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Biomedical subjects

K Brown

Publications and source records attributed to K Brown.

At least 163 records · Page 9Linked to original sources
PubMed1998

Genomic organization and structure of alpha-hydroxynitrile lyase in cassava (Manihot esculenta Crantz).

Two clones with homology to the alpha-hydroxynitrile lyase (HNL) cDNA clone, MeHNL10, were isolatedfrom a lambdaEMBL3 cassava (Manihot esculenta Crantz) genomic library. Analysis of the sequences showed that both genomic clones contain HNL genes (MeHNL4, MeHNL24) which are interrupted by two introns. RT-PCR analysis of MeHNL4 shows that it is expressed at high levels in seedling roots and at lower levels in cotyledons and young leaves. The deduced amino acid sequences of MeHNL4, MeHNL10, and MeHNL24 show high sequence identity and homology to the HNL from Hevea brasiliensis whose tertiary structure has been solved at 1.9-A resolution by X-ray crystallography. This high homology allowed the construction of model structures for all of the cassava proteins using the MODELLER program. Homology modeling indicates that the short variable exon 2 encodes the "cap" region which is thought to influence the substrate specificity of the protein. Two hybrid proteins were modeled using the core alpha/beta domain of MeHNL10 and the cap region of either the Hevea HNL or a structurally related Zea protein of unknown function. This analysis suggests that changes in the active site can be engineered by swapping exons.

Aldehyde-Lyases↗
PubMed1998

Risk of morbidity from renovascular disease in elderly patients with congestive cardiac failure.

BACKGROUND: Renovasular disease commonly affects elderly people. Elderly patients with heart failure are routinely treated with angiotensin-converting-enzyme (ACE) inhibitors, which may increase risk of renal dysfunction. We investigated the frequency of renovascular disease among elderly people with heart failure. METHODS: From the local population of Salford, UK, we recruited 86 patients with heart failure with a mean age of 77.5 (SD 5.6) years, who were admitted as acute emergencies or who attended general medical clinics. We selected patients by intention to treat with ACE inhibitors. We used captopril renography to screen for renovascular disease. All patients with abnormal renograms underwent magnetic-resonance angiography of the renal arteries as well as 40% of patients with normal renograms as negative controls. FINDINGS: Magnetic-resonance angiography showed severe renovascular disease (>50% renal-artery stenosis or occlusion) in 29 (34%) patients. Captopril renography had an estimated sensitivity of 78.8% (95% CI 72.7-97.8) and specificity of 94.3% (67.6-97.3) for detection of renovascular disease. The estimated positive predictive value of captopril renography was 89.7% and the negative predictive value was 87.5%. Patients with renovascular disease had worse renal function (mean creatinine 201 [SD 56] vs 136 [40] pmol/L, p<0.001), were older (mean age 80.7 [5.6] vs 76.8 [5.3] years, p<0.01), and were more likely than patients without renovascular disease to have peripheral arterial disease. INTERPRETATION: Some elderly patients with occult renovascular disease on ACE inhibitors will be at risk of developing uraemia. Renal function should be closely monitored to detect any deterioration early.

Aged↗
PubMed1998

Design of a new class of orally active fibrinogen receptor antagonists.

The integrin receptor recognition sequence Arg-Gly-Asp was successfully used as a template from which to develop a series of potent, selective, orally active, peptide-based fibrinogen receptor antagonists with a long duration of action. Simple modifications centered on the Arg and Gly residues quickly led to a modified peptide (1) with significantly enhanced ability to inhibit in vitro platelet aggregation. Substitution of the guanidino group in 1 by piperidine provided 3, which showed not only a further increase in potency but also a modest degree of oral efficacy. Finally, exploration of the nature of the C-terminal amino acid, with respect to its side-chain functionality and the carboxy terminus, yielded a group of molecules that showed excellent in vitro potency for inhibiting platelet aggregation, excellent integrin selectivity, a high level of oral efficacy, and an extended duration of action.

Administration, Oral↗
PubMed1998

Epithelial carcinogenesis in the mouse: correlating the genetics and the biology.

Tumour formation relies on a complex combination of genetic and environmental factors. In particular, the contributions from inherited predisposition genes as well as carcinogens, for example from cigarettes or in the diet, are amongst the major contributors to tumorigenesis. Since the study of such processes in particularly difficult in human cancers, the availability of a well-defined model system is of obvious benefit. The mouse skin model of multistage carcinogenesis offers an excellent tool for the study of the target cells, the target genes and the biological events associated with neoplasia. In this system, tumorigenesis occurs in a series of defined stages, each of which is characterized by specific and reproducible alterations in genes such as H-ras, cyclin D1, p53 and p16INK4A. Additional changes occur in the production of, or response to, factors such as transforming growth factor beta (TGF beta). These genetic and biological alterations are mirrored in human tumours of epithelial origin. Hence, research into the general principles of tumour initiation, promotion and progression in the context of the mouse skin model is likely to prove valuable in the continual search for new methods for the diagnosis, prevention, and therapeutic treatment of human cancers.

Animals↗
PubMed1998

Vitamin E, lipids, and lipid peroxidation products in tardive dyskinesia.

BACKGROUND: Lipid peroxidation has been postulated as a possible mechanism for neuronal damage in tardive dyskinesia, and this is supported by evidence of increased lipid peroxidation products in the cerebrospinal fluid of dyskinetic subjects. METHODS: In this study plasma levels of vitamin E and vitamin A, measured by high-performance liquid chromatography, and of thiobarbituric acid-reactive substances (TBARS), were determined in 16 schizophrenic patients with tardive dyskinesia, 16 nondyskinetic patients all assessed by Abnormal Involuntary Movement Scale (AIMS), and 10 normal control subjects. Plasma cholesterol and triglyceride were also measured throughout. Vitamin E levels in plasma were corrected for total lipids. RESULTS: Multivariate analysis of covariance showed significant differences when vitamin E and TBARS were compared in the three groups. Univariate t tests showed a significantly lower lipid-corrected vitamin E (p = .018) between the normal and dyskinetic group but not between the normal and the nondyskinetic schizophrenic patients. There was no difference in vitamin A levels between patients and normal controls. TBAR results showed a significant positive correlation between AIMS score and lipid-corrected TBARS. CONCLUSIONS: This study confirms an abnormality associating lipid peroxidation and tardive dyskinesia and extends this abnormality to measurements of lipid-corrected vitamin E in plasma.

Aged↗
PubMed1998

Increased skin tumorigenesis in mice lacking pi class glutathione S-transferases.

The activity of chemical carcinogens is a complex balance between metabolic activation by cytochrome P450 monooxygenases and detoxification by enzymes such as glutathione S-transferase (GST). Regulation of these proteins may have profound effects on carcinogenic activity, although it has proved impossible to ascribe the observed effects to the activity of a single protein. GstP appears to play a very important role in carcinogenesis, although the precise nature of its involvement is unclear. We have deleted the murine GstP gene cluster and established the effects on skin tumorigenesis induced by the polycyclic aromatic hydrocarbon 7, 12-dimethylbenz anthracene and the tumor promoting agent 12-O-tetradecanoylphorbol-13-acetate. After 20 weeks, a highly significant increase in the number of papillomas was found in the GstP1/P2 null mice [GstP1/P2(-/-) mice, 179 papillomas, mean 9.94 per animal vs. GstP1/P2(+/+) mice, 55 papillomas, mean 2.89 per animal, (P < 0.001)]. This difference in tumor incidence provides direct evidence that a single gene involved in drug metabolism can have a profound effect on tumorigenicity, and demonstrates that GstP may be an important determinant in cancer susceptibility, particularly in diseases where exposure to polycyclic aromatic hydrocarbons is involved, for instance in cigarette smoke-induced lung cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1998

The malignant capacity of skin tumours induced by expression of a mutant H-ras transgene depends on the cell type targeted.

BACKGROUND: . Pinpointing the cells from which tumours arise is a major challenge n tumour biology. Previous work has shown that the targeted expression of a mutant ras gene within the interfollicular cell compartment of mouse skin induces the formation of benign papillomas, but these do not spontaneously progress to malignancy. We have investigated the carcinogenic effects of expressing the same oncogene in a different population of epidermal cells. RESULTS: Expression of mutant ras from a truncated keratin 5 gene promoter, which directs expression to the follicular and interfollicular cells of newborn mice and the hair follicle cells of adults, stimulated the development of acanthotic areas in newborn mice. Within one week of birth, the acanthotic skin developed areas of carcinoma in situ and adult mice developed papillomas and keratoacanthomas, the latter having a high frequency of spontaneous malignant transformation to squamous and occasionally spindle carcinomas. The benign tumours that arose had several hallmarks of tumours at a high risk of malignant progression, including suprabasal cell proliferation and heterogeneous expression of keratin 13. In contrast to tumours induced by expressing mutant ras under the control of the keratin 10 or keratin 1 gene promoters, the formation of these lesions was not dependent on wounding or a tumour promoter. CONCLUSIONS: Benign tumours that are at a risk of malignant conversion are primarily derived from cells located within the hair follicle, and the nature of the cell in which tumour initiation occurs is a major determinant of malignant potential.

Animals↗
PubMed1998

Human T cell lymphotropic virus type I Tax protein trans-activates interleukin 15 gene transcription through an NF-kappaB site.

Interleukin 15 (IL-15) mRNA is expressed in a wide variety of tissue types. However, with the exception of some T cell lines, IL-15 transcript expression has not been described in T cells. Herein we demonstrate that IL-15 mRNA can be detected in freshly isolated normal T cells and T cell lines. Furthermore, its expression is 3- to 4-fold higher in human T cell lymphotropic virus type I (HTLV-I)-infected T cells. By using reporter constructs bearing the 5' regulatory region of the IL-15 gene, we observed a positive correlation between HTLV-I Tax protein expression and IL-15 promoter activity in HTLV-I-infected T cells. Additionally, by using a Jurkat T cell transfectant that expresses Tax under an inducible promoter, we demonstrated that the expression of IL-15 mRNA increased 3-fold as Tax was expressed, suggesting that the Tax protein activates IL-15 transcription. An NF-kappaB consensus sequence is located at the -75 and -65 region of the IL-15 5' regulatory region. Mutations in the NF-kappaB motif or deletion of this sequence abrogated the promoter activity in both HTLV-I-positive and Jurkat Tax-transfectant cells. These data represent evidence for trans-activation of the IL-15 gene by the HTLV-I Tax protein through an NF-kappaB motif and suggest a potential role for IL-15 in HTLV-I-associated diseases such as adult T cell leukemia and HTLV-I-associated myopathy/tropical spastic paraparesis.

Base Sequence↗
PubMed1998

Factor V Cambridge: a new mutation (Arg306-->Thr) associated with resistance to activated protein C.

A new factor V mutation associated with resistance to activated protein C and thrombosis (factor V Cambridge, Arg306-->Thr) was found in one patient from a carefully selected group of 17 patients with venous thrombosis and confirmed APC resistance in the absence of the common Gln506 mutation. The Arg306 mutation was also present in a first degree relative who also had APC resistance. Other potential causes of APC resistance, such as a mutation at the Arg679 site and the factor V HR2 haplotype, were excluded. Subsequent screening of 585 patients with venous thromboembolism and 226 blood donors did not show any other individual with this mutation. Factor VThr306 is the first description of a mutation affecting the Arg306 APC cleavage site and is the only mutation, other than factor V Leiden (Arg506-->Gln), that has been found in association with APC resistance. This finding confirms the physiologic importance of the Arg306 APC-cleavage site in the regulation of the prothrombinase complex. It also supports the concept that APC resistance and venous thrombosis can result from a variety of genetic mutations affecting critical sites in the factor V cofactor.

Arginine↗
PubMed1998

Identification and initial structure-activity relationships of a novel class of nonpeptide inhibitors of blood coagulation factor Xa.

The discovery and some of the basic structure-activity relationships of a series of novel nonpeptide inhibitors of blood coagulation Factor Xa is described. These inhibitors are functionalized beta-alanines, exemplified by 2a. Docking experiments placing 2a in the active site of Factor Xa implied that the most expeditious route to enhancing in vitro potency was to modify the group occupying the S3 site of the enzyme. Increasing the hydrophobic contacts between the inhibitor and the enzyme in this region led to 8, which has served as the prototype for this series. In addition, an enantioselective synthesis of these substituted beta-alanines was also developed.

Animals↗
PubMed1998

Mice deficient in nuclear factor (NF)-kappa B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture.

p52 is a subunit of nuclear factor (NF)-kappa B transcription factors, most closely related to p50. Previously, we have shown that p52, but not p50 homodimers can form transactivating complexes when associated with Bcl-3, an unusual member of the I kappa B family. To determine nonredundant physiologic roles of p52, we generated mice deficient in p52. Null mutant mice were impaired in their ability to generate antibodies to T-dependent antigens, consistent with an absence of B cell follicles and follicular dendritic cell networks in secondary lymphoid organs, and an inability to form germinal centers. Furthermore, the splenic marginal zone was disrupted. These phenotypes are largely overlapping with those observed in Bcl-3 knockout animals, but distinct from those of p50 knockouts, supporting the notion of a physiologically relevant complex of p52 homodimers and Bcl-3. Adoptive transfer experiments further suggest that such a complex may be critical in accessory cell functions during antigen-specific immune reactions. Possible roles of p52 and Bcl-3 are discussed that may underlie the oncogenic potential of these proteins, as evidenced by recurrent chromosomal translocations of their genes in lymphoid tumors.

Adoptive Transfer↗
PubMed1998

Can a difference in chest wall mechanics explain the lower respiratory drive during propofol versus halothane anesthesia in children?

This article extends previous work which suggested that respiratory drive was lower during propofol compared with halothane anesthesia. The aim of this study was to assess simultaneously chest wall motion, measured with respiratory inductive plethysmography (RIP), and respiratory drive measured by P0.1 the pressure generated during the initial 100 msec of an occluded inspiratory effort. Ten healthy children age 3 to 6 years who presented for a dental restorative procedure that required in excess of 2.5 hours were recruited. Patients were anesthetized with propofol (2.5 mg x kg(-1); 15 mg x kg(-1) x hr) or halothane (1.25%), in a randomized crossover study design. Following induction of anesthesia, RIP bands were placed at the level of the nipples and the umbilicus for the measurement of rib cage and abdomen excursion, respectively. Flow and airway pressure were measured. A manually operated pneumatic balloon was used for brief airway occlusion. Following a 60-minute washin/out of the anesthetic, the children were removed from mechanical ventilation and spontaneous ventilation was reinstated. The RIP signals were calibrated by the method of simultaneous solution of equations. The phase lag was calculated. During airway occlusion the maximal excursion of the calibrated rib cage trace (RMAX) was measured; a negative value indicated retraction of the rib cage. Respiratory drive was assessed both at a fixed interval (100 msec) (P0.1) and fixed proportion (10%) (P10%) of the occluded inspiratory effort. Significance of differences were assessed with a paired t-test (P-value < 0.05). Thoracoabdominal asynchrony was greater during halothane than propofol anesthesia, as was the amount of rib cage retraction, evidenced by lower values of RMAX; respiratory drive was higher during halothane than propofol anesthesia, as evidenced by higher values of both P0.1, and P10%. We conclude that during halothane anesthesia altered chest wall mechanics may result in a greater respiratory drive than during propofol anesthesia.

Anesthesia, General↗
PubMed1998

Donor factor V Leiden mutation and vascular thrombosis following liver transplantation.

The most commonly detected hypercoagulable state involves an abnormal factor V protein synthesized by the liver in which arginine at position 506 is replaced by glutamine as a result of a single-point mutation in the factor V gene (factor V Leiden). Liver transplantation is complicated by hepatic vascular thrombosis in up to 15% of cases, resulting in graft loss in most instances. This retrospective study examined the effect of the factor V Leiden mutation on the risk of hepatic vessel thrombosis after liver transplantation. The mutation was sought by polymerase chain reaction and Mnl I digestion of DNA where available from 214 recipients and 276 donors receiving 319 liver transplants. No donors or patients were homozygous for the factor V Leiden mutation. The prevalence of the heterozygous mutation was 19 of 276 (6.9%) in donors and 19 of 214 (8.9%) in recipients. Forty-one thrombotic episodes occurred after transplantation in the 276 transplants in which donor DNA was available for analysis; 22 involved the hepatic artery, 9 involved the portal vein, and 10 were deep venous thromboses. A donor factor V Leiden mutation was detected in the donor in 6 of 41 (14.6%) with any thrombotic event compared with 13 of 235 (5.5%) without (P = 0.03). The relative risk of any thrombosis with this mutation was therefore 2.32 (95% confidence interval [CI], 1.12-4.81). The factor V Leiden mutation was present in the donor in 4 of 31 (12.9%) cases complicated by hepatic vessel thrombosis (which always led to graft loss or death) and 15 of 245 (6.1%) cases without (P = 0.16). The relative risk of hepatic vessel thrombosis in the presence of this allele was therefore 2.00 (95% CI, 0.78-5.14). As anticipated, the presence of this allele in the recipient was not associated with deep venous or hepatic vessel thrombosis. The factor V Leiden mutation in the donor liver is not a major risk factor for hepatic vessel thrombosis and subsequent graft loss after liver transplantation.

Adolescent↗
PubMed1998

Determination of DNA damage in F344 rats induced by geometric isomers of tamoxifen and analogues.

To investigate the activation mechanisms involved in tamoxifen carcinogenicity, analogues of tamoxifen isomers modified at the ethyl group were synthesized and assessed for their ability to induce hepatic DNA damage following their administration to female F344 rats. The cis isomer was prepared by acid-catalyzed isomerization of tamoxifen and isolated by preparative HPLC. The active metabolite alpha-hydroxytamoxifen and geometric isomers of bromotamoxifen and C-desmethylenetamoxifen, analogues in which the ethyl group has been replaced by a bromine atom and methyl group, respectively, were synthesized according to published procedures. The levels of hepatic DNA adducts induced were determined by 32P-postlabeling. Bromotamoxifen and tamoxifen 1,2-epoxide caused no detectable DNA damage relative to controls. Trans isomers of tamoxifen, C-desmethylenetamoxifen, and alpha-hydroxytamoxifen all produced DNA adducts at a 5-90-fold higher level than the corresponding cis isomers. In contrast, both the cis and trans isomers of alpha-hydroxytamoxifen showed similar reactivity toward calf thymus DNA in vitro. Molecular models of alpha-hydroxytamoxifen isomers suggest this difference in DNA adduct-forming ability is due to steric hindrance of the enzymes involved in the activation of this metabolite. There were high adduct levels in the liver, but no uterine DNA adducts were detected in rats treated with alpha-hydroxytamoxifen. This suggests that in contrast to the liver, alpha-hydroxytamoxifen is not further activated in rat uterus. This may help to explain the absence of uterine tumors in rats following long-term tamoxifen treatment.

Animals↗
PubMed1998

The psychosocial health status of carers of persons with dementia: a comparison with the chronically ill.

This project aimed to determine overall psychosocial health (measured using the psychosocial dimension of the Functional Limitations Profile) and factors which influence this in a group of carers of those with dementia and to compare their psychosocial health with that of older people attending general practitioners (GPs); arthritis support groups and a pain clinic (out-patients) and a group of community dwellers undergoing renal dialysis. The carer group showed a significant decrease in recreation and pastimes and social interactions compared to older GP attenders. The carers showed similar restrictions in social interactions and recreation to those with chronic arthritis, but the latter were more impaired in the domains of emotional behaviour and sleep and rest. The older people attending a pain clinic did not differ in the areas of alertness and social interactions compared to the carer group. The dialysis group demonstrated the greatest dysfunction overall. These results suggest that the psychosocial health of carers of those with dementia is impaired, the profile of which differs from those suffering with chronic diseases. Social and recreation activities appear most affected in the carers. Commensurate with studies exploring the health status of those suffering from diseases, the measurement of the psychosocial health status of carers should also be considered in the scope of assessment and intervention.

Analysis of Variance↗
PubMed1998

Changes in the role of general practitioners in child health surveillance.

BACKGROUND: Changes in their Contract in 1990 gave general practitioners the opportunity to become more involved in child health surveillance. This study aimed to describe and compare child health surveillance services provided by general practitioners before and after the changes of the 1990 GP contract. METHODS: A questionnaire was sent to all general practices within the Nottingham Health Authority area in 1990, and this process was repeated in 1994, ascertaining the services provided for child health surveillance. Outcome measures were: the reported provision of services, keeping of records and facilities for following up non-attenders. Also recorded were the training and qualifications of general practitioners and their attitudes towards child health surveillance. RESULTS: Response rates were 62% in 1990 and 80% in 1994. More practices were involved in the provision of child health surveillance services in 1994, more held a baby clinic and more reported having a recall system for non-attenders. There was little change in the training or qualifications of GPs in child health between 1990 and 1994. In 1994, there was evidence of GPs meeting regularly with Health Visitors. There remained a small number of practices who were not interested in child health surveillance. CONCLUSION: The 1990 GP contract appears to have increased the provision of child health surveillance services by GPs and improved liaison with Health Visitors in general practice.

Child Health Services↗