Biomedical subjects
Publications and source records attributed to J Stevens.
This paper outlines the implementation of a multidisciplinary integrated community and hospital leg ulcer service in 1993 and its effect on the health outcomes and quality of life of patients living in the area of the Hounslow and Spelthorne Community and Mental Health Trust prior to and following the establishment of the service.
In the context of studying the medicalization of women, we sought insight into the reflexive and mutually influential relationships between the prevailing social agenda and the formal knowledge base by analyzing the content, purpose and funding source of the scholarly work published in the three major, English-language obstetrics and gynecology journals. Our analysis of the 6103 articles published in 1975, 1980, 1985, 1990, and 1993 led us to the conclusion that, rather than responding to changing social needs and life-styles, the obstetrics and gynecology specialty has continued to emphasize the reproductive nature of women rather than the health and well-being requirements of non-pregnant and non-fertile women. The social values and attitudes toward women inferred from the priorities evident in these data are ideologically consistent with the view that women's primary role is that of reproduction. The implied importance of certain themes and the consequent allocation of resources may serve to perpetuate the politically oppressive view of women as biologically motivated and determined.
OBJECTIVE: To determine the association of coronary heart disease (CHD) incidence with diabetes, fasting serum glucose, and insulin in a biracial cohort of middle-aged men and women. RESEARCH DESIGN AND METHODS: We examined a population-based sample (n = 13,446 free of baseline CHD) from four U.S. communities in 1987-1989. We defined diabetes on the basis of baseline fasting glucose concentration (> or = 7.8 mmol/l), medical history, and current medications. A central laboratory measured fasting insulin with a nonspecific radioimmunoassay. After 4-7 years, 209 men and 96 women developed CHD. RESULTS: After adjustment for sociodemographic characteristics, smoking status, ethanol intake, sports participation, and hormone replacement therapy, the relative risk of CHD for people with diabetes versus those without diabetes was 3.45 (95% CI 2.16-5.50) among women and 2.52 (1.78-3.56) among men. Relative risks of CHD with diabetes were somewhat lower in blacks than non-blacks, but because diabetes was more than twice as prevalent in blacks, the percentage of CHD cases attributable to diabetes (population attributable risk) was 27% for black women, 15% for non-black women, 8% for black men, and 12% for non-black men. Among people without diabetes, fasting glucose was not independently associated with CHD incidence. Among women without diabetes, there was a positive association between fasting insulin and CHD; multivariable adjusted relative risks of CHD across quintiles of fasting insulin were 1.00, 0.76, 2.08, 2.08 and 2.82 (P for linear trend = 0.02). However, among men without diabetes, fasting insulin and CHD were not associated. CONCLUSIONS: Diabetes conveys a high risk of CHD in black and non-black middle-aged men and women. Fasting insulin, however, is a CHD risk factor only among women in this cohort.
This statistical comparison between patients with cervical myelopathy secondary to horizontal atlantoaxial subluxation and those with vertical translocation is designed to elucidate the mechanisms responsible for cranial settling and the effect of translocation on the development of spinal cord compression. In a 10-year study of a cohort of 256 patients, 186 suffered from myelopathy and 116 (62%) of these exhibited vertical translocation according to the Redlund-Johnell criteria. Vertical translocation occurred after a significantly longer period of disease than atlantoaxial subluxation (p < 0.001). Translocation was characterized clinically by a high cervical myelopathy with features of a cruciate paralysis present in 35% of individuals compared with 26% who exhibited horizontal atlantoaxial subluxation (p = 0.29), but there was a surprising paucity of cranial nerve problems. The patients with vertical translocation had a greater degree of neurological disability (p = 0.002) and poorer survival rates (p = 0.04). Radiologically, vertical translocation was secondary to lateral mass collapse and associated with a progressive decrease in the atlantodens interval ([ADI], r = 0.4; p < 0.001) and pannus (p = 0.003). Thirty percent of patients exhibited an ADI of less than 5 mm. This phenomenon has been termed pseudostabilization. The authors' studies emphasize that the ADI (frequently featured in the literature) is totally unreliable as an indicator of neuraxial compromise in the presence of vertical translocation.
This is a prospective observational study in 116 patients with rheumatoid arthritis and vertical translocation who underwent cervical spine surgery after developing symptomatic myelopathy. These patients, whose mean age was 62 years, had suffered from rheumatoid arthritis for almost 25 years. Surgery was performed via a combination of anterior (67 transoral decompressions) and posterior approaches. Surgical morbidity was recorded in 39% of patients, with a 30-day mortality rate of 10.3%, which was largely related to poor preoperative neurological grade. Neurological improvement of at least one Ranawat class was observed in 55 patients. Univariate analysis revealed the following clinical variables to be associated with a good neurological outcome (Ranawat class): younger age and good preoperative muscle power. Significant radiological variables included the degree of vertical translocation as measured by the Redlund-Johnell method and the preoperative spinal cord area. The degree of transgression in the foramen magnum did not significantly affect neurological outcome. Neither the anterior nor the posterior atlantodens interval predicted neurological recovery. Multiple logistic regression models were constructed based on the preliminary evidence of the authors' univariate analysis and these confirmed the importance of preoperative neurological function, spinal cord area, and the degree of vertical translocation in influencing the final neurological grade.
Cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) isoenzymes involved in riluzole oxidation and glucuronidation were characterized in (1) kinetic studies with human hepatic microsomes and isoenzyme-selective probes and (2) metabolic studies with genetically expressed human CYP isoenzymes from transfected B-lymphoblastoid and yeast cells. In vitro incubation of [14C]riluzole (15 microM) with human hepatic microsomes and NADPH or UDPGA cofactors resulted in formation of N-hydroxyriluzole (K(m) = 30 microM) or an unidentified glucuroconjugate (K(m) = 118 microM). Human microsomal riluzole N-hydroxylation was most strongly inhibited by the CYP1A2 inhibitor alpha-naphthoflavone (IC50 = 0.42 microM). Human CYP1A2-expressing yeast microsomes generated N-hydroxyriluzole, whereas human CYP1A1-expressing yeast microsomes generated N-hydroxyriluzole, two additional hydroxylated derivatives and an O-dealkylated derivative. CYP1A2 was the only genetically expressed human P450 isoenzyme in B-lymphoblastoid microsomes to metabolize riluzole. Riluzole glucuronidation was inhibited most potently by propofol, a substrate for the human hepatic UGT HP4 (UGT1.8/9) isoenzyme. In vitro, human hepatic microsomal hydroxylation of riluzole (15 microM) was weakly inhibited by amitriptyline, diclofenac, diazepam, nicergoline, clomipramine, imipramine, quinine and enoxacin (IC50 approximately 200-500 microM) and cimetidine (IC50 = 940 microM). Riluzole (1 and 10 microM) produced a weak, concentration-dependent inhibition of CYP1A2 activity and showed competitive inhibition of methoxyresorufin O-demethylase. Thus, riluzole is predominantly metabolized by CYP1A2 in human hepatic microsomes to N-hydroxyriluzole; extrahepatic CYP1A1 can also be responsible for the formation of several other metabolites. Direct glucuronidation is a relatively minor metabolic route. In vivo, riluzole is unlikely to exhibit significant pharmacokinetic drug interaction with coadministered drugs that undergo phase I metabolism.
OBJECTIVE: To study the validity and feasibility of a computerized version of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index. METHODS: Thirty patients with osteoarthritis (OA) of the knee completed both a paper and a computerized version of WOMAC in random order. The visual analog scaled version of WOMAC, VA3.0, was used. We studied criterion validity by comparing the paper and computerized versions. RESULTS: All patients completed the computerized version without undue difficulty. Criterion validity, based on aggregated subscale scores, was excellent: Pain, ICC = 0.89, Stiffness, ICC = 0.87, Physical Function, ICC = 0.95. CONCLUSION: The computerized version of WOMAC VA3.0 is a valid alternative to the paper version.
The enzyme system xanthine dehydrogenase (XD):xanthine oxidase, which generates the superoxide anion as a by-product of action on endogenous substrates, is believed to play a role in mediating pathophysiological changes through its contribution to total superoxide production. To aid with analysis of factors that regulate XD, we have developed a reverse transcription (RT)-coupled competitive quantitative polymerase chain reaction (PCR) assay which enables XD mRNA to be determined from small amounts of cultured cells where constitutive XD levels are low. A homologous insertion mutant of wild-type XD cDNA was prepared and used as an internal standard to normalize intersample PCR efficiency differences. XD mRNA levels determined by RT-PCR also were normalized to tubulin mRNA to compensate for RT differences and loading effects among samples. We report that XD mRNA levels, determined by RT-PCR, were increased twofold in hypoxic (3% oxygen) rat pulmonary microvascular endothelial cells relative to normoxic controls (20% oxygen). Conversely, XD mRNA was decreased threefold within 24 h under hyperoxic (95% oxygen) conditions. These data support the hypothesis that XD is regulated by oxygen tension in the pulmonary vasculature.
Dietary enrichment of membrane phospholipids with n-3 (fish-oil-derived) fatty acids has attracted attention as a putative therapeutic regimen for suppression of inflammatory and coagulatory events. Use of n-3 fatty-acid-enriched lipid infusions for parenteral nutrition results in micromolar concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DCHA) in the plasma-free fatty acid fraction. We investigated the influence of free EPA and DCHA on platelet thromboxane (Tx) A2 and A3 formation by using a recently developed high performance liquid chromatography-ELISA technique for separate quantification of the stable hydrolysis products TxB2 and TxB3. Washed human thrombocytes were incubated with free arachidonic acid (AA; 1 microM), A23187 (0.1 microM) or thrombin (5 U/mL) for stimulation; all regimens provoked large quantities of TxA2 in the absence of TxA3. Simultaneous admixture of free EPA or free DCHA to the incubation medium (concentration range, 0.01-50 microM) largely suppressed platelet TxA2 generation in response to all stimuli used in a dose-dependent manner. The effective concentration with 50% influence of arachidonic acid was 4.2 microM, whereas the inhibitory concentration with 50% effect of EPA and DCHA were both in the same order of magnitude but differed with the nature of the agonist (0.2-7 microM). Platelet (co-)incubation with EPA, but not DCHA, provoked dose-dependent synthesis of n-3-lipid-derived thromboxane: kinetics of formation and absolute quantities of TxA3 approximated 20% of the respective TxA2 data upon stimulation with AA. Both EPA and DCHA dose-dependently suppressed U46619-provoked platelet aggregation. We conclude that EPA and DCHA are potent competitive inhibitors of TxA2 generation by intact platelets, with EPA acting as poor substrate and DCHA being no substrate for the cyclooxygenase/thromboxane synthase complex. Enrichment of the plasma-free fatty acid fraction with n-3 lipids may offer a therapeutic regimen to suppress the synthesis of the potent proaggregatory and vasoconstrictory agent TxA2.
The blowflies Lucilia cuprina Wiedmann and Lucilia sericata Meigen (Diptera:Calliphoridae) are facultative ectoparasites of warm blooded vertebrates, particularly domestic sheep. Despite being similar in morphology and ecology, the two species and different populations of each species, are known to vary in their importance as pests in different regions of the world. To elucidate the genetic basis of these species and population level differences, flies were collected from sites in Africa, Europe, Australasia, North America and the islands of Hawaii, and examined using a combination of morphology, the random amplified polymorphic DNA technique and a complementary mitochondrial DNA analysis. The results confirm the species integrity of L. sericata and L. cuprina and support the existence of intra-specific genetic variation in L. cuprina, but not L. sericata.
DOC-2 is a human gene originally identified as a 767-bp cDNA fragment isolated from normal ovarian epithelial cells by differential display against ovarian carcinoma cells. We have now determined the complete cDNA sequence of the 3.2-kb DOC-2 transcript and localized the gene to chromosome 5. A 12.5-kb genomic fragment at the 5'-end of DOC-2 has also been sequenced, revealing the intron-exon structure of the first eight exons (788 bases) of the DOC-2 gene. Translation of the DOC-2 cDNA predicts a hydrophobic protein of 770 amino acid residues with a molecular weight of 82.5 kDa. Comparison of the DNA and amino acid sequences of DOC-2 to publicly accessible sequence databases revealed 83% identify to p96, a murine protein of similar size, thought to be a mitogen-responsive phosphoprotein. In addition, about 45% identity was observed between the first 140 N-terminal residues of DOC-2 and the Caenorhabditas elegans M110.5 and Drosophila melanogaster Dab genes.
BACKGROUND: Opinions differ on the timing of surgery for rheumatoid arthritis patients with atlanto-axial subluxation. Some clinicians wait for development of neurological signs; others favour prophylactic fusion and decompression. We examined the results of surgery in relation to neurological state at the time of operation. METHODS: 134 patients underwent surgery for rheumatoid involvement of the cervical spine, after development of objective signs of myelopathy. Surgical outcomes were examined prospectively in two groups-patients who were still ambulant at the time of presentation (Ranawat class III A) and patients who had lost the ability to walk (Ranawat class III B)-by means of neurological and functional grading systems in conjunction with standard measures of postoperative morbidity and mortality. FINDINGS: 58% of the ambulant patients attained Ranawat neurological grades I or II compared with only 20% of the non-ambulant patients (p<0.0001). The non-ambulant group also fared worse in terms of postoperative complication rate, length of hospital stay, functional outcome, and ultimately survival. Radiologically, the non-ambulant patients were characterised by a smaller cross-sectional spinal cord area. INTERPRETATION: The strong likelihood of surgical complications, the poor survival, and the limited prospects for functional recovery in non-ambulant patients make a strong case for earlier surgical intervention. At a late stage of disease most patients will have irreversible cord damage.
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The discs-large family is a collection of proteins that have a common structural organization and are thought to be involved in signal transduction and mediating protein-protein interactions at the cytoplasmic surface of the cell membrane. The defining member of this group of proteins is the gene product of the Drosophila lethal (1) discs large (dlg) 1 locus, which was originally identified by the analysis of recessive lethal mutants. Germline mutations in dlg result in loss of apical-basolateral polarity, disruption of normal cell-cell adhesion, and neoplastic overgrowth of the imaginal disc epithelium. We have isolated and characterized a novel human gene, DLG3, that encodes a new member of the discs-large family of proteins. The putative DLG3 gene product has a molecular weight of 66 kDa and contains a discs-large homologous region, a src oncogene homology motif 3, and a domain with homology to guanylate kinase. The DLG3 gene is located on chromosome 17, in the same segment, 17q12-q21, as the related gene, DLG2. The products of the DLG2 and DLG3 genes show 36% identity and 58% similarity to each other, and both show nearly 60% sequence similarity to p55, an erythroid phosphoprotein that is a component of the red cell membrane. We suggest that p55, DLG2, and DLG3 are closely related members of a gene family, whose protein products have a common structural organization and probably a similar function.
BACKGROUND: omega-3 Fatty acids may have a major impact on immune responses involved in heart transplant rejection. We compared the effects of posttransplant intravenous supplementation with omega-3-rich versus omega-6-rich lipid emulsions on graft survival, plasma fatty acid profiles, and levels of arachidonic acid versus eicosapentaenoic acid-derived lipid mediators. METHODS AND RESULTS: Inbred PVG and Wistar-Kyoto rats were used as donors and recipients, respectively, in a model of heterotopic heart transplantation. Animals received 9 g/kg body wt per day of either fish oil-derived (n = 8) or soybean oil-derived fat (n = 7) in the form of a continuously infused lipid emulsion; controls were sham-infused with saline (n = 8). Graft rejection was assessed by loss of activity of the transplant. The fish oil-derived preparation but not that originating from soybean oil caused an increase in total and free plasma fatty acids. Substantial quantities of eicosapentaenoic acid and docosahexaenoic acid appeared in the free fatty acid fraction, surpassing those of arachidonic acid. Ex vivo stimulation of neutrophils with the Ca2+ ionophore A23187 demonstrated an increase in 5-series leukotriene (LT) generation in animals undergoing omega-3 lipid infusion (LTB5, omega-oxidation products of LTB5, LTA5 secretion), with 5-series/4-series LT ratios ranging between 0.08 and 0.36. Ratios of TX B3/B2 liberated from ex vivo stimulated platelets even approached 1:1 in omega-3 supplemented rats. Graft survival was 7.6 +/- 0.3 (mean +/- SEM) days in saline-infused, 10.4 +/- 0.7 in omega-6 lipid-infused, and 12.9 +/- 0.4 in omega-3 lipid-infused animals. CONCLUSIONS: Posttransplant intravenous alimentation with fish oil-derived lipid emulsions prolongs heart transplant survival in excess to omega-6 lipids. Profound changes in fatty acid profiles and lipid mediator generation may underlie this finding.
Enzyme immunoassays were developed for quantification of polymerase chain reaction (PCR) products, referred to as amplicons. Amplicons were dual labelled simultaneously by enzymatic incorporation of digoxigenin and biotin during PCR. For total amplicon quantification, Microfluor B polystyrene wells, compatible with chemiluminescent detection, were coated with streptavidin. Dual labelled amplicons were bound, treated with anti-digoxigenin antibody conjugated to alkaline phosphatase to complete the two-site sandwich immunoassay configuration, and detected by the chemiluminescence generated upon hydrolysis of a phosphate substituted dioxetane substrate, AMPPD. For specific amplicon quantification, the Microfluor B wells were coated with an unlabelled DNA probe complementary to the labelled amplicon target. Subsequent steps were performed as described above. This assay detects 2 pg of specifically amplified DNA. Chemiluminescent detection provides a linear range of four orders of magnitude for amplicon quantification. The non-radioactive labels are safe and stable. PCR as described here obviates the need for labelled primers and constitutes the initial report of concurrent dual non-radioactive labelling of DNA by a DNA polymerase.
The cauda equina syndrome is a rare but well-recognised complication of longstanding ankylosing spondylitis, usually presenting when the joint disease is quiescent. The clinical and radiological findings in a patient with only a 3-year history, in whom the onset of joint and neurological symptoms was apparently simultaneous, are presented. MRI revealed characteristic expansion of the lumbar spinal canal with scalloping of the pedicles, laminae and spinous processes, related to numerous posterior dural diverticula. The quantity and extent of such diverticula are unusual. We demonstrated adherence of individual nerve roots to the arachnoid surface of these diverticula and to each other. In a second patient, with a much longer history of both ankylosing spondylitis and cauda equina syndrome, MRI again showed florid, multilocular dural ectasia, marked irregularity and thickening of nerves, and adherence to the dural diverticula. These cases provide evidence for the role of arachnoiditis in the pathogenesis of the cauda equina syndrome of ankylosing spondylitis.