Biomedical subjects

D Knight

Publications and source records attributed to D Knight.

At least 19 recordsLinked to original sources

PubMed1997

Localization of leukaemia inhibitory factor to airway epithelium and its amplification of contractile responses to tachykinins.

1. In neural tissue, leukaemia inhibitory factor (LIF) is an important trophic cytokine. In this investigation, we determined if LIF was present in human and guinea-pig airways and examined the role of this cytokine in modulating airway responses to endogenous and exogenous tachykinins as well as muscarinic receptor and beta-adrenoceptor stimulation. 2. The presence of LIF in both human and guinea-pig airways was determined by immunohistochemistry. Guinea-pig tracheal explants were incubated in CRML-1066 media containing LIF (0.5, 5 or 50 ng ml-1) for periods of 3, 6, 24 and 48 h. Tracheal rings were then transferred to organ baths for measurement of isometric force in response to carbachol, capsaicin, the neurokinin1 (NK1) receptor agonist [Sar9,Met(O2)11]-substance P (SP), the NK2 receptor agonist neurokinin A (NKA) and isoprenaline. 3. LIF immunoreactivity was observed primarily in basally situated cells in the airway epithelium of both large and small airways. Less intense immunoreactivity was observed in vascular endothelium and glandular epithelium. 4. Treatment with LIF (0.5 ng ml-1) for 3 and 6 h significantly increased contractile responses to capsaicin by 42% and 43%, respectively, compared to time controls, whereas higher concentrations of LIF (5 and 50 ng ml-1) enhanced capsaicin-induced contractions only after 6 h. After 24 h, responses to capsaicin were not significantly different from 0 h control. Contractile responses to capsaicin following exposure to LIF at any concentration for 24 h were not significantly different from relative time control values. 5. Responses to [Sar9,Met(O2)11]-SP, carbachol and isoprenaline were not influenced by time in culture or by exposure to LIF for up to 48 h. Contractile responses induced by NKA were not influenced by 3 or 6 h exposure to LIF, but at 24 and 48 h the mean maximum contractile responses to NKA were significantly increased by 33% and 35%, respectively, compared to control. 6. These results demonstrate that LIF is present in guinea-pig and human airway epithelium, and modulates airway responses to tachykinins. In the acute setting LIF augments the capsaicin-induced release of endogenous tachykinins, whilst in the longer term (> 24 h), LIF increases airway smooth muscle responses to tachykinins via an NK2 receptor selective mechanism. We conclude that LIF may be an important effector molecule in the response of airways to injury or inflammation.

Animals↗

PubMed1996

Influence of angioscopic vein graft preparation on development of neointimal hyperplasia in an organ culture model of human saphenous vein.

PURPOSE: Angioscopy for in situ vein graft preparation has been criticized on the basis that the trauma of instrumentation may predispose to accelerated intimal hyperplasia, jeopardizing patency rates following infrainguinal revascularization. The aim of this study was to assess the effects of angioscopic preparation on endothelial integrity and smooth muscle cell (SMC) behavior in an established organ culture model of human saphenous vein (HSV). METHODS: HSV was harvested from 12 patients during bypass surgery before and after angioscopic preparation. Endothelial integrity was evaluated by immunohistochemical staining with JC-70 and scanning electron microscopy (SEM); remaining segments of pre- and postangioscopy vein were maintained in culture for 14 days in medium supplemented with 30% fetal calf serum. Viability was confirmed by measurement of tissue adenosine triphosphate on day 14 and thickness of the neointima was measured by computerized image analysis of histologic sections. Monoclonal antibodies to proliferating cell nuclear antigen (PCNA) were used as an immunohistochemical marker for proliferating SMCs. RESULTS: There was a significant reduction in the percentage staining by JC-70 (71.3% versus 20.4%) in pre- versus postangioscopy vein (p = 0.002 by Wilcoxon's rank test; n = 12). This was supported by SEM images. Despite this, there were no significant differences between the pre- and postangioscopy HSVs after 14 days of culture with respect to neointimal thickness (61 versus 56 microns) and staining with PCNA (4.80 versus 4.08 nuclei per 10 microns), all according to Wilcoxon's rank test. CONCLUSIONS: Angioscopic vein graft preparation is associated with endothelial cell loss but does not induce additional neointimal hyperplasia in HSV in vitro. These results suggest that angioscopic manipulation does not alter SMC behavior.

Adenosine Triphosphate↗

PubMed1996

General practitioners and clinical guidelines: a survey of knowledge, use and beliefs.

BACKGROUND: Clinical practice guidelines are being developed for a variety of reasons. To date, there has been little investigation of the perspectives of those who are recommended to use them. AIM: The survey reported here set out to investigate how familiar general practitioners are with a range of published guidelines, to assess whether they have used them, and to describe their attitudes to the guidelines and the methods of implementing them. METHOD: A postal questionnaire was sent to a random sample of 559 general practitioners in the North and Yorkshire region in March 1995. Questions were organized around the topics of: knowledge; use; practice change; beliefs; pressure felt to use the guidelines; and methods of implementation. Basic classificatory data on gender; year of qualification; partnership and fundholding status were also collected. RESULTS: Replies were received from 300 doctors (54%). Knowledge and use of the three selected guidelines varied, but was generally towards the 'high' end of the scale. Doctors showed a high degree of homogeneity in their attitudes to guidelines, which were generally positive. Only single-handed practitioners varied from this pattern of responses. Most of the pressure to use the guidelines was felt to come from the Department of Health, and the least pressure from patients. Doctors felt that the methods of implementation that involved them in educational events and discussion with colleagues were most likely to have an impact on them. CONCLUSION: General practitioners are receptive to guideline initiatives, and their views are in line with existing or proposed implementation strategies. More investigation of the concept of 'use' is needed.

Attitude of Health Personnel↗

PubMed1995

Lipopolysaccharide (LPS) neutralizing peptides reveal a lipid A binding site of LPS binding protein.

Endotoxic shock follows a cascade of events initiated by release of lipopolysaccharide during infection with Gram-negative organisms. Two overlapping 15-mer peptides were identified, corresponding to residues 91-108 of human lipopolysaccharide binding protein that specifically bound the lipid A moiety of lipopolysaccharide with high affinity. The peptides inhibited binding of lipopolysaccharide to lipopolysaccharide binding protein, inhibited the chromogenic Limulus amebocyte lysate reaction, and blocked release of tumor necrosis factor alpha following lipopolysaccharide challenge both in vitro and in vivo. These results suggest lipopolysaccharide binding protein residues 91-108 form at least part of the lipopolysaccharide binding site. Moreover, derivatives of lipopolysaccharide binding protein residues 91-108 might modulate lipopolysaccharide toxicity in the clinical setting.

Acute-Phase Proteins↗

PubMed1995

Attributions for illness and treatment interventions by community nurses.

The present study evaluated community nurses' attributions for a case patient's heart attack and their recommendations for treatment. Eighty-nine district nurses and health visitors completed a set of rating scales following a case vignette describing a patient who had suffered a heart attack and prior to which had either adopted a healthy lifestyle (n = 47) or had maintained unhealthy behaviours (n = 42). The results suggest that subjects in the unhealthy-behaviour condition rated the case patient as less likely to follow advice, more responsible for his/her condition and rated the heart attack as more preventable. In addition, the results suggest that subjects were more likely to offer recommendations for behavioural change to the unhealthy case patient and that these recommendations were significantly related to internal attributions of patient responsibility. The results are discussed in terms of theories of health professionals' beliefs and behaviours.

Adult↗

PubMed1994

The effects of two acylcoenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cyclandelate and a non-hydrolysable ether analogue, benzyl3,3,5-trimethylcyclohexanol on low density lipoprotein metabolism in macrophages and hepatocytes.

Cyclandelate (3,3,5-trimethylcyclohexanylmandelate) caused a dose-dependent decrease in the metabolism of radioiodinated low density lipoprotein [125I-LDL] by J774 mouse macrophages. This was probably an indirect effect due to the inhibition of cholesterol esterification by the cells rather than a direct one on the interaction of LDL with its receptor, since no inhibition was seen in cells which had been cholesterol-depleted by prior incubation with lipoprotein-depleted serum for 48 hr. Cyclandelate also inhibited immediately de novo synthesis of cholesterol from [1-14C]acetate in J774 cells, suggesting a direct action of the drug on an enzyme of the cholesterol biosynthetic pathway. The drug was an efficient inhibitor of hamster and rat intestinal acylcoenzyme A: cholesterol acyltransferase (ACAT) activity in vitro with an IC50 of 20 microM. Addition of cyclandelate to the diet of meal-fed rats caused a marked inhibition of the rate of appearance of dietary [4-14C]cholesterol in the plasma. A nonhydrolysable ether analogue of cyclandelate, benzyl3,3,5-trimethylcyclohexanol, was prepared to compare hepatic and extrahepatic actions of the two molecules. The analogue inhibited cholesterol esterification in J774 cells, transformed human macrophages U937 and human umbilical vein endothelial cells with an IC50 of 20 microM and had effects similar to those of cyclandelate on 125I-LDL metabolism in J774 cells. Differences between the analogue and cyclandelate were seen in hepatocytes and hepatic microsomal fractions, where preincubation with the analogue inhibited cholesterol esterification in both systems while cyclandelate had no inhibitory action in either. Consequently, preincubation of rat hepatocytes with benzyl3,3,5-trimethylcyclohexanol for 17 hr caused a marked decrease in the binding of 125I-LDL to the cells, whereas binding to cells preincubated with cyclandelate was the same as to control cells.

Acyl Coenzyme A↗

PubMed1994

Respiratory distress syndrome in New Zealand: evidence from the OSIRIS trial of exogenous surfactant (Exosurf).

AIMS: To assess the impact, mortality, morbidity and economic costs, of respiratory distress syndrome severe enough to warrant ventilation in one year in New Zealand. METHODS: Review of data from all five New Zealand regional neonatal intensive care units' participation in the international OSIRIS trial of exogenous surfactant (Exosurf) treatment for respiratory distress syndrome (involving 6700 infants in 21 countries), and extrapolation of these data to a full year. RESULTS: There were 265 New Zealand infants entered in the OSIRIS trial; the mean birthweight was 1335 g and mean gestation 29 weeks; 61% of infants were less than 30 weeks gestation. Forty-seven infants (17.7%) died prior to discharge from hospital, 40 deaths being attributed to prematurity or respiratory distress syndrome. One hundred and two infants (38.5% of the cohort; 45% of surviving infants) were oxygen dependent and 36 infants (13.6%) were dead at 28 days of age. Thirty-four infants (12.8% of the cohort; 15% of surviving infants) were oxygen dependent and 40 infants (15%) were dead at the expected date of delivery. Infants were intubated for a mean 12.5 days, with surviving infants of less than 27 weeks gestation intubated for a disproportionately long period of time. Seventy-two infants (29% of the 246 infants examined) had an abnormality detected by cranial ultrasound scan at 1 or 6 weeks of age and in 23 (9%) this was a major abnormality. Of surviving infants 16 (7.5% of 213 examined) had a major abnormality on cranial ultrasound scan. Amongst infants at high risk for respiratory distress syndrome (gestation less than 30 weeks) 53% received antenatal steroids, compared with 22% in the OSIRIS trial overall. In a full year the cost of caring for infants with respiratory distress syndrome sufficiently severe enough to warrant ventilation is estimated to be NZ$12.5 million. The average cost of caring for a surviving infant was roughly NZ$52,500 and a nonsurviving infant was NZ$24,500. CONCLUSIONS: In a full year (total births 60,000) approximately 350 New Zealand infants may require ventilation for respiratory distress syndrome. Increasing the percentage of infants who receive antenatal steroids is likely to be extremely cost effective. In the era of antenatal steroids and exogenous surfactant, 85% of infants with respiratory distress syndrome requiring ventilation survive to discharge home and over 90% of survivors are likely to be healthy normal adults.

Birth Weight↗

PubMed1994

Popliteal pseudoaneurysm as a complication of an adjacent osteochondroma.

A 19-year-old man presented to our institution with a 4-month history of a pulsatile mass in the left popliteal fossa. Evaluation including plain x-ray films, MRI, and arteriography revealed a pseudoaneurysm associated with an underlying exostosis of the distal femur. The pseudoaneurysm was repaired with a saphenous vein patch and the exostosis was excised. This case is reported in conjunction with an extensive review of the literature, which yielded only 25 similar cases reported in the English language since 1953. The majority of cases involved young men (20/26), whose ages ranged from 9 to 45 years (mean 20 years). Fifteen of the 26 cases involved isolated exostoses, and in less than half (12/26), antecedent trauma was identified as a cause of the pseudoaneurysm. The origin of exostoses and their relationship to popliteal pseudoaneurysms are discussed. Repair of the pseudoaneurysm and excision of the involved exostosis are recommended.

Adult↗

PubMed1994

Oxygen and 99mTc-MAA shunt estimations in patients with pulmonary arteriovenous malformations: effects of changes in posture and lung volume.

BACKGROUND: Patients with arteriovenous malformations are routinely monitored with arterial oxygen saturation (SaO2) estimations (breathing air) from which an oxygen shunt fraction can be calculated. This simple estimation has been compared with an anatomically defined estimate of the right to left shunt using a radioisotopic method. The fall in SaO2 which occurs in patients with pulmonary arteriovenous malformations in the erect posture and at high lung volumes was used to test the ability of SaO2 alone to follow changes in right to left shunt. METHODS: Radiolabelled albumin macroaggregates (99mTc-MAA) or microspheres (MS) were injected intravenously and kidneys and lungs were imaged. The shunt fraction (QS/QTTc) in the supine position at functional residual capacity (baseline) was obtained by quantifying right kidney radioactivity. On standing or while breath holding at total lung capacity, shunt fraction was calculated from baseline QS/QTTc and from lung counts and the injected dose. Arterial oxygen saturation (SaO2) was recorded by a pulse oximeter for calculation of the oxygen shunt (QS/QTO2) (breathing air). RESULTS: In the postural study (n = 8) SaO2 decreased from a mean (SD) value of 89 (5)% supine to 80 (6)% erect, corresponding to QS/QTO2 28 (8)% and 44 (8)% respectively. QS/QTTc increased from 28.7 (10.3)% to 39 (14.3)%. In the lung volume study (n = 8) QS/QTTc increased from 16.6 (11.5)% at functional residual capacity to 23.3 (11.9)% at total lung capacity while QS/QTO2 increased from 19.5 (7.5)% to 25.9 (10.6)% respectively. When all measurements were compared for QS/QTTc% and QS/QTO2% (n = 32) the difference in the mean values was 2.5% (absolute) and the limits of agreement between the two methods were +38% to -18% (relative). In neither the postural nor the volume study did delta (QS/QTO2) reliably predict delta (QS/QTTc)%. CONCLUSIONS: In pulmonary arteriovenous malformations the simple physiological shunt calculated from SaO2 breathing air agreed well with the anatomical right to left shunt measured with 99mTc-MAA, but predicted poorly the changes in anatomical shunt induced by postural or lung volume changes.

Adult↗

PubMed1994