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1.
Science ; 377(6602): 222-228, 2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35857540

RESUMO

G protein-coupled receptors (GPCRs) recruit ß-arrestins to coordinate diverse cellular processes, but the structural dynamics driving this process are poorly understood. Atypical chemokine receptors (ACKRs) are intrinsically biased GPCRs that engage ß-arrestins but not G proteins, making them a model system for investigating the structural basis of ß-arrestin recruitment. Here, we performed nuclear magnetic resonance (NMR) experiments on 13CH3-ε-methionine-labeled ACKR3, revealing that ß-arrestin recruitment is associated with conformational exchange at key regions of the extracellular ligand-binding pocket and intracellular ß-arrestin-coupling region. NMR studies of ACKR3 mutants defective in ß-arrestin recruitment identified an allosteric hub in the receptor core that coordinates transitions among heterogeneously populated and selected conformational states. Our data suggest that conformational selection guides ß-arrestin recruitment by tuning receptor dynamics at intracellular and extracellular regions.


Assuntos
Receptores CXCR , beta-Arrestinas , Regulação Alostérica , Ligantes , Espectroscopia de Ressonância Magnética , Mutação , Ligação Proteica , Conformação Proteica , Receptores CXCR/química , Receptores CXCR/genética , beta-Arrestinas/química
2.
Proc Natl Acad Sci U S A ; 117(7): 3627-3636, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32019878

RESUMO

The chaperone protein SmgGDS promotes cell-cycle progression and tumorigenesis in human breast and nonsmall cell lung cancer. Splice variants of SmgGDS, named SmgGDS-607 and SmgGDS-558, facilitate the activation of oncogenic members of the Ras and Rho families of small GTPases through membrane trafficking via regulation of the prenylation pathway. SmgGDS-607 interacts with newly synthesized preprenylated small GTPases, while SmgGDS-558 interacts with prenylated small GTPases. We determined that cancer cells have a high ratio of SmgGDS-607:SmgGDS-558 (607:558 ratio), and this elevated ratio is associated with reduced survival of breast cancer patients. These discoveries suggest that targeting SmgGDS splicing to lower the 607:558 ratio may be an effective strategy to inhibit the malignant phenotype generated by small GTPases. Here we report the development of a splice-switching oligonucleotide, named SSO Ex5, that lowers the 607:558 ratio by altering exon 5 inclusion in SmgGDS pre-mRNA (messenger RNA). Our results indicate that SSO Ex5 suppresses the prenylation of multiple small GTPases in the Ras, Rho, and Rab families and inhibits ERK activity, resulting in endoplasmic reticulum (ER) stress, the unfolded protein response, and ultimately apoptotic cell death in breast and lung cancer cell lines. Furthermore, intraperitoneal (i.p.) delivery of SSO Ex5 in MMTV-PyMT mice redirects SmgGDS splicing in the mammary gland and slows tumorigenesis in this aggressive model of breast cancer. Taken together, our results suggest that the high 607:558 ratio is required for optimal small GTPase prenylation, and validate this innovative approach of targeting SmgGDS splicing to diminish malignancy in breast and lung cancer.


Assuntos
Neoplasias da Mama/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Neoplasias Pulmonares/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinogênese , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Prenilação de Proteína , Splicing de RNA
3.
BMJ ; 362: k2953, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29997114
4.
Virology ; 498: 181-191, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27596537

RESUMO

The weak polyadenylation site (PAS) of Rous sarcoma virus (RSV) is activated by the juxtaposition of SR protein binding sites within the spatially separate negative regulator of splicing (NRS) element and the env RNA splicing enhancer (Env enhancer), which are far upstream of the PAS. Juxtaposition occurs by formation of the NRS - 3' ss splicing regulatory complex and is thought to provide a threshold of SR proteins that facilitate long-range stimulation of the PAS. We provide evidence for the threshold model by showing that greater than three synthetic SR protein binding sites are needed to substitute for the Env enhancer, that either the NRS or Env enhancer alone promotes polyadenylation when the distance to the PAS is decreased, and that SR protein binding sites promote binding of the polyadenylation factor cleavage factor I (CFIm) to the weak PAS. These observations may be relevant for cellular PASs.


Assuntos
Poliadenilação , RNA Mensageiro , RNA Viral , Proteínas de Ligação a RNA/metabolismo , Vírus do Sarcoma de Rous/genética , Vírus do Sarcoma de Rous/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Animais , Sítios de Ligação , Linhagem Celular , Ordem dos Genes , Fases de Leitura Aberta , Poli A , Ligação Proteica
5.
Dent J (Basel) ; 4(2)2016 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29563454

RESUMO

The aim of this study was to describe Dental Foundation year one dentists' attitudes towards prosthodontic decision making for edentulous patients, and identify whether there are gender differences in these attitudes. All South West Deanery trainees were invited to take part in the study between May and June 2011 and a previously piloted questionnaire was administered to the trainees by their training programme directors. The questionnaire posed questions based upon a clinical scenario of discussing treatment options with patients. Seventy-two questionnaires were used in the analysis (91% overall response rate). Trainees perceived their own values to be less important than the patient's values (p < 0.001) in decision making, but similar to the patient's friend's/relative's values (p = 0.1). In addition, the trainees perceived the patient's values to be less important than their friend's/relatives (p < 0.001). Sixty-six per cent of trainees acknowledged an influence from their own personal values on their presentation of material to patients who are in the process of choosing among different treatment options, and 87% thought their edentulous patients were satisfied with the decision making process when choosing among different treatment options. Fifty-eight per cent of trainees supported a strategy of negotiation between patients and clinicians (shared decision making). There was no strong evidence to suggest gender had an influence on the attitudes towards decision making. The finding of a consensus towards shared decision making in the attitudes of trainees, and no gender differences is encouraging and is supportive of UK dental schools' ability to foster ethical and professional values among dentists.

6.
Dent J (Basel) ; 4(2)2016 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29563458

RESUMO

This paper reviews the literature regarding possible complications, complication-free survival, and overall survival of fixed dental prostheses that use both implants and natural teeth as abutments. The paper also provides clinical guidelines for treatment based on this literature review. An electronic search utilizing the MEDLINE, BIOSIS Citation Index, and Web of Science™ Core Collection databases was undertaken, and a review of the 25 selected texts studying 22 different patient cohorts was carried out. From a total of 1610 implants reviewed, 40 were lost (33 due to loss of integration and 7 due to fracture), whereas, out of a total of 1301 teeth, 38 were lost, of which 16 were due to fracture. Seventy-three cases of tooth intrusion were detected. From a total of 676 frameworks reviewed (metal n = 645, Zirconia n = 31), 7 fractured, while veneer material fracture occurred in 70 out of 672 bridges. Overall, 502 out of 531 tooth-implant fixed prostheses (TIPFs) remained functional, and 336 out of 439 prostheses showed no technical or biological complications and remained functional. Rigid TIFPs permanently cemented to teeth with sufficient coronal structure and with limited use of prosthetic attachments offer a good long-term treatment option to patients with good oral hygiene following sound implant placement. This mode of treatment should be used when free-standing implant-supported options may not be possible. Larger randomized control studies and other clinical studies comparing tooth-to-implant-connected treatment with other forms of treatment are needed to better understand the place of TIFP treatment in oral rehabilitation.

7.
J Dent ; 43(3): 362-72, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25511302

RESUMO

OBJECTIVES: The aims of this study were to synthesise a range of chlorhexidine-containing nanoparticles (CHX-NPs), and investigate the feasibility of using these as an antifungal coating for dental silicones. METHODS: CHX-NPs were precipitated in aqueous reaction by mixing solutions of CHX digluconate with solutions of sodium triphosphate (TP), trimetaphosphate (TMP) or hexametaphosphate (HMP). CHX-NPs were deposited on commercial dental silicones by immersion coating, and these were characterised for hydrophilicity (contact angle) and water uptake (mass change). Soluble CHX elution into artificial saliva was measured using ultraviolet spectrophotometry. Antifungal efficacy against Candida albicans was investigated using a cell proliferation assay. RESULTS: Coating silicones with CHX-NPs did not significantly affect hydrophilicity, as assessed using water contact angle, or water uptake as assessed by mass change following 16 weeks' immersion in artificial saliva. CHX-NP-coated silicone specimens released soluble CHX into artificial saliva. The salt of CHX and the immersion time affected the rate, concentration and duration of CHX release, with CHX-HMP exhibiting a slow, sustained release and CHX-TP and CHX-TMP exhibiting a faster, more concentrated release. C. albicans metabolic activity was inhibited by presence of CHX-HMP-NPs in suspension. CONCLUSIONS: CHX-NPs provided a localised, controlled dose of soluble CHX at the surface of dental silicones without adversely affecting hydrophilicity or water uptake. CHX-HMP NPs provided effective antifungal control of C. albicans in a cell proliferation assay. Coating materials with these nanoparticles could be an effective way of delivering low, but clinically relevant, concentrations of chlorhexidine in the oral environment. CLINICAL SIGNIFICANCE: Denture stomatitis is a common oral infection and is associated with fungal infestation of denture soft lining and obturator materials, which are often silicones such as those used here. Our study suggests that CHX-NPs may be a useful strategy in design of antifungal coatings for these materials.


Assuntos
Antifúngicos/farmacologia , Clorexidina/farmacologia , Materiais Dentários , Reembasadores de Dentadura , Nanopartículas , Silicones , Materiais Dentários/química , Testes de Sensibilidade Microbiana
8.
Br J Health Psychol ; 19(4): 795-809, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24289715

RESUMO

OBJECTIVES: The National Health Service (NHS) Stop Smoking Service (SSS) is an extremely cost-effective method of enabling smoking cessation. However, the SSS is only used by a minority of smokers. Developing interventions to maintain service attendance may help to increase the number of quitters. This study pilots an intervention aimed at maintaining attendance by (1) increasing motivation to attend through a booklet providing evidence of service effectiveness and (2) strengthening the link between motivation to attend and attendance through forming an implementation intention. DESIGN: A factorial randomized controlled trial. METHODS: A total of 160 newly enrolled smokers at the Surrey NHS SSS were recruited and randomly assigned to one of four conditions: (1) standard care (SC), (2) SC + effectiveness booklet, (3) SC + implementation intention, and (4) SC + effectiveness booklet + implementation intention. The outcome measures included attendance at the SSS and the 4-week quit rate. RESULTS: The booklet increased service attendance (OR = 2.93, p < .01, 95% CI = 1.45-5.93; Number Needed to Treat = 3.3) but had no impact on the 4-week quit rate (OR = 1.55, 95% CI = 0.75-3.21). Forming an implementation intention had no impact on service attendance or the 4-week quit rate. Attending the service was associated with a higher 4-week quit rate (ρ = 87.52, p < .001). CONCLUSIONS: Presenting information about the effectiveness of the service improved service attendance. A larger trial now needs to evaluate whether this intervention can also increase the quit rate. STATEMENT OF CONTRIBUTION: What is already known on this subject? The NHS Stop Smoking Service is an effective yet underused method of enabling smoking cessation. Low uptake levels may be due to smokers' misconception that the service will not improve their chances of quitting successfully. Improving smokers' perceptions of service efficacy may be valuable for maintaining service attendance, and subsequently improving smoking cessation levels in the United Kingdom. What does this study add? This pilot randomized controlled trial is the first to target service attendance rather than cessation levels. The results demonstrate that providing evidence of service efficacy in a simple icon array format can significantly improve service attendance.


Assuntos
Cooperação do Paciente/psicologia , Abandono do Hábito de Fumar/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Educação em Saúde/métodos , Humanos , Intenção , Masculino , Pessoa de Meia-Idade , Motivação , Projetos Piloto , Abandono do Hábito de Fumar/psicologia , Medicina Estatal , Adulto Jovem
9.
J Acquir Immune Defic Syndr ; 59(1): 1-9, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21963936

RESUMO

BACKGROUND: Induction of HIV-1-specific CD4(+) T-cell responses by therapeutic vaccination represents an attractive intervention to potentially increase immune control of HIV-1. METHODS: We performed a double-blinded, randomized, placebo-controlled clinical trial to determine the safety and immunogenicity of GlaxoSmithKline Biologicals' HIV-1 gp120/NefTat subunit protein vaccine formulated with the AS02(A) Adjuvant System in subjects with well-controlled chronic HIV-1 infection on highly active antiretroviral therapy. Ten individuals received the vaccine; whereas adjuvant alone or placebo was given to 5 subjects each. Immunogenicity was monitored by intracellular cytokine flow cytometry and carboxyfluorescein succinimidyl ester-based proliferation assays. RESULTS: The vaccine was well tolerated with no related serious adverse events. Vaccine recipients had significantly stronger gp120-specific CD4(+) T-cell responses which persisted until week 48 and greater gp120-specific CD4(+) T-cell proliferation activity as compared with controls. In the vaccine group, the number of participants who demonstrated positive responses for both gp120-specific CD4(+) T-cell interleukin-2 production and gp120-specific CD8(+) T-cell proliferation were significantly higher at week 6. CONCLUSIONS: The gp120/NefTat/AS02(A) vaccine induced strong gp120-specific CD4(+) T-cell responses and a higher number of vaccinees developed both HIV-1-specific CD4(+) T-cell responses and CD8(+) T-cell proliferation. The induction of these responses may be important in enhancing immune-mediated viral control.


Assuntos
Vacinas contra a AIDS/imunologia , Fármacos Anti-HIV/uso terapêutico , Linfócitos T CD4-Positivos/citologia , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/fisiologia , Proliferação de Células , Método Duplo-Cego , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Vacinas de Subunidades Antigênicas/imunologia , Adulto Jovem , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/imunologia
10.
BMC Health Serv Res ; 11: 190, 2011 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-21846379

RESUMO

BACKGROUND: Tobacco dependence among people with mental health problems is an issue that deserves attention both from a clinical and from a public health perspective. Research suggests that Stop Smoking Services often fail to ask clients about underlying mental health problems and thus fail to put in place the treatment adaptations and liaison procedures often required to meet the needs of clients with a mental health condition who want to stop smoking. This study assesses the recording of mental health problems in a large NHS stop smoking service in England and examines the effect of implementing a short screening procedure on recording mental health conditions. METHODS: Treatment records from the Stop Smoking Service covering a period of 13 months were audited. The prevalence of reported mental health problems in the six month period before the implementation of the mental health screening procedure was compared with that of the six month period following implementation. The screening procedure was only implemented in the support services directly provided by the Stop Smoking Service. Comparisons were also made with third-party sections of the service where no such screening procedure was introduced. RESULTS: The prevalence of reported mental health problems among a total of n = 4999 clients rose from less than 1% before implementation of the screening procedure to nearly 12% in the period following implementation, with the change being statistically significant. No significant rise was observed over the same period in the sections of the service where no screening procedure was implemented. CONCLUSIONS: The absence of standard procedures to record mental health problems among service users in many stop smoking services is currently likely to prevent the detection of co morbidity. Implementing a simple screening procedure appears suitable to increase the routine recording of mental health problems in a stop smoking service, which is an essential step to ensure services can be tailored and delivered appropriately to the client group.


Assuntos
Serviços de Saúde , Programas de Rastreamento/estatística & dados numéricos , Transtornos Mentais/epidemiologia , Prevenção do Hábito de Fumar , Adulto , Inglaterra/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medicina Estatal
11.
J Clin Virol ; 50(4): 334-7, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21300566

RESUMO

BACKGROUND: Vaccine-induced antibodies to envelope proteins frequently cause HIV seroconversion in uninfected recipients of HIV vaccine candidates and may thus have an impact on the vaccinee's ability to donate blood or acquire a life insurance policy. OBJECTIVE: To determine the occurrence of positive test results when commonly used HIV immunoassays are used to screen sera of HIV-uninfected volunteers who received an adjuvanted HIV-1 vaccine candidate containing HIV-1 antigens p24, reverse transcriptase, Nef and p17. STUDY DESIGN: Sera of 50 subjects who received this polyprotein vaccine in a single center in Belgium were tested with 6 HIV screening assays and 1 confirmation test. All samples were drawn one year after the administration of the first of two vaccine doses given with one month interval. RESULTS: Forty-five (90%) sera showed a positive test result in at least one of the 7 HIV tests used. The positivity rates were 88% in the Elecsys HIV Combi assay, 74% in the ADVIA Centaur EHIV and 48% in the PRISM HIV O Plus assay. CONCLUSIONS: Interpretation of HIV test results is becoming increasingly complex with the growing number of volunteers participating in prophylactic HIV vaccine trials worldwide and the rising number of viral antigens included in these vaccine candidates. The results of this study in recipients of a highly immunogenic adjuvanted polyprotein HIV vaccine candidate devoid of envelope proteins, illustrate the increasing need for approaches that can discriminate HIV infection-induced antibodies from those elicited by a vaccine.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Anti-HIV/imunologia , Soropositividade para HIV/imunologia , HIV-1/imunologia , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/efeitos adversos , Bélgica , Anticorpos Anti-HIV/biossíntese , Anticorpos Anti-HIV/sangue , Antígenos HIV/imunologia , Proteína do Núcleo p24 do HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Transcriptase Reversa do HIV/imunologia , Soropositividade para HIV/sangue , Humanos , Vacinação , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia
12.
Clin Infect Dis ; 52(4): 522-31, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21208909

RESUMO

BACKGROUND: This phase I/II partially blinded, randomized, dose-ranging study assessed the safety and immunogenicity of a novel human immunodeficiency virus type 1 (HIV-1) vaccine candidate consisting of a recombinant fusion protein (F4) containing 4 HIV-1 clade B antigens (Gag p24, Pol reverse transcriptase, Nef, and Gag p17) adjuvanted with AS01 in HIV-seronegative volunteers. Methods. Two doses of the recombinant F4 protein (10, 30, or 90 µg/dose), adjuvanted with AS01 or reconstituted with water for injection, were administered 1 month apart to 180 healthy volunteers aged 18-40 years. F4-specific CD4(+) T cell responses were measured using intracellular cytokine staining after in vitro stimulation by overlapping peptide pools covering the 4 individual antigens. Results. Reactogenicity was higher during the 7-day period after each vaccine dose in the adjuvanted than in the nonadjuvanted groups. In the adjuvanted groups, the overall immune response rate was high after the second vaccine dose, with highest responder rates seen in the 10-µg F4/AS01 group (100% to 3 HIV-1 antigens and 80% to all 4 HIV-1 antigens). High and long-lasting CD4(+) T cell frequencies were observed (up to a median value of 1.2% F4-specific CD4(+) T cells at day 44), with strongest responses directed against reverse transcriptase. Antigen-specific CD4(+) T cells exhibited a polyfunctional phenotype, expressing at least CD40 ligand and interleukin 2, often in combination with tumor necrosis factor α and/or interferon γ. Vaccine-induced CD4(+) T cell responses were broadly cross-reactive to all 4 antigens derived from HIV-1 clades A and C. Conclusions. These results support further clinical investigation of this HIV-1 vaccine candidate both in a prophylactic setting (alone, in conjunction with an envelope-based antigen or in combination with other vaccine approaches in a heterologous prime-boost regimen) and as a potentially disease-modifying therapeutic vaccine in HIV-1-infected subjects. CLINICAL TRIALS REGISTRATION: NCT00434512.


Assuntos
Vacinas contra a AIDS/imunologia , Adjuvantes Imunológicos/administração & dosagem , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Vacinas contra a AIDS/efeitos adversos , Adjuvantes Imunológicos/efeitos adversos , Adolescente , Adulto , Citocinas/biossíntese , Feminino , Infecções por HIV/imunologia , Soronegatividade para HIV/imunologia , Humanos , Imunização Secundária/métodos , Masculino , Proteínas Recombinantes de Fusão/imunologia , Vacinação/métodos , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologia , Vacinas Sintéticas/imunologia , Adulto Jovem
13.
Vaccine ; 28(43): 7016-24, 2010 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-20728522

RESUMO

This randomized double-blind study aimed to determine the safety and immunogenicity of a gp120/NefTat candidate human immunodeficiency virus type 1 (HIV-1) vaccine formulated with one of three different Adjuvant Systems (AS02(A), AS02(V) and AS01(B)) in healthy HIV-seronegative adults. All vaccine formulations induced strong HIV-specific CD4(+) T-cell responses characterized by high lymphoproliferative capacity and IL-2 production that were still detectable 18 months after last immunization, with strongest responses seen in the AS01(B) group. Broad coverage was demonstrated against gp120, and to a lesser extent Nef, derived from the most common circulating clades (B, C and circulating recombinant form [CRF]-01). All vaccine formulations exhibited acceptable safety and reactogenicity profiles. The demonstration of superior CD4(+) T-cell induction by AS01(B) provides important guidance for future HIV vaccine development.


Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos T CD4-Positivos/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/prevenção & controle , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/imunologia , Vacinas contra a AIDS/efeitos adversos , Adjuvantes Imunológicos/farmacologia , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Reações Cruzadas , Método Duplo-Cego , Feminino , Anticorpos Anti-HIV/sangue , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Imunidade Celular , Interleucina-2/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
BMC Health Serv Res ; 10: 179, 2010 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-20576123

RESUMO

BACKGROUND: People with mental health problems exhibit smoking rates up to three times that of the general population. Metabolic interactions between hydrocarbon agents in tobacco smoke and some antipsychotic drugs account for a change in medication metabolism on stopping smoking, and potentially for increased blood levels. Nicotine withdrawal can mimic or exacerbate symptoms of mental illness. Therefore, appropriate screening for mental health problems and liaison with local mental health care providers should be a priority for NHS Stop Smoking Services. The present study aimed to examine this issue through surveys with NHS Stop Smoking Service staff in London. METHODS: Semi-structured telephone interviews were conducted with one senior staff member from 27 of the 29 NHS Stop Smoking Services in London. RESULTS: It was found that only a minority of services routinely check the mental health status or mental health service use of their clients. In addition, most services do not routinely implement special checks or actions when mental health problems are revealed. It was notable that respondents reported a lack of strategic drivers supporting work with mental health patients (such as targets relating to successful quits) as well as a low level of partnership working with local mental health care providers. CONCLUSIONS: NHS Stop Smoking Services may not be operating appropriate procedures for supporting people with mental health problems. There is a need for local protocols to be implemented that include routine screening for mental health issues and liaison with mental health care providers.


Assuntos
Transtornos Mentais , Abandono do Hábito de Fumar , Apoio Social , Medicina Estatal , Estudos Transversais , Humanos , Entrevistas como Assunto , Londres , Serviços de Saúde Mental
15.
Mol Cell Biol ; 30(10): 2552-62, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20308327

RESUMO

Heterogeneous nuclear ribonucleoprotein (hnRNP) H and F are members of a closely related subfamily of hnRNP proteins that are implicated in many aspects of RNA processing. hnRNP H and F are alternative splicing factors for numerous U2- and U12-dependent introns. The proteins have three RNA binding domains and two glycine-rich domains and localize to both the nucleus and cytoplasm, but little is known about which domains govern subcellular localization or splicing activity. We show here that the central glycine-tyrosine-arginine-rich (GYR) domain is responsible for nuclear localization, and a nonclassical nuclear localization signal (NLS) was mapped to a short, highly conserved sequence whose activity was compromised by point mutations. Glutathione S-transferase (GST) pulldown assays demonstrated that the hnRNP H NLS interacts with the import receptor transportin 1. Finally, we show that hnRNP H/F are transcription-dependent shuttling proteins. Collectively, the results suggest that hnRNP H and F are GYR domain-dependent shuttling proteins whose posttranslational modifications may alter nuclear localization and hence function.


Assuntos
Transporte Ativo do Núcleo Celular/fisiologia , Glicina/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H , beta Carioferinas/metabolismo , Processamento Alternativo , Sequência de Aminoácidos , Núcleo Celular/química , Núcleo Celular/metabolismo , Células HeLa , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/metabolismo , Humanos , Dados de Sequência Molecular , Mutação , Sinais de Localização Nuclear/metabolismo , Processamento de Proteína Pós-Traducional , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Alinhamento de Sequência , beta Carioferinas/genética
16.
Lancet ; 369(9571): 1440-1451, 2007 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-17467514

RESUMO

BACKGROUND: HIV-related pneumonia is the main cause of paediatric hospital admissions in southern Africa. We aimed to measure predictors of treatment failure and the cause of non-responsive pneumonia in children admitted to hospital with severe pneumonia in Durban, South Africa. METHODS: We investigated 358 children aged 1-59 months who presented with WHO-defined severe or very severe pneumonia. Children were recruited irrespective of HIV status and started on a standard antimicrobial regimen of benzylpenicillin and gentamicin. All infants also received high-dose trimethoprim-sulfamethoxazole. The primary outcome measure was treatment failure at 48 h. FINDINGS: 242 (68%) children were HIV infected, 41 (12%) HIV exposed, uninfected, and 75 (21%) HIV uninfected. Failure to respond by 48 h was predicted by age under 1 year (adjusted odds ratio 6.38, 95% CI 2.72-14.91, p<0.0001), very severe disease (2.47, 1.17-5.24, p=0.0181), HIV status (HIV infected 10.3, 3.26-32.51; HIV exposed, uninfected 6.02, 1.55-23.38; p=0.0003), and polymicrobial disease (one organism 2.06, 1.05-4.05; two organisms 10.75, 4.38-26.36; p<0.0001) on logistic regression analysis. All children with three organisms failed treatment. 72/110 treatment failures had at least two organisms isolated. Three of nine HIV-exposed, uninfected infants, 29/74 HIV-infected, but no HIV-uninfected infants who failed study therapy had Pneumocystis jirovecii pneumonia. INTERPRETATION: For children younger than 1 year, the WHO guidelines are inadequate and need to be revised since both HIV-infected and HIV-exposed, uninfected infants had more treatment failures than did HIV-uninfected infants. Polymicrobial disease is an important reason for treatment failure, and we need to identify rapid low-cost diagnostic methods to assist clinicians.


Assuntos
Antibacterianos/uso terapêutico , Soropositividade para HIV , HIV-1 , Mortalidade Hospitalar , Pneumonia/tratamento farmacológico , Fatores Etários , Pré-Escolar , Feminino , Humanos , Lactente , Modelos Logísticos , Masculino , Bem-Estar Materno , Pneumonia/complicações , Pneumonia/microbiologia , Estudos Prospectivos , Índice de Gravidade de Doença , África do Sul , Falha de Tratamento
17.
Eur J Dent Educ ; 11(1): 54-9, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17227397

RESUMO

In 2000, the University of Bristol Dental School Division of Restorative Dentistry carried out a review of the assessment methods used within the undergraduate programme. Following this review, a number of key recommendations were made and the system of formative assessment within the division was changed. Audits were conducted immediately prior to the introduction of the new system and 2 years after it had been introduced, the results of these audits are presented. There was no change in the number of failed appointments between the initial audit and the second audit. There was a reduction in the number of patients treated by more than one student from 25% to 14% (approximating to 3% if student withdrawal from the course is taken into account). The length of time taken to complete treatment reduced between the two audits with more than half of all patients having their treatment completed within 3 months of their initial examination in the second audit. Ninety-five percent of treatment plans were completed in the second audit compared with only 62% in the first audit. In the second audit, the outstanding 5% of cases were signed off as incomplete for satisfactory reasons by the member of supervisory staff (e.g. patients who had moved away or were discharged due to poor attendance). Student comments were mostly positive, the small number of negative comments related to some students being confused by the paperwork in the new system. The overall process has been an extremely positive experience which has resulted in an assessment system with increased clarity which appears to have reduced the stress levels reported by the undergraduate students on the programme and improved the quality of patient care within restorative dentistry.


Assuntos
Dentística Operatória/educação , Educação em Odontologia/normas , Avaliação Educacional/métodos , Auditoria Odontológica , Clínicas Odontológicas/normas , Dentística Operatória/normas , Inglaterra , Retroalimentação , Humanos , Avaliação de Programas e Projetos de Saúde , Qualidade da Assistência à Saúde , Inquéritos e Questionários
18.
J Clin Microbiol ; 44(10): 3781-3, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17021110

RESUMO

We assessed neutralizing antibody titers to adenovirus serotype 5 (Ad5) and six rare adenovirus serotypes, serotypes 11, 35, 50, 26, 48, and 49, in pediatric populations in sub-Saharan Africa. We observed a clear age dependence of Ad5-specific neutralizing antibody titers. These data will help to guide the development of Ad vector-based vaccines for human immunodeficiency virus type 1 and other pathogens.


Assuntos
Infecções por Adenovirus Humanos/imunologia , Adenovírus Humanos/imunologia , Envelhecimento , Anticorpos Antivirais/sangue , Infecções por Adenovirus Humanos/sangue , Infecções por Adenovirus Humanos/epidemiologia , Adolescente , África Subsaariana/epidemiologia , Criança , Pré-Escolar , Humanos , Lactente , Transmissão Vertical de Doenças Infecciosas , Estudos Soroepidemiológicos
19.
J Infect Dis ; 194(3): 385-90, 2006 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16826488

RESUMO

We investigated the nasopharyngeal carriage of Streptococcus pneumoniae and Staphylococcus aureus in 355 children hospitalized with severe pneumonia. Of the children, 239 (67.3%) were human immunodeficiency virus (HIV)-1 positive; 169 (47.6%) carried S. pneumoniae, 91 (25.6%) carried S. aureus, and 33 (9.3%) carried both. S. pneumoniae carriage was not related to HIV-1 status. The HIV-1-positive children had a significantly higher rate of S. aureus carriage than did the HIV-1-negative children (31.4% vs. 13.8%; P<.001). The rate of S. aureus carriage in the HIV-1-negative S. pneumoniae carriers was significantly lower than that in the noncarriers (5.5% vs. 21.3%; P=.013), but the rate of S. aureus carriage in the HIV-1-positive S. pneumoniae carriers was not significantly lower than that in the noncarriers (26.3% vs. 36.0%; P=.11). We did not find a negative association between S. pneumoniae and S. aureus carriage in HIV-1-positive hospitalized children with severe pneumonia.


Assuntos
Infecções por HIV/microbiologia , HIV-1/crescimento & desenvolvimento , Nasofaringe/microbiologia , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/virologia , Staphylococcus aureus/isolamento & purificação , Streptococcus pneumoniae/isolamento & purificação , Pré-Escolar , Feminino , Infecções por HIV/virologia , Humanos , Lactente , Recém-Nascido , Masculino , África do Sul , Staphylococcus aureus/crescimento & desenvolvimento , Streptococcus pneumoniae/crescimento & desenvolvimento
20.
J Public Health (Oxf) ; 28(3): 192-6, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16809790

RESUMO

BACKGROUND: Although the move to smoke-free hospital settings is generally a popular initiative, it may be a more challenging and controversial issue in mental health care. A survey was carried out to investigate differences in attitudes between clinical staff in psychiatric and general medical settings to smoke-free policy and intervention. METHOD: The sample comprised 2574 NHS staff working in two Acute Hospital Trusts and one Mental Health Trust in England. Attitudes were examined on two factors: health care settings as smoke-free environments and the role of staff in stop smoking intervention. RESULTS: The findings indicated that attitudes on the two factors were only moderately correlated. Psychiatric staff expressed significantly less favourable attitudes than general staff to smoke-free health care settings and also to the role of staff in stop smoking intervention. The largest difference between the settings concerned the implementation of smoking bans. While approximately 1 in 10 staff in the general setting disagreed with a smoking ban in their wards or clinics, nearly one in three psychiatric staff was against such a ban in their setting. CONCLUSIONS: Staff attitudes need to be carefully considered, particularly in psychiatric settings, in attempts to implement smoke-free policies in health care settings.


Assuntos
Atitude do Pessoal de Saúde , Hospitais Gerais/organização & administração , Hospitais Psiquiátricos/organização & administração , Recursos Humanos em Hospital/psicologia , Abandono do Hábito de Fumar , Prevenção do Hábito de Fumar , Análise de Variância , Humanos , Política Organizacional , Abandono do Hábito de Fumar/psicologia , Inquéritos e Questionários
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