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Biomedical subjects

A Johnston

Publications and source records attributed to A Johnston.

At least 37 records · Page 2Linked to original sources
PubMed2003

Therapeutic monitoring of sirolimus: its contribution to optimal prescription.

It is now common practice to measure immunosuppressive drugs in blood as a guide to therapy. The immunosuppressive drug sirolimus, recently approved for use following kidney transplantation, was developed in the context of this clinical approach. Throughout the early clinical studies, validated analytical techniques based on chromatographic techniques were used to measure the drug. After a brief period in which an immunoassay was available, routine measurements are again being performed by chromatographic assays. In this article the use of blood concentration measurements in the assessment of the early and pivotal clinical trials of the drug is documented. Then, the rationale for the routine monitoring of the drug in clinical practice, a regulatory requirement in some countries, is set out. It is concluded that the development of this compound has benefited from experience gained during the pharmacokinetic assessment of other immunosuppressive drugs. The pharmacokinetic data accumulated on sirolimus have been a key element in formulating guidelines on dosing with this drug, both when used in combination with cyclosporine and when used after cyclosporine withdrawal.

Binding Sites↗
PubMed2002

Improved clinical outcomes for liver transplant recipients using cyclosporine monitoring based on 2-hr post-dose levels (C2).

BACKGROUND: A prospective, open-label, study was conducted at 29 centers in 9 countries, involving 307 de novo liver transplant patients to compare the clinical usefulness of monitoring 2-hr post-dose cyclosporine (CsA) levels (C2) with conventional trough cyclosporine blood levels (pre-dose) (C0). METHODS: Neoral oral therapy was initiated at 15 mg/kg/day and dose adjusted according to predetermined C2 or C0 target level ranges. The primary efficacy variable was treatment failure at 3 months, where evaluation was based on a composite endpoint of biopsy-proven rejection, treatment for rejection, graft loss, death, or premature withdrawal/discontinuation from the study. RESULTS: Baseline characteristics were similar between groups. Graft loss at 12 weeks (retransplantation or death) occurred in 6.8% C2 and in 7.0% C0 patients. Overall incidence of treated acute rejection was lower for C2 (23.6%) than C0 patients (31.6%) (P=0.144, Cochran-Mantel-Haenszel [CMH] test). In hepatitis C virus (HCV)-negative patients, the incidence of rejection in the C2 group was significantly less than in the C0 group (21.2% vs. 33.0%; P<0.05), whereas in HCV-positive patients, the rejection rate was similar in both groups (26.7% for C2 group vs. 27.3% for C0 group: P=0.81). C2 patients (n=16) who reached minimum target CsA levels by day 3 had a notably low incidence of rejection (12.5%), whereas there was no difference in the incidence of rejection in C0 patients, irrespective of time to reach target level. For biopsy-proven acute rejections (21.6% for C2 vs. 30.4% for C0), the incidence of moderate and severe histological diagnosis was significantly lower in the C2 group than in the C0 group (47% vs. 73%; P=0.01). Safety profiles were similar between the two groups, with few patient withdrawals due to adverse events (9.5% for C2; 7.0% for C0). CONCLUSIONS: Using C2 monitoring, the overall incidence of acute cellular rejection was lower compared with the C0 group, and the histological severity of acute rejections was shown to be significantly milder for the C2 group, indicative of good long-term prognosis. These data demonstrate that the use of C2 monitoring is superior to C0 and results in a reduction in the incidence and severity of acute cellular rejection without detrimental effect on the drug safety profile.

Administration, Oral↗
PubMed2002

Early discharge following nasal pack removal: is it feasible?

A prospective study of 50 consecutive patients admitted for nasal packing for epistaxis reveals that only 20% re-bled after removal of packs and that 96% of those recurrences occurred during the first 4 h after pack removal. No patients required repacking or blood transfusion. The need for a 24-h observation period following nasal pack removal therefore appears not to be required, and the implementation of an early discharge policy for patients treated for epistaxis by nasal packing is therefore potentially feasible, and would result in significant cost savings.

Adolescent↗
PubMed2002

Treatment with flutamide decreases cortisol clearance: implications for therapy in congenital adrenal hyperplasia.

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by a defect in cortisol and often aldosterone secretion, and adrenal hyperandrogenism. Current treatment is to provide adequate glucocorticoid and mineralocorticoid substitution to prevent adrenal crises and to suppress excess adrenocortical androgen secretion. Anti-androgen therapy with flutamide is an option that allows control of hyperandrogenism without recourse to supraphysiological doses of glucocorticoid. METHODS: We examined the pharmacokinetic parameters of hydrocortisone administered i.v. as a bolus at a dose of 15 mg/m2 in a 17.3 year-old female patient with classic CAH before and four weeks after institution of flutamide treatment by determining serum cortisol concentrations at 10 min intervals for 6 h following the i.v. bolus of hydrocortisone. RESULTS: Treatment with flutamide resulted in a decrease in cortisol clearance from 420 ml/l to 305 ml/l (27% reduction), and a decrease in volume of distribution from 51.61 to 451 (12.9% reduction). The half-life of cortisol increased from 85.3 min to 102.1 min. CONCLUSIONS: Flutamide treatment decreases cortisol clearance, thereby prolonging its half-life. These findings indicate that a reduction in the daily dose of glucocorticoid replacement may need to be considered when flutamide is added to the treatment regimen of patients receiving hydrocortisone.

Adolescent↗
PubMed2001

A new approach to analysing texture-defined motion.

It has been widely accepted that standard low-level computational approaches to motion processing cannot extract texture-defined motion without applying some pre-processing nonlinearity. This has motivated accounts of motion perception in which luminance- and texture-defined motion are processed by separate mechanisms. Here, we introduce a novel method of image description where motion sequences may be described in terms of their local spatial and temporal gradients. This allows us to assess the local velocity information available to standard low-level motion mechanisms. Our analysis of several texture-motion stimuli shows that the information indicating correct texture-motion velocity and/or direction is present in the raw luminance measures. This raises the possibility that luminance-motion and texture-motion may be processed by the same cortical mechanisms. Our analysis offers a way of looking at texture-motion processing that is, to our knowledge, new and original.

Electrophysiology↗
PubMed2001

2-[1-(Hydroxyimino)ethyl]-2,5,5-trimethylperhydropyrimidine-butane-2,3-dione monooxime (1/1).

The title compound, C(9)H(19)N(3)O.C(4)H(7)NO(2), displays strong intramolecular O-H...N [O...N 2.6743 (13) A] and N-H...N [N...N 2.6791 (15) A] hydrogen bonds, and strong intermolecular O-H...N [O...N 2.7949 (15) A] and N-H...O [N...O 3.0924 (16) A] hydrogen bonds. This creates chains of perhydropyrimidine molecules, linked by hydrogen bonds. Each chain is linked to a partner chain, through hydrogen bonds to two butane-2,3-dione monooxime molecules, in a structure reminiscent of a ladder.

Journal Article↗
PubMed2001

Categorizing sex and identity from the biological motion of faces.

Head and facial movements can provide valuable cues to identity in addition to their primary roles in communicating speech and expression [1-8]. Here we report experiments in which we have used recent motion capture and animation techniques to animate an average head [9]. These techniques have allowed the isolation of motion from other cues and have enabled us to separate rigid translations and rotations of the head from nonrigid facial motion. In particular, we tested whether human observers can judge sex and identity on the basis of this information. Results show that people can discriminate both between individuals and between males and females from motion-based information alone. Rigid head movements appear particularly useful for categorization on the basis of identity, while nonrigid motion is more useful for categorization on the basis of sex. Accuracy for both sex and identity judgements is reduced when faces are presented upside down, and this finding shows that performance is not based on low-level motion cues alone and suggests that the information is represented in an object-based motion-encoding system specialized for upright faces. Playing animations backward also reduced performance for sex judgements and emphasized the importance of direction specificity in admitting access to stored representations of characteristic male and female movements.

Communication↗
PubMed2001

Time perception: brain time or event time?

Recent experiments show that synchronous events can appear to an observer to occur at different times. Neural processing time delays are offered as an explanation of these temporal illusions, but equating perceived time with processing time leads to some thorny philosophical problems.

Brain↗
PubMed2001

Prevalence, age of onset and demographic relationships of different areca nut habits amongst children in Tower Hamlets, London.

OBJECTIVE: To examine prevalence and demographic relationships of different areca nut habits amongst children. DESIGN: Self-administered questionnaire. SUBJECTS: Children aged between 11 and 15. Of 800 questionnaires distributed, 704 were fully completed (88%). SETTING: Two secondary schools in the London district of Tower Hamlets. MEASURES: Demographic, areca nut habits used, age first used, still using, frequency of use. RESULTS: Users of any areca nut habit were exclusively from the South Asian population. Of this population, 77% had engaged in a habit, and dependent upon habit between 54 and 92% of these still remained current users. The highest prevalence of current use for boys and girls respectively was for areca nut alone (36%, 43%), followed by mistee pan (35%, 29%), betel-quid (27%, 26%) and pan masala (14%, 16%). Of the current users, 44% engaged in one habit only, 24% two, 20% three and 13% all four. The highest period of risk for starting to use areca nut alone, betel-quid and mistee pan was between ages 5 and 12, whilst for pan masala it was after 10. Boys had a significantly higher risk of beginning use before 10 (P < .001) and a higher frequency of use for pan masala (P< .01), areca nut alone (P< .05) and betel-quid (P = .06) than girls. The frequency of using each habit was between 3 and 5 episodes per week, however boys use pan masala approximately 10 times per week. CONCLUSION: South Asian children may already be experienced users of areca nut. Greater attention should be directed towards identifying signs of oral submucous fibrosis, oral cancer and other potentially malignant lesions within the South Asian population.

Adolescent↗
PubMed2001

A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation.

A phase I study of nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m(2)24 h(-1). 8 patients were evaluable for toxicity. In the 6 patients treated at 768 mg/m(2)24 h(-1), dose-limiting oral mucositis and myelosuppression were observed. Plasma nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg(-1)ml(-1)min(-1), 50 mg ml(-1)min(-1)and 80 mg ml(-1)min(-1)at the 3 dose levels studied. Whereas no toxicity was encountered if the nolatrexed AUC was <45 mg ml(-1)min(-1), Grade 3 or 4 toxicity was observed with AUC values of >60 mg ml(-1)min(-1). Elevated plasma deoxyuridine levels, measured as a surrogate marker of thymidylate synthase inhibition, were seen at all of the dose levels studied. One patient with a spinal primitive neuroectodermal tumour had stable disease for 11 cycles of therapy, and in two patients with acute lymphoblastic leukaemia a short-lived 50% reduction in peripheral lymphoblast counts was observed. Nolatrexed can be safely administered to children with cancer, and there is evidence of therapeutic activity as well as antiproliferative toxicity. Phase II studies of nolatrexed in children at the maximum tolerated dose of 640 mg/m(2)24 h(-1)are warranted.

Acute Disease↗
PubMed2001

Oxidative stress could precede endothelial dysfunction and insulin resistance in Indian Mauritians with impaired glucose metabolism.

AIMS/HYPOTHESIS: To measure oxidative stress, endothelial dysfunction and insulin resistance in Indian Mauritians at different stages of development of Type II (non-insulin-dependent) diabetes mellitus. METHODS: Plasma total 8-epi-PGF2alpha, an indicator of oxidative stress, was determined in age-matched subjects with normal glucose metabolism (n = 39), impaired glucose tolerance (n = 14), newly diagnosed diabetes (n = 8) and established diabetes (n = 14). Plasma glucose and insulin were measured at baseline and 2 h following an oral glucose tolerance test. Endothelial function was assessed by non-invasive digital pulse wave photoplethysmography. RESULTS: Plasma 8-epi-PGF2alpha increased in subjects with impaired glucose tolerance (p < 0.05) compared with control subjects, and was even higher in newly diagnosed diabetic patients (p < 0.01) and established (p < 0.01) diabetic patients. A tendency towards reduced endothelial function in subjects with impaired glucose tolerance became significant in patients with newly diagnosed and established diabetes (p < 0.01), and was correlated with 8-epi-PGF2alpha (r = 0.36, p < 0.01). Insulin resistance (homeostasis model assessment) did not change in subjects with impaired glucose tolerance compared with control subjects, but increased in newly diagnosed (p < 0.01) and established (p < 0.001) diabetic subjects. The 8-epi-PGF2alpha was correlated with fasting glucose (r = 0.50, p < 0.001), triglycerides (r = 0.40, p < 0.001) and insulin resistance (r = 0.35, p < 0.001). CONCLUSION/INTERPRETATION: Oxidant stress is an early event in the evolution of Type II diabetes and could precede the development of endothelial dysfunction and insulin resistance.

Blood Glucose↗
PubMed2001

Result of two randomized trials comparing nolatrexed (Thymitaq) versus methotrexate in patients with recurrent head and neck cancer.

We report on two randomized trials performed in the USA and Europe, which compared methotrexate and nolatrexed as treatment for patients with recurrent head and neck cancer. Eligibility criteria included: histologically confirmed squamous-cell carcinoma, measurable disease, adequate hematological, renal and hepatic functions, failure of a first-line chemotherapy, and informed consent. Methotrexate 40 mg/m2 was weekly given by short infusion, and nolatrexed 725 mg/m2 per day was administered as a five-day continuous infusion, every three weeks. A total of 139 patients (63 in the USA. 76 in Europe) were randomized based on a ratio of 2/1: 93 and 46 received nolatrexed and methotrexate, respectively. Patient characteristics included 115 males and 24 females; median age 60 years. In the nolatrexed arm, the following grade 3-4 toxicities occurred: neutropenia (29.9%) with 3.1% of febrile neutropenia, mucositis (33.3%), and vomiting (10.3%). In the MTX arm, the grade 3-4 toxicities were neutropenia (7.1%) and mucositis (6.9%). There was no difference in activity between the nolatrexed and the methotrexate treatment: 3.3% and 10.8% of objective responses, 1.9 versus 1.5 months of disease-free progression and 3.5 versus 3.7 months of overall survival, respectively. Nolatrexed has demonstrated a similar activity to methotrexate.

Adult↗
PubMed2001

Plasma nitrate concentrations in children with infectious and noninfectious diarrhea.

BACKGROUND: In patients with intact renal function and low dietary nitrate intake, plasma nitrate concentrations reflect endogenous nitric oxide production and are shown to be increased during inflammatory processes. The aim of this study was to compare plasma nitrate concentrations and hence endogenous nitric oxide production in children with infectious and noninfectious diarrhea and to determine whether plasma nitrate concentrations could serve as a discriminant test between acute and chronic diarrhea in children. METHODS: Three groups of patients were identified: 14 patients with acute gastroenteritis, 13 patients with chronic noninfectious diarrhea, and 14 patients with no evidence of gastrointestinal pathology and no underlying infectious process, who served as control subjects. Plasma nitrate concentrations were determined spectrophotometrically using the Greiss reaction before reduction to nitrite with a copper-coated cadmium column. RESULTS: Mean plasma nitrate concentrations were 405.3 micromol/L +/- 281.6 micromol/L (standard deviation) in patients with infectious diarrhea, 134.7 micromol/L +/- 77.0 micromol/L in patients with chronic diarrhea, and 54.1 micromol/L +/- 20.1 micromol/L in control subjects (F = 42.6, P < 0.0001; analysis of variance). Plasma nitrate concentrations were significantly higher in the infectious diarrhea group compared with the noninfectious diarrhea and control groups (Student-Newman-Keuls test, P < 0.5). CONCLUSIONS: Although an optimal cutoff concentration cannot be defined, plasma nitrate concentrations in excess of 300 micromol/L are suggestive of an infectious process whereas values less than 100 micromol/L are indicative of noninfectious diarrhea.

Acute Disease↗