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Biomedical subjects

Michael Farrell

Publications and source records attributed to Michael Farrell.

50 records · Page 3Linked to original sources
PubMed2002

Thymidylate synthase as a translational regulator of cellular gene expression.

Studies from our laboratory have shown that the folate-dependent enzyme, thymidylate synthase (TS), functions as an RNA binding protein. There is evidence that TS, in addition to interacting with its own TS mRNA, forms a ribonucleoprotein complex with a number of other cellular mRNAs, including those corresponding to the p53 tumor suppressor gene and the myc family of transcription factors. Using both in vitro and in vivo model systems, we have demonstrated that the functional consequence of binding of TS protein to its own cognate mRNA, as well as binding of TS to the p53 mRNA, is translational repression. Herein, we review current work on the translational autoregulatory control of TS expression and discuss the molecular elements that are required for the TS protein-TS mRNA interaction. TS may play a critical role in regulating the cell cycle and the process of apoptosis through its regulatory effects on expression of p53 and perhaps other cell cycle related proteins. Finally, the ability of TS to function as a translational regulator may have important consequences with regard to the development of cellular resistance to various anticancer drugs.

Animals↗
PubMed2002

Prison based detoxification for opioid dependence: a randomised double blind controlled trial of lofexidine and methadone.

This paper reports results from the first controlled trial of opioid withdrawal treatment in the UK using lofexidine in a prison setting. Seventy-four opioid dependent male inmates at a Southern England prison were randomised to receive either methadone (the standard prison treatment) or lofexidine using a randomised double-blind design. No significant statistical difference between the treatment groups was found in relation to the primary variable of severity of withdrawal symptoms (effect size=0.12). No discernible difference was found in the sitting blood pressure or heart rate of the two groups during the trial. These results provide support for the use of lofexidine for the management of opioid detoxification in the prison setting.

Adult↗
PubMed2002

Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics.

The biosynthesis of CoA from pantothenic acid (vitamin B5) is an essential universal pathway in prokaryotes and eukaryotes. The CoA biosynthetic genes in bacteria have all recently been identified, but their counterparts in humans and other eukaryotes remained mostly unknown. Using comparative genomics, we have identified human genes encoding the last four enzymatic steps in CoA biosynthesis: phosphopantothenoylcysteine synthetase (EC ), phosphopantothenoylcysteine decarboxylase (EC ), phosphopantetheine adenylyltransferase (EC ), and dephospho-CoA kinase (EC ). Biological functions of these human genes were verified using a complementation system in Escherichia coli based on transposon mutagenesis. The individual human enzymes were overexpressed in E. coli and purified, and the corresponding activities were experimentally verified. In addition, the entire pathway from phosphopantothenate to CoA was successfully reconstituted in vitro using a mixture of purified recombinant enzymes. Human recombinant bifunctional phosphopantetheine adenylyltransferase/dephospho-CoA kinase was kinetically characterized. This enzyme was previously suggested as a point of CoA biosynthesis regulation, and we have observed significant differences in mRNA levels of the corresponding human gene in normal and tumor cells by Northern blot analysis.

Blotting, Northern↗
PubMed2002

Alpha2-adrenergic agonists in opioid withdrawal.

OBJECTIVES: This paper presents the main findings of a systematic (Cochrane) review of the effectiveness of alpha2-adrenergic agonists in managing opioid withdrawal. DESIGN: The original systematic review included controlled trials that compared alpha2-adrenergic agonists with another form of treatment (or placebo) in participants who were primarily opioid-dependent. MAIN FINDINGS: Ten studies compared a treatment regime based on an alpha2-adrenergic agonist with one based on reducing doses of methadone. Withdrawal intensity is similar to, or marginally greater with alpha2-adrenergic agonists, but signs and symptoms of withdrawal occur and resolve earlier in treatment. Participants stay in treatment longer with methadone. The likelihood of completing withdrawal is similar, or slightly less, with clonidine or lofexidine. Clonidine is associated with more adverse effects than reducing doses of methadone. Three studies compared the alpha2-adrenergic agonists, clonidine and lofexidine. Lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine. CONCLUSIONS: Participants stay in treatment longer with methadone regimes, which may provide greater opportunity for psychosocial intervention. Methadone regimes may be preferable for withdrawal in outpatient settings where the risk of relapse to heroin use is high. The use of methadone may also facilitate transfer to maintenance treatment should completion of withdrawal become unlikely. For those who are well prepared for withdrawal and seeking earlier resolution of withdrawal symptoms, alpha2-adrenergic agonist treatment may be preferred. Clonidine and lofexidine appear equally effective for inpatient settings, but the lower incidence of hypotension makes lofexidine more suited to use in outpatient settings.

Adrenergic alpha-Agonists↗
PubMed2002

Pharmacological treatment of cocaine dependence: a systematic review.

AIMS: Cocaine dependence is a common and serious condition, associated with severe medical, psychological and social problems, including the spread of infectious diseases. This systematic review assesses critically the efficacy of pharmacotherapy for treating cocaine dependence. METHODS: The literature search strategy included: electronic searches of Cochrane Library holdings, EMBASE, MEDLINE, PsycLIT, Biological Abstracts and LILACS; scans of reference lists of relevant articles, personal communications, conference abstracts, unpublished trials from the pharmaceutical industry and book chapters on the treatment of cocaine dependence. Randomized controlled trials (RCTs) focusing on the use of antidepressants (ADs), carbamazepine (CBZ), dopamine agonists (DAs) and other drugs used in the treatment of cocaine dependence were included. The reviewers extracted data independently, and relative risks (RR) with 95% confidence interval (CI) were estimated. Qualitative assessments were carried out using a Cochrane validated checklist. Where possible, analysis was carried out according to 'intention-to-treat' principles. FINDINGS: The search strategy generated 45 different trials. Most studied drugs were ADs (20 studies), DAs and CBZ. Data were very heterogeneous, with dropout rates within the studies between 0 and 84%. A non-significant trend favoring CBZ was found in terms of dropouts (RR 0.88; 95% CI 0.75-1.03) and results from one trial suggest that fluoxetine patients are less likely to drop out. The main efficacy outcome reported in the studies was the presence of cocaine metabolites in the urine. No significant results were found, regardless the type of drug or dose used for all relevant outcomes assessed. CONCLUSIONS: There is no current evidence supporting the clinical use of CBZ, antidepressants, dopamine agonists, disulfiram, mazindol, phenytoin, nimodipine, lithium and NeuRecover-SA in the treatment of cocaine dependence. Larger randomized investigation must be considered, while taking into account that these time-consuming efforts should be reserved for medications showing more relevant and promising evidence. Given the high dropout rate among the test population, clinicians may wish to consider adding psychotherapeutic supportive measures aimed at keeping patients in treatment programs.

Antidepressive Agents↗
PubMed2002

A method comparison study to assess the reliability of urine collection pads as a means of obtaining urine specimens from non-toilet-trained children for microbiological examination.

BACKGROUND: In young, non-toilet-trained children, the collection of a urine sample for microbiology can be challenging, with the application of a urine bag being the main method of collection. However, recent research has shown that absorbent pads can be used yielding similar results to bag specimens. However, weaknesses in study design erode confidence in research findings. Therefore, improvements in research design are required to fully evaluate the reliability of pad collection. AIMS OF THE STUDY: This pilot study sought to test the feasibility of a technique for the collection of concurrent bag/pad urine samples from non-toilet-trained children, and to assess the reliability of urine pads over bags as a collection method for urine specimens for microbiological evaluation. DESIGN: A pilot, method comparison study. METHODS: Twenty concurrent bag and pad specimens were collected from non-toilet-trained children, following parental consent. Urine specimens were analysed for presence or absence of white cell count (WBC), and bacterial growth, using standard laboratory methods. DATA ANALYSIS: The Kappa (kappa) statistics and confidence interval (CI) estimation were used to assess agreement between the two collection methods. RESULTS: Despite concurrent samples there was a lack of agreement between bag and pad specimens on both main outcome measures. Agreement between bag and pad specimens for the presence of WBC yielded a kappa=0.10 (95% CI: 0.19, 0.39), indicating poor agreement, while a kappa of 0.5 (95% CI: 0.12, 0.88) was calculated for the degree of agreement in bacterial growth reflecting moderate agreement. Differences in proportions of the presence of WBC between bag and pad did not quite reach significance at the 5% level 0.2 (95% CI: 0.00, 0.42, P=0.062). For cultures the difference was calculated as 0.15 (95% CI: 0.05, 0.35, P=0.125). CONCLUSION: The pilot study demonstrates that concurrent urine samples can be obtained without difficulty. Despite poor to moderate agreement on outcome measures the level of agreement is greater than reported in those other studies, that use non-current methods of urine collection, suggesting an advantage of the concurrent technique. It is recommended that larger scale studies be undertaken using the concurrent collection technique to assess reliability of these findings.

Child, Preschool↗
PubMed2002

The relative impact of waiting time and treatment entry on drug and alcohol use.

One hundred and twenty-three treatment-seeking substance misusers were recruited to a study assessing the early impact of treatment. Participants were interviewed at treatment entry and 3 and 6 months later, regardless of their treatment status (i.e. including those who had dropped out of treatment), while additional data were obtained from the two assessment interviews carried out prior to the initiation of treatment. Three consistent observations can be applied to both the opiate misuser (n = 61) and problem drinker samples (n = 62): (1) the period of pre-treatment wait (mean of 8 weeks) was characterized by stable patterns of substance misuse with no significant 'spontaneous' improvement in indices of severity of drug or alcohol problems; (2) the period immediately following initiation of treatment was associated with substantial reductions in the quantity and frequency of substance use, an effect not influenced by the length of time for treatment initiation; (3) these benefits are maintained to 6 months after treatment initiation. The waiting period for treatment initiation does not seem to be characterized by significant changes in drug or alcohol use patterns, at least among those who made it into treatment, with clear and sustained improvements irrespective of the length of treatment wait.

Adult↗
PubMed2002

From genetic footprinting to antimicrobial drug targets: examples in cofactor biosynthetic pathways.

Novel drug targets are required in order to design new defenses against antibiotic-resistant pathogens. Comparative genomics provides new opportunities for finding optimal targets among previously unexplored cellular functions, based on an understanding of related biological processes in bacterial pathogens and their hosts. We describe an integrated approach to identification and prioritization of broad-spectrum drug targets. Our strategy is based on genetic footprinting in Escherichia coli followed by metabolic context analysis of essential gene orthologs in various species. Genes required for viability of E. coli in rich medium were identified on a whole-genome scale using the genetic footprinting technique. Potential target pathways were deduced from these data and compared with a panel of representative bacterial pathogens by using metabolic reconstructions from genomic data. Conserved and indispensable functions revealed by this analysis potentially represent broad-spectrum antibacterial targets. Further target prioritization involves comparison of the corresponding pathways and individual functions between pathogens and the human host. The most promising targets are validated by direct knockouts in model pathogens. The efficacy of this approach is illustrated using examples from metabolism of adenylate cofactors NAD(P), coenzyme A, and flavin adenine dinucleotide. Several drug targets within these pathways, including three distantly related adenylyltransferases (orthologs of the E. coli genes nadD, coaD, and ribF), are discussed in detail.

Anti-Bacterial Agents↗
PubMed2002

The National Survey of Psychiatric Morbidity among prisoners and the future of prison healthcare.

It has long been known that psychiatric disorders are highly prevalent among prisoners (Coid, 1984; Gunn et al., 1991; Maden et al., 1995; Joukamaa, 1995; Bland et al., 1998; Lamb and Weinberger, 1998). However, the Survey of Psychiatric Morbidity Among Prisoners in England and Wales (Singleton et al., 1998) represents a considerable advance on earlier surveys. By using the same standardized psychiatric assessment procedures, and similar questions on medication, service use and social functioning, its findings can be compared with previous national surveys of adults living in private households (Meltzer et al., 1995), residents in institutions (Meltzer et al., 1996), homeless persons (Gill et al., 1996), and with the forthcoming household survey in England, Wales and Scotland. It should also inform the future organisation of healthcare for prisoners, following recent recommendations from a joint Home Office/Department of Health Working Party that Health Authorities must work with prisons in their catchment areas to carry out joint health needs assessments, agree prison healthcare improvement strategies and jointly plan and commission services (HM Prison Service and NHS Executive 1999). The ultimate test of the survey will be whether it provides a benchmark to evaluate the future effectiveness of the new policy changes.

England↗
PubMed2002

Wartime Paris, cirrhosis mortality, and the ceteris paribus assumption.

OBJECTIVE: This article critiques the ceteris paribus assumption, which tacitly sustains the epidemiologic literature's inference that the sharp decline in cirrhosis mortality observed in Paris during the Second World War derived from a sharp constriction in wine consumption. Paris's wartime circumstances deviate substantially from the "all else being equal" assumption, and at least three other hypotheses for the cirrhosis decline may be contemplated. METHOD: Historical and statistical review. RESULTS: Wartime Paris underwent tumultuous changes. Wine consumption did decline, but there were, as well, a myriad of other changes in diet and life experience, many involving new or heightened hardships, nutritional, experiential, institutional, health and mortality risks. Three competing hypotheses are presented: (1) A fraction of the candidates for cirrhosis mortality may have fallen to more sudden forms of death; (2) alcoholics, heavy drinkers and Paris's clochard subpopulation may have been differentially likely to become removed from the city's wartime population, whether by self-initiated departure, arrest and deportation, or death from other causes, even murder; and (3) there was mismeasurement in the cirrhosis mortality decline. CONCLUSIONS: The alcohol-cirrhosis connection provided the template for the alcohol research effort (now more than 20 years old) aimed at re-establishing scientific recognition of alcohol's direct alcohol-problems-generating associations and causal responsibilities. In a time given to reports of weaker associations of the alcohol-cirrhosis connection, the place and importance of the Paris curve in the wider literature, as regards that connection, remains. For this reason, the Paris findings should be subjected to as much research scrutiny as they undoubtedly deserve.

Alcohol Drinking↗
PubMedDate not supplied

Testicular hamartomas in Cowden disease.

We report a case of testicular hamartomas in association with Cowden disease. Clinical examination of the patient, a 39-year-old man, revealed a palpable mass in the right side of the scrotum. Sonographic examination showed that the mass was either a spermatocele or an epididymal cyst and that multiple hyperechoic lesions were present in both testes. On subsequent MRI, the appearance of these lesions was consistent with that of fat-containing hamartomas. Testicular biopsy was not performed, but follow-up serial sonographic examination was recommended. To our knowledge, this report is the first to describe testicular hamartomas as a probable manifestation of Cowden disease.

Adult↗
PubMedDate not supplied

Predictors of mental health service utilization in the 12 months before imprisonment: analysis of results from a national prisons survey.

OBJECTIVE: To describe the self-reported history of health service utilization and help-seeking to those who are drug-dependent in the period of time prior to imprisonment. METHOD: A cross-section survey of 3142 sentenced or remand prisoners in English prisons completed private, face-to-face interviews with trained Office for National Statistics staff covering a full structured psychiatric assessment interview. Specific questions about service utilization prior to imprisonment were included, as were questions on patterns of drug use and dependence prior to imprisonment. RESULTS: Receipt of any form of help was demographically most strongly associated with being older, white and female. Women were about twice as likely as men to report having received help for mental or emotional problems. Older age was also consistently associated with greater levels of reporting having received help, for both genders but only for use of general practitioners. Being black was strongly associated with reduced likelihood of receiving help and this was maintained after adjusting for other sociodemographic variables. Opioid dependence alone or opioid dependence with stimulant dependence, psychiatric disorder alone and probable psychosis were all most predictive of service use in the 12 months prior to imprisonment. CONCLUSIONS: In the year prior to imprisonment, the majority of mental health needs of these individual prisoners were not able to access help prior to imprisonment. Future strategies should aim for better health access before, during and after imprisonment.

Adolescent↗
PubMedDate not supplied

A review of age differences in the neurophysiology of nociception and the perceptual experience of pain.

OBJECTIVE: To better understand the nature of age differences in pain and nociception with the aging of the worlds' population. METHODS: The evidence from numerous neurophysiologic and psychological studies suggest a small, but demonstrable age-related impairment in the early warning functions of pain. The increase in pain perception threshold and the widespread change in the structure and function of peripheral and CNS nociceptive pathways may place the older person at greater risk of injury. Moreover, the reduced efficacy of endogenous analgesic systems, a decreased tolerance of pain and the slower resolution of postinjury hyperalgesia may make it more difficult for the older adult to cope, once injury has occurred. RESULTS: These age-related changes may be best conceptualized as a reduced capacity in the functional reserve of the pain system, at both ends of the intensity spectrum. DISCUSSION: The clinical implications are obvious; older persons are likely to be especially vulnerable to the negative impacts of pain and pain associated events.

Adaptation, Psychological↗