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Biomedical subjects

F Oakley

Publications and source records attributed to F Oakley.

14 recordsLinked to original sources
PubMed2006

Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis.

Myofibroblasts are critical cellular elements of wound healing generated at sites of injury by transdifferentiation of resident cells. A paradigm for this process is conversion of hepatic stellate cells (HSC) into hepatic myofibroblasts. Treatment of HSC with DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-azadC) blocked transdifferentiation. 5-azadC also prevented loss of IkappaBalpha and PPARgamma expression that occurs during transdifferentiation to allow acquisition of proinflammatory and profibrogenic characteristics. ChIP analysis revealed IkappaBalpha promoter is associated with transcriptionally repressed chromatin that converts to an active state with 5-azadC treatment. The methyl-CpG-binding protein MeCP2 which promotes repressed chromatin structure is selectively detected in myofibroblasts of diseased liver. siRNA knockdown of MeCP2 elevated IkappaBalpha promoter activity, mRNA and protein expression in myofibroblasts. MeCP2 interacts with IkappaBalpha promoter via a methyl-CpG-dependent mechanism and recruitment into a CBF1 corepression complex. We conclude that MeCP2 and DNA methylation exert epigenetic control over hepatic wound healing and fibrogenesis.

Animals↗
PubMed2006

Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats.

AIM: The aim of this study was to investigate the hypothesis that the opioid system is involved in the development of hepatic fibrosis. METHODS: The effect of naltrexone (an opioid receptor antagonist) on hepatic fibrosis in bile duct ligated (BDL) or sham rats was assessed by histology and hepatic hydroxyproline levels. Liver matrix metalloproteinase 2 (MMP-2) was measured by zymography, and alpha smooth muscle actin (alpha-SMA) and CD45 (leucocyte common antigen) by immunohistochemistry. The redox state of the liver was assessed by hepatic glutathione (GSH)/oxidised glutathione (GSSG) and S-nitrosothiol levels. Subtypes of opioid receptors in cultured hepatic stellate cells (HSCs) were characterised by reverse transcriptase-polymerase chain reaction, and the effects of selective delta opioid receptor agonists on cellular proliferation, tissue inhibitor of metalloproteinase 1 (TIMP-1), and procollagen I expression in HSCs determined. RESULTS: Naltrexone markedly attenuated the development of hepatic fibrosis as well as MMP-2 activity (p<0.01), and decreased the number of activated HSCs in BDL rats (p<0.05). The development of biliary cirrhosis altered the redox state with a decreased hepatic GSH/GSSG ratio and increased concentrations of hepatic S-nitrosothiols, which were partially or completely normalised by treatment with naltrexone, respectively. Activated rat HSCs exhibited expression of delta1 receptors, with increased procollagen I expression, and increased TIMP-1 expression in response to delta(1) and delta(2) agonists, respectively. CONCLUSIONS: This is the first study to demonstrate that administration of an opioid antagonist prevents the development of hepatic fibrosis in cirrhosis. Opioids can influence liver fibrogenesis directly via the effect on HSCs and regulation of the redox sensitive mechanisms in the liver.

Animals↗
PubMed2005

The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis.

Liver fibrosis and its end-stage disease cirrhosis are major world health problems arising from chronic injury of the liver by a variety of etiological factors including viruses, alcohol and drug abuse, the metabolic syndrome, autoimmune disease and hereditary disorders of metabolism. Fibrosis is a progressive pathological process in which wound-healing myofibroblasts of the liver respond to injury by promoting replacement of the normal hepatic tissue with a scar-like matrix composed of cross-linked collagen. Until recently it was believed that this process was irreversible. However emerging experimental and clinical evidence is starting to show that even cirrhosis is potentially reversible. Key to this is the discovery that reversion of fibrosis is accompanied by clearance of hepatic stellate cells (HSC) by apoptosis. Furthermore, proof-of-concept studies in rodents have demonstrated that experimental augmentation of HSC apoptosis will promote the resolution of fibrosis. Consequently there is now considerable interest in determining the molecular events that regulate HSC apoptosis and the discovery of drugs that will stimulate HSC apoptosis in a selective manner. This review will consider the regulatory role played by growth factors (e.g. NGF, IGF-1, TGFbeta), death receptor ligands (TRAIL, FAS), components and regulators of extracellular matrix (integrins, collagen, matrix metalloproteinases and their tissue inhibitors) and signal transduction proteins and transcription factors (Rho/Rho kinase, Jun N-terminal Kinase (JNK), IkappaKinase (IKK), NF-kappa B). The potential for known pharmacological agents such as gliotoxin, sulfasalazine, benzodiazepine ligands, curcumin and tanshinone I to induce HSC apoptosis and therefore to be used therapeutically will be explored.

Animals↗
PubMed2005

Novel sulfasalazine analogues with enhanced NF-kB inhibitory and apoptosis promoting activity.

The NF-kB transcription factor plays a key role in the regulation of apoptosis by modulating expression of a wide range of cell death control molecules. NF-kB also plays an important role in human diseases by promoting inappropriate cell survival. Small molecule inhibitors of NF-kB are therefore likely to provide novel therapeutic opportunities. Sulfasalazine (SFZ) is a synthetic anti-inflammatory comprising an aminosalicylate, 5-amino salicylic acid (5-ASA), linked to an antibiotic, sulfapyridine (SPY). SFZ, but not 5-ASA or SPY, inhibits activation of NF-kB. We synthesised a small number of SFZ analogues and determined their ability to inhibit NF-kB activity and promote apoptosis in chronic lymphocytic leukaemia and hepatic stellate cells, where NF-kB plays an important role in cell survival. Remarkably, 3 of the 6 analogues synthesised were significantly more effective (up to 8-fold) inhibitors of NF-kB dependent transcription and this increased activity was associated with enhanced apoptosis. Therefore, it is possible to readily improve the NF-kB inhibiting activity of SFZ and analogues of SFZ may be attractive therapeutic agents for malignancies and chronic liver disease where NF-kB is thought to play a significant role.

Animals↗
PubMed2005

Herpesvirus saimiri-based vector biodistribution using noninvasive optical imaging.

Herpesvirus saimiri (HVS) is capable of infecting a range of human cell types with high efficiency and the viral genome persists as high copy number, circular, nonintegrated episomes which segregate to progeny upon cell division. This allows the HVS-based vector to stably transduce a dividing cell population and provide sustained transgene expression for an extended period of time both in vitro and in vivo. Here we assess the dissemination of HVS-based vectors in vivo following intravenous and intraperitoneal administration. Bioluminescence imaging of an HVS-based vector expressing luciferase demonstrates that the virus can infect and establish a persistent latent infection in a variety of mouse tissues. Moreover, the long-term in vivo maintenance of the HVS genome as a nonintegrated circular episome provided sustained expression of luciferase over a 10-week period. A particularly high level of transgene expression in the liver and the ability of HVS to infect and persist in hepatic stellate cells suggest that HVS-based vectors may have potential for the treatment of inherited and acquired liver diseases.

Animals↗
PubMed2004

Histidine-stimulated divalent metal uptake in human erythrocytes and in the erythroleukaemic cell line HEL.92.1.7.

The uptake of 65Zn by human erythrocytes was investigated in the presence of high (40 mM) and low (5 mM) concentrations of histidine and 0-500 microM cobalt, nickel, manganese and zinc. Varying concentrations of metal mono- and bis-histidine complexes will be formed and the inhibition of 65Zn uptake could be correlated with the calculated complex concentrations to investigate competition between metals. For each metal, the calculated concentrations of bis-histidine complex giving 50% inhibition of 65Zn uptake were similar at both 5 mM and 40 mM histidine. Manganese-bis-histidine appeared to have a much higher affinity for the binding site than the other metal-bis-histidine complexes, which had similar affinities to each other. Studies of the inhibition of histidine-stimulated 54Mn uptake by the addition of manganese confirmed that manganese-bis-histidine does act as a substrate for the transporter in a similar fashion to the other metals studied. In addition, human erythroleukaemic cells (HEL cells) were used as a model for erythroid precursor cells. L-histidine, but not D-histidine, stimulated 65Zn uptake in a saturable fashion. The other metals competed with zinc in a similar manner to that seen in erythrocytes, and the affinity for manganese-bis-histidine was much greater than for the bis-histidine complexes of the other three metals. Both the capacity for metal transport per cell, and the affinity of the transporter for the metal-bis-histidine complexes, were much greater in the HEL cells than in the erythrocyte. It is suggested that histidine-stimulated metal transport may play a role in the supply of metals to maturing erythroid cells.

Cations, Divalent↗
PubMed2004

Patient and operator dose during fluoroscopic examination of swallow mechanism.

Dose-area product (DAP) measurements were made for 21 patients undergoing a modified barium swallow. The procedures were performed by a radiologist and speech and language therapist, to characterize swallowing disorders in patients with head or spinal injury, stroke, other neurological conditions or simple globus symptoms, in order to inform feeding strategies. The DAP values were used to estimate effective dose to the patient, in order to provide a measure of the radiation risk associated with the procedure. Whole body doses to operators, together with equivalent doses to extremities and eyes were also measured to inform the employer's risk assessment. Median DAP for the series was 3.5 (3.1-5.2) Gycm(2) with a corresponding effective dose to the patient of 0.85 (0.76-1.3) mSv, and a low associated risk, mainly of cancer induction, of about 1 in 16 000. The organ receiving the greatest dose was the thyroid, with a calculated median equivalent dose of 13.9 (12.3-20.7) mSv. Median screening time was 3.7 (2.5-4.3) min. Mean operator doses were 0.5 mSv equivalent dose (eyes), 0.9 mSv (extremities), and less than 0.3 mSv whole body dose. Extrapolating for an annual workload of 50 patients per year, this work will lead to annual operator doses of less than 0.6 mSv whole body dose, and approximately 1 mSv equivalent dose (eyes) and 1.8 mSv (extremities), against corresponding legal dose limits of 20 mSv, 150 mSv and 500 mSv, respectively.

Barium Sulfate↗
PubMed2002

Improvement in activities of daily living in elderly following treatment for post-bereavement depression.

OBJECTIVE: To determine if elderly bereaved depressed subjects display difficulty with activities of daily living (ADL) and if their ADL difficulty improves with psychopharmacologic intervention. METHOD: The Assessment of Motor and Process Skills (AMPS), an ADL assessment measuring ADL motor and ADL process skills, was administered to a pilot sample of elderly persons with post-bereavement depression prior to psychopharmacologic intervention and subsequently during treatment response. RESULTS: In the pretreatment phase, subjects displayed difficulty with ADL motor and ADL process skills that significantly improved during the treatment response phase. CONCLUSION: Results suggest that elderly bereaved depressed individuals demonstrated ADL difficulty that responds positively to psychopharmacologic intervention.

Activities of Daily Living↗
PubMed1999

A validation study of the daily activities questionnaire: an activities of daily living assessment for people with Alzheimer's disease.

The Daily Activities Questionnaire (DAQ) was developed to assess activities of daily living (ADL) independence in people with Alzheimer's disease. After administering it to 276 people diagnosed with Alzheimer's disease, we examined the quality of the rating scale and its structure using a Rasch measurement approach. Results indicated that the original 10-point rating scale should be restructured to a 5-point rating scale to improve the quality of the instrument. In addition, we found that all but two ADL items defined the same construct and could be combined into a single summary measure of ADL independence. The remaining items were positioned along a hierarchical continuum, with IADL tasks more difficult than PADL tasks. Furthermore, the tasks were logically ordered by difficulty. We therefore report that the DAQ is a valid scale and conclude that it is a viable measure of ADL independence for studies of Alzheimer's disease.

Activities of Daily Living↗
PubMed1997

Assessment of motor and process skills as a measure of IADL functioning in pharmacologic studies of people with Alzheimer's disease: a pilot study.

The purpose of this pilot study was to evaluate the usefulness of the Assessment of Motor and Process Skills (AMPS) as an outcome measure of instrumental activities of daily living (IADL) in pharmacologic studies of people with Alzheimer's disease. The AMPS simultaneously measures motor and process skills and their effect on the ability of the person to perform familiar IADL tasks. We administered the AMPS to 11 Alzheimer inpatients in a 3 1/2-month, double-blind, placebo-controlled, crossover study of fluoxetine and selegiline administered as single agents and in combination with physostigmine. Results indicated that there was a significant difference in IADL ability among study conditions for process skills, but not for motor skills, thereby suggesting that the AMPS is useful as a sensitive outcome measure of IADL ability in drug trials with this population.

Activities of Daily Living↗
PubMed1995

Comparing the roles of community-living persons and patient populations.

OBJECTIVES: This study compares the occupational role profile of a large sample of community-living persons without disabilities with the profile of a population of patients with psychosocial or physical disabilities and suggests areas of occupational therapy intervention. METHODS: The Role Checklist was used to compare the roles of 1,020 community-living persons without disabilities with the roles of 292 adults with physical or psychosocial disabilities. Specifically, community-living persons were matched to the entire patient group, a group of patients with psychosocial dysfunction, and a group of patients with physical dysfunction to compare the groups in terms of their past, present, and future role profiles and the value they assigned to those roles. RESULTS: There were significant differences in the types of roles identified. In general, the patients identified involvement in fewer present roles than the community-living persons. Differences between the two groups also appeared in the identification of future roles and value of those roles. CONCLUSIONS: Roles appear to be affected by disability, whether physical or psychosocial in nature. If role participation is seen as part of the occupational functioning of the person, occupational therapy needs to address this area.

Adult↗
PubMed1985

An occupational therapy approach to assessing psychiatric patients' adaptive functioning.

This study focused on the relative utility of the model of human occupation for occupational therapy assessment of persons having mental disorders. The organizational status of the human system and its relationship to adaptive level of functioning and degree of symptomatology were examined in a sample of 30 adult psychiatric patients. We used a six-test assessment battery developed for this study, which was based on the model of human occupation, to measure the organizational status of the following components of the human system: locus of control, goals, temporal orientation, interests, roles, and skills. Subtests of the American Association on Mental Deficiency (AAMD) Adoptive Behavior Scale and the Modified Brief Psychiatric Rating Scale were used to measure adaptive level functioning and symptomatology, respectively. When we compared organizational status with psychiatric diagnosis and symptomatology, we found organizational status to be the more significant index of adaptive level of functioning.

Adaptation, Psychological↗
PubMedDate not supplied

Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society.

OBJECTIVE: A consensus conference on the diagnosis and treatment of Alzheimer disease (AD) and related disorders was organized by the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society on January 4 and 5, 1997. The target audience was primary care physicians, and the following questions were addressed: (1) How prevalent is AD and what are its risk factors? What is its impact on society? (2) What are the different forms of dementia and how can they be recognized? (3) What constitutes safe and effective treatment for AD? What are the indications and contraindications for specific treatments? (4) What management strategies are available to the primary care practitioner? (5) What are the available medical specialty and community resources? (6) What are the important policy issues and how can policymakers improve access to care for dementia patients? (7) What are the most promising questions for future research? PARTICIPANTS: Consensus panel members and expert presenters were drawn from psychiatry, neurology, geriatrics, primary care, psychology, nursing, social work, occupational therapy, epidemiology, and public health and policy. EVIDENCE: The expert presenters summarized data from the world scientific literature on the questions posed to the panel. CONSENSUS PROCESS: The panelists listened to the experts' presentations, reviewed their background papers, and then provided responses to the questions based on these materials. The panel chairs prepared the initial drafts of the consensus statement, and these drafts were read by all panelists and edited until consensus was reached. CONCLUSIONS: Alzheimer disease is the most common disorder causing cognitive decline in old age and exacts a substantial cost on society. Although the diagnosis of AD is often missed or delayed, it is primarily one of inclusion, not exclusion, and usually can be made using standardized clinical criteria. Most cases can be diagnosed and managed in primary care settings, yet some patients with atypical presentations, severe impairment, or complex comorbidity benefit from specialist referral. Alzheimer disease is progressive and irreversible, but pharmacologic therapies for cognitive impairment and nonpharmacologic and pharmacologic treatments for the behavioral problems associated with dementia can enhance quality of life. Psychotherapeutic intervention with family members is often indicated, as nearly half of all caregivers become depressed. Health care delivery to these patients is fragmented and inadequate, and changes in disease management models are adding stresses to the system. New approaches are needed to ensure patients' access to essential resources, and future research should aim to improve diagnostic and therapeutic effectiveness.

Alzheimer Disease↗