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Biomedical subjects

R Sinclair

Publications and source records attributed to R Sinclair.

At least 19 recordsLinked to original sources
PubMed2000

Importance of nitric oxide in the regulation of burn oedema, proteinuria and urine output.

Burn injuries trigger a pronounced inflammatory response in the burned skin, resulting in oedema formation and impaired circulation. This response involves activation of the nitric oxide (NO) synthetic pathway, which could play a key role in the complex hemodynamic and hemostatic changes occurring as a result of a burn trauma. The results presented in full-thickness skin burns of rats show that the NO-precursor, L-arginine (n = 10), inhibit burn-induced plasma extravasation as compared to saline-treated burned controls (n = 10) (p<0.001) to a level not significantly different from nonburned animals. Administration of the NO-synthase inhibitor. NG-nitro-L-arginine (L-NNA) (n = 10), did not significantly influence burn extravasation compared to burned controls. Accumulated urine volume 90 min post-burn increased ten-fold in burned animals treated with L-arginine compared to saline-treated burned controls (p<0.001) and nonburned animals (p<0.001), while L-NNA had no significant effect on diuresis. A significantly increased proteinuria occurred in L-arginine treated burned animals as compared to burned controls and nonburned controls (p<0.001), whereas L-NNA did not significantly influence the leakage of protein in the urine. Activation of NO synthesis significantly suppresses burn edema and strongly increases diuresis along with increased proteinuria.

Albumins↗
PubMed2000

Role of nitric oxide in the control of burn perfusion.

Vascular changes following deep skin burns are characterised by vasoconstriction and progressive ischemia. Nitric oxide (NO) has been shown to be a potent regulator of vascular smooth muscle tone and tissue perfusion. We assessed the importance of NO on post-burn skin perfusion in rats using laser Doppler. The present results show that neither the NO-synthase inhibitor, NG-nitro-L-arginine (L-NNA) (n = 6) nor the NO precursor, L-arginine, significantly influenced skin perfusion in nonburned skin compared to saline-treated animals. In the area of full-thickness skin burn, neither L-arginine (n = 6) nor L-NNA (n = 6) had significant influence on post-burn perfusion compared to saline-treated controls (n = 6). Administration of L-NNA (n = 6) significantly impaired skin perfusion in the area adjacent to the contact burn representing a partial-thickness burn, while the NO precursor, L-arginine (n = 6) had no significant effect on burn perfusion as compared to saline-treated controls (n = 6). In conclusion, impairment of perfusion in a full thickness burn following administration of NO-synthase inhibitor suggests that nitric oxide is involved in the mechanisms responsible for maintaining adequate circulation post-burn. The lack of additional improvement of perfusion in response to L-arginine may suggest that NO synthesis in response to the thermal trauma is already at a peak.

Animals↗
PubMed2000

Ultrastructural appearance of renal and other basement membranes in the Bull terrier model of autosomal dominant hereditary nephritis.

Bull terrier hereditary nephritis may represent a model for autosomal dominant Alport's syndrome because affected dogs have the typically lamellated glomerular basement membrane (GBM) and father-to-son disease transmission occurs. This study examined the ultrastructural appearance of the renal and extrarenal basement membranes and their composition in affected Bull terriers. Affected stillborn animals and puppies had subepithelial frilling and vacuolation of the GBM. In adult dogs, lamellation was common, and subepithelial frilling and vacuolation were less prominent. Foot-process effacement and mesangial matrix expansion occurred frequently. Basement membranes in the glomeruli, tubules, and Bowman's capsule were significantly thickened and often mineralized. Immunohistochemical examination showed alpha 1(IV) and alpha 2(IV) collagen chains in all renal basement membranes; alpha 3(IV), alpha 4(IV), and alpha 5(IV) chains in the GBM, distal tubular basement membrane, and Bowman's capsule; and the alpha 6(IV) chain in Bowman's capsule. Conversely, the basement membranes from the affected Bull terrier cornea, lens capsule, retina, skin, lung, and muscle had a normal ultrastructural appearance and were not thickened compared with membranes in normal age-matched dogs. The distribution of basement membrane abnormalities in Bull terrier hereditary nephritis may occur because the defective protein is present exclusively or more abundantly in the kidney and is structurally more important in the kidney or because of local intrarenal stresses.

Age Factors↗
PubMed2000

Immunity to equine influenza: relationship of vaccine-induced antibody in young Thoroughbred racehorses to protection against field infection with influenza A/equine-2 viruses (H3N8).

Field outbreaks of influenza that occurred in vaccinated Thoroughbred racehorses in Newmarket in 1995 and 1996 were investigated by nucleoprotein ELISA and serology. Investigations showed that serum levels of vaccine-induced single radial haemolysis (SRH) antibody correlated closely with protective immunity against equine influenza and were consistent with observations made in previous experimental studies using nebulised aerosol challenge. In the second part of this study, antibody levels stimulated by vaccination were investigated to examine probable protection in high risk groups, such as yearlings and horses in training. Results for yearlings correlated closely with experimentally derived antibody profiles described for several equine influenza vaccines. The horses in training had levels of antibody immediately prior to revaccination, which were higher than those measured in the yearlings. In conclusion, SRH antibody, used in the investigation of outbreaks and surveillance of post vaccination responses, was shown to correlate with and validate experimental vaccination and challenge models currently used in ponies in the licensing of modern vaccines. There may be benefit from serological monitoring of horses following vaccination through identification of susceptible periods to infection and demonstration of poor vaccine responders. This would allow appropriate and timely amendment of vaccination strategies to maximise protective immunity against influenza.

Animals↗
PubMed1999

Comparative histopathology of radial artery versus internal thoracic artery and risk factors for development of intimal hyperplasia and atherosclerosis.

BACKGROUND: In this study, we examined the comparative histopathology, morphometry, and risk factors for the development of intimal hyperplasia and atherosclerosis in the radial artery (RA) and the internal thoracic artery (ITA). METHODS AND RESULTS: Paired specimens of RAs and ITAs, obtained from 150 patients who underwent CABG, were evaluated with histopathology; 110 pairs of arteries were suitable for morphometric analysis. The severity of disease was evaluated on the basis of percentage of luminal narrowing, intimal thickness index, and intima-to-media ratio. Risk factors were determined with stepwise linear regression. Intimal hyperplasia was seen in 141 RAs (94%) and 103 ITAs (69%) (P<0.001). Atherosclerosis was seen in 5% of RAs and 0.7% of ITAs (P=0.04). Medial calcification was found only in RAs (20 of 150, 13.3%) (P<0.001). Morphometric analysis showed that compared with ITAs, RAs had a significantly higher intimal area, medial area, percentage of luminal narrowing, intimal thickness index, and intima-to-media ratio (all P<0.001) Factors found to be significant (P<0.05) predictors of the 3 severity indices of intimal hyperplasia, including atherosclerosis, in RAs were peripheral vascular disease, smoking, age, and diabetes. Risk factors for intimal hyperplasia in ITAs were age and smoking. CONCLUSIONS: The RA is more likely to have atherosclerosis, intimal hyperplasia, and medial calcification than the ITA. Morphometric analysis indices showed marked differences between the RA and the ITA. Care should be taken when selecting the RA as a conduit in CABG, particularly in patients who are elderly, diabetic, smoke, or have peripheral vascular disease.

Adult↗
PubMed1999

Topical wound anaesthesia in children--a temporary postoperative pain relief.

BACKGROUND: Administration of local anaesthetics into the surgical wound may modulate pain at the peripheral level. A previous study in adults has shown good analgesic effects of topical lidocaine in wounds after herniorrhaphy. METHODS: Postoperative pain relief after topical administration of 10% lidocaine aerosol in the surgical wound was investigated in a randomised, double-blind study in children undergoing inguinal hernia repair. Forty-four patients aged between 9 months and 11 years were randomised into three groups. One group received active treatment with a lidocaine aerosol 2.5-4.7 mg kg-1, one group received a placebo aerosol and one control group was untreated. Postoperative pain was evaluated by nurse assessment, self-assessment and wound palpation 0, 1, 4 and 12 h after arrival in the recovery room. RESULTS: After 1 h the incidence of pain, as estimated by behavioural assessment and self-assessment, was significantly reduced in the lidocaine group in comparison to the placebo group, but not in comparison to the control group. The reaction on wound palpation was significantly reduced in the lidocaine group compared to both the placebo and control groups. At 0, 4 and 12 h no significant differences between the groups were observed. Plasma lidocaine concentrations were measured in six patients. Maximum individual concentrations were low, ranging from 0.17 to 0.86 microgram ml-1. CONCLUSION: A very short and clinically insignificant pain relief is obtained following the administration of a lidocaine aerosol in the surgical wound. A low pain level in this model may limit the possibility to detect an effect of lidocaine.

Administration, Topical↗
PubMed1999

Effects of amide local anaesthetics on eicosanoid formation in burned skin.

BACKGROUND: Previous studies have demonstrated potent inhibition of burn oedema and progressive ischaemia by local anaesthetics. Since eicosanoids have been suggested to play an important role in the pathophysiology of burns, we compared in the present ex vivo study the effects of topical lidocaine/prilocaine cream (EMLA, ASTRA, Sweden) and intravenous lidocaine with that of saline on eicosanoid formation by normal and burned rat skin. METHODS: A full-thickness burn trauma was induced in the abdominal skin. All the agents were given 5 min postburn until 2 h after the trauma. The experimental skin was subsequently removed and incubated in Krebs solution for 1 h. Eicosanoid concentrations in the solution were analysed by radioimmunoassay. RESULTS: EMLA cream induced a significant inhibition of TXB2 (P<0.05) and 6-Keto-PGF1alpha (P<0.01) but not of PGE release from burned skin as compared to saline treatment. Intravenous lidocaine infusions did not significantly influence the release of any of the measured eicosanoids versus saline. CONCLUSION: In conclusion, the lack of effect of intravenous lidocaine could relate to the severe burn trauma inducing rapid ischaemia which may have interfered with the delivery of the agent to the burned tissues or to insufficient concentrations achieved in the burn area. Topical treatment of burned skin with a local anaesthetic cream significantly reduced the release of TXB2 and 6-Keto-PGF1alpha, suggesting a possible mechanism of action in progressive burn ischaemia.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Digital image analysis of erythema development after experimental thermal injury to human skin: effect of postburn topical local anesthetics (EMLA).

UNLABELLED: Local anesthetics inhibit edema and improve circulation in experimental burns. We evaluated the effect of topical local anesthetics on human skin burns in volunteers using computerized color analysis that allowed repeated noninvasive quantitative measurements. A standardized partial-thickness burn (1 cm2) was induced in one forearm of 10 healthy volunteers and in the opposite forearm a week later. The burned areas were treated with lidocaine/prilocaine cream (EMLA; Astra, Sweden) or a placebo cream for 1 h. The experimental skin area was photographed before and 1, 2, 4, and 12 h postburn. Digitized images were evaluated using normalized red-green-blue and Hue-Saturation-Intensity. Differences in erythema between skin treated with EMLA and placebo were not significant during the first 4 h postburn. However, 12 h postburn, a pronounced decrease in the degree of erythema was observed in EMLA-treated skin compared with placebo-treated skin. We conclude that topical local anesthetics administered for 1 h postburn significantly reduces the duration of erythema after a mild thermal injury, which suggests a potential use in clinical practice in the treatment of minor skin burns. IMPLICATIONS: Burn injury constitutes a serious type of tissue damage that activates inflammatory mechanisms, often causing pain, disfiguration, or malfunction. We treated burns using an anesthetic cream and demonstrated a reduction in burn-induced inflammation by using computer-based color image analysis.

Administration, Topical↗
PubMed1998

L-Mandelate dehydrogenase from Rhodotorula graminis: cloning, sequencing and kinetic characterization of the recombinant enzyme and its independently expressed flavin domain.

The l-mandelate dehydrogenase (L-MDH) from the yeast Rhodotorula graminis is a mitochondrial flavocytochrome b2 which catalyses the oxidation of mandelate to phenylglyoxylate coupled with the reduction of cytochrome c. We have used the N-terminal sequence of the enzyme to isolate the gene encoding this enzyme using the PCR. Comparison of the genomic sequence with the sequence of cDNA prepared by reverse transcription PCR revealed the presence of 11 introns in the coding region. The predicted amino acid sequence indicates a close relationship with the flavocytochromes b2 from Saccharomyces cerevisiae and Hansenula anomala, with about 40% identity to each. The sequence shows that a key residue for substrate specificity in S. cerevisiae flavocytochrome b2, Leu-230, is replaced by Gly in L-MDH. This substitution is likely to play an important part in determining the different substrate specificities of the two enzymes. We have developed an expression system and purification protocol for recombinant L-MDH. In addition, we have expressed and purified the flavin-containing domain of L-MDH independently of its cytochrome domain. Detailed steady-state and pre-steady-state kinetic investigations of both L-MDH and its independently expressed flavin domain have been carried out. These indicate that L-MDH is efficient with both physiological (cytochrome c, kcat=225 s-1 at 25 degrees C) and artificial (ferricyanide, kcat=550 s-1 at 25 degrees C) electron acceptors. Kinetic isotope effects with [2-2H]mandelate indicate that H-C-2 bond cleavage contributes somewhat to rate-limitation. However, the value of the isotope effect erodes significantly as the catalytic cycle proceeds. Reduction potentials at 25 degrees C were measured as -120 mV for the 2-electron reduction of the flavin and -10 mV for the 1-electron reduction of the haem. The general trends seen in the kinetic studies show marked similarities to those observed previously with the flavocytochrome b2 (L-lactate dehydrogenase) from S. cerevisiae.

Alcohol Oxidoreductases↗
PubMed1998

Re-design of Saccharomyces cerevisiae flavocytochrome b2: introduction of L-mandelate dehydrogenase activity.

Flavocytochrome b2 from Saccharomyces cerevisiae is an l-lactate dehydrogenase which exhibits only barely detectable activity levels towards another 2-hydroxyacid, l-mandelate. Using protein engineering methods we have altered the active site of flavocytochrome b2 and successfully introduced substantial mandelate dehydrogenase activity into the enzyme. Changes to Ala-198 and Leu-230 have significant effects on the ability of the enzyme to utilize l-mandelate as a substrate. The double mutation of Ala-198-->Gly and Leu-230-->Ala results in an enzyme with a kcat value (25 degrees C) with L-mandelate of 8.5 s-1, which represents an increase of greater than 400-fold over the wild-type enzyme. Perhaps more significantly, the mutant enzyme has a catalytic efficiency (as judged by kcat/Km values) that is 6-fold higher with l-mandelate than it is with L-lactate. Closer examination of the X-ray structure of S. cerevisiae flavocytochrome b2 led us to conclude that one of the haem propionate groups might interfere with the binding of L-mandelate at the active site of the enzyme. To test this idea, the activity with l-mandelate of the independently expressed flavodehydrogenase domain (FDH), was examined and found to be higher than that seen with the wild-type enzyme. In addition, the double mutation of Ala-198-->Gly and Leu-230-->Ala introduced into FDH produced the greatest mandelate dehydrogenase activity increase, with a kcat value more than 700-fold greater than that seen with the wild-type holoenzyme. In addition, the enzyme efficiency (kcat/Km) of this mutant enzyme was more than 20-fold greater with L-mandelate than with l-lactate. We have therefore succeeded in constructing an enzyme which is now a better mandelate dehydrogenase than a lactate dehydrogenase.

Alcohol Oxidoreductases↗
PubMed1998

Effect of a comprehensive quality management process on compliance with protocol in an emergency medical dispatch center.

STUDY OBJECTIVE: Modern emergency medical dispatch provides appropriate resource responses with the use of an emergency medical dispatch priority reference system (EMDPRS). The EMDPRS is a systematic protocol for all aspects of the dispatch process, including interrogating the caller, matching responses with severity, and providing pre-arrival care. We tested the hypothesis that appropriate performance feedback would increase dispatcher compliance with the protocol. METHODS: We examined how emergency medical dispatchers complied with the protocols contained in the Advanced Medical Priority Dispatch System, a commercially available EMDPRS. Six key areas and overall compliance were studied. Dispatchers performed for 2 months without feedback and for a further 2 months with performance feedback. We used statistical methods to compare the dispatchers' compliance with the protocols each month. RESULTS: The mean overall compliance score improved from 76.4%+/-10.2% (mean+/-SD) in the absence of performance feedback to 96.2%+/-4.0% (n=217; P <.001) when performance feedback was provided. Five of 6 key areas showed similar improvements. CONCLUSION: Providing emergency medical dispatchers with regular and objective feedback regarding their performance dramatically improves how rigorously they follow a systematized dispatch protocol.

Emergency Medical Service Communication Systems↗
PubMed1998

Hirsutes. I: Diagnosis.

Hirsutes, the coarse, androgen-dependent growth of hair in women, is a common problem faced by doctors. Whether a woman presents to a clinician or not depends on cultural and racial factors. The clinician must differentiate normal biological variation from cases of hirsutes. In the vast majority of cases, androgen excess is only found locally at the level of the hair follicle; that is, the hirsutism is idiopathic. Important causes of androgen excess, such as an ovarian tumour, need to be excluded. Part one describes the causes of hirsutism and how to differentiate them using history, examination and investigation.

Adrenocortical Hyperfunction↗
PubMed1998

Hirsutes. II: Treatment.

The treatment of hirsutes includes cosmetic measures, such as bleaching, plucking, electrical epilation and, more recently, laser epilation. Pharmacological therapy consists of anti-androgens and includes the androgen receptor blockers spironolactone and cyproterone acetate. Other drugs reducing androgen expression include oral contraceptives and corticosteroids. A new follicular 5 alpha reductase inhibitor, finasteride, is currently under evaluation, as is the anti-androgen flutamide. Gonadotrophin-releasing hormone agonists reduce androgen expression and show early promise in the treatment of hirsutes.

5-alpha Reductase Inhibitors↗