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Biomedical subjects

D Gordon

Publications and source records attributed to D Gordon.

At least 91 records · Page 5Linked to original sources
PubMed2000

Atherosclerosis progression in LDL receptor-deficient and apolipoprotein E-deficient mice is independent of genetic alterations in plasminogen activator inhibitor-1.

Impaired fibrinolysis has been linked to atherosclerosis in a number of experimental and clinical studies. Plasminogen activator inhibitor type 1 (PAI-1) is the primary inhibitor of plasminogen activation and has been proposed to promote atherosclerosis by facilitating fibrin deposition within developing lesions. We examined the contribution of PAI-1 to disease progression in 2 established mouse models of atherosclerosis. Mice lacking apolipoprotein E (apoE-/-) and mice lacking the low density lipoprotein receptor (LDLR-/-) were crossbred with transgenic mice overexpressing PAI-1 (resulting in PAI-1 Tg(+)/apoE-/- and PAI-1 Tg(+)/LDLR-/-, respectively) or were crossbred with mice completely deficient in PAI-1 gene expression (resulting in PAI-1-/-/apoE-/- and PAI-1-/-/LDLR-/-, respectively). All animals were placed on a western diet (21% fat and 0.15% cholesterol) at 4 weeks of age and analyzed for the extent of atherosclerosis after an additional 6, 15, or 30 weeks. Intimal and medial areas were determined by computer-assisted morphometric analysis of standardized microscopic sections from the base of the aorta. Atherosclerotic lesions were also characterized by histochemical analyses with the use of markers for smooth muscle cells, macrophages, and fibrin deposition. Typical atherosclerotic lesions were observed in all experimental animals, with greater severity at the later time points and generally more extensive lesions in apoE-/- than in comparable LDLR-/- mice. No significant differences in lesion size or histological appearance were observed among PAI-1-/-, PAI-1 Tg(+), or PAI-1 wild-type mice at any of the time points on either the apoE-/- or LDLR-/- genetic background. We conclude that genetic modification of PAI-1 expression does not significantly alter the progression of atherosclerosis in either of these well-established mouse models. These results suggest that fibrinolytic balance (as well as the potential contribution of PAI-1 to the regulation of cell migration) plays only a limited role in the pathogenesis of the simple atherosclerotic lesions observed in the mouse.

Animals↗
PubMed2000

Regulation of lysyl oxidase by interferon-gamma in rat aortic smooth muscle cells.

Lysyl oxidase is an essential catalyst for the cross-linking of extracellular collagen and elastin. Abnormalities in lysyl oxidase activity may contribute to the pathogenesis of arterial diseases characterized by abnormal matrix remodeling. This study tested the hypothesis that interferon (IFN)-gamma, a proinflammatory cytokine present in aortic aneurysm and arteriosclerotic plaque rupture, downregulates lysyl oxidase gene expression in rat aortic smooth muscle cells. Steady-state lysyl oxidase mRNA levels decreased in a concentration- and time-dependent manner to 30% of control levels after 24 hours of treatment with IFN-gamma. Cell layer lysyl oxidase activity decreased in parallel with the observed changes in steady-state mRNA. Nuclear runoff studies suggested that transcriptional regulation was responsible for at least 40% of the observed downregulation. mRNA decay studies suggested that IFN-gamma also decreased lysyl oxidase mRNA half-life from 9 to 6 hours. Downregulation of lysyl oxidase by IFN-gamma did not appear to require new protein synthesis. This study documents that IFN-gamma downregulates lysyl oxidase gene expression in rat aortic smooth muscle cells by transcriptional and posttranscriptional mechanisms. If similar regulation occurs in vivo, it is possible that IFN-gamma-mediated changes in lysyl oxidase may contribute to arterial diseases characterized by abnormal extracellular matrix.

Animals↗
PubMed2000

Use of fluorescent microspheres to localize in vivo gene transfer injection sites.

The potential for using gene therapy to treat a variety of disease states is growing rapidly. Many vector types and delivery systems have been developed that allow the optimization of protein production levels and kinetics for a given therapeutic gene product. In cases in which a transient, localized delivery of gene product is desired, any determination of the locale of transfected tissue by non-marker genes is problematic. We describe a technique by which the use of fluorescent microspheres can help in identifying potentially transfected tissue. Adenovirus containing the gene for beta-galactosidase (beta-gal) was mixed with fluorescent microspheres and injected into rat skeletal muscle and porcine myocardium. The injection sites could be visualized under ultraviolet light and correlated with beta-gal enzyme expression. This method is simple, inexpensive and generally useful for in vivo gene transfer experiments.

Adenoviridae↗
PubMed2000

Rat sponge implant model: a new system for evaluating angiogenic gene transfer.

Therapeutic angiogenesis, either by protein injection or gene therapy, holds considerable promise for the treatment of coronary and peripheral artery diseases. Given the large number of angiogenic genes available, a simple, well defined, standard system to compare the relative angiogenic efficacy of such genes would be valuable. We have employed a replication-deficient adenovirus vector (complete E1a-, partial E1b- and partial E3-) to deliver the beta-galactosidase (beta-gal, AdLacZ) reporter gene or the human VEGF121 gene (AdGV VEGF121.10) to a rat sponge implant model of angiogenesis. beta-gal staining results reveal a transfection efficiency as high as 60% 24 h after 2x1010 particle units AdLacZ injection. Our results also indicate that a single injection of 2x1010 particle units of AdGVVEGF121.10 in the sponge results in >10, 000 pg VEGF protein expression per milligram of sponge tissue 24 h later. VEGF121 protein concentrations decreased 10-fold within 3 days and 100-fold within 7 days after injection. Significant VEGF121 protein levels were still detectable 14 days after initial virus injection. The high level of gene transfection efficiency was accompanied by enhanced angiogenesis in the sponge, a tissue devoid of any vessels before implantation. Compared to control (AdNull: adenovirus vector without the VEGF gene), AdGVVEGF121.10 induced a 2- to 3-fold up-regulation of angiogenesis at 7 and 14 days post vector injection as determined by both increased capillary number and increased tissue ingrowth. The angiogenic effects of AdGVVEGF121. 10 were dose-related in this model system. These findings demonstrate a dose-related angiogenic response to adenovirus-mediated gene therapy in this model.

Adenoviridae↗
PubMed2000

The significance of the American Urological Association symptom index score in the evaluation of women with bladder outlet obstruction.

PURPOSE: The American Urological Association (AUA) symptom index was originally designed to assess the severity of lower urinary tract symptoms in men with benign prostatic hyperplasia. Data concerning the clinical application of the AUA symptom index to women are sparse. We evaluated the significance of the AUA symptom index in women with urodynamically defined bladder outlet obstruction. MATERIALS AND METHODS: From a urodynamic database of 587 consecutive women 38 (6.5%) were identified with bladder outlet obstruction, defined as a maximum flow rate of less than 12 ml. per second on repeat noninvasive uroflowmetry studies with a detrusor pressure at a maximum flow of greater than 20 cm. water on pressure flow study. All patients underwent a complete clinical and urodynamic evaluation, and completed the AUA symptom index questionnaire. Results in women with urodynamic obstruction were compared with those in 2 control groups, including women without obstruction but with sphincteric incontinence and asymptomatic healthy women. RESULTS: Mean symptom score was significantly higher in women with obstruction than in those with sphincteric incontinence or no symptoms (15.8+/-8.4 versus 10.3+/-6.4 and 2.1+/-2.7, respectively). Likewise, scores were classified as severe in 34% of women with obstruction compared with only 7% of those with sphincteric incontinence. However, no correlation was noted between symptom index scores and objective urodynamic parameters, which is similar to data already reported in male populations. CONCLUSIONS: The AUA symptom index score may be useful as a bothersomeness index in women with bladder outlet obstruction. However, subjective symptoms associated with bladder outlet obstruction are nonspecific and a complete urodynamic evaluation is essential for making the diagnosis.

Female↗
PubMed2000

Duties of a doctor: UK doctors and good medical practice.

OBJECTIVE: To assess the responses of UK doctors to the General Medical Council's (GMC) Good Medical Practice and the Duties of a Doctor, and to the GMC's performance procedures for which they provide the professional underpinning. DESIGN: Questionnaire study of a representative sample of UK doctors. SUBJECTS: 794 UK doctors, stratified by year of qualification, sex, place of qualification (UK v non-UK), and type of practice (hospital v general practice) of whom 591/759 (78%) replied to the questionnaire (35 undelivered). MAIN OUTCOME MEASURES: A specially written questionnaire asking about awareness of Good Medical Practice, agreement with Duties of a Doctor, amount heard about the performance procedures, changes in own practice, awareness of cases perhaps requiring performance procedures, and attitudes to the performance procedures. Background measures of stress (General Health Questionnaire, GHQ-12), burnout, responses to uncertainty, and social desirability. RESULTS: Most doctors were aware of Good Medical Practice, had heard the performance procedures being discussed or had received information about them, and agreed with the stated duties of a doctor, although some items to do with doctor-patient communication and attitudes were more controversial. Nearly half of the doctors had made or were contemplating some change in their practice because of the performance procedures; a third of doctors had come across a case in the previous two years in their own professional practice that they thought might merit the performance procedures. Attitudes towards the performance procedures were variable. On the positive side, 60% or more of doctors saw them as reassuring the general public, making it necessary for doctors to report deficient performance in their colleagues, did not think they would impair morale, were not principally window dressing, and were not only appropriate for problems of technical competence. On the negative side, 60% or more of doctors thought the performance procedures were not well understood by most doctors, were a reason for more defensive practice, and could not be used for problems of attitude. Few differences were found among older and younger doctors, hospital doctors, or general practitioners, or UK and non-UK graduates, although some differences were present. CONCLUSIONS: Most doctors working in the UK are aware of Good Medical Practice and the performance procedures, and are in broad sympathy with Duties of a Doctor. Many attitudes expressed by doctors are not positive, however, and provide areas where the GMC in particular may wish to encourage further discussion and awareness. The present results provide a good baseline for assessing changes as the performance procedures become active and cases come before the GMC over the next few years.

Attitude of Health Personnel↗
PubMed2000

Is amniotic fluid volume influenced by a 24-hour fast?

OBJECTIVE: To assess the influence of fasting for 24 hours on the amniotic fluid index (AFI). STUDY DESIGN: The AFI of 22 parturients in the second trimester of uncomplicated pregnancy was evaluated on the morning after a 24-hour fast. Patients were prospectively matched to another group of 25 patients who did not fast. Both groups were reevaluated after one week. Two different observers, blind to each other's results, performed the examinations. RESULTS: A statistically significant difference was found in the AFI between the two groups on the day after fasting (11.73 +/- 2.12 versus 15.4 +/- 1.2, respectively; P < .01). After one week there was no difference in AFI between the two groups (15.35 +/- 1.2 and 15.42 +/- 1.2, respectively; P > .01). CONCLUSION: Fasting may reduce the amniotic fluid volume as shown by the AFI, and fluid intake may restore the normal amount of amniotic fluid volume.

Amniotic Fluid↗
PubMed2000

The impact of a structured programme of asthma care in general practice.

The impact of a new GP programme of asthma care was examined using: a) a retrospective pre- and post-casenote survey of 400 asthma patients, comparing patients in practices using the health board programme (HBP) and other programmes (OP); and b) a patient satisfaction questionnaire, completed by 532 people on asthma clinic lists in HBP and OP practices. Outcomes assessed were health service use, perceived change in symptoms and asthma self-management. The casenote survey indicated improved health service use by patients in HBP practices, with fewer patient-initiated (p < 0.05), emergency (p < 0.05) and other chest-related attendances (p < 0.01) and increased clinic attendance (p < 0.05) post intervention. OP practices also showed reduced patient-initiated (p < 0.01) and increased asthma clinic use (p < 0.01). Increased use of management plans (p < 0.01) and peak flow diaries (p < 0.01) was noted post intervention for HBP practices. Responders to the questionnaire survey perceived that clinic attendance improved asthma symptoms, including severity and control, sleep disturbance and early morning wheeze. People in HBP practices were more likely than those in OP practices to possess a peak flow meter, a diary and a personal management plan (all p < 0.01 or above) but were not more likely to use a peak flow diary. Notwithstanding methodological difficulties in the selection of practices, both studies showed trends towards improvement in health service use and asthma self-management. The HBP was associated with greater improvement in self-management processes and outcomes, and greater patient satisfaction with asthma care.

Adolescent↗
PubMed1999

[PVT--tension-free vaginal tape--a new minimally invasive surgical technique for female stress incontinence: preliminary results].

We evaluated the safety and efficacy of the tension-free vaginal tape procedure (TVT) in 20 consecutive women with urodynamically proven genuine stress incontinence. Mean operating time under spinal analgesia was 37.2 +/- 13 minutes and 80% were discharged within 24 hours. There were 5 uncomplicated, intraoperative bladder perforations, but no defects in healing nor tape rejection. The objective cure rate was 95%, while the subjective rate was 100%. Although follow-up was short (9-16 months), the TVT method seems to be safe and effective for stress urinary incontinence.

Female↗
PubMed1999

Are UK doctors particularly stressed?

Doctors are thought to have higher levels of stress than the general population. However, in a survey of a nationally representative sample of UK doctors, we found that stress levels were equivalent to those in the general population; previous findings may have been biased by inappropriate use of the general health questionnaire.

Analysis of Variance↗
PubMed1999

A scorpion alpha-like toxin that is active on insects and mammals reveals an unexpected specificity and distribution of sodium channel subtypes in rat brain neurons.

Several scorpion toxins have been shown to exert their neurotoxic effects by a direct interaction with voltage-dependent sodium channels. Both classical scorpion alpha-toxins such as Lqh II from Leiurus quiquestratus hebraeus and alpha-like toxins as toxin III from the same scorpion (Lqh III) competitively interact for binding on receptor site 3 of insect sodium channels. Conversely, Lqh III, which is highly toxic in mammalian brain, reveals no specific binding to sodium channels of rat brain synaptosomes and displaces the binding of Lqh II only at high concentration. The contrast between the low-affinity interaction and the high toxicity of Lqh III indicates that Lqh III binding sites distinct from those present in synaptosomes must exist in the brain. In agreement, electrophysiological experiments performed on acute rat hippocampal slices revealed that Lqh III strongly affects the inactivation of voltage-gated sodium channels recorded either in current or voltage clamp, whereas Lqh II had weak, or no, effects. In contrast, Lqh III had no effect on cultured embryonic chick central neurons and on sodium channels from rat brain IIA and beta1 subunits reconstituted in Xenopus oocytes, whereas sea anemone toxin ATXII and Lqh II were very active. These data indicate that the alpha-like toxin Lqh III displays a surprising subtype specificity, reveals the presence of a new, distinct sodium channel insensitive to Lqh II, and highlights the differences in distribution of channel expression in the CNS. This toxin may constitute a valuable tool for the investigation of mammalian brain function.

Animals↗
PubMed1999

Prostate cancer expression profiling by cDNA sequencing analysis.

Prostate cancer is a frequently diagnosed solid tumor that is originated mostly from prostate epithelium. One of the key issues in prostate cancer research is to develop molecular markers that can effectively detect and distinguish the progression and malignancy of prostate tumors. Automated, single-pass cDNA sequencing was utilized to rapidly identify expressed genes in a number of cDNA libraries constructed from various normal and tumor prostatic tissues. These included cell lines as well as short-term epithelial culture. A total of 6604 expressed sequence tags (ESTs) were generated and searched against on-line nucleotide and protein databases. A relational database centric software system was constructed to process, store, and analyze EST data rapidly. cDNA contigs were also obtained by assembly of multiple EST sequences. Protein structural signatures were annotated using motif analysis tools including BLOCKS and an in-house-designed neural network. Cross-library comparisons revealed their unique gene expression profiles. Several differentially expressed cDNA clones were identified, and their expression patterns were confirmed by RNA dot blot and RT-PCR analyses.

Cell Line↗
PubMed1999

[Pelvic floor exercise and biofeedback in women with urinary stress incontinence].

Stress urinary incontinence is a medical and social problem. In the past decade there has been increased awareness of this condition and the number of those affected who seek help is increasing. Treatment is usually surgical-elevation of the bladder neck. Pelvic floor exercise is an accepted conservative treatment modality used for mild to moderate cases who have not yet completed their families. We present our results in 30 women, aged 28-71 years, av. 49% with genuine stress incontinence treated with pelvic floor exercise and biofeedback. 14 patients (46.7%) were completely cured and 15 (50%) were improved. In only 1 was there no improvement. Our results show significant improvement in the duration and intensity of pelvic floor contractions after treatment. Pelvic floor exercise with biofeedback is a very important treatment modality, requiring a highly motivated patient and a physiotherapist specialized in pelvic floor exercise.

Adult↗
PubMed1999

Lifetime prevalence, characteristics, and associated problems of non-consensual sex in men: cross sectional survey.

OBJECTIVE: To identify the lifetime prevalence of non-consensual sexual experiences in men, the relationship between such experiences as a child and as an adult, associated psychological and behavioural problems, and help received. DESIGN: Cross sectional survey. SETTING: England. SUBJECTS: 2474 men (mean age 46 years) attending one of 18 general practices. MAIN OUTCOME MEASURES: Experiences of non-consensual and consensual sex before and after the age of 16 years-that is, as a child and adult respectively-psychological problems experienced for more than 2 weeks at any one time, use of alcohol (CAGE questionnaire), self harm, and help received. RESULTS: 2474 of 3142 men (79%) agreed to participate; 71/2468 (standardised rate 2.89%, 95% confidence interval 2.21% to 3.56%) reported non-consensual sexual experiences as adults, 128/2423 (5.35%, 4.39% to 6.31%) reported non-consensual sexual experiences as children, and 185/2406 (7.66%, 6.54% to 8.77%) reported consensual sexual experiences as children that are illegal under English law. Independent predictors of non-consensual sex as adults were reporting male sexual partners (odds ratio 6.0, 2.6 to 13.5), non-consensual sex in childhood (4.2, 2.1 to 8.6), age (0.98, 0.96 to 0.99), and sex of interviewer (2.0, 1.2 to 3.5). Non-consensual sexual experiences were associated with a greater prevalence of psychological problems, alcohol misuse, and self harm. These sexual experiences were also significant predictors of help received from mental health professionals. CONCLUSION: Almost 3% of men in England report non-consensual sexual experiences as adults. Medical professionals need to be aware of the range of psychological difficulties in men who have had such experiences. They also need to be aware of the relationship between sexual experiences in childhood and adulthood in men.

Adolescent↗
PubMed1999

The putative bioactive surface of insect-selective scorpion excitatory neurotoxins.

Scorpion neurotoxins of the excitatory group show total specificity for insects and serve as invaluable probes for insect sodium channels. However, despite their significance and potential for application in insect-pest control, the structural basis for their bioactivity is still unknown. We isolated, characterized, and expressed an atypically long excitatory toxin, Bj-xtrIT, whose bioactive features resembled those of classical excitatory toxins, despite only 49% sequence identity. With the objective of clarifying the toxic site of this unique pharmacological group, Bj-xtrIT was employed in a genetic approach using point mutagenesis and biological and structural assays of the mutant products. A primary target for modification was the structurally unique C-terminal region. Sequential deletions of C-terminal residues suggested an inevitable significance of Ile73 and Ile74 for toxicity. Based on the bioactive role of the C-terminal region and a comparison of Bj-xtrIT with a Bj-xtrIT-based model of a classical excitatory toxin, AaHIT, a conserved surface comprising the C terminus is suggested to form the site of recognition with the sodium channel receptor.

Amino Acid Sequence↗