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Biomedical subjects

T Harrison

Publications and source records attributed to T Harrison.

At least 37 records · Page 2Linked to original sources
PubMed2001

Barriers that further disablement: a study of survivors of polio.

This exploratory study of polio survivors was undertaken to clarify current level of function, comorbidity, and secondary conditions and to discover the relationships between perceived barriers to health, functional limitation, comorbidity, secondary conditions, and disability in a small convenience sample. Given the underrepresentation of research in the literature explaining the health status, perceived function, and barriers to health in this disabled population, a descriptive study with correlation was conducted. Thirty-one individuals living with the effects of polio were surveyed. Disability was correlated with perceived barriers to health but not with functional limitations, comorbidity, or secondary conditions. Secondary conditions were correlated with the number of years living with the illness. The findings support a model of disablement and allostatic load. Further research is needed to test these models and to provide direction for nurses caring for those aging with the effects of polio.

Activities of Daily Living↗
PubMed2000

L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity.

Progressive cerebral amyloid beta-protein (A beta) deposition is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). Elevated levels of A beta(42) peptide formation have been linked to early-onset familial AD-causing gene mutations in the amyloid beta-protein precursor (A beta PP) and the presenilins. Sequential cleavage of A beta PP by the beta- and gamma-secretases generates the N- and C-termini of the A beta peptide, making both the beta- and gamma-secretase enzymes potential therapeutic targets for AD. The identity of the A beta PP gamma-secretase and the mechanism by which the C-termini of A beta are formed remain uncertain, although it has been suggested that the presenilins themselves are novel intramembrane-cleaving gamma-secretases of the aspartyl protease class [Wolfe, M. S., Xia, W., Ostaszewski, B. L., Diehl, T. S., Kimberly, W. T., and Selkoe, D. J. (1999) Nature 398, 513-517]. In this study we report the identification of L-685,458 as a structurally novel inhibitor of A beta PP gamma-secretase activity, with a similar potency for inhibition of A beta(42) and A beta(40) peptides. This compound contains an hydroxyethylene dipeptide isostere which suggests that it could function as a transition state analogue mimic of an aspartyl protease. The preferred stereochemistry of the hydroxyethylene dipeptide isostere was found to be the opposite to that required for inhibition of the HIV-1 aspartyl protease, a factor which may contribute to the observed specificity of this compound. Specific and potent inhibitors of A beta PP gamma-secretase activity such as L-685,458 will enable important advances toward the identification and elucidation of the mechanism of action of this enigmatic protease.

Amino Acid Sequence↗
PubMed2000

Vacuolar uptake of host components, and a role for cholesterol and sphingomyelin in malarial infection.

Erythrocytes, which are incapable of endocytosis or phagocytosis, can be infected by the malaria parasite Plasmodium falciparum. We find that a transmembrane protein (Duffy), glycosylphosphatidylinositol (GPI)-anchored and cytoplasmic proteins, associated with detergent-resistant membranes (DRMs) that are characteristic of microdomains in host cell membranes, are internalized by vacuolar parasites, while the major integral membrane and cytoskeletal proteins are not. The internalized host proteins and a plasmodial transmembrane resident parasitophorous vacuolar membrane (PVM) protein are detected in DRMs associated with vacuolar parasites. This is the first report of a host transmembrane protein being recruited into an apicomplexan vacuole and of the presence of vacuolar DRMs; it establishes that integral association does not preclude protein internalization into the P.FALCIPARUM: vacuole. Rather, as shown for Duffy, intracellular accumulation occurs at the same rate as that seen for a DRM-associated GPI-anchored protein. Furthermore, novel mechanisms regulated by the DRM lipids, sphingomyelin and cholesterol, mediate (i) the uptake of host DRM proteins and (ii) maintenance of the intracellular vacuole in the non-endocytic red cell, which may have implications for intracellular parasitism and pathogenesis.

Animals↗
PubMed2000

Pharmacological blockade or genetic deletion of substance P (NK(1)) receptors attenuates neonatal vocalisation in guinea-pigs and mice.

The regulation of stress-induced vocalisations by central NK(1) receptors was investigated using pharmacological antagonists in guinea-pigs, a species with human-like NK(1) receptors, and transgenic NK1R-/- mice. In guinea-pigs, i.c.v. infusion of the selective substance P agonist GR73632 (0.1 nmol) elicited a pronounced vocalisation response that was blocked enantioselectively by the NK(1) receptor antagonists CP-99,994 and L-733,060 (0.1-10 mg/kg). GR73632-induced vocalisations were also markedly attenuated by the antidepressant drugs imipramine and fluoxetine (30 mg/kg), but not by the benzodiazepine anxiolytic diazepam (3 mg/kg) or the 5-HT(1A) agonist buspirone (10 mg/kg). Similarly, vocalisations in guinea-pig pups separated from their mothers were blocked enantioselectively by the highly brain-penetrant NK(1) receptor antagonists L-733,060 and GR205171 (ID(50) 3 mg/kg), but not by the poorly brain-penetrant compounds LY303870 and CGP49823 (30 mg/kg). Separation-induced vocalisations were also blocked by the anxiolytic drugs diazepam, chlordiazepoxide and buspirone (ID(50) 0.5-1 mg/kg), and by the antidepressant drugs phenelzine, imipramine, fluoxetine and venlafaxine (ID(50) 3-8 mg/kg). In normal mouse pups, GR205171 attenuated neonatal vocalisations when administered at a high dose (30 mg/kg) only, consistent with its lower affinity for the rat than the guinea-pig NK(1) receptor. Ultrasound calls in NK1R-/- mouse pups were markedly reduced compared with those in WT pups, confirming the specific involvement of NK(1) receptors in the regulation of vocalisation. These observations suggest that centrally-acting NK(1) receptor antagonists may have clinical utility in the treatment of a range of anxiety and mood disorders.

Animals↗
PubMed2000

Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1.

Cleavage of amyloid precursor protein (APP) by the beta- and gamma-secretases generates the amino and carboxy termini, respectively, of the A beta amyloidogenic peptides A beta40 and A beta42--the major constituents of the amyloid plaques in the brain parenchyma of Alzheimer's disease patients. There is evidence that the polytopic membrane-spanning proteins, presenilin 1 and 2 (PS1 and PS2), are important determinants of gamma-secretase activity: mutations in PS1 and PS2 that are associated with early-onset familial Alzheimer's disease increase the production of A beta42 (refs 4-6), the more amyloidogenic peptide; gamma-secretase activity is reduced in neuronal cultures derived from PS1-deficient mouse embryos; and directed mutagenesis of two conserved aspartates in transmembrane segments of PS1 inactivates the ability of gamma-secretase to catalyse processing of APP within its transmembrane domain. It is unknown, however, whether PS1 (which has little or no homology to any known aspartyl protease) is itself a transmembrane aspartyl protease or a gamma-secretase cofactor, or helps to colocalize gamma-secretase and APP. Here we report photoaffinity labelling of PS1 (and PS2) by potent gamma-secretase inhibitors that were designed to function as transition state analogue inhibitors directed to the active site of an aspartyl protease. This observation indicates that PS1 (and PS2) may contain the active site of gamma-secretase. Interestingly, the intact, single-chain form of wild-type PS1 is not labelled by an active-site-directed photoaffinity probe, suggesting that intact wild-type PS1 may be an aspartyl protease zymogen.

Alzheimer Disease↗
PubMed2000

Etomidate versus succinylcholine for intubation in an air medical setting.

The objective was to compare rates of successful endotracheal intubation (ETI) and requirement for multiple ETI attempts in patients receiving etomidate (ETOM) versus succinylcholine (SUX). This retrospective study analyzed adults in whom oral ETI was attempted by a helicopter EMS (HEMS) service between July 1997 to July 1999. Data were from records of the HEMS service, which uses a RN/EMTP crew; analysis was with chi-square and logistic regression (P = .05). ETI was successful in 269 (97.8%) of 275 patients, with multiple attempts occurring in 54 (20.1%) of 269. Success rates for SUX (209 of 213, 98.1%) and ETOM (60 of 62, 96.8%) were similar (P = .62). However, of 60 ETOM patients successfully intubated, 7 (11.7%) required rescue succinylcholine. When these patients are tallied as ETOM failures and SUX successes, resultant success rates for ETOM (86.9%) and SUX (98.2%) are different (P = .001). ETOM patients were more likely (P = .004) than SUX patients to require multiple attempts (33.3% versus 16.3%). ETI success rates were high in patients receiving SUX or ETOM as primary adjuncts for airway control, but initial success was more likely with SUX, and ETOM patients were more likely to require multiple attempts.

Adolescent↗
PubMed2000

Rationalised prescribing for community acquired pneumonia: a closed loop audit.

AIMS: To audit the management of community acquired pneumonia before and after the introduction of a protocol. To determine the aetiology of pneumonia using routine investigations and polymerase chain reaction (PCR). METHODS: Retrospective and prospective audit following the introduction of a management protocol. Prospective cases were investigated routinely and with PCR on blood and nasopharyngeal aspirate. RESULTS: There was a significant increase in rational prescribing following introduction of the protocol with 75% of children receiving intravenous penicillin or erythromycin compared with 26% beforehand. Of 89 children in the prospective group, 51 microbiological diagnoses were achieved in 48 children. Seven children had Streptococcus pneumoniae infection, 14 had Mycoplasma infection, six had pertussis, and one had Chlamydia pneumoniae infection. Twenty three children had a viral cause of which respiratory syncytial virus was commonest. CONCLUSIONS: Introduction of the protocol led to improved prescribing. PCR increased the diagnostic yield and the results support the management protocol.

Adolescent↗
PubMed2000

Sex, social class, and estimating IQ: middle-class male subjects rate themselves most intelligent.

153 sociology students specified parental occupation and job status before estimating their own and their parents' overall IQ. Male subjects, as predicted, gave a higher mean self-estimated score to themselves than did female subjects (113 vs 106). Fathers were awarded higher IQ scores than mothers (114 vs 107). Male subjects who had mothers in a higher social class gave themselves the highest mean score.

Adolescent↗
PubMed2000

A cluster of cases of legionnaires' disease associated with exposure to a spa pool on display.

Interviews with four apparently sporadic cases of legionnaires' disease identified by laboratory reporting in one health district revealed that three of the four cases had been exposed to a new design of spa pool on display at a retail outlet. The fourth case had been exposed to the same design of spa pool in a private home. None had bathed in the spa pool. Legionella pneumophila serogroup 1 mAB subgroup 'Philadelphia' was isolated from samples taken from both spa pools. The display pool had not been maintained as recommended for a public spa pool in use by bathers. Revised maintenance instructions were issued to all purchasers of these spa pools in the United Kingdom (UK) and overseas. Patients may not remember specific exposures; scrutiny of activity diaries helped to identify exposure to a common location. Even when not in use by bathers, spa pools on display can be a source of legionella infection and should be maintained according to current hygiene guidelines.

Biofilms↗
PubMed1999

Taxonomy and phylogenetic relationships of early Miocene catarrhines from Sihong, China.

Paleontological investigations at sites in Sihong County, Jiangsu Province, China since 1981 have yielded a sizeable collection of previously undescribed fossil catarrhines from the Xiacaowan Formation. The associated vertebrate fauna indicates a late early Miocene age (correlating with MN 4, late Orleanian of Europe, approximately 17-18 Ma), which establishes the Sihong primates as the earliest known catarrhines from Eurasia. The fossil primates are assigned to two species: Dionysopithecus shuangouensis Li, 1978 and Platodontopithecus jianghuaiensis Gu & Lin, 1983. Although the new material from Sihong consists mainly of isolated teeth, it does provide important new information on the anatomy of Dionysopithecus and Platodontopithecus that helps to clarify their phylogenetic and taxonomic status. Previous studies have suggested that the Sihong catarrhines might be closely related to the proconsulids from the early Miocene of East Africa. However, with more extensive material available for comparison, the Sihong primates can now be shown to share a number of key derived features with pliopithecids. This new evidence helps to resolve a longstanding problem concerning the origins of the Pliopithecidae. It was previously considered that specialized pliopithecids migrated into Europe during MN 5, originating from an unknown antecedent and location in Africa. Recognition that the Sihong primates have affinities with pliopithecids, but are more primitive, suggests that the initial differentiation and diversification of the clade may have taken place in Asia rather than Africa. The earliest Eurasian catarrhines probably migrated into tropical Asia as part of a major faunal interchange with Africa that occurred during MN 3.

Animals↗
PubMed1999

Culture-positive Bartonella quintana endocarditis.

A 50-year-old alcoholic man with a 1-year history of pyrexia of unknown origin was admitted with symptoms of endocarditis. Large vegetations on his mitral and aortic valve were found on echocardiography. Using the Bactec 9240 system. Bartonella quintana could be grown from two culture sets of blood collected before the start of antimicrobial therapy. This is the first case report of culture-proven bartonella infection in the UK. and is noteworthy because Bartonella quintana was detected in conventional blood culture systems after prolonged incubation.

Bacteremia↗
PubMed1999

Automated erythrocytapheresis in the treatment of severe falciparum malaria.

Removal of parasitized erythrocytes is generally considered to be of value as adjunctive therapy in severe falciparum malaria with high parasitaemia. This is commonly achieved by exchange transfusion. We describe three cases of severe falciparum malaria treated by automated erythrocytapheresis (red cell exchange) in addition to quinine and conventional supportive therapy. Erythrocytapheresis consists of removal of the red-cell fraction by apheresis. Plasma, leukocyte and platelet fractions are returned to the patient. In all cases, dramatic reduction in parasitaemia was achieved within 2 h with subsequent complete clinical recovery. Erythrocytapheresis has significant advantages over exchange transfusion in terms of speed, efficiency, haemodynamic stability and retention of plasma components such as clotting factors and may thus represent an improvement in adjunctive therapy for severe malaria.

Adult↗
PubMed1999

The built environment as a component of quality care: understanding and including the patient's perspective.

BACKGROUND: Although there has been little systematic assessment of how the built environment of health care facilities affects the quality of care, the built environment is a major element of structure of care--one of three facets of quality. Yet in contrast to the growing trend of using consumer perceptions of both processes and outcomes of care in QI activities, quality assessments of the structure of care do not currently rely on patient feedback. PURPOSE OF PROJECT: During the initial phase of a multiphase project, nine focus groups were conducted in 1997 to identify the salient dimensions of experience from the patient's perspective. The content of these focus groups guided the development of assessment tools in the second phase of the project, which began in February 1998. FINDINGS: Participants in three focus groups that were held in each of three settings--ambulatory care, acute care, and long term care--described in detail a variety of reactions to the built environment. Analysis revealed eight consistent themes in what patients and family member consumers look for in the built environment of health care. In all three settings, they want an environment, for example, that facilitates a connection to staff and caregivers, is conducive to a sense of well-being, and facilitates a connection to the outside world. DISCUSSION: Data derived from the focus group research has guided the development of quantitative survey and assessment tools. For each setting, patient-centered checklists and questionnaires are designed to help institutions set priorities for the improvement of facility design from the patient's perspective.

Facility Design and Construction↗
PubMed1999

Globalization and the trade in human body parts.

Since the early 1980s, the number and variety of organ transplantations has increased enormously worldwide. Accompanying this increase has been the emergence of a market for human body parts. This paper argues that, while the trade in human body parts is conditioned by technological advances, it must be understood in the broader context of globalization, specifically the extension and intensification of a capitalist mode of exchange. In this regard, it is argued that the trade in human body parts mirrors the "normal" system of unequal exchanges that mark other forms of trade between the developed and undeveloped regions of the world.

Commerce↗
PubMed1998

4,4-Disubstituted piperidine high-affinity NK1 antagonists: structure-activity relationships and in vivo activity.

Previously reported studies from these laboratories described the design of a novel series of high-affinity NK1 antagonists based on the 4,4-disubstituted piperidine ring system. Further structure-activity studies have now established that for high NK1 affinity the benzyl ether side chain must be 3,5-disubstituted and highly lipophilic, the optimal side chain being the 3, 5-bis(trifluoromethyl)benzyl ether, 12 (hNK1 IC50 = 0.95 nM). Additional studies have shown that this class of NK1 antagonist tolerates a wider range of substituents on the piperidine nitrogen, including acyl (38) (hNK1 IC50 = 5.3 nM) and sulfonyl (39) (hNK1 IC50 = 5.7 nM) derivatives. Following preliminary pharmacokinetic analysis, two compounds (32 and 43) were selected for in vivo study in the resiniferotoxin-induced vascular leakage model, both showing excellent profiles (ID50 = 0.22 and 0.28 mg/kg, respectively).

Animals↗
PubMed1998

Distinct mechanism for antidepressant activity by blockade of central substance P receptors.

The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

Adolescent↗