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1.
Lancet ; 402 Suppl 1: S73, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37997118

RESUMO

BACKGROUND: Multimorbidity, defined as the presence of two or more long-term conditions, is a growing public health challenge, especially in terms of prevention and accumulation of long-term conditions among particular population cohorts. To date, efforts to understand multimorbidity has focused mainly on specific disease combinations, with little known about the sociodemographic factors associated with it. The study aimed to assess the factors associated with multimorbidity in England. METHODS: A cross-sectional study was conducted using the English Longitudinal Study of Ageing (ELSA), a dataset of people aged 50 years and older. The study identified ten long-term conditions from waves 2 to 9. Wave 2 to 9 were conducted between June 2004 to July 2005, May 2006 to August 2007, May 2008 to July 2009, June 2010 to July 2011, May 2012 to June 2013, June 2014 to May 2015, May 2016 to June 2017 and June 2018 to July 2019, respectively. The study included people with two or more long-term conditions. We identified the number of long-term conditions and multimorbidity, and we examined their association with age, gender, ethnicity, marital status, employment status, education, weekly contact with relative, and feeling lonely, sad or depressed using multinomial logistic regression. FINDINGS: Of 16 731 people recruited from wave 2 to wave 9, we identified 10 026 people with multimorbidity aged 50 years and older. The majority had two conditions (39%) and were female (55%), aged 50-69 years (32%), of white ethnicity (96%), married (69%) and unemployed (65·3%). The adjusted odds ratio (aOR) of having more than two long-term conditions increased with age, after adjusting for sex and ethnicity (≥5 conditions: aOR 12·89, 95% CI 2·23-3·76). Being female was associated with an increased risk of having more than two long-term conditions (≥5 conditions: aOR 1·21, 1·04-1·42). Similarly, being separated, divorced, or widowed were associated with having more than two long-term conditions (≥5 conditions: aOR 1·45, 1·21-1·74). Not owning a home was independently associated with more than two long-term conditions (≥5 conditions: aOR 1·59, 1·35-1·88). INTERPRETATION: The current analysis used only ten long-term conditions that were available in the ELSA data, so a different association might have arisen if other conditions had been considered. Our findings provide insights into which particular groups of the multimorbid population could be the target of preventive public health strategies and wider clinical and social care interventions in England to reduce the burden of multimorbidity. FUNDING: National Institute for Health and Care Research (NIHR).


Assuntos
Envelhecimento , Multimorbidade , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Longitudinais , Estudos Transversais , Inglaterra/epidemiologia
2.
Curr Issues Mol Biol ; 45(8): 6634-6650, 2023 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-37623238

RESUMO

Fructan 1-exohydrolase (1-FEH) is one of the major enzymes in water-soluble carbohydrate (WSC) remobilisation for grains in wheat. We investigated the functional role of 1-FEH w1, w2, and w3 isoforms in WSC remobilisation under post-anthesis water deficit using mutation lines derived from the Australian wheat variety Chara. F1 seeds, developed by backcrossing the 1-FEH w1, w2, and w3 mutation lines with Chara, were genotyped using the Infinium 90K SNP iSelect platform to characterise the mutated region. Putative deletions were identified in FEH mutation lines encompassing the FEH genomic regions. Mapping analysis demonstrated that mutations affected significantly longer regions than the target FEH gene regions. Functional roles of the non-target genes were carried out utilising bioinformatics and confirmed that the non-target genes were unlikely to confound the effects considered to be due to the influence of 1-FEH gene functions. Glasshouse experiments revealed that the 1-FEH w3 mutation line had a slower degradation and remobilisation of fructans than the 1-FEH w2 and w1 mutation lines and Chara, which reduced grain filling and grain yield. Thus, 1-FEH w3 plays a vital role in reducing yield loss under drought. This insight into the distinct role of the 1-FEH isoforms provides new gene targets for water-deficit-tolerant wheat breeding.

3.
Zygote ; 31(2): 157-162, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36617977

RESUMO

This study was performed to analyze the morphometric traits and indices in 3000 animals of five registered sheep breeds in the Himalayan region under a multivariate approach. Data were recorded under field conditions with equal coverage of the five breeds, viz., Karnah, Gurez, Poonchi, Bakerwal and Changthangi on body length (BL), height at withers (HW), chest girth (CG), ear length (EL), and tail length (TL). Furthermore, four derived traits (indices) were studied, which included an index of body frame (IBF), an index of thorax development (ITD), a Baron-Crevat index (BCI), and an index of body weight (IBW). Multivariate principal component analysis (PCA) was undertaken on nine morphometric traits. Kaiser's criterion was used to reduce the number of principal components for further analysis and interpretation. The adequacy of sampling was evaluated using Kaiser-Meyer-Olkin (KMO) test and Bartlett's test of sphericity. The mean BL ranged from 52.15 (Changthangi) to 71.13 (Gurez). The estimates of HW, CG, EL and TL were highest in Gurez (63.49), Bakerwal (84.82), Bakerwal (7.26), and Karnah (8.18) breeds, respectively. Among the derived traits, the highest IBF was observed in the Gurez breed with an estimate of 112.22. Upon multivariate PCA on the dataset, the first four principal components were able to explain 92.117% of the total variance. The KMO test, Bartlett's test of sphericity and estimated communalities showed the appropriateness of PCA on the evaluated traits. Four eigenvalues were greater than one and were extracted for further analysis. Morphometric traits were highly correlated, except for EL and TL that showed lower correlation estimates with other traits. The Changthangi population showed the lowest estimates of BL, HW, CG and rectangular body frame. The present study ascertained important morphometric traits/indices that can help in developing selection criteria and formulating sustainable breeding and conservation plans vis-à-vis the unique sheep breeds of the temperate Himalayas.


Assuntos
Análise de Componente Principal , Animais , Ovinos , Índia
4.
BMC Med Educ ; 23(1): 495, 2023 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-37407987

RESUMO

BACKGROUND: The clinical placements of our medical students are almost equally distributed across private and public sectors. This study aims to assess medical students' perceptions of their Clinical learning Environment (CLE) across these two different healthcare settings, using the Undergraduate Clinical Education Environment Measure (UCEEM). METHODS: 76 undergraduate medical students (Year 5 and 6), were invited to participate. Data were collected using an online UCEEM with additional questions related to demographics and case load exposure. The UCEEM consists of two overarching domains of experiential learning and social participation, with four subdomains of learning opportunities, preparedness, workplace interaction, and inclusion. RESULTS: 38 questionnaires were received. Of 225 responses to the individual UCEEM items, 51 (22.6%) scored a mean of ≥ 4 (range 4-4.5, representing strong areas), 31 (13.7%) scored a mean of ≤ 3 (range 2.1-3, needing attention) and 143 (63.6%) scored a mean of 3.1-3.9 (areas that could be improved). The majority (63%) of the case load exposure responses scored a mean of ≥ 4 (range 4-4.5). Compared to the private sittings, there is a significant reduction in total UCEEM (p = 0.008), preparedness for student entry (p = 0.003), and overarching dimension of social participation (p = 0.000) scores for the public sector. Similarly, both workplace interaction patterns and student inclusion and equal treatment scored significantly lower for the public sector (p = 0.000 and p = 0.011 respectively). Two out of three case load exposure items scored significantly higher for the public sector (p = 0.000). DISCUSSION: The students' CLE perceptions were generally positive. The lower UCEEM ratings in the public sector items were related to student entry preparedness, workplace interactions, student inclusiveness and workforce equity of treatment. In contrast the students were exposed to more variety and larger number of patients in the public sector. These differences indicated some significantly different learning environments between the two sectors.


Assuntos
Educação de Graduação em Medicina , Estudantes de Medicina , Humanos , Aprendizagem , Atenção à Saúde , Aprendizagem Baseada em Problemas , Local de Trabalho , Inquéritos e Questionários
5.
Trop Anim Health Prod ; 55(4): 250, 2023 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-37354287

RESUMO

The exploration of additive genetic variance for the selection of animals is the central paradigm in quantitative genetics and it is important to use appropriate animal models considering important factors. This study compares various factor effects for heritability and breeding values estimations on data collected on the Corriedale. Overall, the heritability estimates were the highest for birthweight (BW). Both the additive genetic variance and the heritability values were reduced upon adding more random effects. Year-effect as random reduced the heritability except for BW. The highest average accuracy for breeding values for birth, weaning, 6, 9, and 12-month-weights for were 0.656, 0.567, 0.519, 0.486, and 0.515. These were observed for models having sex or sex and parity as fixed effects. It is concluded that fixed and random factors have a significant impact on genetic-factors and breeding-value accuracies and should be considered during selection programs and make the selection program more effective.


Assuntos
Modelos Genéticos , Parto , Gravidez , Feminino , Animais , Peso ao Nascer/genética , Paridade , Desmame , Modelos Animais , Fenótipo , Peso Corporal/genética
6.
Langenbecks Arch Surg ; 407(7): 2905-2913, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35670859

RESUMO

PURPOSE: Textbook outcome (TO) is a composite measure of outcome and provides superior assessment of quality of care after surgery. TO after major living donor hepatectomy (MLDH) has not been assessed. The objective of this study was to determine the rate of TO and its associated factors, after MLDH. METHODS: This was a single center retrospective review of living liver donors who underwent MLDH between 2012 and 2021 (n = 1022). The rate of TO and its associated factors was determined. RESULTS: Among 1022 living donors (of whom 693 [67.8%] were males, median age 26 [range, 18-54] years), TO was achieved in 714 (69.9%) with no donor mortality. Majority of donors met the cutoffs for individual outcome measures: 908 (88.8%) for no major complications, 904 (88.5%) for ICU stay ≤ 2 days, 900 (88.1%) for hospital stay ≤ 10 days, 990 (96.9%) for no perioperative blood transfusion, 1004 (98.2%) for no 30-day re-admission, and 1014 (99.2%) for no post-hepatectomy liver failure. Early donation era (before streamlining of donor operative pathways) was associated with failure to achieve TO [OR 1.4, CI 1.1-1.9, P = 0.006]. TO was achieved in 506/755 (67%) donors in the early donation era versus 208/267 (77.9%) in the later period (P = 0.001). CONCLUSION: Despite zero mortality and low complication rate, TO was achieved in approximately 70% donors. TO was modifiable and improved with changes in donor operative pathway.


Assuntos
Transplante de Fígado , Doadores Vivos , Masculino , Humanos , Adulto , Feminino , Hepatectomia/efeitos adversos , Coleta de Tecidos e Órgãos/efeitos adversos , Transplante de Fígado/efeitos adversos , Fígado , Estudos Retrospectivos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia
7.
Stem Cells ; 38(2): 261-275, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31721342

RESUMO

The tunica adventitia ensheathes arteries and veins and contains presumptive mesenchymal stem cells (MSCs) involved in vascular remodeling. We show here that a subset of human adventitial cells express the CD10/CALLA cell surface metalloprotease. Both CD10+ and CD10- adventitial cells displayed phenotypic features of MSCs when expanded in culture. However, CD10+ adventitial cells exhibited higher proliferation, clonogenic and osteogenic potentials in comparison to their CD10- counterparts. CD10+ adventitial cells increased expression of the cell cycle protein CCND2 via ERK1/2 signaling and osteoblastogenic gene expression via NF-κB signaling. CD10 expression was upregulated in adventitial cells through sonic hedgehog-mediated GLI1 signaling. These results suggest that CD10, which marks rapidly dividing cells in other normal and malignant cell lineages, plays a role in perivascular MSC function and cell fate specification. These findings also point to a role for CD10+ perivascular cells in vascular remodeling and calcification.


Assuntos
Calcificação Fisiológica/genética , Neprilisina/metabolismo , Células-Tronco/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células , Humanos , Pessoa de Meia-Idade
8.
Trop Anim Health Prod ; 53(2): 197, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33677706

RESUMO

In the present study, an attempt was made to elucidate the genetic parameters for body weight traits of lambs from Corriedale sheep population at different ages. Data were collected from 6874 lambs born over a span of 49 years from 1969 to 2017. The traits under study included body weight at birth (BW), weaning (WW), 6 months of age (6MW), 9 months of age (9MW) and yearling stage (YW). Data were statistically analyzed using restricted maximum likelihood (REML) algorithm in WOMBAT program. A multi-variate animal model was fitted to the data incorporating season and period of lambing, sex of lamb and litter size as fixed effects. Variance and covariance components were estimated using the animal model after incorporating direct additive genetic effect of animal as random factor. Genetic and phenotypic correlations with corresponding standard errors were also estimated. The heritability estimates for BW, WW, 6MW, 9MW and YW were 0.130 ± 0.023, 0.300 ± 0.029, 0.292 ± 0.030, 0.191 ± 0.025 and 0.169 ± 0.024, respectively. The genetic correlation between different traits under study was high, except between BW and 9MW for which the estimate was moderate. Phenotypic correlation ranged from low to high for different trait combinations. Among different traits under study, only two traits showed moderate heritability i.e. WW and 6MW while heritability of other traits was low. Both these traits showed high correlation with all subsequent traits. Selection programme for Corriedale sheep should be based on WW which is expressed early in life and shall lead to moderate genetic response to selection.


Assuntos
Peso Corporal/genética , Modelos Genéticos , Carneiro Doméstico/genética , Animais , Peso ao Nascer/genética , Feminino , Tamanho da Ninhada de Vivíparos , Masculino , Análise Multivariada , Fenótipo , Estações do Ano , Desmame
9.
J Pak Med Assoc ; 71(7): 1838-1842, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34410258

RESUMO

OBJECTIVE: To report long-term outcomes after pancreaticoduodenectomy from a single centre. METHODS: The retrospective study was conducted at Shifa International Hospital, Islamabad and comprised pancreaticoduodenectomy procedures performed by four surgeons at a single centre from January 2011 to June 2019. Outcome was assessed on the basis of morbidity, in-hospital mortality and survival. Data was analysed using SPSS 20. RESULTS: Of the 155 patients, 103(66.5%) were males. The overall mean age was 56.8±13.5 years (range: 8-85 years). Overall morbidity was 84 (54.2%). Multivisceral and venous resections were performed in 22(14.2%) and 20(12.9%) patients respectively. Grade B pancreatic fistula was seen in 5(3.2%) patients and grade C in 6(3.8%). In-hospital mortality was 5(3.2%). The difference between the estimated 5-year overall survival for pancreatic and non-pancreatic cancers was non-significant (p=0.2), while the difference in the estimated 3-year overall survival rate was significant (p<0.05). CONCLUSIONS: With standardisation of operative technique and peri-operative management, low in-hospital mortality and acceptable long-term outcomes were achieved with standard and extended pancreaticoduodenectomy.


Assuntos
Neoplasias Pancreáticas , Pancreaticoduodenectomia , Adulto , Idoso , Anastomose Cirúrgica , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Fístula Pancreática , Neoplasias Pancreáticas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento
10.
Trop Anim Health Prod ; 53(1): 190, 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33660098

RESUMO

The present study aimed to estimate the genetic parameters of different fibre traits, viz., greasy fleece weight, staple length, and fibre diameter in Rambouillet sheep population using a multi-trait animal model. Data, spanning over 10 years (1998-2007) and pertaining to fibre traits at first clip, were collected for a total of 4186 Rambouillet sheep maintained at an organized farm. (Co)Variance structure and genetic parameters were estimated using a multi-trait animal model. The genetic analysis of data was performed based on restricted maximum likelihood (REML) procedure using WOMBAT software. The model incorporated sex of lamb (i = 1, 2), year of birth (j = 1-10), season of birth (k = 1-2), and litter size (l = 1-2) as fixed effects while direct additive genetic and maternal genetic effects were included as random effects. The direct additive genetic heritability estimates were 0.120±0.034, 0.136±0.037, and 0.356±0.070 for greasy fleece weight, staple length, and fibre diameter, respectively. The maternal genetic heritability of all fibre traits under study was very low. Additive genetic correlation was positive and low between greasy fleece weight and staple length; and between staple length and fibre diameter. In conclusion, fibre diameter was moderately heritable which implies that selection may lead to moderate improvement in this trait. The results from the present study will help in formulating optimal breeding plans for improvement of fibre traits in Rambouillet sheep.


Assuntos
Carneiro Doméstico , , Animais , Peso ao Nascer , Peso Corporal , Feminino , Tamanho da Ninhada de Vivíparos/genética , Fenótipo , Gravidez , Ovinos/genética , Carneiro Doméstico/genética
11.
BMC Cancer ; 20(1): 754, 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32787864

RESUMO

BACKGROUND: Living donor liver transplantation (LDLT) is an acceptable treatment option for hepatocellular carcinoma (HCC). Traditional transplant criteria aim at best utilization of donor organs with low risk of post transplant recurrence. In LDLT, long term recurrence free survival (RFS) of 50% is considered acceptable. The objective of the current study was to determine preoperative factors associated with high recurrence rates in LDLT. METHODS: Between April 2012 and December 2019, 898 LDLTs were performed at our center. Out of these, 242 were confirmed to have HCC on explant histopathology. We looked at preoperative factors associated with ≤ 50%RFS at 4 years. For survival analysis, Kaplan Meier curves were used and Cox regression analysis was used to identify independent predictors of recurrence. RESULTS: Median AFP was 14.4(0.7-11,326.7) ng/ml. Median tumor size was 2.8(range = 0.1-11) cm and tumor number was 2(range = 1-15). On multivariate analysis, AFP > 600 ng/ml [HR:6, CI: 1.9-18.4, P = 0.002] and microvascular invasion (MVI) [HR:5.8, CI: 2.5-13.4, P <  0.001] were independent predictors of 4 year RFS ≤ 50%. When AFP was > 600 ng/ml, MVI was seen in 88.9% tumors with poor grade and 75% of tumors outside University of California San Francisco criteria. Estimated 4 year RFS was 78% for the entire cohort. When AFP was < 600 ng/ml, 4 year RFS for well-moderate and poor grade tumors was 88 and 73%. With AFP > 600 ng/ml, RFS was 53% and 0 with well-moderate and poor grade tumors respectively (P <  0.001). CONCLUSION: Patients with AFP < 600 ng/ml have acceptable outcomes after LDLT. In patients with AFP > 600 ng/ml, a preoperative biopsy to rule out poor differentiation should be considered for patient selection.


Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Doadores Vivos , Recidiva Local de Neoplasia , Adulto , Idoso , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Cuidados Pré-Operatórios , Análise de Regressão , Carga Tumoral , alfa-Fetoproteínas/metabolismo
12.
Eur J Epidemiol ; 35(8): 743-748, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32656618

RESUMO

In low and middle-income countries (LMICs), strict social distancing measures (e.g., nationwide lockdown) in response to the COVID-19 pandemic are unsustainable in the long-term due to knock-on socioeconomic and psychological effects. However, an optimal epidemiology-focused strategy for 'safe-reopening' (i.e., balancing between the economic and health consequences) remain unclear, particularly given the suboptimal disease surveillance and diagnostic infrastructure in these settings. As the lockdown is now being relaxed in many LMICs, in this paper, we have (1) conducted an epidemiology-based "options appraisal" of various available non-pharmacological intervention options that can be employed to safely lift the lockdowns (namely, sustained mitigation, zonal lockdown and rolling lockdown strategies), and (2) propose suitable application, pre-requisites, and inherent limitations for each measure. Among these, a sustained mitigation-only approach (adopted in many high-income countries) may not be feasible in most LMIC settings given the absence of nationwide population surveillance, generalised testing, contact tracing and critical care infrastructure needed to tackle the likely resurgence of infections. By contrast, zonal or local lockdowns may be suitable for some countries where systematic identification of new outbreak clusters in real-time would be feasible. This requires a generalised testing and surveillance structure, and a well-thought out (and executed) zone management plan. Finally, an intermittent, rolling lockdown strategy has recently been suggested by the World Health Organization as a potential strategy to get the epidemic under control in some LMI settings, where generalised mitigation and zonal containment is unfeasible. This strategy, however, needs to be carefully considered for economic costs and necessary supply chain reforms. In conclusion, while we propose three community-based, non-pharmacological options for LMICs, a suitable measure should be context-specific and based on: (1) epidemiological considerations, (2) social and economic costs, (3) existing health systems capabilities and (4) future-proof plans to implement and sustain the strategy.


Assuntos
Controle de Doenças Transmissíveis/métodos , Infecções por Coronavirus/prevenção & controle , Máscaras , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Quarentena , Isolamento Social , Betacoronavirus , COVID-19 , Coronavirus , Infecções por Coronavirus/epidemiologia , Humanos , Máscaras/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Saúde Pública , Quarentena/estatística & dados numéricos , SARS-CoV-2
13.
Blood Cells Mol Dis ; 75: 48-55, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30616104

RESUMO

Zebrafish is emerging as a promising model for the study of human cancers. Several xenograft models of zebrafish have been developed, particularly in larval stages (<48 h post fertilization) when the immune system of fish is not developed. However, xenografting in adult zebrafish requires laborious and transient methods of immune suppression (γ- irradiation or dexamethasone) that limits engraftment and survival of the tumor or fail to recapitulate specific characteristics of malignancies. Thus, the availability of a simple protocol to successfully engraft adult zebrafish, remains a challenge. The current study addresses this limitation and describes a robust method of xenografting in adult zebrafish. We describe a protocol that involves pre-conditioning of Casper, a pigmentation mutant of zebrafish with busulfan that led to a higher rate of engraftment of hepatocellular carcinoma and acute myeloid leukemia cells. To further ascertain the homing characteristics of the injected cancer cells, we transplanted adult zebrafish by two routes of administration and then studied their compartmentalization. This model presents a valuable alternative to rodents to study the biology of these cancers and also a cost-effective platform for evaluation of potential anti-cancer agents.


Assuntos
Carcinoma Hepatocelular/patologia , Modelos Animais de Doenças , Xenoenxertos , Leucemia Mieloide Aguda/patologia , Neoplasias Hepáticas Experimentais/patologia , Peixe-Zebra , Animais , Bussulfano/farmacologia , Compartimento Celular , Humanos , Métodos
14.
Bioconjug Chem ; 30(9): 2404-2416, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31436412

RESUMO

Current chemotherapeutic regimens for acute myeloid leukemia (AML) have been modestly effective in patients and are associated with poor long-term survival (<30% at 5 years). Viral vector-based suicide gene therapy is an attractive option, if these vectors can target the AML cells with high specificity and efficiency. In this study, we have developed a receptor-specific adeno-associated virus (AAV) based vector to target the CD33 antigen which is overexpressed in leukemic cells. A targeting peptide was rationally designed from the antigen-binding regions of a CD33 monoclonal antibody. This peptide was further expressed on the capsid of the AAV6 vector, since this serotype was most efficient among AAV1-rh10 vectors to infect the pro-monocytic, human myeloid leukemia cells (U937). AAV6-CD33 vectors expressing a suicide gene, the inducible caspase 9 (iCasp9), and its prodrug AP20187 significantly reduced (∼59%) the viability of U937 cells. To further test its efficacy and specificity in vivo, AAV6-CD33 vectors were administered into a xenotransplantation model of AML in zebrafish through systemic delivery. We observed a significant antileukemic effect with AAV6-CD33 vectors, with a markedly higher survival (100% for AAV6-CD33 vectors vs 15% for mock-treated) and a higher number of TUNEL positive apoptotic cells after systemic vector delivery. Taken together, our work demonstrates the efficacy and translational potential of CD33-targeted AAV6 vectors for cytotoxic gene therapy in AML.


Assuntos
Caspase 9/genética , Dependovirus/genética , Genes Transgênicos Suicidas/genética , Terapia Genética/métodos , Vetores Genéticos/genética , Leucemia Mieloide Aguda/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Expressão Gênica , Humanos , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Peixe-Zebra
15.
Bioconjug Chem ; 30(6): 1754-1762, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31181889

RESUMO

Current treatment approaches for hepatocellular carcinoma (HCC) have a narrow therapeutic index and alternate modes of treatment are thus required. We have utilized a gene delivery vector containing inducible caspase 9 (iCasp9) gene, which is a synthetic analogue based on the mammalian caspase 9 and fused to a human FK506 binding protein that allows its conditional dimerization to a synthetic, small molecule [chemical inducer of dimerization, AP20187] and results in target cell apoptosis. In our studies, we have tested these synthetic vectors based on an adeno-associated virus platform for their potential anti-tumorigenic effect in human HCC cells in vitro and in a HCC tumor model developed in nude mice. Our data demonstrates that the iCasp9-AP20187 bioconjugate is able to trigger terminal effectors of cellular apoptosis and presents a viable approach for the potential treatment of HCC.


Assuntos
Carcinoma Hepatocelular/terapia , Caspase 9/genética , Dependovirus/genética , Técnicas de Transferência de Genes , Vetores Genéticos/uso terapêutico , Neoplasias Hepáticas/terapia , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Terapia Genética , Vetores Genéticos/genética , Humanos , Neoplasias Hepáticas/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Ligação a Tacrolimo/genética
16.
World J Surg ; 42(4): 1111-1119, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28936685

RESUMO

BACKGROUND: There is paucity of data on intermediate-term post liver transplant outcomes from South Asia. The objective of this study was to determine survival outcomes in patients who underwent living donor liver transplantation (LDLT) in a busy liver transplant center in Pakistan. METHODS: This study was a review of patients who underwent LDLT between 2012 and 2016. A total of 321 patients were included in this study. Early (within 90 days) and late (>90 days) morbidity and mortality was assessed. Estimated 1- and 4-year survival was determined. RESULTS: Median age was 48 (18-73) years. Male to female ratio was 4.5:1. Out of total 346 complications, 184 (57.3%) patients developed 276 (79.7%) complications in early post-transplant period, whereas there were 70 (21.3%) late complications. Most common early complication was pleural effusion in 46 (16.6%) patients. Biliary complications were the most common late complication and were seen in 31/70 (44.2%) patients. Overall 21.4% patients had a biliary complication. The 3-month mortality was 14%. The estimated 1- and 4-year OS for a MELD cutoff of 30 was 84.5 versus 72 and 80 versus 57% (P = 0.01). There was no donor mortality. CONCLUSION: Acceptable intermediate-term post-transplant outcomes were achieved with LDLT. There is a need to improve outcomes in high-MELD patients.


Assuntos
Sobrevivência de Enxerto , Falência Hepática/cirurgia , Transplante de Fígado/efeitos adversos , Doadores Vivos , Complicações Pós-Operatórias/epidemiologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
17.
Liver Transpl ; 28(2): 336, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34536329
19.
New Phytol ; 205(1): 293-305, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25250511

RESUMO

In wheat stems, the levels of fructan-dominated water-soluble carbohydrates (WSC) do not always correlate well with grain yield. Field drought experiments were carried out to further explain this lack of correlation. Wheat (Triticum aestivum) varieties, Westonia, Kauz and c. 20 genetically diverse double haploid (DH) lines derived from them were investigated. Substantial genotypic differences in fructan remobilization were found and the 1-FEH w3 gene was shown to be the major contributor in the stem fructan remobilization process based on enzyme activity and gene expression results. A single nucleotide polymorphism (SNP) was detected in an auxin response element in the 1-FEH w3 promoter region, therefore we speculated that the mutated Westonia allele might affect gene expression and enzyme activity levels. A cleaved amplified polymorphic (CAP) marker was generated from the SNP. The harvested results showed that the mutated Westonia 1-FEH w3 allele was associated with a higher thousand grain weight (TGW) under drought conditions in 2011 and 2012. These results indicated that higher gene expression of 1-FEH w3 and 1-FEH w3 mediated enzyme activities that favoured stem WSC remobilization to the grains. The CAP marker residing in the 1-FEH w3 promoter region may facilitate wheat breeding by selecting lines with high stem fructan remobilization capacity under terminal drought.


Assuntos
Carboidratos/análise , Secas , Variação Genética , Proteínas de Plantas/genética , Caules de Planta/metabolismo , Sementes/metabolismo , Triticum/metabolismo , Irrigação Agrícola , Alelos , Biomassa , Frutanos/metabolismo , Frutose/metabolismo , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Marcadores Genéticos , Genótipo , Haploidia , Proteínas de Plantas/metabolismo , Solubilidade , Triticum/enzimologia , Triticum/genética , Água/química , Austrália Ocidental
20.
Cureus ; 16(3): e56027, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38606244

RESUMO

BACKGROUND AND OBJECTIVE: This study aims to assess the prevalence and antimicrobial susceptibility patterns of bacterial infections associated with both early-onset sepsis (EOS) and late-onset sepsis (LOS). METHODOLOGY: This descriptive retrospective surveillance research was conducted on all neonates admitted to the neonatal ICU with bacterial sepsis, where positive cultures were isolated from sterile sites (either cerebrospinal fluid or blood) at Tawam Hospital, Al Ain, Emirate of Abu Dhabi, UAE, from January 2012 and December 2021. Antimicrobial susceptibility analysis was performed. RESULTS: The incidence of LOS (94.43%) was higher compared to EOS (5.56%). The most prevalent isolates (59.2%) were gram-positive bacteria, with gram-negative bacteria accounting for 40.8%. The leading isolates included coagulase-negative Staphylococci (CONS, 40.98%), Klebsiella (16.04%), Staphylococcus aureus (8.46%), Escherichia coli (8.24%), Pseudomonas (7.57%), and Group B Streptococcus (GBS, 5.12%). CONS were predominant in LOS cases (42.9%), while GBS was the main pathogen in EOS cases (44%). CONCLUSIONS: We observed reduced resistance levels of CONS against ampicillin, benzylpenicillin, clindamycin, erythromycin, fusidic acid, gentamicin, oxacillin, rifampicin, and trimethoprim/sulfa. S. aureus exhibited increased resistance to erythromycin, fusidic acid, gentamicin, and levofloxacin, while E. coli demonstrated decreased resistance against cephalothin, gentamicin, and trimethoprim/sulfa. The antibiotics currently employed empirically appear to provide adequate coverage against the most prevalent bacteria causing early- and late-onset neonatal infections.

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