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1.
Artigo em Inglês | MEDLINE | ID: mdl-32430905

RESUMO

BACKGROUND: Primary hyperparathyroidism (PHPTH) is a common endocrine disorder and an estimated 10% of cases are hereditary, related to syndromes including; multiple endocrine neoplasia (MEN) type 1, MEN type 4, MEN2A and hereditary hyperparathyroidism-jaw tumour syndrome. Establishing the underlying genetic cause for PHPTH allows for personalized and cost-effective management. Familial hypocalicuric hypercalcaemia (FHH) is a benign disorder of hypercalcaemia associated with an inappropriately low urinary calcium excretion, which is quantified by the calcium creatinine clearance ratio (CCCR). Recent NHS England National Genomic Test Directory testing criteria for familial hyperparathyroidism state testing patients presenting with PHPTH and CCCR > 0.02 presenting (i) <35 years of age, or (ii) <45y with one of (a) multiglandular disease, or (b) hyperplasia on histology, or (c) ossifying fibroma(s) of the maxilla and/ or mandible, or (d) a family history of unexplained PHPTH. The testing criterion for FHH is a CCCR < 0.02. AIMS AND METHODS: A retrospective review of patients referred for genetic testing over a 4 year period for suspected hereditary HPTH was performed. Genetic analysis was performed by next-generation sequencing of the following genes; MEN1, CDC73, CASR, CDKN1A, CDKN1B, CDKN2B, CDKN2C, RET, GCM2, GNA11, and AP2S1 in NHS-accredited Regional Genetic laboratories. Aims of this study were to better define testing criteria for suspected hereditary PHPTH in a UK cohort. RESULTS: A total of 121 patients were included in this study (92 female) with a mean age of 41 years (SD 17). A pathogenic germline variant was identified in 16% (n = 19). A pathogenic variant was identified in the PHPTH genes CDC73 in a single patient and MEN1 in six patients (6% of total), in the FHH genes, CASR in 11 patients and AP2S1 in a single paediatric case (10% of total). A variant of uncertain significance (VUS) was identified in eight patients (6%) but over the course of this study familial segregation studies and computational analysis enabled re-classification of four of the variants, with two VUS's in the CASR gene being upgraded to likely pathogenic variants. Age at diagnosis and multiglandular disease as sole risk factors were not predictive of a pathogenic germline variant in this cohort but a positive family history was strongly predictive (P = .0002). A significant difference in the mean calcium creatinine clearance ratio (CCCR) in those patients with an identified CASR pathogenic variant versus those without (P = .0001) was demonstrated in this study. Thirty-three patients were aged over 50 years and the diagnostic rate of a pathogenic variant was 15.1% in those patients >50 years of age compared to 15.9% in those <50 years. Five patients >50 years and with a CCCR of <0.01, were diagnosed with a pathogenic variant in CASR. CONCLUSION: Family history was the strongest predictor of hereditary PHPTH in this cohort. This study has highlighted the importance of re-evaluating VUS's in order to inform patient management and enable appropriate genetic counselling. Finally, this study has demonstrated the need to consider genetic testing for PHPTH in patients of any age, particularly those with additional risk factors.

2.
Int J Integr Care ; 19(3): 15, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31523219

RESUMO

Introduction: Integrated care has been posited as an important strategy for overcoming service fragmentation problems and achieving the Quadruple Aim of health care. This paper describes the Central Coast Integrative Care Program (CCICP) a complex, multi-component intervention addressing 3 target populations and more than 40 sub-projects of different scale, priority and maturity. Details are provided of the implementation including activities undertaken for each target population, in the context of the Central Coast Local Health District (CCLHD) strategies and priorities. Key lessons are drawn from the formative evaluation. Methods: A mixed methods approach to the formative evaluation was taken. Key stakeholders, professional staff with an in-depth knowledge of the program, were invited to complete surveys (n = 27) and semi-structured interviews (n = 23). The evaluation employed co-design principles with dialogue between CCICP partners and researchers throughout the process and sought to achieve a shared understanding of the dynamic context of the program, and the barriers and enablers for the various interventions. Key lessons and conclusion: Seven interdependent key lessons have been identified. These distil down to the setting of clear objectives aligning with all the goals of partners, developing strong relationships, leadership at multiple levels and communication and the building of a common language.

3.
Nurse Educ Pract ; 33: 107-113, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30273803

RESUMO

The aim of this study was to determine the effectiveness of an education intervention for the implementation of the clinical handover tool iSoBAR, in an acute setting. A quantitative, descriptive survey design, using pre and post survey data before and after the implementation of an education intervention was used. Twenty nine nurses, doctors and allied health personnel employed at the study site participated in the study. The educational intervention consisted of an electronic presentation plus simulated video recorded exemplars of clinical handover. Outcome measures were the efficacy of the education intervention on the confidence of practitioners using the iSoBAR handover tool. Participants' understanding of the iSoBAR tool using Mann-Whitney U test was 2.54 pre-intervention and 4.32 post-intervention. Confidence in using the tool also increased post educational intervention from 2.7 (pre-intervention) to 4.07 (post-intervention). Focus groups identified several factors relating to the implementation of iSoBAR, creating two dominant themes: challenges concerning patient factors and change management processes and systems. Opportunities were identified: Practice enhancement, patient centred care, professional practice, and grassroots initiatives. The use of an interprofessional educational program increased the confidence and understanding of a range of health care practitioners when using the clinical handover tool iSoBAR.


Assuntos
Protocolos Clínicos , Continuidade da Assistência ao Paciente/organização & administração , Pessoal de Saúde/educação , Hospitais , Transferência da Responsabilidade pelo Paciente/organização & administração , Adulto , Austrália , Feminino , Grupos Focais , Humanos , Masculino , Inquéritos e Questionários , Gravação em Vídeo/métodos
4.
J Midwifery Womens Health ; 63(6): 682-692, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29883047

RESUMO

INTRODUCTION: Access to quality care is a problem in Texas, an ethnically diverse state with large birth numbers. The state has over 300 areas designated as medically underserved, and a severe lack of obstetricians and midwives. Minimal data exist on midwifery's contribution, and no known study compares the work environment and clinical practice of the 2 state-recognized midwifery paths, licensed midwives (LMs) and certified nurse-midwives (CNMs). The purpose of this study was to determine the differences in practice by CNMs and LMs, the latter of whom are generally certified professional midwives. The specific aims were to 1) describe the differences in demographic and employment characteristics of CNMs and LMs, 2) identify the geographic areas and population groups served by CNMs and LMs, and 3) compare the nature and scope of CNM and LM clinical practices. METHODS: Online parallel surveys of Texas LMs and CNMs were conducted in December 2015 and January 2016. The REDCap data management system housed the 123- and 125-item surveys for LMs and CNMs, respectively, addressing demographics, populations served, and clinical practice. A comparative statistical analysis, using Fisher's exact test, Pearson's chi-squared test, and Independent Samples t-tests, was performed. RESULTS: The survey response rates of LMs and CNMs were 35.4% (n = 75) and 31.9% (n = 143), respectively. Differences in demographics, employment status, workload, scope of practice, risk assessment, time-based care management, and technology use were observed. DISCUSSION: Findings represent the first attempt to describe the Texas midwifery workforce. In a large state with health care provider shortages, this step is pivotal in addressing strategies for providing services for women and infants. This groundwork can provide the foundation for including midwifery in a state health plan.


Assuntos
Certificação , Emprego , Mão de Obra em Saúde , Licenciamento , Tocologia , Enfermeiras Obstétricas , Prática Profissional , Grupos Étnicos , Feminino , Humanos , Serviços de Saúde Materno-Infantil , Padrões de Prática em Enfermagem , Gravidez , Papel Profissional , Inquéritos e Questionários , Texas , Carga de Trabalho
6.
Br J Hosp Med (Lond) ; 71(1): 26-30, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20081638

RESUMO

Patients with Parkinson's disease have an illness which shortens their life and involves a heavy symptom burden for patient and carer. This article discusses some common palliative care issues pertinent to patients with Parkinson's disease.


Assuntos
Acesso aos Serviços de Saúde , Cuidados Paliativos/organização & administração , Doença de Parkinson/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/psicologia , Planejamento de Assistência ao Paciente , Qualidade de Vida , Assistência Terminal/organização & administração
7.
J Pain Symptom Manage ; 38(3): 460-5, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19735905

RESUMO

Persistent hiccups may have a considerable impact on general health through disturbance of diet, sleep, and mood. They can cause exhaustion, malnutrition, dehydration, wound dehiscence, and even death in extreme cases. We report a complex clinical case of intractable hiccups in a patient with cancer of the pancreas and Parkinson's disease and some of the problems encountered when attempting symptom control. We also discuss a potential therapeutic response to a novel agent, amantadine, unlicensed in the treatment of hiccups.


Assuntos
Amantadina/uso terapêutico , Analgésicos não Entorpecentes/uso terapêutico , Soluço/tratamento farmacológico , Idoso , Antidepressivos/uso terapêutico , Evolução Fatal , Humanos , Masculino , Qualidade de Vida , Sertralina/uso terapêutico , Acidente Vascular Cerebral/complicações , Doença de Whipple/complicações
8.
Org Biomol Chem ; 5(17): 2800-2, 2007 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-17700848

RESUMO

The title compound (+)-, required for production of transition state analogue inhibitors of enzymes involved in T-cell-dependent disorders, was synthesized in five steps. A 1,3-dipolar cycloaddition of the nitrone formed from formaldehyde and N-benzylhydroxylamine to diethyl maleate gave the racemic cis-isoxazolidine (+/-)-. Reduction of the N-O bond of this compound gave pyrrolidone (+/-)- in excellent yield. A very efficient enzymic resolution of this racemic product led to the title enantiomer (+)-. This route employs only one chromatographic purification.


Assuntos
Pirrolidinas/síntese química , Estrutura Molecular , Pirrolidinas/química
9.
Genome Res ; 17(6): 691-707, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17567990

RESUMO

We generated high-resolution maps of histone H3 lysine 9/14 acetylation (H3ac), histone H4 lysine 5/8/12/16 acetylation (H4ac), and histone H3 at lysine 4 mono-, di-, and trimethylation (H3K4me1, H3K4me2, H3K4me3, respectively) across the ENCODE regions. Studying each modification in five human cell lines including the ENCODE Consortium common cell lines GM06990 (lymphoblastoid) and HeLa-S3, as well as K562, HFL-1, and MOLT4, we identified clear patterns of histone modification profiles with respect to genomic features. H3K4me3, H3K4me2, and H3ac modifications are tightly associated with the transcriptional start sites (TSSs) of genes, while H3K4me1 and H4ac have more widespread distributions. TSSs reveal characteristic patterns of both types of modification present and the position relative to TSSs. These patterns differ between active and inactive genes and in particular the state of H3K4me3 and H3ac modifications is highly predictive of gene activity. Away from TSSs, modification sites are enriched in H3K4me1 and relatively depleted in H3K4me3 and H3ac. Comparison between cell lines identified differences in the histone modification profiles associated with transcriptional differences between the cell lines. These results provide an overview of the functional relationship among histone modifications and gene expression in human cells.


Assuntos
Genoma Humano/fisiologia , Histonas/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Transcrição Genética/fisiologia , Células HeLa , Humanos , Células K562
10.
Genome Res ; 17(6): 708-19, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17567991

RESUMO

Butyrate is a histone deacetylase inhibitor (HDACi) with anti-neoplastic properties, which theoretically reactivates epigenetically silenced genes by increasing global histone acetylation. However, recent studies indicate that a similar number or even more genes are down-regulated than up-regulated by this drug. We treated hepatocarcinoma HepG2 cells with butyrate and characterized the levels of acetylation at DNA-bound histones H3 and H4 by ChIP-chip along the ENCODE regions. In contrast to the global increases of histone acetylation, many genomic regions close to transcription start sites were deacetylated after butyrate exposure. In order to validate these findings, we found that both butyrate and trichostatin A treatment resulted in histone deacetylation at selected regions, while nucleosome loss or changes in histone H3 lysine 4 trimethylation (H3K4me3) did not occur in such locations. Furthermore, similar histone deacetylation events were observed when colon adenocarcinoma HT-29 cells were treated with butyrate. In addition, genes with deacetylated promoters were down-regulated by butyrate, and this was mediated at the transcriptional level by affecting RNA polymerase II (POLR2A) initiation/elongation. Finally, the global increase in acetylated histones was preferentially localized to the nuclear periphery, indicating that it might not be associated to euchromatin. Our results are significant for the evaluation of HDACi as anti-tumourogenic drugs, suggesting that previous models of action might need to be revised, and provides an explanation for the frequently observed repression of many genes during HDACi treatment.


Assuntos
Adenocarcinoma/metabolismo , Butiratos/farmacologia , Neoplasias do Colo/metabolismo , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Proteínas de Neoplasias/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Inibidores de Histona Desacetilases , Histona Desacetilases/metabolismo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos
12.
Hum Mol Genet ; 14(22): 3435-47, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16221759

RESUMO

We present a detailed in vivo characterization of hepatocyte transcriptional regulation in HepG2 cells, using chromatin immunoprecipitation and detection on PCR fragment-based genomic tiling path arrays covering the encyclopedia of DNA element (ENCODE) regions. Our data suggest that HNF-4alpha and HNF-3beta, which were commonly bound to distal regulatory elements, may cooperate in the regulation of a large fraction of the liver transcriptome and that both HNF-4alpha and USF1 may promote H3 acetylation to many of their targets. Importantly, bioinformatic analysis of the sequences bound by each transcription factor (TF) shows an over-representation of motifs highly similar to the in vitro established consensus sequences. On the basis of these data, we have inferred tentative binding sites at base pair resolution. Some of these sites have been previously found by in vitro analysis and some were verified in vitro in this study. Our data suggests that a similar approach could be used for the in vivo characterization of all predicted/uncharacterized TF and that the analysis could be scaled to the whole genome.


Assuntos
Pareamento de Bases/genética , Imunoprecipitação da Cromatina , Cromatina/metabolismo , Doenças Metabólicas/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Transcrição/metabolismo , Sítios de Ligação/genética , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina/métodos , Sequência Consenso , Genoma Humano , Fator 3-beta Nuclear de Hepatócito/fisiologia , Fator 4 Nuclear de Hepatócito/fisiologia , Hepatócitos/metabolismo , Histonas/metabolismo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Regiões Promotoras Genéticas , Análise de Sequência de DNA , Fatores de Transcrição/genética , Fatores Estimuladores Upstream/metabolismo
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