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1.
Pediatr Surg Int ; 38(4): 617-621, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35175403

RESUMO

AIM: Several studies have addressed the long-term functional, psychosexual and psychosocial outcomes following sacrococcygeal teratoma (SCT) excision. It is well reported that the classical chevron incision and reconstruction can leave a cosmetically unsatisfactory result; however, there is little in the literature focussed on improving this outcome. In our institution the preference is to perform a midline reconstruction, where possible, this is felt to improve appearance without compromising the oncological or functional outcome. The aim of this study was to evaluate patient-perceived cosmetic outcomes of the midline reconstruction. METHODS: All patients undergoing surgery for SCT between 2007 and 2020 were included in the study. Patient demographics, operation type, functional outcome and recurrence were all recorded. The primary outcome measure was patient/parent satisfaction with the cosmetic appearance. This was assessed using both qualitative and quantitative methodologies. Following ethical approval parents were asked questions from two existing validated patient outcome questionnaires: "Patient and Observer Scar Assessment Scale" (POSAS) v2.0 and the "Patient Scar Assessment Questionnaire". RESULTS: Thirty-two patients underwent surgery at our institution for SCT during the study period. Twenty-four had a posterior approach with midline reconstruction, two laparotomy and excision (excluded from this study) and six had a combined approach. Median follow-up was 35 months (8.5-96 months). There were no recurrences. 4/30 (13%) have persistent urological symptoms, and 1/30 (3%) has constipation requiring bowel management. Questionnaires were sent to 26/30 families with a 77% return rate. Median total score was 11 (7.4-17.5) on a 60-point scale (6, as normal skin, 60, worst imaginable scar). Twenty (95%) reported that the scar never affects the child's activities and 15 (71%) said they are "not at all" conscious of the scar. CONCLUSION: Scars can lead to an array of cosmetic, functional, and psychological consequences and as such consideration needs to be given to scarring following surgery for sacrococcygeal teratomas. This study demonstrates that a midline reconstruction produces a cosmetically favourable outcome. We, therefore, recommend where appropriate a midline reconstruction should be considered for SCT.


Assuntos
Neoplasias Pélvicas , Teratoma , Criança , Cicatriz , Humanos , Satisfação do Paciente , Região Sacrococcígea/cirurgia , Inquéritos e Questionários , Teratoma/cirurgia
2.
Epidemiol Infect ; 149: e42, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33551007

RESUMO

During a disease outbreak, healthcare workers (HCWs) are essential to treat infected individuals. However, these HCWs are themselves susceptible to contracting the disease. As more HCWs get infected, fewer are available to provide care for others, and the overall quality of care available to infected individuals declines. This depletion of HCWs may contribute to the epidemic's severity. To examine this issue, we explicitly model declining quality of care in four differential equation-based susceptible, infected and recovered-type models with vaccination. We assume that vaccination, recovery and survival rates are affected by quality of care delivered. We show that explicitly modelling HCWs and accounting for declining quality of care significantly alters model-predicted disease outcomes, specifically case counts and mortality. Models neglecting the decline of quality of care resulting from infection of HCWs may significantly under-estimate cases and mortality. These models may be useful to inform health policy that may differ for HCWs and the general population. Models accounting for declining quality of care may therefore improve the management interventions considered to mitigate the effects of a future outbreak.


Assuntos
Epidemias , Pessoal de Saúde , Nível de Saúde , Modelos Biológicos , Humanos , Mortalidade , Garantia da Qualidade dos Cuidados de Saúde , Vacinação
3.
Pediatr Surg Int ; 36(10): 1243-1247, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32833126

RESUMO

INTRODUCTION: Oesophageal atresia ± tracheoesophageal fistula (EA/TEF) associated with congenital heart disease (CHD) carries a worse prognosis than EA/TEF alone. Though the Spitz classification takes major CHD into account, there are no data regarding survival with the specific combination of EA/TEF and Tetralogy of Fallot (TOF). With advances in postnatal care, we hypothesised that, survival is improving in these complex patients. This study reports morbidity and mortality outcomes of newborns with oesophageal atresia and TOF cardiac malformations METHODS: All patients with EA/TEF and TOF treated at Alder Hey Children's Hospital between the years 2000-2020, were identified. Data sets regarding gestation, birth weight, associated anomalies, operative intervention, morbidity, and mortality were analysed. RESULTS: Of a total of 350, EA/TEF patients 9 (2.6%) cases had EA/TEF associated with TOF (M:F 4:5). The median gestational age was 35/40 (range 28-41 weeks) with a median birth weight of 1790 g (range 1060-3350 g). Overall survival was 56% (5/9 cases) and all survivors remain under follow up (range 37-4458 days). Surgical strategies for managing EA/TEF with Fallot's tetralogy included 6/9 primary repairs and 3/9 cases with TEF ligation only (+ gastrostomy ± oesophagostomy). CONCLUSIONS: This study reports outcome data from one of the largest series of EA TEF patients with Fallot's tetralogy. Whilst outcomes may be challenging for this unique patient cohort, survival metrics provide important prognostic information that can be widely shared with health care teams and parents.


Assuntos
Atresia Esofágica/mortalidade , Previsões , Hospitais Pediátricos/estatística & dados numéricos , Fístula Traqueoesofágica/mortalidade , Atresia Esofágica/diagnóstico , Feminino , Seguimentos , Humanos , Lactente , Mortalidade Infantil/tendências , Recém-Nascido , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Tetralogia de Fallot/diagnóstico , Tetralogia de Fallot/mortalidade , Fístula Traqueoesofágica/diagnóstico , Reino Unido/epidemiologia
4.
BMC Bioinformatics ; 20(Suppl 5): 180, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31272389

RESUMO

BACKGROUND: Stem cells and stem cell lines are widely used in biomedical research. The Cell Ontology (CL) and Cell Line Ontology (CLO) are two community-based OBO Foundry ontologies in the domains of in vivo cells and in vitro cell line cells, respectively. RESULTS: To support standardized stem cell investigations, we have developed an Ontology for Stem Cell Investigations (OSCI). OSCI imports stem cell and cell line terms from CL and CLO, and investigation-related terms from existing ontologies. A novel focus of OSCI is its application in representing metadata types associated with various stem cell investigations. We also applied OSCI to systematically categorize experimental variables in an induced pluripotent stem cell line cell study related to bipolar disorder. In addition, we used a semi-automated literature mining approach to identify over 200 stem cell gene markers. The relations between these genes and stem cells are modeled and represented in OSCI. CONCLUSIONS: OSCI standardizes stem cells found in vivo and in vitro and in various stem cell investigation processes and entities. The presented use cases demonstrate the utility of OSCI in iPSC studies and literature mining related to bipolar disorder.


Assuntos
Ontologias Biológicas , Pesquisa Biomédica/normas , Animais , Humanos , Células-Tronco
5.
BMC Microbiol ; 19(1): 81, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-31023224

RESUMO

BACKGROUND: Concern exists that frequent use of topically-applied fusidic acid (FA) and chlorhexidine (CHX) for canine pyoderma is driving clinically relevant resistance, despite rare description of FA and CHX genetic resistance determinants in canine-derived staphylococci. This study aimed to determine minimum inhibitory concentrations (MICs) and investigate presence of putative resistance determinants for FA and CHX in canine-derived methicillin-resistant (MR) and -susceptible (MS) staphylococci. Plasmid-mediated resistance genes (fusB, fusC, fusD, qacA/B, smr; PCR) and MICs (agar dilution) of FA and CHX were investigated in 578 staphylococci (50 MR S. aureus [SA], 50 MSSA, 259 MR S. pseudintermedius [SP], 219 MSSP) from Finland, U.S.A., North (NUK) and South-East U.K. (SEUK) and Germany. In all isolates with FA MIC ≥64 mg/L (n = 27) fusA and fusE were amplified and sequenced. RESULTS: FA resistance determinants (fusA mutations n = 24, fusB n = 2, fusC n = 36) were found in isolates from all countries bar U.S.A. and correlated with higher MICs (≥1 mg/L), although 4 SP isolates had MICs of 0.06 mg/L despite carrying fusC. CHX MICs did not correlate with qacA/B (n = 2) and smr (n = 5), which were found in SEUK SA, and SP from NUK and U.S.A. CONCLUSIONS: Increased FA MICs were frequently associated with fusA mutations and fusC, and this is the first account of fusB in SP. Despite novel description of qacA/B in SP, gene presence did not correlate with CHX MIC. Selection pressure from clinical use might increase prevalence of these genetic determinants, but clinical significance remains uncertain in relation to high skin concentrations achieved by topical therapy.


Assuntos
Clorexidina/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Ácido Fusídico/farmacologia , Staphylococcus/efeitos dos fármacos , Staphylococcus/genética , Animais , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Desinfetantes/farmacologia , Cães/microbiologia , Finlândia , Alemanha , Resistência a Meticilina/genética , Testes de Sensibilidade Microbiana , Fator G para Elongação de Peptídeos/genética , Pioderma/microbiologia , Pioderma/veterinária , Fatores R , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Estados Unidos
6.
Osteoporos Int ; 30(12): 2429-2435, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31463589

RESUMO

This cross-sectional study assessed cortical bone properties via impact microindentation in adults with normoglycemia, prediabetes, and early-stage T2D. Bone material strength index was stable across the glycemia categories in whites but it declined in blacks. Blacks may be more susceptible than whites to impaired cortical bone properties in early diabetes. INTRODUCTION: Individuals with long-standing type 2 diabetes (T2D) have altered cortical bone material properties as determined by impact microindentation. This cross-sectional study was done to determine whether altered cortical bone material properties could be detected in adults with prediabetes or early-stage T2D. METHODS: Men and postmenopausal women aged ≥ 50 years with no diabetes (50 white, 6 black), prediabetes (75 white, 13 black), and T2D of ≤ 5 years duration (24 white and 16 black) had assessments of bone material strength index (BMSi) by impact microindentation, trabecular bone score (TBS), and bone mineral density (BMD) by DXA and the advanced glycation end product, urine pentosidine. RESULTS: The association between glycemia category and BMSi differed by race (interaction p = 0.037). In the whites, BMSi did not differ across the glycemia categories, after adjustment for age, sex, and BMI (no diabetes 76.3 ± 1.6 (SEM), prediabetes 77.2 ± 1.3, T2D 76.2 ± 2.5, ANCOVA p = 0.887). In contrast, in the blacks, BMSi differed (ANCOVA p = 0.020) and was significantly lower in subjects with T2D than in those with prediabetes (p < 0.05) and no diabetes (p < 0.05) (mean ± SEM BMSi in no diabetes 86.0 ± 4.3, prediabetes 91.0 ± 3.2, and T2D 71.6 ± 2.9). Neither TBS nor urine pentosidine differed significantly across the glycemia categories in either whites or blacks. CONCLUSIONS: These findings suggest different associations of glycemia with cortical bone material properties in blacks and whites, with blacks possibly being more susceptible to impaired cortical bone properties than whites in early diabetes. A larger study is needed to verify these observations.


Assuntos
Densidade Óssea/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Hiperglicemia/fisiopatologia , Estado Pré-Diabético/fisiopatologia , Absorciometria de Fóton/métodos , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Arginina/análogos & derivados , Arginina/urina , Glicemia/metabolismo , Estudos Transversais , Diabetes Mellitus Tipo 2/etnologia , Feminino , Colo do Fêmur/fisiopatologia , Humanos , Hiperglicemia/etnologia , Lisina/análogos & derivados , Lisina/urina , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/etnologia , Tíbia/fisiopatologia , Estados Unidos/epidemiologia , População Branca/estatística & dados numéricos
7.
Osteoarthritis Cartilage ; 26(12): 1691-1698, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30248503

RESUMO

OBJECTIVE: Juvenile osteochondritis dissecans (JOCD) is similar to osteochondrosis dissecans (OCD) in animals, which is the result of failure of the cartilage canal blood supply, ischemic chondronecrosis and delayed ossification, or osteochondrosis. The aim of the current study was to determine if osteochondrosis lesions occur at predilection sites for JOCD in children. METHOD: Computed tomographic (CT) scans of 23 knees (13 right, 10 left) from 13 children (9 male, 4 female; 1 month to 11 years old) were evaluated for lesions consisting of focal, sharply demarcated, uniformly hypodense defects in the ossification front. Histological validation was performed in 11 lesions from eight femurs. RESULTS: Thirty-two lesions consisting of focal, uniformly hypodense defects in the ossification front were identified in the CT scans of 14 human femurs (7 left, 7 right; male, 7-11 years old). Defects corresponded to areas of ischemic chondronecrosis in sections from all 11 histologically validated lesions. Intra-cartilaginous secondary responses comprising proliferation of adjacent chondrocytes and vessels were detected in six and two lesions, whereas intra-osseous responses including accumulation of chondroclasts and formation of granulation tissue occurred in 10 and six lesions, respectively. One CT cyst-like lesion contained both a pseudocyst and a true cyst in histological sections. CONCLUSION: Changes identical to osteochondrosis in animals were detected at predilection sites for JOCD in children, and confirmed to represent failure of the cartilage canal blood supply and ischemic chondronecrosis in histological sections.


Assuntos
Cartilagem Articular/irrigação sanguínea , Isquemia/complicações , Articulação do Joelho/irrigação sanguínea , Osteocondrite Dissecante/etiologia , Osteocondrose/complicações , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologia , Criança , Pré-Escolar , Condrócitos/patologia , Feminino , Fêmur/diagnóstico por imagem , Fêmur/patologia , Humanos , Lactente , Articulação do Joelho/diagnóstico por imagem , Masculino , Osteocondrite Dissecante/diagnóstico por imagem , Osteocondrite Dissecante/patologia , Osteocondrose/diagnóstico por imagem , Osteocondrose/patologia , Tomografia Computadorizada por Raios X/métodos
8.
Nanotechnology ; 29(16): 165704, 2018 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-29485106

RESUMO

Moiré patterns in scanning transmission electron microscopy (STEM) images of epitaxial perovskite oxides are used to assess strain and defect densities over fields of view extending over several hundred nanometers. The patterns arise from the geometric overlap of the rastered STEM electron beam and the samples' crystal periodicities and we explore the emergence and application of these moiré fringes for rapid strain analysis. Using the epitaxial functional oxide perovskites BiFeO3 and Pr1-x Ca x MnO3, we discuss the impact of large degrees of strain on the quantification of STEM moiré patterns, identify defects in the fringe patterns and quantify strain and lattice rotation. Such a wide-area analysis of crystallographic strain and defects is crucial for developing structure-function relations of functional oxides and we find the STEM moiré technique to be an attractive means of structural assessment that can be readily applied to low dose studies of damage sensitive crystalline materials.

9.
Epidemiol Infect ; 146(4): 468-475, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29465027

RESUMO

Measles eradication efforts have been successful at achieving elimination in many countries worldwide. Such countries actively work to maintain this elimination by continuing to improve coverage of two routine doses of measles vaccine following measles elimination. While improving measles vaccine coverage is always beneficial, we show, using a steady-state analysis of a dynamical model, that the correlation between populations receiving the first and second routine dose also has a significant impact on the population immunity achieved by a specified combination of first and second dose coverage. If the second dose is administered to people independently of whether they had the first dose, high second-dose coverage improves the proportion of the population receiving at least one dose, and will have a large effect on population immunity. If the second dose is administered only to people who have had the first dose, high second-dose coverage reduces the rate of primary vaccine failure, but does not reach people who missed the first dose; this will therefore have a relatively small effect on population immunity. When doses are administered dependently, and assuming the first dose has higher coverage, increasing the coverage of the first dose has a larger impact on population immunity than does increasing the coverage of the second. Correlation between vaccine doses has a significant impact on the level of population immunity maintained by current vaccination coverage, potentially outweighing the effects of age structure and, in some cases, recent improvements in vaccine coverage. It is therefore important to understand the correlation between vaccine doses as such correlation may have a large impact on the effectiveness of measles vaccination strategies.


Assuntos
Erradicação de Doenças , Esquemas de Imunização , Vacina contra Sarampo/administração & dosagem , Sarampo/prevenção & controle , Adolescente , Adulto , Idoso , Algoritmos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Sarampo/epidemiologia , Pessoa de Meia-Idade
10.
Epidemiol Infect ; 145(2): 227-235, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27760574

RESUMO

Measles was eliminated in the Americas in 2002 by a combination of routine immunizations and supplementary immunization activities. Recent outbreaks underscore the importance of reconsidering vaccine policy in order to maintain elimination. We constructed an age-structured dynamical model for the distribution of immunity in a population with routine immunization and without disease, and analysed the steady state for an idealized age structure and for real age structures of countries in the Americas. We compared the level of immunity maintained by current policy in these countries to the level maintainable by an optimal policy. The optimal age target for the first routine dose of measles vaccine depends on the timing and coverage of both doses. Similarly, the optimal age target for the second dose of measles vaccine depends on the timing and coverage of the first dose. The age targets for the first and second doses of measles vaccine should be adjusted for the post-elimination era, by specifically accounting for current context, including realized coverage of both doses, and altered maternal immunity. Doing so can greatly improve the proportion immune within a population, and therefore the chances of maintaining measles elimination, without changing coverage.


Assuntos
Erradicação de Doenças , Esquemas de Imunização , Vacina contra Sarampo/administração & dosagem , Sarampo/prevenção & controle , Adolescente , Adulto , Fatores Etários , Idoso , América/epidemiologia , Criança , Pré-Escolar , Feminino , Política de Saúde , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Adulto Jovem
11.
Mol Cell Neurosci ; 73: 63-83, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26608002

RESUMO

Bipolar disorder (BP) is a chronic neuropsychiatric condition characterized by pathological fluctuations in mood from mania to depression. Adoption, twin and family studies have consistently identified a significant hereditary component to BP, yet there is no clear genetic event or consistent neuropathology. BP has been suggested to have a developmental origin, although this hypothesis has been difficult to test since there are no viable neurons or glial cells to analyze, and research has relied largely on postmortem brain, behavioral and imaging studies, or has examined proxy tissues including saliva, olfactory epithelium and blood cells. Neurodevelopmental factors, particularly pathways related to nervous system development, cell migration, extracellular matrix, H3K4 methylation, and calcium signaling have been identified in large gene expression and GWAS studies as altered in BP. Recent advances in stem cell biology, particularly the ability to reprogram adult somatic tissues to a pluripotent state, now make it possible to interrogate these pathways in viable cell models. A number of induced pluripotent stem cell (iPSC) lines from BP patient and healthy control (C) individuals have been derived in several laboratories, and their ability to form cortical neurons examined. Early studies suggest differences in activity, calcium signaling, blocks to neuronal differentiation, and changes in neuronal, and possibly glial, lineage specification. Initial observations suggest that differentiation of BP patient-derived neurons to dorsal telencephalic derivatives may be impaired, possibly due to alterations in WNT, Hedgehog or Nodal pathway signaling. These investigations strongly support a developmental contribution to BP and identify novel pathways, mechanisms and opportunities for improved treatments.


Assuntos
Transtorno Bipolar/patologia , Técnicas de Cultura de Células/métodos , Células-Tronco Pluripotentes Induzidas/citologia , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Sinalização do Cálcio , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Modelos Biológicos , Neurogênese , Transcriptoma
12.
Nature ; 466(7307): 769-73, 2010 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-20686575

RESUMO

Long interspersed element-1 (LINE-1 or L1) retrotransposition continues to affect human genome evolution. L1s can retrotranspose in the germline, during early development and in select somatic cells; however, the host response to L1 retrotransposition remains largely unexplored. Here we show that reporter genes introduced into the genome of various human embryonic carcinoma-derived cell lines (ECs) by L1 retrotransposition are rapidly and efficiently silenced either during or immediately after their integration. Treating ECs with histone deacetylase inhibitors rapidly reverses this silencing, and chromatin immunoprecipitation experiments revealed that reactivation of the reporter gene was correlated with changes in chromatin status at the L1 integration site. Under our assay conditions, rapid silencing was also observed when reporter genes were delivered into ECs by mouse L1s and a zebrafish LINE-2 element, but not when similar reporter genes were delivered into ECs by Moloney murine leukaemia virus or human immunodeficiency virus, suggesting that these integration events are silenced by distinct mechanisms. Finally, we demonstrate that subjecting ECs to culture conditions that promote differentiation attenuates the silencing of reporter genes delivered by L1 retrotransposition, but that differentiation, in itself, is not sufficient to reactivate previously silenced reporter genes. Thus, our data indicate that ECs differ from many differentiated cells in their ability to silence reporter genes delivered by L1 retrotransposition.


Assuntos
Células-Tronco de Carcinoma Embrionário/metabolismo , Epigênese Genética/genética , Inativação Gênica , Retroelementos/genética , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Cromatina/efeitos dos fármacos , Cromatina/genética , Cromatina/metabolismo , Imunoprecipitação da Cromatina , Células-Tronco de Carcinoma Embrionário/patologia , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Genes Reporter/genética , Engenharia Genética , Vetores Genéticos/genética , Genoma Humano/genética , HIV/genética , Inibidores de Histona Desacetilases/farmacologia , Humanos , Elementos Nucleotídeos Longos e Dispersos/genética , Masculino , Camundongos , Modelos Genéticos , Vírus da Leucemia Murina de Moloney/genética , Peixe-Zebra/genética
14.
J Biol Chem ; 289(30): 20858-70, 2014 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-24876386

RESUMO

COPII-coated vesicles mediate the transport of newly synthesized proteins from the endoplasmic reticulum to the Golgi. SEC24 is the COPII component primarily responsible for recruitment of protein cargoes into nascent vesicles. There are four Sec24 paralogs in mammals, with mice deficient in SEC24A, -B, and -D exhibiting a wide range of phenotypes. We now report the characterization of mice with deficiency in the fourth Sec24 paralog, SEC24C. Although mice haploinsufficient for Sec24c exhibit no apparent abnormalities, homozygous deficiency results in embryonic lethality at approximately embryonic day 7. Tissue-specific deletion of Sec24c in hepatocytes, pancreatic cells, smooth muscle cells, and intestinal epithelial cells results in phenotypically normal mice. Thus, SEC24C is required in early mammalian development but is dispensable in a number of tissues, likely as a result of compensation by other Sec24 paralogs. The embryonic lethality resulting from loss of SEC24C occurs considerably later than the lethality previously observed in SEC24D deficiency; it is clearly distinct from the restricted neural tube phenotype of Sec24b null embryos and the mild hypocholesterolemic phenotype of adult Sec24a null mice. Taken together, these results demonstrate that the four Sec24 paralogs have developed unique functions over the course of vertebrate evolution.


Assuntos
Vesículas Revestidas pelo Complexo de Proteína do Envoltório/metabolismo , Embrião de Mamíferos/embriologia , Desenvolvimento Embrionário/fisiologia , Proteínas de Transporte Vesicular/metabolismo , Animais , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/genética , Embrião de Mamíferos/citologia , Fígado/citologia , Fígado/embriologia , Camundongos , Camundongos Mutantes , Especificidade de Órgãos/fisiologia , Pâncreas/citologia , Pâncreas/embriologia , Proteínas de Transporte Vesicular/genética
15.
Nature ; 460(7259): 1127-31, 2009 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-19657334

RESUMO

Long interspersed element 1 (LINE-1 or L1) retrotransposons have markedly affected the human genome. L1s must retrotranspose in the germ line or during early development to ensure their evolutionary success, yet the extent to which this process affects somatic cells is poorly understood. We previously demonstrated that engineered human L1s can retrotranspose in adult rat hippocampus progenitor cells in vitro and in the mouse brain in vivo. Here we demonstrate that neural progenitor cells isolated from human fetal brain and derived from human embryonic stem cells support the retrotransposition of engineered human L1s in vitro. Furthermore, we developed a quantitative multiplex polymerase chain reaction that detected an increase in the copy number of endogenous L1s in the hippocampus, and in several regions of adult human brains, when compared to the copy number of endogenous L1s in heart or liver genomic DNAs from the same donor. These data suggest that de novo L1 retrotransposition events may occur in the human brain and, in principle, have the potential to contribute to individual somatic mosaicism.


Assuntos
Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Retroelementos/genética , Regiões 5' não Traduzidas/genética , Encéfalo/citologia , Linhagem Celular , Imunoprecipitação da Cromatina , Metilação de DNA , Feto/citologia , Dosagem de Genes , Humanos , Reação em Cadeia da Polimerase
16.
Epidemiol Infect ; 142(2): 379-87, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23731707

RESUMO

This paper examined whether previously identified community-level factors (high proportion of crowded households and/or persons below the poverty level) remained associated with childhood pneumococcal carriage in the heptavalent pneumococcal conjugate vaccine (PCV7) era. Using logistic regression, individual factors were used to develop base models to which community-level factors were added to evaluate impact on pneumococcal carriage within two paediatric study cohorts from Massachusetts (urban Boston, outside Boston). Six years after introduction of universal childhood PCV7 vaccination, we found no consistent evidence that census tract characteristics (e.g. population size and density, age and race distribution, percent participating in group childcare, parental education, percent lacking in-unit plumbing, poverty, and community stability) affected odds of pneumococcal carriage when added to individual predictors (e.g. younger age, current respiratory tract infections, and attendance in group childcare). How community-level factors influence pneumococcal carriage continues to change in the era of increasing immunization coverage.


Assuntos
Portador Sadio/epidemiologia , Infecções Pneumocócicas/epidemiologia , Vacinas Pneumocócicas/uso terapêutico , Boston/epidemiologia , Portador Sadio/microbiologia , Pré-Escolar , Características da Família , Feminino , Vacina Pneumocócica Conjugada Heptavalente , Humanos , Lactente , Recém-Nascido , Masculino , Massachusetts/epidemiologia , Infecções Pneumocócicas/prevenção & controle , Características de Residência/estatística & dados numéricos , Vacinas Conjugadas/uso terapêutico
17.
J Musculoskelet Neuronal Interact ; 14(2): 229-38, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24879027

RESUMO

OBJECTIVE: Exercise-induced weight loss (WL) can lead to decreased areal bone mineral density (aBMD). It is unknown whether this translates into decreased volumetric BMD (vBMD) or bone strength. The purpose of this pilot study was to determine whether exercise-induced WL results in decreased vBMD and bone strength in postmenopausal women. METHODS: Fourteen subjects participated in a 4-month endurance exercise WL intervention. A weight stable (WS) control group (n=10) was followed for 4 months. Proximal femur aBMD was measured by DXA. Femoral neck vBMD and estimates of bone strength (cross-sectional moment of inertia (CSMI) and section modulus (SM)) were measured by quantitative CT. RESULTS: Women were 54.6±2.4 years, BMI 32.1±5.9 kg/m(2) and 54.4±2.9 years, BMI 27.9±3.6 kg/m(2) in the WL and WS groups, respectively. The WL group lost 3.0±2.6 kg which was predominately fat mass. There was a significant decrease in SMmax. Changes in CSMImax and total hip aBMD were not significant. Total hip vBMD did not decrease significantly in response to WL. There were no significant changes in the WS group. CONCLUSIONS: WL may lead to decreased bone strength before changes in BMD are detected. Further studies are needed to determine whether bone-targeted exercise can preserve bone strength during WL.


Assuntos
Densidade Óssea/fisiologia , Osso e Ossos/fisiopatologia , Terapia por Exercício/efeitos adversos , Obesidade , Pós-Menopausa/fisiologia , Redução de Peso/fisiologia , Absorciometria de Fóton , Idoso , Exercício Físico/fisiologia , Feminino , Colo do Fêmur/diagnóstico por imagem , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Tomografia Computadorizada por Raios X , Programas de Redução de Peso/métodos
18.
Dev Dyn ; 242(3): 230-53, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23288605

RESUMO

BACKGROUND: Delineating the cascades of growth and transcription factor expression that shape the developing nervous system will improve our understanding of its molecular histogenesis and suggest strategies for cell replacement therapies. In the current investigation, we examined the ability of the proneural gene, Neurogenin1 (Neurog1; also Ngn1, Neurod3), to drive differentiation of pluripotent embryonic stem cells (ESC). RESULTS: Transient expression of Neurog1 in ESC was sufficient to initiate neuronal differentiation, and produced neuronal subtypes reflecting its expression pattern in vivo. To begin to address the molecular mechanisms involved, we used microarray analysis to identify potential down-stream targets of Neurog1 expressed at sequential stages of neuronal differentiation. CONCLUSIONS: ESC expressing Neurogenin1 begin to withdraw from cycle and form precursors that differentiate exclusively into neurons. This work identifies unique patterns of gene expression following expression of Neurog1, including genes and signaling pathways involved in process outgrowth and cell migration, regional differentiation of the nervous system, and cell cycle.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Diferenciação Celular/fisiologia , Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica/fisiologia , Proteínas do Tecido Nervoso/biossíntese , Células-Tronco Neurais/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular , Movimento Celular/fisiologia , Células-Tronco Embrionárias/citologia , Perfilação da Expressão Gênica , Camundongos , Proteínas do Tecido Nervoso/genética , Células-Tronco Neurais/citologia , Neurônios/citologia , Neurônios/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Transdução de Sinais/fisiologia
19.
Cells ; 13(14)2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39056776

RESUMO

Bipolar disorder (BP) is a recurring psychiatric condition characterized by alternating episodes of low energy (depressions) followed by manias (high energy). Cortical network activity produced by GABAergic interneurons may be critical in maintaining the balance in excitatory/inhibitory activity in the brain during development. Initially, GABAergic signaling is excitatory; with maturation, these cells undergo a functional switch that converts GABAA channels from depolarizing (excitatory) to hyperpolarizing (inhibitory), which is controlled by the intracellular concentration of two chloride transporters. The earliest, NKCC1, promotes chloride entry into the cell and depolarization, while the second (KCC2) stimulates movement of chloride from the neuron, hyperpolarizing it. Perturbations in the timing or expression of NKCC1/KCC2 may affect essential morphogenetic events including cell proliferation, migration, synaptogenesis and plasticity, and thereby the structure and function of the cortex. We derived induced pluripotent stem cells (iPSC) from BP patients and undiagnosed control (C) individuals, then modified a differentiation protocol to form GABAergic interneurons, harvesting cells at sequential stages of differentiation. qRT-PCR and RNA sequencing indicated that after six weeks of differentiation, controls transiently expressed high levels of NKCC1. Using multi-electrode array (MEA) analysis, we observed that BP neurons exhibit increased firing, network bursting and decreased synchrony compared to C. Understanding GABA signaling in differentiation may identify novel approaches and new targets for treatment of neuropsychiatric disorders such as BP.


Assuntos
Transtorno Bipolar , Diferenciação Celular , Neurônios GABAérgicos , Células-Tronco Pluripotentes Induzidas , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Neurônios GABAérgicos/metabolismo , Transtorno Bipolar/metabolismo , Transtorno Bipolar/patologia , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/genética , Interneurônios/metabolismo
20.
Vaccines (Basel) ; 12(7)2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39066427

RESUMO

Chlamydia trachomatis (Ct) is the most common cause of bacterial sexually transmitted infections (STIs) worldwide. Ct infections are often asymptomatic in women, leading to severe reproductive tract sequelae. Development of a vaccine against Chlamydia is crucial. The Chlamydia major outer membrane protein (MOMP) is a prime vaccine antigen candidate, and it can elicit both neutralizing antibodies and protective CD4+ T cell responses. We have previously designed chimeric antigens composed of immunogenic variable regions (VDs) and conserved regions (CDs) of MOMP from Chlamydia muridarum (Cm) expressed into a carrier protein (PorB), and we have shown that these were protective in a mouse model of Cm respiratory infection. Here, we generated corresponding constructs based on MOMP from Ct serovar F. Preliminary structure analysis of the three antigens, PorB/VD1-3, PorB/VD1-4 and PorB/VD1-2-4, showed that they retained structure features consistent with those of PorB. The antigens induced robust humoral and cellular responses in mice with different genetic backgrounds. The antibodies were cross-reactive against Ct, but only anti-PorB/VD1-4 and anti-PorB/VD1-2-4 IgG antibodies were neutralizing, likely due to the antigen specificity. The cellular responses included proliferation in vitro and production of IFN-γ by splenocytes following Ct re-stimulation. Our results support further investigation of the PorB/VD antigens as potential protective candidates for a Chlamydia subunit vaccine.

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