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1.
Clin Exp Dermatol ; 46(8): 1626-1628, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34490932
3.
Pilot Feasibility Stud ; 7(1): 1, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33390191

RESUMO

BACKGROUND: Cystic fibrosis (CF) is a life-limiting genetic condition in which daily therapies to maintain lung health are critical, yet treatment adherence is low. Previous interventions to increase adherence have been largely unsuccessful and this is likely due to a lack of focus on behavioural evidence and theory alongside input from people with CF. This intervention is based on a digital platform that collects and displays objective nebuliser adherence data. The purpose of this paper is to identify the specific components of an intervention to increase and maintain adherence to nebuliser treatments in adults with CF with a focus on reducing effort and treatment burden. METHODS: Intervention development was informed by the Behaviour Change Wheel (BCW) and person-based approach (PBA). A multidisciplinary team conducted qualitative research to inform a needs analysis, selected, and refined intervention components and methods of delivery, mapped adherence-related barriers and facilitators, associated intervention functions and behaviour change techniques, and utilised iterative feedback to develop and refine content and processes. RESULTS: Results indicated that people with CF need to understand their treatment, be able to monitor adherence, have treatment goals and feedback and confidence in their ability to adhere, have a treatment plan to develop habits for treatment, and be able to solve problems around treatment adherence. Behaviour change techniques were selected to address each of these needs and were incorporated into the digital intervention developed iteratively, alongside a manual and training for health professionals. Feedback from people with CF and clinicians helped to refine the intervention which could be tailored to individual patient needs. CONCLUSIONS: The intervention development process is underpinned by a strong theoretical framework and evidence base and was developed by a multidisciplinary team with a range of skills and expertise integrated with substantial input from patients and clinicians. This multifaceted development strategy has ensured that the intervention is usable and acceptable to people with CF and clinicians, providing the best chance of success in supporting people with CF with different needs to increase and maintain their adherence. The intervention is being tested in a randomised controlled trial across 19 UK sites.

7.
Clin Exp Dermatol ; 43(3): 315-318, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29336047

RESUMO

Methylmalonic acidaemia (MMA) is an inborn error of amino acid metabolism that may be associated with cutaneous manifestations mimicking other diagnoses, including staphylococcal scalded skin syndrome (SSSS), psoriasis and acrodermatitis enteropathica. Whether this is due to the underlying metabolic disorder itself or occurs as a consequence of dietary restriction has yet to be elucidated. Skin biopsies typically show histological features shared by a number of other metabolic disorders and nutritional deficiency-associated diseases. Some presentations, especially SSSS-like eruptions, may be associated with acute metabolic decompensation. An underlying metabolic disorder, such as MMA, should be considered in a diagnosed adult or undiagnosed child presenting with skin eruptions that resemble those listed above, so that specialist management may be initiated early.


Assuntos
Acrodermatite/etiologia , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Pele/patologia , Acrodermatite/diagnóstico , Acrodermatite/patologia , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Biópsia , Diagnóstico Diferencial , Feminino , Humanos
8.
J Vestib Res ; 27(2-3): 113-125, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29064827

RESUMO

BACKGROUND: Movements may be generated consistent with imagining one's own body transformed or "disembodied" to a new position. Based on this concept we hypothesized that patients with objective balance deficits (obj-BD) would have altered neural transformation processes executing own body transformation (OBT) with functional consequences on balance control. Also we examined whether feeling unstable due to dizziness only (DO), without an obj-BD, also lead to an impaired OBT. METHODS: 32 patients with chronic dizziness were tested: 16 patients with obj-BD as determined by balance control during a sequence of stance and gait tasks, 16 patients with dizziness only (DO). Patients and 9 healthy controls (HCs) were asked to replicate roll trunk movements of an instructor in a life size video: first, with spontaneously copied (SPO) or "embodied" egocentric movements (lean when the instructor leans); second, with "disembodied" or "transformed" movements (OBT) with exact replication - lean left when the instructor leans left. Onset latency of trunk roll, rise time to peak roll angle (interval), roll velocity, and amplitude were measured. RESULTS: SPO movements were always mirror-imaged. OBT task latencies were significantly longer and intervals shorter than for SPO tasks (p < 0.03) for all groups. Obj-BD but not DO patients had more errors for the OBT task and, compared to HCs, had longer onset latencies (p < 0.05) and smaller velocities (p < 0.003) and amplitudes (p < 0.001) in both the SPO and OBT tasks. Measures of DO patients were not significantly different from those of HCs. CONCLUSIONS: Mental transformation (OBT) and SPO copying abilities are impaired in subjects with obj-BD and dizziness, but not with dizziness only. We conclude that processing the neuropsychological representation of the human body (body schema) slows when balance control is deficient.


Assuntos
Imaginação , Doenças Vestibulares/psicologia , Adulto , Idoso , Imagem Corporal , Doença Crônica , Cognição , Tontura/psicologia , Feminino , Marcha , Humanos , Masculino , Pessoa de Meia-Idade , Movimento , Equilíbrio Postural , Reflexo Vestíbulo-Ocular
9.
Int J Obes (Lond) ; 41(12): 1798-1804, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28775376

RESUMO

BACKGROUND: Metabolic function is regulated by the interplay of central and peripheral factors that ultimately regulate food intake (FI) and energy expenditure. The tachykinin substance P (SP) has been identified as a novel regulator of energy balance, however, the mechanisms underlying this effect are ill-defined and conflicting data regarding the role of SP on FI have been reported by different groups. OBJECTIVE: To further characterize the metabolic role of the Tac1 gene products (SP and neurokinin A) in mice through a series of genetic, metabolic and behavioral studies in Tac1-deficient mice. RESULTS: Tac1-/- mice are leaner than controls and display reduced FI and altered feeding circadian rhythm, supported by disrupted expression of the clock genes Cry1/2, Per1/2 in the suprachiasmatic nucleus, mediobasal hypothalamus (MBH) and liver, as well as increased proopiomelanocortin expression in the MBH. Tac1 ablation induced resistance to obesity, improved glucose tolerance, prevented insulin resistance under high-fat diet, increased activation of brown adipose tissue and improved hepatic steatosis. Moreover, deletion of Tac1 in ob/ob mice ameliorated body weight gain in females only but was sufficient to decrease fat and triglyceride content in the liver of males. CONCLUSIONS: These results provide further evidence that Tac1 controls circadian feeding behavior and metabolism in mice through mechanisms that involve the regulation of the melanocortin system. In addition, these studies suggest that the blockade of SP may offer a new method to treat metabolic syndrome.


Assuntos
Comportamento Alimentar/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Receptores da Neurocinina-1/efeitos dos fármacos , Substância P/farmacologia , Taquicininas/deficiência , Animais , Ritmo Circadiano , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Camundongos , Camundongos Knockout , Camundongos Obesos , Transdução de Sinais
10.
Chirality ; 29(8): 403-408, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28608629

RESUMO

Chirality strongly influences many biological properties of materials, such as cell accumulation, enzymatic activity, and toxicity. In the past decade, it has been shown that quantum dots (QDs), fluorescent semiconductor nanoparticles with unique optical properties, can demonstrate optical activity due to chiral ligands bound on their surface. Optically active QDs could find potential applications in biomedical research, therapy, and diagnostics. Consequently, it is very important to investigate the interaction of QDs capped with chiral ligands with living cells. The aim of our study was to investigate the influence of the induced chirality of Mn-doped ZnS QDs on the viability of A549 cells. These QDs were stabilized with D- and L-cysteine using a ligand exchange technique. The optical properties of QDs were studied using UV-Vis, photoluminescence (PL), and circular dichroism (CD) spectroscopy. The cytotoxicity of QDs was investigated by high content screening analysis. It was found that QDs stabilized by opposite ligand enantiomers, had identical PL and UV-Vis spectra and mirror-imaged CD spectra, but displayed different cytotoxicity: QDs capped with D-cysteine had greater cytotoxicity than L-cysteine capped QDs.

11.
J R Coll Physicians Edinb ; 46(3): 157-159, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27959348

RESUMO

Non-motor features of Parkinson's disease are receiving greater recognition. Constipation affects up to 50% of patients with Parkinson's disease and sigmoid volvulus remains an under recognised complication with mortality rates up to 50%. The incidence of sigmoid volvulus in the general population is 1.7/100,000/year. The specific incidence in Parkinson's disease is not known; however, this case series suggests that it is noticeably more than in the general population at 100/100,000/year. This paper highlights the importance of early recognition and treatment of constipation to prevent volvulus developing and thevarious treatments currently available.


Assuntos
Colo Sigmoide/patologia , Constipação Intestinal/etiologia , Volvo Intestinal/etiologia , Doença de Parkinson/complicações , Idoso , Idoso de 80 Anos ou mais , Constipação Intestinal/patologia , Feminino , Humanos , Masculino
13.
Gene Ther ; 23(4): 380-92, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26836117

RESUMO

Adeno-associated virus (AAV) vectors are showing promise in gene therapy trials and have proven to be extremely efficient biological tools in basic neuroscience research. One major limitation to their widespread use in the neuroscience laboratory is the cost, labor, skill and time-intense purification process of AAV. We have recently shown that AAV can associate with exosomes (exo-AAV) when the vector is isolated from conditioned media of producer cells, and the exo-AAV is more resistant to neutralizing anti-AAV antibodies compared with standard AAV. Here, we demonstrate that simple pelleting of exo-AAV from media via ultracentrifugation results in high-titer vector preparations capable of efficient transduction of central nervous system (CNS) cells after systemic injection in mice. We observed that exo-AAV is more efficient at gene delivery to the brain at low vector doses relative to conventional AAV, even when derived from a serotype that does not normally efficiently cross the blood-brain barrier. Similar cell types were transduced by exo-AAV and conventionally purified vector. Importantly, no cellular toxicity was noted in exo-AAV-transduced cells. We demonstrated the utility and robustness of exo-AAV-mediated gene delivery by detecting direct GFP fluorescence after systemic injection, allowing three-dimensional reconstruction of transduced Purkinje cells in the cerebellum using ex vivo serial two-photon tomography. The ease of isolation combined with the high efficiency of transgene expression in the CNS, may enable the widespread use of exo-AAV as a neuroscience research tool. Furthermore, the ability of exo-AAV to evade neutralizing antibodies while still transducing CNS after peripheral delivery is clinically relevant.


Assuntos
Dependovirus/genética , Exossomos , Terapia Genética/métodos , Vetores Genéticos/genética , Animais , Anticorpos Neutralizantes/imunologia , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Linhagem Celular , Técnicas de Transferência de Genes , Humanos , Camundongos , Transdução Genética , Transgenes
14.
Leukemia ; 29(1): 218-29, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24935722

RESUMO

We evaluated a cocktail of HLA-A2-specific peptides including heteroclitic XBP1 US184-192 (YISPWILAV), heteroclitic XBP1 SP367-375 (YLFPQLISV), native CD138260-268 (GLVGLIFAV) and native CS1239-247 (SLFVLGLFL), for their ability to elicit multipeptide-specific cytotoxic T lymphocytes (MP-CTLs) using T cells from smoldering multiple myeloma (SMM) patients. Our results demonstrate that MP-CTLs generated from SMM patients' T cells show effective anti-MM responses including CD137 (4-1BB) upregulation, CTL proliferation, interferon-γ production and degranulation (CD107a) in an HLA-A2-restricted and peptide-specific manner. Phenotypically, we observed increased total CD3(+)CD8(+) T cells (>80%) and cellular activation (CD69(+)) within the memory SMM MP-CTL (CD45RO(+)/CD3(+)CD8(+)) subset after repeated multipeptide stimulation. Importantly, SMM patients could be categorized into distinct groups by their level of MP-CTL expansion and antitumor activity. In high responders, the effector memory (CCR7(-)CD45RO(+)/CD3(+)CD8(+)) T-cell subset was enriched, whereas the remaining responders' CTL contained a higher frequency of the terminal effector (CCR7(-)CD45RO(-)/CD3(+)CD8(+)) subset. These results suggest that this multipeptide cocktail has the potential to induce effective and durable memory MP-CTL in SMM patients. Therefore, our findings provide the rationale for clinical evaluation of a therapeutic vaccine to prevent or delay progression of SMM to active disease.


Assuntos
Proteínas de Ligação a DNA/imunologia , Epitopos/imunologia , Mieloma Múltiplo/imunologia , Peptídeos/imunologia , Sindecana-1/imunologia , Linfócitos T Citotóxicos/imunologia , Fatores de Transcrição/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células , Progressão da Doença , Feminino , Humanos , Memória Imunológica , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Fatores de Transcrição de Fator Regulador X , Linfócitos T Citotóxicos/citologia , Proteína 1 de Ligação a X-Box
15.
Age Ageing ; 44(2): 331-3, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25349152

RESUMO

INTRODUCTION: The Royal Victoria Hospital, a geriatric medicine assessment and rehabilitation hospital in Edinburgh, was re-provided into a new 130 bed purpose-built unit on the Western General Hospital site in June 2012. All patient rooms in the new unit are single occupancy with en-suite facilities. METHODS: We surveyed inpatients on their room preference in 2008 and repeated the survey with inpatients in the new unit in 2013. Patients were asked whether they would prefer to be in a shared room or a single room and to explain the reason behind their choice. They were also asked whether they would prefer to eat their meals in a day/dining room or by their bed. The patients in the 2013 survey were also questioned as to whether they felt lonely in their single room. Forty-three inpatients agreed to participate in the 2008 survey and 46 in the 2013 survey. All had an abbreviated mental test score≥8/10. In 2008, those surveyed had a mean age of 78. In 2013, the mean age was 83. RESULTS: In 2008, 37.2% of patients expressed a preference for single room accommodation, whereas in 2013, 84.8% said that they preferred a single room. The majority of patients, 60.5% in 2008 and 76.1% in 2013, preferred to eat their meal at their bedside. Only 8.7% of patients in 2013 would consider eating in a day/dining room compared with 34.9% in 2008. In the 2013 survey, 60.9% of patients reported that they never felt lonely in a single room. DISCUSSION: The benefits of single room versus multi-occupancy room hospital accommodation has been recently debated. The results from our survey indicate a marked difference in the preference for a single room between 2008 and 2013. The introduction of open visiting and care rounding has reduced the risk of isolation in single rooms. Our survey introduces new discussion about social isolation, privacy, noise levels and patient well-being and recovery.


Assuntos
Pacientes Internados/psicologia , Preferência do Paciente , Quartos de Pacientes , Fatores Etários , Idoso , Envelhecimento/psicologia , Arquitetura de Instituições de Saúde , Comportamento Alimentar , Feminino , Pesquisas sobre Serviços de Saúde , Hospitais Gerais , Humanos , Solidão , Masculino , Privacidade , Escócia , Isolamento Social , Fatores de Tempo
16.
Forensic Sci Int Genet ; 8(1): 1-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24315582

RESUMO

The National DNA Database (NDNAD) of England and Wales was established on April 10th 1995. The NDNAD is governed by a variety of legislative instruments that mean that DNA samples can be taken if an individual is arrested and detained in a police station. The biological samples and the DNA profiles derived from them can be used for purposes related to the prevention and detection of crime, the investigation of an offence and for the conduct of a prosecution. Following the South East Asian Tsunami of December 2004, the legislation was amended to allow the use of the NDNAD to assist in the identification of a deceased person or of a body part where death has occurred from natural causes or from a natural disaster. The UK NDNAD now contains the DNA profiles of approximately 6 million individuals representing 9.6% of the UK population. As the science of DNA profiling advanced, the National DNA Database provided a potential resource for increased intelligence beyond the direct matching for which it was originally created. The familial searching service offered to the police by several UK forensic science providers exploits the size and geographic coverage of the NDNAD and the fact that close relatives of an offender may share a significant proportion of that offender's DNA profile and will often reside in close geographic proximity to him or her. Between 2002 and 2011 Forensic Science Service Ltd. (FSS) provided familial search services to support 188 police investigations, 70 of which are still active cases. This technique, which may be used in serious crime cases or in 'cold case' reviews when there are few or no investigative leads, has led to the identification of 41 perpetrators or suspects. In this paper we discuss the processes, utility, and governance of the familial search service in which the NDNAD is searched for close genetic relatives of an offender who has left DNA evidence at a crime scene, but whose DNA profile is not represented within the NDNAD. We discuss the scientific basis of the familial search approach, other DNA-based methods for eliminating individuals from the candidate lists generated by these NDNAD searches, the value of filtering these lists by age, ethnic appearance and geography and the governance required by the NDNAD Strategy Board when a police force commissions a familial search. We present the FSS data in relation to the utility of the familial searching service and demonstrate the power of the technique by reference to casework examples. We comment on the uptake of familial searching of DNA databases in the USA, the Netherlands, Australia, and New Zealand. Finally, following the adverse ruling by the European Court of Human Rights against the UK in regard to the S & Marper cases and the consequent introduction of the Protection of Freedoms Act (2012), we discuss the impact that changes to regulations concerning the storage of DNA samples will have on the continuing provision of familial searching of the National DNA Database in England and Wales.


Assuntos
Criminosos , DNA/genética , Bases de Dados Genéticas , Família , Genética Forense , Humanos , Reino Unido
17.
Minerva Cardioangiol ; 61(3): 263-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23681129

RESUMO

Patients with symptomatic aortic valve disease who are inoperable or have high surgery-related risks may be treated with transcatheter aortic valve implantation devices. With this method increasingly applied, device innovations are aimed at achieving improved procedural results and therapeutic outcome. This paper describes the innovations implemented in the St. Jude Medical Portico™ system for transcatheter aortic valve implantation, the application of this system and initial clinical experience.


Assuntos
Estenose da Valva Aórtica/cirurgia , Idoso Fragilizado , Implante de Prótese de Valva Cardíaca/instrumentação , Próteses Valvulares Cardíacas , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/patologia , Estudos de Viabilidade , Feminino , Implante de Prótese de Valva Cardíaca/métodos , Humanos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
18.
Health Technol Assess ; 14(32): 1-206, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20594533

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in the UK: incidence increases with age, median age at diagnosis being over 70 years. Approximately 25% of cases occur in individuals with a family history of CRC, including 5% caused by familial adenomatous polyposis (FAP) or hereditary non-polyposis CRC (HNPCC). Most develop from adenomatous polyps arising from the intestine lining. Individuals with these polyps undergo polypectomy and are invited for endoscopic surveillance. Screening via faecal occult blood testing has been rolled out across the UK. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of drug and micronutrient interventions for the prevention of CRC and/or adenomatous polyps. Interventions considered include: non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and cyclo-oxygenase-2 (COX-2) inhibitors; folic acid; calcium; vitamin D and antioxidants (including vitamin A, vitamin C, vitamin E, selenium and beta-carotene). Chemoprevention was assessed in the general population, in individuals at increased risk of CRC, and in individuals with FAP or HNPCC. DATA SOURCES: A systematic review identified randomised controlled trials (RCTs) assessing drug and nutritional agents for the prevention of CRC or adenomatous polyps. A separate search identified qualitative studies relating to individuals' views, attitudes and beliefs about chemoprevention. MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, CINAHL, the Cochrane Database of Systematic Reviews, Cochrane CENTRAL Register of Controlled Trials, DARE, NHS-EED (NHS Economic Evaluation Database), HTA database, Science Citation Index, BIOSIS previews and the Current Controlled Trials research register were searched in June 2008. Data were extracted by one reviewer and checked by a second. REVIEW METHODS: The synthesis methods used were systematic review and meta-analysis for RCTs and qualitative framework synthesis for qualitative studies. A health economic model was developed to assess the cost-effectiveness of chemoprevention for two populations with different levels of risk of developing CRC: the general population and an intermediate-risk population. RESULTS: The search identified 44 relevant RCTs and six ongoing studies. A small study of aspirin in FAP patients produced no statistically significant reduction in polyp number but a possible reduction in polyp size. There was a statistically significant 21% reduction in risk of adenoma recurrence [relative risk (RR) 0.79, 95% confidence interval (CI) 0.68 to 0.92] in an analysis of aspirin versus no aspirin in individuals with a history of adenomas or CRC. In the general population, a significant 26% reduction in CRC incidence was demonstrated in studies with a 23-year follow-up (RR 0.74, 95% CI 0.57 to 0.97). Non-aspirin NSAID use in FAP individuals produced a non-statistically significant reduction in adenoma incidence after 4 years of treatment and follow-up and reductions in polyp number and size. In individuals with a history of adenomas there was a statistically significant 34% reduction in adenoma recurrence risk (RR 0.66, 95% CI 0.60 to 0.72) and a statistically significant 55% reduction in advanced adenoma incidence (RR 0.45, 95% CI 0.35 to 0.58). No studies assessed the effect of non-aspirin NSAIDs in the general population. There were no studies of folic acid in individuals with FAP or HNPCC. There was no significant effect of folic acid versus placebo on adenoma recurrence (RR 1.16, 95% CI 0.97 to 1.39) or advanced adenoma incidence in individuals with a history of adenomas. In the general population there was no significant effect of folic acid on risk of CRC (RR 1.13, 95% CI 0.77 to 1.64), although studies were of relatively short duration. Calcium use by FAP patients produced no significant reduction in polyp number or disease progression. In individuals with a history of adenomas there was a statistically significant 18% reduction in risk of adenoma recurrence (RR 0.82, 95% CI 0.69 to 0.98) and a non-significant reduction in risk of advanced adenomas (RR 0.77, 95% CI 0.50 to 1.17). In the general population there was no significant effect of calcium on risk of CRC (RR 1.08, 95% CI 0.87 to 1.34), although studies were of relatively short duration. There were no studies of antioxidant use in individuals with FAP or HNPCC, and in individuals with a history of adenomas no statistically significant differences in relative risk of adenoma recurrence were found. In the general population there was no difference in incidence of CRC (RR 1.00, 95% CI 0.88 to 1.13) with antioxidant use compared with no antioxidant use. Twenty studies reported qualitative findings concerning chemoprevention. People are more likely to use NSAIDs if there is a strong perceived need. Perceptions of risk and benefit also influence decision-making and use. People have fewer concerns about using antioxidants or other supplements, but their perception of the benefits of these agents is less well-defined. The model analysis suggested that the most cost-effective age-range policy in the general population would be to provide chemoprevention to all individuals within the general population from age 50 to 60 years. The use of aspirin in addition to screening within the general population is likely to result in a discounted cost per life-year gained of around 10,000 pounds and a discounted cost per quality-adjusted life-year (QALY) gained of around 23,000 pounds compared with screening alone. In the intermediate-risk group the most economically viable age-range policy would be to provide chemoprevention to individuals following polypectomy aged 61 to 70 years. Calcium is likely to have a discounted cost per QALY gained of around 8000 pounds compared with screening alone. Although aspirin in addition to screening should be more effective and less costly than screening alone, under the current assumptions of benefits to harms of aspirin and calcium, aspirin is expected to be extendedly dominated by calcium. LIMITATIONS: Whilst a number of studies were included in the review, the duration of follow-up was generally insufficient to detect an effect on cancer incidence. Given the uncertainties and ambiguities in the evidence base, the results of the health economic analysis should be interpreted with caution. CONCLUSIONS: Aspirin and celecoxib may reduce recurrence of adenomas and incidence of advanced adenomas in individuals with an increased risk of CRC and calcium may reduce recurrence of adenomas in this group. COX-2 inhibitors may decrease polyp number in patients with FAP. There is some evidence for aspirin reducing the incidence of CRC in the general population. Both aspirin and NSAIDs are associated with adverse effects so it will be important to consider the risk-benefit ratio before recommending these agents for chemoprevention. The economic analysis suggests that chemoprevention has the potential to represent a cost-effective intervention, particularly when targeted at intermediate-risk populations following polypectomy.


Assuntos
Neoplasias Colorretais/prevenção & controle , Polipose Adenomatosa do Colo/economia , Polipose Adenomatosa do Colo/epidemiologia , Polipose Adenomatosa do Colo/prevenção & controle , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Cálcio/uso terapêutico , Neoplasias Colorretais/economia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/economia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Ácido Fólico/uso terapêutico , Humanos , Incidência , Modelos Econômicos , Prognóstico , Medição de Risco , Selênio/uso terapêutico , Reino Unido/epidemiologia , beta Caroteno/uso terapêutico
19.
Sci Transl Med ; 2(31): 31ra34, 2010 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-20463368

RESUMO

Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA. In a separate experiment with five patients who had glioblastoma, we prospectively secured baseline and serial tumor tissue, developed patient-specific cell lines of glioblastoma and putative glioblastoma stem cells (CD133(+), nestin(+) cells), and treated each patient with oral DCA for up to 15 months. DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. The dose-limiting toxicity was a dose-dependent, reversible peripheral neuropathy, and there was no hematologic, hepatic, renal, or cardiac toxicity. Indications of clinical efficacy were present at a dose that did not cause peripheral neuropathy and at serum concentrations of DCA sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Ácido Dicloroacético/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Adulto , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Feminino , Glioblastoma/irrigação sanguínea , Glioblastoma/patologia , Humanos , Técnicas In Vitro , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/tratamento farmacológico , Piruvato Desidrogenase Quinase de Transferência de Acetil , Espécies Reativas de Oxigênio/metabolismo
20.
Cancer Gene Ther ; 16(8): 664-71, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19197327

RESUMO

Glioblastoma multiforme (GBM) is the most aggressive type of all primary brain tumors, with an overall median survival <1 year after diagnosis. Despite introduction of multimodal treatment approaches, the prognosis has not improved significantly over the past 50 years. In this study we investigated the effect of intracerebroventricular (ICV) injection of an adeno-associated virus (AAV) vector encoding human interferon-beta (AAV-hIFN-beta) on glioblastoma growth. Recently, we found that peritumoral parenchymal transduction with an AAV-hIFN-beta was exceptionally efficient in eradicating GBM brain tumors. However, the extensive infiltration and migration displayed by glioblastoma cells in patients may leave a significant number of tumor cells outside a local therapeutic zone created by intraparenchymal delivery of AAV vectors. Here we show that pretreatment of mice by ICV infusion of an AAV-IFN-beta completely prevents tumor growth in an orthotopic model of GBM. Furthermore, ICV infusion of AAV-IFN-beta into mice bearing preestablished U87 intracranial tumors improved their survival compared to mice infused through the same route with a control AAV vector. These data suggest that ICV injection of AAV vectors encoding antitumor proteins is a promising approach deserving further consideration for the treatment of GBM.


Assuntos
Neoplasias Encefálicas/terapia , Dependovirus/genética , Vetores Genéticos/administração & dosagem , Glioblastoma/terapia , Interferon beta/genética , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Terapia Genética/métodos , Vetores Genéticos/metabolismo , Vetores Genéticos/farmacocinética , Glioblastoma/metabolismo , Humanos , Injeções Intraventriculares , Interferon beta/administração & dosagem , Interferon beta/farmacocinética , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias
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