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Biomedical subjects

N Walker

Publications and source records attributed to N Walker.

At least 37 records · Page 2Linked to original sources
PubMed1999

A catalytic mechanism for caspase-1 and for bimodal inhibition of caspase-1 by activated aspartic ketones.

We have evaluated 619 aspartic ketones with 9 different types of prime-side groups (acyloxymethyl, aryloxymethyl, arylthiomethyl, alkylthiomethyl, acylamino-oxymethyl, sulfonylaminomethyl, alpha-ketoamide, alpha-(1-phenyl-3-trifluoromethyl-pyrazol-5-yl)oxymethyl (PTP), and aliphatic ketones) as inhibitors of caspase-1. The inhibitory behaviors could be classified as reversible, inactivating, or bimodal (i.e. reversible inhibition followed by slow inactivation) based on the kinetically observed formation of reversible thiohemiketal complexes and conversion to an irreversible thioether adduct, and the mechanism of any given ketone was only poorly predictable on the basis of leaving group structure and chemistry. Among 201 bimodal inhibitors, the rate of conversion of the reversible thiohemiketal complex to the inactive thioether (k(i)) was strictly first-order, consistent with direct conversion of the thiohemiketal to the thioether with no intermediate collapse to free ketone and thiolate. We have examined 22 crystallographic structures of caspase-1 complexed as a thiohemiketal with the inhibitors from 8 different ketone classes, and found the Cys285S-C-C(alpha)-leaving group dihedral angle to be near either to 60 degrees or to 180 degrees. Only the 180 degrees conformation was permissive for SN2 displacement of the leaving group and, furthermore, positioned His237Ndelta to stabilize developing charge on the leaving group. Among these structures and 19 additional complexes, all showed a strong interaction between His237Ndelta and the ketone or thiohemiketal oxygen. We therefore propose a proteolytic mechanism for caspase-1 involving polarization of the scissile carbonyl by the His237 imidazolium group. During thiohemiketal/thioether conversion (but probably not during peptide hydrolysis), the leaving group is stabilized by the His237 imidazolium.

Caspase 1↗
PubMed1999

Carbon monoxide and cerebral microvascular tone in newborn pigs.

The present study addresses the hypothesis that CO produced from endogenous heme oxygenase (HO) can dilate newborn cerebral arterioles. HO-2 protein was highly expressed in large and small blood vessels, as well as parenchyma, of newborn pig cerebrum. Topically applied CO dose-dependently dilated piglet pial arterioles in vivo over the range 10(-11)-10(-9) M (maximal response). CO-induced cerebrovascular dilation was abolished by treatment with the Ca2+-activated K+ channel inhibitors tetraethylammonium chloride and iberiotoxin. The HO substrate heme-L-lysinate also produced tetraethylammonium-inhibitable, dose-dependent dilation from 5 x 10(-8) to 5 x 10(-7) M (maximal). The HO inhibitor chromium mesoporphyrin blocked dilation of pial arterioles in response to heme-L-lysinate. In addition to inhibiting dilation to heme-L-lysinate, chromium mesoporphyrin also blocked pial arteriolar dilations in response to hypoxia but did not alter responses to hypercapnia or isoproterenol. We conclude that CO dilates pial arterioles via activation of Ca2+-activated K+ channels and that endogenous HO-2 potentially can produce sufficient CO to produce the dilation.

Animals↗
PubMed1998

Tissue distribution and cellular localization of the levocabastine-sensitive neurotensin receptor mRNA in adult rat brain.

The aim of this study was to determine the regional and cellular distribution of the neurotensin type 2 receptor (NT-2R) mRNA in the rat brain. Using a radioactive in situ hybridization approach, the distribution of NT-2R transcripts was quantified from autoradiograms, and the cellular localization was examined in liquid emulsions. In rat brain, NT-2R mRNAs, are more widespread than the neurotensin type 1 receptor mRNA. NT-2R transcripts are diffusely distributed throughout the brain, with higher quantities found in the pia mater, the ventricles, the subfornical organ, the subiculum, the substantia nigra, the ventral tegmental area, the superior colliculus, the periaqueductal gray matter, the Purkinje cells and certain hypothalamic and brainstem nuclei. At the cellular level, silver grains appear to be concentrated on glia, neurons and ependymal cells, such as cell bodies of the glia-rich corpus callosum, Purkinje neurons in the cerebellum and ependymal cells lining the ventricles. In contrast, the thalamus and the amygdala contain low amounts of NT-2R mRNA. We discuss the anatomical location of NT-2R mRNA in relation to possible roles for this new receptor subtype.

Animals↗
PubMed1998

Intra-articular corticosteroids in the treatment of juvenile rheumatoid arthritis.

Intra-articular injection of long-acting insoluble corticosteroids produces rapid resolution of active arthritis in nearly all injected joints. Almost all of our information on the use of intra-articular corticosteroids in children comes from observational or retrospective analyses or, by inference, from studies in adult patients with arthritis. The duration of response has been found to vary according to the subtype of arthritis, the dose of injected steroids, the accuracy of injection, the duration of disease prior to injection, and possibly the age of the patient. Although the duration of follow-up in most studies has been short, intra-articular steroid therapy seems to be remarkably free of clinically important detrimental effects. Side effects are relatively uncommon and include subcutaneous atrophy and radiologically detectable structural changes or calcification. There is transient suppression of endogenous cortisol production, which may not be clinically important. Although intra-articular steroid therapy is most effective in pauciarticular juvenile rheumatoid arthritis, there are still no solid data to indicate whether it should be used earlier in the course of the disease instead of or along with systemic anti-inflammatory therapy. It has been suggested that repeated injection of the same joint decreases the likelihood of a favorable response. There are still many unanswered questions about how steroids exert their beneficial effects. Newer imaging techniques promise to provide insight into the mechanism of action and possibly to a more informed basis for the use of intra-articular steroids.

Adrenal Cortex Hormones↗
PubMed1998

Functional limitations to daily living tasks in the aged: a focus group analysis.

We assessed constraints on daily living of 59 healthy, active adults 65-88 years of age in focus group interviews. Individual comments about specific problems were coded along the dimensions of (a) the locus of the problem (motor, visual, auditory, cognitive, external, or health limitations); (b) the activity involved (e.g., transportation, leisure, housekeeping); (c) whether the problem was attributable to task difficulty or the perception of risk; and (d) response to limitations (perseverance, cessation, compensation, or self-improvement). The data provide information about the types of difficulties encountered in everyday activities as well as the way in which individuals respond to such difficulties. Each comment was also coded in terms of whether it was remediable via training, design changes, or some combination of the two. More than half of the problems that were reported had the potential to be improved in some way, thus providing direction for future research in human factors and aging. Actual or potential applications of this research include identifying problems and difficulties that older adults encounter in daily activities such as transportation and leisure; more specifically, determining the degree to which such problems are potentially remediable by human factors solutions. Applications of this research also include understanding the types of systems, products, and technologies that older adults interact with currently, or are interested in learning to use.

Activities of Daily Living↗
PubMed1998

Effects of variation in system responsiveness on user performance in virtual environments.

System responsiveness (SR) is defined as the elapsed time until a system responds to user control. SR fluctuates over time, so it must be described statistically with mean (MSR) and standard deviation (SDSR). In this paper, we examine SR in virtual environments (VEs), outlining its components and methods of experimental measurement and manipulation. Three studies of MSR and SDSR effects on performance of grasp and placement tasks are then presented. The studies used within-subjects designs with 11, 12, and 10 participants, respectively. Results showed that SDSR affected performance only if it was above 82 ms. Placement required more frequent visual feedback and was more sensitive to SR. We infer that VE designers need not tightly control SDSR and may wish to vary SR control based on required visual feedback frequency. These results may be used to improve the human-computer interface in a wide range of interactive graphical applications, including scientific visualization, training, mental health, and entertainment.

Data Display↗
PubMed1997

Partnership nursing home care for dementia: the Glasgow experience--one-year follow-up.

The outcome of the transfer of 60 elderly patients suffering from dementia from hospital to nursing home care under a partnership contract was reviewed at 6 and 12 months following transfer. The nursing home population had fared badly compared with patients remaining in hospital during the first 3 months. This difference was less evident at 6 months follow-up and had disappeared at 12 months follow-up. It seems that a partnership agreement such as this can deliver a quality of health care at least as good as hospital treatment as long as the transfer is handled carefully.

Aged↗
PubMed1997

Partnership nursing home care for dementia: the Glasgow experience--one-year follow-up.

The outcome of the transfer of 60 elderly patients suffering from dementia from hospital to nursing home care under a partnership contract was reviewed at 6 and 12 months following transfer. The nursing home population had fared badly compared with patients remaining in hospital during the first 3 months. This difference was less evident at 6 months follow-up and had disappeared at 12 months follow-up. It seems that a partnership agreement such as this can deliver a quality of health care at least as good as hospital treatment as long the transfer is handled carefully.

Aged↗
PubMed1997

Chronic pain/dysaesthesiae in spinal cord injury patients: results of a multicentre study.

The aim of the multicentre study entitled 'Description and Documentation of Painful States in Spinal Cord Injury Patients', in addition to the description and documentation of chronic pain and stressful dysaesthesiae in SCI patients, was the search for correlations between these symptoms and medical and psychosocial variables. To this end, the sample was selected to be as representative as possible. All patients referred for in-patient or out-patient treatment at the centres taking part were enrolled in the study in order of presentation, providing they gave consent and met the inclusion criteria. Psychosocial, medical and demographic data were elicited by a standardized battery of questions and a standardized physical examination, as were any chronic pain/dysaesthesiae (P/D) present in any localization. Among 901 patients, 34% had no chronic pain or dysaesthesiae, 50% had pain only, 11% had painful dysaesthesiae and 5%, non-painful but chronic and distressing dysaesthesiae. The intensity of P/D was noted as seven or more on a 10 cm visual analogue scale by 61% of the patients affected and was experienced as rather or very distressing in 75% of cases. Most (86%) P/D were located below the spinal lesion or in the transition zone. There were significant correlations between the presence of P/D and age on questioning and at onset of the paraplegia/tetraplegia, problems with rectal paralysis, expectations of life as a paraplegic/tetraplegic, and subjective assessment of changes in working life. Highly significant correlations were found with subjective distress resulting of paraplegia/tetraplegia as such, depressed mood and psychosomatic disturbances of wellbeing. Overall, among the selected variables of our study, we found that correlations between P/D and psychosocial variables were more frequent and closer than those between P/D and medical variables.

Adolescent↗
PubMed1997

Age-related differences in movement control: adjusting submovement structure to optimize performance.

In this experiment older and younger adults were compared on their ability to position a cursor with an electromechanical mouse. Distance of the movement, size of the target, and relative emphasis on the speed or accuracy of the movement were manipulated. The study was designed to isolate and evaluate the effects of age-related differences in the noise-to-force ratio, perceptual feedback efficiency, strategy differences, and the ability to produce force as explanations for age-related differences in movement control. This was done by using two types of movement tasks and by analyzing movement performance according to stages of movement. The study showed that all four factors, when isolated, are significantly different for the two age groups. However, in the task component where all factors could simultaneously affect performance, the age-related difference in performance was less than the difference in either the measure of noise-to-force ratio or perceptual efficiency. Analysis of the submovement structure revealed how older adults compensated for the greater noise and less perceptual efficiency by adjusting the velocity and number of submovements. These findings are discussed in light of the optimized submovement model.

Adolescent↗
PubMed1997

Campylobacteriosis in New Zealand: results of a case-control study.

STUDY OBJECTIVE: To identify and assess the contributions of major risk factors for campylobacteriosis in New Zealand. DESIGN: Case-control study. Home interviews were conducted over nine months using a standardised questionnaire to assess recent food consumption and other exposures. SETTING: Four centres in New Zealand with high notification rates of campylobacter infections--Auckland, Hamilton, Wellington, and Christchurch. PARTICIPANTS: Case patients were 621 people notified between 1 June 1994 and 28 February 1995 as having campylobacter infection. Control subjects were selected randomly from telephone directories, and were matched 1:1 with case patients in relation to sex, age group, and home telephone prefix. RESULTS: Risk of campylobacteriosis was strongly associated with recent consumption of raw or undercooked chicken (matched odds ratio 4.52, 95% confidence interval 2.88, 7.10). There was also an increased risk with chicken eaten in restaurants (matched odds ratio 3.85; 2.52, 5.88). Recent consumption of baked or roasted chicken seemed to be protective. Campylobacteriosis was also associated with recent overseas travel, rainwater as a source of water at home, consumption of raw dairy products, and contact with puppies and cattle, particularly calves. CONCLUSIONS: Improperly cooked chicken seems to be associated with a large proportion of campylobacteriosis in New Zealand. Thorough cooking of chicken in homes and restaurants could reduce considerably the incidence of this disease.

Campylobacter Infections↗
PubMed1997

Aging and decision making: driving-related problem solving.

We examined age-related effects on decision making in a task environment familiar to most younger and older adults. Participants made route-selection decisions in real time. Participants received information about traffic density and expected speed limits of main and alternative routes, from which they determined the optimality of their present route versus alternative routes. The experiment evaluated the effects of information type, amount of congestion, alternative route speed limit, and age on speed and quality of decision making. Measures of optimal route selection revealed main effects of alternative route speed limit, congestion level, and message type, but there was not a main effect of age, and age did not interact with any variable. In terms of decision speed (but not quality of decision making), older participants were slower, and age interacted with alternative route speed and with message type. The data are interpreted in relation to previous data examining everyday problem solving and aging.

Adolescent↗
PubMed1996

The nuclear channel system in endometrial adenocarcinoma exposed to medroxyprogesterone acetate.

The nuclear channel system (NCS), giant mitochondria and subnuclear glycogen form a triad of ultrastructural features observed in normal human endometrial epithelium in response to progestational steroids. Both the giant mitochondria and subnuclear glycogen have been described in endometrial adenocarcinoma, but the NCS has not. This article reports the development of the NCS in adenocarcinoma treated with medroxyprogesterone acetate. Previous studies suggest that the NCS in normal tissue is a response to the acyl group in the 17-beta position of the D-ring of some progestational steroids, such as medroxyprogesterone acetate. Medroxyprogesterone acetate was administered to 12 postmenopausal women with endometrial adenocarcinoma. Hysterectomies were performed 8 to 20 days after treatment. Pretreatment specimens were also obtained on 8 of the 12 patients. Using standard electron microscopy procedures, light microscopy on plastic semithin sections was first used to confirm the presence of tumor. Thin sections of malignant endometrium were prepared and evaluated ultrastructurally for progestational alterations. Abnormal giant mitochondria and subnuclear glycogen were found both before and after treatment. The third element of the triad, the NCS, was not observed in any of the available pretreatment biopsies, but was seen in three of the treated specimens. Thus it appears that the NCS is a response to the given progesterone therapy.

Adenocarcinoma↗