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Biomedical subjects

M E Stewart

Publications and source records attributed to M E Stewart.

At least 19 recordsLinked to original sources
PubMed2004

Detecting the dangerous, violent or criminal patient: an analysis of referrals to maximum security psychiatric care.

Britain's high security hospitals provide care for mentally disordered patients who have dangerous, violent or criminal propensities. The State Hospital, Carstairs, takes referrals from the population of Scotland and Northern Ireland. This retrospective case-control study describes the sociodemographic and clinical characteristics of referrals (n=149) to the State Hospital during a 12-month period, and delineates differences between admitted (n=57) and rejected (n=92) patients. The referrals had an average age of 31.1 years, and were mostly male (86.6%), single (64.4%) and unemployed (90.6%). Admitted patients were more likely to have a criminal history, to be psychotic, to have a family history of mental disorder and to be viewed by the assessor as having psychotic beliefs which contributed to the behaviour or alleged offence leading to the referral. Rejected patients were more likely to have been remanded to prison or assessed by specialist registrars. Patients admitted to high security psychiatric care are more likely to show dangerous behaviour secondary to psychosis. These findings are in keeping with the requirements of mental health legislation and the admissions policy.

Adult↗
PubMed2002

A phase III placebo-controlled study in advanced head and neck cancer using intratumoural cisplatin/epinephrine gel.

Patients with recurrent or refractory head and neck squamous cell carcinoma received cisplatin/epinephrine injectable gel or placebo gel injected directly into the clinically dominant tumour. The double-blind phase III trial comprised of up to 6 weekly treatments over 8 weeks, 4 weekly evaluation visits, and then monthly follow-up; open-label dosing began as needed after three blinded treatments. Tumour response was defined as complete (100% regression) or partial (50-99% regression) sustained for > or =28 day, and patient benefit as attainment of palliative or preventive goals prospectively selected by investigators and patients. With cisplatin/epinephrine gel, 25% (14 out of 57) of tumours responded (16% complete regression, 9% partial regression), vs 3% (one out of 35, complete regression) with placebo (P=0.007). Patient benefit was positively associated with target tumour response in the blinded period among cisplatin/epinephrine gel recipients (P=0.024): 43% (six out of 14) of responders benefited, vs 12% (five out of 43) of non-responders. The most frequent adverse event was pain during injection and the next most frequent was local cytotoxic effects consistent with the gel's mode of action. Systemic adverse events typical of intravenous cisplatin were uncommon. Intratumoural therapy with cisplatin/epinephrine gel provided safe, well-tolerated, effective palliative treatment for patients with locally advanced head and neck squamous cell carcinoma, who lack other satisfactory treatment options.

Adrenergic Agonists↗
PubMed2001

A prognostic model for ovarian cancer.

About 6000 women in the United Kingdom develop ovarian cancer each year and about two-thirds of the women will die from the disease. Establishing the prognosis of a woman with ovarian cancer is an important part of her evaluation and treatment. Prognostic models and indices in ovarian cancer should be developed using large databases and, ideally, with complete information on both prognostic indicators and long-term outcome. We developed a prognostic model using Cox regression and multiple imputation from 1189 primary cases of epithelial ovarian cancer (with median follow-up of 4.6 years). We found that the significant (P< or = 0.05) prognostic factors for overall survival were age at diagnosis, FIGO stage, grade of tumour, histology (mixed mesodermal, clear cell and endometrioid versus serous papillary), the presence or absence of ascites, albumin, alkaline phosphatase, performance status on the ZUBROD-ECOG-WHO scale, and debulking of the tumour. This model is consistent with other models in the ovarian cancer literature; it has better predictive ability and, after simplification and validation, could be used in clinical practice.

Adolescent↗
PubMed2001

The omega-hydroxyceramides of pig epidermis are attached to corneocytes solely through omega-hydroxyl groups.

The cornified outer cells of mammalian epidermis possess a monolayer of omega-hydroxyceramides that are ester-linked to the exterior of a cross-linked protein envelope. In the present study, conclusive evidence was sought on which of the ceramide hydroxyl groups are involved in the linkage to protein. This was obtained by derivatizing all free hydroxyl groups in isolated solvent-extracted porcine stratum corneum using triisopropylsilyl (TIPS) chloride in pyridine in the presence of silver nitrate. After an 18-h reaction, the tissue was recovered, rinsed, and the derivatized ceramides were then released from protein linkage by hydrolysis with 1M KOH in 95% methanol. This gave a single ceramide product that was shown by nuclear magnetic resonance to contain two triisopropyl groups. Acetylation of the product using acetic anhydride in pyridine resulted in a downfield shift of the NMR signal for the omega-methylene protons, showing that it was the omega-hydroxyl that was free in the initial reaction product, and subsequently was acetylated. These results show that all of the omega-hydroxyceramides of corneocyte lipid envelopes are attached to protein through their omega-hydroxyl groups.

Acetylation↗
PubMed1999

A new 6-hydroxy-4-sphingenine-containing ceramide in human skin.

A new ceramide consisting of 6-hydroxysphingosine linked to a non-hydroxyacid was found in human epidermal lipid. This ceramide was sought because its fatty acid and sphingoid moieties are present in other combinations in human epidermal ceramides. To isolate the new ceramide, the mixture of ceramides in human epidermal lipid was first separated into fractions by thin-layer chromatography (TLC), and then each fraction was further purified by TLC after acetylation of all hydroxyl groups. TLC after acetylation revealed that one of the fractions isolated in the first TLC step contained two components, namely, the ceramide consisting of sphingosine linked to an alpha-hydroxyacid and an unknown ceramide. The new ceramide constituted about 9% of the total ceramides, and was shown by NMR spectroscopy to be N-acyl-6-hydroxysphingosine.

Acetylation↗
PubMed1996

X-ray diffraction analysis of isolated skin lipids: reconstitution of intercellular lipid domains.

Low- and wide-angle X-ray diffraction were used to determine the structural organization of lipids isolated from the stratum corneum extracellular matrix that forms the major water permeability barrier in mammalian epidermis. Hydrated pig skin ceramides gave a single low-angle reflection of about 62 angstroms and a wide-angle-reflection at 4.15 angstroms. The addition of either cholesterol or fatty acid, the other major lipid components of the skin stratum corneum extracellular matrix, modified this diffraction pattern, depending on the lipid mole ratios. In the absence of water, lipid mixtures exhibited lipid phase separation, as shown by low- and wide-angle reflections typical of a separate cholesterol phase. However, a hydrated 2:1:1 mole ratio of ceramide:cholesterol:palmitic acid (similar to that found in stratum corneum) produced a diffraction pattern with a single sharp wide-angle reflection at 4.10 angstroms and low-angle reflections which indexed as the first eight orders of a single repeat period of 130 angstroms. The repeat period and intensity distribution of the low-angle data were similar to those found in intact stratum corneum [White et al. (1988) Biochemistry 27, 3725-3732; Bouwstra et al. (1994) Biochim. Biophys. Acta 1212, 183-192]. Higher concentrations of cholesterol or palmitic acid resulted in lipid phase separations. The 130 angstrom repeat period decreased only about 3 angstroms as water was removed by incubation in low-relative humidity atmospheres. The 130 angstrom repeat period depended on the presence of a particular ceramide, N-(omega-acyloxy)-acylsphingosine, which is found only in the epidermis. In contrast, 2:1:1 mixtures of brain ceramide:cholesterol:palmitic acid gave reflections of 56 and 34 angstroms. These results indicate that a structure with dimensions similar to those of the lamellar repeating unit found in skin stratum corneum does not depend on the presence of protein but does depend on the presence of specific skin ceramides and appropriate concentrations of cholesterol and fatty acid.

Animals↗
PubMed1995

Free sphingosines of human skin include 6-hydroxysphingosine and unusually long-chain dihydrosphingosines.

Ceramides containing 6-hydroxysphingosine, a previously unknown long-chain base, have recently been found in human skin. The present study investigated whether human skin also contains 6-hydroxysphingosine as the free base. Human skin surface lipids were obtained by washing with ethanol. A fraction enriched in sphingoid bases was isolated by preparative thin-layer chromatography and reacted with 2,4-dinitrofluorobenzene. The resulting N-dinitrophenyl derivatives were separated by thin-layer chromatography into three components, the most polar of which accounted for 15% of the total. After acetylation of the hydroxyl groups and repurification, each component was examined by nuclear magnetic resonance spectroscopy. The spectrum of the most polar of the derivatives indicated that it was 6-hydroxysphingosine or homologues of that substance. The spectra of the other two derivatives were virtually identical to those of derivatives prepared from authentic sphingosine and dihydrosphingosine. The chain-length distributions of the skin sphingoid bases were examined by gas chromatography after conversion of the dinitrophenyl acetates to dinitrophenyl trimethylsilyl derivatives. The analysis showed that the sphingosines and 6-hydroxysphingosines ranged from 17 to 22 carbons in length, with the 18- and 20-carbon species predominating. Surprisingly, the dihydrosphingosines included species with up to 26 carbons, with the 24-, 25-, and 26-carbon species accounting for about half of the total. Examination of the sphingoid bases of pig epidermis indicated that 6-hydroxysphingosine was not present and that the major chain length in the dihydrosphingosines was the 22-carbon species.

Animals↗
PubMed1994

6-Hydroxy-4-sphingenine in human epidermal ceramides.

The solvent-extractable lipids of human epidermal stratum corneum consist predominantly of ceramides. In addition two non-extractable ceramides are chemically bound to the stratum corneum protein. One of the bound ceramides, constituting 50% of the bound lipids, was previously shown to consist of very long chan omega-hydroxyacids in amide linkage with sphingosine. The second bound caramide, which forms 25% of the bound lipids, was shown to contain the same hydroxyacids, but the sphingoid base was neither sphingosine nor phytosphingosine. In the present study, the undefined bound ceramide was shown by NMR and chemical procedures to be the omega-hydroxyacid derivative of a new base, 6-hydroxy-4-sphingenine. In addition, a ceramide previously known to constitute 25% of the extractable human stratum corneum ceramides has been found to contain the same novel sphingoid base, amide-linked to long-chain alpha-hydroxyacids. Finally, a new acylceramide has been isolated and identified that consists of very long chain omega-hydroxyacids in amide linkage with the novel sphingolipid, with fatty acids esterified wit the terminal hydroxyl group of the hydroxyacid.

Adult↗
PubMed1993

The relationship between tests of lung function and three chest radiological scoring systems in patients with cystic fibrosis.

The chest radiographs and lung function tests of 41 patients attending the cystic fibrosis clinic at Royal Prince Alfred Hospital were reviewed. The chest radiographs were scored using three different scoring systems: the Shwachman and Kulczycki system (as modified by Doershuk), the National Institute of Health (NIH) system described by Taussig in 1973 and the Brasfield system. The scores were correlated with lung function tests. Significant correlations were found between the radiological scores and the respiratory variables; the best correlation was with the forced expiratory volume in one second (FEV1 % predicted). All three scoring systems showed a high degree of reproducibility of scores when a second radiologist was asked to score the same radiographs independently. The difference in scores between the radiologists was not significant for the NIH and the Brasfield systems. The Brasfield system is, however, the system of choice because it allows the assessment of all the major pathological features seen in cystic fibrotic chest films and consistently has the best agreement with all the lung function variables. It was also found that radiological evidence of lung hyperinflation may not be a good indicator of disease progression.

Adolescent↗
PubMed1992

A phase I and pharmacology study of GR63178A, a water-soluble analogue of mitoquidone.

GR63178A is a water-soluble analogue of mitoquidone, a pentacyclic pyrroloquinone. This group of drugs exhibit a novel structure and activity against several murine solid tumours and xenografts. In the present phase I study the toxicity and pharmacokinetics of GR63178A given on 5 consecutive days of a 21-day cycle were examined. A total of 24 patients presenting with a wide range of tumours were treated at 5 doses escalated to reach the maximal tolerated dose (MTD). Linear pharmacokinetics was documented over the dose range studied, and there was no difference in parent drug handling between day 1 and day 4 of dosing. A number of metabolites were detected. The toxicity profile was unusual in that pain occurred in 20/24 patients, most often at the site of known disease. This was the dose-limiting toxicity. Other side effects included nausea and vomiting (23/24), phlebitis at the infusion site (6/24) and headache (7/24). No treatment response was seen in this study. The MTD was demonstrated to be 160 mg/m2 daily (total, 800 mg/m2 per treatment cycle). The drug has now entered phase II trials at 120 mg/m2 daily x 5, repeated every 21 days.

Adult↗
PubMed1992

Sebaceous gland activity and serum dehydroepiandrosterone sulfate levels in boys and girls.

BACKGROUND AND DESIGN: Increases in sebaceous gland activity are often the earliest sign of the approach of puberty in children. These increases have been attributed to increases in the secretion of adrenal androgens, but the supporting data are sparse and are based on measurements of urinary, rather than serum, androgen concentrations. In this study, we examined sebum composition, serum levels of dehydroepiandrosterone sulfate, and pubertal stage in 111 boys and girls, aged 2 to 15 years. Sebum composition was evaluated by measuring the ratio of wax esters/(cholesterol + cholesterol esters), a ratio known to increase with increasing sebaceous gland activity. RESULTS: Both wax esters/(cholesterol + cholesterol esters) ratios and serum dehydroepiandrosterone sulfate levels began to increase in children 7 to 10 years old. These changes occurred in many children before the appearance of any physical signs of puberty. Wax esters/(cholesterol + cholesterol esters) ratios were correlated with dehydroepiandrosterone sulfate levels in both boys and girls. In prepubertal children, the regression lines passed through the origin. In subjects who were in early or late puberty, the y intercepts of the regression lines had positive values. CONCLUSION: Adrenal androgens appear to be the major determinants of sebaceous gland activity during the prepubertal period and to be additive to another hormone or hormones during puberty.

Adolescent↗
PubMed1992

Sebaceous gland lipids.

Human sebum contains squalene, wax esters, triglycerides, cholesterol esters, and possibly free cholesterol. The fatty acids of the ester lipids include species with chain branching or with unusual double-bond positions. The alcohol moieties of the wax esters contain unusual chain types similar to those of the fatty acids. Genetic and hormonal factors cause individual differences in sebaceous lipid composition. Genetic factors seem to influence the proportions of the various types of branched-chain fatty acids. Androgenic stimulation of the glands causes an increase in lipid synthesis, and therefore in the ratio of endogenously synthesized lipid to exogenous lipid. Because the endogenously synthesized lipids tend to be different from lipids that are derived exogenously, the overall composition of the secretion changes. Differences in sebum composition are particularly evident when the sebum of prepubertal children is compared with that of young adults. One difference that may be of clinical significance is the different concentrations of linoleate. Higher concentrations of sebum linoleate may protect young children from comedonal acne by preventing an essential fatty acid deficiency from developing in the follicular epithelium.

Fatty Acids↗
PubMed1991

Phase I study of the anthrapyrazole biantrazole: clinical results and pharmacology.

In a phase I study the anthrapyrazole biantrazole (Warner-Lambert Company) was given to 41 patients with tumour refractory to existing therapy. The drug was given i.v. weekly for 3 weeks, with a 3-week interval between courses. At the 1st week a full pharmacokinetic study was performed, and at weeks 2 and 3, blood samples were taken at 1 and 6 h following treatment to check for drug accumulation. Biantrazole pharmacokinetics were linear with respect to the AUC (r = 0.924) over the full range of doses studied (4-36 mg/m2) but exhibited large inter-patient variations at each dose level. Elimination was triphasic, comprising two rapid early phases and a long terminal half-life (mean, 14.1 +/- 7.8 h). There was no evidence of drug accumulation over the 3-week treatment period. Approximately 12% of the parent drug was excreted unchanged in the urine together with two non-circulating, more water-soluble metabolites. Biantrazole was well tolerated but did cause moderate emesis at doses of greater than 18 mg/m2 and mild alopecia. The dose-limiting side effect was leucopenia, with no other major toxicity being observed. One patient developed biventricular failure that was not clearly related to biantrazole administration. On the present schedule, the recommended dose of biantrazole is 24 mg/m2. No response were seen in this patient population.

Adolescent↗
PubMed1990

A phase II trial of mitomycin C and 5-fluorouracil as second-line therapy in advanced breast cancer.

Fifty-five patients who had relapsed or progressed from chemotherapy for advanced disease were treated with mitomycin C and 5-FU on a 6 weekly regimen. After a median of 2 cycles of therapy the overall response rate was 12% with no complete responses. Significant leucopenia but no thrombocytopenia was seen and despite the low overall response rate the regimen was tolerable and did produce responses in patients primarily resistant to Adriamycin combination chemotherapy. Low overall activity indicates the need for more effective second line treatment.

Adult↗
PubMed1990

Prognosis at presentation of small cell carcinoma of the lung.

Prognostic factors in 411 patients with small cell lung carcinoma have been retrospectively analysed. Univariate analysis of continuous variables showed that prognosis was worse with deteriorating performance status, extensive disease, positive bone scan, increasing age, elevated total white cell count, alkaline phosphatase, lactate dehydrogenase, and decreased serum chloride and albumin. Low serum sodium was less clearly associated with poor survival. Cox multivariate regression showed that performance status, disease extent, age and raised lactate dehydrogenase and white cell count were independent prognostic factors. When disease extent was excluded from analysis, performance status, age, total white cell count, lowered serum chloride and raised lactate dehydrogenase were significant independent prognostic variables.

Adult↗
PubMed1990

Potentiation of cisplatin by alpha-interferon in advanced non-small cell lung cancer (NSCLC): a phase II study.

Studies in experimental human lung cancer models have suggested that interferon may enhance significantly the response to some cytotoxic drugs. We have performed a phase II study of cisplatin (100 mg/m2 q.21 or 28 days) and alpha-2 interferon (3 or 5 MU three times weekly) in 68 patients with advanced non-small cell lung cancer and good performance status. As toxicity was acceptable, the dose of interferon and schedule of cisplatin were increased at the midpoint of the study. 46% (11/24) of patients with squamous carcinoma responded and an overall partial response rate of 30% was attained in 60 evaluable patients. There was no potentiation of haematological, renal or neurological toxicity but nausea and vomiting were severe. These results suggest that the combination has activity in this usually refractory disease.

Adult↗
PubMed1990

Unusual cholesterol esters in the sebum of young children.

Cholesterol esters (CE) having fatty acids of more than 18 carbons are a prominent feature of fetal skin surface lipid (vernix caseosa), but are a minor component of adult lipid. The difference may be related to the fact that fetal sebaceous glands generally synthesize little lipid. If so, it would be expected that prepuberal children, who also have very inactive glands, would secrete CE with a large proportion of very-long-chain fatty acids. To test this conjecture, skin surface CE from young children were isolated and analyzed. Sebum was extracted from the hair of 38 children, aged six to nine. To obtain a measure of sebaceous lipogenesis, the class composition of the lipid was determined by quantitative thin-layer chromatography and the ratio of wax esters/[cholesterol + cholesterol esters] (WE/[CH + CE]) was calculated. CE were then isolated from the lipid and hydrolyzed. The freed fatty acids were converted to fatty acid methyl esters (FAME) and analyzed by capillary gas chromatography to determine the proportion with more than 18 carbons. FAME from five of the subjects were then separated into saturated and monounsaturated fractions and analyzed again by gas chromatography to identify chain types. Ratios of WE/[CH + CE] ranged from 0.08 to 2.8 in the subjects. The proportion of CE FAME with more than 18 carbons ranged from 15 to 72%, with the highest proportion being found in the children with the lowest WE/[CH + CE]. The saturated FAME were mostly iso- or anteiso-branched, whereas the monounsaturated FAME were mostly straight-chain extension products of 16: 1 delta 9 or 18: 1 delta 9.

Child↗