Biomedical subjects

K Richardson

Publications and source records attributed to K Richardson.

At least 37 records · Page 2Linked to original sources

PubMed1997

Consistency and validity of patient administered assessment of quality of life by the MOS SF-36; its association with disease activity and damage in patients with systemic lupus erythematosus.

OBJECTIVE: To investigate the metric properties and validity of the assessment of quality of life by the MOS Short Form 36 (SF-36) in patients with systemic lupus erythematosus (SLE) and to examine the effect of disease on quality of life. METHODS: Cross sectional study of 150 patients with SLE (age: mean 39.7 yrs, SD 11.4 yrs; 95% female) attending 2 specialist lupus clinics between November 1994 and April 1995. Shortly before or after the consultation patients completed the SF-36 and the MOS SF-20 with an additional question about fatigue (SF-20+) in random order. Disease activity was measured by the British Isles Lupus Activity Group System (BILAG), disease damage by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SLICC). RESULTS: SF-36 domains were shown to be internally consistent (Cronbach's coefficient alpha > or = 0.71). Significant associations of the SF-36 domains with the corresponding domains of the SF-20+ and with global disease activity measured by BILAG were observed. SF-36 scores in patients with SLE were significantly lower than in controls. Different disease activity levels were significantly associated with different quality of life scores, with excellent ability to record the continuum from good health to serious illness by the SF-36. Disease activity had greater effect on quality of life than age, cumulative damage, or disease duration. CONCLUSION: This study shows the SF-36 is internally consistent and proves construct, discriminatory, and criterion validity for the SF-36 and construct validity for the SF-20+ in patients with SLE. The SF-36 is preferred because of its broader scope of questions, its widespread use, and previous international validation for a wide variety of diseases.

Adult↗

PubMed1996

Motility mutants of Vibrio cholerae O1 have reduced adherence in vitro to human small intestinal epithelial cells as demonstrated by ELISA.

Vibrio cholerae must colonize the human small intestine to cause diarrhoeal disease. V.cholerae strains N16961 (EI Tor, Inaba) and 395 (classical, Ogawa) adhered to the epithelial cell surface and the mucus layer of isolated human small intestinal epithelial cells. They adhered specifically to the mucosa and apical membrane in thin sections of small intestine. No binding to the basolateral membrane of dissected epithelial tissue or to intracellular components of the epithelial cells was observed by either light or indirect immunofluorescence microscopy. Based on these results, a modified ELISA was developed to quantitatively study adherence of V. cholerae to human small intestinal epithelial cells. The assay used homogenized human small intestinal mucosal tissue as the substrate for binding. Treatment of the epithelial cell homogenate with 2-mercaptoethanol to disrupt protein and glycoprotein secondary structure inhibited the binding of V. cholerae strains, suggesting that binding was to specific receptors. Several V. cholerae strains and mutants from both biotypes were tested for adherence in the modified ELISA. Wild-type strains of both biotypes and non-enterotoxigenic strains, which were known to colonize humans, adhered. V. cholerae mutants defective in motility, flagellar structure of chemotaxis, which were known to exhibit reduced colonization in animal models, exhibited decreased adherence. The specificity of the assay and its ability to quantify binding should facilitate identification and the study of adherence factors involved in the colonization of human small intestinal epithelial cells by V. cholerae.

Bacterial Adhesion↗

PubMed1996

Analogical reasoning and the nature of context: a research note.

Recent theorising about children's reasoning has tended to move towards a 'contextualist' view of cognition and away from the idea of an overall, context-free, mechanism, varying in efficiency, which is the presupposition underlying traditional standardised reasoning tests. An earlier study suggesting improved reasoning performance among children on socio-cognitively meaningful versions of Raven's Matrices tended to support this shift. The main purpose of the study reported here was to observe whether a similar improvement would be found with contextually-based analogical reasoning problems as well. Ten analogy items from a standardised test were administered to 11-year-olds together with 10 structurally-equivalent knowledge-based items. The results reflected improved performance on the latter, overall, and additional analyses led to further suggestions about the nature of the 'contextual advantage' and the origins of item difficulty.

Attention↗

PubMed1996

Object recognition from point-light stimuli: evidence of covariation structures in conceptual representation.

Current theories of concepts and categorization involve easily identifiable attributes or features as the basic informational fodder of representation, and some composite of such features as the conceptual representation. This 'standard model' is now being questioned on a number of empirical and theoretical grounds, especially those concerning the informational origins of features. In this paper we examine the evocation of conceptual functions by point-light stimuli in which objects and constituent features are not directly given at all, but have to be constructed and construed in some way. We have maintained in previous studies that conceptual representation depends upon nested covariation hierarchies, and here suggest that the evocativeness of point-light stimuli can be explained by the structured covariation information they present. In two studies we found evidence that variation in the overall amount and the structure of covariation information in point-light stimuli is associated with variation in a number of conceptual response functions, such as the recognizability of objects from the stimuli, and the dispersion of responses. We take these results as evidence that conceptual representation depends upon, and features and other constituents are generated 'on-line' from, nested covariation hierarchies.

Adult↗

PubMed1996

Comparison of rear-entry (two-incision) and endoscopic techniques for reconstruction of the anterior cruciate ligament.

In this series of patients having reconstruction of the anterior cruciate ligament (ACL), the rear-entry (two-incision) technique with fixation from lateral incision into cortical bone was compared with the endoscopic technique with fixation from inside to more cancellous bone. The rear-entry technique was used in 44 cases of ACL deficiency (8 chronic and 36 acute), and the endoscopic technique was used in 42 cases (19 chronic and 23 acute). Both groups had similar demographics. Objective and subjective criteria were evaluated at an average of 22 months postoperatively. Follow-up KT-1000 arthrometer findings, range of motion, and results of the Lachman and pivot shift tests were compared. There were no significant differences between the two groups at 22 months' follow-up. Subjective assessment of intensity of pain, swelling, and giving way was done by visual analog scales (0 to 10 rating). None of these parameters showed any statistically significant differences between the two techniques. This study shows that both of these techniques for reconstruction of the ACL render satisfactory objective and subjective results.

Adult↗

PubMed1995

Nitric oxide production by lymphatic endothelial cells in vitro.

The present study demonstrates that confluent monolayer cultures of lymphatic endothelial cells produce and secrete NO. Immunofluorescent studies showed that eNOS activity can be stimulated with Ca ionophore to enhance the production of NO. Cells exposed to LPS and various cytokines stimulated the production of iNOS which showed the greatest increase in activity at 4 hrs and declined at 18 and 24 hrs. These studies provide evidence that, within the lymphatic vascular lumen, nitric oxide may be produced by the lymphatic endothelium which interact with various vasoactive substances to regulate lymphatic vascular tone. In addition, the production of NO by LEC may be important in the regulation of lymphatic vascular tone in order to more readily accommodate sudden fluctuations in lymph flow and pressure that normally occur during the process of lymph formation and propulsion.

Animals↗

PubMed1995

Fractionated radioimmunotherapy of human colon carcinoma xenografts with 131I-labeled monoclonal antibody CC49.

Radiolabeled monoclonal antibodies (MoAbs) have been used for radioimmunotherapy (RIT) of human colon cancer xenografts in an attempt to develop promising clinical approaches to improving therapy success. Several strategies have been investigated to accomplish this task while decreasing toxicity. The CC49 antibody was selected for the present studies because of its relatively high affinity constant (16.2 x 10(9) M-1) for the high molecular weight TAG-72 mucinous antigen secreted by human colon cancer cells. In previous studies, when CC49 was labeled with 131I, it demonstrated a substantial therapeutic advantage over the lower affinity antibody (B72.3) reactive with TAG-72. One of the chief problems in achieving cures with RIT is that hematological toxicity limits the quantity of radionuclide that can be administered. In other studies of dose fractionation using athymic nude mice and 131I-labeled intact MoAbs reactive with human colon cancer xenografts, multiple administrations at approximately 1-week intervals were found to produce more prolonged tumor growth inhibition and less toxicity than single administrations. The purpose of this study was to investigate the therapeutic efficacy and toxicity of 131I-labeled CC49 MoAb administered with short fractionation schedules against human colon cancer xenografts to determine the optimal treatment schedule, with the ultimate aim of applying this approach in clinical trials. The results reported here demonstrate that in an animal colon cancer xenograft model, RIT delivered in a fractionated schedule clearly presents a therapeutic advantage. For example, one administration of 600 microCi 131I-labeled CC49 to LS174T tumor-bearing mice was lethal to approximately 25% of mice but produced no tumor regressions. Fractionation of this dose to two administrations of 300 microCi 131I-labeled CC49 at a 3-day interval resulted in tumor regression in approximately 30% of the animals, accompanied by a similar 25% death rate. The administration of 300 microCi 131I-labeled CC49 at a 7-day interval resulted in 15% animal lethality, but no complete tumor regressions. When three administrations of 300 microCi 131I-labeled CC49 were given over a 1-week period on days 0, 3, and 7, tumor regressions occurred in approximately 40% of the animals, accompanied by a 30% death rate. Moreover, three administrations of 300 microCi 131I-labeled CC49 resulted in 20% tumor recurrence, whereas two administrations of 131I-labeled CC49 resulted in 60% tumor recurrence.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

Novel antagonists of platelet-activating factor. 1. Synthesis and structure-activity relationships of benzodiazepine and benzazepine derivatives of 2-methyl-1-phenylimidazo[4,5-c]pyridine.

Following the discovery of moderately potent antagonist activity platelet-activating factor (PAF) in 2-methyl-1-phenylimidazo[4,5-c]pyridine (2) (IC50 = 840 nM), 19 derivatives (3-21) were prepared which incorporated various lipophilic groups attached to the phenyl 4-position. Structure-activity relationships were evaluated where PAF antagonist activity was measured in vitro by determining the concentration of compound (IC50) required to inhibit the PAF-induced aggregation of rabbit washed platelets and in vivo by determining the oral dose (ED50) which protected mice from a lethal injection of PAF. [1,5]Benzodiazepines, e.g., 14 (2,3-dihydro-1-methyl-4-[4-(2-methylimidazo[4,5-c] pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-one) (IC50 = 4.9 nM, Ed50 = 0.03 mg/kg po), were found to possess equivalent or superior potency to the 1,4-dihydropyridine PAF antagonist UK-74,505 (1,4-(2-chlorophenyl)-1,4-dihydro-3-(ethoxycarbonyl)-6-methyl-2- [4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-5-[N-(2-pyridyl) carbamoyl]pyridine) in vitro and in vivo. Furthermore, a potent benzazepine, 21 (7,8-dichloro-1-methyl-4-[4-(methylimidazo[4,5-c]pyrid-1-yl) phenyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one) (IC50 = 0.5 nM, ED50 = 0.03 mg/kg po), was discovered. These investigations prompted the synthesis and evaluation of additional diazepine derivatives, which are described in the following paper. The relationship between the key PAF antagonist pharmacophores of 2-methyl-1-phenylimidazo[4,5-c]pyridine, a triazolothienodiazepine (WEB2170), and a pyrrolothiazolidine (RP-52,770) is discussed.

Animals↗

PubMed1995

Software trapping: a strategy for finding genes in large genomic regions.

We present an approach to the gene identification phase of positional cloning that combines sparse sampling of DNA sequences from large genomic regions with computational analysis. We call the method "software trapping." The goal is to find coding exons while avoiding massive DNA sequence determination and contig assembly. Instead, rapid sequence sampling is combined with exon screening software such as a newly developed package called XPOUND to identify coding sequences. We have tested the approach using a set of model genomic sequences with known intron/exon structures as well as with bona fide P1 genomic clones. The results suggest that the strategy is a useful complement to other methods for finding genes in poorly characterized regions of genomes.

Bacteriophage P1↗

PubMed1995

Release of sialyltransferases from rat liver Golgi membranes by a cathepsin D-like proteinase: comparison of the release of Gal beta 1-4GlcNAc alpha 2-6 sialyltransferase, Gal beta 1-3(4)GlcNAc alpha 2-3 sialyltransferase and lactosylceramide alpha 2-3 sialyltransferase (SAT-1).

The activities of Gal beta 1-3(4)GlcNAc alpha 2-3 sialyltransferase and SAT-1 were measured in rat liver Golgi in inflammation; both enzymes decreased by about 50%. This compares with increases of about 3-fold for the Gal beta 1-4GlcNAc alpha 2-6 sialyltransferase. All three sialyltransferases were released from disrupted Golgi membranes by incubation at reduced pH which activates an endogenous cathepsin D which is believed to be the lysosomal enzyme. Pepstatin A was found to block the release of all three sialyltransferases providing support for the role of cathepsin D as the proteinase that clips the catalytic portions of the enzymes from their membrane anchor and stem regions.

Animals↗

PubMed1995

T-Fix endoscopic meniscal repair: technique and approach to different types of tears.

Endoscopic meniscus repair using the T-Fix suture device (Acufex Microsurgical, Inc, Mansfield, MA) allows ease of suture placement for meniscus stability without the problems associated with ancillary incisions such as neurovascular compromise. It is ideal for the central posterior horn tears that are difficult using conventional techniques. Vertical tears, bucket handle tears, flap tears, and horizontal tears can be approached using a temporary "anchor stitch" to stabilize the meniscus before T-Fix repair. The basic method of repair and our approach to these different types of tears is presented.

Humans↗

PubMed1995

Mutagenesis of the BC1 and BV1 genes of African cassava mosaic virus identifies conserved amino acids that are essential for spread.

The products of three open reading frames encoded by the bipartite geminiviruses have been implicated in viral spread: AC2, BV1 and BC1. Alignment of the DNA B encoded gene products, BV1 and BC1, from African cassava mosaic virus (ACMV) with six other bipartite geminiviruses showed several highly conserved regions. Specific amino acids were selected for mutagenic studies to ascertain the tolerance of the virus to change and to identify the regions within these two proteins required for normal functioning. Various mutant DNA B constructs, and a wild-type construct, were inoculated onto three host plant species with an equivalent DNA A construct. Three of the mutant constructs were infectious on Nicotiana benthamiana and N. clevelandii, but only two induced ACMV disease symptoms on N. tabacum cv. Samsun. Sequencing of the viral DNA extracted from the sap of systemically infected plants confirmed the maintenance of introduced base changes. The amino acid at position 95 on the BV1 gene product was identified as non-essential for normal functioning of the protein. The alteration of the amino acid at position 145 in BC1 demonstrated the ability of the virus to tolerate a conservative change. The lack of tolerance to other changes in amino acids has given an indication of the importance of maintaining protein structure for these proteins to function normally.

Amino Acid Sequence↗

PubMed1995

Developing standards for patient information. Highlights that effective communication can improve health care delivery.

Presents a review of the patient information literature used in the Taunton and Somerset NHS Trust. Describes the changes made to this literature in an attempt to improve the patient experience of the health care delivery. Highlights that appropriate, timely and effective communication with patients can improve the effectiveness of care and the efficiency with which it is delivered.

Communication↗

PubMed1995

Combined single-strand distal semitendinosus-iliotibial band tenodesis (Puddu) for anterior cruciate ligament augmentation.

Anterior cruciate ligament (ACL) reconstruction using the semitendinosus tendon has seen renewed interest recently. Puddu described a procedure in which the tendon is harvested at its insertion on the tibia with a bone plug. This study evaluates the efficacy of this approach and examines the long-term results. Between 1982 and 1986, 77 patients underwent this type of procedure; 51 (66%) patients who were reexamined comprised the study group. Thirty-five patients had acute tears, and 16 patients had chronic tears. Follow-up was both objective and subjective with an average follow-up of 7 years and 3 months (range: 5.8 to 9.2 years). In the acute group, six patients (17%) had a 2+ Lachman and seven (22%) had a 1+ Lachman. Pivot shift was 2+ to 3+ in three patients (8.6%) and 1+ in seven patients (22%). KT-100 results were > 5 mm in eight patients (23.3%). In the chronic group, four patients (25%) had 2+ and four had a 1+ Lachman. Seven patients (44%) had a positive pivot shift test. Five patients had > 5 mm difference. Using regression analysis, the KT-1000 results correlated well with the Lachman and pivot shift tests. Chronicity and partial meniscectomy were associated with a poor result. Although this technique has undergone an evolution and improvement to a four-strand reconstruction in recent years, the results of this review indicate satisfactory results can be obtained, especially in the acute setting.

Acute Disease↗

PubMed1993

Regulation of distal esophageal mucosal blood flow: the roles of nitric oxide and substance P.

BACKGROUND: An increase in esophageal mucosal blood flow (MBF) may be an important protective mechanism against mucosal injury from noxious agents that are ingested or refluxed. This study investigated the changes in MBF and the regulation thereof after intraluminal application of noxious chemical stimuli. The role, if any, of substance P (SP) and nitric oxide (NO), two potent vasodilatory substances, and the vascular distribution of SP in the distal esophagus were evaluated. METHODS: Esophageal MBF was measured in anesthetized dogs with a laser Doppler flow probe attached to manometry and pH probes. MBF was measured before and after topical application of HCl (2 ml; 1N) or capsaicin (2 ml; 0.5%) in the distal esophagus. The effects on MBF of intraarterial SP and bradykinin were also determined. Pharmacologic antagonists and denervation procedures were used to delineate the mechanisms that regulate MBF. RESULTS: Sequential luminal applications of hydrochloric acid (HCl) or a single application of capsaicin increased MBF (p < 0.01). Topical intraluminal lidocaine blocked the response to capsaicin (p > 0.2) but not to HCl (p < 0.05). Abrupt increases in MBF occurred with intraarterial SP or bradykinin (p < 0.01). Neither atropine nor truncal vagotomy blocked the increase in MBF from these peptides or noxious stimuli. The NO synthesis antagonist NG-nitro-L-arginine methyl ester (L-NAME) blocked the response to bradykinin and attenuated the response to HCl (p < 0.05). NG-nitro-L-arginine methyl ester did not affect the response to SP or capsaicin. A substance P antagonist blocked the effects of both capsaicin (p > 0.6) and SP (p > 0.1) but not that of HCl (p < 0.01) or bradykinin (p > 0.01). CONCLUSIONS: Intraluminal applications of HCl or capsaicin appear to stimulate increases in esophageal MBF by different mechanisms. HCl produces an adaptive response that appears dependent on the paracrine effect of NO. Capsaicin-sensitive neurons mediate vasodilation through SP neurotransmission, independent of extrinsic vagal or cholinergic innervation.

Animals↗

PubMed1992

1,4-Dihydropyridines as antagonists of platelet activating factor. 1. Synthesis and structure-activity relationships of 2-(4-heterocyclyl)phenyl derivatives.

A novel class of 2-(4-heterocyclylphenyl)-1,4-dihydropyridines (2-38) possessing antagonist activity against platelet activating factor (PAF) was prepared by the Hantzsch synthesis from a variety of ethyl 4'-heterocyclic-substituted benzoylacetates, aryl or heteroaryl aldehydes, and substituted 3-aminocrotonamides or 3-aminocrotonate esters. Structure-activity relationships were evaluated where PAF antagonist activity was measured in vitro by determining the concentration of compound (IC50) required to inhibit the PAF-induced aggregation of rabbit washed platelets, and in vivo by determining the oral dose (ED50) which protected mice from a lethal injection of PAF. The nature of the substituent at the dihydropyridine 2-position was found to be important for both in vitro and in vivo activity, whereas there was greater flexibility for structural variation at the 4- and 5-positions. The most potent compound was 4-(2-chlorophenyl)-1,4-dihydro-3-(ethoxycarbonyl)-6-methyl-2-[4-(2- methylimidazo[4,5-c]pyrid-1-yl)phenyl]-5-[N-(2- pyridyl)carbamoyl]pyridine (17, UK-74,505), IC50 = 4.3 nM, ED50 = 0.26 mg/kg po, which was found to be approximately 33 times more potent in vitro (rabbit platelet aggregation) and about 8 times more potent in vivo (murine lethality) than WEB2086. Compound 17 also exhibited a long duration of action in the dog (inhibition of PAF-induced whole blood aggregation ex vivo was maintained for greater than 24 h following a single oral dose of 75 micrograms/kg) and was highly selective as a PAF antagonist, showing only weak affinity (IC50 = 6600 nM) for the [3H]nitrendipine binding site. As a result of its high oral potency, selectivity, and duration of action, UK-74,505 has been selected for clinical evaluation.

Animals↗

PubMed1992

Angiotensin II receptor binding associated with nigrostriatal dopaminergic neurons in human basal ganglia.

In the human brain, receptor binding sites for angiotensin are found in the striatum and in the substantia nigra pars compacta overlying dopamine-containing cell bodies. In contrast, angiotensin-converting enzyme occurs in the substantia nigra pars reticulata and is enriched in the striosomes of the striatum. In this study, using quantitative in vitro autoradiography, we demonstrate decreased angiotensin receptor binding in the substantia nigra and striatum of postmortem brains from patients with Parkinson's disease. In the same brains the density of binding to angiotensin-converting enzyme shows no consistent change. We propose, from these results, that angiotensin receptors in the striatum are located presynaptically on dopaminergic terminals projecting from the substantia nigra. In contrast, the results support previous studies in rats demonstrating that angiotensin-converting enzyme is associated with striatal neurons projecting to the substantia nigra pars reticulata. These findings raise the possibility that newly emerging drugs that interact with the angiotensin system, particularly converting enzyme inhibitors and new nonpeptide angiotensin receptor blockers, may modulate the brain dopamine system.

Aged↗

PubMed1992

Regulation of the activities of African cassava mosaic virus promoters by the AC1, AC2, and AC3 gene products.

DNA fragments comprising each of the promoter regions from the geminivirus African cassava mosaic virus (ACMV) were cloned into the pUC18-based vector, pG1, producing transcriptional fusions with the beta-glucuronidase gene (GUS) and nopaline synthase terminator sequence. The relative activity of each promoter construct was analyzed by a GUS expression assay of extracts from Nicotiana clevelandii protoplasts coelectroporated with the GUS reporter constructs and constructs in which individual ACMV open reading frames (ORFs) were placed under control of a cauliflower mosaic virus 35 S promoter. Results suggest repression of the AC1 gene by its gene product, which is required for ACMV DNA synthesis. The promoter activity observed for the single promoter for the DNA A genes encoding functions of spread and the regulation of replication (AC2 and AC3 ORFs) was unaffected by coelectroporation with any of the ACMV ORF constructs. Promoters for the AV1 (coat protein) gene and the two DNA B genes (BV1 and BC1) were activated by electroporation of the AC2 ORF construct. To a lesser extent promoters for the AV1 and BV1 genes were activated with the AC3 ORF construct. The same pattern of promoter repression and activation was observed when transgenic N. benthamiana plants expressing the GUS reporter constructions were inoculated with ACMV DNA A.

DNA-Directed DNA Polymerase↗