Anti-TNF alpha therapy is useful in rheumatoid arthritis and Crohn's disease: analysis of the mechanism of action predicts utility in other diseases.
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Anti-Inflammatory Agents↗
Biomedical subjects
P Taylor
Publications and source records attributed to P Taylor.
Toxins selective for subunit interfaces as probes of nicotinic acetylcholine receptor structure.
The pentameric structure of the nicotinic acetylcholine receptor with two of the five subunit interfaces serving as ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits and their ligand specificity characteristics. This problem has been approached through the study of assembly of subunits and binding characteristics of selective peptide toxins. The receptor, with its circular order of homologous subunits (alpha gamma alpha delta beta), assembles in only one arrangement, and through mutagenesis, the residues governing assembly can be ascertained. Selectivity of certain toxins is sufficient to readily distinguish between sites at the alpha gamma and alpha delta interfaces. By interchanging residues on the gamma and delta subunits, and ascertaining how they interact with the alpha-subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins, which contain two disulfide loops and 12-14 amino acids, show a 10,000-fold preference for the alpha delta over the alpha gamma subunit interface with alpha epsilon falling between the two. The waglerins, as 22-24 amino acid peptides with a single core disulfide loop, show a 2000-fold preference for alpha epsilon over the alpha gamma and alpha delta interfaces. Finally, the 6700 Da short alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alpha gamma and alpha delta interfaces over alpha epsilon. Selective mutagenesis enables one to also distinguish alpha-neurotoxin binding at the alpha gamma and alpha delta subunits. This information, when coupled with homology modeling of domains and site-directed residue modification, reveals important elements of receptor structure and conformation.
Amino Acid Sequence↗
Retinal vascular changes following supplementation with alpha-tocopherol or beta-carotene.
PURPOSE: To examine if long-term supplementation with alpha-tocopherol (AT) or beta-carotene (BC) was associated with the prevalence of vascular changes in retinal arterioles. METHODS: An end-of-trial subsample from a double-blind, placebo-controlled clinical trial designed to study the effects of alpha-tocopherol and beta-carotene on lung cancer incidence (ATBC Study). SETTING: Source population of Helsinki and the surrounding province. PARTICIPANTS: 1072 men 50-69 years old and smoking at least 5 cigarettes per day at study entry. INTERVENTIONS: Random allocation to one of four supplementation regimens: 50 mg per day alpha-tocopherol, 20 mg per day beta-carotene, both alpha-tocopherol and beta-carotene, or placebo. Median follow-up time was 6.6 years (range 5.2-8.0 years). MAIN OUTCOME MEASURE: Presence of vascular changes in retinal arterioles as determined from end-of-trial retinal color photographs. RESULTS: Retinal vascular changes were most prevalent in the AT (161 men, 62%), and in the BC (163 men, 62%) groups. The prevalence rate was lowest in the AT plus BC group (161 men, 55%), and slightly higher in the placebo group (145 men, 57%). There was no statistically significant association of either AT (OR 0.9, 95% CI 0.7-1.2) or BC (OR 1.0, 95% CI 0.8-1.3) supplementation with the prevalence of retinal vascular changes after adjusting for major risk factors. CONCLUSIONS: Supplementation with alpha-tocopherol or beta-carotene for a median of 6.6 years does not protect against retinal vascular changes among smoking males.
Aged↗
Six-year supplementation with alpha-tocopherol and beta-carotene and age-related maculopathy.
PURPOSE: Animal research and observational studies in man suggest a protective effect of antioxidant vitamins in the development of age-related maculopathy (ARM). METHODS: The ATBC study, a population-based, controlled clinical trial of alpha-tocopherol and beta carotene to prevent lung cancer, took place in Finland between 1984 and 1993. Over 29,000 smoking males aged 50 to 69 years were randomly assigned to alpha-tocopherol (AT; 50 mg/day), beta-carotene (BC; 20 mg/day), both of these, or placebo. We performed an end-of-trial ophthalmological examination on a random sample of 941 participants aged 65 years or more from two of the fourteen study areas, to discover if the five to eight-year intervention with alpha-tocopherol and/or beta-carotene had been associated with a difference in ARM prevalence. Age-related maculopathy was assessed using colour photographs of the macula. RESULTS: Altogether, 269 cases of ARM were found; there were more cases in the AT group (32%; 75/237), BC group (29%; 68/234), and combined antioxidant group (28%; 73/257) than in the placebo group (25%; 53/213). However, neither substance was significantly associated with the risk of ARM in a logistic regression analysis controlling for possible risk factors. CONCLUSIONS: No beneficial effect of long-term supplementation with alpha-tocopherol or beta-carotene on the occurrence of ARM was detected among smoking males.
Aged↗
Expression of adhesion molecules by lp(a): a potential novel mechanism for its atherogenicity.
Lp(a) is a major inherited risk factor for premature atherosclerosis. The mechanism of Lp(a) atherogenicity has not been elucidated, but likely involves both its ability to interfere with plasminogen activation and its atherogenic potential as a lipoprotein particle after receptor-mediated uptake. We demonstrate that Lp(a) stimulates production of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin in cultured human coronary artery endothelial cells (HCAEC). This effect resulted from a rise in intracellular free calcium induced by Lp(a) and could be inhibited by the intracellular calcium chelator, BAPTA/AM. The involvement of the LDL and VLDL receptors in Lp(a) activation of HCAEC were ruled out since Lp(a) induction of adhesion molecules was not prevented by an antibody (IgGC7) to the LDL receptor or by receptor-activating protein, an antagonist of ligand binding to the VLDL receptor. Addition of alpha2-macroglobulin as well as treatment with heparinase, chondroitinase ABC, and sodium chlorate did not decrease levels of VCAM-1 and E-selectin stimulated by Lp(a), suggesting that neither the low density lipoprotein receptor-related protein nor cell-surface proteoglycans are involved in Lp(a)-induced adhesion molecule production. Neither does the binding site on HCAEC responsible for adhesion molecule production by Lp(a) appear to involve plasminogen receptors, as levels of VCAM-1 and E-selectin were not significantly decreased by the addition of glu-plasminogen, the lysine analog epsilon-aminocaproic acid, or by trans-4-(aminomethyl)-cyclohexanecarboxymethylic acid (tranexamic acid), which acts by binding to the lysine binding sites carried on the kringle structures in plasminogen. In contrast, recombinant apolipoprotein (a) [r-apo(a)] competed with Lp(a) and attenuated the expression of VCAM-1 and E-selectin. In summary, we have identified a calcium-dependent interaction of Lp(a) with HCAEC capable of inducing potent surface expression of VCAM-1 and E-selectin that does not appear to involve any of the known potential Lp(a) binding sites. Because leukocyte recruitment to the vessel wall appears to represent one of the important early events in atherogenesis, this newly described endothelial cell-activating effect of Lp(a) places it at a crucial juncture in the initiation of atherogenic disease and may lead to a better understanding of the role of Lp(a) in the vascular biology of atherosclerosis.
Arteriosclerosis↗
Preliminary studies of the use of nail as a material for reconstructive or cosmetic surgery.
The purpose of this study was to assess the biocompatibility and stability of implanted nail as a preliminary step in the assessment of its potential as a material for small scale reconstructive or cosmetic surgery. Rat nails were placed subcutaneously in the back of 12 Lewis rats, which were then sacrificed in groups of 4 at 4, 8, and 12 months for macroscopic and microscopic examination of the implants. A layer of strongly adherent connective tissue, containing inflammatory cells, had formed around the nails at 4 months, but by 8 to 12 months this reaction had subsided, leaving the nails imbedded in connective tissue adhering to the dermal wall, with no evidence of implant rejection, granuloma formation, or degradation. The results suggest that nail merits further study as a surgical implant material, because of its staying power and lack of immunogenicity.
Animals↗
The nurse as patient advocate.
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Esophageal Neoplasms↗
Residues at the subunit interfaces of the nicotinic acetylcholine receptor that contribute to alpha-conotoxin M1 binding.
The two binding sites in the pentameric nicotinic acetylcholine receptor of subunit composition alpha2 beta gamma delta are formed by nonequivalent alpha-gamma and alpha-delta subunit interfaces, which produce site selectivity in the binding of agonists and antagonists. We show by sedimentation analysis that 125I-alpha-conotoxin M1 binds with high affinity to the alpha-delta subunit dimers, but not to alpha-gamma dimers, nor to alpha, gamma, and delta monomers, a finding consistent with alpha-conotoxin M1 selectivity for the alpha delta interface in the intact receptor measured by competition against alpha-bungarotoxin binding. We also extend previous identification of alpha-conotoxin M1 determinants in the gamma and delta subunits to the alpha subunit interface by mutagenesis of conserved residues in the alpha subunit. Most mutations of the alpha subunit affect affinity similarly at the two sites, but Tyr93Phe, Val188Lys, Tyr190Thr, Tyr198Thr, and Asp152Asn affect affinity in a site-selective manner. Mutant cycle analysis reveals only weak or no interactions between mutant alpha and non-alpha subunits, indicating that side chains of the alpha subunit do not interact with those of the gamma or delta subunits in stabilizing alpha-conotoxin M1. The overall findings suggest different binding configurations of alpha-conotoxin M1 at the alpha-delta and alpha-gamma binding interfaces.
Amino Acid Sequence↗
School based bicycle safety education and bicycle injuries in children: a case-control study.
OBJECTIVES: To evaluate possible benefits of a school based bicycle safety education program ("Bike Ed") on the risk of bicycle injury in children. METHODS: A population based case-control study was undertaken in a region of Melbourne, Australia. Cases were children presenting at hospital emergency departments with injuries received while riding bicycles. Controls were recruited by calling randomly selected telephone numbers. Data were collected by personal interview. RESULTS: Analysis, based on 148 cases and 130 controls aged 9 to 14 years, showed no evidence of a protective effect and suggested a possible harmful effect of exposure to the bicycle safety course (odds ratio (OR) 1.64, 95% confidence interval (CI) 0.98 to 2.75). This association was not substantially altered by adjustment for sex, age, socioeconomic status, and exposure, measured as time or distance travelled. Subgroup analysis indicated that the association was strongest in boys (OR 2.0, 95% CI 1.1 to 3.8), younger children, children from families with lower parental education levels, and children lacking other family members who bicycle. CONCLUSIONS: It is concluded that this educational intervention does not reduce the risk of bicycle injury in children and may possibly produce harmful effects in some children, perhaps due to inadvertent encouragement of risk taking or of bicycling with inadequate supervision.
Case-Control Studies↗
Telemedicine in the NHS for the millennium and beyond.
This article defines telemedicine, discusses evidence of its effectiveness, looks at its advantages and disadvantages (and barriers to implementation), and considers its role in the NHS for the millennium and beyond.
Diffusion of Innovation↗
Measuring line-related bacteraemia in intensive care patients.
All patients with an intravascular device in the intensive care units at Prince of Wales and Prince Henry Hospitals between July and September 1995 were followed for the development of line-related bacteraemia per 1000 line days. Cases of sepsis related to an intravascular device were identified using a case definition which incorporated clinical and laboratory parameters. Data were collected prospectively for the dates of insertion and removal of devices for 188 lines inserted in 69 patients. The majority (90%) of lines had both date of insertion and removal documented allowing the calculation of the rate of primary bacteraemia over 832 at-risk line days. Multiple concurrent lines were more common (88.4%) than single lines, with one central and one or two peripheral lines being the most common (42.3%) combination. Five cases of bacteraemia were diagnosed clinically and confirmed microbiologically. The incidence density of primary bacteraemia was 6.0 per 1000 line days (CI 95% 5.7-6.3).
APACHE↗
Development of acetylcholinesterase inhibitors in the therapy of Alzheimer's disease.
Acetylcholinesterase (AChE) inhibitors were first administered in Europe to human subjects in the 1860s, and synthetic derivatives of the natural alkaloid inhibitors were developed in the 1930s to modulate peripheral cholinergic function. However, only within the last decade have these agents been systematically studied for therapy of central cholinergic deficits. This time interval parallels the cloning of the gene and determination of the structure of the target molecule, AChE. Because AChE in mammals is encoded by a single gene and the portion of the gene encoding the catalytic domain is invariant, selectivity of action can be achieved only by altering parameters of disposition and pharmacokinetics of action of the inhibitor rather than its specificity for particular AChE isozymes in various regions of the CNS. This article describes the mechanism of action of short-acting, carbamoylating, and phosphorylating inhibitors of cholinesterase and suggests possible strategies for enhancing therapeutic efficacy.
Alzheimer Disease↗
A survey of research in telemedicine. 1: Telemedicine systems.
Published work in telemedicine has been surveyed in order to consider the range of current research, highlight some pitfalls and point out areas where it seems that more work is required. This article deals with tests of the safety and efficacy of telemedicine systems. This work can be seen as moving through three phases: first, identify the technical specification of equipment required for the particular telemedicine application; second, test that this is appropriate in particular settings; third, establish a set of standards and guidelines to ensure that the telemedicine system is used to the best advantage. Work in teleradiology seems to be in the second phase. Work in teledermatology, for example, is still in the first phase. Telemedicine is an important and growing area of academic research. The quality of the research ought also to be increasing. While there have been a number of well designed, robust studies with clear conclusions that show the value of telemedicine in certain settings, much more remains to be done.
Computer Communication Networks↗
A survey of research in telemedicine. 2: Telemedicine services.
This article deals with research which attempts to demonstrate the value of health care delivered via telemedicine. A great variety of telemedicine services have been proposed. Much of the published work concentrates on the power of the technology and the content and quality of interaction it supports. There are other parameters to be considered in assessing telemedicine as a component of a health-care system, parameters which in practice determine the nature of the service being provided. Despite the fact that much work in telemedicine is published as short accounts of pilot projects, there is little research that explicitly addresses the difficulties involved in setting up new telemedicine services. Some studies have been performed which attempt to evaluate telemedicine services, but relatively few studies have been able to collect the data required to provide an unambiguous demonstration of their value.
Consumer Behavior↗
Prognosis of patients with lung cancer found in a single chest radiograph screening.
BACKGROUND: The prognosis of patients with lung cancer is better when the diagnosis is made early; the disease is localized, and radical surgery is possible. Screening for lung cancer with mass radiography or sputum cytology should contribute to a more favorable prognosis. Large-scale screening studies have improved the survival rates for lung cancer but have yielded no reduction in mortality rates. METHODS: The histologic types, stages, treatments, and survival rates were studied in 93 men who were found to have lung cancer in a single chest radiograph screening of more than 33,000 men who smoked and were 50 to 69 years old ("screened cases"), and in 239 men of the same age range whose lung cancer was detected through ordinary health care system ("other cases") during the screening period. RESULTS: The distribution of the histology was similar in the two groups, but screening detected more instances of early-stage disease that were resectable more often than in the other group (37 vs 19%). The 5-year survival rate for men in the screened cases was 19%, and that of men in the other cases was 10% (relative risk, 0.65; 95% confidence interval [CI], 0.50 to 0.84). The survival rate of men in the screened cases remained significantly higher than that of men in the other cases even after adjustments for age, smoking status, histology, stage of the disease, and resectability of the disease (relative risk, 0.74; 95% CI, 0.55 to 1.00). CONCLUSIONS: According to this study, chest radiograph screening might improve the prognosis of lung cancer. Our results are, however, subject to many factors that were only partially controlled for, and they should be interpreted cautiously.
Adenocarcinoma↗
Recovery of human mycoplasmas.
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Bacteriological Techniques↗
Medical significance of mycoplasmas.
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Animals↗
DSM-IV intermittent explosive disorder: a report of 27 cases.
BACKGROUND: The authors' objective was to provide data regarding the demographic, phenomenological, course of illness, associated psychiatric and medical comorbidity, family history, and psychiatric treatment response characteristics of rigorously diagnosed subjects who met DSM-IV criteria for intermittent explosive disorder. METHOD: Twenty-seven subjects meeting DSM-IV criteria for a current or past history of intermittent explosive disorder were given structured diagnostic interviews. The subjects' medical histories, family histories of psychiatric disorders, and responses to psychiatric treatments were also assessed. RESULTS: Most subjects described their intermittent explosive disorder symptoms as very distressing and/or highly problematic. All 27 subjects described aggressive impulses prior to their aggressive acts. Of 24 subjects who were systematically queried, 21 (88%) experienced tension with the impulses; 18 (75%), relief with the aggressive acts; and 11 (48%), pleasure with the acts. Most subjects stated that their aggressive impulses and acts were also associated with affective symptoms, particularly changes in mood and energy level. Twenty-five (93%) subjects had lifetime DSM-IV diagnoses of mood disorders; 13 (48%), substance use disorders; 13 (48%), anxiety disorders; 6 (22%), eating disorders; and 12 (44%), an impulse-control disorder other than intermittent explosive disorder. Subjects also displayed high rates of comorbid migraine headaches. First-degree relatives displayed high rates of mood, substance use, and impulse-control disorders. Twelve (60%) of 20 subjects receiving monotherapy with an antidepressant or a mood stabilizer reported moderate or marked reduction of their aggressive impulses and/or episodes. CONCLUSION: Intermittent explosive disorder appears to be a bona fide impulse-control disorder that may be related to mood disorder and may represent another form of affective spectrum disorder.
Adolescent↗