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1.
Hemasphere ; 8(5): e64, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38756352

RESUMO

Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing "immune classes" among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune "risk factors." By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.

2.
BJU Int ; 133(4): 375-386, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38069544

RESUMO

OBJECTIVE: To compare intra- and postoperative outcomes between off-clamp and on-clamp robot-assisted partial nephrectomy (RAPN), using data from randomised controlled trials (RCTs) or covariate-matched studies (propensity score-matched or matched-pair analysis). METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant literature review was conducted on PubMed, EMBASE, Scopus and CENTRAL for relevant studies comparing off-clamp to on-clamp RAPN. Primary outcomes were estimated blood loss, postoperative percentage decrease in estimated glomerular filtration rate (eGFR), and margin positive rate. Secondary outcomes were operative time, postoperative eGFR, length of stay, all postoperative complications, major complications, and need for transfusion. Random-effects meta-analyses were performed to generate mean differences (MDs) or odds ratios (ORs). RESULTS: A total of 10 studies (2307 patients) were shortlisted for analysis. There was no significant difference in estimated operative blood loss between off-clamp and on-clamp RAPN (MD 21.9 mL, 95% confidence interval [CI] -0.9 to 44.7 mL; P = 0.06, I2 = 58%). Off-clamp RAPN yielded a smaller postoperative eGFR deterioration (MD 3.10%, 95% CI 1.05-5.16%; P = 0.008, I2 = 13%) and lower odds of margin positivity (OR 0.62, 95% CI 0.40-0.94; P = 0.03, I2 = 0%). No significant differences were found for all secondary outcomes. CONCLUSIONS: Off-clamp and on-clamp RAPN are similarly effective approaches for selected renal masses. Within the classic trifecta of PN outcomes, off-clamp RAPN yields similar rates of perioperative complications and may possibly offer better preservation of renal function and reduced margin-positive rates.


Assuntos
Neoplasias Renais , Procedimentos Cirúrgicos Robóticos , Robótica , Humanos , Neoplasias Renais/cirurgia , Nefrectomia , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Taxa de Filtração Glomerular , Resultado do Tratamento , Estudos Retrospectivos
3.
Clin Ophthalmol ; 17: 2171-2179, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37547173

RESUMO

Purpose: Secondary glaucoma following childhood cataract surgery remains the most common complication in the paediatric population. This study aimed to determine the incidence, time to progression and risk factors associated with the development of secondary glaucoma following childhood cataract surgery in a paediatric population. Outcome measures were the detection of secondary glaucoma, postoperative time frame to development of glaucoma and risk factors in its development. Patients and Methods: A retrospective case series was conducted between 2003 and 2017 at a tertiary children's hospital in Sydney. The patient population included those 16 years or less of age who underwent congenital cataract extraction, with or without an intraocular lens implantation and who had been followed up for a minimum of six months following surgery. Patients were excluded if they had cataract aetiology other than congenital idiopathic cataract. Multivariate Cox Regression analysis was used to determine relevant risk factors. Results: A total of 320 eyes in 216 patients were included in the study. Secondary glaucoma developed in 11.9% of eyes. In those that developed secondary glaucoma, the average time to onset from surgery was 3.2 years (median 2.75 years). The mean age of diagnosis of secondary glaucoma was 4.58 years (median 3.5 years, range 2.5 months to 13.23 years). Microcornea was the only adverse characteristic significantly associated with an increased risk of secondary glaucoma (HR 6.30, p 0.003). Conclusion: Despite modern surgical techniques, glaucoma remains a significant long-term sequela in children following cataract surgery.

4.
Stem Cell Reports ; 18(1): 175-189, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36630901

RESUMO

Characterizing cell identity in complex tissues such as the human retina is essential for studying its development and disease. While retinal organoids derived from pluripotent stem cells have been widely used to model development and disease of the human retina, there is a lack of studies that have systematically evaluated the molecular and cellular fidelity of the organoids derived from various culture protocols in recapitulating their in vivo counterpart. To this end, we performed an extensive meta-atlas characterization of cellular identities of the human eye, covering a wide range of developmental stages. The resulting map uncovered previously unknown biomarkers of major retinal cell types and those associated with cell-type-specific maturation. Using our retinal-cell-identity map from the fetal and adult tissues, we systematically assessed the fidelity of the retinal organoids in mimicking the human eye, enabling us to comprehensively benchmark the current protocols for retinal organoid generation.


Assuntos
Células-Tronco Pluripotentes Induzidas , Células-Tronco Pluripotentes , Adulto , Humanos , Retina/metabolismo , Células-Tronco Pluripotentes/metabolismo , Neurônios , Organoides , Diferenciação Celular , Células-Tronco Pluripotentes Induzidas/metabolismo
5.
Stem Cell Reports ; 17(6): 1476-1492, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35523177

RESUMO

Advances in the study of neurological conditions have been possible because of pluripotent stem cell technologies and organoids. Studies have described the generation of neural ectoderm-derived retinal and brain structures from pluripotent stem cells. However, the field is still troubled by technical challenges, including high culture costs and variability. Here, we describe a simple and economical protocol that reproducibly gives rise to the neural retina and cortical brain regions from confluent cultures of stem cells. The spontaneously generated cortical organoids are transcriptionally comparable with organoids generated by other methods. Furthermore, these organoids showed spontaneous functional network activity and proteomic analysis confirmed organoids maturity. The generation of retinal and brain organoids in close proximity enabled their mutual isolation. Suspension culture of this complex organoid system demonstrated the formation of nerve-like structures connecting retinal and brain organoids, which might facilitate the investigation of neurological diseases of the eye and brain.


Assuntos
Células-Tronco Pluripotentes Induzidas , Células-Tronco Pluripotentes , Encéfalo , Diferenciação Celular , Organoides , Proteômica , Retina
6.
EClinicalMedicine ; 44: 101271, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35112072

RESUMO

BACKGROUND: Non-invasive pneumococcal pneumonia causes significant morbidity and mortality in older adults. Understanding pneumococcal sero-epidemiology in adults ≥50 years is necessary to inform vaccination policies and the updating of pneumococcal vaccines. METHODS: We conducted a systematic review and random-effects meta-analysis to determine the proportion of community-acquired pneumonia (CAP) in people ≥50 years due to pneumococcus and the proportion caused by pneumococcal vaccine serotypes. We searched MEDLINE, EMBASE and PubMed from 1 January 1990 to 30 March 2021. Heterogeneity was explored by subgroup analysis according to a) patient group (stratified versus age) and depth of testing, b) detection/serotyping method, and c) continent. The protocol is registered with PROSPERO (CRD42020192002). FINDINGS: Twenty-eight studies were included (34,216 patients). In the period 1-5 years after introduction of childhood PCV10/13 immunisation, 18% of CAP cases (95% CI 13-24%) were attributable to pneumococcus, with 49% (43-54%) of pneumococcal CAP due to PCV13 serotypes. The estimated proportion of pneumococcal CAP was highest in one study that used 24-valent serotype-specific urinary-antigen detection (ss-UAD)(30% [28-31%]), followed by studies based on diagnostic serology (28% [24-33%]), PCR (26% [15-37%]), ss-UAD14 (17% [13-22%]), and culture alone (14% [10-19%]). A higher estimate was observed in Europe (26% [21-30%] than North America (11% [9-12%](p<0·001). PCV13-serotype estimates were also influenced by serotyping methods. INTERPRETATION: Non-invasive pneumococcal CAP and vaccine-type pneumococcal CAP remains a burden in older adults despite widespread introduction of pneumococcal infant immunisation. Studies heavily reliant on ss-UADs restricted to vaccine-type serotypes may overestimate the proportion of potentially vaccine-preventable pneumococcal pneumonia. Sero-epidemiological data from low-income countries are lacking.

7.
J Environ Manage ; 280: 111752, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33358429

RESUMO

Turfgrass is an important component of the urban landscape frequently considered as an alternative land cover to offset anthropogenic CO2 emissions. However, quantitative information of the potential to directly remove CO2 from the atmosphere by turfgrass systems is lacking, especially in the tropics. Most assessments have considered the carbon accumulated by grass shoots and soil, but not the release of CO2 to the atmosphere by soil respiration (i.e., soil CO2 efflux). Here, we measured at high-temporal resolution (30-min) soil CO2 efflux, production, and storage rate for nearly three years in a residential lawn of Singapore. Furthermore, we quantified the carbon capture related to biomass production and CO2 emissions from fossil fuel consumption associated with maintenance activities (e.g., mowing equipment). Warm and humid conditions resulted in relatively constant rates of soil CO2 efflux, CO2 storage in soil, and aboveground biomass production (3370, 652, 1671 Mg CO2 km-2 yr-1; respectively), while the systematic use of mowing machinery emitted 27 Mg CO2 km-2 yr-1. Soil CO2 efflux and CO2 mowing emissions represent carbon losses to the atmosphere, while CO2 storage in soil and biomass productivity represent gains of carbon into the ecosystem. Under a steady state in which soil CO2 losses are only compensated by atmospheric CO2 uptake by photosynthesis, an ideal clipping waste disposal management, in which no CO2 molecule returns to the atmosphere (i.e., clippings are not burnt), and a 3-week mowing regime, this site can act as a sink of 2296 Mg CO2 km-2 yr-1. In the scenario of incinerating all clippings, the lawn acts as an emission source of 1046 Mg CO2 km-2 yr-1. Thus, management practices that reduce mowing frequency together with clipping disposal practices that minimize greenhouse gas emissions are needed to make urban lawns a potential natural solution to mitigate global environmental change.


Assuntos
Dióxido de Carbono , Ecossistema , Dióxido de Carbono/análise , Cidades , Singapura , Solo
8.
Restor Dent Endod ; 45(3): e28, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32839709

RESUMO

OBJECTIVES: To evaluate the outcome of in vitro studies comparing the effectiveness of QMix irrigant in removing the smear layer in the root canal system compared with other irrigants. MATERIALS AND METHODS: The research question was developed by using Population, Intervention, Comparison, Outcome and Study design framework. Literature search was performed using 3 electronic databases PubMed, Scopus, and EBSCOhost until October 2019. Two reviewers were independently involved in the selection of the articles and data extraction process. Risk of bias of the studies was independently appraised using revised Cochrane Risk of Bias tool (RoB 2.0) based on 5 domains. RESULTS: Thirteen studies fulfilled the selection criteria. The overall risk of bias was moderate. QMix was found to have better smear layer removal ability than mixture of tetracycline isonomer, an acid and a detergent (MTAD), sodium hypochlorite (NaOCl), and phytic acid. The efficacy was less effective than 7% maleic acid and 10% citric acid. No conclusive results could be drawn between QMix and 17% ethylenediaminetetraacetic acid due to conflicting results. QMix was more effective when used for 3 minutes than 1 minute. CONCLUSIONS: QMix has better smear layer removal ability compared to MTAD, NaOCl, Tubulicid Plus, and Phytic acid. In order to remove the smear layer more effectively with QMix, it is recommended to use it for a longer duration.

9.
Restor Dent Endod ; 45(2): e23, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32483540

RESUMO

OBJECTIVES: This study aimed to summarize the outcome of in vitro studies comparing the antibacterial effectiveness of QMix with other irrigants against Enterococcus faecalis. MATERIALS AND METHODS: The research question was developed by using population, intervention, comparison, outcome, and study design framework. The literature search was performed using 3 electronic databases: PubMed, Scopus, and EBSCOhost until October 2019. The additional hand search was performed from the reference list of the eligible studies. The risk of bias of the studies was independently appraised using the revised Cochrane Risk of Bias tool (RoB 2.0). RESULTS: Fourteen studies were included in this systematic review. The overall risk of bias for the selected studies was moderate. QMix was found to have a higher antimicrobial activity compared to 2% sodium hypochlorite (NaOCl), 17% ethylenediaminetetraacetic acid (EDTA), 2% chlorhexidine (CHX), mixture of tetracycline isonomer, an acid and a detergent (MTAD), 0.2% Cetrimide, SilverSol/H2O2, HYBENX, and grape seed extract (GSE). QMix had higher antibacterial efficacy compared to NaOCl, only when used for a longer time (10 minutes) and with higher volume (above 3 mL). CONCLUSIONS: QMix has higher antibacterial activity than 17% EDTA, 2% CHX, MTAD, 0.2% Cetrimide, SilverSol/H2O2, HYBENX, GSE and NaOCl with lower concentration. To improve the effectiveness, QMix is to use for a longer time and at a higher volume. TRIAL REGISTRATION: PROSPERO International prospective register of systematic reviews Identifier: CRD42018096763.

10.
J Infect ; 81(2): 266-275, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32473235

RESUMO

OBJECTIVES: In previous influenza pandemics, bacterial co-infections have been a major cause of mortality. We aimed to evaluate the burden of co-infections in patients with COVID-19. METHODS: We systematically searched Embase, Medline, Cochrane Library, LILACS and CINAHL for eligible studies published from 1 January 2020 to 17 April 2020. We included patients of all ages, in all settings. The main outcome was the proportion of patients with a bacterial, fungal or viral co-infection. . RESULTS: Thirty studies including 3834 patients were included. Overall, 7% of hospitalised COVID-19 patients had a bacterial co-infection (95% CI 3-12%, n=2183, I2=92·2%). A higher proportion of ICU patients had bacterial co-infections than patients in mixed ward/ICU settings (14%, 95% CI 5-26, I2=74·7% versus 4%, 95% CI 1-9, I2= 91·7%). The commonest bacteria were Mycoplasma pneumonia, Pseudomonas aeruginosa and Haemophilus influenzae. The pooled proportion with a viral co-infection was 3% (95% CI 1-6, n=1014, I2=62·3%), with Respiratory Syncytial Virus and influenza A the commonest. Three studies reported fungal co-infections. CONCLUSIONS: A low proportion of COVID-19 patients have a bacterial co-infection; less than in previous influenza pandemics. These findings do not support the routine use of antibiotics in the management of confirmed COVID-19 infection.


Assuntos
Infecções Bacterianas/virologia , Coinfecção/microbiologia , Coinfecção/virologia , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Infecções Bacterianas/complicações , Infecções Bacterianas/epidemiologia , Betacoronavirus , COVID-19 , Coinfecção/epidemiologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Humanos , Micoses/complicações , Micoses/epidemiologia , Micoses/virologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , SARS-CoV-2 , Viroses/complicações , Viroses/epidemiologia , Viroses/microbiologia
11.
Case Rep Ophthalmol ; 10(1): 116-119, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32231551

RESUMO

We present a case whereby standard immunohistochemistry and flow cytometry studies for a conjunctival biopsy were unable to reliably differentiate between the two distinct pathological processes of benign reactive lymphoid hyperplasia from conjunctival lymphoma. A tissue diagnosis was only able to be conclusively attained after the application of immunoglobulin heavy chain rearrangement studies to the specimen. This is unusual and to our knowledge has not been previously expressed in the literature. Hence, the use of these further molecular studies may have great potential clinical implications in helping resolve such diagnostic dilemmas.

12.
Comput Biol Chem ; 62: 47-59, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27082784

RESUMO

The coactivators CBP (CREBBP) and its paralog p300 (EP300), two conserved multi-domain proteins in eukaryotic organisms, regulate gene expression in part by binding DNA-binding transcription factors. It was previously reported that the CBP/p300 KIX domain mutant (Y650A, A654Q, and Y658A) altered both c-Myb-dependent gene activation and repression, and that mice with these three point mutations had reduced numbers of platelets, B cells, T cells, and red blood cells. Here, our transient transfection assays demonstrated that mouse embryonic fibroblast cells containing the same mutations in the KIX domain and without a wild-type allele of either CBP or p300, showed decreased c-Myb-mediated transcription. Dr. Wright's group solved a 3-D structure of the mouse CBP:c-Myb complex using NMR. To take advantage of the experimental structure and function data and improved theoretical calculation methods, we performed MD simulations of CBP KIX, CBP KIX with the mutations, and c-Myb, as well as binding energy analysis for both the wild-type and mutant complexes. The binding between CBP and c-Myb is mainly mediated by a shallow hydrophobic groove in the center where the side-chain of Leu302 of c-Myb plays an essential role and two salt bridges at the two ends. We found that the KIX mutations slightly decreased stability of the CBP:c-Myb complex as demonstrated by higher binding energy calculated using either MM/PBSA or MM/GBSA methods. More specifically, the KIX mutations affected the two salt bridges between CBP and c-Myb (CBP-R646 and c-Myb-E306; CBP-E665 and c-Myb-R294). Our studies also revealed differing dynamics of the hydrogen bonds between CBP-R646 and c-Myb-E306 and between CBP-E665 and c-Myb-R294 caused by the CBP KIX mutations. In the wild-type CBP:c-Myb complex, both of the hydrogen bonds stayed relatively stable. In contrast, in the mutant CBP:c-Myb complex, hydrogen bonds between R646 and E306 showed an increasing trend followed by a decreasing trend, and hydrogen bonds of the E665:R294 pair exhibited a fast decreasing trend over time during MD simulations. In addition, our data showed that the KIX mutations attenuate CBP's hydrophobic interaction with Leu302 of c-Myb. Furthermore, our 500-ns MD simulations showed that CBP KIX with the mutations has a slightly lower potential energy than wild-type CBP. The CBP KIX structures with or without its interacting protein c-Myb are different for both wild-type and mutant CBP KIX, and this is likewise the case for c-Myb with or without CBP, suggesting that the presence of an interacting protein influences the structure of a protein. Taken together, these analyses will improve our understanding of the exact functions of CBP and its interaction with c-Myb.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Modelos Moleculares , Simulação de Dinâmica Molecular , Mutação , Proteínas Nucleares/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Sequência de Aminoácidos , Animais , Proteínas de Ligação a DNA , Proteínas de Membrana/química , Camundongos , Proteínas Nucleares/química , Proteínas de Transporte Nucleocitoplasmático/química , Estabilidade Proteica , Proteínas de Ligação a RNA , Alinhamento de Sequência , Eletricidade Estática , Fatores de Transcrição
13.
Hum Vaccin Immunother ; 8(10): 1401-6, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23022710

RESUMO

Group A rotavirus (RV-A) genotypes isolated in Malaysia was studied to estimate the effectiveness of a universal RV-A vaccination in Malaysia. A simple mathematical model was used, with input from a two-year, two-center, prospective study on hospitalization of RV-A gastroenteritis (RVGE) in young children, published data on RV-A hospitalizations and genotypes, mortality on childhood GE and published genotype-specific efficacy data on two RV-A vaccines. Assuming a 95% vaccine coverage, the overall projected effectiveness was 75.7 to 88.1% for Rotateq and 78.7 to 90.6% for Rotarix® against RVGE-related hospitalizations. The projected annual reduction in RVGE-related deaths was 27 to 32 deaths (from 34 deaths) for Rotateq and 28 to 32 deaths annually for Rotarix. A universal RV-A vaccine is efficacious in reducing RVGE-related hospitalizations and mortality in Malaysia.


Assuntos
Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/uso terapêutico , Rotavirus/genética , Rotavirus/patogenicidade , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Malásia/epidemiologia , Masculino , Modelos Teóricos , Rotavirus/classificação , Infecções por Rotavirus/epidemiologia , Vacinação/estatística & dados numéricos
14.
IEEE Trans Syst Man Cybern B Cybern ; 42(1): 163-80, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21859628

RESUMO

Interactions between multiple tunable protocol parameters and multiple performance metrics are generally complex and unknown; finding optimal solutions is generally difficult. However, protocol tuning can yield significant gains in energy efficiency and resource requirements, which is of particular importance for sensornet systems in which resource availability is severely restricted. We address this multi-objective optimization problem for two dissimilar routing protocols and by two distinct approaches. First, we apply factorial design and statistical model fitting methods to reject insignificant factors and locate regions of the problem space containing near-optimal solutions by principled search. Second, we apply the Strength Pareto Evolutionary Algorithm 2 and Two-Archive evolutionary algorithms to explore the problem space, with each iteration potentially yielding solutions of higher quality and diversity than the preceding iteration. Whereas a principled search methodology yields a generally applicable survey of the problem space and enables performance prediction, the evolutionary approach yields viable solutions of higher quality and at lower experimental cost. This is the first study in which sensornet protocol optimization has been explicitly formulated as a multi-objective problem and solved with state-of-the-art multi-objective evolutionary algorithms.


Assuntos
Algoritmos , Inteligência Artificial , Técnicas de Apoio para a Decisão , Modelos Teóricos , Reconhecimento Automatizado de Padrão/métodos , Transdutores , Simulação por Computador
15.
Proc Natl Acad Sci U S A ; 106(28): 11731-6, 2009 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-19564623

RESUMO

GABA cell dysfunction in both schizophrenia (SZ) and bipolar disorder (BD) involves decreased GAD(67) expression, although this change involves fundamentally different networks of genes in the 2 disorders. One gene that is common to these 2 networks is cyclin D2, a key component of cell cycle regulation that shows increased expression in SZ, but decreased expression in BD. Because of the importance of cell cycle regulation in maintaining functional differentiation and DNA repair, the current study has examined the genes involved in the G(1) and G(2) checkpoints to generate new hypotheses regarding the regulation of the GABA cell phenotype in the hippocampus of SZ and BD. The results have demonstrated significant changes in cell cycle regulation in both SZ and BD and these changes include the transcriptional complex (TC) that controls the expression of E2F/DP-1 target genes critical for progression to G(2)/M. The methyl-CpG binding domain protein (MBD4) that is pivotal for DNA repair, is significantly up-regulated in the stratum oriens (SO) of CA3/2 and CA1 in SZs and BDs. However, other genes associated with the TC, and the G(1) and G(2) checkpoints, show complex changes in expression in the SO of CA3/2 and CA1 of both SZs and BDS. Overall, the patterns of expression observed have suggested that the regulation of functional differentiation and/or genomic integrity of hippocampal GABA cells varies according to diagnosis and their location within the trisynaptic pathway.


Assuntos
Transtorno Bipolar/metabolismo , Ciclo Celular/fisiologia , Hipocampo/citologia , Neurônios/metabolismo , Esquizofrenia/metabolismo , Reparo do DNA/fisiologia , Endodesoxirribonucleases/metabolismo , Regulação da Expressão Gênica/fisiologia , Glutamato Descarboxilase/metabolismo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ácido gama-Aminobutírico/metabolismo
16.
Proc Natl Acad Sci U S A ; 105(52): 20935-40, 2008 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-19104056

RESUMO

Significant reductions in GABAergic cell numbers and/or activity have been demonstrated in the hippocampus of subjects with schizophrenia and bipolar disorder. To understand how different subpopulations of interneurons are regulated, laser microdissection and gene expression profiling have been used to "deconstruct" the trisynaptic pathway, so that subtypes of GABA cells could be defined by their location in various layers of CA3/2 and CA1. The results suggest that the cellular endophenotypes for SZ and BD may be determined by multiple factors that include unique susceptibility genes for the respective disorders and altered integration among hippocampal GABA cells with extrinsic and intrinsic afferent fiber systems. The extensive and intricate data that has come from this study has provided insights into how a complex circuit, like the trisynaptic pathway, may be regulated in human hippocampus in both health and disease.


Assuntos
Transtorno Bipolar/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hipocampo/metabolismo , Esquizofrenia/metabolismo , Sinapses/metabolismo , Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Feminino , Hipocampo/patologia , Humanos , Masculino , Microdissecção , Esquizofrenia/genética , Esquizofrenia/patologia , Sinapses/patologia , Ácido gama-Aminobutírico/genética , Ácido gama-Aminobutírico/metabolismo
17.
Proc Natl Acad Sci U S A ; 104(24): 10164-9, 2007 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-17553960

RESUMO

GABAergic dysfunction is present in the hippocampus in schizophrenia (SZ) and bipolar disorder (BD). The trisynaptic pathway was "deconstructed" into various layers of sectors CA3/2 and CA1 and gene expression profiling performed. Network association analysis was used to uncover genes that may be related to regulation of glutamate decarboxylase 67 (GAD(67)), a marker for this system that has been found by many studies to show decreased expression in SZs and BDs. The most striking change was a down-regulation of GAD(67) in the stratum oriens (SO) of CA2/3 in both groups; CA1 only showed changes in the SO of schizophrenics. The network generated for GAD(67) contained 25 genes involved in the regulation of kainate receptors, TGF-beta and Wnt signaling, as well as transcription factors involved in cell growth and differentiation. In SZs, IL-1beta, (GRIK2/3), TGF-beta2, TGF-betaR1, histone deacetylase 1 (HDAC1), death associated protein (DAXX), and cyclin D2 (CCND2) were all significantly up-regulated, whereas in BDs, PAX5, Runx2, LEF1, TLE1, and CCND2 were significantly down-regulated. In the SO of CA1 of BDs, where GAD67 showed no expression change, TGF-beta and Wnt signaling genes were all up-regulated, but other transcription factors showed no change in expression. In other layers/sectors, BDs showed no expression changes in these GAD(67) network genes. Overall, these results are consistent with the hypothesis that decreased expression of GAD(67) may be associated with an epigenetic mechanism in SZ. In BD, however, a suppression of transcription factors involved in cell differentiation may contribute to GABA dysfunction.


Assuntos
Transtorno Bipolar/metabolismo , Regulação da Expressão Gênica , Hipocampo/metabolismo , Esquizofrenia/metabolismo , Ácido gama-Aminobutírico/metabolismo , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/patologia , Estudos de Casos e Controles , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Glutamato Descarboxilase/metabolismo , Hipocampo/patologia , Humanos , Isoenzimas/metabolismo , Masculino , Modelos Biológicos , Fenótipo , RNA Mensageiro/metabolismo , Esquizofrenia/diagnóstico , Esquizofrenia/patologia
18.
Environ Res ; 96(2): 156-62, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15325876

RESUMO

We conducted a cleaning trial in 40 northern New Jersey homes where home renovation and remodeling (R&R) activities were undertaken. Two cleaning protocols were used in the study: a specific method recommended by the US Department of Housing and Urban Development (HUD), in the 1995 "Guidelines for the Evaluation and Control of Lead-Based Paint Hazards in Housing," using a high-efficiency particulate air (HEPA)-filtered vacuum cleaner and a tri-sodium phosphate solution (TSP); and an alternative method using a household vacuum cleaner and a household detergent. Eligible homes were built before the 1970s with potential lead-based paint and had recent R&R activities without thorough cleaning. The two cleaning protocols were randomly assigned to the participants' homes and followed the HUD-recommended three-step procedure: vacuuming, wet washing, and repeat vacuuming. Wipe sampling was conducted on floor surfaces or windowsills before and after cleaning to evaluate the efficacy. All floor and windowsill data indicated that both methods (TSP/HEPA and non-TSP/non-HEPA) were effective in reducing lead loading on the surfaces (P < 0.001). When cleaning was applied to surfaces with initial lead loading above the clearance standards, the reductions were even greater, above 95% for either cleaning method. The mixed-effect model analysis showed no significant difference between the two methods. Baseline lead loading was found to be associated with lead loading reduction significantly on floors (P < 0.001) and marginally on windowsills (P = 0.077). Such relations were different between the two cleaning methods significantly on floors (P < 0.001) and marginally on windowsills (P = 0.066), with the TSP/HEPA method being favored for higher baseline levels and the non-TSP/non-HEPA method for lower baseline levels. For the 10 homes with lead abatement, almost all post-cleaning lead loadings were below the standards using either cleaning method. Based on our results, we recommend that contractors or homeowners can use a household vacuum cleaner and a household detergent to clean lead-contaminated environments after R&R activities when HUD-recommended equipment is not available.


Assuntos
Poluição do Ar em Ambientes Fechados/análise , Poluição do Ar em Ambientes Fechados/prevenção & controle , Zeladoria/métodos , Poeira , Filtração , Pisos e Cobertura de Pisos , Habitação , Humanos , Chumbo/análise , Intoxicação por Chumbo/prevenção & controle , Distribuição Aleatória , Gestão da Segurança/métodos , Estatísticas não Paramétricas , Inquéritos e Questionários
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