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Biomedical subjects

G Smith

Publications and source records attributed to G Smith.

At least 235 records · Page 13Linked to original sources
PubMed1998

Relationship between degenerative joint disease and hip joint laxity by use of distraction index and Norberg angle measurement in a group of cats.

OBJECTIVE: To determine the relationship between degenerative joint disease (DJD) and passive laxity of the hip joint in a group of cats. DESIGN: Prospective study. ANIMALS: A select (nonrandomized) group of 78 cats. PROCEDURE: Standard hip-extended radiographic views and compression and distraction views of the pelvis were obtained from cats during sedation. Radiographs were evaluated, using an Orthopedic Foundation for Animals (OFA)-like scoring system for dogs. Passive joint laxity was measured, using Norberg angle (NA) and distraction index (DI). Hip laxity in cats with DJD was compared with hip laxity in cats without DJD. RESULTS: Hip dysplasia (HD) was subjectively diagnosed radiographically in 25 of 78 (32%) cats using the OFA-like scoring system. Nineteen cats had mild HD 4 had moderate HD, and 2 had severe HD. Fifteen of the 25 cats with HD had DJD. The NA ranged from 56 to 105. The mean NA in cats with DJD was (84 degrees) significantly lower than in cats without DJD (95 degrees). The DI ranged from 0.2 to 0.84. The mean DI for cats with DJD was (0.6) significantly higher than that for cats without DJD (0.49). Cats with a DI < 0.4 did not have DJD. Cats had an increased likelihood of having DJD with increased laxity in the coxofemoral joint, as measured by NA or DI. CLINICAL IMPLICATIONS: The mean NA for radiographically normal cats (92.4 degrees) was lower than that in radiographically normal dogs (103 degrees). The overall mean DI for cats in this group (0.51) is similar to dogs of breeds with high joint laxity, such as the Labrador Retriever (0.5). As in dogs, there is a relationship between DJD and laxity in the hip joint of cats.

Animals↗
PubMed1998

Confidential inquiry into quality of care before admission to intensive care.

OBJECTIVE: To examine the prevalence, nature, causes, and consequences of suboptimal care before admission to intensive care units, and to suggest possible solutions. DESIGN: Prospective confidential inquiry on the basis of structured interviews and questionnaires. SETTING: A large district general hospital and a teaching hospital. SUBJECTS: A cohort of 100 consecutive adult emergency admissions, 50 in each centre. MAIN OUTCOME MEASURES: Opinions of two external assessors on quality of care especially recognition, investigation, monitoring, and management of abnormalities of airway, breathing, and circulation, and oxygen therapy and monitoring. RESULTS: Assessors agreed that 20 patients were well managed (group 1) and 54 patients received suboptimal care (group 2). Assessors disagreed on quality of management of 26 patients (group 3). The casemix and severity of illness, defined by the acute physiology and chronic health evaluation (APACHE II) score, were similar between centres and the three groups. In groups 1, 2, and 3 intensive care mortalities were 5 (25%), 26 (48%), and 6 (23%) respectively (P=0.04) (group 1 versus group 2, P=0.07). Hospital mortalities were 7 (35%), 30 (56%), and 8 (31%) (P=0.07) and standardised hospital mortality ratios (95% confidence intervals) were 1.23 (0.49 to 2.54), 1.4 (0.94 to 2.0), and 1.26 (0.54 to 2.48) respectively. Admission to intensive care was considered late in 37 (69%) patients in group 2. Overall, a minimum of 4.5% and a maximum of 41% of admissions were considered potentially avoidable. Suboptimal care contributed to morbidity or mortality in most instances. The main causes of suboptimal care were failure of organisation, lack of knowledge, failure to appreciate clinical urgency, lack of supervision, and failure to seek advice. CONCLUSIONS: The management of airway, breathing, and circulation, and oxygen therapy and monitoring in severely ill patients before admission to intensive care units may frequently be suboptimal. Major consequences may include increased morbidity and mortality and requirement for intensive care. Possible solutions include improved teaching, establishment of medical emergency teams, and widespread debate on the structure and process of acute care.

Adult↗
PubMed1998

Determinants of the substrate specificity of human cytochrome P-450 CYP2D6: design and construction of a mutant with testosterone hydroxylase activity.

Cytochrome P-450 CYP2D6, human debrisoquine hydroxylase, metabolizes more than 30 prescribed drugs, the vast majority of which are small molecules containing a basic nitrogen atom. In contrast, the similar mouse protein Cyp2d-9 was first characterized as a testosterone 16alpha-hydroxylase. No common substrates have been reported for the two enzymes. Here we investigate the structural basis of this difference in substrate specificity. We have earlier used a combination of NMR data and homology modelling to generate a three-dimensional model of CYP2D6 [Modi, Paine, Sutcliffe, Lian, Primrose, Wolf, C.R. and Roberts (1996) Biochemistry 35, 4541-4550]. We have now generated a homology model of Cyp2d-9 and compared the two models to identify specific amino acid residues that we believe form the substrate-binding site in each protein and therefore influence catalytic selectivity. Although there are many similarities in active site structure, the most notable difference is a phenylalanine residue (Phe-483) in CYP2D6, which in the model is located such that the bulky phenyl ring is positioned across the channel mouth, thus limiting the size of substrate that can access the active site. In Cyp2d-9, the corresponding position is occupied by an isoleucine residue, which imposes fewer steric restraints on the size of substrate that can access the active site. To investigate whether the amino acid residue at this position does indeed influence the catalytic selectivity of these enzymes, site-directed mutagenesis was used to change Phe-483 in CYP2D6 to isoleucine and also to tryptophan. CYP2D6, Cyp2d-9 and both mutant CYP2D6 proteins were co-expressed with NADPH cytochrome P-450 reductase as a functional mono-oxygenase system in Escherichia coli and their relative catalytic activities towards bufuralol and testosterone were determined. All four proteins exhibited catalytic activity towards bufuralol but only Cyp2d-9 catalysed the formation of 16alpha-hydroxytesterone. Uniquely, the CYP2D6F483I mutant acquired the ability to metabolize testosterone to a novel product, which was identified by MS and proton NMR spectroscopy as 15alpha-hydroxytestosterone. NMR spin relaxation experiments were used to measure distances between the haem iron and protons of testosterone bound to the CYP2D6F483I mutant. These experiments demonstrate that very minor modifications to the active site structure of CYP2D6 can have a profound influence on the substrate specificity of the enzyme.

Amino Acid Sequence↗
PubMed1998

Individual risk factors for hip osteoarthritis: obesity, hip injury, and physical activity.

Hip osteoarthritis is a major cause of pain and disability. The authors explored individual risk factors for hip osteoarthritis in a population-based case-control study. The study was performed in two English health districts (Portsmouth and North Staffordshire) from 1993 to 1995. A total of 611 patients (210 men and 401 women) listed for hip replacement because of osteoarthritis over an 18-month period were compared with an equal number of controls selected from the general population and individually matched for age, sex, and family practitioner. Information about suspected risk factors was obtained by a questionnaire administered at interview and a short physical examination. Obesity (odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.3-2.4; highest vs. lowest third of body mass index), previous hip injury (OR = 4.3, 95% CI 2.2-8.4), and the presence of Heberden's nodes (OR = 1.6, 95% CI 1.2-2.2) were independent risk factors for hip osteoarthritis among men and women. Hip injury was more closely related to unilateral as compared with bilateral disease. There were a negative association between cigarette smoking and osteoarthritis among men and a weak positive association with prolonged regular sporting activity. Obesity and hip injury are important independent risk factors for hip osteoarthritis, which might be amenable to primary prevention. Hip osteoarthritis may also arise as part of the polyarticular involvement found in generalized osteoarthritis.

Aged↗
PubMed1998

[Infectious endocarditis at Ullevål hospital 1988-94. Echocardiographic investigation].

During a seven-year period (1998-94) 68 patients with infectious endocarditis were diagnosed at a university hospital. Staphylococcus aureus was the most common etiological agent (38%), followed by Streptococcus viridans (21%). In seven patients the diagnosis infectious endocarditis was first made during autopsy, all seven of them had the clinical diagnosis septicaemia. Surgery was performed on 41% of the patients. Case fatality was 34%. Case fatality was significantly higher for S aureus endocarditis than for S viridans endocarditis, 48% vs. 7% (p = 0.01). The advantages of transthoracic and transoesophageal echocardiography in the diagnosis and follow up of patients with infectious endocarditis is emphasized. In spite of these new diagnostic tools a definitive clinical diagnosis of infectious endocarditis was not made for 23% of the patients.

Adolescent↗
PubMed1998

Protection from Plasmodium berghei infection by priming and boosting T cells to a single class I-restricted epitope with recombinant carriers suitable for human use.

The desirability of inducing cytotoxic T cell responses to defined epitopes in humans has led to the development of a variety of recombinant delivery systems. Recombinant protein particles derived from a yeast retrotransposon (Ty) and the modified Ankara vaccinia (MVA) virus can deliver large epitope strings or even whole proteins. Both have previously been administered safely in humans. Immunization with recombinant Ty and MVA containing a single Plasmodium berghei class I-binding epitope provided 95% sterile protection against malaria in mice. The sequence of immunization, Ty followed by MVA, was critical to elicit high levels of IFN-gamma-producing cells and protection. The reciprocal sequence (MVA/TY) or homologous boosting was not protective. Both constructs (Ty and MVA) contain the H-2Kd-restricted pb9 CTL epitope from the circumsporozoite protein of P. berghei among a string of 8-15 human P. falciparum-derived CTL epitopes restricted through 7 common HLA alleles as well as widely recognized CD4 T cell epitopes. Thus, the novel recombinant Ty/MVA prime/boost combination with these constructs provides a safe alternative for evaluation for human vaccination against P. falciparum malaria.

Animals↗
PubMed1998

Parallel loss of presynaptic and postsynaptic dopamine markers in normal aging.

Aging of the human brain is associated with a decline in dopamine (DA) function, generally interpreted as reflecting DA cell loss. Positron emission tomography studies revealed that in healthy individuals, the age-related losses in DA transporters (presynaptic marker) were associated with losses in D2 receptors (postsynaptic marker) rather than with increases as is known to occur with DA cell loss. This association was specific for DA synaptic markers, because they were not correlated with striatal metabolism. Furthermore, the association was independent of age, suggesting that a common mechanism regulates the expression of receptors and transporters irrespective of age.

Adult↗
PubMed1998

Pharmacological administration of granulocyte/macrophage-colony-stimulating factor is of significant importance for the induction of a strong humoral and cellular response in patients immunized with recombinant carcinoembryonic antigen.

Eighteen colorectal carcinoma patients without macroscopic disease after surgery were immunized using recombinant (r) human (h) carcinoembryonic antigen (CEA) with (n=9) or without (n=9) the addition of soluble granulocyte/macrophage-colony-stimulating factor (GM-CSF). The dose of rhCEA per immunization was 100 microg (n=6), 316 microg (n=6) or 1000 microg (n=6). rhCEA was given s.c. on day 1 and 80 microg/day of GM-CSF s.c. on days 1-4. The schedule was repeated six times during a period of 9 months. All patients in the GM-CSF group developed a strong rhCEA-dose-dependent IgG antibody response while only one-third of the non-GM-CSF patients mounted a weak antibody response. All patients (9/9) in the GM-CSF group developed a strong rhCEA-specific proliferative T cell response as well as type I T cells (interferon gamma secretion). In 45% of the patients also a weak type II T cell response (interleukin-4 secretion) was evoked. Both MHC-class-I- and -II restricted rhCEA-specific T cells were noted. A specific cellular response (proliferation and/or cytokine secretion) against native hCEA could be found in 8/9 patients in the GM-CSF group, although at a significantly lower level than against rhCEA. In the non-GM-CSF group a weak rhCEA-specific T cell response was induced. Three patients had a proliferative response, 4 patients type I T cells and 6 patients type II T cells. No signs of autoimmune reactions were noted. Local pharmacological administration of GM-CSF seemed to be a prerequisite for the induction of a strong immunity against baculovirus-produced hCEA protein. However, the cellular response against native CEA was of a significantly lower magnitude.

Adjuvants, Immunologic↗
PubMed1998

Further characterization of the latency-associated transcription unit of Marek's disease virus.

Previous studies have identified a large (L) and a small (S) RNA transcript antisense to the MDV homologue of the ICP4 gene of herpes simplex virus (HSV) in cells infected with Marek's disease virus (MDV) and in lymphoblastoid cell lines. In this study the 5' and 3' ends of the L RNA and of the sense ICP4 transcript of MDV were mapped by Northern hybridization and RNase protection assays. The results showed that L RNA is approximately 10.6 kb and that the ICP4 sense transcript is initiated in the region of genomic DNA where the L RNA terminates whereas L RNA is initiated where the ICP4 transcript terminates. L RNA was abundant in chick embryo fibroblasts (CEF) infected with virus strain HPRS16/attenuated whereas S RNA was predominant in CEF infected with oncogenic HPRS16 and in RPL-1 cell line. Results of cycloheximide experiments showed that the ICP4 gene of MDV was transcribed as an immediate-early gene in infected CEF whereas transcription of the L RNA required protein synthesis. Sequencing of cDNA and Northern hybridization using oligonucleotide probes showed that S RNA shared similar intron/exon boundaries as the cDNAs from several cell lines indicating that there might be a relationship between the S RNA and the antisense transcripts that generated the cDNAs.

Animals↗
PubMed1998

Evaluation of diagnostic ultrasound as a mass screening technique for the detection of hydatid cysts in the liver and lung of sheep and goats.

Ultrasound examination of the liver and lung followed by post-mortem examination was performed in 16 sheep and 284 goats. Thirty-one (10.3%) were positive for hydatid cysts on ultrasound examination and 46 (15.3%) were positive on post-mortem examination. Twenty-one positive on post-mortem examination were falsely identified as negative on ultrasound examination. Of the 254 animals negative on post-mortem examination, six (2.4%) were falsely identified as positive on ultrasound examination. The sensitivity and specificity of ultrasound examination for detecting hydatid cysts in sheep and goats was 54.36% and 97.64%, respectively (positive predictive value: 80.64%; negative predictive value: 92.19%).

Abattoirs↗
PubMed1998

Incidence of latex sensitization among latex glove users.

BACKGROUND: Although there are several reports of the prevalence of latex sensitization among health care workers, the incidence of sensitization is unknown. OBJECTIVE: The objective of this study was to estimate the incidence of sensitization among latex glove users at a hospital in Hamilton, Ontario, Canada. METHODS: Workers with negative results to the skin test at baseline were followed prospectively over 1 year, some wearing powdered gloves and others using powder-free gloves. They were reevaluated in 1995 with a questionnaire and skin prick test (SPT) sensitivity to latex reagents, three common inhalants, and six foods. A conversion was defined as a (new) latex SPT with wheal diameter at least 4 mm greater than saline control. Glove extracts were assayed for antigenic protein, and air samples were obtained to estimate exposure to airborne latex protein. RESULTS: During powdered glove use, personal exposures ranged from 5 to 616 ng/m3, whereas during powder-free glove use, all but two results for air samples were below the limit of detection (about 0.1 ng/m3). During the study period, the protein concentration in the powdered gloves, initially mean 557 microg/gm of sample, declined at a rate of 295 microg/gm per year (p < 0.0001). Of the 1075 SPT-negative participants at baseline, 479 were working in eligible wards, and of these, 435 (91%) participated in follow-up, 227 using powder-free gloves and 208 using powdered gloves. We identified four conversions, two (1.0%) in the powdered glove group and two (0.9%) in the powder-free group. The two participants using powdered gloves were the only converters who were symptomatic. The significance of skin test conversions identified in the powder-free group, both asymptomatic patients, is unclear. The limitations of the study are discussed, including the limited power, the declines in latex protein concentrations, and the possibility of information (observer) bias. CONCLUSION: To our knowledge, this represents the first reported estimate (about 1%) of incidence of sensitization in hospital personnel using latex gloves.

Cross-Sectional Studies↗
PubMed1998

Evaluation of bovine viral diarrhea virus control using a mathematical model of infection dynamics.

A mathematical model for infection with bovine viral diarrhea virus (BVDV) was created comprising a series of coupled differential equations. The model architecture is a development of the traditional model framework using susceptible, infectious and removed animals (the SIR model). The model predicts 1.2% persistent infection (within the range of field estimates) and is fairly insensitive to alterations of structure or parameter values. This model allows us to draw important conclusions regarding the control of BVD, particularly with respect to the importance of persistently infected (PI) animals in maintaining BVD as an endemic entity in the herd. Herds without PI animals are likely to experience episodic reproductive losses at intervals of two to three years, unlike herds with PI animals which will not see such marked episodic manifestations of infection. Instead, these herds will experience an initial peak of disease which will settle to low-level chronic reproductive losses. The model indicates that vaccine coverage for herd immunity (to avoid episodic manifestations of disease) need be only 57% without PI animals, although 97% coverage is required when PI animals are present. Analysis of model behavior suggests a program of detection and removal of PI animals may enhance the effectiveness of a vaccine program provided these animals are in the herd for 10 days or less. The best results would be seen with PI animals in the herd for 5 or fewer days.

Animals↗
PubMed1998

The United Kingdom pre-hospital study of active compression-decompression resuscitation.

This prospective, controlled trial with crossover group design compares the effectiveness of active compression-decompression (ACD) cardiopulmonary resuscitation (CPR) and standard CPR on the outcomes of victims of prehospital cardiac arrest. In three UK cities, victims of non-traumatic, out of hospital cardiac arrest, over the age of 8 years received either standard or ACD-CPR on arrival of ambulance personnel. Main outcome measures were return of spontaneous circulation, survival to be admitted to the intensive care unit, survival to hospital discharge, and neurological outcome. A total of 576 patients (STD-CPR, n=309; ACD-CPR, n=267) were analysed. The treatment groups were similar with respect to age, gender, proportion of witnessed arrests, initial cardiac rhythm, and call to advanced life support interval. The proportion of patients receiving bystander CPR was higher in the ACD group (37.1% vs. 28.5%; P=0.028). The interval between collapse and defibrillation was longer in the ACD group (12.3 min vs. 10.4 min; P=0.028). There was no difference between the STD-CPR and ACD-CPR groups in survival to admission to the intensive care unit (13.6% vs. 13.8%; P=0.93) or hospital discharge (4.8% vs. 6.0%; P=0.67). There was no difference between the groups with respect to the neurological outcome of those patients surviving to hospital discharge. Analysis of important subgroups also showed no benefit for ACD-CPR. We conclude that there was no improvement in outcome with ACD-CPR when used by ambulance personnel in Cardiff and Portsmouth.

Aged↗
PubMed1998

Burn management in a patient with autism.

The successful use of elective post-operative sedation and ventilation following tangential surgical excision of burns in an autistic child. non-compliant with conventional management is reported. Other strategies for treating autistic children are discussed.

Adolescent↗
PubMed1998

Serotonin in aging, late-life depression, and Alzheimer's disease: the emerging role of functional imaging.

Serotonin (5-HT) neuron and neurotransmitter loss in normal aging and neuropsychiatric diseases of late life may contribute to behavioral changes commonly observed in the elderly population. Extensive evidence implicates a deficit in serotonergic neurotransmission in the development of major depression. It has been further suggested that the age-related changes in 5-HT neurons may predispose the elderly to develop depression. There is also increasing evidence that a combination of disturbances in cholinergic and serotonergic function may play a role in cognitive impairment in Alzheimer's disease (AD), with serotonergic dysfunction potentially responsible for a significant portion of the behavioral aspects of the disease. This implication of the 5-HT system in aging and age-related cognitive and mood disorders rests in large part on post mortem studies and animal models, which are limited in their capacity to predict dynamic human biochemical-behavior relationships or to accurately model the living human brain. Initial applications of functional brain imaging with positron emission tomography (PET) in the in vivo study of the brain in aging depression, and dementia focused on characterizing alterations in physiological measurements of cerebral metabolism and perfusion. However, recent advances in PET radiochemistry, instrumentation, and image processing have paved the way for noninvasive means to test specific hypotheses regarding the direct involvement of 5-HT neurons in the behavioral features of aging and to define and monitor therapeutic regimens for neuropsychiatric conditions of late life. Coupling of clinical trials in well-characterized subject populations with PET imaging using ligands specific for 5-HT receptor subtypes and transporter proteins promises to increase our understanding of the role of the 5-HT system in affective and cognitive aspects of treatment response. Longitudinal studies in aging, late-life depression, and AD are also needed to evaluate the complex interplay between neurodegenerative processes and serotonergic neurotransmission.

Aged↗
PubMed1998

Patch engineering: a general approach for creating proteins that have new binding activities.

Patch engineering is a technique for creating folded proteins that have new binding activities. Different protein scaffolds are used to present a patch of discontinuous residues on a folded-protein surface. By varying simultaneously the residues in these patches and displaying these mutant proteins on phage, one can select proteins that have new binding activities. Patch engineering is applicable to any protein fold. Novel proteins derived by this approach might replace antibodies in certain applications or provide lead molecules for the design of non-peptide analogues.

Binding Sites↗
PubMed1998

Intravitreal penetration of teicoplanin.

Teicoplanin is a glycopeptide antibiotic, similar to vancomycin, but safer and better tolerated. The purpose of this study was to evaluate the penetration of teicoplanin into the vitreous when administered topically and intravenously. Twenty-five patients undergoing routine vitrectomy were recruited. Twenty were given intravenous teicoplanin: five 1 h pre-operatively, five 12 h pre-operatively, five 24 h pre-operatively and five 24 h as well as 48 h pre-operatively. Five received teicoplanin drops half-hourly for the 6 h immediately preceding vitrectomy. Undiluted vitreous specimens were obtained at the beginning of each vitrectomy procedure. Teicoplanin levels were measured using a biological assay with Staphylococcus aureus as the indicator organism. Teicoplanin activity was detected in 8 of the 20 specimens from those patients receiving the intravenous antibiotic. Teicoplanin did not penetrate readily into the vitreous cavities in these eyes despite the blood-ocular barrier being compromised in some patients, although there was evidence of accumulation with time. No activity was detected in the vitreous of those patients who received topical teicoplanin.

Adolescent↗