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Biomedical subjects

G Jones

Publications and source records attributed to G Jones.

At least 217 records · Page 12Linked to original sources
PubMed1997

Psoriatic arthritis: a quantitative overview of therapeutic options. The Psoriatic Arthritis Meta-Analysis Study Group.

The objective of this study was to use the technique of meta-analysis to undertake a systematic review of published and unpublished randomized controlled trials of pharmacological agents to determine their relative efficacy and toxicity in the treatment of psoriatic arthritis. The main outcome measure was the change in pooled disease index with component variables derived from OMERACT. Nineteen randomized trials were identified, of which 12 were included in the quantitative analysis with data from 792 subjects. Although all agents were better than placebo, parenteral high-dose methotrexate, salazopyrin, azathioprine and etretinate were the agents that achieved statistical significance (although it should be noted that only one component variable was available for azathioprine and only one trial with a high dropout rate was available for etretinate suggesting some caution is necessary in interpreting these results). In all trials, the placebo group improved over baseline (pooled improvement 0.43 disease index (DI) units, 95% CI 0.28-0.59). There were insufficient data to examine toxicity. In conclusion, parenteral high-dose methotrexate and salazopyrin are the only two agents with well-demonstrated published efficacy in psoriatic arthritis. The magnitude of the effect seen with etretinate, oral low-dose methotrexate, azathioprine and perhaps colchicine suggests that they may be effective, but that further multicentre clinical trials are required to establish their efficacy. Furthermore, the magnitude of the improvement observed in the placebo group strongly suggests that uncontrolled trials should not be used to guide management decisions in this condition.

Antirheumatic Agents↗
PubMed1997

Management of the infected median sternotomy wound with muscle flaps. The Emory 20-year experience.

OBJECTIVE: The purpose of the study is to define those patient variables that contribute to morbidity and mortality of median sternotomy wound infection and the results of treatment by debridement and closure by muscle flaps. BACKGROUND: Infection of the median sternotomy wound after open heart surgery is a devastating complication associated with significant mortality. Twenty years ago, these wounds were treated with either open packing or antibiotic irrigation, with a mortality approaching 50% in some series. In 1975, the authors began treating these wounds with radical sternal debridement followed by closure using muscle or omental flaps. The mortality of sternal wound infection has dropped to < 10%. METHODS: The authors' total experience with 409 patients treated over 20 years is described in relation to flap choices, hospital days after sternal wound closure, and incidence rates of morbidity and mortality. One hundred eighty-six patients treated since January 1988 were studied to determine which patient variables had impact on rates of flap closure complications, recurrent sternal wound infection, or death. Variables included obesity, history of smoking, hypertension, diabetes, poststernotomy septicemia, internal mammary artery harvest, use of intra-aortic balloon pump, and perioperative myocardial infarction and were analyzed using chi square tests. Fisher's exact tests, and multivariable logistic regression analysis. RESULTS: The mortality rate over 20 years was 8.1% (33/49). Additional procedures for recurrent sternal wound infection were necessary in 5.1% of patients. Thirty-one patients (7.6%) required treatment for hematoma, and 11 patients (2.7%) required hernia repair. Among patients treated since 1988, variables strongly associated with mortality were septicemia (p < 0.00001), perioperative myocardial infarction (p = 0.006), and intra-aortic balloon pump (p = 0.0168). Factors associated with wound closure complications were intra-aortic balloon pump (p = 0.0287), hypertension (p = 0.0335), and history of smoking (p = 0.0741). Factors associated with recurrent infection were history of sternotomy (p = 0.008) and patients treated for sternal wound infection from 1988 to 1992 (p = 0.024). Mean hospital stay after sternal wound reconstruction declined from 18.6 days (1988-1992) to 12.4 days (1993-1996) (p = 0.005). To clarify management decisions of these difficult cases, a classification of sternal wound infection is presented. CONCLUSIONS: Using the principles of sternal wound debridement and early flap coverage, the authors have achieved a significant reduction in mortality after sternal wound infection and have reduced the mean hospital stay after sternal wound closure of these critically ill patients. Further reductions in mortality will depend on earlier detection of mediastinitis, before onset of septicemia, and ongoing improvements in the critical care of patients with multisystem organ failure.

Debridement↗
PubMed1997

Functional magnesium deficiency in critically ill patients identified using a magnesium-loading test.

OBJECTIVE: To determine the feasibility of the magnesium-loading test in the critically ill and to validate serum ionized magnesium assay using the magnesium-loading test as a reference in this same patient population. DESIGN: Double-blind, randomized, controlled clinical investigation. SETTING: Tertiary level intensive care unit. PATIENTS: Forty-four consecutive critically ill patients without evidence of renal insufficiency. INTERVENTION: Patients were randomly allocated to receive 30 mmol (7.5 g) of magnesium sulfate daily for 3 days, or an equivalent amount of normal saline. MEASUREMENTS AND MAIN RESULTS: We recorded baseline characteristics, and serial serum biochemical measurements included creatinine, glucose, sodium, potassium, phosphate, total calcium, ionized calcium, total magnesium, and ionized magnesium. Serum assays were accompanied by 24-hr urine collections of creatinine and magnesium over the 3-day period. Baseline characteristics were comparable in both groups. In patients receiving magnesium, serum ionized magnesium and total magnesium concentrations were increased by 43% (p = .0001) and 59% (p = .0002), respectively, on day 1 as compared with the control group. Magnesium excretion in the control group averaged 4.8 +/- 2.3 mmol/day during the 3-day study period, while the magnesium excretion in the magnesium-loaded group was significantly increased to 22.7 +/- 10.9 mmol/day (p < .0001). Following day 1 magnesium loading, patients who excreted < 70% of the total magnesium (30 mmol infused magnesium plus 4.8 mmol basal excretion) were termed as functionally magnesium-deficient retainers (n = 12), and patients who excreted > 70% of the total magnesium were termed as nonretainers (n = 7). In addition, magnesium retainers on day 2 (nine of ten patients) and day 3 (five of six patients) excreted > 70% of the total magnesium, indicating a replenishment of body magnesium stores. In contrast, nonretainers on day 2 (four of five patients), and day 3 (four of four patients) continued to excrete excess amounts of magnesium. In the retainer group, only two patients had a low serum ionized magnesium concentration, while two other patients had low total serum magnesium values. In addition, magnesium retention was associated with low ionized calcium and high phosphate values. CONCLUSIONS: The magnesium-loading test is feasible and appears to be valid based on its performance during the 3-day evaluation. Using the magnesium-loading test as a reference, serum ionized magnesium appears to be an insensitive biochemical marker of functional hypomagnesemia. Larger cohort studies using the magnesium-loading test will help establish the true prevalence of magnesium deficiency and its associated risk factors in critically ill patients.

APACHE↗
PubMed1997

Reassessment of the phylogenetic position of Caulobacter subvibrioides.

Determination of the 16S rRNA gene sequence of Caulobacter subvibrioides ATCC 15264T (T = type strain) confirmed that this species is a member of the alpha subclass of the Proteobacteria and showed that it is phylogenetically most closely related to the Caulobacter group comprising the species Caulobacter bacteroides, Caulobacter crescentus, and Brevundimonas (Pseudomonas) diminuta, for which 16S rRNA sequences of the type strains are currently available. The closest known relative of strain ATCC 15264T among these species is B. diminuta (level of direct pairwise sequence similarity, 95%). On the basis of its previously determined 16S rRNA sequence (accession number M83797), C. subvibrioides is most closely related to Sphingomonas adhaesiva in the alpha-4 subgroup (level of similarity, 97.7%). Analysis of the hydroxy fatty acids of C. subvibrioides ATCC 15264T showed that the 2-hydroxymyristic acid which is characteristic of the genus Sphingomonas was absent.

Caulobacter↗
PubMed1997

The vitamin D analog, KH1060, is rapidly degraded both in vivo and in vitro via several pathways: principal metabolites generated retain significant biological activity.

Vitamin D analogs are valuable drugs with established and potential uses in hyperproliferative disorders. Lexacalcitol (KH1060) is over 100 times more active than 1alpha,25-dihydroxyvitamin D3 [1alpha,25-(OH)2D3], as judged by in vitro antiproliferative and cell differentiating assays. The underlying biochemical reasons for the increased biological activity of KH1060 are unknown, but are thought to include 1) metabolic considerations in addition to explanations based upon 2) enhanced stability of KH1060-liganded transcriptional complexes. In this study we explored the in vivo and in vitro metabolism of KH1060. We established by physicochemical techniques the existence of multiple side-chain hydroxylated metabolites of KH1060, including 24-, 24a-, 26-, and 26a-hydroxylated derivatives as well as side-chain truncated forms. KH1060 metabolism could be blocked by the cytochrome P450 inhibitor, ketoconazole. KH1060 was not an effective competitor of C24 oxidation of 1alpha,25-(OH)2D3. Certain hydroxylated metabolites of KH1060 retained significant biological activity in vitamin D-dependent reporter gene systems (chloramphenicol acetyltransferase). Likewise, those metabolites accumulating in the target cell culture models in metabolism studies, particularly 24a-hydroxy-KH1060 and 26-hydroxy-KH1060, retained biological activities superior to those of 1alpha,25-(OH)2D3 in native gene expression systems in vitamin D target cells (osteopontin and P450cc24). We conclude that KH1060 is rapidly metabolized by a variety of cytochrome P450-mediated enzyme systems to products, many of which retain significant biological activity in vitamin D-dependent assay systems. These results provide an explanation for the considerable biological activity advantage displayed by KH1060 compared with 1alpha,25-(OH)2D3 in various in vitro assay systems.

Animals↗
PubMed1997

Neonatal feeding of infants born with cleft lip and/or palate: parental perceptions of their experience in south Wales.

OBJECTIVE: This paper describes the responses of 100 parents of children born with cleft lip and/or palate in South East Wales to a postal questionnaire survey of their experiences of the services available to help with the feeding of their children in the immediate postnatal period. RESULTS & CONCLUSIONS: Prior to birth, the majority of mothers intended to breast feed their child; after birth, the majority of infants were bottle fed. The majority of mothers felt that they had been a part of the decision to change methods. Advice on feeding was obtained from a variety of sources, both in hospital and on discharge. Mothers of cleft children who were first born in the family were less critical of the support offered in hospital than were mothers whose cleft child was a second or subsequent child. Isolated clefts of the palate were associated with a high proportion of feeding via nasogastric tube both on discharge from hospital and at home. The major criticism of the service offered to parents and their children was the poor quality of advice on feeding their children, both in hospital and on discharge. A variety of mechanisms for service improvement are suggested.

Attitude to Health↗
PubMed1997

Antecedents of intensity and direction dimensions of competitive anxiety as a function of skill.

Described here is a follow-up and extension of the study reported by Hanton and Jones in 1995. Situational antecedents of both 'intensity' (level) and 'direction' (facilitative/debilitative) dimensions of precompetitive state anxiety in 97 elite and 114 nonelite competitive swimmers were examined. Antecedents were assessed via the modified swimming version of the PreRace Questionnaire, while cognitive anxiety, somatic anxiety, and self-confidence were measured via the modified version of the Competitive State Anxiety Inventory-2 one hour before competition. Step-wise multiple regression analyses on the intensity scores indicated that cognitive anxiety in the elite group was significantly related to Perceived readiness (5.6%) and Internal environment (9.6%), while no predictors emerged in the nonelite group; scores on somatic anxiety correlated with those on Internal environment (9.4%) and Position goal (14.4%) in the elite group, and by Attitude towards previous performance (4.7%) and Internal environment (8.5%) in the nonelite group. Self-confidence was predicted by Perceived readiness in the elite group (30.3%) and the nonelite group (16.9%). In the case of the direction scores (facilitative/debilitative interpretations), no significant correlations of scores on cognitive anxiety or somatic anxiety emerged for the elite group; however, in the nonelite group the Coach influence factor predicted cognitive anxiety (4.5%) and somatic anxiety (4.9%). These findings show that common and unique antecedents of 'intensity' and 'direction' exist for swimmers as a function of their skill and also highlight the important role of the coach in the maintenance of facilitative interpretations of anxiety by nonelite performers.

Adolescent↗
PubMed1997

Human colorectal carcinoma cells in vitro as a means to assess the metabolism of analogs of mycophenolic acid.

Cultures of the human colorectal carcinoma line, HT29, were used to assess the susceptibility to glucuronidation of the cytostatic, immunosuppressive drug mycophenolic acid (MPA) and 19 of its analogs. Removal of the metabolically vulnerable 7-hydroxyl group or its replacement by a fluorine atom, amino group, or nitrile group resulted in compounds that were completely resistant to metabolism, but that had substantially lower antiproliferative potency against the EMT6 carcinoma line that is unable to glucuronidate MPA. In compounds retaining the 7-hydroxy function replacement of the lactone moiety of the phthalane ring of MPA by either a cyclopentanone or a 6-membered lactam afforded some protection against metabolism, but also partially or completely suppressed antiproliferative activity. Some lipophilic substituents at position 2 of the hexenoic side chain in analogs with the 7-hydroxy function resulted in increased metabolism, whereas several substituents with increased steric bulk in this position (including benzyl, p-hydroxyphenyl, trifluoroacetamidophenyl,S-methyl, and methoxymethyl) markedly inhibited metabolism. The last three of these derivatives also maintained or exceeded the antiproliferative potency of MPA. We suggest that cultures of human colorectal carcinoma cells lines may provide a rapid and convenient means of assessing the susceptibility of novel synthetic compounds to both phase I and phase II metabolic conversions.

Antibiotics, Antineoplastic↗
PubMed1997

Effect of citrate concentration in specimen collection tubes on the International Normalized Ratio.

PROBLEM: Does citrate concentration in specimen collection tubes affect the International Normalized Ratio? METHODS: The International Normalized Ratio was determined on quadruplicate plasma specimens from 32 patients treated long term with oral anticoagulants-two from tubes with 3.2% citrate and two with 3.8% citrate. Two laboratories, using two different coagulometers, tested the specimens. RESULTS: International Normalized Ratios of plasma from tubes with 3.8% citrate were significantly higher than those from tubes with 3.2% citrate when tested with either coagulometer. Patients given adequate anticoagulation on the basis of the International Normalized Ratio at one concentration of citrate appeared either overanticoagulated and at risk of bleeding or underanticoagulated and at risk of thromboembolism at the other concentration of citrate. CONCLUSION: Results emphasize the need for using a single concentration of citrate for prothrombin time testing. We recommend 3.2% citrate.

Anticoagulants↗
PubMed1996

Identification of the retinoic acid-inducible all-trans-retinoic acid 4-hydroxylase.

Retinoic acid (RA) metabolites of vitamin A are key regulators of gene expression involved in embryonic development and maintenance of epithelial tissues. The cellular effects of RA are dependent upon the complement of nuclear receptors expressed (RARs and RXRs), which transduce retinoid signals into transcriptional regulation, the presence of cellular retinoid-binding proteins (CRABP and CRBP), which may be involved in RA metabolism, and the activity of RA metabolizing enzymes. We have been using the zebrafish as a model to study these processes. To identify genes regulated by RA during exogenous RA exposure, we utilized mRNA differential display. We describe the isolation and characterization of a cDNA, P450RAI, encoding a novel member of the cytochrome P450 family. mRNA transcripts for P450RAI are expressed normally during gastrulation, and in a defined pattern in epithelial cells of the regenerating caudal fin in response to exogenous RA. In COS-1 cells transfected with the P450RAI cDNA, all-trans-RA is rapidly metabolized to more polar metabolites. We have identified 4-oxo-RA and 4-OH-RA as major metabolic products of this enzyme. P450RAI represents the first enzymatic component of RA metabolism to be isolated and characterized at the molecular level and provides key insight into regulation of retinoid homeostasis.

Amino Acid Sequence↗
PubMed1996

Construction of a P450c27 fusion enzyme: a useful tool for analysis of vitamin D3 25-hydroxylase activity.

Liver mitochondrial P450c27, encoded by the CYP27 gene, can catalyse the 25-hydroxylation of vitamin D3 and the 27-hydroxylation of sterols. To facilitate the study of this enzyme in cell culture systems, we engineered a fusion protein consisting of P450c27 coupled to its electron-transport accessory proteins, ferredoxin and ferredoxin reductase, and assessed its enzyme activity by measuring the C-25 and C-27 (side-chain) hydroxylation of 1 alpha-hydroxyvitamin D3 (1 alpha-OH-D3). When incubated with 1 alpha-OH-D3, COS-1 cells transfected with a vector expressing the fusion protein produced 1 alpha,25-(OH)2D2 and 1 alpha,27-(OH)2D3 about four times more efficiently than did cells transfected with three individual components of the fusion. When incubated with the natural substrate, vitamin D3, the efficiency of hydroxylation was lower than that for 1 alpha-OH-D3 but still 1.7-fold higher for the fusion protein than for its individual components. The fusion protein was also able to reproduce qualitatively and quantitatively the activity shown by P450c27 in liver cells in situ. The P450c27-ferredoxin reductase-ferredoxin fusion construct represents a valuable tool for establishing the substrate specificity of this liver cytochrome and for evaluating its potential for activating pro-drug analogues of vitamin D.

Animals↗
PubMed1996

Prevention and management of osteoporosis: consensus statements from the Scientific Advisory Board of the Osteoporosis Society of Canada. 8. Vitamin D metabolites and analogs in the treatment of osteoporosis.

OBJECTIVE: To review recent findings on the skeletal actions of vitamin D and to examine results of the latest clinical trials of vitamin D in the treatment of osteoporosis. OPTIONS: The vitamin D analog 1-alpha hydroxycholecalciferol (1 alpha-OH-D3); the vitamin D metabolite calcitriol. OUTCOMES: Fracture and loss of bone mineral density in osteoporosis; increased bone mass, prevention of fractures and improved quality of life associated with vitamin D therapies. EVIDENCE: Relevant laboratory and clinical studies and reports were examined. Greatest reliance was placed on recent large-scale, randomized, controlled trials; others were noted and their methods critiqued. Clinical practice in Japan was also considered. VALUES: Reducing fractures, increasing bone mineral density and minimizing side effects of treatment were given a high value. BENEFITS, HARMS AND COSTS: Vitamin D maintains the dynamic nature of bone and so presumably helps to keep it healthy. Calcitriol and 1 alpha-OH-D3 may be effective in increasing bone mass and preventing fractures in osteoporosis. Calcitriol may be an alternative treatment in the prevention and management of corticosteroid-induced osteoporosis. Possible side effects of vitamin D analogs and metabolites are hypercalcemia, hypercalciuria, renal calcification and renal stones. RECOMMENDATIONS: The use of 1 alpha-OH-D3 for the treatment of osteoporosis in Canada cannot be supported without larger and longer randomized, controlled clinical trials. Calcitriol appears to prevent vertebral fractures in patients with osteoporosis. More information is needed on its mechanism of action and efficacy in preventing hip fractures. Future studies should focus on comparisons with other effective therapies and on determining whether its effect on fractures is greater than that achieved through improved vitamin D nutrition. Patients taking calcitriol at dose levels required for antifracture effects should be monitored for serum and urine calcium response to the drug. Calcitriol should not be given to patients whose calcium intake is at current generally recommended levels. At present, prescription of calcitriol for the treatment of osteoporosis should be reserved for physicians with a special interest in the treatment of metabolic bone disease.

Aged↗
PubMed1996

Identification of regulatory sequences of juvenile hormone-sensitive and -insensitive serum protein-encoding genes.

The promoters of three juvenile hormone (JH)-sensitive, and one JH-insensitive hexamerin-encoding genes (Hex) were isolated from Trichoplusia ni, and sequences necessary for, or affecting, transcriptional activity were identified by biochemical and functional methods. The transcription start points (tsp) for each of the four Hex were determined biochemically, by both primer extension and the sequencing of multiple, independent full-length cDNA clones. The function of each inferred tsp, as an actual tsp, was confirmed by in vitro transcription assay. The transcription initiator sequence, GNACAGT, was identical for three of the Hex, while the fourth used a divergent motif. Using the in vitro transcription system, a minimal core promoter of 60 bp (bp -34 to +24) of the BJHSP1 (basic JH suppressible protein 1) gene, containing a single TATA box motif approximately 30 bp upstream of the tsp, was functionally sufficient to support alpha-amanitin-sensitive transcription. The same construct was also transcriptionally functional in a homologous cell line transfection assay. The corresponding region of the other Hex also contains a similarly positioned TATA box motif, and promoter constructs for each, that included that included the tsp, initiator and inferred basal transcription apparatus binding site, were all transcriptionally functional in a cell line transfection assay. The action of sequences 5' to the minimal promoter region in modulating the rate of transcription was shown by a cell line transfection assay of a nested deletion series of the promoter for the BJHSP1 gene, in which the results identified a strongly suppressive element between positions -160 and -109. This system of Hex genes, including those sensitive to JH and one not sensitive, should be useful in a comparative approach toward identifying those regulatory motifs that are functionally necessary to transduce the regulatory action of JH.

Animals↗
PubMed1996

Anti-proliferative activity and target cell catabolism of the vitamin D analog 1 alpha,24(S)-(OH)2D2 in normal and immortalized human epidermal cells.

Vitamin D analogs represent valuable new agents for the suppression of proliferation of a variety of cell types, including those of the skin. One such analog is the vitamin D2 metabolite, 1 alpha,24(S)-dihydroxyvitamin D2, which binds strongly to the vitamin D receptor and induces vitamin D-dependent gene expression in vitro. In the work described here, we studied the anti-proliferative activity and target cell metabolism of 1 alpha,24(S)-dihydroxyvitamin D2 in cells of human epidermal origin. We found this analog to be equally potent in its anti-proliferative effect to the hormone 1 alpha,25-dihydroxyvitamin D3. Furthermore, 1 alpha,24(S)-dihydroxyvitamin D2 was metabolized by the human keratinocyte cell line HPK1A-ras at a slower rate than either 1 alpha,25-dihydroxyvitamin D3 or calcipotriol, a drug used effectively in the treatment of psoriasis. We characterized the metabolic products of 1 alpha,24(S)-dihydroxyvitamin D2 as a mixture of side-chain truncated and hydroxylated products. The main product was identified by GC-MS and NMR techniques as 1 alpha,24(S),26-trihydroxyvitamin D2. The biological activity of this main product was determined in a vitamin D-dependent, growth-hormone reporter gene expression system to be lower than that of the parent molecule. We conclude from these data that 1 alpha,24(S)-dihydroxyvitamin D2 is a valuable new anti-proliferative agent with a slower rate of catabolism by cells of epidermal origin. Preliminary evidence suggests that the parent molecule, and not its products, is responsible for this biological activity in vitro.

3T3 Cells↗
PubMed1996

Substrate-bound agrin induces expression of acetylcholine receptor epsilon-subunit gene in cultured mammalian muscle cells.

Expression of the epsilon-subunit gene of the acetylcholine receptor (AChR) by myonuclei located at the neuromuscular junction is precisely regulated during development. A key role in this regulation is played by the synaptic portion of the basal lamina, a structure that is also known to contain agrin, a component responsible for the formation of postsynaptic specializations. We tested whether agrin has a function in synaptic AChR gene expression. Synaptic basal lamina from native adult muscle and recombinant agrin bound to various substrates induced in cultured rat myotubes AChR clusters that were colocalized with epsilon-subunit mRNA. Estimation of transcript levels by Northern hybridization analysis of total RNA showed a significant increase when myotubes were grown on substrate impregnated with agrin, but were unchanged when agrin was applied in the medium. The effect was independent of the receptor aggregating activity of the agrin isoform used, and agrin acted, at least in part, at the level of epsilon-subunit gene transcription. These findings are consistent with a role of agrin in the regulation of AChR subunit gene expression at the neuromuscular junction, which would depend on its binding to the synaptic basal lamina.

Agrin↗