoic acids and metal ions to generate metal-ligated multilayers, can be employed to produce registered nanogaps between metal features. Expansion of this methodology to include molecules with other chemical functionalities could greatly expand the overall versatility, and thus the utility, of this process. Herein, we explore the use of alkanethiol molecules as the terminating layer of metal-ligated multilayers. During this study, it was discovered that the solution deposition of alkanethiol molecules resulted in low overall surface coverage with features that varied in height. Because features with varied heights are not conducive to the production of uniform nanogaps via the molecular-ruler process, the vapor-phase deposition of alkanethiol molecules was explored. Unlike the solution-phase deposition, alkanethiol islands produced by vapor-phase deposition exhibited markedly higher surface coverages of uniform heights. To illustrate the applicability of this method, metal-ligated multilayers, both with and without an alkanethiol capping layer, were utilized to create nanogaps between Au features using the molecular-ruler process.

6.
Am J Hum Genet ; 101(2): 267-273, 2017 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-28777933

RESUMO

Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5'- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.


Assuntos
Encefalopatias/genética , Nucléolo Celular/patologia , Doenças Neurodegenerativas/genética , Proteínas Pol1 do Complexo de Iniciação de Transcrição/genética , RNA Ribossômico 18S/biossíntese , Adolescente , Adulto , Atrofia/genética , Encéfalo/patologia , Encefalopatias/patologia , Criança , Cromatina/metabolismo , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Doenças Neurodegenerativas/patologia , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Adulto Jovem
7.
Int J Sports Physiol Perform ; 12(9): 1192-1198, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28182509

RESUMO

PURPOSE: To examine the influence of knowledge of exercise duration on pacing and performance during simulated rugby league match play. METHODS: Thirteen male university rugby players completed 3 simulated rugby league matches (RLMSP-i) on separate days in a random order. In a control trial, participants were informed that they would be performing 2 × 23-min bouts (separated by 20 min) of the RLMSP-i (CON). In a second trial, participants were informed that they would be performing 1 × 23-min bout of the protocol but were then asked to perform another 23-min bout (DEC). In a third trial, participants were not informed of the exercise duration and performed 2 × 23-min bouts (UN). RESULTS: Distance covered and high-intensity running were higher in CON (4813 ± 167 m, 26 ± 4.1 m/min) than DEC (4764 ± 112 m, 25.2 ± 2.8 m/min) and UN (4744 ± 131 m, 24.4 m/min). Compared with CON, high-intensity running and peak speed were typically higher for DEC in bout 1 and lower in bout 2 of the RLMSP-i, while UN was generally lower throughout. Similarly, DEC resulted in an increased heart rate, blood lactate, and rating of perceived exertion than CON in bout 1, whereas these variables were lower throughout the protocol in UN. CONCLUSIONS: Pacing and performance during simulated rugby league match play depend on an accurate understanding of the exercise endpoint. Applied practitioners should consider informing players of their likely exercise duration to maximize running.


Assuntos
Desempenho Atlético/psicologia , Futebol Americano/psicologia , Esforço Físico , Adulto , Desempenho Atlético/fisiologia , Futebol Americano/fisiologia , Frequência Cardíaca , Humanos , Ácido Láctico/sangue , Masculino , Corrida/fisiologia , Corrida/psicologia , Fatores de Tempo , Adulto Jovem
8.
Eur J Hum Genet ; 25(4): 509-511, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28098151

RESUMO

Gain-of-function variants in some RAS-MAPK pathway genes, including PTPN11 and NRAS, are associated with RASopathies and/or acquired hematological malignancies, most notably juvenile myelomonocytic leukemia (JMML). With rare exceptions, the spectrum of germline variants causing RASopathies does not overlap with the somatic variants identified in isolated JMML. Studies comparing these variants suggest a stronger gain-of-function activity in the JMML variants. As JMML variants have not been identified as germline defects and have a greater impact on protein function, it has been speculated that they would be embryonic lethal. Here we identified three variants, which have previously only been identified in isolated somatic JMML and other sporadic cancers, in four cases with a severe pre- or neo-natal lethal presentation of Noonan syndrome. These cases support the hypothesis that these stronger gain-of-function variants are rarely compatible with life.


Assuntos
GTP Fosfo-Hidrolases/genética , Mutação em Linhagem Germinativa , Leucemia Mielomonocítica Juvenil/genética , Proteínas de Membrana/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Feminino , Humanos , Recém-Nascido , Síndrome de Noonan/diagnóstico , Gravidez
9.
Int J Sports Physiol Perform ; 12(2): 264-267, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27193085

RESUMO

This aim of this study was to examine the validity of energy expenditure derived from microtechnology when measured during a repeated-effort rugby protocol. Sixteen male rugby players completed a repeated-effort protocol comprising 3 sets of 6 collisions during which movement activity and energy expenditure (EEGPS) were measured using microtechnology. In addition, energy expenditure was estimated from open-circuit spirometry (EEVO2). While related (r = .63, 90%CI .08-.89), there was a systematic underestimation of energy expenditure during the protocol (-5.94 ± 0.67 kcal/min) for EEGPS (7.2 ± 1.0 kcal/min) compared with EEVO2 (13.2 ± 2.3 kcal/min). High-speed-running distance (r = .50, 95%CI -.66 to .84) was related to EEVO2, while PlayerLoad was not (r = .37, 95%CI -.81 to .68). While metabolic power might provide a different measure of external load than other typically used microtechnology metrics (eg, high-speed running, PlayerLoad), it underestimates energy expenditure during intermittent team sports that involve collisions.


Assuntos
Acelerometria , Metabolismo Energético , Futebol Americano/fisiologia , Sistemas de Informação Geográfica , Frequência Cardíaca/fisiologia , Humanos , Ácido Láctico/sangue , Masculino , Percepção , Condicionamento Físico Humano , Esforço Físico/fisiologia , Corrida/fisiologia , Adulto Jovem
10.
Pract Radiat Oncol ; 6(6): 429-435, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27209311

RESUMO

PURPOSE: Tools for assessing the severity and risk of near-miss events in radiation oncology are few and needed. Recent work has described guidelines for the use of a 5-tier near-miss risk index (NMRI) for the classification of near-miss events. The purpose of this study was to assess the reliability of the NMRI among users in a radiation oncology department. METHODS AND MATERIALS: Reliability of the NMRI was assessed using an online survey distributed to members of a radiation oncology department. The survey contained 70 events extracted from the department's incident learning system (ILS). Survey participants rated each event using the NMRI guidelines, reported their attendance to weekly ILS meetings (used as a surrogate for familiarity with the ILS), and indicated their familiarity with the radiation oncology workflow. Interrater reliability was determined using Krippendorff's alpha. Use of the NMRI to rate actual events during 5 weekly ILS meetings was also assessed and interrater reliability determined. RESULTS: Twenty-eight survey respondents represented a wide variety of care providers. Krippendorff's alpha was calculated for the whole respondent cohort to be 0.376, indicating fair agreement among raters. Respondents who had the most participation at ILS meetings (n = 4) had moderate agreement with an alpha of 0.501. Interestingly, there were significant differences in reliability and median NMRI scores between professions. NMRI use during weekly NMRI meetings (80 events rated), participants showed moderate reliability (alpha = 0.607). CONCLUSIONS: Using the NMRI guidelines, raters from a wide variety of professions were able to assess the severity of near-miss incidents with fair agreement. Those experienced with the ILS showed better agreement, and higher agreement was seen during multidisciplinary ILS meetings. These data support the use the indices such as the NMRI for near-miss risk assessment in patient safety and prioritization of process improvements in radiation oncology.


Assuntos
Near Miss/estatística & dados numéricos , Variações Dependentes do Observador , Radioterapia (Especialidade) , Medição de Risco/métodos , Humanos , Reprodutibilidade dos Testes , Inquéritos e Questionários , Fluxo de Trabalho
11.
Pract Radiat Oncol ; 5(5): e409-e416, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26231595

RESUMO

PURPOSE: There is a growing interest in the application of incident learning systems (ILS) to radiation oncology. The purpose of the present study is to define statistical metrics that may serve as benchmarks for successful operation of an incident learning system. METHODS AND MATERIALS: A departmental safety and quality ILS was developed to monitor errors, near-miss events, and process improvement suggestions. Event reports were reviewed by a multiprofessional quality improvement committee. Events were scored by a near-miss risk index (NMRI) and categorized by event point of origination and discovery. Reporting trends were analyzed over a 2-year period, including total number and rates of events reported, users reporting, NMRI, and event origination and discovery. RESULTS: A total of 1897 reports were evaluated (1.0 reports/patient, 0.9 reports/unique treatment course). Participation in the ILS increased as demonstrated by total events (2.1 additional reports/month) and unique users (0.5 new users/month). Sixteen percent of reports had an NMRI of 0 (none), 42% had an NMRI of 1 (mild), 25% had an NMRI of 2 (moderate), 12% had an NMRI of 3 (severe), and 5% had an NMRI of 4 (critical). Event NMRI showed a significant decrease in the first 6 months (1.68-1.42, P < .001). Trends in origination and discovery of reports were broadly distributed between radiation therapy process steps and staff groups. The highest risk events originated in imaging for treatment planning (NMRI = 2.0 ± 1.1; P < .0001) and were detected in on-treatment quality management (NMRI = 1.7 ± 1.1; P = .003). CONCLUSIONS: Over the initial 2-year period of ILS operation, rates of reporting increased, staff participation increased, and NMRI of reported events declined. These data mirror previously reported findings of improvement in safety culture endpoints. These metrics may be useful for other institutions seeking to create or evaluate their own ILS.


Assuntos
Segurança do Paciente/normas , Aprendizagem Baseada em Problemas/métodos , Radioterapia (Especialidade)/normas , Gestão de Riscos/métodos , Gestão de Riscos/normas , Consenso , Humanos , Melhoria de Qualidade
12.
Int J Sports Physiol Perform ; 10(6): 746-53, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25932657

RESUMO

It is important to understand the extent to which physical contact changes the internal and external load during rugby simulations that aim to replicate the demands of match play. Accordingly, this study examined the role of physical contact on the physiological and perceptual demands during and immediately after a simulated rugby league match. Nineteen male rugby players completed a contact (CON) and a noncontact (NCON) version of the rugby league match-simulation protocol in a randomized crossover design with 1 wk between trials. Relative distance covered (ES = 1.27; ± 0.29), low-intensity activity (ES = 1.13; ± 0.31), high-intensity running (ES = 0.49; ± 0.34), heart rate (ES = 0.52; ± 0.35), blood lactate concentration (ES = 0.78; ± 0.34), rating of perceived exertion (RPE) (ES = 0.72; ± 0.38), and session RPE (ES = 1.45; ± 0.51) were all higher in the CON than in the NCON trial. However, peak speeds were lower in the CON trial (ES = -0.99; ± 0.40) despite unclear reductions in knee-extensor (ES = 0.19; ± 0.40) and -flexor (ES = 0.07; ± 0.43) torque. Muscle soreness was also greater after CON than in the NCON trial (ES = 0.97; ± 0.55). The addition of physical contact to the movement demands of a simulated rugby league match increases many of the external and internal demands but also results in players' slowing their peak running speed during sprints. These findings highlight the importance of including contacts in simulation protocols and training practices designed to replicate the demands of real match play.


Assuntos
Atletas , Desempenho Atlético , Futebol Americano , Atividade Motora , Músculo Esquelético/fisiologia , Corrida , Aceleração , Adulto , Atletas/psicologia , Desempenho Atlético/psicologia , Fenômenos Biomecânicos , Comportamento Competitivo , Estudos Cross-Over , Futebol Americano/psicologia , Humanos , Masculino , Fadiga Muscular , Força Muscular , Resistência Física , Análise e Desempenho de Tarefas , Fatores de Tempo , Torque , Adulto Jovem
13.
Scanning ; 37(1): 6-16, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25377299

RESUMO

Strategies to regulate the self-assembly of adsorbates to create surface structures with molecular-scale features and organization are of broad interest to nanoscience, biochemistry, and engineering. One approach utilizes molecules with tailored intermolecular interaction strengths and topologies to direct molecular self-assembly as exemplified by the adsorption of 1-adamantanethiol molecules on Au{111} substrates. 1-Adamantanethiolate self-assembled monolayers exhibit decreased packing densities and weaker intermolecular interaction strengths than n-alkanethiolate self-assembled monolayers, which result in their complete displacement upon exposure to n-alkanethiol molecules. Herein, we explore the capabilities of the atomic force microscopy-based lithographic technique, nanografting, to fabricate chemical patterns comprised of 1-adamantanethiolate monolayers. Positive 1-adamantanethiolate patterns are generated by nanografting 1-adamantanethiol molecules into preexisting n-alkanethiolate self-assembled monolayers, and negative 1-adamantanethiolate patterns are created by nanografting n-alkanethiol molecules into preexisting 1-adamantanethiolate self-assembled monolayers. The patterned 1-adamantanethiolate regions are displaced upon exposure to solutions of n-alkanethiol molecules. This two-step nanografting-displacement strategy minimizes pattern dissolution as 1-adamantanethiol molecules do not intercalate into the preexisting self-assembled monolayer during nanografting. 1-Adamantanethiol can be utilized create high-resolution sacrificial chemical patterns with feature sizes beyond those afforded other 1-adamantanethiol patterning strategies for applications such as resists for metallic and organic structures.

14.
Langmuir ; 30(25): 7447-55, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24897619

RESUMO

Hybrid chemical patterning strategies that combine the sophistication of lithography with the intrinsic precision of molecular self-assembly are of broad interest for applications including nanoelectronics and bioactive surfaces. This approach is exemplified by the molecular-ruler process where the sequential deposition of mercaptoalkanoic acid molecules and coordinated metal ions is integrated with conventional lithographic techniques to fabricate registered, nanometer-scale spacings. Herein, we illustrate the capabilities of atomic force microscopy characterization and lithography to investigate the morphology, quality, and local thickness of Cu-ligated mercaptohexadecanoic acid multilayers on Au{111} substrates. These multilayers are a key component utilized in the molecular-ruler process. The rich and varied topographic features of each layer are investigated via contact-mode atomic force microscopy. Using nanoshaving, an atomic force microscopy lithographic strategy that reveals the underlying Au{111} substrate via tip-induced desorption of a molecular film, the local thicknesses of these multilayers are ascertained; these thicknesses are consistent with the anticipated heights for Cu-ligated mercaptohexadecanoic acid multilayers as well as previous ensemble surface analytical measurements. By regulating the force set point utilized during nanoshaving, the upper layer of a Cu-ligated mercaptohexadecanoic acid bilayer is removed, revealing the carboxyl moiety of the lower mercaptohexadecanoic acid layer. This selective nanoshaving demonstrates a simple and practical means to generate three-dimensional multilayers and to reveal buried chemical functionalities within metal-ligated multilayers.

15.
PLoS One ; 9(2): e89673, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24586954

RESUMO

mRNA synthesis, processing, and destruction involve a complex series of molecular steps that are incompletely understood. Because the RNA intermediates in each of these steps have finite lifetimes, extensive mechanistic and dynamical information is encoded in total cellular RNA. Here we report the development of SnapShot-Seq, a set of computational methods that allow the determination of in vivo rates of pre-mRNA synthesis, splicing, intron degradation, and mRNA decay from a single RNA-Seq snapshot of total cellular RNA. SnapShot-Seq can detect in vivo changes in the rates of specific steps of splicing, and it provides genome-wide estimates of pre-mRNA synthesis rates comparable to those obtained via labeling of newly synthesized RNA. We used SnapShot-Seq to investigate the origins of the intrinsic bimodality of metazoan gene expression levels, and our results suggest that this bimodality is partly due to spillover of transcriptional activation from highly expressed genes to their poorly expressed neighbors. SnapShot-Seq dramatically expands the information obtainable from a standard RNA-Seq experiment.


Assuntos
RNA Mensageiro/metabolismo , Processamento Alternativo , Biflavonoides/farmacologia , Células HeLa/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Íntrons , Modelos Teóricos , Método de Monte Carlo , RNA/genética , Precursores de RNA , Processamento de RNA , Estabilidade de RNA , RNA Mensageiro/genética , Análise de Sequência de RNA/métodos , Transcrição Genética
16.
Head Neck ; 35(6): E197-201, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22367919

RESUMO

BACKGROUND: Esophageal strictures are a common sequela of chemoradiation and/or surgery to the head and neck cancers and can lead to stenosis and significant dysphagia. Endoscopic dilation endoscopic and placement of self-expanding stents are often to used relieve dysphagia symptoms. However, these stents are not without risks and complications. METHODS: We present a case of a 58-year-old man who had the rare complication of cervical osteomyelitis as a result of plastic esophageal stent placement for palliation of chemoradiation-induced strictures. RESULTS: The patient was successfully managed with immobilization of the cervical spine in a halo vest and appropriate antibiotics. CONCLUSION: To the best of our knowledge, this is the first reported case of cervical spine osteomyelitis after self-expanding plastic stent (SEPS) placement for esophageal stricture. It was successfully treated with immobilization and antibiotic therapy. The treating physician should be aware of this rare complication to make an early diagnosis. Literature on esophageal stent-induced cervical osteomyelitis is reviewed.


Assuntos
Quimiorradioterapia Adjuvante/efeitos adversos , Estenose Esofágica/cirurgia , Osteomielite/etiologia , Cuidados Paliativos , Stents/efeitos adversos , Antibacterianos/uso terapêutico , Carcinoma de Células Escamosas/terapia , Cefepima , Cefalosporinas/uso terapêutico , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/cirurgia , Estenose Esofágica/complicações , Estenose Esofágica/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Osteomielite/tratamento farmacológico , Neoplasias Faríngeas/terapia , Vancomicina/uso terapêutico
17.
Am J Med Genet A ; 158A(8): 1909-17, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22786811

RESUMO

Norrie disease (ND) is an X-linked recessive disorder characterized by congenital blindness, progressive sensorineural hearing loss and cognitive impairment. The ocular phenotype has been well described, while the extraocular manifestations of the disorder are not well understood. We present the data from the Norrie Disease Registry, which consists of 56 patients with detailed clinical histories and genotype data. This study represents the largest, detailed investigation into the phenotypic spectrum of ND to date and more importantly expands knowledge of the extraocular clinical manifestations. We identify several novel aspects of the syndrome that will improve the management of these patients. In particular, we expand our understanding of the neurologic manifestations in ND and identify a chronic seizure disorder in approximately 10% of all patients. In addition, details of the hearing phenotype are described including the median age of onset (12 years of age) and how genotype affects onset. Moreover, we find vascular disease to be a significant component of ND; and vascular health should be, in the future, a component of patient clinical care. In summary, the results expand our understanding of the phenotypic variability and genotypic heterogeneity in ND patients.


Assuntos
Cegueira/congênito , Doenças do Sistema Nervoso/patologia , Espasmos Infantis/patologia , Cegueira/genética , Cegueira/patologia , Doenças Genéticas Ligadas ao Cromossomo X , Genótipo , Humanos , Masculino , Doenças do Sistema Nervoso/genética , Testes Neuropsicológicos , Fenótipo , Degeneração Retiniana , Espasmos Infantis/genética , Inquéritos e Questionários
18.
Amyotroph Lateral Scler ; 13(2): 217-22, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22292843

RESUMO

SOD1, ANG, TARDBP and FUS mutations have been associated with amyotrophic lateral sclerosis (ALS). Our goal was to extend molecular genetic analysis to newly identified ALS genetic loci and to determine the frequency of mutations, distribution of disease genes, and variant spectrum of these genes in a large United States ALS-phenotype cohort. We screened 1220 probands with an ALS phenotype, referred originally for SOD1 molecular genetic analysis. 1128 SOD1-negative probands were screened for ANG, and 277 and 223 SOD1- and ANG-negative samples were screened for TARDBP and FUS, respectively. One hundred additional probands were specifically screened only for FUS exon 15. We identified a total of 36 different SOD1 mutations, including three novel mutations, in 92 probands. ANG screening identified three mutations, including two novel mutations, and TARDBP screening identified two previously reported TARDBP mutations. We also identified four mutations in FUS, including the reported FUS in-frame deletion, c.430_447del, p.Gly144_Tyr149del, in a patient with inclusion body myositis, and two known FUS missense mutations. From this study, we estimate frequencies for SOD1, ANG, TARDBP and FUS mutations, in this United States cohort, to be 7.5%, 0.71%, 0.72% and 1.9%, respectively. In conclusion, we identify novel variants in SOD1, ANG, TARDBP and FUS, and expand the FUS-associated clinicopathologic phenotype.


Assuntos
Esclerose Amiotrófica Lateral/genética , Técnicas de Laboratório Clínico , Proteínas de Ligação a DNA/genética , Proteína FUS de Ligação a RNA/genética , Ribonuclease Pancreático/genética , Superóxido Dismutase/genética , Esclerose Amiotrófica Lateral/fisiopatologia , Predisposição Genética para Doença , Testes Genéticos , Humanos , Mutação , Fenótipo , Superóxido Dismutase-1 , Estados Unidos
19.
Biochem J ; 441(3): 789-802, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22248339

RESUMO

Sphingolipid metabolism in metazoan cells consists of a complex interconnected web of numerous enzymes, metabolites and modes of regulation. At the centre of sphingolipid metabolism reside CerSs (ceramide synthases), a group of enzymes that catalyse the formation of ceramides from sphingoid base and acyl-CoA substrates. From a metabolic perspective, these enzymes occupy a unique niche in that they simultaneously regulate de novo sphingolipid synthesis and the recycling of free sphingosine produced from the degradation of pre-formed sphingolipids (salvage pathway). Six mammalian CerSs (CerS1-CerS6) have been identified. Unique characteristics have been described for each of these enzymes, but perhaps the most notable is the ability of individual CerS isoforms to produce ceramides with characteristic acyl-chain distributions. Through this control of acyl-chain length and perhaps in a compartment-specific manner, CerSs appear to regulate multiple aspects of sphingolipid-mediated cell and organismal biology. In the present review, we discuss the function of CerSs as critical regulators of sphingolipid metabolism, highlight their unique characteristics and explore the emerging roles of CerSs in regulating programmed cell death, cancer and many other aspects of biology.


Assuntos
Oxirredutases/fisiologia , Esfingolipídeos/metabolismo , Esfingolipídeos/fisiologia , Animais , Biologia/tendências , Ceramidas/metabolismo , Ceramidas/fisiologia , Humanos , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Mamíferos/genética , Mamíferos/metabolismo , Modelos Biológicos , Oxirredutases/genética , Oxirredutases/metabolismo
20.
Anticancer Agents Med Chem ; 12(4): 340-63, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21707511

RESUMO

Programmed cell death, or apoptosis, is a complex process whereby eukaryotic cells react to physiologic or pathophysiologic stimuli by undergoing genetically programmed suicide. Programmed cell death involves many well-characterized signaling pathways including permeabilization of the mitochondrial outer membrane and activation of caspases. Other pathways, such as pro-apoptotic lipid signaling, are less understood despite many years of study. The sphingolipid ceramide has received considerable attention as a key regulator of programmed cell death, yet the mechanisms of its up-regulation and ability to control cell fate remain ill-defined. In this review, we will examine the connections between sphingolipid metabolism and programmed cell death with a focus on the role of de novo sphingolipid synthesis and sphingosine salvage in producing pro-apoptotic ceramide. We will also highlight the evidence supporting an increasingly complex role for ceramide in regulating apoptosis and provide a framework in which to ask new questions about the functions of this enigmatic lipid.


Assuntos
Apoptose , Ceramidas/metabolismo , Esfingolipídeos/metabolismo , Animais , Ceramidas/química , Humanos , Oxirredutases/metabolismo , Serina C-Palmitoiltransferase/metabolismo , Transdução de Sinais , Esfingolipídeos/química , Esfingomielina Fosfodiesterase/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA